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Compounds
This invention relates to compounds that are inhibitors
of serine proteases. More particularly, it relates to their
use as serine protease inhibitors in the treatment of the
human or animal body.
The serine proteases are a group of proteolytic enzymes
which have a common catalytic mechanism characterized by a
particularly reactive Ser residue. Examples of serine
proteases include trypsin, tryptase, chymotrypsin, elastase,
thrombin, plasmin, kallikrein, Complement C1, acrosomal
protease, lysosomal protease, cocoonase, a-lytic protease,
protease A, protease B, serine carboxypeptidase II,
subtilisin, urokinase, Factor VIIa, Factor IXa, and Factor
Xa. The serine proteases have been investigated extensively
over a period of several decades and the therapeutic value
of inhibitors of serine proteases is well understood. (For a
recent review, see, for example, Donmienne Leung et al., J.
Med. Chem., Vol. 43, No. 3, 2000, pages 305-341).
Serine protease inhibitors play a central role in the
regulation of a wide variety of physiological processes
including coagulation, fibrinolysis, fertilization,
development, malignancy, neuromuscular patterning and
inflammation. It is well known that these compounds inhibit
a variety of circulating proteases as well as proteases that
are activated or released in tissue. It is also becoming
clear that serine protease inhibitors inhibit critical
cellular processes, such as adhesion, migration, free
radical production and apoptosis. In addition, animal
experiments indicate that intravenously administered serine
protease inhibitors, variants or cells expressing serine
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protease inhibitors, provide a protective effect against
tissue damage.
Serine protease inhibitors have also been predicted to
have potential beneficial uses in the treatment of disease
in a wide variety of clinical areas such as oncology,
neurology, haematology, pulmonary medicine, immunology,
inflammation and infectious disease.
In particular serine protease inhibitors may be
beneficial in the treatment of thrombotic diseases, asthma,
emphysema, cirrhosis, arthritis, carcinoma, melanoma,
restenosis, atheroma, trauma, shock and reperfusion injury.
Thus for example an inhibitor of Factor Xa has value as
a therapeutic agent as an anticoagulant, e.g. in the
treatment and prevention of thrombotic disorders. The use of
a Factor Xa inhibitor as an anticoagulant is desirable in
view of the selectivity of its effect. Many clinically
approved anticoagulants have been associated with adverse
events owing to the non-specific nature of their effects on
the coagulation cascade.
Also, there are well-known associations of al protease
inhibitor deficiency with emphysema and cirrhosis and C1
esterase inhibitor deficiency with angioedema.
Tryptase is the major secretory protease of human mast
cells and is proposed to be involved in neuropeptide
processing and tissue inflammation.
Mature human tryptase is a glycosylated, heparin
associated tetramer of catalytically active subunits. Its
amino-acid structure appears to have no close counterpart
among the other serine proteases which have been
characterised. Tryptase is stored in mast cell secretory
granules and after mast cell activation, human tryptase can
be measured readily in a variety of biological fluids. For
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example, after anaphylaxis, tryptase appears in the blood
stream where it is readily detectable for several hours.
Tryptase also appears in samples of nasal and lung lavage
fluid from atopic subjects challenged with specific antigen.
Tryptase has been implicated in a variety of biological
processes where activation and degranulation of mast cells
occur. Accordingly, mast cell tryptase inhibition may be of
great value in the prophylaxis and treatment of a variety of
mast cell mediated conditions. Mast cells can degranulate
by both IgE-dependent and independent mechanisms thereby
implicating tryptase in both atopic and non-atopic
inflammatory conditions. Tryptase can activate proteases
such as pro-urokinase and pro-MMP3 (pro-matrix
metalloprotease 3, pro-stromelysin), thereby indicating a
pathological role in tissue inflammation and remodelling.
Furthermore, the recent evidence that tryptase can activate
certain G-protein coupled receptors (e9 PAR2) and induce
neurogenic inflammation points to a broader physiological
role, for example in modulating pain mechanisms. Given
tryptase's multiple mechanisms of action, it has been
proposed that tryptase inhibitors may be beneficial in a
broad range of diseases. These include conditions such as:
asthma (specifically influencing the inflammatory component,
the underlying hyperreactivity, and the chronic fibrotic
damage due to smooth muscle thickening); chronic obstructive
pulmonary disease (COPD) and pulmonary fibrotic diseases;
rhinitis; psoriasis; urticaria; dermatitis; arthritis;
Crohn's disease; colitis; angiogenesis; atherosclerosis;
multiple sclerosis; interstitial cystitis; migraine
headache; neurogenic inflammation and pain mechanisms; wound
healing; cirrhosis of the liver; Kimura's disease; pre-
eclampsia; bleeding problems associated with menstruation
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and the menopause; cancer (particularly melanoma and tumour
metastasis); pancreatitis; and certain viral infections
(Yong, Exp. Toxic Pathol, 1997, 49, 409; Steinhoff et al.,
Nat. Med., 2000, 6, 151; Downing and Miyan, Immunol. Today,
2000, 21, 281; Tetlow and Wooley, Ann. Rheum. Dis., 1995,
54, 549; Jeziorska, Salamonsen and Wooley, Biol. Reprod.,
1995, 53, 312; Brain, Nat. Med., 2000, 6, 134; Olness et
al., Headache, 1999, 39, 101.) The underlying principle is
that a tryptase inhibitor should have utility where mast
cells have being induced to degranulate by whatever
mechanism, including anaphylactic reactions due to exogenous
substances, e.g. morphine-induced bronchoconstriction
(Bowman and Rand, 2nd edt., 1980.)
It has now been found that certain aromatic compounds
carrying lipophilic side chains are particularly effective
as inhibitors of serine proteases, especially serine
proteases with negatively charged P1 specificity pockets,
such as factor Xa, thrombin and tryptase. Depending upon
their structure, certain of these compounds have been found
to be selective for the serine protease, Factor Xa. Others
have been found to be dual inhibitors of Factor Xa and
thrombin. Yet others have been found to be selective for the
serine protease, tryptase.
The Factor Xa inhibitors of this invention are
potentially useful for the prophylaxis or treatment of
thrombotic disorders such as amongst others venous
thrombosis, pulmonary embolism, arterial thrombosis,
myocardial ischaemia, myocardial infarction, and cerebral
thrombosis. They potentially have benefit in the treatment
of acute vessel closure associated with thrombolytic therapy
and restenosis, e.g. after transluminal coronary angioplasty
or bypass grafting of the coronary or peripheral arteries
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and in the maintenance of vascular access patency in long
term hemodialysis patients.
Factor Xa inhibitors of this invention may, with
benefit, form part of a combination therapy with an
5 anticoagulant with a different mode of action or with a
thrombolytic agent.
Hence, the invention also provides the use of certain
compounds which have been found to be inhibitors of both
Factor Xa and thrombin. These compounds have excellent
potential therapeutic value and may synergistically boost
Fxa antithrombotic effect.
It is envisaged that the compounds that are tryptase
inhibitors will be useful not only in the treatment and
prophylaxis of asthma but also of other allergic and
inflammatory conditions mediated by tryptase such as
allergic rhinitis, skin conditions such as eczema,
psoriasis, atopic dermatitis and urticaria, rheumatoid
arthritis, conjunctivitis, inflammatory bowel disease,
neurogenic inflammation, atherosclerosis and cancer.
It has been reported in W099/11658 and W099/11657 that
certain benzamidine and aminoisoquinoline derivatives
carrying a bulky lipophilic side chain are excellent
inhibitors of serine proteases. Unfortunately, it has since
been found that benzamidine compounds of WO 99/11658 in
general demonstrate poor oral bioavailability.
Surprisingly, it has now been found that certain other
aromatic compounds also show inhibitory activity against
serine proteases, in particular Factor Xa, despite the lack
of the amidino or 1-aminoisoquinoline functionality
previously believed to be crucial for activity as a factor
Xa inhibitor, thrombin or tryptase. Many of these compounds
also possess structural features in addition to the aromatic
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group or properties (such as activity as tryptase
inhibitors) that further distinguish them from the compounds
of W099/11658 and W099/11657.
Where compounds of the invention have been tested, they
have generally demonstrated superior oral bioavailability in
comparison with benzamidines disclosed in WO 99/11658. Also,
it has been found that Factor Xa inhibitor compounds of the
invention perform excellently in the prothrombin time assay
(PT) when compared to aminoisoquinolines of similar Factor
Xa activity and structure. The PT assay is a coagulation
assay and it is widely accepted that direct acting Factor Xa
inhibitors which perform well in the PT assay are more
likely to be good antithrombotics.
In W099/09053 certain 2-aminobenzamide compounds are
disclosed as potential motilin receptor antagonists and in
US 3268513 similar 2-aminobenzamide compounds are suggested
as potential antibacterial agents. However, the novel
compounds of the present invention have not before been
suggested as potential serine protease inhibitors.
In W096/09297, W095/32945, W094/20527 and US 5,525,623
a variety of peptide based compounds are suggested as
potential inhibitors of the mast cell protease tryptase. In
W095/03333 a tryptase inhibitor is provided by a polypeptide
obtainable from the leech hirudo medicinalis. In W096/08275
secretory leukocyte protease inhibitor (SLPI) and active
fragments thereof have been found to inhibit the proteolytic
activity of tryptase. In W099/55661 certain 4-
aminomethylbenzoic ester derivatives are proposed as
potential tryptase inhibitors.
Thus viewed from an one aspect the invention provides a
method of treatment of the human or non-human animal body
(e.g. a mammalian, avian or reptilian body) to combat a
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condition responsive to a serine protease inhibitor, said
method comprising administering to said body an effective
amount of a serine protease inhibitor compound of formula
(I)
R~X\X/Y\L/LP~D)n
2
(I)
where R2 represents a 5 or 6 membered aromatic carbon ring
optionally interrupted by a nitrogen, oxygen or sulphur ring
atom, optionally being substituted in the 3 and/or 4
position (in relation to the point of attachment of X-X) by
halo, vitro, thiol, haloalkoxy, hydrazido, alkylhydrazido,
amino, cyano, haloalkyl, alkylthio, alkenyl, alkynyl,
acylamino, tri or difluoromethoxy, carboxy, acyloxy, MeS02-
or R1, or the substituents at the 3 and 4 positions taken
together form a fused ring which is a 5 or 6 membered
carbocyclic or heterocyclic ring optionally substituted by
halo, haloalkoxy, haloalkyl, cyano, vitro, amino, hydrazido,
alkylthio, alkenyl, alkynyl or R1~, and optionally
substituted in the position alpha to the X-X group (i.e. 6
position for a six membered aromatic ring etc) by amino,
hydroxy, halo, alkyl, carboxy, alkoxycarbonyl, cyano, amido,
aminoalkyl, hydroxyalkyl, alkoxy or alkylthio with the
proviso that R2 cannot be aminoisoquinolyl;
each X independently is a C, N, O or S atom or a CO,
CRla, C(R1a)2 or NRla group, at least one X being C, CO,
CRla or C(R1a)2%
each R1a independently represents hydrogen or hydroxyl,
alkoxy, alkyl, aminoalkyl, hydroxyalkyl alkoxyalkyl,
alkoxycarbonyl, alkylaminocarbonyl, alkoxycarbonylamino,
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acyloxymethoxycarbonyl or alkylamino optionally substituted
by hydroxy, alkylamino, alkoxy, oxo, aryl or cycloalkyl;
L is an organic linker group containing 1 to 5 backbone
atoms selected from C, N, O and S, or a branched alkyl or
cyclic group;
Y (the a-atom) is a nitrogen atom or a CRlb group;
Cy is a saturated or unsaturated, mono or poly cyclic,
homo or heterocyclic group, preferably containing 5 to 10
ring atoms and optionally substituted by groups R3a or
phenyl optionally substituted by R3a%
each R3a independently is Rlc, amino, halo, cyano,
nitro, thiol, alkylthio, alkylsulphonyl, alkylsulphenyl,
triazolyl, imidazolyl, tetrazolyl, hydrazido, alkyl
imidazolyl, thiazolyl, alkyl thiazolyl, alkyl oxazolyl,
oxazolyl, alkylsulphonamido, alkylaminosulphonyl,
aminosulphonyl, haloalkoxy and haloalkyl;
Lp is a lipophilic organic group;
D is a hydrogen bond donor group; and n is 0, 1 or 2;
and
R1. Rlb, Rlc and R1~ are as defined for Rla,
or a physiologically tolerable salt thereof, e.g. a
halide, phosphate or sulphate salt or a salt with ammonium
or an organic amine such as ethylamine or meglumine.
As used herein, the term " treatment" includes
prophylaxis, amelioration or elimination of a condition for
which a human or non-human animal body is being treated.
The " effective amount" or dosage of the inhibitor
compound of formula (I) will depend upon the nature and
severity of the condition being treated, the administration
route and the size and species of the patient. However in
general, quantities of from 0.01 to 100 ~.mol/kg bodyweight
will be administered.
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Viewed from a further aspect the invention provides the
use of a serine protease inhibitor compound of formula I as
defined hereinabove, or physiologically tolerable salt
thereof, for the manufacture of a medicament for use in a
method of treatment of the human or non-human animal body
(e. g. a mammalian, avian or reptilian body) to combat (i.e.
treat or prevent) a condition responsive to said inhibitor.
The serine protease is preferably a serine protease
with a negatively charged P1 specificity pocket (i.e.
trypsin-like).
It has further been found that compounds of formula (I)
in which R1 is an unsubstituted aminoalkyl group, are
selective inhibitors of tryptase. Compounds of formula (I)
in which R1 represents other than an unsubstituted
aminoalkyl group have been found to be selective inhibitors
of Factor Xa, or selective dual inhibitors of Factor Xa and
thrombin.
According to another aspect, therefore, the present
invention provides a method of treatment of the human or
non-human animal body (e. g. a mammalian, avian or reptilian
body) to combat a condition responsive to a Factor Xa
inhibitor (e. g. a condition such as a thrombotic disorder,
including venous thrombosis, pulmonary embolism, arterial
thrombosis, myocardial ischaemia, myocardial infarction and
cerebral thrombosis, acute vessel closure associated with
thrombolytic therapy and restenosis, including after
transluminal coronary angioplasty or bypass grafting of the
coronary or peripheral arteries and in the maintenance of
vascular access patency in long term hemodialysis patients),
said method comprising administering to said body an
effective amount of a serine protease inhibitor compound of
formula (I) as defined hereinabove, provided that R1 is not
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an unsubstituted aminoalkyl group, or a physiologically
tolerable salt thereof.
According to another aspect, therefore, the present
invention provides a method of treatment of the human or
5 non-human animal body (e. g. a mammalian, avian or reptilian
body) to combat a condition responsive to a tryptase
inhibitor (e. g. a condition such as asthma, allergic
rhinitis, eczema, psoriasis, atopic dermatitis, urticaria,
rheumatoid arthritis, conjunctivitis, inflammatory bowel
10 disease, neurogenic inflammation, atherosclerosis or
cancer), said method comprising administering to said body
an effective amount of a serine protease inhibitor compound
of formula (I) as defined hereinabove which is substituted
in the 3 and/or 4 position by R1 and in which R1 is an
unsubstituted aminoalkyl group, or a physiologically
tolerable salt thereof.
The present invention further provides the use of a
serine protease inhibitor compound of formula (I) as defined
hereinabove, provided that R1 is not an unsubstituted
aminoalkyl group, or a physiologically tolerable salt
thereof for the manufacture of a medicament for use as a
Factor Xa inhibitor.
The present invention further provides the use of a
serine protease inhibitor compound of formula (I) as defined
hereinabove, which is substituted in the 3 and/or 4 position
by R1 and in which R1 is an unsubstituted aminoalkyl group,
or a physiologically tolerable salt thereof for the
manufacture of a medicament for use as a tryptase inhibitor.
In the compounds of formula (I), where the alpha atom
is carbon it preferably has the conformation that would
result from construction from a D-a-aminoacid
NH2-CRlb(Cy)-COOH where the NH2 represents part of X-X.
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Likewise the fourth substituent Rlb at an alpha carbon is
preferably a methyl or hydroxymethyl group or hydrogen.
In the compounds of formula (I), unless otherwise
indicated, aryl groups preferably contain 5 to 10 ring atoms
optionally including 1, 2 or 3 heteroatoms selected from O,
N and S; alkyl, alkenyl or alkynyl groups or alkylene
moieties preferably contain up to 6 carbons, e.g. C1_6 or
C1-3; cyclic groups preferably have ring sizes of 3 to 8
atoms; and fused multicyclic groups preferably contain 8 to
16 ring atoms.
Examples, of particular values for Rla are: hydrogen,
methyl or ethyl. Rla is preferably a hydrogen atom.
The linker group from the R2 group to the alpha atom is
preferably selected from -CH=CH-, -CONH-, -CONRla-, -NH-CO-,
-NH-CH2-, -CH2-NH-, -CH20-, -OCH2-, -COO-, -OC=O- and
-CH2CH2-. Preferably, the X moiety nearest to the alpha
atom is an NH or O atom, most preferably a NH group. The X
moiety alpha to the aromatic ring is preferably a carbon
based group such as CH2 or CO, preferably CO. Thus a
particularly preferred linker X-X is -CONH-. In an
alternative embodiment the linker is preferably a -OCH2-
group.
Examples of particular values for Rlb are: hydrogen,
(1-4C)alkyl, such as methyl or hydroxy(1-4C)alkyl, such as
hydroxymethyl. Rlb is preferably a hydrogen atom.
The alpha atom (Y) is preferably a CH or C(CH3) group,
especially CH.
The linker group from the alpha atom to the lipophilic
group is preferably CO, CH2NH, CONRld(CH2)m,
(CH2)mN(Rld)CO(CH2)m, (CH2)m+2, CO(CH2)m, (CH2)mCO,
(CH2)mOC=O, (CH2)m0, CH=CH(CH2)m, 502, S02NRld, S02(CH2)m,
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(CH2)mS02 or (CH2)mS02NRld (where each m is independently 0
or 1 and Rld is as defined for Rla).
Examples of particular values for Rld are: hydrogen;
for alkyl optionally substituted by hydroxy, alkylamino,
alkoxy, oxo, aryl or cycloalkyl: (1-6C)alkyl, such as methyl
or ethyl, or aryl(1-6C)alkyl, such as benzyl or phenylethyl;
for aminoalkyl optionally substituted by hydroxy,
alkylamino, alkoxy, oxo, aryl or cycloalkyl: (2-
6C)carboxamido, such as carboxamidomethyl;
for hydroxyalkyl optionally substituted by hydroxy,
alkylamino, alkoxy, oxo, aryl or cycloalkyl: (1-
6C)carboxyalkyl, such as carboxymethyl, carboxyethyl or
carboxypropyl;
for alkoxyalkyl optionally substituted by hydroxy,
alkylamino, alkoxy, oxo, aryl or cycloalkyl: (1-
5C)alkoxycarbonyl(1-6C)alkyl, such as methoxycarbonylmethyl,
methoxycarbonylethyl, methoxycarbonylpropyl,
ethoxycarbonylmethyl, ethoxycarbonylethyl and
ethoxycarbonylpropyl.
Rld is preferably a hydrogen atom.
The linker may be optionally branched, for example, to
incorporate a polar functionality.
Examples of particular values for L are CO, CONH,
CH2NHC0 and CONHCH2.
It will be appreciated by those skilled in the art that
a diverse range of organic groups are lipophilic, and that
it is therefore impractical to define with precision each
and every structure that may be incorporated into a serine
protease inhibitor compound of formula (I). Accordingly, it
is being assumed that the addressee of this specification
will not require an exhaustive computer listing of
structures of lipophilic groups, but will instead make use
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of the structures of lipophilic groups disclosed in the
specification, especially those exemplified; the test
systems described herein for identifying serine protease
inhibitors; and common general knowledge of the
lipophilicity, synthesis and stability of organic compounds,
to obtain novel serine protease inhibitor compounds of
formula (I).
The lipophilic group may be, for example, an alkyl,
alkenyl, carbocyclic or heterocyclic group, or a combination
of two or more such groups linked by a spiro linkage or a
single or double bond or by C=O, O, S, SO, 502, CONRle,
NRle-CO-, NRle linkage (where Rle is as defined for Rla),
optionally substituted by one or more oxo or R3 groups in
which R3 is alkylaminocarbonyl, alkoxycarbonylamino, N-
alkylaminoalkanoyl, N-alkanoylaminoalkanoyl, C-
hydroxyaminoalkanoyl or as defined for R3a.
By way of illustration, representative lipophilic
groups include methylcyclohexyl, methylcyclohexylmethyl,
methylphenylmethyl, phenylethyl, benzylpiperidinyl,
benzoylpiperidinyl, bispiperidinyl and phenylpiperazinyl.
Phenylethyl is an example of a combination of an alkyl
group and a carbocyclic group linked through a single bond.
Benzylpiperidinyl is an example of a combination of an
alkyl group, a carbocyclic group and a heterocyclic group
linked by single bonds.
Benzoylpiperidinyl is an example of a combination of a
carbocyclic group and a heterocyclic group linked through
C=O.
Methylcyclohexylmethyl is an example of a combination
of an alkyl group (methyl) and a carbocyclic group
(cyclohexyl) linked by a single bond and having a
substituent R3 (methyl) on cyclohexyl. It will be
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appreciated that this group could alternatively have been
regarded as a combination of two alkyl groups and a
carbocyclic group. However, in order to provide clarity, in
this specification any terminal alkyl group in Lp will be
treated as a substituent R3.
When the lipophilic group comprises an alkyl group,
this may be, for example, a (1-3C) alkyl group, such as
methyl, ethyl or propyl. Preferably an alkyl group is
unsubstituted.
When the lipophilic group comprises a carbocyclic
group, this may be, for example, a non-aromatic or aromatic,
mono or polycyclic hydrocarbon group containing up to 25,
more preferably up to 10 carbon atoms. The carbocyclic group
may thus be, for example, a cycloalkyl, polycycloalkyl,
phenyl or naphthyl group, or a cycloalkyl group fused with a
phenyl group.
Examples of particular values for a cycloalkyl group
are (3-6C) cycloalkyl groups, such as cyclopentyl and
cyclohexyl. A cycloalkyl group is preferably unsubstituted
or substituted by one group R3, preferably amino or an alkyl
group, such as methyl.
Examples of particular values for a polycycloalkyl
group are (6-lOC) polycycloalkyl groups, such as
bicycloalkyl, for example decalinyl, norbornyl or adamantyl.
A polycycloalkyl group is preferably unsubstituted or
substituted by one, two or three R3 groups, for example
alkyl such as methyl. An example of a polycycloalkyl group
substituted by alkyl is isopinocamphenyl.
A phenyl group is preferably unsubstituted or
substituted by one or two R3 groups. More preferably it is
substituted by one or two R3 groups.
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A naphthyl group is preferably unsubstituted or
substituted by one R3 group.
Examples of a cycloalkyl or cycloalkenyl group fused
with a phenyl group are indanyl and tetrahydronaphthyl. This
5 group is preferably unsubstituted or substituted by oxo or
one or two R3 groups. Examples of groups substituted by oxo
are 1-oxoindan-5-yl, 1-oxo-5,6,7,8-tetrahydronaphth-5-yl and
1-oxo-5,6,7,8-tetrahydronaphth-6-yl.
When the lipophilic group comprises a heterocyclic
10 group, this may be, for example, a non-aromatic or aromatic,
mono or polycyclic group containing one or two oxygen,
nitrogen or sulfur atoms in the ring system, and in total up
to 25, more preferably up to 10 ring system atoms.
Examples of a heterocyclic group when it is a non-
15 aromatic monocyclic group are azacycloalkyl groups, such as
pyrrolidinyl and piperidinyl; azacycloalkenyl groups, such
as pyrrolinyl; diazacycloalkyl groups, such as piperazinyl;
oxacycloalkyl groups, such as tetrahydropyranyl; and
thiacycloalkyl groups, such as tetrahydrothiopyranyl. A non-
aromatic monocyclic group preferably contains 5, 6 or 7 ring
atoms and is preferably unsubstituted or substituted by one
group R3, preferably alkyl, such as methyl or ethyl, or
hydroxyalkyl, such as hydroxymethyl.
Examples of a heterocyclic group when it is a non-
aromatic polycyclic group are bicyclic groups, such as
azacycloalkyl fused with phenyl, for example dihydroindolyl,
dihydroisoindolyl, tetrahydroquinolinyl and
tetrahydroisoquinolinyl; azacycloalkyl fused with
cycloalkyl, such as decahydroisoquinolyl, and tricyclic
groups, such as azacycloalkyl fused with indolyl, for
example tetrahydropyrido[3,4-b]indole. This group is
preferably unsubstituted.
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Examples of a heterocyclic group when it is an aromatic
monocyclic group are furyl, pyrrolyl, thienyl, imidazolyl,
pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl,
oxadiazolyl (such as 1,3,4-oxadiazolyl), thiadiazolyl (such
as 1,3,4-thiadiazolyl), triazinyl and thiazolyl. This group
is preferably unsubstituted or substituted by one or two R3
groups.
Examples of a heterocyclic group when it is an aromatic
polycyclic group are bicyclic groups such as benzofuryl,
quinolinyl, isoquinolinyl, benzothienyl, indolyl and
benzothiazolyl. This group is preferably unsubstituted or
substituted by one R3.
The lipophilic group preferably comprises a cycloalkyl,
azacycloalkyl, diazacycloalkyl, phenyl, naphthyl, adamantyl,
bicycloalkyl, mono- or diazabicycloalkyl, mono- or bicyclo
heteroaromatic or a linear or branched alkyl or alkenyl
group all optionally substituted by one or more oxo or
groups R3, or a combination of at least two such groups
linked by a spiro linkage or a single or double bond or by
C=O, O, S, SO, 502, CONRIe, NRle-CO- or NRle linkage (where
R1e is as defined for R1a).
where Lp comprises a combination of at least two
groups, it preferably comprises a combination of two or
three such groups. The groups are preferably linked by a
single bond, C=O, 0 or NRle.
Examples of particular values for R1e are hydrogen and
(1-6C)alkyl, such as methyl or ethyl.
The lipophilic group Lp may be selected, for example,
f rom
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O R4
S
N~R3 N R3 N R3 \ Rs
O Ra
O
N\ / R3 N\ / R3 N\ / R3
Rs
O
O
\~--R3 -N O
/N / X
m
R3
-X
O
\~R3 -N
/N / X
m
X
R3
Rs R3
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O O
O
N ~-~-R3 -N
m
-~Rs
X
Ra O
O Ra
-N -N
/ Ra
O Ra
\N Rs ~ Rs Rs
\~ \ / -N~ \ / - ~ \ /
Ra S
-N~ / X~H
-N x
X
O Ra
X=X
XRs X-XRs \N
\ ~X ~ \ ~X / Rs
O Ra
X- X R3 X- R X- R
-N ~~ / 3 N ~~ 3
\~ x \---/ x /
0
~N X- -X
Rs R
R3 -N~ ~ -N 3
\-/ x / \-/ \
x
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Ra
_X
N ~ ~Rs N ~ R- ~ X R
3 3
X / N
O/ ~ X
O Ra
X- R X- R -N
3 3 R3
-~ ~ X
X o/
X- Rs O \
N \ X N I / R
3
/
Ra
\ /
R3 R3
/N / R3 /N \
O Ra
/ N Rs / N Rs Rs
N \
R3 I R3 Rs
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Ra
\ \ /
R3 ~ /J
N
N ~ \ Rs
R3 N
R3
m3
a
Ra
R
- N R3 s
~R3
X-X
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21
XRs
X=X " X=
R3 R
3
N N
N- Rs
~3
N N
I~ o
s
N N
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~l IV-R3 \ /N N-R3
N ~l N
\N
N - N X-R3 N N-R3
N N
Rs ~ Rs
N-
N N N
R3 ~ R3
N N
~N ~ ~ N
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23
N N N
Rs
-N
N Ni
R3 ~ Rs
N N ~ / X ~N ~ X
R3
N~ N
/X
N -N
/ R3 ~ R3
N/
N
-N
R3
N~ Rs
N
/~ N~
N N S
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-N
R
3
-N O
N / -N"N Rs
R \~--~/s
N
N, .N Rs ~ Ra
N"N
~N
R3
-N N O
N N -N N
N~
R3 R3
N
R3
S
~R3
/ N N
/ ~ R3
U o
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R3
R3
Rs , ~ N
N
3
R3
J
N
Rs Rs
O/ ~ ~N
N
N\ Rs Rs
O
~S N
R3
N
R3
N
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26
wherein R3 is as hereinbefore defined;
m represents 0 or 1;
R4 represents hydrogen, (CH2)wCOOH or (CH2)wCONH2;
w represents an integer from 0 to 4; and
X represents CH or N.
Where two or more X atoms are present in a ring,
preferably at least one is CH.
In the Lp groups depicted above, preferably L
represents CO when the Lp group is linked to L through N, or
CONH when the Lp group is linked to L through C.
Examples of particular values for R3 are:-
for alkylaminocarbonyl: N-methyl-N-ethylaminocarbonyl,
methylaminocarbonyl or dimethylaminocarbonyl;
for N-alkylaminoalkanoyl: N-methylacetyl;
for N-alkanoylaminoalkanoyl: 2-N-acetylaminoacetyl or 2-N-
acetylaminopropanoyl;
for C-hydroxyaminoalkanoyl: 2-amino-3-hydroxypropanoyl or 2-
amino-3-hydroxybutanoyl;
hydrogen;
hydroxyl;
for alkoxy optionally substituted by hydroxy, alkylamino,
alkoxy, oxo, aryl or cycloalkyl: alkoxy such as methoxy or
ethoxy;
for alkyl optionally substituted by hydroxy, alkylamino,
alkoxy, oxo, aryl or cycloalkyl: (1-6C)alkyl, such as
methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl,
pentyl, 2-pentyl or 3-pentyl, (1-6C)alkylamino(1-6C)alkyl,
such as isopropylaminomethyl, dimethylamino-methyl,
diethylaminomethyl or dimethylaminoethyl, or (1-6C)alkanoyl,
such as acetyl, propionyl or isobutyryl;
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for hydroxyalkyl optionally substituted by hydroxy,
alkylamino, alkoxy, oxo, aryl or cycloalkyl: (1-
6C)hydroxyalkyl, such as hydroxymethyl, or 1-hydroxyethyl or
2-hydroxyethyl, carboxy, carboxy(1-5C)alkyl or hydroxy(1-
6C)alkanoyl, such as 2-hydroxyacetyl or 2-hydroxypropanoyl;
for alkoxyalkyl optionally substituted by hydroxy,
alkylamino, alkoxy, oxo, aryl or cycloalkyl: (1-6C)alkoxy(1-
6C)alkyl, such as methoxymethyl;
for alkoxycarbonyl: methoxycarbonyl or ethoxycarbonyl:
for aminoalkyl optionally substituted by hydroxy,
alkylamino, alkoxy, oxo, aryl or cycloalkyl: amino(1-
6C)alkyl such as aminomethyl, aminocarbonyl, aminocarbonyl-
(1-5C)alkyl, or amino(1-6C)alkanoyl, such as aminoacetyl
(COCH2NH2), aminopropionyl (COCH2CH2NH2~ or 2-aminopropionyl
( COCH ( CH3 ) NH2 ) ;
for alkylamino optionally substituted by hydroxy,
alkylamino, alkoxy, oxo, aryl or cycloalkyl: (1-
6C)alkylamino such as methylamino, dimethylamino or
ethylamino, or (1-6C)alkanoylamino, such as formylamino or
acetylamino;
amino;
for halo: fluoro or chloro;
cyano;
nitro;
thiol;
for alkylthio: methylthio;
for alkylsulphonyl: methylsulphonyl, ethylsulphonyl or
isopropylsulphonyl;
for alkylsulphenyl: methylsulphenyl;
for triazolyl: 1,2,4-triazol-2-yl, 1,2,4-triazol-4-yl or
1,2,3-triazol-4-yl;
for imidazolyl: 1,3-imidazol-1-yl or 1,3-imidazol-4-yl;
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for tetrazolyl: tetrazol-1-yl or tetrazol-5-yl;
hydrazido;
for alkylsulphonamido: methylsulphonamido, ethylsulphonamido
or propylsulphonamido;
for alkylaminosulphonyl: methylaminosulphonyl,
ethylaminosulphonyl or propylaminosulphonyl;
aminosulphonyl;
for haloalkoxy: trifluoromethoxy; and
for haloalkyl: trifluoromethyl or trichloromethyl.
When R3 is present as a substituent on an aromatic
ring, it may be selected, for example, from hydrogen,
alkylsulphonyl, aminosulphonyl, alkylaminosulphonyl,
alkylaminocarbonyl, amino, amido, alkoxycarbonyl,
acetylamino, chloro, fluoro, cyano, methoxy, ethoxy, nitro,
hydroxy, alkylsulphonylamino, triazolyl and tetrazolyl.
When R3 is present as a substituent on a saturated
ring, it may be selected, for example, from hydrogen,
hydroxy, amino, (1-3C)alkoxy, (1-3C)hydroxyalkyl, (1-
3C)alkyl, carboxy, methoxycarbonyl and ethoxycarbonyl.
It has been found that certain groups L and,
especially, Lp are associated with selectivity for Factor
Xa, whereas others are associated with selectivity for
tryptase.
One group of compounds of particular interest as Factor
Xa inhibitors are compounds of formula (I) in which Lp
comprises an azacycloalkyl or diazacycloalkyl group of
formula
a b
\(CH2lr
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29 ,
in which r is 1 or 2, one of Xa and Xb is N and the other is
CH or N, provided that when r is 1, Xa and Xb are not both
N.
Preferred compounds comprising this group are those in
which Lp is a group of formula:
L -G-L -R
xa b ~ a~s ~ ~t ~ b~u 10
\(CH2j~
in which:
r is 1 or 2;
one of Xa and Xb is N and the other is CH or N provided that
when r is 1, Xa and Xb are not both N;
s, t and a are each 0 or 1;
La and Lb are each independently selected from a single
bond, C=O, 0 and NRle, in which Rle is hydrogen or (1-
6C)alkyl;
G is (1-6C)alkanediyl; and
R10 is (1-6C)alkyl; (3-6C)cycloalkyl which is unsubstituted
or substituted by (1-6C)alkyl; indanyl; pyridyl;
tetrahydropyranyl; tetrahydrothiopyranyl; phenyl which is
unsubstituted or substituted by one or two R3 groups;
pyrrolinyl; or a group of formula
R
/d 11
\(CH2jv
in which v is 1, 2 or 3; one of Xc and Xd is N and the other
is CH or N, provided that when v is 1, Xc and Xd are not
both N; and R11 is hydrogen, (1-6C)alkyl or when Xd is CH,
hydroxy(1-6C)alkyl; provided that when t is 0, the sum of s
and a is 1; when Xb is N, La is a bond or C=O; when Xc is N,
Lb is a bond or C=O; when Xb and Xc are both N, t is 1; and
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when (La)S-(G)t-(Lb) represents an alkyl group and Xb and X~
both represent N, the alkyl group contains at least two
chain carbon atoms.
It will be appreciated that the provisos exclude
5 compounds having two heteroatoms bonded directly together or
separated by an alkyl group having only one carbon atom in
the chain.
When Xa is N, L is preferably CO or CH2C0.
When Xa is CH, L is preferably CONH, CONHCH2 or
10 CH2NHC0.
Examples of values for G are CH2, (CH2)2 and (CH2)3.
Examples of values for R11 are hydrogen, methyl, ethyl
or 2-propyl, or when Xd is CH, hydroxymethyl.
Examples of values for R10 are:
15 for (1-6C)alkyl: methyl, ethyl, 2-propyl and 3-pentyl;
for (3-6C)cycloalkyl which is unsubstituted or substituted
by (1-6C)alkyl: cyclopentyl, 3-methylcyclopentyl, cyclohexyl
and 4-methylcyclohexyl;
for indanyl: 2-indanyl;
20 for pyridylx pyrid-2-yl, pyrid-3-yl and pyrid-4-yl;
for tetrahydropyranyl: tetrahydropyran-4-yl;
for tetrahydrothiopyranyl: tetrahydrothiopyran-4-yl;
for phenyl which is unsubstituted or substituted by one or
two R3 groups: phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-
25 fluorophenyl, 2-(methylthio)phenyl, 2-ethylphenyl, 2-
methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-
methanesulphonylphenyl, 3-methanesulphonylphenyl, 4-
methanesulphonylphenyl, 4-fluoro-2-methanesulphonylphenyl,
4-amino-2-methanesulphonylphenyl, 4-amido-2-
30 methanesulphonyl-phenyl, 4-nitro-2-methanesulphonylphenyl,
2-aminosulphonylphenyl, 2-methylaminosulphonylphenyl, 2-
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dimethylaminosulphonylphenyl, 2-methylsulphonylamino-phenyl,
2-carboxamidophenyl and 2-acetamidophenyl;
for pyrrolinyl: pyrrolin-1-yl; and
for a group of formula
R
d 11
\(CH21"
piperidin-1-yl, 4-methyl-piperidin-1-yl, piperidin-4-yl, 1-
methylpiperidin-4-yl, 1-(2-propyl)piperidin-4-yl,
pyrrolidin-1-yl, 3-methylpyrrolidin-1-yl, pyrrolidin-3-yl,
1-methyl-pyrrolidin-3-yl, 1-(2-propyl)pyrrolidin-3-yl, 1-
methyl-piperazin-4-yl, 1-ethylpiperazin-4-yl, 1-(2-
propyl)piperazin-4-yl, hexahydro-1,4-diazapin-1-yl and 4-
methyl-hexahydro-1,4-diazapin-1-yl.
Another group of compounds of particular interest as
Factor Xa inhibitors are compounds of formula (I) in which
-L-Lp (D) n is
G
N~(CH2) Q
4
0
q is 1 or 2;
(a) Q is a direct bond; and Rq is piperidin-4-yl which
may bear a C1-3alkyl substituent at the 1-position; or Rq is
NRaRb in which each of Ra and Rb independently is hydrogen
or C1_3alkyl; or one of Ra and Rb is hydrogen or methyl and
the other of Ra and Rb is -CH2-RC or-CH2-Rd in which Rc is
pyridyl or phenyl (which phenyl may bear a fluoro, chloro,
methyl, CONH2, S02NH2, methylaminosulphonyl,
dimethylaminosulphonyl, methylsulphonylamino, methoxy or
methylsulphonyl substituent) and in which Rd is isopropyl or
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cyclopentyl, or NRaRb is pyrrolidino, piperidino,
morpholino, piperazino, or tetrahydro-1,4-diazepino in which
a pyrrolidino or piperidino may be a 3,4-didehydro
deriviative and in which a pyrrolidino, piperidino,
piperazino, or tetrahydro-1,4-diazepino may bear a methyl
group at the 4-position (preferably Rq is piperidin-4-yl
which may bear a (1-3C)alkyl substituent at the 1-position);
(b) Q is -O- or -NH-; and Rq is Rc which is
defined as above (R~ is preferably pyrid-2-yl, pyrid-3-yl or
pyrid-4-yl); or
(c) Q is methylene; and Rq is NRaRb which is defined as
above.
q is preferably 2.
Another group of compounds of particular interest as
Factor Xa inhibitors are compounds of formula (I) in which
-L-Lp (D) n is
O
- Rr
in which Rr is -(CH2)c-Rc, -CHReRf, -CH2-CHReRf, or Rg in
which c is 1 or 2 and Rc is defined as above; each of Re and
Rf independently is hydrogen or C1-3alkyl; or CHReRf is
cyclopentyl (which may bear a methyl, ethyl or hydroxymethyl
substituent at the 3- or 4-position), cyclohexyl(which may
bear a methyl, ethyl or hydroxymethyl substituent at the 3-
or 4-position), tetrahydropyran-4-yl, tetrahydrothiopyran-4-
y1, pyrrolidin-3-yl (which may bear a 1-methyl substituent),
piperidin-4-yl (which may bear a 1-methyl substituent), or
indan-2-yl; and Rg is 2-methylsulphonylphenyl which may bear
a 4-fluoro substituent or Rg is 7~6-1,1-
dioxobenzo[b]thiophen-7-yl.
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Preferably c is 2.
Preferably R~ is pyrid-2-yl, pyrid-3-yl or pyrid-4-yl.
Another group of compounds of particular interest as
Factor Xa inhibitors are compounds of formula (I) in which
-L-Lp (D) n is
~N RS
~(CH2)5 (CH2)a
O
in which q is 1 or 2;
s is 0 or 1; and
Rs is -(CH2)c-Rc, -CHReRf, or -CH2-CHReRf each of which
is defined as above.
Preferably s is 1.
Another group of compounds of particular interest as
Factor Xa inhibitors are compounds of formula (I) in which
-L-Lp (D) n is
H
N R~
in which Rt is piperidin-4-yl, piperidin-3-yl or pyrrolidin-
3-yl (especially piperidin-4-yl), any of which may bear a
C1-3 alkyl substituent at the 1-position (preferably methyl,
ethyl or, more preferably, 2-propyl); or Rt is phenyl (which
phenyl may bear a fluoro, chloro, C1-4 alkyl, methoxy or
methylsulphonyl substituent).
Another group of compounds of particular interest as
Factor Xa inhibitors are compounds of formula (I) in which
-L-Lp (D) n is
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(CH2)nRn
Het
in which Het is a divalent 5 membered heteroaromatic group
containing 1, 2 or 3 heteroatoms selected from O, N and S
and having the two ring atoms at which it is connected
separated by one ring atom;
h is 0 or 1; and
Rh is phenyl which may bear one or more R3
substituents, for example independently selected from, for
an ortho or a para substituent: C1_5 alkyl, fluoro, chloro,
difluoromethyl, trifluoromethyl, methoxy, dimethylamino,
methylsulphonyl, and C1-2 acyl, and for a meta substituent:
fluoro, chloro and methyl.
Within this sub-group, a particularly preferred group
of compounds is that in which -L-Lp(D)n is
(CH2)nRn
Z~ Z2
in which Rh is phenyl which may bear one or two R3
substituents, for example an ortho and/or a para substituent
independently selected from, for an ortho: methyl, fluoro,
chloro, methylsulphonyl and acetyl, and for a para
substituent: methyl, fluoro, chloro, methoxy and
dimethylamino;
Z1 is S, Z2 is CH, h is 0; or
Z1 is NH, Z2 is N, h is 1.
One group of lipophilic groups Lp that has been found
to be associated with Factor Xa inhibitor activity is that
of formula
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N ~X - N
R
3
in which LX represents O or NH.
Examples of specific lipophilic groups of interest in
Factor Xa inhibitors include
R8
/ wN H
~N ~ Ra
5 /N /N /
-N N
R8
'N
-N
N
N
N R.
-N, .N N-R
-N"N
/N N
N
N
N"N
10 \R'
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36
N N O
N-
-,
N
-N,\ /Y-0 -N\/?-O
H H
N N N N
N/
N
where Rg is as defined for R3 (preferably as defined for a
substituent on an aromatic ring), especially where Rg
represents H, OMe, S02Me, F, cyano, amido, amino, N02, C1 or
OH; and Ri is hydrogen or (1-6C)alkyl (such as methyl, ethyl
or 2-propyl).
Another highly preferred lipophilic group in compounds
of interest as Factor Xa inhibitors is of formula (DP)
Rs R
A N
R3
(DP)
wherein A represents N or CH (preferably N) and R3 is as
hereinbefore defined. When the lipophilic group is (DP) it
is preferred that the group L represents CO, CH2 or 502.
Also, it is preferred if the R3 groups in the formula DP are
hydrogen.
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Hence, preferred compounds of formula (I) for use as
Factor Xa inhibitors are those of formula (J)
Rs R
X
R~ ~X L-A I N-
R3
(J)
where R2, X-X, and Cy are as hereinbefore defined and L
represents C0, CH2 or S02.
Another highly preferred lipophilic group in Factor Xa
inhibitors is based on the formula (K)
S02
Xz
(K)
wherein X2 is halo, hydrogen, amino, nitro or CONH2.
Preferably X2 is hydrogen or fluoro. Compounds in which
the lipophilic group is based on the formula (K) or (J) have
been found to perform relatively well in the prothrombin
time assay, when compared with corresponding
aminoisoquinolines of W099/11657.
One group of compounds of particular interest as
tryptase inhibitors is that in which L represents CO and Lp
represents
R3
N, > N
R3
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Rs ( \ Rs
-N R3 / NJ / NJ
In this group of compounds, R3 preferably represents
hydrogen, hydroxyl or alkylaminocarbonyl.
Examples of particular values for Lp in this sub-group
are pyrrolidin-1-yl, piperidin-1-yl, 3-N-methyl, N-
ethylaminocarbonylpiperidin-1-yl, decahydroisoquinolin-2-yl
and 2,3-dihydroindol-1-yl.
Another group of compounds of particular interest as
tryptase inhibitors is that in which L represents CONH and
Lp represents
R3
R3
\ S \ S
~~Rs ~~Ra
/ N such as / N
R3
~3
/ ~ ~ /
N v such as N
such as
\ Rs \ Rs
O / /
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Rs
N
O
R3
N
in which X is CH or N.
In this group of compounds, R3 is preferably hydrogen,
amino, hydroxy, alkyl or aminoalkyl.
Examples of particular values are:
(i) 2-aminocyclohexyl or 4-aminomethylcyclohexyl;
(ii) adamantyl;
(iii) 2-aminobenzothiazol-6-yl;
(iv) quinolin-3-yl;
(v) 4-piperidin-1-ylphenyl or 4-piperazin-1-ylphenyl;
(vi) 1-oxoindan-5-yl;
(vii) indan-5-yl;
(viii) tetrahydronaphth-6-yl or 1-methyltetrahydronaphth-6-
y1;
(ix) 1-oxotetrahydronaphth-6-yl or 1-oxotetrahydronaphth-7-
y1;
(x) 2,3-dimethylindol-5-yl; and
(xi) (N-benzyl-3-acetylindol-5-yl or N-benzyl-3-acetylindol-
7-yl.
Another group of compounds of particular interest as
tryptase inhibitors is that in which L represents CONH and
Lp represents
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R3
in which R3 is alkylaminocarbonyl, N-alkylaminoalkanoyl, N-
alkanoylaminoalkanonyl, C-hydroxyaminoalkanoyl, hydrogen,
alkoxy, alkyl, aminoalkyl, aminocarbonyl, hydroxyalkyl,
5 alkoxyalkyl, alkoxycarbonyl, acyloxymethoxycarbonyl,
alkylamino, amino, halo, cyano, nitro, thiol, alkylthio,
alkylsulphonyl, alkylsulphenyl, triazolyl, imidazolyl,
tetrazolyl, hydrazido, alkyl imidazolyl, thiazolyl, alkyl
thiazolyl, alkyl oxazolyl, oxazolyl, alkylsulphonamido,
10 alkylaminosulphonyl, aminosulphonyl, haloalkoxy or
haloalkyl.
Preferably the phenyl group is unsubstituted or
substituted by one or two R3 groups.
Examples of particular values are phenyl, 3-cyano-4-
15 methylphenyl, 3-aminocarbonylphenyl, 4-aminocarbonyl-phenyl,
4-chloro-3-aminocarbonyl-phenyl, 4-chlorophenyl, 3,5-
dichlorophenyl, 3-aminomethylphenyl, 4-methyl-3-
acetylaminophenyl, 4-(1-hydroxethyl)phenyl and 4-
isopropylphenyl.
20 Another particular group of compounds of formula I of
interest as tryptase inhibitors is that in which L
represents CONH and Lp represents
N
RsX
in which R3X represents R3 or a group of formula
25 - (CO)p- (G1) -R~
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in which p is 0 or 1; G1 represents (1-3C)alkanediyl or,
when p is 1, a bond; and R~ represents a carbocyclic or
heterocyclic group, optionally substituted by R3.
It will be appreciated that when Lp represents a group
as described above, it corresponds to a group in which Lp is
a combination of a heterocyclic group (2,3-dihydroindolyl),
a carbocyclic or heterocyclic group (R~) and optionally an
alkyl group (G1), which groups are linked by a single bond
or a carbonyl group. Accordingly, examples of particular
values for R~ are the examples given above for a carbocyclic
or heterocyclic group forming part of Lp. Particular
mention may be made of pyyrolidinyl, such as pyrrolidin-1-
y1, phenyl, thiazolyl, such as thiazol-4-yl, imidazolyl,
such as imidazol-4-yl, and pyridyl, such as pyrid-2-yl,
pyrid-3-yl and pyrid-4-yl.
Examples of values for G are -CH2-, and CH2CH2.
The 2,3-dihydroindolyl group in the above formula is
preferably a 2,3-dihydroindol-5-yl or -6-yl group,
especially a 2,3-dihydroindol-6-yl group.
Examples of structures of compounds comprising a 2,3-
dihydroindolyl group as described above are:
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\ \
N~ ~ N/
R3
° N °/ ~
\ \
/ N~ / N
Rs Rs
°/ ~ ~N °
/ N
N R3 Rs
O
S
When R3 is a substituent on the 1-position of a 2,3-
dihydroindolyl group, it preferably represents
alkylaminocarbonyl; N-alkylaminoalkanoyl; N-
alkanoylaminoalkanonyl; C-hydroxyaminoalkanoyl; hydrogen;
alkyl; alkanoyl; alkoxycarbonyl; acyloxymethoxycarbonyl;
aminoalkyl; aminoalkanoyl; hydroxyalkyl; hydroxyalkanoyl;
alkoxyalkyl; or alkanoylamino. Examples of particular values
are: N-methylaminoacetyl, N-acetylaminoacetyl, N-
acetylalaninoyl, serinoyl, threoninoyl, hydrogen, methyl,
acetyl, propanoyl, 2-methylpropanoyl, 3-methylbutyryl, 2-
hydroxypropanoyl, hydroxyacetyl, aminoacetyl and alaninoyl.
Accordingly, examples of particular values for Lp are:
1-(N-methylaminoacetyl)-2,3-dihydroindol-6-yl; 1-(N-
acetylaminoacetyl)-2,3-dihydroindol-6-yl; 1-(N-
acetylalaninoyl)-2,3-dihydroindol-6-yl; 1-(serinoyl)-2,3-
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dihydroindol-6-yl; 1-(threoninoyl)-2,3-dihydroindol-6-yl;
2,3-dihydroindol-5-yl; 1-methyl-2,3-dihydroindol-6-yl; 1-
acetyl-2,3-dihydroindol-6-yl; 1-propanoyl-2,3-dihydroindol-
6-yl; 1-(2-methylpropanoyl)-2,3-dihydroindol-6-yl; ; 1-(3-
methylbutyryl)-2,3-dihydroindol-6-yl; 1-(2-hydroxpropanoyl)-
2,3-dihydroindol-6-yl; 1-hydroxacetyl-2,3-dihydroindol-6-yl;
1-aminoacetyl-2,3-dihydroindol-6-yl and 1-alaninoyl-2,3-
dihydroindol-6-yl.
When R3 is a substituent on a phenyl, thiazolyl,
imidazolyl or pyridyl group, it is preferably hydrogen,
amino, alkyl or aminoalkyl. Examples of particular values
are hydrogen, amino, alkyl or aminomethyl.
Accordingly, further examples of particular values for
Lp are: 2,3-dihydroindol-5-yl, 1-prolinoyl-2,3-dihydroindol-
6-yl, 1-phenylacetyl-2,3-dihydroindol-6-yl, 1-(2-
hydroxy)phenylacetyl-2,3-dihydroindol-6-yl, 1-(3-
hydroxy)phenylacetyl-2,3-dihydroindol-6-yl, 1-(4-
hydroxy)phenylacetyl-2,3-dihydroindol-6-yl, 1-(4-
pyridyl)acetyl-2,3-dihydroindol-6-yl, 1-(3-pyridyl)acetyl-
2,3-dihydroindol-6-yl, 1-imidazol-4-ylacetyl-2,3-
dihydroindol-6-yl, 1-(2-aminothiazol-4-yl)acetyl-2,3-
dihydroindol-6-yl, and 1-(2-formamidothiazol-4-yl)acetyl-
2,3-dihydroindol-6-yl.
The hydrogen bond donor group which may be attached to
the lipophilic group preferably has a nitrogen or oxygen
atom as the hydrogen bearing donor atom and conveniently is
a hydroxyl group, a primary, secondary or tertiary amine, or
a primary or secondary imine group (as part of an amidine or
guanidine) or a saturated or unsaturated heterocyclic group
containing a ring nitrogen, preferably a group containing 5
to 7 ring atoms. Where the donor atom is a ring nitrogen,
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the remote portion of the heterocyclic ring may be part of
the lipophilic group.
The cyclic group attached to the alpha carbon is
preferably an optionally R3a substituted phenyl, pyridyl
(such as pyrid-2-yl, pyrid-3-yl or pyrid-4-yl), thienyl
(such as thien-2-yl or thien-3-yl), thiazolyl (such as
thiazol-2-yl, thiazol-4-yl or thiazol-5-yl), naphthyl (such
as naphth-1-yl), piperidinyl (such as piperidin-4-yl) or
cycloalkyl, such as a cyclohexyl group.
Examples of particular values for R3a are:-
hydrogen;
hydroxyl;
for alkoxy: methoxy or ethoxy;
for alkyl optionally substituted by hydroxy, alkylamino,
alkoxy, oxo, aryl or cycloalkyl: alkyl, such as methyl or
ethyl, or alkylaminoalkyl, such as methylaminomethyl or
dimethylaminomethyl;
for hydroxyalkyl optionally substituted by hydroxy,
alkylamino, alkoxy, oxo, aryl or cycloalkyl: hydroxymethyl
or carboxy;
for alkoxyalkyl: methoxymethyl;
for alkoxycarbonyl: methoxycarbonyl or ethoxycarbonyl;
for alkylaminocarbonyl: methylaminocarbonyl or
dimethylaminocarbonyl;
for aminoalkyl optionally substituted by hydroxy,
alkylamino, alkoxy, oxo, aryl or cycloalkyl: aminomethyl,
CONHz, CHZCONHz or aminoacetyl;
for alkylamino optionally substituted by hydroxy,
alkylamino, alkoxy, oxo, aryl or cycloalkyl: (1-
6C)alkanoylamino, such as formylamino or acetylamino;
for alkoxycarbonylamino: methoxycarbonylamino,
ethoxycarbonylamino or t-butoxycarbonylamino;
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amino;
for halo: fluoro or chloro;
cyano;
nitro;
5 thiol;
for alkylthio: methylthio;
for alkylsulphonyl: methylsulphonyl or ethylsulphonyl;
for alkylsulphenyl: methylsulphenyl;
for imidazolyl: imidazol-4-yl;
10 hydrazido;
for alkylimidazolyl: 2-methylimidazol-4-yl;
for alkylsulphonamido: methylsulphonylamido or
ethylsulphonylamido;
for alkylaminosulphonyl: methylaminosulphonyl or
15 ethylaminosulphonyl;
aminosulphonyl;
for haloalkoxy: trifluoromethoxy; and
for haloalkyl: trifluoromethyl.
Examples of particular values for Rlc are:
20 hydrogen;
hydroxyl;
for alkoxy: methoxy or ethoxy;
for alkyl optionally substituted by hydroxy, alkylamino,
alkoxy, oxo, aryl or cycloalkyl: alkyl, such as methyl or
25 ethyl, or alkylaminoalkyl, such as methylaminomethyl or
dimethylaminomethyl;
for hydroxyalkyl: hydroxymethyl;
for alkoxyalkyl: methoxymethyl;
for alkoxycarbonyl: methoxycarbonyl or ethoxycarbonyl;
30 for alkylaminocarbonyl: methylaminocarbonyl or
dimethylaminocarbonyl;
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for alkoxycarbonylamino: methoxycarbonylamino,
ethoxycarbonylamino or t-butoxycarbonylamino;
for alkylamino optionally substituted by hydroxy,
alkylamino, alkoxy, oxo, aryl or cycloalkyl: (1-
6C)alkanoylamino, such as formylamino or acetylamino; and
for aminoalkyl substituted by hydroxy, alkylamino, alkoxy,
oxo, aryl or cycloalkyl: aminomethyl, CONH2, CH2CONH2 or
aminoacetyl.
Cy is preferably unsubstituted or substituted by one or
two R3a groups.
Preferably R3a is hydrogen, hydroxyl, methoxy, methyl,
amino, aminomethyl, hydroxymethyl, formylamino, acetylamino,
aminoacetyl, fluoro, chloro, ethylsulphonylamino, amido or
methylaminocarbonyl.
Examples of particular values for Cy are phenyl, 4-
aminophenyl, 4-amidophenyl, 4-(N-methyl)amidophenyl, 4-(N,N-
dimethyl)amidophenyl, 2-chlorophenyl, 2-methylphenyl, 2-
fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-
hydroxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 3-
aminomethylphenyl, 4-aminomethylphenyl, 2-
hydroxymethylphenyl, 3-hydroxymethylphenyl, 4-
hydroxymethylphenyl, 4-carboxyphenyl, 3-
ethylsulphonylaminophenyl, thien-2-yl, thien-3-yl, thiazol-
4-yl, thiazol-5-yl, 2-methylthiazol-4-yl, 2-aminothiazol-4-
y1, 2-formylaminothiazol-4-yl, 2-aminothiazol-5-yl, 2-
formylaminothiazol-5-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl,
4-aminopyrid-3-yl, 4-aminopyrid-4-yl, piperidin-4-yl, 1-
methylpiperidin-4-yl, cyclohexyl and naphth-1-yl.
Referring to the group R2, examples of a 5 or 6
membered aromatic carbon ring optionally interrupted by a
nitrogen, oxygen or sulphur ring atom are phenyl; pyrrolyl,
such as 2-pyrrolyl; pyridyl, such as 3-pyridyl; pyrazinyl,
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such as 2-pyrazinyl; furyl, such as 2-furyl; and thienyl,
such as 2-thienyl or 3-thienyl. Preferably the ring is
interrupted (i.e. a carbon atom is replaced) by at most one
heteroatom. More preferably the ring is phenyl, 2-thienyl
or 2-pyrrolyl. Most preferably, the ring is phenyl.
When the ring is phenyl, the group R2 may be a group of
formula
R
R.
Rs
in which R5 is amino, hydroxy, aminomethyl, hydroxymethyl or
hydrogen, and R6 and R7 which may be the same or different
represent halo, nitro, thiol, cyano, haloalkyl, haloalkoxy,
amido, hydrazido, amino, alkylthio, alkenyl, alkynyl or R1
or taken together form a 5 or 6 membered fused carbocyclic
ring or 5 membered heterocyclic ring, which may itself be
substituted by R1~, amino, halo, cyano, nitro, thiol,
alkylthio, haloalkyl, haloalkoxy.
When the substituents at the 3 and 4 positions taken
together form a fused ring which is a 5 or 6 membered
carbocyclic or heterocyclic ring, examples of the resultant
bicyclic ring are naphthyl, such as 2-naphthyl;
benzimidazolyl, such as benzimidazol-5-yl or benzimidazol-6-
yl; isoquinolinyl, such as isoquinolin-7-yl; indolyl, such
as indol-2-yl, indol-5-yl or indol-6-yl; indazolyl, such as
indazol-5-yl; indazol-6-yl; 3,4-methylenedioxyphenyl;
dihydroindolyl, such as 2,3-dihydroindol-6-yl;
benzothiazolyl, such as benzothiazol-2-yl or benzothiazol-6-
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y1; benzo[b]thiophenyl, such as benzo[b]thiophen-2-yl;
benzofuryl, such as benzofur-2-yl; imidazo[1,2-
a]pyrimidinyl, such as imidazo[1,2-a]pyrimidin-2-yl;
tetrahydroimidazo[1,2-a]pyrimidinyl, such as
tetrahydroimidazo[1,2-a]pyrimidin-2-yl; and benzisoxazolyl,
such as benzisoxazol-5-yl.
R2 preferably represents:
(i) phenyl optionally being substituted in the 3
and/or 4 position by halo, nitro, thiol, haloalkoxy,
hydrazido, alkylhydrazido, amino, cyano, haloalkyl,
alkylthio, alkenyl, alkynyl, acylamino, tri or
difluoromethoxy, carboxy, acyloxy, MeS02- or R1, and
optionally substituted at the 6 position by amino, hydroxy,
halo, alkyl, carboxy, alkoxycarbonyl, cyano, amido,
aminoalkyl, alkoxy or alkylthio;
(ii) naphth-2-yl optionally substituted at the 6 or 7
position by halo, haloalkoxy, haloalkyl, cyano, nitro,
amino, hydrazido, alkylthio, alkenyl, alkynyl or R1~ and
optionally substituted at the 3 position by amino, hydroxy,
halo, alkyl, carboxy, cyano, amido, aminoalkyl, alkoxy or
alkylthio;
(iii) isoquinolin-7-yl, indol-5-yl, indol-6-yl,
indazol-5-yl, indazol-6-yl, benzothiazol-6-yl or
benzisoxazol-5-yl optionally substituted at the 3 position
by halo, haloalkoxy, haloalkyl, cyano, nitro, amino,
hydrazido, alkylthio, alkenyl, alkynyl or R1~;
(iv) benzimidazol-5-yl or benzothiazol-6-yl optionally
substituted at the 2 position by amino;
(v) thien-2-yl or thien-3-yl optionally substituted at
the 4 or 5 position by halo, haloalkoxy, haloalkyl, cyano,
nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or R1;
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(vi) 3,4-methylenedioxyphenyl, 2,3-dihydroindol-6-yl,
3,3-dichloro-2-oxo-indol-6-yl or 1-methyl-3-aminoindazol-5-
yl;
(vii) benzothiazol-2-yl, imidazo[1,2-a]pyrimidin-2-yl
or tetrahydroimidazo[1,2-a]pyrimidin-2-yl;
(viii) pyrazol-2-yl optionally substituted at the 5
position by halo, haloalkoxy, haloalkyl, cyano, nitro,
amino, hydrazido, alkylthio, alkenyl, alkynyl or R1;
(ix) pyrid-2-yl optionally substituted at the 5
position by halo, haloalkoxy, haloalkyl, cyano, nitro,
amino, hydrazido, alkylthio, alkenyl, alkynyl or R1;
(x) pyrid-3-yl optionally substituted at the 6
position by halo, haloalkoxy, haloalkyl, cyano, nitro,
amino, hydrazido, alkylthio, alkenyl, alkynyl or R1;
(xi) benzofur-2-yl optionally substituted at the 3
position by amino, hydroxy, halo, alkyl, carboxy, cyano,
amido, aminoalkyl, alkoxy or alkylthio and at the 5 or 6
position by halo, haloalkoxy, haloalkyl, cyano, nitro,
amino, hydrazido, alkylthio, alkenyl, alkynyl or R1~;
(xii) indol-2-yl optionally substituted on the indole
nitrogen atom by alkyl and optionally substituted at the 5
or 6 position by halo, haloalkoxy, haloalkyl, cyano, nitro,
amino, hydrazido, alkylthio, alkenyl, alkynyl or R1~;
(xiii) indol-6-yl substituted at the 5 position by
amino, hydroxy, halo (such as fluoro or chloro), alkyl,
carboxy, alkoxycarbonyl, cyano, amido, aminoalkyl, alkoxy or
alkylthio and optionally substituted at the 3 position by
halo (such as chloro), haloalkoxy, haloalkyl, cyano, nitro,
amino, hydrazido, alkylthio, alkenyl, alkynyl or R1~; or
(xiv) benzo[b]thiophen-2-yl optionally substituted at
the 3 position by amino, hydroxy, halo, alkyl, carboxy,
cyano, amido, aminoalkyl, alkoxy or alkylthio and at the 5
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or 6 position by halo, haloalkoxy, haloalkyl, cyano, nitro,
amino, hydrazido, alkylthio, alkenyl, alkynyl or R1~.
Examples of particular values for substituents that may
be present on R2 are:
5 for halo: fluoro, chloro, bromo or iodo;
nitro;
thiol;
for haloalkoxy: difluoromethoxy or trifluoromethoxy;
hydrazido;
10 for alkylhydrazido: methylhydrazido;
amino;
cyano;
for haloalkyl: trifluoromethyl;
for alkylthio: methylthio;
15 for alkenyl: vinyl;
for alkynyl: ethynyl;
for acylamino: acetylamino;
carboxy;
for acyloxy: acetoxy;
20 hydroxy;
for alkyl: methyl or ethyl;
amido (CONH2);
for aminoalkyl: aminomethyl; and
for alkoxy: methoxy or ethoxy.
25 Examples of particular values for R1 are:
hydrogen;
hydroxy;
for alkoxy: methoxy or ethoxy;
for alkyl optionally substituted by hydroxy, alkylamino,
30 alkoxy, oxo, aryl or cycloalkyl: alkyl, such as methyl or
ethyl, alkylaminoalkyl, such as dimethylaminomethyl, or
alkanoyl, such as acetyl;
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for hydroxyalkyl: hydroxymethyl;
for alkoxyalkyl: methoxymethyl;
for alkoxycarbonyl: methoxycarbonyl;
for alkylaminocarbonyl: methylaminocarbonyl;
for alkylamino: methylamino, ethylamino or dimethylamino;
for hydroxyalkyl substituted by hydroxy, alkylamino, alkoxy,
oxo, aryl or cycloalkyl: carboxyl or carboxymethyl; and
for aminoalkyl substituted by hydroxy, alkylamino, alkoxy,
oxo, aryl or cycloalkyl: amido (CONH2) or amidomethyl.
Examples of particular values for R1~ are:
hydrogen;
hydroxy;
for alkoxy: methoxy or ethoxy;
for alkyl optionally substituted by hydroxy, alkylamino,
alkoxy, oxo, aryl or cycloalkyl: alkyl, such as methyl or
ethyl, or alkanoyl, such as acetyl;
for hydroxyalkyl: hydroxymethyl;
for alkoxyalkyl: methoxymethyl;
for alkoxycarbonyl: methoxycarbonyl;
for alkylamino: methylamino, ethylamino or dimethylamino;
for hydroxyalkyl substituted by hydroxy, alkylamino, alkoxy,
oxo, aryl or cycloalkyl: carboxyl or carboxymethyl; and
for aminoalkyl substituted by hydroxy, alkylamino, alkoxy,
oxo, aryl or cycloalkyl: amido (CONH2) or amidomethyl.
More preferably R2 represents:
(i) phenyl optionally being substituted in the 3
and/or 4 position by fluoro, chloro, bromo, iodo, nitro,
difluoromethoxy, trifluoromethoxy, amino, cyano,
trifluoromethyl, methylthio, vinyl, carboxy, acetoxy,
MeS02-, hydroxy, methoxy, ethoxy, methyl, aminomethyl,
methoxycarbonyl, methylamino, ethylamino or amido, and
optionally substituted at the 6 position by amino, hydroxy,
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fluoro, methoxycarbonyl, cyano or aminomethyl (preferably
phenyl substituted in the 4 position by chloro, amino,
vinyl, methylamino, methyl or methoxy, optionally at the 3
position with amino or hydroxy, and optionally at the 6
position with amino or hydroxy);
(ii) naphth-2-yl optionally substituted at the 6,
position by hydroxy and optionally substituted at the 3
position by amino or hydroxy;
(iii) isoquinolin-7-yl, indol-5-yl, indol-6-yl,
indazol-5-yl, indazol-6-yl, benzothiazol-6-yl or
benzisoxazol-5-yl optionally substituted at the 3 position
by chloro, bromo, amino, methyl or methoxy (preferably
indol-6-yl optionally substituted at the 3 position by
chloro, bromo, methyl or methoxy);
(iv) benzimidazol-5-yl or benzothiazol-6-yl optionally
substituted at the 2 position by amino;
(v) thien-2-yl or thien-3-yl optionally substituted at
the 4 or 5 position by methylthio, methyl or acetyl;
(vi) 3,4-methylenedioxyphenyl, 2,3-dihydroindol-6-yl,
3,3-dichloro-2-oxo-indol-6-yl or 1-methyl-3-aminoindazol-5-
yl;
(vii) benzothiazol-2-yl, imidazo[1,2-a]pyrimidin-2-yl
or tetrahydroimidazo[1,2-a]pyrimidin-2-yl;
(viii) pyrazol-2-yl substituted at the 5 position by
methyl;
(ix) pyrid-2-yl optionally substituted at the 6
position by chloro;
(x) pyrid-3-yl optionally substituted at the 4
position by chloro;
(xi) benzofur-2-yl optionally substituted at the 3
position by chloro, methyl or methoxy, at the 5 or 6
position by methyl and at the 6 position by methoxy;
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(xii) indol-2-yl optionally substituted on the indole
nitrogen atom by methyl and optionally substituted at the 5
or 6 position by fluoro, chloro, bromo, methyl or methoxy;
(xiii) indol-6-yl substituted at the 5 position by
chloro, fluoro or hydroxy and optionally substituted at the
3 position by chloro or methyl; or
(xiv) benzofb]thiophen-2-yl optionally substituted at
the 3 position by fluoro, chloro or methyl, and optionally
substituted at the 5 or 6 position by fluoro, chloro,
methyl, hydroxy, or methoxy.
Examples of particular values for R2 are:
(i) phenyl, 2-aminophenyl, 3-aminophenyl, 2-amino-3-
fluorophenyl, 2-amino-4-fluorophenyl, 2-amino-4-
chlorophenyl, 2-amino-3-bromophenyl, 2-amino-3-nitrophenyl,
2-amino-4-nitrophenyl, 3,4-dimethoxy-5-aminophenyl, 2-amino-
4-methylphenyl, 2-amino-3-methylphenyl, 2-amino-3-
methoxyphenyl, 3,4-diaminophenyl, 3,5-diaminophenyl, 3-
amino-4-fluorophenyl, 3-amino-4-chlorophenyl, 3-amino-4-
bromophenyl, 3-amino-4-hydroxyphenyl, 3-amino-4-
carboxymethylphenyl, 3-amino-4-methylphenyl, 3-amino-4-
methoxyphenyl, 2-fluorophenyl, 4-fluoro-3-cyanophenyl, 3-
chlorophenyl, 3-chloro-4-hydroxphenyl, 3-chloro-5-
hydroxyphenyl, 4-chlorophenyl, 4-chloro-2-hydroxyphenyl, 4-
chloro-3-hydroxyphenyl, 4-chloro-3-methylphenyl, 4-chloro-3-
methoxyphenyl, 4-bromophenyl, 4-bromo-3-methylphenyl, 4-
iodophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-
cyano-5-aminophenyl, 2-hydroxphenyl, 2-hydroxy-4-
methoxyphenyl, 3-hydroxphenyl, 3-hydroxy-4-methylphenyl,
2,4-dihydroxyphenyl, 3,4-dihydroxyphenyl, 3-hydroxy-4-
methoxyphenyl, 4-difluoromethoxyphenyl, 4-
trifluoromethoxphenyl, 4-trifluoromethylphenyl, 4-
methylthiophenyl, 4-methoxycarbonylphenyl, 4-acetoxyphenyl,
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4-methanesulfonylphenyl, 3-methylphenyl, 3-
aminomethylphenyl, 3-aminomethyl-6-aminophenyl, 3-methyl-5-
aminophenyl, 4-methylphenyl, 4-vinylphenyl, 4-methoxyphenyl,
4-ethoxyphenyl, 4-methoxy-3-chlorophenyl, 4-methoxy-3-
methylphenyl, 3-methylaminophenyl, 4-methylaminophenyl, 4-
ethylaminophenyl or 2-aminomethylphenyl;
(ii) naphth-2-yl, 3-aminonaphth-2-yl, 3-hydroxynaphth-
2-yl or 6-hydroxynaphth-2-yl;
(iii) isoquinolin-7-yl, indol-5-yl, indol-6-yl, 3-
chloroindol-6-yl, 3-bromoindol-6-yl, 3-methylindol-6-yl, 3-
methoxyindol-6-yl, indazol-5-yl, 3-aminoindazol-5-yl,
indazol-6-yl, benzothiazol-6-yl, 3-aminobenzisoxazol-5-yl;
(iv) benzimidazol-5-yl, 2-aminobenzimidazol-5-yl, or
benzothiazol-6-yl;
(v) thien-2-yl, 5-methylthien-2-yl, 5-methylthio-thien-
2-yl, 5-acetylthien-2-yl or thien-3-yl;
(vi) 3,4-methylenedioxyphenyl, 2,3-dihydroindol-6-yl,
3,3-dichloro-2-oxo-indol-6-yl or 1-methyl-3-aminoindazol-5-
y1;
(vii) benzothiazol-2-yl, imidazofl,2-a]pyrimidin-2-yl
or tetrahydroimidazo[1,2-a]pyrimidin-2-yl;
(viii) 5-methylpyrazol-2-yl;
(ix) 5-chloropyrid-2-yl;
(x) pyrid-3-yl, 6-chloropyrid-3-yl;
(xi) benzofur-2-yl, 5-chlorobenzofur-2-yl, 3-
methylbenzofur-2-yl, 5-methylbenzofur-2-yl, 6-
methoxybenzofur-2-yl;
(xii) indol-2-yl, 5-fluoroindol-2-yl, 5-chloroindol-2-
y1, 5-methylindol-2-yl, 5-methoxindol-2-yl, 6-methoxyindol-
2-yl and 1-methyl-indol-2-yl;
(xiii) 5-fluoroindol-6-yl; or
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(xiv) benzo[bJthiophen-2-yl, 5-chloro-
benzo[b]thiophen-2-yl or 6-chlorobenzo[b]thiophen-2-yl.
It has been found that in compounds of formula (I) that
have been found to be tryptase inhibitors, the aromatic R2
5 group is of the formula
R5
HZN Rsa
in which RS is amino, hydroxy, aminomethyl, hydroxymethyl or
hydrogen, and R6a is hydrogen or methyl.
For a tryptase inhibitor, preferably RZ is 3-
10 aminomethylphenyl or 3-aminomethyl-6-aminophenyl. Most
preferably it is 3-aminomethylphenyl.
In one embodiment the aromatic R2 group is an
optionally substituted phenyl, naphthyl, indolyl or
isoindolyl group and accordingly, preferred compounds of
15 formula ( I ) are of formula ( I I )
RS Ar
X\ ~ /Lp'(~)"
X L~
R~
~s
(II)
wherein R5 is amino, hydroxy or hydrogen, and R6 and R~
which may be the same or different represent halo, nitro,
20 thiol, cyano, haloalkyl, haloalkoxy, amido, hydrazido,
amino, alkylthio, alkenyl, alkynyl or R1 or taken together
form a 5 or 6 membered fused carbocyclic ring or 5 membered
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heterocyclic ring, which may itself be substituted by R1~,
amino, halo, cyano, nitro, thiol, alkylthio, haloalkyl,
haloalkoxy;
Ar is an unsubstituted or substituted aryl group,
preferably phenyl;
X-X is -CONH-, -CH2CH2-, CH20-, -COO-, -CH2NH-, -OCH2-
or -NHCH2-, especially -CONH-;
L1 is a valence bond or an organic linker group
containing 1 to 4 backbone atoms selected from C, N, O and
S;
Lp1 is a cycloalkyl, azacycloalkyl, diazacycloalkyl,
phenyl, naphthyl, adamantyl, decalinyl, bicycloalkyl, mono-
or diazabicycloalkyl, mono- or bicyclo heteroaromatic or a
linear or branched alkyl, alkylene, alkenyl or alkenylene
group all optionally substituted by a group R3, or a
combination of at least two such groups linked by a spiro
linkage or a single or double bond or by C=O, O, S, SO, 502,
CONRIe, NRle-CO-, NRle linkage (for example, representative
lipophilic groups include a methyl-cyclohexyl,
methylcyclohexylmethyl, bispiperidinyl, methylphenylmethyl,
phenylethyl, benzylpiperidinyl, benzoylpiperidinyl or
phenylpiperazinyl and those as hereinbefore described);
D is a hydrogen bond donor group;
and n is 0, 1 or 2.
Suitable R2 groups may be
R5 fZ5
R3 R3 fZ3
N R5 I / N / N
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Rs
\ ~ ~ ~ ~ ~ ~ Rs
N ( / / Rs Rs
/ /
R3 Rs N
Rs \ ~ Rs \ \
R3 ~ / / / R3 ~ / / "' R3
~N
R N
Rs \ \ \ \ Rs ~ \ N
'/ R3 ~ / // Rs ~ Rs
N N
\ N R5 \ N
N
Rs / ~ R5 / S / S
Rs R5 Rs Ra
\ ~
\~N I /N I ~NH
R / O / ~ R / O
5 5
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Rs \ \ R3 \
R3 R3
/ IN
Rs _~ Rs
Rs \ * \ N \ N
~Rs I
R /
s p Rs O R3
Rs a Rs \ N
\ NH \ Rs I \~NHZ
Rs / O H
R ~ Rs N N
s \ \ \
R3
/ R3
wherein R5 is hydrogen, amino or hydroxy and R3 (in relation
to R2) is halo, haloalkoxy, haloalkyl, cyano, nitro, amino,
hydrazido, alkylthio, alkenyl, alkynyl or Rlj.
In a particularly favoured embodiment the R2 group is
an indole as marked by a * above in which R5 is hydrogen and
R3 is a hydrogen or halogen present at the 3 position.
It is preferred that at least one of R6 and R~ be other
than hydrogen and that R6, if present, is preferably a
substituent containing one or more polar hydrogens such as
hydroxy, amino, alkylamino, aminoalkyl, alkylaminoalkyl,
aminocarbonyl, alkylaminocarbonyl, hydrazo and alkylhydrazo;
alternatively R6 and R~ are joined together in the formation
of a naphthyl or indolyl or azaindolyl or diazaindolyl
group.
It is especially preferred that R6 be amino and R~ be
chloro, bromo, methyl, methoxy or vinyl; or that R6 and R~
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taken together form an indolyl ring with the NH at the 6-
position or taken together form a naphthyl ring.
In a further preferred embodiment the compounds of
formula (I) are of formula (A)
R~ Ar
L2
\LPi~~~n
R8a R9a
R.
(A)
(wherein R5, R6, R~, Ar, X-X, Lpl, Dn are as hereinbefore
defined; L2 is a valence bond or an organic linker group
containing 1 to 3 backbone atoms selected from C, N, O and S
and Rga and R9a are hydrogen or taken together with the
carbon atom to which they are attached form a carbonyl
group). Again, in an alternative embodiment the phenyl
derivative forming part of the R2 functionality may instead
be a nitrogen heterocyclic group, e.g. pyridine.
In one embodiment, L2 comprises the backbone of an
alpha amino acid, the lipophilic group being the side chain
of the amino acid.
In one preferred embodiment Rga and R9a are hydrogen
and L2 is a OC=O or NHC=0 group.
In a preferred embodiment, L2 represents a valence bond
and the lipophilic group is bound directly to a carbonyl
alpha to the alpha atom via a nitrogen atom which forms part
of the lipophilic group. Suitable lipophilic groups in this
case therefore include piperidinyl, pyrrolidinyl and
piperazinyl. In a preferred embodiment the piperidine or
piperazinyl group is further substituted by a phenyl,
benzyl, phenoxy, piperidine, pyridine or benzoyl group,
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optionally substituted on the phenyl ring by one or more R3
groups. In a more preferred embodiment a piperazine is
substituted with a phenyl group substituted at the 2-
position with an electron withdrawing group such as fluoro,
5 nitro, triazolyl, cyano, alkoxycarbonyl, aminocarbonyl,
aminosulphonyl, alkylaminosulphonyl and, especially
preferred, alkylsulphonyl; and, at the 4-position, with
hydrogen, fluoro, alkoxy or hydroxy. In another more
preferred embodiment a piperidine is substituted at the 4-
10 position with 4-piperidine which itself may be substituted
on nitrogen by alkyl or aminocarbonylalkyl or
alkylaminocarbonyl alkyl.
In a further embodiment, the lipophilic group has
attached a group of the formula -COORlg or -CON-aminoacid or
15 ester derivative thereof (where Rlg is as defined for Rla).
Particularly preferred compounds are those of formula (G)
R5 O Ar
N
w
O
R~
Rs
(G)
(wherein Ar, R6 and R~ are as hereinbefore defined, R5
20 represents hydrogen or amino and
represents a cyclic group) or of formula (H)
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~N
R5 O Ph
N
w
O
R~
Rs
(H)
(wherein R6 and R~ are as hereinbefore defined, and R5
represents hydrogen or amino). In a preferred embodiment R6
is amino and R~ a halogen, especially chlorine.
Again, in an alternative embodiment the phenyl
derivative forming part of the R2 functionality in formulae
(G) and (H) may instead be a nitrogen heterocyclic group,
e.g. pyridine, indole.
In another embodiment the group binding the alpha
carbon atom to the lipophilic group comprises a heterocyclic
group. Accordingly, preferred compounds of formula (I) also
include those of formula (III)
R~ Ar
~He~
CH2 m Lp~(D)
R.
(III)
(wherein R5, R6, R~, Ar, X-X, Lpl, Dn are as hereinbefore
defined;
m is 0, 1 or 2;
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Het is a 5 or 6-membered heterocyclic group interrupted
by 1, 2 or 3 heteroatoms selected from O, N and S optionally
substituted by a group R3b where R3b is as defined for R3).
Again, in an alternative embodiment the phenyl
derivative forming part of the R2 functionality may instead
be a nitrogen heterocyclic group, e.g. pyridine.
Where Het is a five membered ring, the two ring atoms
at which it is connected are preferably separated by one
ring atom. Where Het is a six-membered ring, the two ring
atoms at which it is connected are preferably separated by
one or two ring atoms. Representative heterocyclic groups
include thiazole, oxazole, oxadiazole, triazole, thiadiazole
or imidazole. Where the heterocyclic group is substituted
by R3b this is preferably a COON or COORlh connected to the
heterocycle via a valence bond or alkylene chain (where Rlh
is as defined for Rla) .
In a further embodiment, the lipophilic group has
attached a group of the formula -COORlg or -CON-aminoacid or
ester derivative thereof.
In an alternative embodiment, the main aromatic R2 ring
in the compounds of the invention is a five membered
aromatic ring leading to compounds of formula (IV) or (IVa)
Ar
X\ ~ /Lp'(O)"
X L~
(IV)
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Ar
\ ~ /L
X L~
R~
(IVa)
(wherein R5, R6, R~, X-X, Ar, L1, Lpl, D and n are as
hereinbefore described for formula (II) and Z represents N,
O or S). It is preferred that at least one of R6 and R~ be
other than hydrogen, or that R6 and R~ taken together enable
the formation of an indolyl, or azaindolyl group or
diazaindolyl group. Preferences for other substituents are
as for formula (A) above. Examples of possible fused
systems are given below.
\ R5 \ R5 \ R5
R3 I R3 I R3 /
/ 0 7' / S l N
H
R5
v
\ R3 ~ \ ~ R3
/ ~
H N H H R5
R5 ~ R3
H S /
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N N _N N _N
S \ N ~ N
Hence in a preferred embodiment the compounds of the
invention are of formula C or D
Ar
Q
L
X 2\LP~(D)n
R8a R9a
R~
(C)
Ar
Rs L2
X i!\ \LP~~D)n
Rsa R9a
(D)
(wherein R5, R6, R~, Ar, X-X, Z, Rg, Rg, LZ Lpl, Dn are as
hereinbefore defined) preferences for Ar, X-X, Rga, Rga, L2,
Lpl, Dn are as for formula (A) above; or compounds of
formula E or F:
O Ar
R5
Rs \ Z O
R~
(E)
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Ar
O
(F)
wherein Lpl is connected to the carbonyl via a nitrogen
atom, R6, R~, Ar, Z, Lpl, Dn are as hereinbefore defined and
R5 is hydrogen or amino) preferences for Ar, Lpl, Dn are as
5 for formula (A) above.
Particularly preferred compounds of formula (I) for use
as Factor Xa inhibitors are the compounds of Examples 35,
63, 66, 73, 100, 318 and 320, and physiologically tolerable
salts thereof.
10 As previously mentioned, a number of compounds of
formula (I) have been found to be excellent mixed inhibitors
in that they inhibit both the serine proteases Factor Xa and
thrombin. Such mixed inhibitors are preferably based on the
formula (L)
x3
O
R"
R'
(L)
wherein R' represents
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H/Ha H/Hal
or
X3 represents hydrogen or a polar group such as amino or
CONH2, especially CONH2; and
R" represents a cyclic group bound to the carbonyl by a
nitrogen atom or an optionally substituted group of formula
J
~~~ i , ,
U
A group of compounds of particular interest for use as
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tryptase inhibitors is that of formula
R5 O Cy
LP~D)n
~N * L~
H
H2N Rsa
in which:
L-Lp(D)n represents CO-LX;
RS represents amino, hydroxy, aminomethyl,
hydroxymethyl or hydrogen;
R6a represents hydrogen or methyl;
Cy is a saturated or unsaturated, mono or poly cyclic,
homo or heterocyclic group, preferably containing 5 to 10
ring atoms and optionally substituted by groups R3a or phenyl
optionally substituted by R3a%
each R3a independently is Rl~, amino, halo, cyano,
nitro, thiol, alkylthio, alkylsulphonyl, alkylsulphenyl,
hydrazido, alkylsulphonamido, alkylamino-sulphonyl,
aminosulphonyl, haloalkoxy, and haloalkyl;
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each Rl~independently represents hydrogen or hydroxyl,
alkoxy, alkyl, aminoalkyl, hydroxyalkyl alkoxyalkyl,
alkoxycarbonyl, acyloxymethoxycarbonyl or alkylamino
optionally substituted by hydroxy, alkylamino, alkoxy, oxo,
aryl or cycloalkyl;
LX is a mono or bicyclic group bound to the carbonyl
via a pendent nitrogen atom or nitrogen atom which forms
part of the mono or bicyclic ring;
or a physiologically tolerable salt thereof, e.g. a
halide, phosphate or sulphate salt or a salt with ammonium
or an organic amine such as ethylamine or meglumine.
It will be appreciated that when LX is bound to the
carbonyl via a pendant nitrogen, the group CO-LX corresponds
with the group L-Lp(D)n in which L is CONH and Lp is a mono
or bicyclic group. When Lx is bound to the carbonyl via a
nitrogen that forms part of the mono or bicyclic ring, the
group CO-Lx corresponds with the group L-Lp(D)" in which L
is CO and Lp is a mono or bicyclic group containing a
nitrogen atom in the ring and bound to L via this nitrogen.
It is believed that an aminomethyl group positioned on
the 3 position of the phenyl ring will give rise to
' excellent binding within the S1 binding pocket of tryptase.
Without wishing to be limited by theory it is believed that
the presence of a hydrogen bond donating group attached to
the phenyl group will be essential for successful inhibition
of tryptase.
RS and R6 are both preferably hydrogen.
Most preferably the Lx group comprises
NH A NH
~ NH
)n ~ )n
B xix ~ g
R1x
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,x
NH I,x
\ X, x N
X, x
)n
,x
X2x R2x
X2x R2x
wherein:
A and B are independently chosen from NH, N, O, S, CH,
CH2 ;
XlX and X2X are independently chosen from
( CHz ) m, ( CHZ ) mCH=CH ( CHZ ) P, CO ( CHZ ) m, NH ( CHz ) m, NHCO ( CHz )
m i
1 O CONH ( CH2 ) "" SOzNH ( CHZ ) m, NHSOZ ( CH2 ) m
n is 1 or 2;
m is 0 to 2;
p is 0 to 2;
RlX and RZX are independently chosen from hydrogen,
alkoxy, alkyl, aminoalkyl, hydroxyalkyl, alkoxyalkyl,
alkoxycarbonyl, amino, halo, cyano, nitro, thiol, alkylthio,
alkylsulphonyl, alkylsulphenyl, oxo, heterocyclo optionally
substituted by R3X, cycloalkyl optionally substituted by R3X
or aryl optionally substituted by R3X; and
R3X is hydrogen, alkoxy, alkyl, amino, hydroxy, alkoxy,
alkoxycarbonyl, halo, cyano, nitro, thiol, sulphonyl, or
sulphenyl.
Examples of heterocyclic RlX and R2X groups are
piperidine, piperazine and pyrrolidine.
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The cyclic group attached to the alpha atom is
preferably an optionally R3a substituted phenyl.
Thus, one group compounds of formula (I) of interest as
tryptase inhibitors are those of formula (II)
5
Lx
II
wherein Lx is as hereinbefore defined. It is envisaged that
10 especially preferred Lx groups will be those in which a
cyclic or bicyclic ring is substituted by hydrogen bond
donating and/or acceptor groups.
The compounds of formula (I) may be prepared by
conventional chemical synthetic routes or by routes as
15 illustrated by the following examples, e.g. by amide bond
formation to couple the aromatic function to the alpha atom
and to couple the lipophilic function to the alpha atom.
Where the alpha atom is a carbon, the cyclic group-alpha
atom combination may conveniently derive from an alpha amino
20 acid with the aromatic deriving from for example an acid
derivative of a compound based on R2, e.g. o-amino-benzoic
acid or aminomethylbenzoic acid. Amide formation from such
reagents (in which any amino or hydroxyl function
(especially in an aminomethyl group) may if desired be
25 protected during some or all of the synthesis steps) yields
a compound of formula (V).
* the alpha atom
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R2-CONH-CH(Cy)-COOH (V)
(where Cy and R2 are as defined above).
Prior to reaction the amino group in an aminoalkyl
group should be protected by an appropriate protecting group
e.g. Boc, Z, Fmoc or Bpoc. The use of protecting groups is
described in McOmie, "Protective Groups in Organic
Chemistry", Plenum, 1973 and Greene, "Protective Groups in
Organic Synthesis", Wiley Interscience, 1981.
The lipophilic group (and optionally simultaneously the
hydrogen bond donor) may then conveniently be introduced by
reaction of a compound of formula (V) (or another analogous
carboxylic acid) optionally after transformation into an
activated form, e.g. an acid chloride or active ester, with
a lipophilic group carrying an amine, hydroxylamine,
hydrazine or hydroxyl group, e.g. to produce compounds with
linkages of -CO-NRld-, -CO-NRld-O-, -CO-NRld-NRld- and
-CO-O- from the alpha atom (where it is a carbon) to the
lipophilic group. Cyclisation can be base induced via
nucleophilic attack of the alpha atom on a leaving group on
the active side chain. If necessary the amide linkage can
be reduced using an appropriate reducing agent employing the
necessary protection depending on whether concurrent
reduction of the carboxylic acid moiety is also desired.
Alternatively a compound of formula V or another analogous
carboxylic acid may be transformed into an alcohol by
reaction with isobutylchloroformate and reduction with
sodium borohydride.
Such an alcohol, e.g. of formula VI
R2 - CONH - CH(Cy)CH20H (VI),
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can be reacted to introduce the lipophilic group by
reactions such as:
alkylation with an alkyl halide in the presence of a
base;
under Mitsunobu conditions, such as reaction with
diethyl azodicarboxylate/triphenylphosphine and a
hydroxylated aryl compound;
by reaction with an activated carboxylic acid (e.g. an
acid chloride) or with a carboxylic acid and
diethylazodicarboxylate/triphenylphosphine;
by reaction with an isocyanate; and
by treatment with methanesulphonyl chloride or
trifluoromethanesulphonic anhydride and reaction with an
amine, or with a thiol optionally followed by oxidation,
e.g. with potassium metaperiodate or hydrogen peroxide.
Alternatively, the reactions described above may be
performed on a corresponding compound of formula (VI) in
which R2 is replaced with a protecting group, such as t-
butoxycarbonyl (Boc), followed by deprotection and
introduction of the group R2.
In this way compounds with linkages of -CH2-O-,
-CH2-O-CO-, -CH2-O-CO-NRld-, -CH2-NRld-, -CH2-S-, -CH2-SO-
and -CH2-S02- between the alpha carbon and the lipophilic
group may be produced.
Alternatively the alcohol can be oxidized to form a
corresponding aldehyde (e. g. by oxidation with manganese
dioxide or DMSO/oxalyl chloride or DMSO/S03 or Dess-Martin
reagent) which may be reacted to introduce the lipophilic
group by reactions such as:
reaction with Wittig reagents or Horner-Emmons
reagents, optionally followed by reduction of the resulting
carbon: carbon double bond using H2/Pd-carbon;
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reaction with an organometallic, eg a Grignard reagent,
optionally followed by reaction on the resulting hydroxyl
group, such as oxidation (eg with Mn02, DMSO/oxalyl chloride
or Dess-Martin reagent), alkylation (eg with an alkyl halide
in the presence of a base in a solvent such as DMF),
arylation (eg with diethylazo dicarboxylate/triphenyl
phosphine and a hydroxyaryl compound), ester formation (eg
with an acid chloride or with a carboxylic acid and
diethylazido dicarboxylate/triphenyl phosphine), or
carbamate formation (eg with an isocyanate);
by reaction with an amine followed by reduction, e.g.
with sodium cyanoborohydride;
by reaction with a hydrazine; or
by reaction with a carbazide.
In this way compounds with linkages of -CH=CRld-,
-CH2-CHRld-, -CHOH-, -CHRld-O-, -CHRld-O-CO-,
-CHRld-O-CO-NRld-, -CO-, -CH2-NRld-, -CH=N-NRld- and
-CH=N-NRld-CO-NRld- between the alpha carbon and the
lipophilic group may be produced.
The transformation of alcohol to amine referred to
above may be used to produce an amine reagent for lipophilic
group introduction, e.g. a compound
R2-CONH-CH(Cy)-CH2-NRldH.
Such an amine reagent may be reacted to introduce the
lipophilic group, e.g. by acylation with an acid halide or
activated ester, by reaction with isocyanate, by reaction
with an isothiocyanate, or by reaction with a sulphonyl
chloride. In this way compounds with linkages of -CH2NRld-
CO-, -CH2-NRld-CO-NR1-, -CH2NRld-CS-NRld- and -CH2NRld-S02-
between the alpha carbon and the lipophilic groups may be
produced.
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The transformation of acid to amide referred to above
may be used to produce an amide reagent for introduction of
the lipophilic group, e.g. a compound
R2-CONH-CH(Cy)-CON(Rld)2~
Such amides may be reacted to introduce lipophilic
groups, e.g. by reaction with a haloketone (e. g. phenacyl
bromide). This provides a linkage
from alpha carbon to lipophilic group.
Analogously the amide may be transformed to a thioamide
by reaction with Lawesson's reagent and then reacted with a
haloketone to form a linkage
~s~
The amide reagent may likewise be transformed to a nitrile
reagent by dehydration, e.g. with trifluoroacetic anhydride.
The nitrile reagent may be reacted with hydrazine then with
acyl halide and then cyclized, (e. g. with trifluoroacetic
anhydride) to produce a linkage
N
N~NR~
Alternatively it may be treated with hydroxylamine then
reacted with acyl halide and cyclized (e. g. with
trifluoroacetic anhydride) to produce a linkage
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N
,O
N
The hydrazide produced by reaction of a carboxylic acid
reagent with hydrazine discussed above may likewise be used
as a reagent for lipophilic group introduction, e.g. as a
5 compound of formula
R2-CONH-CH(Cy)-CO-NR1-N(R1d)2~
Thus the hydrazide reagent can be reacted with an acyl
halide and cyclized, e.g. with trifluoroacetic anhydride to
yield a linkage
N~
N
or reacted with an acyl halide or an isocyanate to yield
linkages -CO-NRld-NRld-CO- and -CO-NRld-NRld-CO-NRld-
respectively.
Alternatively the hydrazide may be transformed by
reaction with Lawesson's reagent and then reacted with an
acyl halide and cyclized (e. g. with trifluoroacetic
anhydride) to produce the linkage
N~
N
S
An alternative route to these compounds is to carry out
any of the above chemical reactions to incorporate the
lipophilic group (and optional H bond donor) into a
protected intermediate such as a compound of formula (VII).
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Cy
PG~
COOH
PG = Protecting group
The protecting group may then be removed before
coupling of the for example o-amino benzoic acid (optionally
protected) .
The protection of amino and carboxylic acid groups is
described in McOmie, Protecting Groups in Organic Chemistry,
Plenum Press, NY, 1973, and Greene and 4Juts, Protecting
Groups in Organic Synthesis, 2nd. Ed., John Wiley & Sons,
NY, 1991. Examples of carboxy protecting groups include C1-
C6 alkyl groups such as methyl, ethyl, t-butyl and t-amyl;
aryl(C1-C4)alkyl groups such as benzyl, 4-nitrobenzyl, 4-
methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl,
2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, benzhydryl
and trityl; si.lyl groups such~as trimethylsilyl and t-
butyldimethylsilyl; and allyl groups such as allyl and 1-
(trimethylsilylmethyl)prop-1-en-3-yl.
Examples of amine protecting groups (PG) include acyl
groups, such as groups of formula RCO in which R represents
C1_6 alkyl, C3_lo cYcloalkyl, phenyl Cl_6 alkyl, phenyl, C1_6
alkoxy, phenyl Cl_6 alkoxy, or a C3_lo cycloalkoxy, wherein a
phenyl group may be optionally substituted, for example by
one or two of halogen, C1-CQ alkyl and C1-C4 alkoxy.
Preferred amino protecting groups include benzyloxycarbonyl
(CBz), t-butoxycarbonyl (Boc) and benzyl.
a-Amino acids of formula (VII) which are not
commercially available can be synthesized by methods known
in the art, for example as described in "Synthesis of
Optically Active a-Amino Acids" by Robert M. williams
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(Pergamon Press, 1989) and "Asymmetric Synthesis of
ArylGlycines", Chem. Rev. 1992, 889-917.
Compounds of the type (VII) made be prepared (for
example) by one or more of the following methods.
(i) from aryl or heteroaryl aldehydes via the Strecker
synthesis or modifications thereof, via Bucherer-Bergs
hydantoin synthesis, or via the Ugi methodology (Isonitrile
Chemistry, Ugi I. Ed.; Academic: New York, 1971; pp145-199)
with removal and replacement of protecting groups;
(ii) from styrenes via Sharpless methodology (J. Am. Chem.
Soc. 1998,120, 1207-1217)
(iii) from aryl boronic acids via Petasis methodology
(Tetrahedron, 1997, 53, 16463-16470) with removal and
replacement of protecting groups;
(iv) from aryl and heteroaryl acetic acids - via Evan's
azidation (Synthesis, 1997, 536-540) or by oximation,
followed by reduction and addition of protecting groups; or
(v) from existing aryl glycines by manipulation of
functional groups, for example, alkylation of hydroxy
groups, palladium assisted carbonylation of triflates
derived from hydroxy groups and further manipulation of the
carboxylic esters to give carboxylic acids by hydrolysis,
carboxamides by activation of the carboxylic acid and
coupling with amines, amines via Curtius reaction on the
carboxylic acid or
(vi) from aliphatic, carbocylic and non-aromatic
heterocyclic aldehydes and ketones using a Horner-Emmons
reaction with N-benzyloxycarbonyl)-a-phosphonoglycine
trimethyl ester (Synthesis, 1992, 487-490).
Examples of synthetic routes are shown below:
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CO H MeOH, SOCIZ z Pd(PPh3)- 4~Zn(~N)2
CO Me
2 ~ , DMF
gr Br
EDC, DMAP
MeOH
COzMe LIOH, THF, H20 I ~ C02H Raney Ni
NC NC NH3, H20
C02H Boc20, NaOH I ~ C02H
H2N~ dio~H20 BocNH
1. KHMDS, THF
COzMe
BocNH I / 2. Trisyl azide, THF
3. AcOH, THF
N3 NHZ
H2, Pd/C, EtOAc
~COzMe ~ I ~ COZMe
BocNH I / 250psi
BocNH
ZCI, NEt3
THF
NHZ NHZ
LiOH, THF, H20
~C02H~ w COZMe
BocNH I / BocNH
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Synthesis of protected 4-piperidylglycine
N Boc N Boc
EtO, ,O LiOH, THF, H20
P'OEt
O ZNH~~ a ZNH I COZMe
DBU, MeCN
NBoc NBoc
EDC, HOAt H2, Pd/C, MeOH
H2N ~
ZNH
ZNH COZH I / I
O
NBoc
HZN ~ W
o I /
Synthesis of protected 2-aminothiaz-4-ylglycine
NHCHO NHCHO
S~N ~. KHMDS, THF S~N H2, Pd/C, Boc20
MeOH
2. Trisyl azide, N
THF
3. AcOH, THF
EtOzC EtO2C
CHO ~ CHO
S ~ N l_iOH, THF, S ~ N
H20
~-NHBoc
NHBoc
EtOZC HOZC
A starting reagent for lipophilic group introduction
where the alpha atom is nitrogen may be produced for example
by reaction of a beta protected hydrazine (such protection
to be chosen as to be compatible with the subsequent
reagents to be employed) with phosgene, diphosgene,
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triphosgene or N,N'carbonyl diimidazole to give a reactive
compound of the type:
Cy
PG ~ CI or imidazole
\~/
O
PG = Protecting group
5 This intermediate may be used as has been described above
for the carboxylic starting reagents where the alpha atom is
carbon.
Removal of the protecting group by standard methods and
coupling with an activated aryl carboxylic acid will give
10 compounds of the type
R2-CONH-N(Cy)-L-Lp(D)n
(where R2, X, Y, Cy, L, Lp and D are as defined above).
15 Thus the compounds of formula (I) may be prepared by a
process which comprises coupling a lipophilic group to a
compound of formula (VIII)
R2-(X)2-Y(Cy)-Z1 (VIII)
(wherein R2, X, Y and Cy are as defined above and Z1 is a
reactive functional group), and optionally subsequently
coupling a hydrogen bond donor group to said lipophilic
group.
Instead of introducing the group L-Lp(D)n as the final
stage process step, the compounds of formula I may
alternatively be prepared by a process in which the group R2
is introduced in the final process step.
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Thus the compounds of formula (I) may also be prepared
by a process which comprises coupling a lipophilic group to
a compound of formula (IX)
Z2-Y(Cy)-L-Lp(D)n (IX)
(wherein Y, Cy, L, Lp D, and n are as defined above and Z2
is HX or a reactive functional group), or a protected
derivative thereof, with a compound of formula (X)
R2- Z3
(wherein R2 is as defined above and Z3 is XH or an
appropriate reactive group), or a protected derivative
thereof, followed if necessary by the removal of any
protecting groups.
Thus, for a compound of formula I in which X-X
represents CONH, a compound of formula (IX) in which Z2 is
H2N may be reacted with a compounds of formula (X) in which
Z3 is COON or a reactive derivative thereof, such as a acyl
halide or an anhydride, for example as described in the
Examples herein.
Where the lipophilic group Lp comprises more than one
group, it may generally be formed by coupling these groups
together at an appropriate stage in the preparation of the
compound of formula I using conventional methods or as
descibed in the Examples.
For a compound of formula I in which Lp comprises an
azacycloalkyl or diazacycloalkyl group of formula
L -G-L -R
a b ~ a~s ~ ~t ~ b~u 10
\(CH2lr
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in which Xb is N and each of s and a is 0, alkylating the
amino group of a corresponding compound in which the
corresponding residue is of formula
Xa N H
\(CH2jf
using a conventional alkylating method. The alkylation may
be carried out using any conventional method; however,
generally preferred is a reductive alkylation using the
appropriate aldehyde or ketone, for example as described in
the Alkylation Methods in the Examples.
Thus, a particular starting material for the alkylation
is one of formula
R2-CO-NH-C(Cy)-L Xa NH
\(CH2j~
in which Xa is N and L is CO or Xa is CH and L is CONH,
CONHCH2 or CH2NHC0.
For a compound of formula I in which Lp comprises an
azacycloalkyl or diazacycloalkyl group of formula
L -G-L -R
Xa b ( a)s ( )t ( b)u 10
\(CH2jf
in which R10 is a group of formula
R
/d 11
\(CH2jv
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in which Xd is N and R11 is (1-6C)alkyl, alkylating the
amino group of a corresponding compound of formula I in
which R11 is hydrogen using a conventional method.
Generally preferred is a reductive alkylation using the
appropriate aldehyde or ketone, for example as described in
the Alkylation Methods in the Examples.
For a compound of formula I in which Lp comprises an
azacycloalkyl or diazacycloalkyl group of formula
L -G-L -R
a b ( a~s ( ~t ( b~u 10
~(CH2j~
to
in which Xb is CH and (La)S-(G)t-(Lb)u is O and Rlo is phenyl
or pyridyl, coupling a corresponding compound containing a
group of formula
Xa OH
(CH2 r
with phenols or 3-hydroxypyridine using Mitsunobu
conditions, eg. DEAD (diethyl azodicarboxylate) /Ph3P or 2-
triphenylphosphonium 4,4-dimethyl-tetrahydro-1,2,5-
thiadiazole to give aryloxy or 3-pyridoxy substituted
piperidines or pyrrolidine. Alternatively the hydroxy group
may be reacted with sodium hydride and 2-chloro or 4-
chloropyridine to give 2-pyridoxy or 4-pyridoxy substituted
piperidines or pyrrolidines.
For a compound of formula I in which -L-Lp(D)n is
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Rq
N
~(CH2)q Q
O
in which Q is a direct bond, reductively alkylating an amine
of formula H-Q using a corresponding compound in which the
corresponding residue is a ketone of formula
N~(CH2) O
For a compound of formula I in which -L-Lp(D)n is
Rq
N
~(CH2)q Q
O
in which Q is methylene, reductively alkylating an amine of
formula H-NRaRb using a corresponding compound in which the
corresponding residue is an aldehyde of formula
N
~(CHZ)q ~ O
O
For example, methyl 1-acetyl-3-formylindole-6-
carboxylic acid may be converted to the 3-formate by the
method of Merour et al (Synthesis, 1994, 411) and then
reacted with trimethyl orthoformate to give methyl 1-acetyl-
3-methoxyindole-6-carboxylate which is then hydrolysed to
methyl 1-acetyl-3-methoxyindole-6-carboxylate.
5-Fluoroindole-6-carboxylic acid may be prepared from
4-fluoro-3-methoxyaniline by the following method. 4-Fluoro-
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3-methoxyaniline is treated with glyoxal-1,1-dimethyl acetal
and then hydrogenated over Pd/C. The product is N-protected
with methanesulphonyl chloride and then cyclised using
titanium tetrachloride in toluene. Demethylation with BBr3
5 to the phenol followed by reaction with triflic anhydride
and then palladium carbonylation in methanol gives the
methyl ester, which is then converted to 5-fluoro-1-
methanesulphonylindole-6-carboxylic acid by hydrolysis with
lithium hydroxide. This 'benzoyl' component may be reacted
10 as previously described and deprotected by hydrolysis with
sodium hydroxide at 100°C.
The compounds of formula (I) may be administered by any
convenient route, e.g. into the gastrointestinal tract (e. g.
rectally or orally), the nose, lungs, musculature or
15 vasculature or transdermally. The compounds may be
administered in any convenient administrative form, e.g.
tablets, powders, capsules, solutions, dispersions,
suspensions, syrups, sprays, suppositories, gels, emulsions,
patches etc. Such compositions may contain components
20 conventional in pharmaceutical preparations, e.g. diluents,
carriers, pH modifiers, sweeteners, bulking agents, and
further active agents. Preferably the compositions will be
sterile and in a solution or suspension form suitable for
injection or infusion. Such compositions form a further
25 aspect of the invention.
The following are examples of pharmaceutical
compositions of compounds of formula (I) or physiologically
tolerable salts thereof.
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Formulation 1
Hard gelatin capsules are prepared using the following
ingredients:
Quantity
(mg/capsule)
Active Ingredient 250
Starch, dried 200
Magnesium stearate 10
Total 460 mg
The above ingredients are mixed and filled into hard
gelatin capsules in 460 mg quantities.
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Formulation 2
Tablets each containing 60 mg of active ingredient are made
as follows:
Active Ingredient 60 mg
Starch 45 mg
Microcrystalline cellulose 35 mg
Polyvinylpyrrolidone 4 mg
Sodium carboxymethyl starch 4.5 mg
Magnesium stearate 0.5 mg
Talc 1 ma
Total 150 mg
The active ingredient, starch, and cellulose are passed
through a No. 45 mesh U.S. sieve and mixed thoroughly. The
solution of polyvinylpyrrolidone is mixed with the resultant
powders which are then passed through a No. 14 mesh U.S.
sieve. The granules so produced are dried at 50°C and
passed through a No. 18 mesh U.S. sieve. The sodium
carboxymethyl starch, magnesium stearate, and talc,
previously passed through a No. 60 mesh U.S. sieve, are then
added to the granules which, after mixing, are compressed on
a tablet machine to yield tablets each weighing 150 mg.
It is believed that the compounds of the invention will
have excellent oral bioavailability.
Thus the compounds of formula (I) and their
physiologically tolerable salts will generally be
adminstered to a patient in pharmaceutical composition which
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comprises a serine protease inhibitor of formula (I)
together with at least one pharmaceutically acceptable
carrier or excipient. The pharmaceutical composition may
also optionally comprise at least one further antithrombotic
and/or thrombolytic agent.
The dosage of the inhibitor compound of formula (I)
will depend upon the nature and severity of the condition
being treated, the administration route and the size and
species of the patient. However in general, quantities of
from 0.01 to 100 ~.mol/kg bodyweight will be administered.
All publications referred to herein are hereby
incorporated by reference.
The following non-limiting Examples illustrate the
preparation of compounds of formula (I) for use as serine
protease inhibitors according to the invention.
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Examples - Part 1
Experimental
Abbreviations used follow IUPAC-IUB nomenclature.
Additional abbreviations are Hplc, high-performance liquid
chromatography; DMF, dimethylformamide; DCM,
dichloromethane; HAOT, 1-hydroxy-7-azabenzotriazole; HATU,
[O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate]; Fmoc, 9-Fluorenylmethoxycarbonyl;
HOBt, 1-hydroxybenzotriazole; TBTU, 2-(1H-(benzotriazol-1
yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate; EDCI, 1-(3-
Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride;
DIPEA, diisopropylethylamine; Boc, tertiary
butyloxycarbonyl; DIPCI, diisopropylcarbodiimide; DBU, 1,8-
diazabicyclo[5.4.0]undec-7-ene; TEA, triethylamine; Rink
linker, p- [ (R, S) -a,- [1- (9H-Fluoren-9-yl)methoxyformamido] -
2,4-dimethoxybenzyl]phenyl acetic acid; TFA, trifluoroacetic
acid; MALDI-TOF, Matrix assisted laser desorption ionisation
- time of flight mass spectrometry, RT, retention time.
Amino acid derivatives, resins and coupling reagents were
obtained, for example, from Novabiochem (Nottingham, UK) and
other solvents and reagents from Rathburn (Walkerburn, UK)
or Aldrich (Gillingham, UK) and were used without further
purification. All solution concentrations are expressed as
%Vol./%Vol. unless otherwise stated.
Purification: Purification was by gradient reverse phase
Hplc on a Waters Deltaprep 4000 at a flow rate of 50 ml/
min. using a Deltapak C18 radial compression column (40 mm x
210 mm, 10-15 mm particle size). Eluant A consisted of
aqTFA (0.1%) and eluant B 90% MeCN in aq TFA(0.1%) with
gradient elution (Gradient 1, 0 min. 20%B then 20% to 100%
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over 36 min., Gradient 2, 0 min. 5%B for 1 min. then 5%B to
20%B over 4 min., then 20% to 60% over 32 min. or Gradient
3, 0 min. 20%B then 20% to 100% over 15 min.). Fractions
were analysed by analytical Hplc and MALDI-TOF before
5 pooling those with >95% purity for lyophilisation.
Analysis: Analytical Hplc was on a Shimadzu LC6 gradient
system equipped with an autosampler, a variable wavelength
detector at flow rates of 0.4 ml/ min. Eluents A and B as
10 for preparative Hplc. Columns used were Techoge115 C18
(2x150mm)(Hplc Technology), Magellan C8 column (2.1x150 mm,
5~m particle size) and Luna C18 (2.1x150 mm, 5~M particle
size). (Phenomenex)) Purified products were further analysed
by MALDI-TOF and nmr. NMR denotes an 1HNMR consistent with
15 the structure was obtained.
Synthesis of inhibitors
Method 1: Using a solid phase strategy on a Protein
20 Technologies, Symphony Multiple Peptide Synthesiser by
attachment of bis amino compounds to Peg-trityl chloride
resin: Trityl chloride resin was typically treated with
greater than 2 fold excess of the di-amine in dry DCM .The
resin was further modified by the attachment of acids.
25 Activation of Fmoc protected amino acid (2-5eq) was by TBTU/
DIPEA, all couplings ( minimum 120 min.) were carried out in
DMF. Deprotection of the Fmoc group was achieved with 20%
piperidine in DMF. In the next stage other acid substituents
were added as the HOBt or HOAt esters either by activation
30 with HBTU/HATU or HATU/EDCI with or without Boc protection
of amino groups. Cleavage of the products from the resin was
by treatment (30 min., ambient) with 10% triethylsilane in
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TFA, filtration, evaporation and trituration with
diethylether.
Synthesis using the Symphony Multiple Peptide Synthesiser.
The Symphony Multiple Peptide Synthesiser is charged with
DMF, DCM, TBTU in DMF(450 mM), DIPEA in DMF (900 mM), 20%
piperidine in DMF. Resins are held in plastic reaction
vessels that allow the introduction of reagents and solvents
and nitrogen for agitation or air drying.
A typical synthesis cycle on the Symphony is as follows:-
The reaction vessel containing the resin (0.1 mmol) is
charged with the Fmoc protected amino acid (0.5 mmol) and
then this is dissolved in DMF (2.5m1), treated with TBTU
(0.56 mmol, 1.25m1) and DIPEA (1.l mmol, 1.25m1) and
agitated with nitrogen for 2 hours (agitation times may
vary). After coupling the resin is washed with DMF (6x 5m1)
then deprotected with 20o piperidine in DMF (2x 5m1 for 1
min. each, then lx 5m1 for 8 min.) the resin is then washed
with DMF (6x 5m1).
Example 1.
1-(2-Amino-4-chlorobenzoyl-D-phenylglycinyl)-4,4~-
bispiperidine
4,4-Bipiperidine.dihydrochloride (4mmol,lg) was dissolved in
water (5m1) and 2M sodium hydroxide solution (lOmmol, 5m1)
added. The solution was extracted with ethylacetate (2x
50m1) the combined extracts were washed with water, dried
over anhydrous sodium carbonate, filtered and evaporated to
give the 4,4 bipiperidine (0.35g) as a white solid. The 4,4
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bipiperidine was dissolved in dry DMF (2m1) and added to
Peg-tritylchloride resin (0.95 mmol/g, 1.5g) pre swollen in
dry DCM (lOml). After 2h the resin was washed with DCM
(6x5m1), DMF (6x5m1) and DCM (6x5m1). The resin was then air
dried to allow aliquots to be taken.
The 4,4 bipiperidine trityl resin (0.1 mmol) was treated
with Fmoc-D-Phenylglycine (0.5 mmol, 187mg), DMF(2.5m1),
TBTU in DMF(1.25m1 of a 450mM solution) and DIPEA in DMF
(1.25m1 of a 900 mM solution). The mixture was agitated with
nitrogen for 2 hours. Deprotection and washing as above.
A solution of 4-chloroanthranilic acid (87mg 0.5mmole) in
dry dimethylformamide (DMF) was treated successively with
HOAt (102mg 0.75mmole) and EDCI (115mg 0.6mmole) and stirred
at room temperature for l0min. The mixture was transferred
to the reaction vessel on the Symphony and agitated for 2
hours with nitrogen. The resin was washed with DMF (6x5m1),
DCM (6x5m1) and air dried. The product was cleaved from the
resin with 10°s triethylsilane in TFA (10m1) for 30 minutes,
the resin filtered off and the TFA solution evaporated to
dryness and triturated with diethyl ether to give the crude
product. The crude product was dissolved in water (lOml),
filtered and purified by preparative reverse phase Hplc.
1H nmr (CD3CN) 7.30 (6H,m); 6.60 (lH,s); 6.55 (lH,d); 5.85
(1H, s); 4.40 (lH,m); 3.75 (1H, m); 2.30-2.95 (6H, m); 1.60
(4H, m); 1.10 (6H, m) MS TOF 456 (M+1+). Hplc (Magellan C8,
Gradient 3, water/acetonitrile/TFA) rt 11.77 min.
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Example 2.
1-(2-Amino-5-bromobenzoyl-D-phenylglycinyl)-4,4'-
bispiperidine
1H nmr (CD3CN) 7.30 (7H,m); 6.50 (lH,d); 5.85 (1H, s); 4.40
(lH,m); 3.75 (1H, m); 2.30-2.95 (6H, m); 1.60 (4H, m); 1.10
(6H, m) MS TOF 500 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 11.31 min.
Example 3.
1-(2-Amino-4-methylbenzoyl-D-phenylglycinyl)-4,4'-
bispiperidine
1H nmr (CD3CN) 7.30 (6H,m); 6.50 (lH,s); 6.45 (lH,d); 5.80
(1H, s); 4.40 (lH,m); 3.75 (1H, m); 2.30-2.95 (6H, m); 2.05
(3H,s); 1.60 (4H, m); 1.10 (6H, m) MS TOF 436 (M+1+). Hplc
(Magellan C8, Gradient 3, water/acetonitrile/TFA) rt 9.22
mm .
Example 4.
1-(2-Amino-5-methylbenzoyl-D-phenylglycinyl)-4,4'-
bispiperidine
1H nmr (CD3CN) 7.30 (7H,m); 6.50 (lH,d); 5.85 (1H, s); 4.40
(lH,m); 3.75 (1H, m); 2.30-2.95 (6H, m); 1.60 (4H, m); 1.10
(6H, m). MS TOF 436 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 8.74 min.
Example 5.
1-(2-Amino-5-methoxybenzoyl-D-phenylglycinyl)-4,4'-
bispiperidine
1H nmr (CD3CN) 7.55 (6H,m); 7.30 (lH,d); 6.95 (lH,m); 6.15
(1H, s); 4.40 (lH,m); 3.75 (1H, m); 3.60 (3H, s); 2.30-2.95
(6H, m); 2.20 (3H, s); 1.60 (4H, m); 1.10 (6H, m) MS TOF 452
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(M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 8.20 min.
Example 6.
1-(3-Methylbenzoyl-D-phenylglycinyl)-4,4'-bispiperidine
1H nmr (CD3CN) 7.40 (2H,m); 7.30 (7H,m); 5.85 (1H, s); 4.40
(lH,m); 3.75 (1H, m); 2.30-2.95 (6H, m); 2.20 (3H, s); 1.60
(4H, m); 1.10 (6H, m) MS TOF 421 (M+1+). Hplc (Magellan C8,
Gradient 3, water/acetonitrile/TFA) rt 10.68 min.
Example 7.
1-(4-Methylbenzoyl-D-phenylglycinyl)-4,4'-bispiperidine
1H nmr (CD3CN) 7.55 (2H,m); 7.30 (5H,m); 7.10 (2H,m); 5.85
(1H, s); 4.40 (lH,m); 3.75 (1H, m); 2.30-2.95 (6H, m); 2.20
(3H,s); 1.60 (4H, m); 1.10 (6H, m) MS TOF 420 (M+1+). Hplc
(Magellan C8, Gradient 3, water/acetonitrile/TFA) rt 10.61
min.
Example 8.
1-(3-Amino-2-naphthoyl-D-phenylglycinyl)-4,4'-bispiperidine
1H nmr (CD3CN) 7.90 (lH,d); 7.60 (lH,d); 7.40 (lH,m); 7.30
(6H,m); 7.05 (lH,m); 6.90 (lH,s); 5.85 (1H, s); 4.40 (lH,m);
3.75 (1H, m); 2.30-2.95 (6H, m); 1.60 (4H, m); 1.10 (6H, m)
MS TOF 471 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 9.87 min.
Example 9.
1-(3-Aminobenzoyl-D-phenylglycinyl)-4,4'-bispiperidine
MS TOF 421 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 9.06 min.
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Example 10.
1-(2-Aminobenzoyl-D-phenylglycinyl)-4,4'-bispiperidine
MS TOF 421 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 9.00 min.
5
Example 11.
1-(2-Amino-4-fluorobenzoyl-D-phenylglycinyl)-4,4'-
bispiperidine
MS TOF 440 (M+1+). Hplc (Magellan C8, Gradient 3,
10 water/acetonitrile/TFA) rt 9.23 min.
Example 12.
1-(2-Amino-5-fluorobenzoyl-D-phenylglycinyl)-4,4'-
bispiperidine
15 MS TOF 440 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 9.14 min.
Example 13.
1-(2-Amino-4-nitrobenzoyl-D-phenylglycinyl)-4,4'-
20 bispiperidine
MS TOF 467 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 10.59 min.
Example 14.
25 1-(2-Amino-5-nitrobenzoyl-D-phenylglycinyl)-4,4'-
bispiperidine
MS TOF (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 10.57 min.
30 Example 15.
1-(2- Amino-4,5-dimethoxybenzoyl-D-phenylglycinyl)-4,4'-
bispiperidine
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MS TOF 481 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 11.67 min.
Example 16.
1-(Benzoyl-D-phenylglycinyl)-4,4'bispiperidine
MS TOF 407 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 9.88 min.
Example 17.
1-(4-Chlorobenzoyl-D-phenylglycinyl)-4,4'-bispiperidine
MS TOF 441 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 10.89 min.
Example 18.
1-(2-Hydroxybenzoyl-D-phenylglycinyl)-4,4'-bispiperidine
MS TOF 423 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 8.97 min.
Method 2: By solution phase strategy: Typically an activated
amino acid was treated with an amine (primary or secondary)
or alcohol (leq.). Activation of the protected amino acid
(Boc or Cbz protection) was by HATU/DIPEA (1:2) by
TBTU/DIPEA (1:2), by HOBt or HOAt and a carbodiimide (EDCI
or DCC), or by diethyl cyanophosphonate and triethylamine or
DIPEA, all couplings (minimum 120min.) were carried out in
DMF without or without dichloromethane as co-solvent. After
an aqueous work up the deprotection of the Boc group was
achieved with TFA. Other acid substituents were added as the
HOBt or HOAt esters either by activation with HBTU/HATU, EDC
or DIPCI with or without Boc protection of amino groups. The
final products were purified by preparative reverse phase
Hplc.
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Examples 19-126
The compounds of Examples 19-126 were prepared by the method
described below, but using the appropriate starting
materials.
Boc D-phenylglycine (251 mg, 1 mmol.) was dissolved in
DMF(3m1) with HATU (380 mg., 1 mmol.) and DIPEA(350~1 .,
2 mmol.). To this mixture was added 4-
methylbenzylamine(121mg., 1 mmol.) and DIPEA (1701., 1
mmol.). The mixture was stirred overnight. The mixture was
then taken up into ethylacetate and washed with water,
sodium carbonate solution, water, 10% hydrochloric acid
solution and water. The ethylacetate was evaporated without
drying and treated immediately with TFA for 30 min. The TFA
was then evaporated to dryness and the product triturated
with diethylether. TEA(lml) was added and evaporated to
dryness. A solution of 3-hydroxymethylbenzoic acid (76mg ,
0.5mmole) in dry dimethylformamide (DMF) was treated with
TBTU (161mg., 0.5mmol.) and DIPEA (1.5 mmol.). The mixture
was then added to the D-phenylglycine-4-methylbenzylamide
(0.5mmol.) and stirred overnight. The crude product was
dissolved in water/acetonitrile (20m1), filtered and
purified by preparative Hplc to yield pure product.
1H nmr (CD3CN) 7.75 (1H, m); 7.65 (2H, m); 7.30 (7H, broad
m); 6.80 (3H, m); 5.40 (1H, s); 4.45 (2H,s); 4.10 (2H, m);
2.10 (3H, s). MS TOF 389 (M+1+). Hplc (Magellan C8,
Gradient 3, water/acetonitrile/TFA) rt 13.51 min.
Compounds made by the above method:-
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Example 19.
1-(2-Aminobenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (DMSO) 7.65 (3H, m); 7.45 (1H, m); 7.35 (5H, m); 7.15
(lH,m); 6.65 (lH,d); 6.55 (lH,m); 6.05 (1H, s); 3.15 (3H,s);
3.00-2.00 (8H,m). MS TOF 511 (M+1+). Hplc (Magellan C8,
Gradient 3, water/acetonitrile/TFA) rt 13.43 min.
Example 20.
1-(2-Amino-4-chlorobenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine .
1H nmr (DMSO) 7.55 (3H, m); 7.45 (1H, m); 7.35 (5H, m); 7.15
(lH,m); 6.75 (lH,s); 6.55 (lH,d); 6.05 (1H, s); 3.15 (3H,s);
3.00-2.00 (8H,m). MS TOF 546 (M+1+). Hplc (Magellan C8,
Gradient 3, water/acetonitrile/TFA) rt 15.18 min.
Example 21.
1-(2-Amino-5-fluorobenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CDC13) 7.75 (1H, m); 7.60 (1H, m); 7.25 (6H, m);
7.15 (lH,m); 6.90 (lH,m); 6.75 (lH,m); 5.85 (1H, s); 3.15
(3H,s); 3.00-2.00 (8H,m). MS TOF 529 (M+1+). Hplc (Magellan
C8, Gradient 3, water/acetonitrile/TFA) rt 13.87 min.
Example 22.
1-(2-Amino-4-methylbenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (DMSO) 7.55 (3H, m); 7.45 (2H, m); 7.35 (5H, m); 6.65
(lH,s); 6.35 (lH,d); 6.05 (1H, s); 3.15 (3H,s); 3.00-2.00
(8H,m) 2.15 (3H,s);. MS TOF 525 (M+1+). Hplc (Magellan C8,
Gradient 3, water/acetonitrile/TFA) rt 13.12 min.
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Example 23.
1-(2-Amino-5-methylbenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CDC13) 7.75 (1H, m); 7.60 (1H, m); 7.25 (6H, m);7.15
(lH,m); 6.90 (lH,m); 6.75 (lH,m); 5.85 (1H, s); 3.15 (3H,s);
3.00-2.00 (8H,m) 2.30 (3H,s). MS TOF 525 (M+1+). Hplc
(Magellan C8, Gradient 3, water/acetonitrile/TFA) rt 12.84
min.
Example 24.
1-(2-Amino-4-nitrobenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CDC13) 7.75 (2H, m); 7.55 (1H, m); 7.35 (7H, m);
7.25 (lH,m); 5.80 (1H, s); 3.15 (3H,s); 3.00-2.00 (8H,m). MS
TOF 556 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 15.35 min.
Example 25.
1-(2-Amino-5-nitrobenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CDC13) 8.25 (1H, d); 7.85 (1H, m); 7.55 (1H, m);
7.25 (7H, m); 7.05 (lH,m); 5.80 (1H, s); 3.15 (3H,s); 3.00-
2.00 (8H,m). MS TOF 556 (M+1+). Hplc (Magellan C8, Gradient
3, water/acetonitrile/TFA) rt 15.08 min.
Example 26.
1-(2-Amino-5-cyanobenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.65 (4H, m); 7.25 (6H, m); 6.65 (lH,d); 5.80
(1H, s); 3.15 (3H,s); 3.00-2.00 (8H,m). MS TOF 536 (M+1+).
Hplc (Magellan C8, Gradient 3, water/acetonitrile/TFA) rt
14.89 min.
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Example 27.
1-(2,5-Diaminobenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CDC13) 7.70 (1H, d) ; 7.45 (7H, m) ; 6.85 (1H, s) ;
6.55 (1H, m); 6.55 (lH,m); 5.90 (1H, s); 3.15 (3H,s); 3.00-
2.00 (8H,m). MS TOF 526 (M+1+). Hplc (Magellan C8, Gradient
3, water/acetonitrile/TFA) rt 11.82 min.
Example 28.
1-(2-Amino-4,5-dimethoxybenzoyl-D-phenylglycinyl)-4-(4-
fluoro-2-methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.65 (2H, m); 7.35 (2H, m); 7.25 (5H, m);
6.75 (lH,d); 6.15 (1H, d);5.80 (1H, s); 3.60 (3H,s); 3.50
(3H,s); 3.15 (3H,s); 3.00-2.00 (8H,m). MS TOF 571 (M+1+).
Hplc (Magellan C8, Gradient 3, water/acetonitrile/TFA) rt
12.84 min.
Example 29.
1-(Benzoyl-D-phenylglycinyl)-4-(4-fluoro-2-methyl-
sulphonylphenyl)piperazine
1H nmr (CD3CN) 7.75 (2H, m); 7.70 (1H, m); 7.40 (10H, m);
6.05 (1H, s); 3.15 (3H,s); 3.00-2.00 (8H,m). MS TOF 496
(M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 12.84 min.
Example 30.
1-(3-Aminobenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.85 (1H, m); 7.60 (1H, m); 7.50 (2H, m);
7.30 (7H, m); 7.05 (1H, d); 6.05 (1H, s); 3.15 (3H,s); 3.00-
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2.00 (BH,m). MS TOF 511 (M+1+). Hplc (Magellan C8, Gradient
3, water/acetonitrile/TFA) rt 11.32 min.
Example 31.
1-(4-Aminobenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CDC13) 7.95 (1H, d); 7.80-7.45 (10H, broad m); 7.35
(lH,d) ; 6.20 (1H, s) ; 3.15 (3H,s) ; 3.00-2.00 (8H,m) . MS TOF
511 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 12.05 min.
Example 32.
1-(3,4 Diaminobenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CDC13) 7.75 (1H, d); 7.40-7.15 (9H, broad m); 6.55
(lH,d); 6.00 (1H, s); 3.15 (3H,s); 3.00-2.00 (8H,m). MS TOF
540 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 11.30 min.
Example 33.
1-(3-Chlorobenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.85 (1H, m); 7.80 (1H, s); 7.60 (2H, m);
7.30 (8H, m); 6.00 (1H, s); 3.20 (3H,s); 3.00-2.00 (8H,m).
MS TOF 531 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 15.40 min.
Example 34.
1-(4-Chlorobenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.95 (1H, m); 7.75 (2H, m); 7.60 (1H, m);
7.40 (8H, m); 6.05 (1H, s); 3.25 (3H,s); 3.00-2.00 (8H,m).
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MS TOF 531 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 16.54 min.
Example 35.
1-(3-Amino-4-chlorobenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CDC13) 8.05 (1H, m); 7.80 (1H, m); 7.70 (1H, s);
7.20-7.60 (8H, broad m); 6.05 (1H, s); 3.25 (3H,s); 3.00-
2.00 (8H,m). MS TOF 546 (M+1+). Hplc (Magellan C8, Gradient
3, water/acetonitrile/TFA) rt 14.53 min.
Example 36.
1-(4-Bromobenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.85 (1H, m); 7.65 (2H, m); 7.60 (2H, d);
7.45 (2H, d); 7.30 (5H, m); 6.00 (1H, s); 3.20 (3H,s); 3.00-
2.00 (8H,m). MS TOF 576 (M+1+). Hplc (Magellan C8, Gradient
3, water/acetonitrile/TFA) rt 15.94 min.
Example 37.
1-(4-Iodobenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN)); 7.75 (2H, m); 7.65 (1H, m 7.55 (2H, d);
7.45 (2H, d); 7.30 (5H, m); 5.95 (1H, s); 3.20 (3H,s); 3.00-
2.00 (8H,m). MS TOF 622 (M+1+). Hplc (Magellan C8, Gradient
3, water/acetonitrile/TFA) rt 15.96 min.
Example 38.
1-(3-Amino-4-methylbenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CDC13) 7.95 (1H, s); 7.60 (1H, d); 7.45 (1H, d);
7.40-7.15 (8H, broad m); 6.00 (1H, s); 3.15 (3H,s); 3.00-
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2.50 (8H,m) 2.20 (3H, s). MS TOF 525 (M+1+). Hplc (Magellan
C8, Gradient 3, water/acetonitrile/TFA) rt 11.71 min.
Example 39.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.85 (2H, d); 7.65 (1H, m); 7.50 (2H, m);
7.40 (5H, m); 6.80 (2H, d); 6.00 (1H, s); 3.80 (3H, s); 3.20
(3H,s); 3.00-2.00 (8H,m). MS TOF 526 (M+1+). Hplc (Magellan
C8, Gradient 3, water/acetonitrile/TFA) rt 14.63 min.
Example 40.
1-(3-Amino-4-methoxybenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CDC13) 7.90 (1H, m); 7.75 (1H, d); 7.60 (2H, m);
7.40-7.15 (6H, broad m); 7.45 (1H, d); 6.10 (1H, s); 3.95
(3H, s); 3.35 (3H,s); 3.00-2.50 (8H,m). MS TOF 541 (M+1+).
Hplc (Magellan C8, Gradient 3, water/acetonitrile/TFA) rt
11.78 min.
Example 41.
1-(3,4-Dihydroxybenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CDC13) 7.55 (1H, m) ; 7.45 (1H, d) ; 7.25 (2H, m) ;
7.15 (5H, m); 7.00 (1H, d); 6.60 (1H, d); 5.80 (1H, s); 3.05
(3H,s); 3.00-2.50 (8H,m). MS TOF 541 (M+1+). Hplc (Magellan
C8, Gradient 3, water/acetonitrile/TFA) rt 11.78 min.
Example 42.
1-(Naphth-2-oyl-D-phenylglycinyl)-4-(4-fluoro-2-methyl-
sulphonylphenyl)piperazine
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1H nmr (CDC13) 8.35 (1H, s); 8.00 (1H, d); 7.85 (5H, m);
7.45 (4H, m); 7.25 (4H, m); 6.10 (1H, s); 3.20 (3H,s); 3.00-
2.50 (8H,m). MS TOF 546 (M+1+). Hplc (Magellan C8, Gradient
3, water/acetonitrile/TFA) rt 16.66 min.
Example 43.
1-(3-Aminonaphth-2-oyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CDC13) 8.15 (1H, d); 8.00 (1H, s); 7.75 (2H, m);
7.65 (1H, d); 7.30 7.60 (9H, m); 6.10 (1H, s); 3.25 (3H,s);
3.00-2.50 (8H,m). MS TOF 561 (M+1+). Hplc (Magellan C8,
Gradient 3, water/acetonitrile/TFA) rt 13.90 min.
Example 44.
1-(Thiophene-3-carbonyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CDC13) 8.15 (1H, s); 7.95 (1H, m); 7.85 (1H, m);
7.60 (8H, m); 6.30 (1H, s); 3.45 (3H,s); 2.00-2.50 (8H,m).
MS TOF 502 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 14.28 min.
Example 45.
1-(Thiophene-2-carbonyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CDC13) 7.65 (2H, m); 7.45 (1H, s); 7.30 (2H, m);
7.20 (5H, m); 6.95 (1H, m); 6.00 (1H, s); 3.05 (3H,s); 3.00-
2.50 (8H,m). MS TOF 502 (M+1+). Hplc (Magellan C8, Gradient
3, water/acetonitrile/TFA) rt 14.52 min.
Example 46.
1-(5-Methylthiophene-2-carbonyl-D-phenylglycinyl)-4-(4-
fluoro-2-methylsulphonylphenyl)piperazine
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1H nmr (CDC13) 7.70 (1H, m); 7.45 (2H, m); 7.35 (6H, m);
6.65 (1H, m); 6.00 (1H, s); 3.05 (3H,s); 3.00-2.50 (8H,m)
2.45 (3H, s). MS TOF 516 (M+1+). Hplc (Magellan C8,
Gradient 3, water/acetonitrile/TFA) rt 14.98 min.
Example 47.
1-(Isoquinolin-7-carbonyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 9.50 (1H, s); 8.75 (1H, s); 8.55 (1H, d);
8.30 (1H, d); 8.10 (2H, m); 7.65 (1H, m); 7.45 (2H, m); 7.35
(5H, m); 6.10 (1H, s); 3.20 (3H,s); 3.00-2.50 (8H,m). MS TOF
547 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 11.39 min.
Example 48.
1-(Pyridin-3-carbonyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 9.00 (1H, s); 8.70 (1H, d); 8.35 (1H, d);
8.10 (1H, m); 7.65 (2H, m); 7.45 (1H, m); 7.30 (5H, m); 6.00
(1H, s); 3.20 (3H,s); 3.00-2.50 (8H,m). MS TOF 497 (M+1+).
Hplc. (Magellan C8, Gradient 3, water/acetonitrile/TFA) rt
11.99 min.
Example 49.
1-(Indol-6-carbonyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.95 (2H, m); 7.60 (2H, m); 7.50 (3H, m);
7.35 (5H, m); 6.45 (1H, s); 6.05 (1H, s); 3.25 (3H,s); 3.00-
2.50 (8H,m). MS TOF 535 (M+1+). Hplc (Magellan C8, Gradient
3, water/acetonitrile/TFA) rt 15.44 min.
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Example 50.
1-(2,5-Diaminobenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
MS TOF 526 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 11.89 min.
Example 51.
1-(4-Methylaminobenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.65 (3H, m); 7.50 (2H, m); 7.35 (5H, m);
6.60 (2H, d); 6.05 (1H, s); 3.30 (3H, s); 3.00-2.50 (8H, m);
2.80 (3H, s). MS TOF 525 (M+1+). Hplc (Magellan C8,
Gradient 3, water/acetonitrile/TFA) rt 13.17 min.
Example 52.
1-(3-Methyl-4-chlorobenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.90 (1H, s); 7.85 (1H, s); 7.80 (1H, s);
7.55 (6H, m); 6.25 (1H, s); 3.45 (3H, s); 3.00-2.50 (8H,
m); 2.60 (3H, s). MS TOF 545 (M+1+). Hplc (Magellan C8,
Gradient 3, water/acetonitrile/TFA) rt 16.39 min.
Example 53.
1-(4-Vinylbenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.75 (2H, d); 7.60 (1H, m); 7.45 (4H, m);
7.35 (5H, m); 6.75 (1H, m); 6.05 (1H, s); 5.90 (1H, d); 5.30
(1H, d); 3.00-2.50 (8H, m); 2.80 (3H, s). MS TOF 522 (M+1+).
Hplc (Magellan C8, Gradient 3, water/acetonitrile/TFA) rt
15.45 min.
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Example 54.
1-(3-Amino-4-hydroxybenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.60 (1H, m); 7.50-7.10 (9H, m); 7.35 (1H,
d); 5.95 (1H, s); 3.25 (3H, s); 3.00-2.50 (8H, m). MS TOF
527 (M+1+). Hplc (Magellan C8, Gradient 2,
water/acetonitrile/TFA) rt 15.46 min.
Example 55.
1-(4-Methylthiobenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.85 (2H, d); 7.80 (1H, m); 7.60 (2H, m);
7.50 (5H, m); 7.40 (2H, d); 6.15 (1H, s); 3.40 (3H, s);
3.10-2.70 (8H, m); 2.60 (3H, s). MS TOF 542 (M+1+). Hplc
(Magellan C8, Gradient 3, water/acetonitrile/TFA) rt 16.67
min.
Example 56.
1-(3-Carboxamidobenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 8.25 (1H, s); 7.95 (2H, d); 7.70 (1H, m);
7.55 (3H, m); 7.40 (5H, m); 6.05 (1H, s); 3.30 (3H, s);
3.00-2.50 (8H, m). MS TOF 539 (M+1+). Hplc (Magellan C8,
Gradient 3, water/acetonitrile/TFA) rt 12.83 min.
Example 57.
1-(3-Amino-4-methylbenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.90 (1H, d); 7.70 (1H, m); 7.55 (2H, m);
7.45 (5H, m); 7.20 (1H, s); 6.95 (1H, d); 6.05 (1H, s); 3.80
(3H, s); 3.30 (3H, s); 3.00-2.50 (8H, m). MS TOF 569 (M+1+).
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Hplc (Magellan C8, Gradient 3, water/acetonitrile/TFA) rt
14.49 min.
Example 58.
1-(3-Methyl-4-bromobenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.65 (3H, m); 7.45 (3H, m); 7.30 (5H, m);
6.00 (1H, s); 3.25 (3H, s); 3.00-2.50 (8H, m); 2.40 (3H, s).
MS TOF 589 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 16.67 min.
Example 59.
1-(4-Ethoxybenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.75 (2H, d); 7.60 (1H, m); 7.50 (2H, m);
7.35 (5H, m); 6.85 (2H, d); 6.00 (1H, s); 4.00 (2H, m); 3.20
(3H, s); 3.00-2.50 (8H, m); 1.30 (3H, t). MS TOF 540 (M+1+).
Hplc (Magellan C8, Gradient 3, water/acetonitrile/TFA) rt
16.58 min.
Example 60.
1-(Indol-5-carbonyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 8.15 (1H, s); 7.95 (1H, m); 7.65 (2H, m);
7.60-7.35 (7H, m); 6.60 (1H, s); 6.10 (1H, s); 3.30 (3H, s);
3.00-2.60 (8H, m). MS TOF 535 (M+1+). Hplc (Magellan C8,
Gradient 3, water/acetonitrile/TFA) rt 13.88 min.
Example 61.
1-(Benzimidazo-5-carbonyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
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1H nmr (CD3CN) 8.75 (1H, s); 8.25 (1H, s); 7.75 (2H, m);
7.60 (1H, m); 7.50 (2H, m); 7.35 (5H, m); 6.60 (2H, d); 6.05
(1H, s); 3.30 (3H, s); 3.00-2.50 (8H, m). MS TOF 536 (M+1+).
Hplc (Magellan C8, Gradient 3, water/acetonitrile/TFA) rt
10.08 min.
Example 62.
1-(3-Aminobenzoyl-D-phenylglycinyl)-1'-methyl-4,4'-
bispiperidine
1H nmr (CD3CN) a mixture of conformers only one recorded
here 7.65 (1H, m); 7.35 (5H, m); 7.05 (1H, m); 6.95 (2H, m);
5.85 (1H, s); 4.45 (1H, m); 3.85 (1H, m); 3.30 (2H, m);
2.90-2.40 (8H, m); 2.55 (3H, s); 1.60 (2H, m); 1.30 (2H, m);
1.00 (2H, m). MS TOF 435 (M+1+). Hplc (Magellan C8,
Gradient 3, water/acetonitrile/TFA) rt 7.65 min.
Example 63.
1-(3-Amino-4-chlorobenzoyl-D-phenylglycinyl)-1'-methyl-4,4'-
bispiperidine
1H nmr (CD3CN) a mixture of conformers only one recorded
here 7.75 (1H, m); 7.30 (5H, m); 7.20 (1H, m); 6.95 (1H, m);
5.85 (1H, s); 4.45 (1H, m); 3.85 (1H, m); 3.30 (2H, m);
2.90-2.40 (8H, m); 2.55 (3H, s); 1.60 (2H, m); 1.30 (2H, m);
1.00 (2H, m). MS TOF 469 (M+1+). Hplc (Magellan C8,
Gradient 3, water/acetonitrile/TFA) rt 9.58 min.
Example 64.
1-(3-Amino-4-methylbenzoyl-D-phenylglycinyl)-1'-methyl-4,4'-
bispiperidine
1H nmr (CD3CN) a mixture of conformers only one recorded
here 7.75 (1H, m); 7.35 (5H, m); 7.05 (2H, m); 5.85 (1H, s);
4.45 (1H, m); 3.85 (1H, m); 3.30 (2H, m); 2.90-2.40 (8H, m);
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2.65 (3H, s); 2.15 (3H, s); 1.60 (2H, m); 1.30 (2H, m); 1.00
(2H, m). MS TOF 449 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 8.03 min
Example 65.
1-(3-Aminonaphth-2-oyl-D-phenylglycinyl)-1'-methyl-4,4'-
bispiperidine
1H nmr (CD3CN) a mixture of conformers only one recorded
here 7.95 (1H, m); 7.65 (1H, d); 7.45 (2H, m); 7.30 (5H, m);
7.15 (1H, m); 6.95 (1H, s) 5.95 (1H, s); 4.45 (1H, m); 3.85
(1H, m); 3.30 (2H, m); 2.90-2.40 (8H, m); 2.65 (3H, s); 1.60
(2H, m) ; 1.30 (2H, m) ; 1.00 (2H, m) . MS TOF 485 (M+1+) .
Hplc (Magellan C8, Gradient 3, water/acetonitrile/TFA) rt
9.94 min.
Example 66.
1-(Indol-6-carbonyl-D-phenylglycinyl)-1'-methyl-4,4'-
bispiperidine
1H nmr (CD3CN) a mixture of conformers only one recorded
here7.78 (2H, s); 7.50 (1H, d); 7.25(7H, m); 6.34 (1H, s);
6.82 (1H, s); 4.40 (1H, m); 3.83 (1H, m); 3.35 (2H, t); 2.9-
2.4 (8H, m) and 2.65 (3H, s) masked by water in solvent;
1.60 (2H, m); 1.40 (2H, m); 1.08 (2H, m). MS TOF 459 (M+1+).
Hplc (Luna2 C18, Gradient 3, water/acetonitrile/TFA rt 10.01
min.
Example 67.
1-(3-Amino-4-fluorobenzoyl-D-phenylglycinyl)-1'-methyl-4,4'-
bispiperidine
1H nmr (d4 methanol) a mixture of conformers only one
recorded here 7.4 (6H, m); 7.1 (1H, m); 7.0 (1H, t); 6.0
(1H, s); 4.63 (1H, m); 4.02 (1H, m); 3.30 (2H, m); 2.90-2.40
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(8H, m); 2.65 (3H, s); 1.60 (2H, m); 1.30 (2H, m); 1.00 (2H,
m) . MS TOF 453 (M+1+) .
Hplc (Symmetry C8, Gradient 3, water/acetonitrile/TFA) rt
5.03 min.
Example 68.
1-(3-Amino-4-bromobenzoyl-D-phenylglycinyl)-1'-methyl-4,4'-
bispiperidine
1H nmr (CD3CN) a mixture of conformers only one recorded
here 7.75 (1H, m); 7.35 (5H, m); 7.05 (1H, m); 6.80 (1H, m);
5.85 (1H, s); 4.45 (1H, m); 3.85 (1H, m); 3.30 (2H, m);
2.90-2.40 (8H, m) and 2.65 (3H, s) masked by water in
solvent; 1.60 (2H, m); 1.30 (2H, m); 1.00 (2H, m). MS TOF
513 and 515 (M+1+).
(Symmetry C8, Gradient 3, water/acetonitrile/TFA) rt 5.70
min.
Example 69.
1-(3-Amino-4-methoxybenzoyl-D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine
1H nmr (CD3CN) a mixture of conformers only one recorded
here 7.70 (1H, m); 7.30 (5H, m); 7.0 (2H, m); 6.72 (1H,
d); 5.80 (1H, s); 4.45 (1H, m); 3.85(1H, m); 3.70(3H, s);
3.30 (2H, m); 2.9-2.4 (8H, m) masked by water in solvent;
1.60 (2H, m); 1.30 (2H, m); 1.00 (2H, m). MS TOF 465 (M+1+).
Hplc (Luna2 C18, Gradient 3, water/acetonitrile/TFA) rt 7.55
min.
Example 70.
1-(4-(Methylamino)benzoyl-D-phenylglycinyl)-1'-methyl-4,4'-
bispiperidine
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1H nmr (CD3CN) a mixture of conformers only one recorded
here 7.70 (3H, m); 7.35 (5H, m); 6.60 (2H, d); 5.90 (1H,
s) ; 4.45 (1H, m) ; 3 .85 (1H, m) ; 3 .40 (2H, m) ; 2.9-2.4 (8H,
m) ; 2.70 (3H, s) ; 1.60 (2H, m) ; 1.30 (2H, m) ; 1.00 (2H, m) .
MS TOF 465 (M+1+).
Hplc (Luna2 C18, Gradient 3, water/acetonitrile/TFA) rt 8.52
min.
Example 71.
1-(4-Ethylaminobenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.65 (3H, m); 7.45 (2H, m); 7.35 (5H, m);
6.60 (2H, d); 6.00 (1H, s); 3.20 (3H, s); 3.10 (2H, q);
3.00-2.50 (8H, m); 1.15 (3H, t). MS TOF 539 (M+1+). Hplc
(Magellan C8, Gradient 3, water/acetonitrile/TFA) rt 12.57
min.
Example 72.
1-(3-Methylaminobenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.75 (1H, d); 7.60 (1H, d); 7.35 (7H, m);
7.15 (1H, t); 7.00 (1H, m); 6.70 (1H, d); 6.00 (1H, s); 3.20
(3H, s); 3.00-2.50 (8H, m); 2.70 (3H, s). MS TOF 525 (M+1+).
Hplc (Magellan C8, Gradient 3, water/acetonitrile/TFA) rt
12.07 min.
Example 73.
1-(4-Chloro-3-aminobenzoyl-D-phenylglycinyl)-4-(2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.95 (1H, d); 7.60 (1H, m); 7.45 (10H, m);
7.00 (1H, d); 6.00 (1H, s); 3.25 (3H, s); 3.00-2.50 (8H, m).
MS TOF 527 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 13.56 min.
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Example 74.
1-(4-Trifluoromethoxybenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.85 (3H, m); 7.65 (1H, d); 7.45 (2H, m);
7.35 (6H, m); 6.00 (1H, s); 3.25 (3H, s); 3.00-2.50 (8H, m).
MS TOF 580 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 16.01 min.
Example 75.
1-(4-Difluoromethoxybenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.85 (3H, m); 7.45 (2H, d); 7.30 (5H, m);
7.15 (2H, d); 6.80 (1H, t); 6.00 (1H, s); 3.20 (3H, s);
3.00-2.50 (8H, m). MS TOF 562 (M+1+). Hplc (Magellan C8,
Gradient 3, water/acetonitrile/TFA) rt 14.99 min.
Example 76.
1-(4-Trifluoromethylbenzoyl-D-phenylglycinyl)-N-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.85 (2H, d); 7.70 (2H, d); 7.45 (2H, m);
7.35 (6H, m); 6.00 (1H, s); 3.20 (3H, s); 3.00-2.50 (8H, m).
MS TOF 564 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 15.00 min.
Example 77.
1-(Indol-3-carbonyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 8.05 (lH,s); 7.85 (1H, d); 7.70 (1H, m); 7.50
(2H, m); 7.35 (6H, m); 7.20 (2H, m); 6.15 (1H, s); 3.20 (3H,
s); 3.00-2.50 (8H, m). MS TOF 535 (M+1+). Hplc (Magellan C8,
Gradient 3, water/acetonitrile/TFA) rt 14.25 min.
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Example 78.
1-(4-Chloro-3-aminobenzoyl-L-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.75 (1H, d) ; 7.60 (1H, d) ; 7.45 (8H, m) ;
6.90 (1H, d); 5.95 (1H, s); 3.20 (3H, s); 3.00-2.50 (8H, m).
MS TOF 545 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 14.53 min.
Example 79.
1-(2-Carboxybenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.75 (1H, d); 7.60 (1H, d); 7.50 (1H, d);
7.25-7.50 (9H, m); 6.00 (1H, s); 3.20 (3H, s); 3.00-2.50 (8H,
m). MS TOF 540 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 12.19 min.
Example 80.
1-(2-Fluorobenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.85 (1H, m); 7.60 (1H, d); 7.25-7.50 (10H,
m); 6.00 (1H, s); 3.20 (3H, s); 3.00-2.50 (8H, m). MS TOF
514 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 13.29 min.
Example 81.
1-(3-Bromoindol-6-carbonyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.85 (2H, m); 7.70-7.20 (10H, m); 6.05 (1H,
s); 3.20 (3H, s); 3.00-2.50 (8H, m). MS TOF 614 (M+1+).
Hplc (Magellan C8, Gradient 3, water/acetonitrile/TFA) rt
16.16 min.
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Example 82.
1-(3-Chloroindol-6-carbonyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.95 (2H, m); 7.70-7.30 (10H, m); 6.05 (1H,
s); 3.25 (3H, s); 3.00-2.50 (8H, m). MS TOF 570 (M+1+).
Hplc (Magellan C8, Gradient 3, water/acetonitrile/TFA) rt
16.18 min.
Example 83.
1-(2-Cyanobenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.25-7.80 (12H, m); 6.05 (1H, s); 3.25 (3H,
s); 3.00-2.50 (8H, m). MS TOF 521 (M+1+). Hplc (Magellan
C8, Gradient 3, water/acetonitrile/TFA) rt 14.85 min.
Example 84.
1-(2-Aminomethylbenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.95 (2H, m); 7.80-7.35 (10H, m); 6.15
(1H, s); 4.30 (2H, s); 3.15 (3H, s); 3.00-2.50 (8H, m). MS
TOF 525 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 12.21 min.
Example 85.
1-(4-Carboxy-3-aminobenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.75 (1H, d); 7.60 (1H, d); 7.45 (7H, m);
7.15 (1H, s); 6.85 (lH,d); 5.95 (1H, s); 3.25 (3H, s);
3.00-2.50 (8H, m). MS TOF 554 (M+1+). Hplc (Magellan C8,
Gradient 3, water/acetonitrile/TFA) rt 13.00 min.
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Example 86.
1-(1H-Indazol-6-carbonyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 8.05 (2H,m); 7.85 (1H, d); 7.70 (1H, d); 7.55
(2H, m); 7.45 (5H, m); 5.95 (1H, s); 3.30 (3H, s); 3.00-2.50
(8H, m). MS TOF 545 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 13.44 min.
Example 87.
1-(4-Methylcarboxybenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.95 (2H, m); 7.80 (2H, m); 7.45 (2H, m);
7.35 (6H, m); 6.00 (1H, s); 3.90 (3H, s); 3.20 (3H, s);
3.00-2.50 (8H, m). MS TOF 554 (M+1+). Hplc (Magellan C8,
Gradient 3, water/acetonitrile/TFA) rt 14.90 min.
Example 88.
1-(4-Acetoxybenzoyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.75 (3H, m); 7.60 (1H, d); 7.45 (2H, m);
7.35 (5H, m); 7.10 (2H,d); 6.00 (1H, s); 3.20 (3H, s); 3.00-
2.50 (8H, m); 2.20 (3H,s).MS TOF 554 (M+1+). Hplc (Magellan
C8, Gradient 3, water/acetonitrile/TFA)
rt 14.53 min.
Example 89.
1-(5-Methylpyrazin-2-carbonyl-D-phenylglycinyl)-4-(4-fluoro-
2-methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 8.90 (lH,s); 8.35 (lH,s); 7.55 (1H, m); 7.40
(2H, m); 7.25 (5H, m); 5.85 (1H, s); 3.10 (3H, s); 3.00-2.50
(8H, m); 2.40 (3H, s). MS TOF 512 (M+1+). Hplc (Magellan
C8, Gradient 3, water/acetonitrile/TFA) rt 14.17 min.
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Example 90.
1-(1,3-Benzodioxol-5-carbonyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.55 (2H, m) ; 7.35 (2H, m) ; 7.25 (6H, m) ;
6.70 (lH,d); 5.85 (2H,s); 5.80 (1H, s); 3.10 (3H, s);
3.00-2.50 (8H, m). MS TOF 540 (M+1+). Hplc (Magellan C8,
Gradient 3, water/acetonitrile/TFA) rt 14.28 min.
Example 91.
1-(4-(Methylsulphonyl)benzoyl-D-phenylglycinyl)-4-(4-fluoro-
2-methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.95 (3H, m); 7.60 (1H, m); 7.50 (2H,m); 7.35
(6H, m); 6.05 (1H, s); 3.25 (3H,s); 3.10 (3H, s); 3.00-2.50
(8H, m). MS TOF 574 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 13.62 min.
Example 92.
1-(2,3-Dichloroindol-6-carbonyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.90 (lH,d); 7.85 (lH,s); 7.55 (2H, m); 7.40
(2H, m); 7.25 (5H, m); 6.05 (1H, s); 3.30 (3H, s); 3.00-2.50
(8H, m); 2.40 (3H, s). MS TOF 614 (M+1+). Hplc (Magellan
C8, Gradient 3, water/acetonitrile/TFA)
rt 16.35 min.
Example 93.
1-(3-Chloro-2-oxo-(1H)indol-6-carbonyl-D-phenylglycinyl)-4-(4-
fluoro-2-methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.90 (lH,d); 7.55 (1H, m); 7.25-7.50 (9H, m);
5.95 (1H, s); 5.20 (lH,s); 3.20 (3H, s); 3.00-2.50 (8H, m).
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MS TOF 585 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 14.38 min.
Example 94.
1-(3,3-Dichloro-2-oxo-(1H)indol-6-carbonyl-D-phenylglycinyl)-
4-(4-fluoro-2-methylsulphonylphenyl)-piperazine
1H nmr (CD3CN) 7.90 (lH,d); 7.65 (2H,m); 7.55 (1H, m); 7.45
(2H,m); 7.35 (5H, m); 5.95 (1H, s); 3.25 (3H, s); 3.00-2.50
(8H, m). MS TOF 619 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 15.13 min.
Example 95.
1-(3-Methylindol-6-carbonyl-D-phenylglycinyl)-1'-methyl-4,4'-
bispiperidine
1H nmr (CD3CN) a mixture of conformers only one recorded
here 7.85 (2H, m); 7.40 (3H, m); 7.30 (3H, m); 7.05 (1H, s);
5.95 (1H, s); 4.55 (1H, m); 3.85 (1H, m); 3.30 (2H, m);
2.90-2.40 (8H, m); 2.55 (3H, s); 2.20 (3H,s); 1.60 (2H, m);
1.30 (2H, m); 1.00 (2H, m). MS TOF 473 (M+1+). Hplc
(Magellan C8, Gradient 3, water/acetonitrile/TFA) rt 12.40
min.
Example 96.
1-(2,3-Dihydroindol-6-carbonyl-D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine
1H nmr (CD3CN) a mixture of conformers only one recorded
here 7.75 (1H, m); 7.30 (7H, m); 5.85 (1H, s); 4.45 (1H, m);
3.85 (1H, m); 3.65 (2H,t); 3.30 (2H, m); 3.10 (2H,t);
2.90-2.40 (8H, m); 2.55 (3H, s); 1.60 (2H, m); 1.30 (2H, m);
1.00 (2H, m). MS TOF 461 (M+1+). Hplc (Magellan C8,
Gradient 3, water/acetonitrile/TFA) rt 8.68 min.
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Example 97.
1-(1H-indazol-6-carbonyl-D-phenylglycinyl)-1'-methyl-4,4'-
bispiperidine
1H nmr (CD3CN) a mixture of conformers only one recorded
here 7.95 (1H, m); 7.85 (2H,m); 7.65 (lH,m); 7.45 (2H, m);
7.30 (3H, m); 5.95 (1H, s); 4.55 (1H, m); 3.95 (1H, m); 3.30
(2H, m) ; 2.90-2.40 (8H, m) ; 2.55 (3H, s) ; 1.60 (2H, m) ; 1.30
(2H, m); 1.00 (2H, m). MS TOF 460 (M+1+). Hplc (Magellan C8,
Gradient 3, water/acetonitrile/TFA) rt 9.72 min.
Example 98.
1-(Benzimidazol-5-carbonyl-D-phenylglycinyl)-1'-methyl-4,4'-
bispiperidine
1H nmr (CD3CN) a mixture of conformers only one recorded
here. 8.05 (lH,s); 7.90 (lH,m); 7.75 (2H, m); 7.30 (5H, m);
5.95 (1H, s); 4.45 (1H, m); 3.85 (1H, m); 3.30 (2H, m);
2.90-2.40 (8H, m); 2.75 (3H, s); 1.60 (2H, m); 1.30 (2H, m);
1.00 (2H, m). MS TOF 460 (M+1+). Hplc (Magellan C8,
Gradient 3, water/acetonitrile/TFA) rt 8.80 min.
Example 99.
1-(Benzthiazol-6-carbonyl-D-phenylglycinyl)-1'-methyl-4,4'-
bispiperidine
1H nmr (CD3CN) a mixture of conformers only one recorded
here 8.40 (lH,s); 7.95 (3H, m); 7.30 (5H, m); 5.85 (1H, s);
4.45 (1H, m); 3.85 (1H, m); 3.30 (2H, m); 2.90-2.40 (8H, m);
2.65 (3H, s); 1.60 (2H, m); 1.30 (2H, m); 1.00 (2H, m). MS
TOF 477 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 9.58 min.
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Example 100.
1-(3-Chloroindol-6-carbonyl- D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine
1H nmr (CD3CN) a mixture of conformers only one recorded
here 7.85 (2H, m); 7.30 (7H, m); 5.85 (1H, s); 4.45 (1H, m);
3.85 (1H, m); 3.30 (2H, m); 2.90-2.40 (8H, m); 2.65 (3H,
s);
1.60 (2H, m); 1.30 (2H, m); 1.00 (2H, m). MS TOF 493 (M+1+).
Hplc (Magellan C8, Gradient 3, water/acetonitrile/TFA) rt
12.22 min.
Example 101.
1-(3-Bromoindol-6-carbonyl-D -phenylglycinyl)-1'-methyl-4,4'-
bispiperidine
1H nmr (CD3CN) a mixture of conformers only one recorded
here 7.85 (2H, m); 7.30 (7H, m); 5.85 (1H, s); 4.45 (1H, m);
3.85 (1H, m); 3.30 (2H, m); 2.90-2.40 (8H, m); 2.65 (3H,
s);
1.60 (2H, m); 1.30 (2H, m); 1.00 (2H, m). MS TOF 539 (M+1+).
Hplc (Magellan C8, Gradient 3, water/acetonitrile/TFA) rt
12.45min.
Example 102.
1-(3-Amino-4-chlorobenzoyl-L -phenylglycinyl)-1'-methyl-4,4'-
bispiperidine
1H nmr (CDC13) a mixture of conformers only one recorded
here 7.65 (1H, m); 7.30 (6H, m); 7.00 (lH,m); 5.85 (1H, s);
4.65 (1H, m); 3.80 (1H, m); 3.55 (2H, m); 2.90-2.40 (8H,
m);
2.65 (3H, s); 1.60 (2H, m); 1.30 (2H, m); 1.00 (2H, m). MS
TOF 469 (M+1+). Hplc (Magel lan C8, Gradient 3,
water/acetonitrile/TFA) rt 0.71min.
1
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Example 103.
1-(4-Vinylbenzoyl-D-phenylglycinyl)-1~-methyl-4,4~-
bispiperidine
1H nmr (CD3CN) a mixture of conformers only one recorded
here 7.85 (1H, m); 7.70 (2H,m); 7.40 (6H, m); 6.75 (lH,m);
6.00 (1H, s); 5.85 (lH,d); 5.50 (lH,d); 4.55 (1H, m); 3.95
(1H, m); 3.30 (2H, m); 2.90-2.40 (8H, m); 2.65 (3H, s); 1.60
(2H, m); 1.30 (2H, m); 1.00 (2H, m). MS TOF 446 (M+1+).
Hplc (Magellan C8, Gradient 3, water/acetonitrile/TFA) rt
11.21min.
Example 104.
1-(3-Amino-4-chlorobenzoyl-D-phenylglycinyl)-4-(4-amino-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.55 (1H, m); 7.45 (3H, m); 7.35 (5H, m);
7.10 (lH,d); 6.90 (1H, d); 6.10 (1H, s); 3.20 (3H, s);
3.00-2.50 (8H, m). MS TOF 542 (M+1+). Hplc (Magellan C8,
Gradient 3, water/acetonitrile/TFA) rt 12.02 min.
Example 105.
1-(3-Aminobenzoyl-D-phenylglycinyl)-4-(4-amino-2-methyl
sulphonylphenyl)piperazine
1H nmr (CD3CN) 7.55 (2H, m); 7.45 (3H, m); 7.35 (5H, m);
7.10 (lH,d); 6.90 (1H, d); 6.10 (1H, s); 3.10 (3H, s);
3.00-2.50 (8H, m). MS TOF 508 (M+1+). Hplc (Magellan C8,
Gradient 3, water/acetonitrile/TFA) rt 9.35 min.
Example 106.
1-(3-Amino-4-chlorobenzoyl-D-phenylglycinyl)-4-(4-carboxamido-
2-methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 8.05 (lH,d); 7.80 (1H, m); 7.35-7.60 (8H, m);
7.10 (lH,d); 6.10 (1H, s); 3.25 (3H, s); 3.00-2.50 (8H, m).
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MS TOF 570 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 12.24 min.
Example 107.
1-(3-Amino-4-chlorobenzoyl-D-phenylglycinyl)-4-(4-nitro-2-
methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 8.70 (lH.s); 8.45 (lH,d); 7.55 (1H, m); 7.45
(5H, m); 7.30 (2H, m); 7.10 (lH,d); 6.10 (1H, s); 3.40 (3H,
s); 3.00-2.50 (8H, m). MS TOF 572 (M+1+). Hplc (Magellan
C8, Gradient 3, water/acetonitrile/TFA) rt 14.25 min.
Example 108.
1-(3-Amino-4-chlorobenzoyl-D-4-aminophenylglycinyl)-4-(4-
fluoro-2-methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.65 (1H, d); 7.45 (4H, m); 7.25 (2H, m);
7.15 (2H,d); 7.05 (1H, d); 6.10 (1H, s); 3.20 (3H, s);
3.00-2.50 (8H, m). MS TOF 560 (M+1+). Hplc (Magellan C8,
Gradient 3, water/acetonitrile/TFA) rt 11.90 min.
Example 109.
1-(3-Amino-4-chlorobenzoyl-D-4-carboxamidophenylglycinyl)-4-
(4-fluoro-2-methylsulphonylphenyl)piperazine
1H nmr (CD3CN) 7.70 (2H, d) ; 7.55 (1H, d) ; 7.45 (2H, d) ;
7.25 (2H,m) ; 7.20 (2H,d) ; 6.90 (1H, d) ; 6.10 (1H, s) ; 3.20
(3H, s); 3.00-2.50 (8H, m). MS TOF 588 (M+1+). Hplc
(Magellan C8, Gradient 3, water/acetonitrile/TFA) rt 12.18
min.
Example 110.
1-(3-Amino-4-chlorobenzoyl-D-4-(methylcarboxamido)phenyl-
glycinyl)-4-(4-fluoro-2-methylsulphonylphenyl)piperazine
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1H nmr (CD3CN) 7.70 (2H, d); 7.55 (1H, d); 7.45 (2H, d);
7.25 (2H,m); 7.20 (2H,d); 6.90 (1H, d); 6.10 (1H, s); 3.20
(3H, s); 2.70 (3H,s); 3.00-2.50 (8H, m). MS TOF 602 (M+1+).
Hplc (Magellan C8, Gradient 3, water/acetonitrile/TFA) rt
12.70 min.
Example 111.
3-Amino-4-chlorobenzoyl-D-phenylglycine 4-methylbenzylamide
1H nmr (CD3CN) 7.55 (1H, m); 7. 35 (7H,m); 7.00 (4H,m); 5.45
(1H, s); 4.25 (2H,m); 2.20 (3H, s). MS TOF 408 (M+1+). Hplc
(Magellan C8, Gradient 3, water/acetonitrile/TFA) rt 14.61
min.
Example 112.
3-Amino-4-chlorobenzoyl-D-4-carboxamidophenylglycine R,S -2-
methylcyclohexylamide
1H nmr (CD3CN) mixture of isomers only one recorded here
7.75 (2H, d); 7. 60 (2H,m); 7.30 (2H,m); 7.10 (lH,d); 5.55
(1H, s); 3.90 (lH,m); 3.25 (lH,m); 1.00-2.00 (8H,m) 0.50
(3H, m). MS TOF 443 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 9.18 min
Example 113.
3-Amino-4-chlorobenzoyl-D-4-carboxamidophenylglycine 2-
indanamide
MS TOF 463 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 12.58 min.
Example 114.
3-Amino-4-chlorobenzoyl-D-4-carboxamidophenylglycine (S)-N -
benzyl-alpha-methylbenzylamide
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MS TOF 541 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 15.34 min.
Example 115.
3-Amino-4-chlorobenzoyl-D-4-carboxamidophenylglycine 1-(S)-1-
naphthylethylamide
MS TOF 5013 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 14.00 min.
Example 116.
3-Amino-4-chlorobenzoyl-D-4-carboxamidophenylglycine 3-(1-
(R,S)-hydroxyethyl)benzamide
MS TOF 443 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 11.81 min.
Example 117.
3-Amino-4-chlorobenzoyl-D-phenylglycine cis,trans-2-
aminocyclohexylamide
MS TOF 401 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 11.00 min.
Example 118.
1-(3-Amino-4-chlorobenzoyl-D,L-(4-piperidinyl)glycinyl)-4-(4-
fluoro-2-methylsulphonylphenyl)piperazine
MS TOF 552 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 11.00 min.
Example 119.
1-(3-Amino-4-chlorobenzoyl-D,L-(4-N-methylpiperidinyl)-
glycinyl)-4-(4-fluoro-2-methylsulphonylphenyl)piperazine
MS TOF 566 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 10.83 min.
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Example 120.
1-(3-Amino-4-chlorobenzoyl-D,L-(4-N-trifluoroacetyl-
piperidinyl)glycinyl-4-(4-fluoro-2-methylsulphonylphenyl)-
piperazine
MS TOF 649 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 12.63 min.
Example 121.
3-Amino-4-chlorobenzoyl-D-phenylglycine (2-chloro-5-
carboxamido)benzenesulphonamide
MS TOF 521 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 10.23 min.
Example 122.
1-(4-Cyanobenzoyl-D-phenylglycinyl)-1'-methyl-4,4'-
bispiperidine
MS TOF 445 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 10.13min.
Example 123.
1-(3-Cyanobenzoyl-D-phenylglycinyl)-1'-methyl-4,4'-
bispiperidine
MS TOF 445 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 10.23min.
Example 124.
1-(4-Chlorobenzoyl-D-phenylglycinyl)-4-(4-pyridyl)-piperazine
MS TOF 435 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 12.11 min.
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Example 125.
1-(4-Methoxybenzyl-D-phenylglycinyl)-4-(4-fluoro-2-
methylsulphonylphenyl)piperazine
MS TOF 512 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 11.91 min.
Example 126.
1-N-(3-Amino-4-chlorobenzoyl)-2-N-(4-methoxybenzoyl)-1,2-
diamino-1-phenylethane
1H nmr (CD30H) 7.45 (2H, m); 7. 35 (3H,m); 7.20 (2H,m);7.10
(3H,m) ; 6.75 (2H,d) ; 4.80 (1H, m) ; 4.25 (2H,m) ; 3.70 (3H,
s). MS TOF 424 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 14.05 min.
Examples 127 to 136.
Preparation of Starting Materials
4-methoxybenzoyl-D-phenylglycinyl-R,S-3-hydroxypyrrolidine
D-phenylglycinyl-R,S-3-hydroxypyrrolidine (3.428, 15.5mmo1)
was dissolved in dichloromethane (100m1) and placed under
argon. Triethylamine (2.27m1, 16.28mmo1) was added followed
by 4-methoxybenzoyl chloride (2.788, 16.3mmol) and the
mixture stirred at room temperature for 3.5h. The organic
solution was washed with 0.5% hydrochloric acid (50m1), sat.
sodium bicarbonate solution (50m1) and brine (50m1). The
organic solution was dried (MgS04) and evaporated to an off-
white solid, 4-methoxybenzoyl-D-phenylglycinyl-R,S-3-
hydroxypyrrolidine, (5.498, 100%)
Hplc (tuna C18, Gradient3, water/acetonitrile/TFA), rt,
11.7min
LCMS M+1 355 Nmr.
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4-methoxybenzoyl-D-phenylglycinyl-4-hydroxypiperidine
By a similar method D-phenylglycinyl-4-hydroxypiperidine was
converted to 4-methoxybenzoyl-D-phenylglycinyl-4-
hydroxypiperidine.
Hplc (tuna C18, Gradient3, water/acetonitrile/TFA), rt,
11.9min
LCMS M+1 369 Nmr
Example 127
1-(4-Methoxybenzoyl-D-phenylglycinyl)-3-(R,S)-(2-
fluorophenoxy)pyrrolidine
To a solution of 4-methoxybenzoyl-D-phenylglycinyl-R,S-3-
hydroxypyrrolidine (400mg, 1.13mmo1) in benzene (lOml) at
lOoC was added 2-triphenylphosphonium 4,4-dimethyl-
tetrahydro-1,2,5-thiadiazolidine 1,1-dioxide (Reference: J.
Castro et al. J. Org. Chem. 1994, 59, 2289-2291) (696mg,
1.69mmo1) and 3-methoxyphenol (210mg) and the mixture
allowed to warm to room temperature overnight. The reaction
mixture was diluted with ether (30m1) and washed with dilute
sodium bicarbonate solution. The organic solution was dried
(MgS04) and concentrated. The residue was purified by by
reverse phase preparative chromatography to give 1-(4-
methoxybenzoyl-D-phenylglycinyl)-3-(R,S)-(3-
methoxyphenoxy)pyrrolidine.
Hplc (Luna C18, Gradient3, water/acetonitrile/TFA), rt,
11.75min.
LCMS M+1 461 Nmr (mixture of diastereomers).
Example 128.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-3-(R,S)-(3-
methoxyphenoxy)pyrrolidine
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From 4-methoxybenzoyl-D-phenylglycinyl-R,S-3-
hydroxypyrrolidine and 3-methoxyphenol:
Hplc (Luna C18, Gradient3, water/acetonitrile/TFA), rt,
11.75min.
LCMS M+1 461 Nmr (mixture of diastereomers).
Example 129.
1-(4-methoxybenzoyl-D-phenylglycinyl)-4-(3-
methoxyphenoxy)piperidine
From 4-methoxybenzoyl-D-phenylglycinyl-4-hydroxypiperidine
and 3-methoxyphenol:
Hplc (tuna C18, Gradient3, water/acetonitrile/TFA),
rt,16.09min
LCMS M+1 475. Nmr
Example 130.
1-(4-methoxybenzoyl-D-phenylglycinyl)-4-(4-
methoxyphenoxy)piperidine
From 4-methoxybenzoyl-D-phenylglycinyl-4-hydroxypiperidine
and 4-methoxyphenol:
Hplc (tuna C18, Gradient3, water/acetonitrile/TFA),
rt,15.8min.
LCMS M+1 475. Nmr.
Example 131.
1-(4-methoxybenzoyl-D-phenylglycinyl)-4-(3-
fluorophenoxy)piperidine
From 4-methoxybenzoyl-D-phenylglycinyl-4-hydroxypiperidine
and 3-fluorophenol:
Hplc (Luna C18, Gradient3, water/acetonitrile/TFA), rt,
12.75min.
LCMS M+1 463 Nmr
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Example 132.
1-(4-methoxybenzoyl-D-phenylglycinyl)-4-(2-
methanesulfonylphenoxy)piperidine
From 4-methoxybenzoyl-D-phenylglycinyl-4-hydroxypiperidine
and 2-methanesulphonylphenol:
Hplc (Luna C18, Gradient3, water/acetonitrile/TFA), rt,
10.8min.
LCMS M+1 523 Nmr.
Example 133.
1-(4-methoxybenzoyl-D-phenylglycinyl)-4-(2-
methylmercaptophenoxy)piperidine
From 4-methoxybenzoyl-D-phenylglycinyl-4-hydroxypiperidine
and 2-methylmercaptophenol:
Hplc (Luna C18, Gradient3, water/acetonitrile/TFA), rt,
12.7min
LCMS M+1 491 Nmr.
Example 134.
1-(4-methoxybenzoyl-D-phenylglycinyl)-4-(2-fluoro-
phenoxy)piperidine
From 4-methoxybenzoyl-D-phenylglycinyl-4-hydroxypiperidine
and 2-fluorophenol:
Hplc (tuna C18, Gradient3, water/acetonitrile/TFA), rt,
15.8min.
LCMS M+1 463 Nmr.
Example 135.
1-(4-methoxybenzoyl-D-phenylglycinyl)-4-(phenoxy)piperidine
From 4-methoxybenzoyl-D-phenylglycinyl-4-hydroxypiperidine
and phenol:
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Hplc (Luna C18, Gradient3, water/acetonitrile/TFA), rt,
16.8min.
LCMS M+1 445
Example 136.
1-(4-methoxybenzoyl-D-phenylglycinyl)-4-(3-
pyridoxy)piperidine
From 4-methoxybenzoyl-D-phenylglycinyl-4-hydroxypiperidine
and 3-hydroxypyridine:
Hplc (Luna C18, Gradient3, water/acetonitrile/TFA), rt,
11.4min
LCMS M+1 446 Nmr
Example 137.
1-(4-methoxybenzoyl-D-phenylglycinyl)-4-(4-
fluorophenoxy)piperidine
To a solution of triphenylphosphine (285mg, 1.09mmol) in dry
THF (5m1) under argon at -lSoC was added slowly (<-lOoC)
diethyl azodicarboxylate (DEAD) (208mg, 1.19mmol) and the
solution stirred at <-lOoC for 5min. To this mixture was
added a solution of 4-methoxybenzoyl-D-phenylglycinyl-4-
hydroxypiperidine (400mg, 1.08mmo1) and 4-fluorophenol
(122mg, 1.09mmo1) in dry THF (5m1) over 5min at <-lOoC. The
reaction was warmed to room temperature and monitored by tlc
(Si02 - ethyl acetate). The reaction mixture was poured into
water (5m1) and extracted with dichloromethane (100m1). The
organic solution was washed with sat. sodium bicarbonate
(50m1) and 0.5% hydrochloric acid (50m1), dried (MgS04) and
concentrated and the residue purified by flash
chromatography, (Si02 - 30% ethyl acetate in hexane to give
1-(4-methoxybenzoyl-D-phenylglycinyl)-4-(4-
fluorophenoxy)piperidine, (107mg, 21%)
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Hplc (tuna C18, Gradient3, water/acetonitrile/TFA), rt,
l6.Omin
LCMS M+1 463. Nmr.
Examples 138 to 142
Preparation of Starting Materials
Benzyloxycarbonyl-D-phenylglycinyl-R,S-3-hydroxypyrrolidine
Benzyloxycarbonyl-D-phenylglycine (18.01g, 63.1mmo1) and
R,S-3-hydroxypyrrolidinol (5.0g, 57.4mmo1) were suspended in
dimethylformamide (300m1). HOAt (8.618, 63.1mmo1) was added,
the mixture stirred for 3min. and then EDCI (12.1g 63.1mmo1)
was added with stirring and the mixture left overnight. The
orange solution was concentrated in vacuo and the residue
taken up in ethyl acetate (300m1). The organic solution was
washed with sat. sodium bicarbonate (2 x 100m1), 0.5°s
aqueous hydrochloric acid (50m1) and brine (100m1). The
organic solution was dried (MgS04) and evaporated in vacuo
to give an orange solid. Flash chromatography (Si02 1:1
dichloromethane: ethyl acetate gave benzyloxycarbonyl-D-
phenylglycinyl-R,S-3-hydroxypyrrolidine, (11.48, 5,60).
Hplc (tuna C18, Gradient3, water/acetonitrile/TFA), rt,
12.7min
LCMS M+1 355 Nmr.
Benzyloxycarbonyl-D-phenylglycinyl-4-hydroxypiperidine
By a similar method using benzyloxycarbonyl-D-phenylglycine
and 4-hydroxypiperidine, benzyloxycarbonyl-D-phenylglycinyl-
4-hydroxypiperidine was prepared.
Hplc (Luna C18, Gradient3, water/acetonitrile/TFA), rt,
11.9min
LCMS M+1 369 Nmr.
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D-Phenylglycinyl-R,S-3-hydroxypyrrolidine
Benzyloxycarbonyl-D-phenylglycinyl-R,S-3-hydroxypyrrolidine,
(5.498, 15.5mmo1) was dissolved in ethanol (120m1) and Pd/C
(10%, 100mg) added. The mixture was hydrogenated at
atmospheric pressure until complete by tlc (Si02 ethyl
acetate - starting material Rf. 0.6, product 0.05). The
catalyst was filtered off through celite and concentrated in
vacuo to give D-phenylglycinyl-R,S-3-hydroxypyrrolidine as 'a
yellow oil, (3.548, 16.1mmo1).
D-Phenylglycinyl-4-hydroxypiperidine
By a similar method benzyloxycarbonyl-D-phenylglycinyl-4-
hydroxypiperidine was converted to D-phenylglycinyl-4-
hydroxypiperidine
Benzyloxycarbonyl-D-phenylglycinyl-4-(3-pyridoxy)piperidine
To a solution of benzyloxycarbonyl-D-phenylglycinyl-4-
hydroxypiperidine (500mg, 1.36mmol), 3-hydroxypyridine
(129mg, 1.36mmo1) and triphenylphosphine (356mg, 1.36mmo1)
in dry THF (20m1) at 0°C, was slowly added diethyl
azodicarboxylate (259mg, 1.19mmo1) and the mixture stirred
for 1h at OoC and then 16h at room temperature. Water (5m1)
was added and the mixture extracted with ethyl acetate (2 x
lOml). The organic solution was washed with water and brine,
dried (MgS04) and concentrated to an oil which was purified
by flash chromatography, (Si02 - hexane/ethyl acetate 1:1)
to give benzyloxycarbonyl-D-phenylglycinyl-4-(3-
pyridoxy)piperidine, (490mg 65% - contaminated with
triphenylphosphine)
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Benzyloxycarbonyl-D-phenylglycinyl-R,S-3-(3-pyridoxy)-
pyrrolidine
A solution of benzyloxycarbonyl-D-phenylglycinyl-R,S-3-
hydroxypyrrolidine (2.0g, 8.64mmo1), 2-triphenylphosphonium
4,4-dimethyl-tetrahydro-1,2,5-thiadiazolidine 1,1-dioxide
(Reference: J. Castro et al. J. 0r8. Chem. 1994, 59, 2289-
2291) (3.4798, 8.47mmo1) and 3-hydroxypyridine (0.8058,
8.47mmol) in benzene (30m1) was stirred at room temperature
for 18h. The mixture was poured onto ether (50m1) and the
organic solution was washed with sat. sodium bicarbonate (2
x 50m1). The product was extracted into 5°s hydrochloric acid
which was then basified (pH8) with 2M sodium hydroxide
solution and extracted with ether (3 x 100m1). The organic
solution was dried (MgS04) and evaporated to give
benzyloxycarbonyl-D-phenylglycinyl-R,S-3-(3-
pyridoxy)pyrrolidine
D-Phenylglycinyl-4-(3-pyridoxy)piperidine
Benzyloxycarbonyl-D-phenylglycinyl-4-(3-pyridoxy)piperidine
(1.188 2.64mmo1) was dissolved in ethanol (120m1) containing
Pd/C 10% (100m8) and acetic acid (0.3m1) and hydrogenated at
atmospheric pressure for 8h - (incomplete by tlc). The
catalyst was removed by filtration and the solution
evaporated to an oil. The oil was re-hydrogenated as before.
The catalyst was removed by filtration and the solvent
evaporated in vacuo to an oil which was taken up in dilute
hydrochloric acid. The aqueous solution was washed with
dichloromethane and then basified with solid sodium
bicarbonate. Extraction with chloroform, drying (MgS04) and
evaporation of the solvent in vacuo gave D-phenylglycinyl-4-
(3-pyridoxy)piperidine, (331m8 40%). Nmr
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D-phenylglycinyl-R,S-3-(3-pyridoxy)pyrrolidine
In a similar manner D-phenylglycinyl-R,S-3-(3-
pyridoxy)pyrrolidine was prepared from benzyloxycarbonyl-D-
phenylglycinyl-R,S-3-(3-pyridoxy)pyrrolidine by
hydrogenation over Pd/C in ethanol. Nmr.
Example 138.
1-(Indole-6-carbonyl-D-phenylglycinyl)-4-(3-
pyridoxy)piperidine
A mixture of EDCI (169mg 0.88mmo1), HOAt (120mg 0.88mmo1)
and indole-6-carboxylic acid (142mg 0.88mmo1) in DMF (5m1)
was stirred for 2min and then added to a solution of D-
phenylglycinyl-4-(3-pyridoxy)piperidine (229mg 0.735mmo1)
and triethylamine (89mg 0.88mmo1) in DMF (20m1). The mixture
was stirred at room temperature for 3h and excess solvent
removed in vacuo. The residue was taken up in ethyl acetate
(150m1) and washed with sat. sodium bicarbonate (50m1). The
solution was dried (MgS04), evaporated and the residue
purified by flash chromatography (Si02 ethyl acetate:
methanol 0% - 5%) to give 1-(indole-6-carbonyl-D-
phenylglycinyl)-4-(3-pyridoxy)piperidine (122mg 41%)
Hplc (Luna C18, Gradient3, water/acetonitrile/TFA), rt,
10.8min.
LCMS M+1 455 Nmr
The following were prepared in a similar manner:
Example 139.
1-(3-Chloroindole-6-carbonyl-D-phenylglycinyl)-4-(3-
pyridoxy)piperidine
From D-phenylglycinyl-4-(3-pyridoxy)piperidine and 3-chloro-
6-indolecarboxylic acid:
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Hplc (tuna C18, Gradient3, water/acetonitrile/TFA), rt
11.95min
LMCS M+1 489 Nmr
Example 140.
1-(Indole-6-carbonyl-D-phenylglycinyl)-3-(R,S)-(3-
pyridoxy)pyrrolidine
From D-phenylglycinyl-R,S-3-(3-pyridoxy)pyrrolidine and 6-
indolecarboxylic acid.
Hplc (tuna C18, Gradient3, water/acetonitrile/TFA), rt,
6.4min.
LCMS M+1 441 Nmr (mixture of diastereomers).
Example 141.
1-(3-Chloroindole-6-carbonyl-D-phenylglycinyl)-3-(R,S)-(3-
pyridoxy)pyrrolidine
From D-phenylglycinyl-R,S-3-(3-pyridoxy)pyrrolidine and 3-
chloro-6-indolecarboxylic acid.
Hplc (Lung C18, Gradient3, water/acetonitrile/TFA), rt,
7.2min.
LCMS M+1 475 Nmr (mixture of diastereomers).
Example 142.
1-(3-Methylindole-6-carbonyl-D-phenylglycinyl)-3-(R,S)-(3-
pyridoxy)pyrrolidine
From D-phenylglycinyl-R,S-3-(3-pyridoxy)pyrrolidine and 3-
methyl-6-indolecarboxylic acid.
Hplc (Luna C18, Gradient3, water/acetonitrile/TFA), rt, 6.84
and 7.Omin.'
LCMS M+1 455 Nmr (mixture of diastereomers).
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Example 143.
(R)-2-(1'-(3-Chloroindole-6-carboxamido)benzyl)-4-
methoxyphenyl-1,3-thiazole
(R)-2-(1'-benzyloxycarbonylamidobenzyl)-4-methoxyphenyl-1,3-
thiazole
To a solution of benzyloxycarbonyl-D-phenylglycine thioamide
(1g, 3.33mmo1.) in acetone (25m1) was added a-bromo-4-
methoxyacetophenone (0.768, 3.32mmo1) and the mixture
stirred at room temperature for 30min. Chloroform (25m1)
and sat. aqueous sodium hydrogen carbonate (30m1) were added
and the organic solution separated, dried (MgS04) and
evaporated in vacuo. The residue was dissolved in
dichloromethane (30m1) and pyridine (0.5m1, 6.18mmo1) and
trifluoroacetic anhydride (0.5m1, 3.54mmo1) were added. The
mixture was stirred at room temperature until complete by
tlc (Si02 dichloromethane - 1h.), washed with 5%
hydrochloric acid, dried (MgS04) and evaporated in vacuo.
Flash chromatography of the residue (0.87g). (Si02 -
dichloromethane) gave (R)-2-(1'-benzyloxycarbonyl-
amidobenzyl)-4-methoxyphenyl-1,3-thiazole (0.748 1.72mmo1.
52%)
Nmr: CDC13 7.85(2H, d), 7.3-7.5 (11H, m), 6.95 (2H, d), 6.44
(0.5H, bd), 6.16 (0.5H, bd), 5.02-5.22 2H, m), 3.83 (3H. m).
(R)-2-(1'-aminobenzyl)-4-methoxyphenyl-1,3-thiazole
(R)-2-(1'-Benzyloxycarbonylamidobenzyl)-4-methoxyphenyl-1,3-
thiazole (0.708, 1.63mmo1) was dissolved in acetic acid
(50m1) and HBr in acetic acid (25m1) added. The mixture was
heated in a 50oC oil bath for 2h when no starting material
remained by tlc (Si02 30% ether in dichloromethane). The
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mixture was evaporated in vacuo, basified with sat. aqueous
sodium hydrogen carbonate and extracted with ethyl acetate
(x3). The organic solution was dried (MgS04) and evaporated
in vacuo. Flash chromatography (Si02 dichloromethane then
30% ether in dichloromethane) gave (R)-2-(1'-aminobenzyl)-4-
methoxyphenyl-1,3-thiazole (172mg, 36%)
Nmr: CDC13 7.7 (2H, d), 7.5 (2H, d), 7.17-7.4 (3H, m), 6.85
(2H, d) , 3.76 (3H, s)
(R)-2-(1'-(3-Chloroindole-6-carboxamido)benzyl)-4-
methoxyphenyl-1,3-thiazole
(R)-2-(1'-Aminobenzyl)-4-methoxyphenyl-1,3-thiazole (80mg,
0.27mmo1) was coupled to 3-chloroindolecarboxylic acid using
EDC/HOAt to give: (R)-2-(1'-(3-Chloroindole-6-
carboxamido)benzyl)-4-methoxyphenyl-1,3-thiazole (49°s)
Hplc (Luna C18 Gradient3) rt 17.2min.
LCMS M+1 474. Nmr.
Examples 144 to 147.
The compounds of Examples 144 to 147 were prepared by
coupling to the appropriate carboxylic acid to D-
phenylglycinyl-4,4'-(1'-methylbispiperidine) using EDC and
HOAt as described previously.
Example 144.
1-(4-Methylbenzoyl-D-phenylglycinyl)-1'-methyl-4,4'-
bispiperidine
Hplc (Luna C18 Gradient3) rt 11.2min.
LCMS M+1 434. Nmr.
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Example 145.
1-(4-Chlorobenzoyl-D-phenylglycinyl)-1'-methyl-4,4'-
bispiperidine
Hplc (Luna C18 Gradient3) rt 11.5min.
LCMS M+1 454. Nmr. ,
Example 146.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-1'-methyl-4,4'-
bispiperidine
Hplc (Luna C18 Gradient3) rt ll.lmin.
LCMS M+1 450. Nmr.
Example 147
1-(3,4-Methylenedioxybenzoyl-D-phenylglycinyl)-1'-methyl--
4,4'-bispiperidine
Hplc (Luna C18 Gradient3) rt 10.65min.
LCMS M+1 464. Nmr.
Example 148.
1-(Indole-6-carbonyl-D-phenylglycinyl)-1'-isopropyl-4,4'-
bispiperidine
Benzyloxycarbonyl-D-phenylglycinyl-4,4'-(1'-bispiperidine)
Benzyloxycarbonyl-D-phenylglycinyl- 1'-isopropyl-4,4'-
bispiperidine
D-phenylglycinyl-1'-isopropyl-4,4'-bispiperidine
1-(Indole-6-carbonyl-D-phenylglycinyl)- 1'-isopropyl-4,4'-
bispiperidine
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Prepared by coupling the appropriate carboxylic acid to D-
phenylglycinyl-4,4'-(1'-(2" -propyl)bispiperidine).
Hplc (Lung C18 Gradient3) rt 11.46min.
LCMS M+1 487. Nmr.
Examples 149 to 154.
The compounds of Examples 149 to 154 were prepared by
coupling Boc-D-4-carboxamidophenylglycine to the appropriate
amine with EDCI/HOAt, deprotection with TFA/DCM and coupling
to 3-amino-4-chlorobenzoic acid with EDCI/HOAt as previously
described.
Example 149.
2-(3-Amino-4-chlorobenzoyl-D-4-carboxamidophenylglycinyl)-
1,2,3,4-tetrahydroisoquinoline
Hplc (tuna C18 Gradient3) rt 13.15min.
LCMS M+1 463. Nmr.
Example 150.
1-(3-Amino-4-chlorobenzoyl-D-4-carboxamidophenyl-
glycinyl)-4-benzylpiperazine
Hplc (tuna C18 Gradient3) rt 11.4min.
LCMS M+1 512. Nmr.
Example 151.
1-(3-Amino-4-chlorobenzoyl-D-4-carboxamidophenylglycinyl)-4-
(2-methylthiophenyl)piperazine
Hplc (Luna C18 Gradient3) rt 14.3min.
LCMS M+1 539. Nmr.
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Example 152.
1-(3-Amino-4-chlorobenzoyl-D-4-carboxamidophenyl-
glycinyl)-4-(2-phenylethyl)piperazine
Hplc (Luna C18 Gradient3) rt ll.lmin.
LCMS M+1 521. Nmr.
Example 153.
1-(3-Amino-4-chlorobenzoyl-D-4-carboxamidophenyl-
glycinyl)-4-benzoylpiperidine
Hplc (Luna C18 Gradient3) rt 12.8min.
LCMS M+1 520. Nmr.
Example 154.
1-(3-Amino-4-chlorobenzoyl-D-4-carboxamidophenyl-
glycinyl)-4-(2-ethylphenyl)piperazine
Hplc (tuna C18 Gradient3) rt 13.9min.
LCMS M+1 521. Nmr.
Example 155.
1-(3-Methoxyindole-6-carbonyl-D-phenylglycinyl)-1'-
methyl-4,4'-bispiperidine
Methyl 1-acetyl-3-formylindole-6-carboxylate
A suspension of methyl 3-formylindole-6-carboxylate (1g,
4.93 mmol) in acetic anhydride (lOml) was refluxed for 2 h.
The acetic anhydride was removed under reduced pressure to
afford a pinkish solid (1.2g, 1000) that was used without
further purification. 1H NMR (CDC13) 2.7 (3H, s), 3.9 (3H,
s), 8.05 (1H, d), 8.15 (1H, s), 8.25 (1H, d), 9.0 (1H, s),
10.1 (1H, s); LCMS M+H 246.
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Methyl 1-acetyl-2,3-dihydroindol-3-one-6-carboxylate
This was prepared from methyl 1-acetyl-3-formylindole-6-
carboxylate (1.038, 4.20 mmol) using the method of Merour et
al. (Synthesis, 1994, 411) to yield the formate (680 mg).
The formate was dissolved in THF (50m1) and treated with
sat. NaHC03 solution (lOml). After 15 min. the reaction
mixture was extracted with ethyl acetate, washed with water,
dried and concentrated to give the ketone (574mg). 1H NMR
(CDC13) 2.3 (3H, br.), 3.9 (3H, s), 4.3 (2H, s), 7.75 (1H,
d), 7.85 (1H, d), 9.1 (1H, br.); LCMS M+H 234.
Methyl 1-acetyl-3-methoxyindole-6-carboxylate
Methyl 1-acetyl-2,3-dihydroindol-3-one-6-carboxylate (233mg,
1 mmol), trimethyl orthoformate (lOml) and p-toluene
sulphonic acid (20 mg) were heated under reflux for 3 h. in
methanol (lOml). The reaction mixture was concentrated under
reduced pressure, poured into water and extracted with
chloroform. After drying and evaporation, the product was
purified by prep hplc; 1H NMR (CD3CN) 2.56 (3H, s), 3.93
(3H, s), 3.97 (3H, s), 7.25 (1H, s), 7.62 (1H, d), 7.90 (1H,
d), 9.0 (1H, br.); LCMS M+H 248.
3-Methoxyindole-6-carboxylic acid
To a solution of methyl 1-acetyl-3-methoxyindole-6-
carboxylate (74 mg, 0.3 mmol) in THF (lOml) and water (2m1)
was added lithium hydroxide hydrate (63 mg, 1.5 mmol). The
reaction mixture was warmed to 50oC and stirred for 3 h. The
THF was removed under reduced pressure and the pH of the
aqueous phase adjusted to 3. Extraction of the aqueous layer
with ethyl acetate, drying and concentration gave the acid
(50 mg, 870); 1H NMR (CD3CN) 3.75 (3H, s), 3.97 (3H, s), 6.9
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(1H, s), 7.45 (1H, d), 7.55 (1H, d), 8.2 (1H, s); LCMS M+H
192.
1-(3-Methoxyindole-6-carbonyl-D-phenylglycinyl)-4,4'-(1'-
methylbispiperidine)
Prepared by coupling to D-phenylglycinyl-4,4~-(1~-
methylbispiperidine) using EDC and HOAt as described
previously.
Hplc (Luna C18, Gradient3) rt 8.35min.
LCMS M+1 489 Nmr.
Example 156.
1-(3-Amirio-4-chlorobenzoyl-D-cyclohexylglycinyl)-4-(4-
fluoro-2-methylsulfonylphenyl)-piperazine
Hplc (tuna C18, Gradient3, water/acetonitrile/TFA) rt
15.37min.
LCMS M+1 551
Example 157.
1-(3-Amino-4-chlorobenzoyl-D,L-1-napthylglycinyl)-4-(4-
fluoro-2-methylsulfonylphenyl)-piperazine
Hplc (tuna C18, Gradient3, water/acetonitrile/TFA) rt
15.69min.
LCMS M+1 595
Example 158.
1-(3-Chloroindole-6-carbonyl-D,L-(2-methylthiazol-4-
yl)glycinyl)-1'-methyl-4,4'-bispiperidine
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Ethyl oximinoacetoacetate
This was prepared from ethyl acetoacetate (10.00g) using the
method of Fischer (Organic Synthesis Coll. Vol. 3, 513-516)
to yield the titled compound (12.45g); 1H NMR (CDC13) 1.25
(3H, t) , 2.35 (3H, s) , 4 .3 (2H, q) , 8.8 (1H, br. ) .
Ethyl-y-chloro-a-oximinoacetoacetate
This was prepared from ethyl oximinoacetoacetate (1.73g)
using the method of Hatanaka et al. (Journal of Medicinal
Chemistry, 1973, 16(9), 978-984) to yield the titled
compound (1.44g); 1H NMR (CDC13) 1.25 (3H, t), 4.3 (2H, q),
4.55 (2H, s), 9.45 (1H, s), contains 20% starting material
by NMR.
Ethyl-a-oximino-2-methylthiazole-4-acetate
This was prepared from ethyl-y-chloro-a-oximinoacetoacetate
(1.44g) using the method of Hatanaka et al. (Journal of
Medicinal Chemistry, 1973, 16(9), 978-984) to yield the
titled compound (0.64g); 1H NMR (CDC13) 1.35 (3H, t), 2.7
(3H, s) , 4.35 (2H, q) , 8.2 (1H, s) .
D,L-(2-methylthiazol-4-yl)glycine ethyl ester
This was prepared from ethyl-a-oximino-2-methylthiazole-4-
acetate (0.62g) using the method of Hatanaka et al. (Journal
of Medicinal Chemistry, 1973, 16(9), 978-984) to yield the
titled compound (0.40g); 1H NMR (CDC13) 1.15 (3H, t), 1.95
(2H, br.), 2.6 (3H, s), 4.15 (2H, m), 4.65 (1H, s), 6.95
( 1H, s ) .
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N-Boc-D,L-(2-methylthiazol-4-yl)glycine ethyl ester
To a solution of D,L-(2-methylthiazol-4-yl)glycine ethyl
ester (0.3978, 1.982 mmol) in tetrahydrofuran (20 cm3), was
added di-tert-butyldicarbonate (0.4758, 2.180 mmol) and
triethylamine (0.304 cm3, 2.180 mmol). This was allowed to
stir for 1 hour and the solution concentrated in vacuo. The
oil was taken up in ethyl acetate (c. a. 50 cm3) washed with
0.5% hydrochloric acid solution (c. a. 20 cm3), and saturated
sodium bicarbonate solution (c. a. 20 cm3). This was then
dried over magnesium sulphate and concentrated in vacuo to
yield a yellow oil (0.6548, 2.177 mmol) [100% yield]; 1H
NMR (CDC13) 1.1 (3H, s), 1.35 (9H, s), 2.6 (3H, s), 4.15
( 3H, m) , 5 . 3 ( 1H, d) , 5 . 7 ( 1H, s ) , 7 . 0 ( 1H, s ) .
N-Boc-D,L-(2-methylthiazol-4-yl)glycine
To a solution of N-Boc-D,L-(2-methylthiazol-4-yl)glycine
ethyl ester (0.5958, 1.982 mmol) in methanol (c. a. 15 cm3),
was added 2M sodium hydroxide (1.98 cm3, 3.964 mmol), and
allowed to stir for 30 minutes. The solution was
concentrated in vacuo and taken up in water (c. a. 50 cm3).
The aqueous solution was washed with ethyl acetate (c.a. 30
cm3), and then acidified to pH 2 with 5% hydrochloric acid
solution (c. a. 50 cm3). The product was extracted with ethyl
acetate (c.a. 3x60 cm3), dried over magnesium sulphate, and
concentrated in vacuo to yield a pale yellow oil (0.6458,
2.368 mmol) [100% yield] ; 1H NMR (CDC13) 1.35 (9H, s) , 2.6
(3H, s), 5.4 (1H, d), 5.9 (1H, s), 7.1 (1H, s).
1-(N-Boc-D,L-(2-methylthiazol-4-yl)glycinyl) 1'-methyl-4,4'-
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bispiperidine
Prepared by coupling N-Boc-D,L-(2-methylthiazol-4-yl)-
glycine to 4,4'-(1'-methylbispiperidine) di-HC1 salt using
EDC and HOAt as described previously; 1H NMR (CDC13) 0.5-1.3
(10H, br.), 1.35 (9H, s), 1.4-1.85 (6H, br.), 2.2 (3H, d),
2.6 (3H, s), 3.75-4.0 (1H, br.), 4.55 (1H, br.), 5.7 (1H,
d), 6.1 (1H, d), 6.95 (1H, d)
1-(D,L-(2-Methylthiazol-4-yl)glycinyl)- 1'-methyl-4,4'-
bispiperidine
Prepared from 1-(N-Boc-D,L-(2-methylthiazol-4-yl)glycinyl)
1'-methyl -4,4'- bispiperidine using DCM/TFA deprotection as
described previously; 1H NMR (CDC13) 0.9-1.8 (10H, br.), 2.1-
2.3 (2H, br.), 2.45 (3H, br.), 2.6 (3H, s), 3.1-3.4 (3H,
br.), 4.6 (1H, br.), 4.95 (1H, s), 6.85 (1H, d).
1-(3-Chloroindole-6-carbonyl- D,L-(2-Methylthiazol-4-
yl)glycinyl)- 1'-methyl-4,4'-bispiperidine
Prepared by coupling 1-(D,L-(2-methylthiazol-4-yl)-
glycinyl)- 1'-methyl-4,4'-bispiperidine to 3-chloroindole-6-
carboxylic acid using EDC and HOAt as described previously;
1H NMR (CDC13) 0.5-1.9 (12H, br. ) , 2.4 (2H, br. ) , 2.55 (3H,
s), 2.65 (3H, s), 3.5 (2H, br.), 4.1 (1H, br.), 4.55 (1H,
br.), 6.15 (1H, d), 7.15 (1H, d), 7.5 (2H, br.), 7.8-8.1
(2H, br.), 8.9-9.25 (1H, br.), 12.2-12.6 (1H, br. d); HPLC
(Luna C18, Gradient3) rt 8.75min; LCMS M+1 514.
Example 159.
1-(3-Chloroindole-6-carbonyl-D,L-4-thiazolylglycinyl)- 1'-
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methyl-4,4'-bispiperidine
Ethyl-a-oximino-thiazole-4-acetate
To a 2 necked r.b. flask (100 cm3) with ethanol thermometer,
concentrated sulphuric acid (25 cm3) was added and cooled to
0°C with stirring. To this solution, was added the ethyl-a-
oximino-2-aminothiazole-4-acetate (5.008, 23.231 mmol).
Water (10 cm3) was then added and cooled to -10°C. A
solution of sodium nitrite (1.6838, 24.393 mmol) in water (5
cm3) was then added slowly over an hour keeping the
temperature below -5°C.
To a separate r.b. flask (500 cm3), water (180 cm3) was added
and cooled to 3°C. The reaction solution was poured on to
the cold water with stirring and then cooled to -5°C. To
this solution, 50o hypophosphoric acid (90 cm3) was added
dropwise over 10 minutes keeping the temperature at -5°C.
The solution was allowed to warm to room temperature and
stirred overnight. The product was extracted with diethyl
ether (c. a. 3x150 cm3) and washed with water. The ether
layer was concentrated in vacuo and treated to flash
chromatography (50% ethyl acetate/n-hexane) to yield a
orange oil upon concentration in vacuo (0.608, 3.00 mmol)
[13°s yield] ; 1H NMR (CDC13) 1.35 (3H, m) , 4.35 (2H, m) , 8.4
(1H, s) , 8. 9 (1H, s) , 14.4 (1H, s) .
D,L-4-thiazolylglycine ethyl ester
This was prepared from ethyl-a-oximino-thiazole-4-acetate
(0.608) using the method of Hatanaka et al. (Journal of
Medicinal Chemistry, 1973, 16(9), 978-984) to yield the
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titled compound (0.468); 1H NMR (CDC13) 1.25 (3H, t), 1.8-2.3
(2H, br.), 4.1 (2H, m), 4.75 (1H, s), 7.25 (1H, d), 8.7 (1H,
d) .
N-Boc-D,L-4- thiazolylglycine ethyl ester
To a solution of D,L-4-thiazolylglycine ethyl ester (0.4608,
2.470 mmol) in tetrahydrofuran (20 cm3), was added di-tert-
butyldicarbonate (0.5308, 2.470 mmol) and triethylamine
(0.344 cm3, 2.470 mmol). This was allowed to stir for 1
hour and the solution concentrated in vacuo. The oil was
taken up in ethyl acetate (c. a. 50 cm3) washed with 0.5°s
hydrochloric acid solution (c. a. 20 cm3), and saturated
sodium bicarbonate solution (c. a. 20 cm3). This was then
dried over magnesium sulphate and concentrated in vacuo to
yield an orange oil (0.7098, 2.477 mmol) [100% yield]; 1H
NMR (CDC13) 1.15 (3H, t), 1.35 (9H, s), 4.1 (2H, m), 5.45
( 1H, d) , 5 . 75 ( 1H, d) , 7 . 3 ( 1H, d) , 8 . 7 ( 1H, d) .
N-Boc-D,L-4- thiazolylglycine
To a solution of N-Boc-D,L-4- thiazolylglycine ethyl ester
(0.7008, 2.470 mmol) in methanol (c.a. 15 cm3), was added 2M
sodium hydroxide (2.47 cm3, 4.940 mmol) and allowed to stir
for 90 minutes. The solution was concentrated in vacuo and
taken up in water (c.a. 20 cm3). The aqueous solution was
washed with ethyl acetate (c. a. 20 cm3), and then acidified
to pH 2 with 5% hydrochloric acid solution (c. a. 50 cm3).
The product was extracted with ethyl acetate (c. a. 3x30
cm3), dried over magnesium sulphate, and concentrated in
vacuo to yield a pale yellow oil (0.5828, 2.254 mmol) [910
yield] ; 1H NMR (CDC13) 1.35 (9H, s) , 5.5 (1H, d) , 5.8 (1H,
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d), 7.35 (1H, d), 8.75 (1H, d), 9.8-10.2 (1H, br.).
1-(N-Boc-D,L-4- thiazolylglycinyl)- 1'-methyl-4,4'-
bispiperidine
Prepared by coupling N-Boc-D,L-4- thiazolylglycine
to 4,4'-(1'-methylbispiperidine) di-HC1 salt using EDC and
HOAt as described previously; 1H NMR (CDC13) 0.8-1.25 (10H,
br.), 1.35 (9H, m), 1.7 (6H, br.), 2.0 (6H, m), 2.4 (3H,
br.), 3.1 (2H, br.), 3.7 (1H, d), 4.6 (1H, d), 5.8 (1H, d),
6.0 (1H, br.), 7.25 (1H, 1H, br.), 8.65 (1H, m).
1-(D,L-4-Thiazolylglycinyl)- 1'-methyl-4,4'- bispiperidine
Prepared from 1-(N-Boc-D,L-4- thiazolylglycinyl)- 1'-methyl-
4,4'- bispiperidine using DCM/TFA deprotection as described
previously. The product was purified by prep HPLC; LCMS M+1
323.
1-(3-Chloroindole-6-carbonyl- D,L- thiazol-4-ylglycinyl- 1'-
methyl-4,4'-bispiperidine
Prepared by coupling 1-(D,L-4-Thiazolylglycinyl)- 1'-methyl-
4,4'- bispiperidine to 3-chloroindole-6-carboxylic acid
using EDC and HOAt as described previously; 1H NMR (CD3CN)
0.5-2.0 (10H, br.), 2.5 (2H, m), 2.8 (3H, br.), 3.1 (2H, m),
3.5 (2H, br.), 4.2 (1H, d), 4.6 (1H, d), 6.4 (1H, m), 7.5
(1H, br.), 7.8 (2H, br.), 8.15 (2H, br.), 9.05 (1H, br.),
9.9 (1H, br.); HPLC (tuna C18, Gradient3) rt 6.69min; LCMS
M+1 500.
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Preparation of starting materials:
Boc-R-4-(carboxymethyl)phenylglycine
R-4-Hydroxyphenylglycine methyl ester hydrochloride.
To a dry 250m1 three necked round bottom flask, equipped
with a low temperature thermometer, a septum for nitrogen
coverage and another for introduction of thionyl chloride by
syringe, was added R-4-hydroxyphenylglycine (12.5g) and dry
methanol (24m1). The mixture was stirred (magnetic stirrer)
and cooled to an internal temperature of -20°C using
cardice/acetone. Using a syringe, thionyl chloride was added
dropwise to the cooled mixture over a period of lOmin.
(Care: the reaction of thionyl chloride with methanol is
very exothermic and rate of addition should be such that the
thionyl chloride is efficiently stirred into the mixture and
that the temperature does not rise above -20°C. Once the
addition was complete the mixture was allowed to warm to
room temperature overnight (16-l8hr). Dry ether (150m1) was
added and the white ppt. that formed was filtered off,
washed with a little more ether and dried. Yield 15.58 95%.
Nmr.
Boc-R-4-Hydroxyphenylglycine methyl ester hydrochloride
To a stirred mixture of R-4-hydroxyphenylglycine methyl
ester hydrochloride 14g and sodium bicarbonate 11.7g in
tetrahydrofuran (THF) 150m1 and water 50m1, was added in one
portion, di- t-butyl dicarbonate 15.98. The mixture was
stirred rapidly to allow thorough mixing for 4h. Hexane
(75m1) was added and the organic layer separated and washed
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with sat. sodium bicarbonate solution, then brine and then
dried with magnesium sulphate. The drying agents was
filtered off and washed with a little THF and evaporated to
dryness, finishing with a high vacuum pump to remove the
last traces of di- t-butyl dicarbonate. Yield 19.7g 96%.
Nmr.
Boc-R-4-(trifluoromethanesulphonyloxy)phenylglycine methyl
ester hydrochloride
To a stirred solution of Boc-R-4-hydroxyphenylglycine methyl
ester 19g in dichloromethane 400m1 was added 2,6-lutidine
9.44m1 and 4-dimethylaminopyridine 1.65g and the mixture
cooled in an ice bath. Trifluoromethanane-sulphonic
anhydride 13.74m1 was added over a period of 5min and then
the reaction left to warm to room temperature over 4h. The
organic solution was washed with water, 2 x 150m1, 1N HC1 2
x 150m1 and the saturated sodium bicarbonate 150m1. The
organics were dried with magnesium sulphate and then
evaporated to and oil. The mixture was purified using flash
chromatography (Si02 250g eluting with 1:1
hexane/dichloromethane and then neat dichloromethane). Pure
product fractions were combined and evaporated, finishing
with a high vacuum pump to remove all traces of solvent, to
give a white solid, 19g 77%. Nmr.
Boc-R-4-(carboxymethyl)phenylglycine methyl ester.
Boc-R-4-trifluoromethanesulphonyloxyphenylglycine methyl
ester (15g), methanol (32.6m1), bis-1,3-
diphenylphosphinylpropane (448mg), palladium (II) acetate
(255mg), triethylamine (10.2m1) and dimethylformamide (72m1)
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were placed in the glass liner of the Parr reactor and the
reactor assembled. The vessel was pressurised to ~l0psi with
nitrogen and the gas released (repeated five times to remove
all oxygen from the system). Carbon monoxide gas was then
carefully introduced (use extreme care -the gas cylinder is
pressurised to far beyond the bursting disc pressure of the
Parr, ideally use a pressure regulator to reduce the
pressure to -100psi) to ~20psi and released three times
(into the back of a fume hood). Carbon monoxide was then
added to ~100psi and the stirrer started. The vessel was
slowly heated to 65°C internal temperature and then stirred
at 65°C overnight. (At the early stages more carbon monoxide
was added to maintain ~100psi) A sample was removed after
18h and examined by tlc. When complete, the reaction was
cooled to ~30°C, the gas released and the vessel flushed
five times with nitrogen as before. The reaction mixture was
partitioned between ethyl acetate and water and the organic
layer washed with 1M hydrochloric acid and then saturated
sodium bicarbonate. The solution was dried with MgS04 and
evaporated. Flash chromatography of the resulting oil gave
the product, pure by tlc, 10.68 90%. Nmr
Boc-R-4-(carboxymethyl)phenylglycine.
To a solution of Boc-R-4-carboxymethylphenylglycine methyl
ester 692mg in THF lOml was added a solution of lithium
hydroxide hydrate 90mg in water 7m1. The mixture immediately
became cloudy and over l5min cleared. After 30min, tlc
showed the reaction to be complete. Ethyl acetate 20m1 and
water 20m1 were added and the aqueous layer separated. The
aqueous solution was acidified with 2M hydrochloric acid and
extracted with ethyl acetate (3 x 20m1). The organic
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solution was then washed with water x 2 and brine x 2, dried
with MgS04 and evaporated to give the mono-ester (650mg,
98%), pure by tlc. Nmr.
Boc-R-4-(carboxybenzyl)phenylglycine methyl ester
By the same method as described above, using 27.68 of Boc-R-
4-trifluoromethanesulphonyloxyphenylglycine methyl ester and
benzyl alcohol to give the Boc-D-4-
(carboxybenzyl)phenylglycine methyl ester 18.78 pure, 70%
plus a further 6g of impure material ( the major contaminant
is benzyl alcohol). Nmr
Boc-R-4-(carboxamido)phenylglycine methyl ester
Boc-R-4-(carboxy)phenylglycine methyl ester
Boc-R-4-(carboxybenzyl)phenylglycine methyl ester (500m9)
was dissolved in THF containing Pd/C 10% (100mg) and
hydrogenated at latm for 2h. Removal of the catalyst by
filtration and evaporation of solvent gave Boc-R-4-
(carboxy)phenylglycine methyl ester (330mg, 87%).
Nmr.
Boc-R-4-(carboxamido)phenylglycine methyl ester
To a solution of Boc-R-4-(carboxy)phenylglycine methyl ester
(3.5g) in DMF 30m1 was added EDCI (2.60g 1.36mmo1) and HOBt
(1.4g 10.4mmol) and the mixture stirred for lOmin before
cooling in a ice bath and bubbling in ammonia gas for 5min.
The mixture was stirred for 2h at room temperature ansd then
diluted with ehtyl acetate and washed with water. The
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aqueous solution was extracted with a little ethyl acetate
and the combined organics washed with brine. The organic
solution was evaporated to an oil which was purified by
flash chromatography (Si02 - dichloromethane/ ethyl acetate
0 - 25%) to give Boc-R-4-(carboxamido)phenylglycine methyl
ester (1.7g 48%). Nmr.
Boc-R-4-(methylcarboxamido)phenylglycine methyl ester
Was prepared by a similar method to that descibed above.
Nmr
Boc-R-4-Methoxyphenylglycine.
Boc-R-4-hydroxyphenylglycine methyl ester was converted to
Boc-R-4-methoxyphenylglycine using the alkylation method
described by Basak et al.(Tetrahedron Lett. 1998, 39 (27),
4883-4886) followed by hydrolysis of the methyl ester with
lithium hydroxide in aqueous THF. Nmr
Boc-D,L-2-chlorophenylglycine
2-Chlorobenzaldehyde (20mmo1., 2.252m1) and 2,4
dimethoxybenzylamine (20mmo1., 3.004m1) were added together
and stirred for 2 hours. DCM (5m1) was added and any water
separated and removed. tert-Butyl isonitrile (20mmo1.,
2.262m1) was added and stirred for l0mins followed by acetic
acid (20mmo1., 1.145m1). Stirring was continued for 3 days.
The reaction mixture was then treated with TFA (30m1) and
triethylsilane (5m1). After 3 hours the mixture was
evaporated to dryness, 6M HC1 (100m1) added and the whole
refluxed overnight at 130°C, stirring rapidly. The mixture
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was allowed to cool and extracted with EtOAc (50m1 x2) the
aqueous fraction was evaporated to dryness and treated with
2M NaOH solution. The mixture was extracted with EtOAc (50m1
x2) excess boc anhydride (5.28) in dioxan (20m1) was added
to the aqueous fraction and stirred overnight. The mixture
was extracted with diethyl ether (100m1 x2) acidified to pH
1 (cHCl) and extracted with EtOAc (50m1 x2). The combined
organic fractions were washed with water and evaporated to
dryness under high vacuo The product Boc -2-chloro
phenylglycine (4.2528, 74.50)
1H nmr (CD3CN/D20) 7.3 (4H, m) ; 5.5 (1H, s) ; 1.3 (9H, s) . MS
286 (M+1)
By a similar method the following amino acids were obtained
Boc-D,L-3-fluorophenylglycine
1H nmr (CD3CN/D20) 7.3 (1H, m), 7.1(3H, m); 5.2 (1H, s); 1.3
(9H, s). MS 270 (M+1)
Boc-D,L-4-fluorophenylglycine
1H nmr (CD3CN/D20) 7.3 (2H, m); 6.9 (2H, m), 5.0 (1H, s);
1.3 (9H, s). MS 270 (M+1)
Boc-D,L-2-methylphenylglycine
1H nmr (CD3CN/D20) 7.3 (4H, m); 5.5 (1H, s); 2.5 (3H, s);
1.3 (9H, s) . MS 266 (M+1)
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Boc-D,L-3-thienylglycine
1H nmr (CD3CN/D20) 7.5 (2H, m); 7.1 (1H, d); 5.3 (1H, s);
1.3 (9H, s). MS 258 (M+1)
Boc-D,L-2-fluorophenylglycine
Was obtained by treating D,L-2-fluorophenylglycine (Aldrich)
with Boc anhydride (l.leq) and 2M NaOH (leq) in Ethanol.
Aqueous work up as described above yielded the protected
amino acid.
Nmr.
These protected aminoacids were then coupled with first an
amine and then, after removal of the Boc protecting group,
with a carboxylic acid by method 2 to give the following
inhibitor examples:
Example 160.
1-(4 Methoxybenzoyl-D,L-3-thienylglycinyl) 4-(2-
methylsulfonylphenyl)-piperazine
Hplc (Luna C18, Gradient3, water/acetonitrile/TFA) rt 10.18
LCMS M+1 514. Nmr.
Example 161.
1-(Indol-6-carbonyl-D,L-3-thienylglycinyl) 4-(2-
methylsulfonylphenyl)-piperazine
Hplc (Luna C18, Gradient3, water/acetonitrile/TFA) rt 10.44
LCMS M+1 523. Nmr.
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Example 162.
1-(4 Methoxybenzoyl-D,L-3-fluorophenylglycinyl) 4-(2-
methylsulfonylphenyl)-piperazine
Hplc (Luna C18, Gradient3, water/acetonitrile/TFA) rt 10.61
LCMS M+1 526. Nmr.
Example 163.
1-(Indol-6-carbonyl-D,L-3-fluorophenylglycinyl) 4-(2-
methylsulfonylphenyl)-piperazine
Hplc (tuna C18, Gradient3, water/acetonitrile/TFA) rt 10.88
LCMS M+1 535. Nmr.
Example 164.
1-(4 Methoxybenzoyl-D,L-4-fluorophenylglycinyl) 4-(2-
methylsulfonylphenyl)-piperazine
Hplc (Lung C18, Gradient3, water/acetonitrile/TFA) rt 10.52
LCMS M+1 526. Nmr.
Example 165.
1-(Indol-6-carbonyl-D,L-4-fluorophenylglycinyl) 4-(2-
methylsulfonylphenyl)-piperazine
Hplc (tuna C18, Gradient3, water/acetonitrile/TFA) rt 10.92
LCMS M+1 535. Nmr.
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Example 166.
1-(4 Methoxybenzoyl-D,L-2-chlorophenylglycinyl) 4-(2-
methylsulfonylphenyl)-piperazine
Hplc (tuna C18, Gradient3, water/acetonitrile/TFA) rt 10.82
LCMS M+1 542 Nmr.
Example 167.
1-(Indol-6-carbonyl-D,L-2-chlorophenylglycinyl) 4-(2-
methylsulfonylphenyl)-piperazine
Hplc (tuna C18, Gradient3, water/acetonitrile/TFA) rt 10.63
LCMS M+1 551 Nmr.
Example 168.
1-(4 Methoxybenzoyl-D,L-2-methylphenylglycinyl) 4-(2-
methylsulfonylphenyl)-piperazine
Hplc (tuna C18, Gradient3, water/acetonitrile/TFA) rt 10.69
LCMS M+1 522 Nmr.
Example 169.
1-(Indol-6-carbonyl-D,L-2-methylphenylglycinyl) 4-(2-
methylsulfonylphenyl)-piperazine
Hplc (Luna C18, Gradient3, water/acetonitrile/TFA) rt 10.76
LCMS M+1 531 Nmr.
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Example 170.
1-(Indol-6-carbonyl-D-2-fluorophenylglycinyl) 4-(4-fluoro -
2-methylsulfonylphenyl)-piperazine
Hplc (Luna 2 C18 3u water/acetonitrile/TFA, gradient = 5-
100%MeCN over 7 min)rt 10.92
LCMS M+1 553 Nmr.
Example 171.
1-(Indol-6-carbonyl-D-(4-carboxyphenylglycinyl)-(4-(1-
methylpiperidin-4-yl)piperazine)
By coupling of Boc-D-4-carboxymethylphenylglycine with 1-(4-
(1-methylpiperidin-4-yl)piperazine) using HOAt and EDCI,
followed by deprotection (TFA), coupling to indol-6-
carboxylic acid using HOAt and EDCI followed by hydrolysis
of the methyl ester with lithium hydroxide.
Hplc (Luna C18, Gradient3, water/acetonitrile/TFA), rt,
6.05min
LCMS M+1 504
Nmr.
Example 172.
1-(Indol-6-carbonyl-D-phenylglycinyl)-4-(4-
hydroxyphenyl)piperazine
By coupling of Boc-D-phenylglycine with 1-(4-
hydroxyphenyl)piperazine using HOAt and EDCI, followed by
deprotection (TFA) and coupling to indol-6-carboxylic acid
using HOAt and EDCI. -
Hplc (Symmetry C8, Gradient3, water/acetonitrile/TFA), rt,
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6.Omin
LCMS M+1 455
Nmr.
Example 173.
1-(3-Chloroindol-6-carbonyl-D-phenylglycinyl)-4-(4-
hydroxyphenyl)piperazine
By coupling of Boc-D-phenylglycine with 1-(4-
hydroxyphenyl)piperazine using HOAt and EDCI, followed by
deprotection (TFA) and coupling to 3-chloroindol-6-
carboxylic acid using HOAt and EDCI.
Hplc (Symmetry C8, Gradient3, water/acetonitrile/TFA), rt,
6.55min
LCMS M+1 489
Nmr.
Example 174.
1-(4-methoxybenzoyl-D-4-methoxyphenylglycinyl)-4-(2-
methylsulphonylphenyl)piperazine
By coupling of Boc-D-4-methoxyphenylglycine with-(2-
methylsulphonylphenyl)piperazine using HOAt and EDCI,
followed by deprotection (TFA) and coupling to 4-
methoxybenzoic acid using HOAt and EDCI.
Hplc (tuna C18, Gradient3, water/acetonitrile/TFA), rt,
10.4min
LCMS M+1 538
Nmr.
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Example 175.
1-(5-Fluoroindole-6-carbonyl-D-phenylglycinyl)-1-methyl-
4,4~-bispiperidine.
N-(2,2-Dimethoxyethyl)-4-fluoro-3-methoxyaniline
To a solution of 4-fluoro-3-methoxyaniline (0.98g 6.9mmo1)
in ethanol (20m1) was added glyoxal 1,1-dimethyl acetal
(0.898 8.27mmol). Pd/C 5% (50mg) was added and the mixture
hydrogenated. Removal of the catalyst by filtration and
evaporation of solvent in vacuo gave N-(2,2-dimethoxyethyl)-
4-fluoro-3-methoxyaniline 1.6g
NMR LCMS M+1 (less Me0) 199
N-(2,2-Dimethoxyethyl)-N-methanesulphonyl-4-fluoro-3-
methoxyaniline
N-(2,2-dimethoxyethyl)-4-fluoro-3-methoxyaniline (1.468,
6.37mmol) in dichloromethane (20m1) was treated with
pyridine (0.5g 6.37mmo1) and methanesulphonyl chloride
(766mg, 6.69mmo1)and the mixture stirred until the reaction
was complete by tlc. Aqueous work up and removal of solvent
in vacuo gave N-(2,2-dimethoxyethyl)-N-methanesulphonyl-4-
fluoro-3-methoxyaniline 1.918
NMR
5-Fluoro-1-methanesulphonyl-6-methoxyindole
To a solution of N-(2,2-dimethoxyethyl)-N-methanesulphonyl-
4-fluoro-3-methoxyaniline (1.91g, 0.65mmo1) in dry toluene
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at 0°C under argon, was added slowly a solution of TiCl4
(0.173g, 0.911mmo1) in dry toluene (10m1). The solution was
then heated to 70°C for 1h. cooled and poured onto ice/sat.
sod. bicarbonate solution (20m1). The organic layer was
separated, washed with sat. sod. bicarbonate solution, 0.5%
hydrochloric acid (2 x 20m1) and water (2 x20m1). The
solution was dried (MgS04) and evaporated in vacuo to give
5-fluoro-1-methanesulphonyl-6-methoxyindole ((0.102g)
NMR
5-Fluoro-6-hydroxy-1-methanesulphonylindole
To a solution of 5-fluoro-1-methanesulphonyl-6-methoxyindole
(O.lOg 0.41mmo1) in dry dichloromethane (3m1) at -10°C was
added a solution of BBr3 (1M in dichloromethane, 1.23m1)
over one minute. The reacture was warmed to room temperature
and stirred for 2h and then poured onto ice/1M hydrochloric
acid (lOml). After stirring for l5min the mixture was
extracted with ethyl acetate (1 x 50m1, 2x 20m1), dried
(MgS04) and evaporated in vacuo to give 5-fluoro-6-hydroxy-
1-methanesulphonylindole (70mg)
NMR
5-Fluoro-1-methanesulphonyl-6-trifluoromethanesulphonyloxy-
indole
To a solution of 5-fluoro-6-hydroxy-1-methanesulphonylindole
(0.57mg, 2.49mmo1) in dry dichloromethane (20m1) at 0°C was
added pyridine (0.24m1, 2.99mmo1) and then
trifluoromethanesulphonic anhydride (0.50m1, 2.99mmo1) and
the mixture stirred for 2h. The reaction mixture was washed
with 0.5% hydrochloric acid (2 x50m1), sodium bicarbonate
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solution (2 x 50m1) and water (50m1), dried (MgS04) and
filtered through a short pad of silica. Evaporation of
solvent in varuo gave 5-fluoro-1-methanesulphonyl-6-
trifluoromethanesulphonyloxy-indole, (0.67g).
NMR
Methyl 5-fluoro-1-methanesulphonyl-indol-6-carboxylate,
To a solution of 5-fluoro-1-methanesulphonyl-6-
trifluoromethanesulphonyloxy-indole, (0.708 1.94mmo1) was
added, Pd (II) acetate (l4mg), bis 1,3-
diphenylphosphinylpropane (24mg), dimethylformamide (4m1)
and methanol (2m1) and triethylamine (0.54m1) and the
mixture stirred for 2 min. Carbon monoxide gas was bubbled
in for l5min and then the mixture was heated to 75°C under
an atmosphere of carbon monoxide and stirred overnight.
After cooling to room temperature the mixture was poured
into ethyl acetate (80m1) and washed with 1M hydrochloric
acid (50m1), sat. sod. bicarbonate (50m1) and water (50m1).
Drying (MgS04), evaporation of solvent gave crude product
(0.53g).Purification of a portion (225mg)by flash
chromatography (Si02 25% ethyl acetate in hexane) gave
methyl 5-fluoro-1-methanesulphonyl-indol-6-carboxylate,
(173mg)
NMR
5-fluoro-1-methanesulphonyl-indol-6-carboxylic acid
To a solution of methyl 5-fluoro-1-methanesulphonyl-indol-6-
carboxylate (173mg) in THF (15m1) and water (2m1) was added
2M lithium hydroxide solution (3 equiv) and the mixture
heated to 50°C for 2h. and then allowed to cool overnight.
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The solution was concentrated in vacuo, diluted with 2M
sodium hydroxide solution (lOml) and washed with ethyl
acetate. The aqueous solution was acidified to pH3 with
conc. hydrochloric acid and extracted with ethyl acetate (3
x 30m1). The organic solution was evaporated in vacuo to
give 5-fluoro-1-methanesulphonyl-indol-6-carboxylic acid
(164mg) - (circa 80% pure)
NMR
1-(5-fluoro-1-methanesulphonyl-indol-6-carbonyl-D-
phenylglycinyl-4,4'-(1'-methylbispiperidine)
5-fluoro-1-methanesulphonyl-indol-6-carboxylic acid (164mg)
was coupled to D-phenylglycinyl-4,4'-(1'-
methylbispiperidine) using EDCI/HOAt as previously described
to give 1-(5-fluoro-1-methanesulphonyl-indol-6-carbonyl-D-
phenylglycinyl-4,4'-(1'-methylbispiperidine) (111mg) - (~70%
pure)
NMR
1-(5-fluoroindol-6-carbonyl-D-phenylglycinyl-4,4'-(1'-
methylbispiperidine)
1-(5-fluoro-1-methanesulphonyl-indol-6-carbonyl-D-
phenylglycinyl-4,4'-(1'-methylbispiperidine) (111mg-~70%
pure) was refluxed in ethanol (5m1) and sodium hydroxide
solution (34mg in 0.34m1) for 2.25h. The mixture was
evaporated to dryness, taken up in water (lOml) and
extracted with chloroform (60m1). The organic solution was
dried (MgS04) and evaporated in vacuo and the residue
purified by Prep Hplc. To give 1-(5-fluoroindol-6-carbonyl-
D-phenylglycinyl-4,4'-(1'-methylbispiperidine) (l9mg)
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Hplc (Luna C18 Gradient 3) rt 11.37min
LCMS M+1 477
NMR
Example 176.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(2-
pyridoxy)piperidinamide
1-t-Butoxycarbonyl-4-(2-pyridoxy)piperidine
1-t-Butoxycarbonyl-4-piperidinol (5.0g 24.88mmo1) in dry
dimethylformamide (60m1) was treated with sodium hydride
(60% 2.99g 74.75mmol) at room temperature under argon and
then with 2-chloropyridine hydrochloride (4.1g 27.33mmo1).
Then mixture was heated at 80°C overnight. After cooling the
reaction was carefully quenched with water (5m1) and then
diluted with more water (20m1) and extracted with ethyl
acetate (30m1). The organic solution was washed with sat.
sodium bicarbonate, dried (MgS04) and evaporated to give 1-
t-butoxycarbonyl-4-(2-pyridoxy)piperidine (4.96g 72%)
4-(2-pyridoxy)piperidine dihydrochloride.
1-t-Butoxycarbonyl-4-(2-pyridoxy)piperidine (6.5g) was
treated with a solution of hydrogen chloride in ethyl
acetate (110m1) for 7h and the mixture evaporated to give 4-
(2-pyridoxy)piperidine dihydrochloride, (7.4g 90%)
1-(Benzyoxycarbonyl-D-phenylglycinyl)-4-(2-
pyridoxy)piperidinamide
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Benzyloxycarbonyl-D-phenylglycine (3.75g 13.14mmol) was
coupled to 4-(2-pyridoxy)piperidine dihydrochloride (3.0g
11.94mmo1) using EDCI (2.52g 13.14g), HOAt (1.798 13.13mmo1)
and triethylamine (3.63g 35.87mmol) to give, after work up
with ethyl acetate and sodium bicarbonate solution, 1-
(benzyoxycarbonyl-D-phenylglycinyl)-4-(2-
pyridoxy)piperidinamide, (4.9g 92%)
1-D-phenylglycinyl-4-(2-pyridoxy)piperidinamide
1-(Benzyoxycarbonyl-D-phenylglycinyl)-4-(2-
pyridoxy)piperidinamide (400mg) was hydrogenated in ethanol
with 5o Pd/C overnight. Removal of catalyst and evaporation
of solvent gave 1-D-phenylglycinyl-4-(2-
pyridoxy)piperidinamide (162mg 580)
Using a similar method and the appropriate starting
materials the following intermediates were also prepared:
1-(D-phenylglycinyl-4-(4-pyridoxy)piperidinamide
1-(D-phenylglycinyl)-3-R,S-(4-pyridoxy)pyrrolidinamide
1-(D-phenylglycinyl)-3-R,S-(2-pyridoxy)pyrrolidinamide
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(2-
pyridoxy)piperidinamide
1-D-phenylglycinyl-4-(2-pyridoxy)piperidinamide (162mg
0.52mmol) was treated with triethylamine (58mg 0.573mmo1)
and p-anisoyl chloride (93mg 0.545mmo1) in dry
dichloromethane for 1h. The reaction mixture was washed
with sodium bicarbonate solution and brine, dried (MgS04)
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and evaporated to an oil. Flash chromatography gave the
product 1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(2-
pyridoxy)piperidinamide, (60mg 26%)
Hplc (Luna C18, Gradient3, water/acetonitrile/TFA), rt,
8.94min
LCMS M+Na 468
Nmr
By a similar method the following compounds were prepared:
Example 177.
1-(Indol-6-carbonyl-D-phenylglycinyl)-4-(2-
pyridoxy)piperidinamide
By the coupling of indol-6-carboxylic acid and 1-D-
phenylglycinyl-4-(2-pyridoxy)piperidinamide using EDCI and
HOAt.
LCMS M+1 455
Nmr
Example 178.
1-(3-Chloroindol-6-carbonyl-D-phenylglycinyl)-4-(2-
pyridoxy)piperidinamide
By the coupling of 3-chloroindol-6-carboxylic acid and 1-D-
phenylglycinyl-4-(2-pyridoxy)piperidinamide using EDCI and
HOAt.
Hplc (tuna C18, Gradient3, water/acetonitrile/TFA), rt,
10.29min
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LCMS M+1 489
Nmr
Example 179.
1-(3-Chloroindol-6-carbonyl-D-phenylglycinyl)-4-(4-
pyridoxy)piperidinamide
By the coupling of 3-chloroindol-6-carboxylic acid and 1-D-
phenylglycinyl-4-(4-pyridoxy)piperidinamide using EDCI and
HOAt.
Hplc (Luna C18, Gradient3, water/acetonitrile/TFA), rt,
8.16min
LCMS M+1 489
Nmr
Example 180.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(4-
pyridoxy)piperidinamide
By the coupling of p-anisoyl chloride and 1-D-phenyl-
glycinyl-4-(4-pyridoxy)piperidinamide in dichloromethane
with triethylamine
Hplc (tuna C18, Gradient3, water/acetonitrile/TFA), rt,
7.Omin
LCMS M+1 446
Nmr
Example 181.
1-(Indol-6-carbonyl-D-phenylglycinyl)-4-(4-
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pyridoxy)piperidinamide
By the coupling of indol-6-carboxylic acid and 1-D-
phenylglycinyl-4-(4-pyridoxy)piperidinamide with EDCI and
HOAt.
Hplc (Luna C18, Gradient3, water/acetonitrile/TFA), rt,
7.08min
LCMS M+1 455
Nmr
Example 182.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-3-R,S-(4-
pyridoxy)pyrrolidinamide
By the coupling of p-anisoyl chloride and 1-(D-
phenylglycinyl)-3-R,S-(4-pyridoxy)pyrrolidinamide in
dichloromethane with triethylamine
LCMS M+1 432
Nmr
Example 183.
1-(Indol-6-carbonyl-D-phenylglycinyl)-3-R,S-(4-
pyridoxy)pyrrolidinamide
By the coupling indol-6-carboxylic acid and 1-(D-
phenylglycinyl)-3-R,S'-(4-pyridoxy)pyrrolidinamide with EDCI
and HOAt
LCMS M+1 441
Nmr
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Example 184.
1-(3-Chloroindol-6-carbonyl-D-phenylglycinyl)-3-R,S-(4-
pyridoxy)pyrrolidinamide
By the coupling 3-chloroindol-6-carboxylic acid and 1-(D
phenylglycinyl)-3-R,S-(4-pyridoxy)pyrrolidinamide with EDCI
and HOAt
LCMS M+1 475
Nmr
Example 185.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-3-R,S-(2-
pyridoxy)pyrrolidinamide
By the coupling of p-anisoyl chloride and 1-(D-phenyl-
glycinyl)-3-R,S-(2-pyridoxy)pyrrolidinamide in
dichloromethane with triethylamine
LCMS M+1 432
Nmr
Example 186.
1-(3-Chloroindol-6-carbonyl-D-phenylglycinyl)-3-R,S-(2-
pyridoxy)pyrrolidinamide
By the coupling 3-chloroindol-6-carboxylic acid and 1-(D-
phenylglycinyl)-3-R,S-(2-pyridoxy)pyrrolidinamide with EDCI
and HOAt
LCMS M+1 475
Nmr
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Example 187.
1-(Indol-6-carbonyl-D-phenylglycinyl)-3-R,S-(2-
pyridoxy)pyrrolidinamide
By the coupling indol-6-carboxylic acid and 1-(D-phenyl-
glycinyl)-3-R,S-(2-pyridoxy)pyrrolidinamide with EDCI and
HOAt
LCMS M+1 441
Nmr
Example 188.
1-(4-methoxybenzoyl-D-4-hydroxyphenylglycinyl)-4-(2-
methylsulphonylphenyl)piperazine
By coupling of Boc-D-4-hydroxyphenylglycine with-(2-
methylsulphonylphenyl)piperazine using HOAt and EDCI,
followed by deprotection (TFA) and coupling to 4-
methoxybenzoic acid using HOAt and EDCI.
Hplc (Luna C18, Gradient3, water/acetonitrile/TFA), rt,
9.lmin
LCMS M+1 524
Nmr.
Example 189.
1-(Indol-6-carbonyl-D-4-hydroxyphenylglycinyl)-4-(2-
methylsulphonylphenyl)piperazine
By coupling of Boc-D-4-hydroxyphenylglycine with-(2-
methylsulphonylphenyl)piperazine using HOAt and EDCI,
followed by deprotection (TFA) and coupling to 6-indole
carboxylic acid using HOAt and EDCI.
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Hplc (tuna C18, Gradient3, water/acetonitrile/TFA), rt,
9.Omin
LCMS M+1 533
Nmr.
Example 190.
1-(Indol-6-carbonyl-D-4-hydroxyphenylglycinyl)- 1'-methyl-
4,4'-bispiperidine
By coupling of Boc-D-4-hydroxyphenylglycine with 4,4'-(1'-
methylbispiperidine) di-HC1 salt using HOAt and EDCI,
followed by deprotection (TFA) and coupling to 6-indole
carboxylic acid using HOAt and EDCI.
Hplc (Luna C18, Gradient3, water/acetonitrile/TFA), rt,
6.8min
LCMS M+1 475
Nmr.
Example 191.
1-(3-Chloroindol-6-carbonyl-D-4-hydroxyphenylglycinyl)- 1'-
methyl-4,4'-bispiperidine
By coupling of Boc-D-4-hydroxyphenylglycine with 4,4'-(1'-
methylbispiperidine) di-HC1 salt using HOAt and EDCI,
followed by deprotection (TFA) and coupling to 3-
chloroindole-6-carboxylic acid using HOAt and EDCI.
Hplc (tuna C18, Gradient3, water/acetonitrile/TFA), rt,
7.3min
LCMS M+1 509
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Nmr.
In the following examples the following additional
abbreviations and meanings are included: CI-MS, chemical
ionization mass spectrum; DMSO, dimethyl sulfoxide
(perdeuterated if for NMR); EtOAc, ethyl acetate; EtOH,
ethanol; IS-MS, ion spray mass spectrum; RPHPLC, reverse
phase HPLC; SCX, strong ration exchange resin; THF,
tetrahydrofuran; TLC, thin layer chromatography with Rf as
relative mobility;
Reagents were obtained from a variety of commercial sources.
IR means an infrared spectrum was obtained. 1NMR, 1H-NMR, or
1H NMR means a proton magnetic resonance spectrum was
obtained.
In general in this specification, "D-" or "R-" in the name
of a product indicates the product was made beginning with a
chiral starting material, for example D-phenylglycine;
however, racemization may have occurred, and the
enantiomeric purity may not have been determined.
Examples 201-210
Preparation of Starting Materials
4-((Benzyloxycarbonyl-D-phenylglycinyl)aminomethyl]-1-Boc-
piperidine
Using Coupling Method C, benzyloxycarbonyl-D-phenylglycine
(10.4 g, 36.5 mmol) and 4-aminomethyl-1-Boc-piperidine (7.3
g, 36.5 mmol) afforded, after purification by column
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chromatography (Si02: 4:1 to 3:2 hexanes:EtOAc), 10.2 g
(58%)of the title compound.
1NMR
IS-MS, m/e 482 (M+1).
4-[(D-Phenylglycinyl)aminomethyl]-1-Boc-piperidine
(Deprotection Method C) A solution of 4-[(benzyloxycarbonyl-
D-phenylglycinyl)aminomethyl]-1-Boc-piperidine (9.00 g, 18.7
mmol) and 10% palladium on carbon (2.34 g) in EtOAc (80
mL):EtOH (200 mL) was placed under an atmosphere of hydrogen
gas (balloon). After 16 h, the mixture was filtered and
concentrated affording 6.31 g (98%) of the title compound,
which was used without further purification.
1NMR
15' IS-MS, m/e 348 (M+1).
4-[(4-Methoxybenzoyl-D-phenylglycinyl)aminomethyl]-1-Boc-
piperidine
(Acylation Method C) A solution of 4-[(D-phenylglycinyl)-
aminomethyl]-1-Boc-piperidine (2.38 g, 6.88 mmol) and
pyridine (8 mL)in methylene chloride was treated with
4-methoxybenzoyl chloride (1.76 g, 10.3 mmol) in methylene
chloride (prepared by treatment of 4-methoxy benzoic acid
with excess oxalyl chloride in methylene chloride followed
by concentration). After 2 days, the mixture was
partitioned between water and methylene chloride. The
organic extracts were washed with 1 N HC1, water, 1 N NaOH
and brine, and concentrated. The residue was purified by
column chromatography (Si02: 1:1 to 1:3 hexanes:EtOAc),
affording 2.33 g (71%)of the title compound.
1NMR
IS-MS, m/e 482 (M+1)
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Analysis for C27H35N305:
Calcd: C, 67.3; H, 7.3; N, 8.7;
Found: C, 67.4; H, 7.4; N, 8.7.
4-[(4-Methoxybenzoyl-D-phenylglycinyl)aminomethyl]-
piperidine
Using Deprotection Method D, 4-[(4-methoxybenzoyl-D-
phenylglycinyl)aminomethyl]-1-Boc-piperidine (2.38 g)
afforded 1.56 g (82%) of 4-[(4-methoxybenzoyl-D-phenyl-
glycinyl)aminomethyl]piperidine.
1NMR
IS-MS, m/e 382 (M+1)
General Procedure: Unless otherwise indicated, the product
of Examples 201-210 was prepared from 4-[(4-methoxybenzoyl-
D-phenylglycinyl)aminomethyl]piperidine and the indicated
aldehyde or ketone using Alkylation Method D.
Example 201.
4-[(4-Methoxybenzoyl-D-phenylglycinyl)aminomethyl]-1-
isopropylpiperidine
4-[(4-Methoxybenzoyl-D-phenylglycinyl)aminomethyl]piperidine
(0.10 g, 0.26 mmol) and acetone afforded 89 mg (81%) of the
title compound.
1NMR
IS-MS, m/e 424 (M+1)
Analysis for C25H33N3~3~
Calcd: C, 70.9; H, 7.9; N, 9.9;
Found: C, 70.8; H, 7.8; N, 9.9.
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Example 202.
4-[(4-Methoxybenzoyl-D-phenylglycinyl)aminomethyl]-1-
(3-pentyl)piperidine
4-[(4-Methoxybenzoyl-D-phenylglycinyl)aminomethyl]piperidine
(0.10 g, 0.26 mmol) and 3-pentanone afforded 57 mg (49%) of
the title compound.
1NMR
IS-MS, m/e 452 (M+1)
Example 203.
4-[(4-Methoxybenzoyl-D-phenylglycinyl)aminomethyl]-1-
(2-indanyl)piperidine
4-[(4-Methoxybenzoyl-D-phenylglycinyl)aminomethyl]piperidine
(0.10 g, 0.26 mmol) and 2-indanone afforded 91 mg (78%) of
the title compound.
1NMR
IS-MS, m/e 498 (M+1)
Analysis for C25H33N3~3~
Calcd: C, 74.8; H, 7.1; N, 8.4;
Found: C, 74.5; H, 7.0; N, 7.9.
Example 204.
4-[(4-Methoxybenzoyl-D-phenylglycinyl)aminomethyl]-1-
cyclopentylpiperidine
4-[(4-Methoxybenzoyl-D-phenylglycinyl)aminomethyl]piperidine
(0.10 g, 0.26 mmol) and cyclopentanone afforded 101 mg (86%)
of the title compound.
1NMR
IS-MS, m/e 450 (M+1)
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Example 205.
4-[(4-Methoxybenzoyl-D-phenylglycinyl)aminomethyl]-1-
(cyclohexylmethyl)piperidine
4-[(4-Methoxybenzoyl-D-phenylglycinyl)aminomethyl]piperidine
(0.10 g, 0.26 mmol) and cyclohexanecarboxaldehyde afforded
98 mg (79%) of the title compound.
1NMR
IS-MS, m/e 478 (M+1)
Example 206.
4-[(4-Methoxybenzoyl-D-phenylglycinyl)aminomethyl]-1-
cyclohexylpiperidine
4-[(4-methoxybenzoyl-D-phenylglycinyl)aminomethyl]piperidine
(0.10 g, 0.26 mmol) and cyclohexanone afforded 95 mg (79~)
of the title compound.
1NMR
IS-MS, m/e 464 (M+1)
Example 207.
4-[(4-Methoxybenzoyl-D-phenylglycinyl)aminomethyl]-1-
(tetrahydropyran-4-yl)piperidine
4-[(4-methoxybenzoyl-D-phenylglycinyl)aminomethyl]piperidine
(0.10 g, 0.26 mmol) and tetrahydro-4H-pyran-4-one afforded
78 mg (65°s) of the title compound.
1NMR
IS-MS, m/e 466 (M+1)
Example 208.
4-[(4-Methoxybenzoyl-D-phenylglycinyl)aminomethyl]-1-
(tetrahydrothiopyran-4-yl)piperidine
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4-[(4-Methoxybenzoyl-D-phenylglycinyl)aminomethyl]piperidine
(0.10 g, 0.26 mmol) and tetrahydro-4H-thiopyran-4-one
afforded 63 mg (50°s) of the title compound.
1NMR
IS-MS, m/e 482 (M+1)
Example 209.
4-[(4-Methoxybenzoyl-D-phenylglycinyl)aminomethyl]-1-methyl-
piperidine
4-[(4-Methoxybenzoyl-D-phenylglycinyl)aminomethyl]piperidine
(60 mg, 0.16 mmol) and paraformaldehyde afforded 59 mg (930)
of the title compound.
1NMR
IS-MS, m/e 396 (M+1)
Example 210.
4-[(4-Methoxybenzoyl-D-phenylglycinyl)aminomethyl]-1-ethyl-
piperidine
4-[(4-Methoxybenzoyl-D-phenylglycinyl)aminomethyl]piperidine
(60 mg, 0.16 mmol) and acetaldehyde afforded 23 mg (35%) of
the title compound.
1NMR
IS-MS, m/e 410 (M+1)
Examples 211-213
Preparation of Starting Materials
4-[(Indole-6-carbonyl-D-phenylglycinyl)aminomethyl]-1-Boc-
piperidine
Using Coupling Method C, 4-[(D-phenylglycinyl)aminomethyl]-
1-Boc-piperidine (2.5 g, 6.8 mmol) and indole-6-carboxylic
acid (1.2 g, 7.6 mmol) afforded, after purification by
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column chromatography (Si02: 2:3 hexanes:EtOAc to EtOAc),
2.57 g (83°s) of the title compound.
1NMR
IS-MS, m/e 491 (M+1)
4-[(Indole-6-carbonyl-D-phenylglycinyl)aminomethyl]-
piperidine
Using Deprotection Method D, 4-[(indole-6-carbonyl-D-
phenylglycinyl)aminomethyl]-1-Boc piperidine (1.6 g, 3.3
mmol) afforded 4-[(indole-6-carbonyl-D-phenylglycinyl)-
aminomethyl]piperidine (1.27 g, 79%).
1NMR
IS-MS, m/e 391 (M+1)
General Procedure: Unless otherwise indicated, the product
of Examples 211-213 was prepared from 4-[(indole-6-carbonyl-
D-phenylglycinyl)aminomethyl]piperidine and the indicated
aldehyde or ketone using Alkylation Method D.
Example 211.
4-[(Indole-6-carbonyl-D-phenylglycinyl)aminomethyl]-1-
isopropylpiperidine
4-[(Indole-6-carbonyl-D-phenylglycinyl)aminomethyl]-
piperidine (0.10 g, 0.26 mmol) and acetone afforded 16 mg
(14%) of the title compound.
1NMR
IS-MS, m/e 433 (M+1)
Example 212.
4-[(Indole-6-carbonyl-D-phenylglycinyl)aminomethyl]-1-
cyclopentylpiperidine
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4-[(Indole-6-carbonyl-D-phenylglycinyl)aminomethyl]-
piperidine (0.10 g, 0.26 mmol) and cyclohexanone afforded
19 mg (16%) of the title compound.
1NMR
IS-MS, m/e 459 (M+1)
Example 213.
4-[(Indole-6-carbonyl-D-phenylglycinyl)aminomethyl]-1-
cyclohexylmethylpiperidine
4-[(Indole-6-carbonyl-D-phenylglycinyl)aminomethyl]-
piperidine (0.10 g, 0.26 mmol) and cyclohexanecarboxaldehyde
afforded 14 mg (11%) of the title compound.
1NMR
IS-MS, m/e 487 (M+1)
Examples 214-217
Preparation of Starting Materials
4-[(Benzyloxycarbonyl-D-phenylglycinyl)]-1-Boc-piperidine
Using Coupling Method C, D-phenylglycine (6.10 g, 21.4 mmol)
and 4-amino-1-Boc-piperidine (4.27 g, 21.4 mmol) afforded,
after purification by column chromatography (Si02: 7:3
hexanes:EtOAc), 8.44 g (84%) of the title compound.
1NMR
IS-MS, m/e 468 (M+1).
Analysis for C26H33N305~
Calcd: C, 66.3; H, 7.1; N, 9.0;
Found: C, 66.5; H, 7.1; N, 9Ø
4-[(D-Phenylglycinyl)amino]-1-Boc-piperidine
Using Deprotection Method C, 4-[(benzyloxycarbonyl-D-
phenylglycinyl)amino]-1-Boc-piperidine (8.0 g, 17 mmol)
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afforded 6.1 g (90%) of the title compound, which was used
without further purification.
1NMR
IS-MS, m/e 334 (M+1).
4-[(4-Methoxybenzoyl-D-phenylglycinyl)amino]-1-Boc-
piperidine
Using Acylation Method C, 4-[(D-phenylglycinyl)amino]-1-Boc
piperidine (2.23 g, 6.7 mmol) afforded, after purification
by column chromatography (Si02: 1:1 hexanes EtOAc), 2.44 g
(78%) of the title compound.
1NMR
IS-MS, m/e 468 (M+1).
4-[(4-Methoxybenzoyl-D-phenylglycinyl)amino]piperidine
Using Deprotection Method D, 4-[(4-methoxybenzoyl-D-
phenylglycinyl)amino]-1-Boc-piperidine (2.32 g) afforded
1.53 g (84%) of 4-[(4-methoxybenzoyl-D-phenylglycinyl)-
amino]piperidine.
1NMR
IS-MS, m/e 368 (M+1).
General Procedure: Unless otherwise indicated, the product
of Examples 214-217 was prepared from 4-[(4-methoxybenzoyl-
D-phenylglycinyl)amino]piperidine and the indicated aldehyde
or ketone using Alkylation Method D.
Example 214.
4-[(4-Methoxybenzoyl-D-phenylglycinyl)aminomethyl]-1-
(3-pentyl)piperidine
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4-[(4-Methoxybenzoyl-D-phenylglycinyl)amino]piperidine
(0.11 g, 0.3 mmol) and 3-pentanone afforded 81 mg (62s) of
the title compound.
1NMR
IS-MS, m/e 438 (M+1).
Example 215.
4-[(4-Methoxybenzoyl-D-phenylglycinyl)amino]-1-(2-indanyl)-
piperidine
4-[(4-Methoxybenzoyl-D-phenylglycinyl)amino]piperidine
(0.11 g, 0.3 mmol) and 2-indanone afforded 121 mg (83°s) of
the title compound.
1NMR
IS-MS, m/e 484 (M+1).
Example 216.
4-[(4-Methoxybenzoyl-D-phenylglycinyl)amino]-1-cyclopentyl-
piperidine
4-[(4-Methoxybenzoyl-D-phenylglycinyl)amino]piperidine
(0.11 g, 0.3 mmol) and cyclopentanone afforded 103 mg (79%)
of the title compound.
1NMR
IS-MS, m/e 436 (M+1).
Example 217.
4-[(4-Methoxybenzoyl-D-phenylglycinyl)amino]-1-cyclohexyl-
piperidine
4-[(4-Methoxybenzoyl-D-phenylglycinyl)amino]piperidine
(0.11 g, 0.3 mmol) and 2-cyclohexanone afforded 112 mg (830)
of the title compound.
1NMR
IS-MS, m/e 450 (M+1).
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Examples 218-220
Preparation of Starting Materials
4-[(Indole-6-carbonyl-D-phenylglycinyl)amino]-1-Boc-
piperidine
Using Acylation Method C, 4-[(D-phenylglycinyl)amino]-1-
Boc-piperidine (2.24 g, 6.15 mmol) and indole-6-
carboxylic acid afforded 4-[(indole-6-carbonyl-D-phenyl-
glycinyl) amino] -1-Boc-piperidine (2 . 66 g, 82%) .
1NMR
IS-MS, m/e 477 (M+1).
4-[(Indole-6-carbonyl-D-phenylglycinyl)amino]piperidine
Using Deprotection Method C, 4-[(indole-6-carbonyl-D-
phenylglycinyl)amino]-1-Boc-piperidine (1.2 g, 2.5 mmol)
afforded 4-[(indole-6-carbonyl-D-phenylglycinyl)amino]-
piperidine (0.81 g, 83%).
1NMR
IS-MS, m/e 377 (M+1).
General Procedure: Unless otherwise indicated, the product
of Examples 218-220 was prepared from 4-[(indole-6-carbonyl-
D-phenylglycinyl)amino]piperidine and the indicated aldehyde
or ketone using Alkylation Method D.
Example 218.
4-[(Indole-6-carbonyl-D-phenylglycinyl)amino]-1-isopropyl-
piperidine
4-[(Indole-6-carbonyl-D-phenylglycinyl)amino]piperidine
(0.10 g, 0.27 mmol) and acetone afforded 21 mg (19%) of
the title compound.
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1NMR
IS-MS, m/e 419 (M+1).
Example 219.
4-[(Indole-6-carbonyl-D-phenylglycinyl)amino]-1-cyclo-
pentylpiperidine
4-[(Indole-6-carbonyl-D-phenylglycinyl)amino]piperidine
(0.10 g, 0.27 mmol) and cyclopentanone afforded 28 mg
(24%) of the title compound.
1NMR
IS-MS, m/e 445 (M+1).
Example 220.
4-[(Indole-6-carbonyl-D-phenylglycinyl)amino]-1-(cyclo-
hexylmethyl)piperidine
4-[(Indole-6-carbonyl-D-phenylglycinyl)amino]piperidine
(0.10 g, 0.27 mmol) and cyclohexanecarboxaldehyde
afforded 17 mg (14%) of the title compound.
1NMR
IS-MS, m/e 473 (M+1).
Examples 221-246
Preparation of Starting Materials
1-Methyl-4,4'-bispiperidine hydrobromide dihydrobromide
A solution of 4,4'-bipyridine (34.2 g, 100 mmol) in
acetone was treated with methyl p-toluenesulfonate.
After 3 days, the salt (28 g, 80%) was isolated by
filtration. The salt (44.0 g) was then treated with 10%
Pd/C in acetic acid (400 mL) and hydrogen gas (4.1 bar)
at 60 °C. After 16 h, the mixture was concentrated, the
residue was dissolved in acetone, and then treated with
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hydrogen bromide in acetic acid. The resulting salt (36
g, 860) was isolated by filtration as a dihydrobromide.
1NMR
1-(D-Phenylglycinyl)-1'-methyl-4,4'-bispiperidine
Using Coupling Method A, benzyloxycarbonyl-D-phenylglycine
(16 g, 56 mmol) and 1-methyl-4,4'-bispiperidine
dihydrobromide (17.2 g, 50 mmol) afforded, after treatment
of the crude acylation product with HBr (150 mL) and acetic
acid (150 mL) at 60 °C for 6 h, 8.4 g (54°s)of the title
compound.
1NMR
IS-MS, m/e 316 (M+1)
Analysis for ClgH2gN30:
Calcd: C, 72.3; H, 9.3; N, 13.3;
Found: C, 71.9; H, 9.2; N, 13.1.
General Procedure: Unless otherwise indicated, the product
of Examples 221-246 (or a protected derivative thereof) was
prepared from 1-(D-phenylglycinyl)-1'-methyl-4,4'
bispiperidine and the indicated acid using procedures
similar to Acylation Method C.
Removal of Protecting Group: Where a protecting group was
present in the acylation procedure, the procedure for its
removal is described.
Example 221.
1-(4-Methoxy-3-methylbenzoyl-D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine
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1-(D-Phenylglycinyl)-1'-methyl-4,4'-bispiperidine (200 mg,
0.64 mmol) and 4-methoxy-3-methylbenzoic acid (116 mg, 0.70
mmol) afforded 159 mg (54%) of the title compound.
1NMR
IS-MS, m/e 464 (M+1)
Analysis for C25H33N3~3'0.35 H20:
Calcd: C, 71.6; H, 8.1; N, 8.9;
Found: C, 71.5; H, 7.8; N, 9Ø
Example 222.
1-[5-Methylthiothiophene-2-carbonyl-D-phenylglycinyl]-1'-
methyl-4,4'-bispiperidine
1-(D-Phenylglycinyl)-1'-methyl-4,4'-bispiperidine (200 mg,
0.64 mmol) and 5-methylthiothiophene-2-carboxylic acid (120
mg, 0.70 mmol) afforded 190 mg (63%) of the title compound.
1NMR
IS-MS, m/e 472 (M+1)
Example 223.
1-(3-Chloro-4-methoxybenzoyl-D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine
1-(D-Phenylglycinyl)-1'-methyl-4,4'-bispiperidine (200 mg,
0.64 mmol) and 3-chloro-4-methoxybenzoic acid (130 mg, 0.70
mmol) afforded 182 mg (59%) of the title compound.
1NMR
IS-MS, m/e 484 (M+1)
Example 224.
1-(5-Methoxybenzofuran-2--carbonyl-D-phenylglycinyl)-1'-
methyl-4,4'-bispiperidine
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1-(D-Phenylglycinyl)-1'-methyl-4,4'-bispiperidine (200 mg,
0.64 mmol) and 5-methoxybenzofuran-2-carboxylic acid (135
mg, 0.70 mmol) afforded 298 mg (96%) of the title compound.
1NMR
IS-MS, m/e 490 (M+1)
Analysis for C29H35N3~4~
Calcd: C, 71.1; H, 7.2; N, 8.6;
Found: C, 71.5; H, 7.4; N, 8.8.
Example 225.
1-(5-Acetylthiophene-2-carbonyl-D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine
1-(D-Phenylglycinyl)-1'-methyl-4,4'-bispiperidine (200 mg,
0.64 mmol) and 5-acetylthiophene-2-carboxylic acid (119 mg,
0.70 mmol) afforded 245 mg (83%) of the title compound.
1NMR
IS-MS, m/e 468 (M+1)
Analysis for C26H33N3~3S~
Calcd: C, 66.8; H, 7.1; N, 9.0;
Found: C, 66.5; H, 7.1; N, 9Ø
Example 226.
1-(4-Chloro-3-methylbenzoyl-D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine
1-(D-Phenylglycinyl)-1'-methyl-4,4'-bispiperidine (315 mg,
1.00 mmol) and 4-chloro-3-methylbenzoic acid (171 mg, 1.00
mmol) afforded 240 mg (51%) of the title compound.
1NMR
IS-MS, m/e 468 (M+1)
Analysis for C26H33N3~3S=
Calcd: C, 69.3; H, 7.3; N, 9.0;
Found: C, 68.9; H, 7.2; N, 8.9.
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Example 227.
1-(5-Methylindole-2-carbonyl-D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine
1-(D-Phenylglycinyl)-1'-methyl-4,4'-bispiperidine (315 mg,
1.00 mmol) and 5-methylindole-2-carboxylic acid (263 mg,
1.50 mmol) afforded 240 mg (51%) of the title compound.
1NMR
IS-MS, m/e 473 (M+1).
Example 228.
1-(5-Methoxyindole-2-carbonyl-D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine
1-(D-Phenylglycinyl)-1'-methyl-4,4'-bispiperidine (315 mg,
1.00 mmol) and 5-methoxyindole-2-carboxylic acid (1.50 mmol)
afforded 77 mg (16%) of the title compound.
1NMR
IS-MS, m/e 489 (M+1)
Analysis for C26H33N3~3S~
Calcd: C, 69.3; H, 7.3; N, 9.0;
Found: C, 68.9; H, 7.2; N, 8.9.
Example 229.
1-(Benzothiazole-2-carbonyl-D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine
1-(D-Phenylglycinyl)-1'-methyl-4,4'-bispiperidine (315 mg,
1.00 mmol) and benzothiazole-2-carboxylic acid (200 mg, 1.12
mmol) afforded 180 mg (160) of the title compound.
1NMR
IS-MS, m/e 477 (M-1)
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Example 230.
1-(5-Fluoroindole-2-carbonyl-D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine
1-(D-Phenylglycinyl)-1'-methyl-4,4'-bispiperidine (315 mg,
1.00 mmol) and 5-fluoroindole-2-carboxylic acid (280 mg,
1.50 mmol) afforded 80 mg (17%) of the title compound.
1NMR
IS-MS, m/e 477 (M+1)
Analysis for C28H33FN402~H20:
Calcd: C, 68.0; H, 7.1; N, 11.3;
Found: C, 68.0; H, 6.7; N, 11.1.
Example 231.
1-(Napthalene-2-carbonyl-D-phenylglycinyl)-1'-methyl-4,4'-
bispiperidine
1-(D-Phenylglycinyl)-1'-methyl-4,4'-bispiperidine (315 mg,
1.00 mmol) and napthalene-2-carboxylic acid (220 mg, 1.28
mmol) afforded 160 mg (38°s) of the title compound.
1NMR
IS-MS, m/e 470 (M+1)
Analysis for C3pH35N3~2'0~5 H20:
Calcd: C, 75.3; H, 7.6; N, 8.8;
Found: C, 75.6; H, 7.4; N, 8.9.
Example 232.
1-(6-Methoxyindole-2-carbonyl-D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine
Using Coupling Method C, 1-(D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine (315 mg, 1.00 mmol) and 6-methoxyindole-
2-carboxylic acid (191 mg, 1.00 mmol) afforded 200 mg (41%)
of the title compound.
1NMR
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IS-MS, m/e 489 (M+1)
Analysis for C29H36N403'0-5 H20:
Calcd: C, 70.0; H, 7.5; N, 11.3;
Found: C, 69.3; H, 7.5; N, 11.1.
Example 233.
1-(5-Chloroindole-2-carbonyl-D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine
Using Coupling Method A, 1-(D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine (315 mg, 1.00 mmol) and 5-chloroindole-2-
carboxylic acid (230 mg, 1.15 mmol) afforded 220 mg (45%) of
the title compound.
1NMR
IS-MS, m/e 493 (M+1)
Analysis for C28H33C1N402-0.75 H20:
Calcd: C, 66.4; H, 6.9; N, 11.1;
Found: C, 66.8; H, 6.6; N, 10.9.
Example 234.
1-(3-Hydroxybenzoyl-D-phenylglycinyl)-1'-methyl-4,4'-
bispiperidine
1-(D-Phenylglycinyl)-1'-methyl-4,4'-bispiperidine (200 mg,
0.635 mmol) and 3-benzyloxybenzoic acid (158 mg, 0.698 mmol)
afforded 100 mg (30%) of 1-(3-benzyloxybenzoyl-D-phenyl-
glycinyl)-1'-methyl-4,4'-bispiperidine. A solution of this
material and 10% Pd/C in 3 mL of EtOH was treated with
hydrogen gas (1 atm). After 16 h, the mixture was filtered,
concentrated, and the residue triturated with EtOAc,
affording 27 mg (32%) of the title compound.
1NMR
IS-MS, m/e 436 (M+1).
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Example 235.
1-(3-Hydroxy-4-methylbenzoyl-D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine
1-(D-Phenylglycinyl)-1'-methyl-4,4'-bispiperidine (200 mg,
0.635 mmol) and 3-acetoxy-4-methylbenzoic acid (135 mg,
0.698 mmol) afforded, after treatment of the crude acylation
mixture with methanolic potassium carbonate and purification
by column chromatography (4% to 6% 2 N NH3 in methanol:
methylene chloride), 132 mg (46%) of the title compound.
1NMR
IS-MS, m/e 450 (M+1).
Analysis for C27H35N303~0.5 H20:
Calcd: C, 71.4; H, 7.9; N, 9.3;
Found: C, 71.4; H, 7.9; N, 9.2.
The protected starting acid for the above procedure was
prepared as follows:
3-Acetoxy-4-methylbenzoic acid
A solution of 3-hydroxy-4-methylbenzoic acid (3.0 g, 19.7
mmol) in acetic anhydride (5.6 mL) was treated with sulfuric
acid (0.03 mL), heated to 70 °C, cooled and diluted with
water. The resulting solid was collected by filtration
yielding 1.14 g (30%) of the title compound, which was used
without further purification.
1NMR
Example 236.
1-(2-Hydroxybenzoyl-D-phenylglycinyl)-1'-methyl-4,4'-
bispiperidine
1-(D-Phenylglycinyl)-1'-methyl-4,4'-bispiperidine (200 mg,
0.635 mmol) and 2-acetoxybenzoic acid (125 mg, 0.698 mmol;
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prepared using methods substantially equivalent to those
described for 3-acetoxy-4-methylbenzoic acid) afforded,
after treatment of the crude acylation mixture with
methanolic potassium carbonate and purification by column
chromatography, 100 mg (36%) of the title compound.
1NMR
IS-MS, m/e 436 (M+1).
Example 237.
1-(4-Chloro-3-hydroxybenzoyl-D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine
1-(D-Phenylglycinyl)-1'-methyl-4,4'-bispiperidine (200 mg,
0.635 mmol) and 4-chloro-3-acetoxybenzoic acid (150 mg,
0.698 mmol; prepared using methods substantially equivalent
to those described for 3-acetoxy-4-methylbenzoic acid)
afforded, after treatment of the crude acylation mixture
with methanolic potassium carbonate and purification by
column chromatography, 110 mg (37%) of the title compound.
1NMR
IS-MS, m/e 470 (M+1).
Example 238.
1-(4-Chloro-2-hydroxybenzoyl-D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine
1-(D-Phenylglycinyl)-1'-methyl-4,4'-bispiperidine (200 mg,
0.635 mmol) and 4-chloro-2-acetoxybenzoic acid (150 mg,
0.698 mmol; prepared using methods substantially equivalent
to those described for 3-acetoxy-4-methylbenzoic acid)
afforded, after treatment of the crude acylation mixture
with methanolic potassium carbonate and purification by
radial chromatography, 60 mg (20%) of the title compound.
1NMR
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IS-MS, m/e 470 (M+1).
Example 239.
1-(4-Chloro-3-methoxybenzoyl-D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine
1-(D-Phenylglycinyl)-1'-methyl-4,4'-bispiperidine (200 mg,
0.635 mmol) and 4-chloro-2-methoxybenzoic acid (130 mg,
0.698 mmol) afforded, after purification by column
chromatography, 120 mg (39%) of the title compound.
1NMR
IS-MS, m/e 484 (M+1)
Analysis for C27H34C1N303:
Calcd: C, 67.0; H, 7.1; N, 8.7;
Found: C, 66.8; H, 7.1; N, 8.8.
Example 240.
1-(3-Hydroxy-4-methoxybenzoyl-D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine
1-(D-Phenylglycinyl)-1'-methyl-4,4'-bispiperidine (200 mg,
0.635 mmol) and 3-acetoxy-4-methoxybenzoic acid (146 mg,
0.698 mmol; prepared using methods substantially equivalent
to those described for 3-acetoxy-4-methylbenzoic acid)
afforded, after treatment of the crude acylation mixture
with methanolic potassium carbonate and purification by
column chromatography, 52 mg (180) of the title compound.
1NMR
IS-MS, m/e 466 (M+1).
Example 241.
1-(2,4-Dihydroxybenzoyl-D-phenylglycinyl)-1'-methyl-4,4'-
bispiperidine
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1-(D-Phenylglycinyl)-1'-methyl-4,4'-bispiperidine (200 mg,
0.635 mmol) and 2,4-diacetoxybenzoic acid (167 mg, 0.698
mmol; prepared using methods substantially equivalent to
those described for 3-acetoxy-4-methylbenzoic acid)
afforded, after treatment of the crude acylation mixture
with methanolic potassium carbonate and purification by
column chromatography, 145 mg (50%) of the title compound.
1NMR
IS-MS, m/e 452 (M+1).
Analysis for C26H33N3~4'0~75 H20:
Calcd: C, 67.2; H, 7.5; N, 9.0;
Found: C, 67.3; H, 7.2; N, 9.3.
Example 242.
1-(2-Hydroxy-4-methoxybenzoyl-D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine
1-(D-Phenylglycinyl)-1'-methyl-4,4'-bispiperidine (200 mg,
0.635 mmol) and 2-acetoxy-4-methoxybenzoic acid (146 mg,
0.698 mmol; prepared using methods substantially equivalent
to those described for 3-acetoxy-4-methylbenzoic acid)
afforded, after treatment of the crude acylation mixture
with methanolic potassium carbonate and purification by ion
exchange chromatography (Varian, SCX), 118 mg (40%) of the
title compound.
1NMR
IS-MS, m/e 466 (M+1).
Analysis for C27H35N304~0.50 H20:
Calcd: C, 68.3; H, 7.7; N, 8.9;
Found: C, 68.2; H, 7.4; N, 9.1.
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Example 243.
1-(5-Chloro-2-hydroxybenzoyl-D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine
1-(D-Phenylglycinyl)-1'-methyl-4,4'-bispiperidine (200 mg,
0.635 mmol) and 2-acetoxy-5-chlorobenzoic acid (150 mg,
0.698 mmol; prepared using methods substantially equivalent
to those described for 3-acetoxy-4-methylbenzoic acid)
afforded, after treatment of the crude acylation mixture
with methanolic potassium carbonate and purification by ion
exchange chromatography (Varian, SCX), 100 mg (33%) of the
title compound.
1NMR
IS-MS, m/e 471 (M+1).
Analysis for C26H32C1N303~0.25 H20:
Calcd: C, 65.8; H, 6.9; N, 8.9;
Found: C, 65.9; H, 7.0; N, 9.2.
Example 244.
1-(3-Chloro-4-hydroxybenzoyl-D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine
1-(D-Phenylglycinyl)-1'-methyl-4,4'-bispiperidine (315 mg,
1.00 mmol) and 4-acetoxy-3-chlorobenzoic acid (321 mg, 1.50
mmol; prepared using methods substantially equivalent to
those described for 3-acetoxy-4-methylbenzoic acid)
afforded, after treatment of the acylation mixture with
methanolic potassium carbonate, 50 mg (270) of the title
compound.
1NMR
IS-MS, m/e 470 (M+1).
Analysis for C26H32C1N303~1.0 H20:
Calcd: C, 64.0; H, 7.0; N, 8.6;
Found: C, 63.7; H, 7.0; N, 8.7.
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Example 245.
1-(3-Hydroxynaphthalene-2-carbonyl-D-phenylglycinyl)-1'-
methyl-4,4'-bispiperidine
1-(D-Phenylglycinyl)-1'-methyl-4,4'-bispiperidine (315 mg,
1.00 mmol) and 3-acetoxynaphthalene-2-carboxylic acid
(300 mg, 1.30 mmol; prepared using methods substantially
equivalent to those described for 3-acetoxy-4-methylbenzoic
acid) afforded, after treatment of the acylation product
with methanolic potassium carbonate, 128 mg (38%) of the
title compound.
1NMR
IS-MS, m/e 486 (M+1).
Example 246.
1-(6-Hydroxynaphthalene-2-carbonyl-D-phenylglycinyl)-1'-
methyl-4,4'-bispiperidine
1-(D-Phenylglycinyl)-1'-methyl-4,4'-bispiperidine (315 mg,
1.00 mmol) and 6-acetoxynaphthalene-2-carboxylic acid
(300 mg, 1.30 mmol; prepared using methods substantially
equivalent to those described for 3-acetoxy-4-methylbenzoic
acid) afforded, after treatment of the acylation product
with methanolic potassium carbonate, 210 mg (43%) of the
title compound.
1NMR
IS-MS, m/e 486 (M+1).
Analysis for C3pH35N3~3'1.0 H20:
Calcd: C, 71.6; H, 7.4; N, 8.3;
Found: C, 71.5; H, 7.3; N, 8.3.
Examples 247-251.
Preparation of Starting Materials
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1-(Benzyloxycarbonyl-D-phenylglycinyl)piperidine-4-methanol
Using Coupling Method C, benzyloxycarbonyl-D-phenylglycine
(8.41 g, 29.5 mmol) and 4-piperidinemethanol (3.85 g, 37.4
mmol) afforded 10.2 g (93%) of the title compound.
1NMR
1-(D-Phenylglycinyl)piperidine-4-methanol
Using Deprotection Method C, 1-(benzyloxycarbonyl-D-
phenylglycinyl)piperidine-4-methanol (3.93 g, 29.5 mmol) and
10% palladium on carbon (1.30 g) afforded 2.31 g (88%) of
the title compound.
1NMR
IS-MS, m/e 249 (M+1).
1-(4-Methoxybenzoyl-D-phenylglycinyl)piperidine-4-methanol
Using methods substantially equivalent Acylation Method C
described prior to Example 201, 1-(D-phenylglycinyl)-
piperidine-4-methanol (1.23 g, 4.96 mmol) and p-anisoyl
chloride (0.888 g, 5.21 mmol) afforded, after purification
by column chromatography (Si02: 1:1 to 1:9 hexanes:EtOAc),
1.26 g (66%) of the title compound.
1NMR
IS-MS, m/e 383 (M+1).
1-(4-Methoxybenzoyl-D-phenylglycinyl)piperidine-4-
carboxaldehyde
A solution of 1-(4-methoxybenzoyl-D-phenylglycinyl)-
piperidine-4-methanol (0.800 g, 2.08 mmol) and N-methyl-
morpholine oxide (0.366 g, 3.13 mmol) in methylene chloride
(15 mL) was treated with tetrapropylammonium perruthenate
(TPAP, 2 mg). After 14 h, the mixture was treated with
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additional TPAP (5 mg). After 20 h, the mixture was treated
with additional TPAP (5 mg). After 32 h, the mixture was
loaded directly onto a column and purified by column
chromatography (Si02: 1:1 to 1:4 hexanes:EtOAc) affording
0.286 g (36%) of the title compound.
1NMR
IS-MS, m/e 381 (M+1).
General Procedure: Unless otherwise indicated, the product
of Examples 247-251 was obtained from the indicated amine
and 1-(4-methoxybenzoyl-D-phenylglycinyl)piperidine-4-
carboxaldehyde using Alkylation Method D.
Example 247.
1-[(4-Methoxybenzoyl-D-phenylglycinyl)]-4-[(isopropylamino)-
methyl]piperidine hydrochloride
1-(4-Methoxybenzoyl-D-phenylglycinyl)piperidine-4-
carboxaldehyde (0.050 g, 0.131 mmol) and isopropylamine
afforded, after treatment of the isolated product with
excess hydrochloric acid in methanol and concentration,
37 mg of the title compound as a hydrochloride salt.
1NMR
IS-MS, m/e 424 (M+1)
Example 248.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-[(dimethylamino)-
methyl]piperidine
1-(4-Methoxybenzoyl-D-phenylglycinyl)piperidine-4-
carboxaldehyde (0.050 g, 0.131 mmol) and dimethylamine
afforded 25 mg (470) of the title compound.
1NMR
IS-MS, m/e 410 (M+1)
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Example 249.
1-[(4-Methoxybenzoyl-D-phenylglycinyl)]-4-[(N,N-diethyl-
amino)methyl]piperidine hydrochloride
1-(4-Methoxybenzoyl-D-phenylglycinyl)piperidine-4-
carboxaldehyde (0.050 g, 0.131 mmol) and diethylamine
afforded, after treatment of isolated product with excess
hydrochloric acid in methanol and concentration, 42 mg of
the title compound as a hydrochloride salt.
1NMR
IS-MS, m/e 438 (M+1)
Example 250.
1-[(4-Methoxybenzoyl-D-phenylglycinyl)]-4-[(1-pyrrolidinyl)-
methyl]piperidine
1-(4-Methoxybenzoyl-D-phenylglycinyl)piperidine-4-
carboxaldehyde (0.050 g, 0.131 mmol) and pyrrolidine
afforded 27 mg (47%) of the title compound.
1NMR
IS-MS, m/e 436 (M+1)
Example 251.
1-[(4-Methoxybenzoyl-D-phenylglycinyl)]-4-[(3-pyrrolin-
1-yl)methyl]piperidine hydrochloride
1-(4-Methoxybenzoyl-D-phenylglycinyl)piperidine-4-
carboxaldehyde (0.050 g, 0.131 mmol) and 3-pyrroline
afforded, after treatment of isolated product with excess
hydrochloric acid in methanol and concentration, 43 mg of
the title compound as a hydrochloride salt.
1NMR
IS-MS, m/e 434 (M+1)
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Examples 252 to 253
Preparation of Starting Materials
4-[(Benzyloxycarbonyl-D-phenylglycinyl)aminomethyl]-
piperidine
Using Deptrotection Method D, 4-[(benzyloxycarbonyl-D-
phenylglycinyl)aminomethyl]-1-Boc piperidine (2.70 g, 5.61
mmol) afforded 1.56 g (73%) of the title compound.
1NMR
IS-MS, m/e 382 (M+1)
4-[(Benzyloxycarbonyl-D-phenylglycinyl)aminomethyl]-1-
cyclopentylpiperidine
Using Alkylation Method D, 4-[(benzyloxycarbonyl-D-
phenylglycinyl)aminomethyl]piperidine (1.50 g, 3.93 mmol)
and cyclopentanone afforded 3.48 g (910) of the title
compound.
1NMR
IS-MS, m/e 450 (M+1)
4-[(D-Phenylglycinyl)aminomethyl]-1-cyclopentylpiperidine
Using a deprotection procedure similar to that described
above for preparation of 1-(D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine, 4-[(benzyloxycarbonyl-D-phenylglycinyl)-
aminomethyl]-1-cyclopentylpiperidine (1.70 g, 3.78 mmol)
afforded 0.75 g (63%) of the title compound.
1NMR
IS-MS, m/e 316 (M+1)
General Procedure: Using Coupling Method A, 4-[(D-phenyl-
glycinyl)aminomethyl]-1-cyclopentylpiperidine was coupled
with the indicated acid.
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Example 252.
4-[(5-Chloroindole-2-carbonyl-D-phenylglycinyl)aminomethyl]-
1-cyclopentylpiperidine
4-[(D-Phenylglycinyl)aminomethyl]-1-cyclopentylpiperidine
(0.100 g, 0.317 mmol) and 5-chloroindole-2-carboxylic
acid (0.075 g, 0.38 mmol) afforded 156 mg (98%) of the
title compound.
1NMR
IS-MS, m/e 493 (M+1)
Example 253.
4-[(3-Methylindole-6-carbonyl-D-phenylglycinyl)aminomethyl]-
1-cyclopentylpiperidine
4-[(D-Phenylglycinyl)aminomethyl]-1-cyclopentylpiperidine
(0.100 g, 0.317 mmol) and 3-methylindole-6-carboxylic
acid (0.067 g, 0.38 mmol) afforded 137 mg (91%) of the
title compound.
1NMR
IS-MS, m/e 473 (M+1)
Particular Analytical Methods for Examples 254-276:
HPLC Analysis (Method A): Dynamax (trademark) C18, 60A
column. The elution system consisted of a linear gradient
from 90:10(95% H20, CH3CN)/(95% CH3CN, H20) to (95% CH3CN,
H20) over 20 min, followed by (95% CH3CN,H20) isocratic
elution over 15 min. The flow rate was 1 mL/min. W
Detection was performed at 254 nm unless otherwise noted.
HPLC Analysis (Method B): Microsorb-MV (trademark) C8 (4.6 x
250 mm) column. The elution system consisted of a linear
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gradient from 95:5 (2.5% TFA in H20):(2.5% TFA in
acetonitrile) to 0:100 (2.5% TFA in H20):(2.5% TFA in
acetonitrile) over 25 min at 30 °C and a flow rate of
1 mL/min. W Detection was performed at 254 nm unless
otherwise noted.
HPLC Analysis (Method C): Dynamax (trademark), C18, 60A
column. The elution system consisted of a linear gradient
from 95:5 (0.2% TFA in H20)/ (0.2% TFA in CH3CN) to 5:95
(0.2% TFA in H20)/ (0.2% TFA in CH3CN) over 20 min, followed
by (0.2% TFA in CH3CN) isocratic elution over 15 min. The
flow rate was 1 mL/min. UV Detection was performed at
254 nm unless otherwise noted.
HPLC Analysis (Method D): Waters Symmetry (trademark), C18
(4.6 x 250 mm) column. The elution system consisted of a
linear gradient from 95:5 (0.2% TFA in H20)/(0.2% TFA in
CH3CN) to 5:95 (0.2% TFA in H20)/(0.2% TFA in CH3CN) over
min, followed by (0.2% TFA in CH3CN) isocratic over 15
20 min. The flow rate was 1 mL/min. UV Detection was
performed at 254 nm unless otherwise noted.
HPLC Analysis (Method E): Microsorb-MV C18 (4.6 x 250 mm)
column. The elution system consisted of a linear gradient
from 90:10 (2.5% TFA in H20):(2.5% TFA in acetonitrile) to
10:90 (2.5% TFA in H20):(2.5% TFA in acetonitrile) over 25
min at 30 °C and a flow rate of 1 mL/min. UV Detection was
performed at 254 nm unless otherwise noted.
API-MS (atmospheric pressure chemical ionization mass
spectra) were obtained on a PESciex (trademark) API 150EX
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with a heated nebulizer and nitrogen as the reagent gas in
positive ion mode.
Examples 254 to 257
Preparation of Starting Materials
(R)-(-)-Boc-phenylglycinol: Di-tert-butyl dicarbonate
(232.4 g, 1.06 mol)was added to a well stirred, ice bath
cooled mixture of (R)-(-)-2-phenylglycinol (121.7 g, 0.887
mol), potassium carbonate (171.7 g, 1.24 mol), 1,4-dioxane
(1 L), and water(1 L). The temperature rose from 5 °C -
11 °C during the addition. The reaction was allowed to stir
overnight. The reaction was diluted with water (1 L), and
cooled in ice-water. The resultant precipitate was
collected by vacuum filtration, washed with water, air
dried, and vacuum dried at 40 °C overnight to afford 201.7 g
(95%) as a white solid.
1H-NMR(CDC13)
TLC Rf = 0.45 (83% CH2C12, EtOAc)
(R) - (-) - [2- [ (Methylsulphonyl) oxy] -1-phenylethyl] carbamic
acid 1,1-dimethylethyl ester
The sulphonate was prepared from the above alcohol according
to J. Med. Chem. 1994, 37, 1819.
1H-NMR(CDC13)
TLC Rf = 0.45 (95% CH2C12, EtOAC)
(R)-2-[(Butoxycarbonyl)amino]-2-phenylethyl azide
The azide was prepared form the above sulphonate according
to J. Med. Chem. 1994, 37, 1819.
1H-NMR(CDC13)
TLC Rf = 0.85 (95% CH2C12, EtOAc)
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(R)-2-(4-Methoxybenzoylamino)-2-phenylethyl azide
(R)-2-[(Butoxycarbonyl)amino]-2-phenylethyl azide (47.8 g,
0.182 mole) was added to trifluoroacetic acid (500 mL) with
stirring and ice-water bath,cooling. The cooling bath was
removed, the reaction was allowed to stir 1 h, and the
solvent was removed in vacuo at 35 °C water bath
temperature. The residue was co-evaporated with toluene to
give a weight of 75.0 g. The residue was dissolved in
1,4-dioxane (500 mL) and water (500 mL), with ice-water bath
cooling, and then potassium carbonate (113.5 g, 0.82 mol),
and anisoyl chloride (37.3 g, 0.219 mol) were added.
Another portion of 1,4-dioxane (300 mL) was added to
facilitate stirring. After stirring over the weekend, water
(1 L) was added. The mixture was cooled to -15 °C, and
vacuum filtered to collect a white solid. The solid was
washed with water, air dried, and then dried under vacuum at
50 °C for 4 h to afford 46.3 g (86%).
1H-NMR(CDC13)
TLC Rf = 0.85 (83% CH2C12, EtOAc)
(R)-2-(4-Methoxybenzoylamino)-2-phenylethylamine
(R)-2-(4-methoxybenzoylamino)-2-phenylethyl azide (46.3 g)
was combined with 10% palladium on carbon in THF (400 mL),
methanol (100 mL) and was stirred under a hydrogen
atmosphere. Analysis by TLC (70% methylene chloride, ethyl
acetate) indicated absence of starting material after
stirring overnight. The solution was filtered through
diatomaceous earth, rinsed with THF, and evaporated. The
resulting solid was recrystallized with ethyl acetate, and
dried under vacuum at 60 °C for 1 h to afford 35.4 g (84%)
of a white crystalline solid.
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1H-NMR(CDC13)
TLC Rf = 0.17 (90% CH2C12, 9% Methanol, 1% NH40H)
Examples 254-257 were prepared from (R)-2-(4-methoxybenzoyl-
amino)-2-phenylethylamine and the indicated acid chloride
using the acylation method described in Example 254
(Acylation Method A).
Example 254.
(R)-N-[2-(4-Methoxybenzoylamino)-2-phenylethyl]-4-methyl-
benzamide
(Acylation Method A) p-Toluoyl chloride (0.22 mL, 1.6 mmol)
was added via syringe to a 15 °C stirring mixture of (R)-2-
(4-methoxybenzoylamino)-2-phenylethylamine (0.40 g, 1.48
mmol), potassium carbonate (0.27 g, 1.9 mmol), 1,4-dioxane
(8 mL), and water (4 mL). TLC analysis (80% methylene
chloride, 18% methanol, 2% ammonium hydroxide) indicated
reaction completion within 1 h. The solution was diluted
with water, and the precipitated solid was collected by
vacuum filtration. The precipitate was recrystallized from
methanol and dried under vacuum at 50 °C overnight to afford
the title compound (0.42 g, 72%) as a white solid.
1H-NMR (DMSO)
IS-MS, m/e = 389(M+1)
Analysis for C24H24N203~
Calcd: C, 74.21; H, 6.23; N, 7.21;
Found: C, 73.82; H, 6.32; N, 7.04.
HPLC Analysis (Method A): 99.3%, RT: 21.35 min.
Melting Point: 230-238 °C
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Example 255,
(R)-N-[2-(4-Methoxybenzoylamino)-2-phenylethyl]-4-ethyl-
benzamide
Prepared from 4-ethylbenzoyl chloride (84%).
1H-NMR (DMSO)
IS-MS, m/e = 403 (M+1)
Analysis for C25H26N203~
Calcd: C, 74.60; H, 6.51; N, 6.96;
Found: C, 74.25; H, 6.63; N, 6.83.
HPLC Analysis (Method A): 95.4%, RT=22.62 min.
Melting Point: 222-229 °C
Example 256.
(R)-N-[2-(4-Methoxybenzoylamino)-2-phenylethyl]-4-isopropyl-
benzamide
Prepared from 4-isopropylbenzoyl chloride (40%).
1H-NMR (DMSO)
IS-MS, m/e = 417 (M+1)
Analysis for C26H28N203:
Calcd: C, 74.97; H, 6.78; N, 6.73;
Found: C, 74.61; H, 6.78; N, 6.61.
HPLC Analysis (Method A): 98.40, RT=23.77 min.
Melting Point: 239-244 °C
Example 257.
(R)-N-[2-(4-Methoxybenzoylamino)-2-phenylethyl]-4-tert-
butylbenzamide
Prepared from 4-tert-butylbenzoyl chloride (89°s).
1H-NMR (DMSO)
IS-MS, m/e = 431 (M+1)
Analysis for C27H30N203~0.25H20:
Calcd: C, 74.54; H, 7.07; N, 6.44;
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Found: C, 74.39; H, 7.13; N, 6.34.
HPLC Analysis (Method A): 96.4%, RT=25.04 min.
Melting Point = 171-175 °C
Examples 258 to 266
Preparation of Starting Materials
(R)-N-[2-(4-Methoxybenzoylamino)-2-phenylethyl]-1-tert-
butoxycarbonylpiperidine-4-carboxamide.
N-Boc-iso-nipecotic acid (2.13 g, 9.5 mmol) followed by
(R)-2-(4-methoxybenzoylamino)-2-phenylethylamine (2.34 g,
8.7 mmol) were added at 2 °C to a stirring mixture of EDCI
(2.5 g, 13.0 mmol), and HOBt (1.64 g, 12.1 mmol) in DMF
(50 mL). Triethylamine (1.8 mL, 13.0 mmol) was added
dropwise. The reaction was allowed to warm to room
temperature, with stirring overnight. Water (100 mL) was
added, and the aqueous mixture was extracted with ethyl
acetate (2 X 200 mL). The extracts were combined, and THF
(200 mL) was added. Next, the organic layers were washed
with water (5 X 70 mL), aqueous NaHC03 (70 mL)~ and brine
(100 mL). The organic layer was dried over Na2S04,
filtered, and evaporated. The crude residue (4.2 g, 100%),
was recrystallized from ethyl acetate and hexanes to afford
2.9 g (71°s) of a white solid.
1H-NMR (DMSO)
IS-MS, m/e = 482 (M+1)
Analysis for C27H3pN203:
Calcd: C, 67.34; H, 7.33; N, 8.73;
Found: C, 67.34; H, 7.46; N, 8.66.
HPLC Analysis (Method A): 98.8%, RT=20.72 min.
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(R)-N-[2-(4-Methoxybenzoylamino)-2-phenylethyl]piperidine-4-
carboxamide trifluoroacetate
(Deprotection Method A) Trifluoroacetic acid was added to a
stirring suspension of (R)-N-[2-(4-methoxybenzoylamino)-2-
phenylethyl]-1-tert-butoxycarbonylpiperidine-4-carboxamide
(2.0 g, 4.2 mmol), methylene chloride (20 mL), and anisole
(0.5 g, 4.6 mmol) at room temperature. A solution was
obtained and bubbling was observed. After 1 h, the reaction
mixture was evaporated at 40 °C. The residue was taken up
in warm methanol, and to this stirring solution was added
ether to precipitate the product. The precipitate was
collected by vacuum filtration, washed with ethyl acetate,
then dried under vacuum at 60 °C overnight to afford 1.9 g
(92°s) of a white solid.
1H-NMR(DMSO)
IS-MS, m/e = 382 (M+1)
Analysis for C24H28F3N305:
Calcd: C, 58.18; H, 5.70; N, 8.48;
Found: C, 58.19; H, 5.78; N, 8.27.
HPLC Analysis (Method C): >99%, RT=20.40 min.
Except as otherwise noted, Examples 258-266 were prepared
from (R) -N- [2- (4-methoxybenzoylamino) -2-phenylethyl] -
piperidine-4-carboxamide trifluoroacetate and the indicated
aldehyde or ketone using the reductive alkylation method
described in Example 258 (Alkylation Method A).
Example 258.
(R)-N-[2-(4-Methoxybenzoylamino)-2-phenylethyl]-1-isopropyl-
piperidine-4-carboxamide
(Alkylation Method A) (R)-N-[2-(4-Methoxybenzoylamino)-2-
phenylethyl]piperidine-4-carboxamide trifluoroacetate
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(0.50 g, 1.0 mmol), acetone (4.5 mL, 61 mmol), acetic acid
(0.28 mL, 4.9 mmol), and sodium cyanoborohydride (0.32 g,
5.1 mmol) were combined in methanol, and stirred. After
4 h, TLC (79% CH2C12, 19% methanol, 1% NH40H) indicated
reaction completion. The solution was diluted with methanol
(100 mL), and passed through H+ form ion exchange resin
(Varian SCX cartridge, Catalog #1225-6035) washed with
methanol, and then with 2 M NH3 in methanol to collect the
product. The product was recrystallized from methanol and
ether to afford 0.30 g (700) of a white crystalline solid.
1H-NMR (DMSO)
IS-MS, m/e = 424 (M+1)
Analysis for C25H33N303~0.75H20:
Calcd: C, 68.70; H, 7.96; N, 9.61;
Found: C, 68.73; H, 7.68; N, 9.29.
HPLC Analysis (Method C): >99°s RT=18.19 min.
Examples 259-262 were purified by passing a solution through
a silica gel column, eluting with 200:10:1 methylene
chloride, methanol, and concentrated ammonium hydroxide.
Example 259.
(R) -N- [2- (4-Methoxybenzoylamino) -2-phenylethyl] -1-
cyclopentylpiperidine-4-carboxamide
Prepared from cyclopentanone (44%).
1H-NMR (DMSO)
IS-MS, m/e = 450 (M+1)
Analysis for C27H35N303'0.25H20:
Calcd: C, 71.42; H, 7.88; N, 9.25;
Found: C, 71.21; H, 7.93; N, 9.18.
HPLC Analysis (Method C): >99%, RT=18.84 min.
Melting Point = 253-257 °C
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Example 260.
(R) -N- [2- (4-Methoxybenzoylamino) -2-phenylethyl] -1-
cyclohexylpiperidine-4-carboxamide
Prepared from cyclohexanone (65%).
1H-NMR (DMSO)
IS-MS, m/e = 464 (M+1)
Analysis for C28H37N303~1.OH20:
Calcd: C, 69.83; H, 8.16; N, 8.72;
Found: C, 69.64; H, 7.84; N, 8.90.
HPLC Analysis (Method C): >990, RT=19.13 min.
Melting Point = 239-243 °C.
Example 261.
(R) -N- [2- (4-Methoxybenzoylamino) -2-phenylethyl] -1-ethyl-
piperidine-4-carboxamide
Prepared from acetaldehyde (360).
1H-NMR (DMSO)
IS-MS, m/e 410 (M+1)
Analysis for C24H31N303~
Calcd: C, 70.39; H, 7.63; N, 10.26;
Found: C, 70.06; H, 7.67; N, 10.00.
HPLC Analysis (Method D): 96.90, RT=16.04 min.
Melting Point = 245-251 °C.
Example 262.
(R)-N-[2-(4-Methoxybenzoylamino)-2-phenylethyl]-1-(1-methyl-
piperidin-4-yl)piperidine-4-carboxamide
Prepared from 1-methylpiperid-4-one (27%).
1H-NMR (DMSO)
IS-MS, m/e 479 (M+1)
Analysis for C2gH3gN403~0.25H20:
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Calcd: C, 69.61; H, 8.03; N, 11.60;
Found: C, 69.72; H, 8.11; N, 11.48.
HPLC Analysis (Method D): 97.0°x, RT=15.42 min.
Melting Point = 252-259 °C.
(No example for Examples 263-264.)
Examples 265-266 were purified by passing a solution through
a silica gel column, eluting with 200:10:1 methylene
chloride, methanol, and concentrated ammonium hydroxide.
Example 265.
(R)-N-[2-(4-Methoxybenzoylamino)-2-phenylethyl]-1-
(3-pyridinylmethyl)piperidine-4-carboxamide
Prepared from pyridine-3-carboxaldehyde (680).
1H-NMR (DMSO)
CI-MS, m/e = 473 (M+1)
HPLC Analysis (Method D): 92.7%, RT=15.39 min.
Example 266.
(R) -N- [2- (4-Methoxybenzoylamino) -2-phenylethyl] -1-
(4-pyridinylmethyl)piperidine-4-carboxamide
Prepared from pyridine-4-carboxaldehyde (63%).
1H-NMR (DMSO)
CI-MS, m/e = 473 (M+1)
HPLC Analysis (Method D): 89.2°x, RT=15.33 min.
Example 267.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(4-piperidinyl-
methyl)piperazine trifluoroacetate
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1-[D-(+)-Benzyloxycarbonylphenylglycinyl]-(4-tert-butoxy-
carbonyl)piperazine.
(Coupling Method A) D-(+)-Benzyloxycarbonylphenylglycine
(58.0 g, 203 mmol) and 1-Boc-piperazine (41.7 g, 224 mmol)
were dissolved in DMF (1 L) and cooled to approximately
-15 °C in an ice-methanol bath. Diethyl cyanophosphonate
(37.0 mL, 244 mmol) was slowly added to the mixture.
Triethylamine (59.4 mL, 426 mmol) was added dropwise to the
solution. The mixture was stirred at -15 °C for 2 h and was
allowed to gradually warm to room temperature overnight.
The mixture was diluted with ethyl acetate and water. The
layers were separated, and the water layer extracted with
ethyl acetate. The organic layers were combined, washed
with 10% citric acid (2 x 500 mL) and brine, dried (Na2S04),
filtered and concentrated under vacuum. The crude product
was filtered through a plug of silica gel (1.2 kg) using 1:1
hexanes:ethyl acetate as eluent to provide 1-[D-(+)-benzyl-
oxycarbonylphenylglycinyl]-4-(tert-butoxycarbonyl)piperazine
(69.9 g, 760) as a colorless oil.
1H-NMR(CDC13)
API-MS, m/e = 454 (M+1)
1-[D-(+)-Phenylglycinyl]-4-(tert-butoxycarbonyl)piperazine
1-[D-(+)-Benzyloxycarbonylphenylglycinyl]-4-(tert-butoxy
carbonyl)piperazine (69.5 g, 153 mmol) was dissolved in
ethanol (500 mL). The mixture was degassed with nitrogen
and Pd/C (6.8 g) was added. Hydrogen was bubbled through
the mixture for 1 h, and it was maintained under a hydrogen
atmosphere for 16 h. The Pd/C was removed by filtration
through cellulose powder. The filter cake was rinsed with
ethanol and ethyl acetate. The filtrate was concentrated
under vacuum to give 1-[D-(+)-phenylglycinyl]-4-(tert-
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butoxycarbonyl)piperazine (45.3 g, 93%) as a light yellow
solid.
1H-NMR(CDC13)
API-MS, m/e = 320 (M+1)
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(tert-butoxy-
carbonyl)piperazine
(Acylation Method B) 1-[D-(+)-phenylglycinyl]-4-(tert-
butoxycarbonyl)piperazine (42.0 g, 131.5 mmol) was dissolved
in 1,4-dioxane (420 mL) and water (210 mL) and was cooled to
10 °C. Potassium carbonate (36.4 g, 263 mmol) was added,
followed by p-anisoyl chloride (24.7 g, 144 mmol). The
mixture was stirred at room temperature overnight. The
mixture was diluted with water and ethyl acetate. The
layers were separated, and the water layer extracted with
ethyl acetate. The organic layers were combined, washed
with brine, dried, filtered and concentrated to provide
1-(4-methoxybenzoyl-D-phenylglycinyl)-(4-tert-butoxy-
carbonyl)piperazine (58.7 g, 98%) as an off-white solid.
1H-NMR(CDC13)
API-MS, m/e = 454 (M+1)
1-(4-Methoxybenzoyl-D-phenylglycinyl)piperazine
trifluoroacetate
1-(4-Methoxybenzoyl-D-phenylglycinyl)-(4-tert-butoxy-
carbonyl)piperazine (20.0 g, 44.1 mmol) was dissolved in
dichloromethane (50 mL) and anisole (20 mL). To this
vigorously stirred mixture was added trifluoroacetic acid
(50 mL). The mixture was stirred for 25 min at room
temperature. The solvents were removed under vacuum. The
residue was triturated in ether and sonicated for 60 min.
The solid was collected by filtration and dried in a vacuum
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pistol overnight to provide 1-(4-methoxybenzoyl-D-phenyl-
glycinyl)piperazine trifluoroacetate (18.2 g, 880) as a
light yellow solid.
1H-NMR(CD30D)
API-MS, m/e = 354 (M+1)
1-Boc-isonipecotic acid
Isonipecotic acid (15.0 g, 116 mmol) was dissolved in THF
(300 mL), water (150 mL) and 6 N NaOH (40 mL). Di-tert-
butyl dicarbonate (26.6 g, 122 mmol) was added and the
mixture stirred overnight. The mixture was diluted with
water and ethyl acetate, and the layers separated. The
water layers were extracted with ethyl acetate, and the
organic layers discarded. The water layer was diluted with
KHS04 (2 N, pH~4) and extracted with ethyl acetate. The
organic layer was washed with brine, dried (Na2S04),
filtered and concentrated to provide 1-Boc-isonipecotic acid
(23.9 g, 90%) as a white solid.
1H-NMR(CDC13)
API-MS, m/e = 230 (M+1)
1-Boc-piperidine-4-methanol
1-Boc-isonipecotic acid (10.0 g, 214 mmol) was dissolved in
THF (400 mL) and cooled to 0 °C. A solution of BH3~THF
(180 mL, 1 N in THF, 180 mmol) was added slowly. The
mixture stirred for 1 h at 0 °C and was allowed to warm to
room temperature for 12 h. The mixture was carefully
quenched with water and diluted with ethyl acetate. The
water layer was extracted with ethyl acetate. The organic
layers were combined, washed with brine, dried (Na2S04),
filtered and concentrated to provide 1-Boc-piperidine-4-
methanol (7.98 g, 85%) as a white solid.
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1H-NMR(CDC13)
API-MS, m/e = 220 (M+1)
1-Boc-piperidine-4-carboxaldehyde
Dimethyl sulfoxide (3.5 mL, 48.7 mmol) was dissolved in
dichloromethane (100 mL) and was cooled to -78 °C. Oxalyl
chloride (3.65 mL, 41.8 mmol) was added. The mixture
stirred for 30 min. To this solution was added a solution
of 1-Boc-piperidine-4-methanol (7.5 g, 34.8 mmol) in
dichloromethane (15 mL), and the mixture stirred for 1 h.
Triethylamine (9.7 mL, 69.6 mmol) was added slowly and the
mixture stirred at -78 °C for 30 min and warmed to room
temperature over the course of 1 h. The mixture was diluted
with water and the layers separated. The water layer was
extracted with dichloromethane and the organic layers
combined, dried (Na2S04), filtered and concentrated to
provide 1-Boc-piperidine-4-carboxaldehyde (6.75 g, 910) as a
yellow oil.
1H-NMR(CDC13)
API-MS, m/e = 214 (M+1)
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(1-Boc-piperidin-4-
ylmethyl)piperazine
(Alkylation Method B) Using Alkylation Method A, except
using sodium triacetoxyborohydride in 1,2-dichloroethane,
1-(4-methoxybenzoyl-D-phenylglycinyl)-4-(1-Boc-piperidin-4-
ylmethyl)piperazine was prepared from 1-(4-methoxybenzoyl-D-
phenylglycinyl)piperazine trifluoroacetate and 1-Boc-
piperidine-4-carboxaldehyde (85%).
1H-NMR(CDC13)
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1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(4-piperidinyl-
methyl)piperazine trifluoroacetate.
Using Deprotection Method A, the title compound was prepared
from 1-(4-methoxybenzoyl-D-phenylglycinyl)-4-(1-Boc-
piperidin-4-ylmethyl)piperazine (90%).
Melting Point = 70-72 °C with decomposition
IR (KBr)
1H-NMR(CD30D)
API-MS, m/e = 451 (M+1)
Analysis for C26H34N403'2.5TFA~0.4H20:
Calcd: C, 50.12; H, 5.06; N, 7.54;
Found: C, 49.81; H, 5.33; N, 7.39.
HPLC Analysis (Method B): 97.1% RT=14.3 min.
Examples 268 to 272
Unless otherwise indicated, using Alkylation Method A or B,
the title compounds were prepared from 1-(4-methoxybenzoyl-
D-phenylglycinyl)-4-(4-piperidinylmethyl)piperazine
trifluoroacetate and the indicated aldehyde or ketone.
Example 268.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(1-methylpiperidin-
4-ylmethyl)piperazine hydrochloride
Prepared from paraformaldehyde using Method A (56%).
IR (KBr)
1H-NMR(CD30D)
CI-MS, m/e = 465 (M+1)
Example 269.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(1-isopropyl-
piperidin-4-ylmethyl)piperazine hydrochloride
Prepared from acetone using Method A (72%).
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Melting Point = 172-180 °C with decomposition
IR (KBr)
1H-NMR(CD30D)
CI-MS, m/e = 493 (M+1)
Analysis for C29H40N403'3HC1:
Calcd: C, 55.85; H, 7.34; N, 8.98;
Found: C, 55.63; H, 7.32; N, 8.66.
HPLC Analysis (Method B): 98.2% RT=14.4 min.
Example 270.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-[3-(3-pyridinyl)-
propyl)piperazine hydrochloride
Prepared from pyridine-3-propionaldehyde (prepared as
described below) using Method B (72%).
1H-NMR(CD30D)
CI-MS, m/e = 473 (M+1)
Pyridine-3-propionaldehyde
(Oxidation Method A) 1,1,1-Triacetoxy-1,1-dihydro-1,2-
benziodoxol-3(1H)-one (5.4 g, 12.7 mmol) was suspended in
dichloromethane (45 mL). 3-Pyridinepropanol (1.59 g, 11.6
mmol) as a solution in dichloromethane (35 mL) was added
slowly. The mixture stirred for 3 h at room temperature.
The mixture was diluted with saturated aqueous NaHC03 and
ether. The mixture was stirred for 10 min and was diluted
with sodium thiosulfate (2 N) and stirred until the solids
dissolved. The layers were separated, and the water layer
was extracted with ether. The organic layers were combined,
washed with water and brine, dried (Na2S04), filtered and
concentrated to provide pyridine-3-propionaldehyde (1.03 g,
66%) as a yellow oil.
1H-NMR(CDC13)
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Example 271.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-[3-(4-pyridinyl)-
propyl]piperazine hydrochloride.
Prepared from pyridine-4-propionaldehyde (prepared as
described below) using Method A; the hydrochloride salt was
prepared using HC1 (2 M) in diethyl ether (76°s).
1H-NMR(CD30D)
CI-MS, m/e = 473 (M+1)
Pyridine-4-propionaldehyde
Prepared from 4-pyridinepropanol using Oxidation Method A
(80%) .
1H-NMR(CDC13)
Example 272.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(2-cyclopentyl-
ethyl)piperazine hydrochloride hydrate
The free base was prepared from cyclopentylacetaldehyde
(prepared as described below) using Method B (58°s).
1H NMR (CDC13)
To a stirred solution of 1-(4-methoxybenzyl-D-phenyl-
glycinyl)-4-(2-cyclopentylethyl)piperazine (260 mg, 0.58
mmol) in ether (10 mL) and methylene chloride (1 mL) was
added hydrogen chloride as a 2 N solution in ether (about
2 mL), and the resulting precipitate was filtered to give
1-(4-methoxybenzoyl-D-phenylglycinyl)-4-(2-cyclopentyl-
ethyl)piperazine hydrochloride as a pale yellow solid.
1H NMR (CD30D)
IS-MS, m/e = 450 (M+1)
Analysis for C27H35N303'HC1-0.5H20:
Calcd: C, 65.51; H, 7.53; N, 8.49;
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Found: C, 65.67; H, 7.58; N, 8.13.
HPLC Analysis (Method E): >99%, RT=15.84
Melting Point = 190-192 °C
Cyclopentylacetaldehyde
Using Oxidation Method A, the title compound was prepared
from 2-cyclopentylethanol and used with trace amounts of
ether and methylene chloride present due to volatility of
product.
1H NMR (CDC13)
Example 273.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(3-pyrrolidinyl)-
piperazine trifluoroacetate.
(R)-(+)-1-Boc-3-pyrrolidinol
To a stirred solution of (R)-(+)-3-pyrrolidinol (2 g, 22.96
mmol) in tetrahydrofuran (60 mL) and water (30 mL) was added
di-tert-butyl dicarbonate (5.27 g, 24.15 mmol) and 3 N
sodium hydroxide (16 mL), and the resulting solution was
stirred for 6 h. Another portion of di-tert-butyl
dicarbonate (0.74 g, 0.34 mmol) was added and the solution
was stirred overnight. The reaction was diluted with water
(40 mL) and extracted with ethyl acetate (2 x 150 mL). The
combined organic extracts were washed with 2 N potassium
hydrogen sulfate (200 mL), saturated sodium bicarbonate (2 x
150 mL), brine (150 mL) and dried over magnesium sulfate.
Removal of solvent in vacuo gave (R) - (+) -1-Boc-3-
pyrrolidinol (4.21 g, 98%) as a yellow oil.
1H-NMR (CDC13)
1-Boc-3-pyrrolidinone
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Using Oxidation Method A, the title compound was prepared
from (R)-(+)-1-Boc-3-pyrrolidinol (85%).
1H NMR (CDC13)
1-(4-Methoxybenzyl-D-phenylglycinyl)-4-(1-Boc-3-
pyrrolidinyl)piperazine
Using Alkylation Method B, the title compound was prepared
(69%) from 1-(4-methoxybenzyl-D-phenylglycinyl)piperazine
trifluoroacetate and 1-Boc-3-pyrrolidinone.
1H NMR (CDC13)
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(3-pyrrolidinyl)-
piperazine trifluoroacetate.
Using Deprotection Method A, the title compound was prepared
from 1-(4-methoxybenzyl-D-phenylglycinyl)-4-(1-Boc-3-
pyrrolidinyl)piperazine.
1H NMR (CD30D)
Example 274.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-[2-(4-pyridinyl)-
ethyl]piperazine
1-Boc-4- [2- (4-pyridinyl) ethyl] piperazine
1-Boc-piperazine (4.0 g, 21.5 mmol), 4-vinylpyridine
(2.94 g, 27.9 mmol), and acetic acid (1.29 g, 21.5 mmol)
were mixed in ethanol and heated to reflux for 48 h. The
mixture was cooled to room temperature and concentrated
under vacuum to provide 1-Boc-4-[2-(4-pyridinyl)ethyl]-
piperazine (2.9 g, 45%) as an off white solid. The product
was used without further purification.
1H-NMR(CDC13)
CI-MS, m/e = 292 (M+1)
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1-[2-(4-Pyridinyl)ethyl]piperazine hydrochloride
(Deprotection Method B) 1-Boc-4-[2-(4-pyridinyl)ethyl]-
piperazine (1.0 g, 3.43 mmol) was dissolved in ethyl ether.
Ethyl acetate (15 mL) saturated with HC1 was added, and the
mixture stirred for 30 min at room temperature. The mixture
was concentrated under vacuum and provided 1-[2-(4-
pyridinyl)ethyl]piperazine hydrochloride (900 mg, 87%) as a
tan solid.
1H-NMR(CD30D)
CI-MS, m/e = 192 (M+1)
1-(D-Boc-phenylglycinyl)-4-[2-(4-pyridinyl)ethyl]piperazine
Using Coupling Method A, the title compound was prepared
from 1-[2-(4-pyridinyl)ethyl]piperazine and
Boc-D-phenylglycine (95%).
1H-NMR(CDC13)
CI-MS, m/e = 425 (M+1)
1-(D-Phenylglycinyl)-4-[2-(4-pyridinyl)ethyl]piperazine
hydrochloride
Using Deprotection Method B, the title compound was prepared
from 1-(D-Boc-phenylglycinyl)-4-[2-(4-pyridinyl)ethyl]-
piperazine (89%).
1H-NMR(CD30D)
CI-MS, m/e = 325 (M+1)
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-[2-(4-pyridinyl)-
ethyl]piperazine
Using Acylation Method B, the title compound was prepared
from 1-(D-phenylglycinyl)-4-[2-(4-pyridinyl)ethyl]piperazine
hydrochloride and p-anisoyl chloride (70%).
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1H-NMR(CDC13)
CI-MS, m/e = 459 (M+1)
HPLC Analysis (Method E): 99.7%, RT=10.98 min.
Examples 275 to 276
Using Alkylation Method B, the title compounds were prepared
from 1-(4-methoxybenzoyl-D-phenylglycinyl)-4-
(3-pyrrolidinyl)piperazine trifluoroacetate and the
indicated aldehyde or ketone.
Example 275.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(1-methylpyrrolidin-
3-yl)piperazine
Prepared from paraformaldehyde (20%).
1H-NMR(CDC13)
Example 276.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(1-isopropyl-
pyrrolidin-3-yl)piperazine.
Prepared from acetone (59 % ) .
1H-NMR(CDC13)
The following analytical methods apply to Examples 277-336.
Analytical RPHPLC Method 1 = Vydac C18, linear gradient of
90/10 - 50/50 (0.1% TFA in water / 0.1% TFA in acetonitrile)
over 40 min, 1 mL/min.
Analytical RPHPLC Method 2 - Vydac C18, linear gradient of
85/20 - 40/60 (0.1% TFA in water / 0.1% TFA in acetonitrile)
over 40 min, 1 mL/min.
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Examples 277 to 290
Unless otherwise indicated, the products of Examples 277
through 290 were obtained from the indicated acid and
1-D-phenylglycinyl-1'-methyl-4,4'-bispiperidine using the
procedure described in Example 277 (Coupling Method B).
Example 277.
1-(2-Chloropyridine-5-carbonyl-D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine
(Coupling Method B) To a stirring solution of 1-[3-
(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
(0.20 g, 1.0 mmol) and 1-hydroxybenzotriazole hydrate
(0.15 g, 1.1 mmol) in DMF (3 mL) was added 2-chloropyridine-
5-carboxylic acid (0.14 g, 0.89 mmol) followed by a solution
of 1-D-phenylglycinyl-1'-methyl-4,4'-bispiperidine (0.25 g,
0.80 mmol) in DMF (2 mL). After stirring for 18 h, the
solvent was removed in vacuo and the residue was partitioned
between dichloromethane and 1 N sodium hydroxide. The
aqueous phase was separated, extracted twice with
dichloromethane, and the combined organic phases were dried
with MgS04, filtered and concentrated in vacuo. The
resulting solid was dissolved in a minimum amount of
dichloromethane and chromatographed over silica gel, eluting
with 10% methanol (containing 2 N ammonia) in
dichloromethane through 15% methanol (containing 2 N
ammonia) in dichloromethane. The product containing
fractions were combined and concentrated in vacuo to give
0.258 g (71%) of a white solid.
1H-NMR
IS-MS, m/e 455.0 (M+1)
Analysis for C25H31N402C1~0.4H20:
Calcd: C, 64.96; H, 6.93; N, 12.13;
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Found: C, 64.68; H, 6.72; N, 12.02.
Analytical RPHPLC, Method 1, RT = 21.28 min (98%)
Example 278.
1-(5-Chloropyridine-2-carbonyl-D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine
Prepared from 2-chloropyridine-5-carboxylic acid (61%).
1H-NMR
IS-MS, m/e 454.9 (M+1)
Analysis for C25H31N4~2C1~0.4H20:
Calcd: C, 64.96; H, 6.93; N, 12.12;
Found: C, 64.75; H, 6.64; N, 12.00.
Analytical RPHPLC, Method 1, RT = 27.23 min (100%)
Example 279.
1-(3-Cyano-4-fluorobenzoyl-D-phenylglycinyl)-1'-methyl-4,4'-
bispiperidine
Prepared from 3-cyano-4-fluorobenzoic acid (66%).
1H-NMR
IS-MS, m/e 463.0 (M+1)
Analysis for C27H31N402F~0.3H20:
Calcd: C, 69.30; H, 6.81; N, 11.97;
Found: C, 68.91; H, 6.58; N, 11.77.
Analytical RPHPLC [Vydac C18, linear gradient of 85/15 -
45/55 (0.1% TFA in water / 0.1% TFA in acetonitrile) over 40
min, 1 mL/min] RT = 21 . 54 ( 99 % ) .
Example 280.
1-(5-Chlorobenzofb]thiophene-2-carbonyl-D-phenylglycinyl)-
1'-methyl-4,4'-bispiperidine
Prepared from 5-chlorobenzo[b]thiophene-2-carboxylic
acid (38%) .
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1H-NMR
IS-MS, m/e 509.9 (M+1)
Analysis for C28H32N302SC1~0.3H20:
Calcd: C, 65.24; H, 6.37; N, 8.15;
Found: C, 65.01; H, 6.12; N, 8.07.
Analytical RPHPLC, Method 1, RT = 36.08 min (990)
Example 281.
1-(2-Benzo[b]thiophenecarbonyl-D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine
Prepared from 2-benzo[b]thiophenecarboxylic acid (82%).
1H-NMR
IS-MS, m/e 475.9 (M+1)
Analysis for C28H33N302S~0.4H20:
Calcd: C, 69.65; H, 7.06; N, 8.70;
Found: C, 69.45; H, 6.90; N, 8.58.
Analytical RPHPLC, Method 2, RT = 22.30 min (100°x)
Example 282.
1-(6-Chlorobenzo[b]thiophene-2-carbonyl-D-phenylglycinyl)-
1'-methyl-4,4'-bispiperidine
Prepared from 6-chlorobenzo[b]thiophene-2-carboxylic
acid (77).
1H-NMR
IS-MS, m/e 509.9 (M+1)
Analysis for C28H32N302SC1~0.3H20:
Calcd: C, 65.24; H, 6.37; N, 8.15;
Found: C, 64.97; H, 6.23; N, 8.07.
Analytical RPHPLC, Method 2, RT = 27.62 min (1000)
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Example 283.
1-(Indole-2-carbonyl-D-phenylglycinyl)-1'-methyl-4,4'-
bispiperidine
Prepared from 2-indolecarboxylic acid (57%).
1H-NMR
IS-MS, m/e 459.0 (M+1)
Analysis for C28H34N402~0.4H20:
Calcd: C, 71.10; H, 7.59; N, 11.85;
Found: C, 70.82; H, 7.25; N, 11.74.
Analytical RPHPLC, Method 1, RT = 29.60 min (99%)
Example 284.
1-(1-Methylindole-2-carbonyl-D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine
Prepared from 1-methylindole-2-carboxylic acid (43%).
1H-NMR
IS-MS, m/e 473.0 (M+1)
Analytical RPHPLC, Method 2, RT = 22.20 min (98%)
Example 285.
1-(Benzofuran-2-carbonyl-D-phenylglycinyl)-1'-methyl-4,4'-
bispiperidine
Prepared from 2-benzofurancarboxylic acid (50%).
1H-NMR
IS-MS, m/e 460.0 (M+1)
Analytical RPHPLC, Method 1, RT = 27.59 min (100%)
Example 286.
1-(3-Methylbenzofuran-2-carbonyl-D-phenylglycinyl)-1'-
methyl-4,4'-bispiperidine
Prepared from 3-methylbenzofuran-2-carboxylic acid (47%).
1H-NMR
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IS-MS, m/e 474.1 (M+1)
Analytical RPHPLC, Method 1, RT = 31.31 min (95%)
Example 287.
1-(5-Methylbenzofuran-2-carbonyl-D-phenylglycinyl)-1'-
methyl-4,4'-bispiperidine
Prepared from 5-methylbenzofuran-2-carboxylic acid (45%).
1H-NMR
IS-MS, m/e 474.3 (M+1)
Analytical RPHPLC, Method 1, RT = 30.91 min (100%)
Example 288.
1-(6-Methoxybenzofuran-2-carbonyl-D-phenylglycinyl)-1'-
methyl-4,4'-bispiperidine
Prepared from 6-methoxybenzofuran-2-carboxylic acid (50%).
1H-NMR
IS-MS, m/e 490.0 (M+1)
Analytical RPHPLC, Method 1, RT = 29.26 min (100%)
Example 289.
1-(5-Chlorobenzofuran-2-carbonyl-D-phenylglycinyl)-1'-
methyl-4,4'-bispiperidine
Prepared from 5-chlorobenzofuran-2-carboxylic acid (59%).
1H-NMR
IS-MS, m/e 493.9 (M+1)
Analysis for C28H32N303C1~0.5H20:
Calcd: C, 66.85; H, 6.61; N, 8.35;
Found: C, 66.46; H, 6.28; N, 8.25.
Analytical RPHPLC, Method 1, RT = 34.86 min (100%)
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Example 290.
1-(2-Aminobenzimidazole-5-carbonyl-D-phenylglycinyl)-1'-
methyl-4,4'-bispiperidine
Prepared from 2-amino-5-carboxybenzimidazole hydrochloride
(32%) .
1H-NMR
IS-MS, m/e 475.2 (M+1)
Analytical RPHPLC [Vydac C18, linear gradient of 98/2 -
58/42 (0.1% TFA in water / 0.1% TFA in acetonitrile) over 40
min, 1 mL/min] RT = 24.56 (90%).
Example 291. 1-(3-Aminobenzisoxazole-5-carbonyl-D-
phenylglycine)-1'-methyl-4,4'-bispiperidine
To a stirring solution of acetoxime (98 mg, 7.1 mmol) in DMF
(5 mL) was added a 1 M solution of potassium tert-butoxide
(1.3 mL, 1.3 mmol) in THF. After 2 min, 1-(3-cyano-4-
fluorobenzoyl-D-phenylglycinyl)-1'-methyl-4,4'-bispiperidine
(303 mg, 0.65 mmol) was added; and, after another hour, the
solvent was partially removed and the residue was
partitioned between brine and dichloromethane. The layers
were separated and the aqueous phase was extracted another
two times with dichloromethane. The combined organics were
dried (MgS04), filtered and concentrated in vacuo.
IS-MS, m/e 516.0 (M+1)
The residue was then dissolved in ethanol (3.6 mL) and 1 N
HC1 was added. The stirring solution was heated to reflux.
After 5 h, the heating mantle was removed and after
cooling, the solution was diluted ethyl acetate and water.
The pH of the aqueous phase was adjusted to 11 with 2 N
sodium hydroxide and extracted twice with dichloromethane.
The combined dichloromethane extracts were dried (MgS04),
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filtered and concentrated in vacuo. The resulting solid was
dissolved in a minimum amount of dichloromethane and
chromatographed over silica gel, eluting with 2% methanol
(containing 2 N ammonia) in dichloromethane through 10%
methanol (containing 2 N ammonia) in dichloromethane. The
product containing fractions were combined and concentrated
in vacuo to give 89 mg (29%) of an off-white solid.
1H-NMR
IS-MS, m/e 476.3 (M+1)
Analytical RPHPLC, Method 1, RT = 19.55 min (99%)
Examples 292 to 303
Preparation of Starting Materials
1-(Boc-D-phenylglycinyl)-4-hydroxypiperidine
(Coupling Method C) To a stirring solution of 1-hydroxy-
7-azabenzotriazole (10.24 g, 75.2 mmol) and EDCI (14.42 g,
75.2 mmol) in DMF (160 mL) was added a solution of Boc-D-
phenylglycine (18.9 g, 75.2 mmol) in DMF (80 mL). After
10 min, 4-hydroxypiperidine (6.85 g, 67.7 mmol) was added.
After stirring over night, the solvent was evaporated in
vacuo and the residue was partitioned between ethyl acetate
and water. The organic phase separated and washed with
saturated aqueous NaHC03, followed by brine, dried over
MgS04, flitered and concentrated in vacuo. Two-thirds of
this material was dissolved in a minimum amount of
dichloromethane and chromatographed over silica gel, eluting
with a gradient of dichloromethane through 1:1
dichloromethane/ethyl acetate. The product containing
fractions were combined and concentrated in vacuo to give
15.71 g (94%) of a white foam.
1H-NMR
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IS-MS, m/e 335.1 (M+1)
Analysis for C18H26N2040:
Calcd: C, 64.65; H, 7.84; N, 8.37;
Found: C, 64.40; H, 7.77; N, 8.12.
1-(D-phenylglycinyl)-4-hydroxypiperidine
(Deprotection Method D) To a stirring solution of 1-(Boc-D-
phenylglycinyl)-4-hydroxypiperidine (5 g, 15 mmol) in
dichloromethane (290 mL) was added anisole, (8 mL) followed
by trifluoroacetic acid (29 mL). After stirring for 4 h,
the solvent was concentrated in vacuo and the residue was
suspended with stirring in diethyl ether. After 1 h, the
mixture was filtered and the solid was partitioned between
ethyl acetate and saturated aqueous NaHC03. The organic
phase was washed with brine, dried with MgS04, filtered and
concentrated to give 0.41 g of white solid. The combined
aqueous phase was back extracted with 3:1 chloroform/-
isopropanol and this organic phase was separated, dried with
MgS04, filtered and concentrated in vacuo to give 1.6 g of
white solid. The two crops of solid were combined to give
2.02 g (90%) of the title compound.
1H-NMR
IS-MS, m/e 235.1 (M+1)
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-hydroxypiperidine
To a stirring solution of 1-[3-(dimethylamino)propyl]-
3-ethylcarbodiimide hydrochloride (1.4 g, 7.4 mmol),
1-hydroxybenzotriazole hydrate (1.0 g, 7.4 mmol) and
N,N-diisopropylethylamine (1.4 mL) in DMF (20 mL) was added
a solution of 1-(D-phenylglycinyl)-4-hydroxypiperidine
(2.0 g, 7.38 mmol) in DMF (10 mL) followed by a solution of
4-methoxybenzoic acid (1.0 g, 6.7 mmol) in DMF (10 mL).
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After stirring overnight at room temperature, the solvent
was removed in vacuo and the residue was partitioned between
ethyl acetate and water. The organic phase was washed again
with water followed by saturated aqueous NaHC03 (2X) and
brine, then dried with MgS04, filtered and concentrated in
vacuo to give 2.4 g of off-white solid. A portion of this
material (2.0 g) was dissolved in a minimal amount of
dichloromethane and chromatographed over silica gel, eluting
with a gradient of dichloromethane through 50% ethyl
acetate/dichloromethane. The product-containing fractions
were combined and concentrated in vacuo to give 1.3 g (60%)
of a white foam.
1H-NMR
IS-MS, m/e 369.2 (M+1)
Analysis for C21H24N204~
Calcd: C, 68.46; H, 6.57; N, 7.60;
Found: C, 67.88; H, 6.73; N, 7.33.
Analytical RPHPLC, Method 1, RT = 24.24 min (100%)
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-oxopiperidine
(Oxidation Method B) To a stirring solution of oxalyl
chloride (0.26 mL, 3 mmol) in dichloromethane (6.5 mL) at
-50 °C, was added a solution of DMSO (0.43 mL, 6 mmol) in
dichloromethane (1.3 mL). After 3 min, a solution of
1-(4-methoxybenzoyl-D-phenylglycinyl)-4-hydroxypiperidine
(1.0 g, 2.7 mmol) in dichloromethane (4 mL) was added and
the solution was allowed to warm to -20 °C over 45 min.
Triethylamine (2 mL) was then added and the solution was
allowed to warm to room temperature. The solution was then
diluted with dichloromethane and water and the layers were
separated. The organic phase was washed with brine, dried
over MgS04, filtered and concentrated in vacuo. The residue
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was dissolved in a minimum amount of dichloromethane and
chromatographed over silica gel, eluting with a gradient of
dichloromethane through 50% ethyl acetate/dichloromethane.
The product containing fractions were combined and
concentrated in vacuo to give 0.77 g (78%) of a white foam.
1H-NMR
IS-MS, m/e 367.2 (M+1)
Analysis for C21H22N2~4~
Calcd: C, 68.84; H, 6.05; N, 7.65;
Found: C, 68.33; H, 6.01; N, 7.27.
Analytical RPHPLC, Method 1, RT = 25.52 min (100%)
General Procedure: Unless otherwise indicated, the product
of Examples 292-303 was obtained from 1-(4-methoxybenzoyl-D-
phenylglycinyl)-4-oxopiperidine and the indicated amine
using the alkylation procedure described for Example 292
(Alkylation Method C).
Example 292.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(1-pyrrolidinyl)-
piperidine
(Alkylation Method C) To a stirring solution of
1-(4-methoxybenzoyl-D-phenylglycinyl)-4-oxopiperidine (50
mg, 0.14 mmol) and pyrrolidine (0.011 mL, 0.13 mmol) in
1,2-dichloroethane (1 mL) was added sodium triacetoxy-
borohydride (45 mg, 0.21 mmol). After stirring overnight,
the mixture was loaded onto an SCX column (pretreated with a
5% glacial acetic acid in methanol solution), rinsed with
methanol (2 column volumes) and eluted with a 30% 2 N
ammonia/methanol in dichloromethane solution. The solution
was concentrated in vacuo. The product containing fractions
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were combined and concentrated in vacuo to give 48 mg (87%)
of the title compound.
1H-NMR
IS-MS, m/e 422.0 (M+1)
Analytical RPHPLC, Method 1, RT = 21.02 min (100%)
Example 293.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(1-piperidinyl)-
piperidine
Prepared from piperidine (49%).
1H-NMR
IS-MS, m/e 436.0 (M+1)
Analytical RPHPLC, Method 1, RT = 22.14 min (1000)
Example 294.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(4-methylpiperidin-
1-yl)piperidine
Prepared from 4-methylpiperidine (78%).
1H-NMR
IS-MS, m/e 450.0 (M+1)
Analytical RPHPLC, Method 1, RT = 24.06 min (100%)
Example 295.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(4-methylpiperazin-
1-yl)piperidine
Prepared from 1-methylpiperazine (980).
1H-NMR
IS-MS, m/e 451.0 (M+1)
Analytical RPHPLC, Method 1, RT = 18.66 min (99%)
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Example 296.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(4-ethylpiperazin-1-
yl)piperidine
Prepared from 1-ethylpiperazine (76%).
1H-NMR
IS-MS, m/e 465.0 (M+1)
Analytical RPHPLC, Method 1, RT = 19.11 min (100%)
Example 297.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(4-isopropyl-
piperazin-1-yl)piperidine
Prepared from 1-isopropylpiperazine (83%).
1H-NMR
IS-MS, m/e 479.2 (M+1)
Analysis for C28H38N403~0.3H20:
Calcd: C, 69.48; H, 8.04; N, 11.58;
Found: C, 69.22; H, 7.91; N, 11.34.
Analytical RPHPLC, Method 1, RT = 19.56 min (99%)
Example 298.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(hexahydro-1,4-
diazapin-1-yl)piperidine hydrochloride
1H-NMR
IS-MS, m/e 451.0 (M+1)
Analytical RPHPLC, Method 1, RT = 16.86 min (100%)
Example 299.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-[4-methyl-
(hexahydro-1,4-diazapin-1-yl)]piperidine
Prepared from 4-methyl-hexahydro-1,4-diazapine (63%).
1H-NMR
IS-MS, m/e 465.0 (M+1)
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Analytical RPHPLC, Method 1, RT = 18.86 min (98%)
Example 300.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(3-pyridylamino)-
piperidine
Prepared from 3-aminopyridine (25%).
1H-NMR
IS-MS, m/e 445.0 (M+1)
Analytical RPHPLC, Method 1, RT = 23.87 min (100%)
Example 301.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-[(N-methyl-N-
benzyl ) amino] piperidine
Prepared from N-methylbenzylamine (89%).
1H-NMR
IS-MS, m/e 472.0 (M+1)
Analysis for C29H33N3~3'O.1H20:
Calcd: C, 73.58; H, 7.07; N, 8.88;
Found: C, 73.39; H, 7.19; N, 9.06.
Analytical RPHPLC, Method 1, RT = 26.27 min (98%)
Example 302.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-[(3-pyridylmethyl)-
amino]piperidine
Prepared from 3-aminomethylpyridine (72%).
1H-NMR
IS-MS, m/e 459.0 (M+1)
Analysis for C27H3pN403~0.2H20:
Calcd: C, 70.17; H, 6.63; N, 12.12;
Found: C, 70.00; H, 6.53; N, 12.13.
Analytical RPHPLC, Method 1, RT = 16.38 min (100%)
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Example 303.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-[(4-pyridylmethyl)-
amino]piperidine
prepared from 4-aminomethylpyridine (46%).
1H-NMR
IS-MS, m/e 459.0 (M+1)
Analysis for C27H3pN403~0.9H20:
Calcd: C, 68.30; H, 6.75; N, 11.80;
Found: C, 67.99; H, 6.42; N, 11.59.
Analytical RPHPLC, Method 1, RT = 18.36 min (100%)
Examples 304 to 314
General Procedure: Unless otherwise indicated, the product
of Examples 304-314 was obtained from 1-(4-methoxybenzoyl-D-
phenylglycinyl)piperazine and the indicated aldehyde or
ketone using the alkylation procedure described for Example
304 (Alkylation Method D).
Example 304.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(2-pyridylmethyl)-
piperazine
(Alkylation Method D) To a stirring solution of
1-(4-methoxybenzoyl-D-phenylglycinyl)piperazine (50 mg, 0.14
mmol) and 2-pyridinecarboxaldehyde (0.020 mL, 23 mg, 0.21
mmol) in 5% acetic acid/methanol (1 mL) was added NaBH3CN
(20 mg, 0.32 mmol). After 4 h, the solution was loaded onto
an SCX column (pretreated with a 5% glacial acetic acid in
methanol solution), rinsed with methanol (2 column volumes)
and eluted with a 30% 2N ammonia/methanol in dichloromethane
solution. The solution was concentrated in vacuo and the
residue was dissolved in a minimum amount of dichloromethane
and chromatographed over silica gel, eluting with
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dichloromethane, followed by 50% ethyl
acetate/dichloromethane, and finally with a gradient of
2%-10% (2 N NH3 in MeOH) in dichloromethane. The product
containing fractions were combined and concentrated in vacuo
to give 30 mg (48%) of the title compound.
1H-NMR
IS-MS, m/e 444.9 (M+1)
Analytical RPHPLC, Method 1, RT = 21.70 min (100%)
Example 305.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(3-pyridylmethyl)-
piperazine
Prepared from 3-pyridine carboxaldehyde (42%).
1H-NMR
IS-MS, m/e 444.9 (M+1)
Analytical RPHPLC, Method 1, RT = 17.84 min (99%)
Example 306.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(4-pyridylmethyl)-
piperazine
Prepared from 4-pyridine carboxaldehyde (45%).
1H-NMR
IS-MS, m/e 444.9 (M+1)
Analytical RPHPLC, Method 1, RT = 18.36 min (99%)
Example 307.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-phenethylpiperazine
Prepared from phenylacetaldehyde (34%).
1H-NMR
IS-MS, m/e 458.0 (M+1)
Analytical RPHPLC, Method 1, RT = 27.44 min (100%)
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Example 308.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(3-pentyl)piperazine
Prepared from 3-pentanone (88%).
1H-NMR
IS-MS, m/e 424.0 (M+1)
Analytical RPHPLC, Method 1, RT = 23.62 min (100%)
Example 309.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-cyclopentyl-
piperazine
Prepared from cyclopentanone (95%).
1H-NMR
IS-MS, m/e 422.0 (M+1)
Analytical RPHPLC, Method 1, RT = 20.76 min (100%)
Example 310.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(4-methyl-
cyclohexyl)piperazine
Prepared from 4-methylcyclohexanone (46%).
1H-NMR
IS-MS, m/e 450.0 (M+1)
Analytical RPHPLC, Method 1, RT = 27.07 min (isomer 1),
27.74 min (isomer 2).
Example 311.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(tetrahydro-
thiopyran-4-yl)piperazine
Prepared from tetrahydro-4H-thiopyran-4-one (86%).
1H-NMR
IS-MS, m/e 453.9 (M+1)
Analytical RPHPLC, Method 1, RT = 22.96 min (100%)
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Example 312.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(2-indanyl)-
piperazine
Prepared f rom 2 - indanone ( 92 0 ) .
1H-NMR
IS-MS, m/e 469.9 (M+1)
Analytical RPHPLC, Method 1, RT = 26.32 min (100%)
Example 313.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-benzylpiperazine
Prepared from benzaldehyde (870).
1H-NMR
IS-MS, m/e 444.0 (M+1)
Analytical RPHPLC, Method 1, RT = 25.78 min (96%)
Example 314.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(cyclohexyl-
methyl)piperazine
Prepared from cyclohexanecarboxaldehyde (860).
1H-NMR
IS-MS, m/e 450.2 (M+1)
Analytical RPHPLC, Method 1, RT = 28.07 min (940)
Examples 315 to 316
Preparation of Starting Materials
1-(Boc-D-Phenylglycinyl)-4-oxopiperidine
Using Oxidation Method B, the title compound was prepared
from 1-(Boc-D-phenylglycinyl)-4-hydroxypiperidine (44%).
1H-NMR
IS-MS, m/e'333.0 (M+1)
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1-(Boc-D-Phenylglycinyl)-4-(4-methylpiperazin-1-yl)-
piperidine
Using Alkylation Method C, the title compound was prepared
from 1-(Boc-D-phenylglycinyl)-4-oxopiperidine and
methylpiperazine (65%).
1H-NMR
IS-MS, m/e 417.3 (M+1)
Analysis for C23H36N403-
Calcd: C, 66.32; H, 8.71; N, 13.45;
Found: C, 66.25; H, 8.58; N, 13.42.
1-D-Phenylglycinyl-4-(4-methylpiperazin-1-yl)piperidine
HCl gas was bubbled through a stirring solution of 1-(Boc-D-
phenylglycinyl)-4-(4-methylpiperazin-1-yl)piperidine (1.36
g, 3.26 mmol) in ethyl acetate (150 mL). A white
precipitate was formed immediately, but then went back into
solution. After about 5 min, a white precipitate again fell
out of solution. After 10 min, the addition of HC1 was
discontinued and after stirring for a total of 1 h, the
mixture was filtered to give 1.38 g (quantitative) of white
solid.
1H-NMR
IS-MS, m/e 317.3 (M+1)
Analysis for C18H28N40~2.9HC1~2.5H20:
Calcd: C, 46.27; H, 7.74; N, 11.99; C1, 22.01;
Found: C, 46.06; H, 7.51; N, 11.63; C1, 21.78.
General Procedure: The product of Examples 315-316 was
prepared from 1-(D-phenylglycinyl)-4-(4-methylpiperazin-
1-yl)piperidine and the indicated acid using Coupling
Method B.
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Example 315.
1-(Indole-6-carbonyl-D-phenylglycinyl)-4-(4-methylpiperazin-
1-yl)piperidine
Prepared from indole-6-carboxylic acid (66%).
1H-NMR
IS-MS, m/e 460.2 (M+1)
Analytical RPHPLC, Method 1, RT = 17.83 min (99%)
Example 316.
1-(3-Chloroindole- 6-carbonyl-D-phenylglycinyl)-4-(4-methyl-
piperazinyl)piperidine
Prepared from 3-chloroindole-6-carboxylic acid (69%).
1H-NMR
IS-MS, m/e 494.3 (M+1)
Analytical RPHPLC, Method 1, RT = 22.99 min (99%)
Examples 317 to 320
Preparation of Starting Materials
(Cbz-D-phenylglycinyl)piperazine.
Using Deprotection Method D, the title compound was prepared
from 1-(Cbz-D-phenylglycinyl)-4-Boc-piperazine (85%)
1H-NMR
IS-MS, m/e 354.2 (M+1)
Analysis for C2pH23N3~3'0.2H20:
Calcd: C, 67.28; H, 6.61; N, 11.77;
Found: C, 67.10; H, 6.46; N, 11.63.
1-(Cbz-D-phenylglycinyl)-4-(1-methylpiperidin-4-yl)-
piperazine
Using Alkylation Method C, the title compound was prepared
from (Cbz-D-phenylglycinyl)piperazine and 1-methylpiperidin-
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4-one (49%). The product was purified using silica gel
chromatography, eluting with a gradient of dichloromethane
through 10% (2 N ammonia in methanol) / dichloromethane.
1H-NMR
IS-MS, m/e 451.3 (M+1)
Analysis for C26H34N4~3~
Calcd: C, 69.31; H, 7.61; N, 12.43;
Found: C, 69.36; H, 7.71; N, 13.14.
1-D-Phenylglycinyl-4-(1-methylpiperidin-4-yl)piperazine
dihydrochloride.
To a stirring suspension of 5% Pd/C (0.6 g) in ethanol
(25 mL) under nitrogen was added a solution of 1-(Cbz-D-
phenylglycinyl)-4-(1-methylpiperidin-4-yl)piperazine (2.6 g,
5.77 mmol) and acetic acid (1.6 mL) in ethanol (50 mL). The
flask was placed under vacuum and the atmosphere was
replaced with hydrogen (balloon). After 4 h, diatomaceous
earth was added and the mixture was filtered through a pad
of diatomaceous earth and concentrated in vacuo. The
residue was dissolved in ethyl acetate and HC1 gas was
bubbled through the stirring solution to precipitate the
dihydrochloride salt. The mixture was filtered and the
solid was dried in vacuo to give 2.6 g (quantitative) of the
title compound.
1H-NMR
IS-MS, m/e 317.3 (M+1)
General Procedure: The product of Examples 317-320 was
prepared from 1-(D-phenylglycinyl)-4-(1-methylpiperidin-4-
yl)piperazine dihydrochloride and the indicated acid using
Coupling Method B.
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Example 317.
1-(4-Methoxybenzoyl-D-phenylglycinyl)-4-(1-methylpiperidin-
4-yl)piperazine
Prepared from 4-methoxybenzoic acid (19%).
1H-NMR
IS-MS, m/e 451.0 (M+1)
Analytical RPHPLC, Method 1, RT = 16.76 min (100%)
Example 318.
1-(Indole-6-carbonyl-D-phenylglycinyl)-4-(1-methylpiperidin-
4-yl)piperazine
Prepared from indole-6-carboxylic acid (65%).
1H-NMR
IS-MS, m/e 460.2 (M+1)
Analytical RPHPLC, Method 1, RT = 16.68 min (100%)
Example 319.
1-(3-Methylindole-6-carbonyl-D-phenylglycinyl)-4-
(1-methylpiperidin-4-yl)piperazine
Prepared from 3-methylindole-6-carboxylic acid (50%).
1H-NMR
IS-MS, m/e 474.3 (M+1)
Analytical RPHPLC, Method 1, RT = 22.20 min (98%)
Example 320.
1-(3-Chloroindole-6-carbonyl-D-phenylglycinyl)-4-
(1-methylpiperidin-4-yl)piperazine
Prepared from 3-chloroindole-6-carboxylic acid (76%).
1H-NMR
IS-MS, m/e 493.9 (M+1)
Analytical RPHPLC, Method 1, RT = 22.66 min (100%)
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Examples 321 to 324
Preparation of Starting Materials
Ethyl hydroxyimino-pyridine-2-acetate
To a stirring solution of ethyl pyridine-2-acetate (12.6 g,
76.3 mmol) in acetic acid (19 mL) at 5 °C was added a
solution of sodium nitrite (6.05 g, 87.7 mmol) in water
(12 mL) at a rate sufficient to maintain the internal.
temperature below 15 °C. After complete addition and an
additional 30 min, an additional 30 mL of water was added.
The resulting white precipitate was filtered, washed with
water, saturated aqueous NaHC03, and again with water. The
solid was then dried under vacuum to give 14.1 g (95%) of
the title compound.
1H-NMR
IS-MS, m/e 194.9 (M+1)
Analysis for C9H1pN203:
Calcd: C, 55.67; H, 5.19; N, 14.43;
Found: C, 55.79; H, 5.14; N, 14.13.
Boc-D,L-(2-Pyridinyl)glycine ethyl ester
To a solution of ethyl hydroxyimino-pyridine-2-acetate
(7.8 g, 40.15 g) in ethanol (175 mL) and glacial acetic acid
(20 mL) was added 5°s Pd/C, and the mixture was shaken in a
hydrogenation apparatus under an atmosphere of hydrogen at
3.1 bar for 4 h. The mixture was filtered through
diatomaceous earth and concentrated in vacuo. The residue
was dissolved in THF/H20 (1:1, 240 mL) and treated with di-
tert-butyl dicarbonate (14.23 g, 65.2 mmol) and sodium
bicarbonate (27.4 g, 326 mmol). After stirring at room
temperature for 2~h, the solution was concentrated in vacuo
and the residue was partitioned between EtOAc and water.
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The organic phase was washed with brine, dried over
magnesium sulfate, filtered and concentrated in vacuo. The
crude material was purified via chromatography over silica
gel, eluting with a stepwise gradient of 10-20% ethyl
acetate in dichloromethane, to give 8.11 g (72%) of a yellow
oil.
1H-NMR
IS-MS, m/e 281.1 (M+1)
1-[Boc-D,L-(2-Pyridinyl)glycinyl]-1'-methyl-4,4'-
bispiperidine
To a stirring solution of Boc-D,L-(2-pyridinyl)glycine ethyl
ester (3.89 g, 13.88 mmol) in 1, 4-dioxane (20 mL) was added
a solution of lithium hydroxide hydrate (0.64 g, 15.27 mmol)
in water (20 mL). After stirring for 2 h, the solution was
concentrated in vacuo. The residue was dried under vacuum
for 15 h then dissolved in DMF (50 mL). The solution was
cooled to 0 °C, purged with nitrogen, and diethyl
cyanophosphonate (2.5 g, 16.66 mmol) was slowly added.
After 2 min, the solution was treated with a solution of
1-methyl-4,4'-bispiperidine dihydrochloride (3.9 g, 15.27
mmol) and triethylamine (6.8 mL, 48.58 mmol) in DMF (50 mL).
After 2 h, the cold bath was removed and the solution was
allowed to stir overnight. The next morning, the solvent
was evaporated in vacuo and the resulting oil was
partitioned between 3:1 chloroform:isopropyl alcohol and
saturated aqueous sodium bicarbonate. The organic phase was
dried over magnesium sulfate, filtered and concentrated in
vacuo. The crude material was purified via chromatography
over silica gel, eluting with a stepwise gradient of 5-9%
(2 N ammonia in methanol) in dichloromethane to give 2.6 g
(45%) of a clear oil.
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1H-NMR
IS-MS, m/e 417.2 (M+1)
1-[D,L-(2-Pyridinyl)glycinyl]-1'-methyl-4,4'-bispiperidine
(Deprotection Method E) To a stirring solution of 1-[Boc-
D,L-(2-pyridinyl)glycinyl]-1'-methyl-4,4'-bispiperidine (1.8
g, 4.32 mmol) in dichloromethane (90 mL) was added anisole
(2.3 mL, 21.6 mmol), followed by trifluoroacetic acid ( 8.3
mL, 108 mmol). After 4 h, the solvents were evaporated in
vacuo, the crude product was dissolved in methanol and
loaded onto an SCX column (pretreated with a 5% glacial
acetic acid in methanol solution), rinsed with methanol (2
column volumes) and eluted with a 30% 2 N ammonia/methanol
in dichloromethane solution. The product containing
fractions were combined and concentrated in vacuo to give
1.08 g (77%) of a yellow oil.
1H-NMR
IS-MS, m/e 317.2 (M+1)
Analysis for C18H28N40~0.55H20:
Calcd: C, 66.25; H, 8.99; N, 17.17;
Found: C, 66.07; H, 8.49; N, 16.66.
General Procedure: The product of Examples 321-324 was
prepared from 1-[D,L-(2-pyridinyl)glycinyl]-1'-methyl-4,4'-
bispiperidine and the indicated acid using the procedure
described for Example 321 (Coupling Method D).
Example 321.
1-[Indole-6-carbonyl-D,L-(2-pyridinyl)glycinyl]-1'-methyl-
4,4'-bispiperidine
(Coupling Method D) To a stirring solution of 1-[D,L-(2-
pyridinyl)glycinyl]-1'-methyl-4,4'-bispiperidine (0.3 g,
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0.95 mmol) in N, N-dimethylformamide (3 mL) was added
indole-6-carboxylic acid (0.15 g, 0.95 mmol) and 1-hydroxy-
benzotriazole hydrate (0.13 g, 0.95 mmol), followed by
1,3-dicyclohexylcarbodiimide (0.19 g, 0.95 mmol). After
stirring overnight, the mixture was filtered and the
filtrate was loaded onto an SCX column (pretreated with a 5%
glacial acetic acid in methanol solution), rinsed with
methanol (2 column volumes) and eluted with a 30% (2 N
ammonia in methanol) in dichloromethane solution. The
product containing fractions were concentrated in vacuo and
the residue was was chromatographed over silica gel, eluting
with a stepwise gradient of 5-9% (2 N ammonia in methanol)
in dichloromethane to give 255 mg (58%) of a tan foam.
1H-NMR
IS-MS, m/e 460.3 (M+1)
Analytical RPHPLC, Method 1, RT = 14.90 min (100%)
Example 322.
1-[4-Methoxybenzoyl-D~L-(2-pyridinyl)glycinyl]-1'-methyl-
4,4'-bispiperidine
Prepared from 4-methoxybenzoic acid (53%).
1H-NMR
IS-MS, m/e 451.2 (M+1)
Analytical RPHPLC, Method 1, RT = 14.79 min (98%)
Example 323.
1-[3-Methylindol-6-carbonyl-D,L-(2-pyridinyl)glycinyl]-1'-
methyl-4,4'-bispiperidine
Prepared from 3-methyl-6-carboxyindole (40%).
1H-NMR
IS-MS, m/e 474.3 (M+1)
Analytical RPHPLC, Method 1, RT = 18.28 min (97%)
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Example 324.
1-[3-Chloroindole-6-carbonyl-D,L-(2-pyridinyl)glycinyl]-1'-
methyl-4,4'-bispiperidine
Prepared from 3-chloro-6-carboxyindole (71%).
1H-NMR
IS-MS, m/e 494.0 (M+1)
Analysis for C27H32N502C1~0.2H20:
Calcd: C, 65.17; H, 6.56; N, 14.07;
Found: C, 65.57; H, 6.56; N, 13.23.
Analytical RPHPLC, Method 1, RT = 20.96 min (99%)
Examples 325 to 328
Preparation of Starting Materials
Ethyl hydroxyimino-pyridine-3-acetate
Using the procedure of Tikk et al. [Acta. Chimica Hungarica,
114(3-4), 355], a mixture of ethyl hydroxyimino-pyridine-3-
acetate and n-butyl hydroxyimino-pyridine-3-acetate was
prepared from ethyl pyridine-3-acetate and n-butyl nitrite.
1H-NMR
IS-MS, m/e 195 (M+1), 223.1 (M+1)
Boc-D,L-(3-Pyridinyl)glycine ethyl ester
Using methods substantially equivalent to those described
above in preparation of Boc-D,L-(2-pyridinyl)glycine ethyl
ester, the title compound was prepared from the above ethyl
hydroxyimino-pyridine-3-acetate (57%).
1H-NMR
IS-MS, m/e 281.1(M+1)
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1-[Boc-D,L-(3-Pyridinyl)glycinyl]-1'-methyl-4,4'-
bispiperidine
Using methods substantially equivalent to those described in
preparation of 1-[Boc-D,L-(2-pyridinyl)glycinyl]-1'-methyl
4,4'-bispiperidine, the title compound was prepared from
Boc-D,L-(3-pyridinyl)glycine ethyl ester (20%).
1H-NMR
IS-MS, m/e 417.2 (M+1)
1-[D,L-(3-Pyridinyl)glycinyl]-1'-methyl-4,4'-bispiperidine
Using methods substantially equivalent to those described in
preparation of 1-[D,L-(2-pyridinyl)glycinyl]-1'-methyl-4,4'-
bispiperidine, the title compound was prepared from
1-[Boc-D,L-(3-pyridinyl)glycinyl]=1'-methyl-4,4'-
bispiperidine (75%).
1H-NMR
IS-MS, m/e 317.2 (M+1)
General Procedure: The product of Examples 325-328 was
prepared from 1-[D,L-(3-pyridinyl)glycinyl]-1'-methyl-4,4'-
bispiperidine and the indicated acid using the procedure
described for Example 325 (Coupling Method D).
Example 325.
1-[4-Methoxybenzoyl-D,L-(3-pyridinyl)glycinyl]-1'-methyl-
4,4'-bispiperidine
Prepared from 4-methoxybenzoic acid (45%).
1H-NMR
IS-MS, m/e 451.2 (M+1)
Analysis for C26H34N4~3'1.2H20:
Calcd: C, 66.13; H, 7.77; N, 11.87;
Found: C, 66.61; H, 7.27; N, 11.87.
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Analytical RPHPLC, Method 1, RT = 12.98 min (98%)
Example 326.
1-[Indole-6-carbonyl-D,L-(3-pyridinyl)glycinyl]-1'-methyl-
4,4'-bispiperidine
Prepared from indole-6-carboxylic acid (36%).
1H-NMR
IS-MS, m/e 460.3 (M+1)
Analysis for C27H33N502~1.5H20:
Calcd: C, 66.64; H, 7.46; N, 14.39;
Found: C, 66.71; H, 6.87; N, 13.89.
Analytical RPHPLC, Method 1, RT = 14.39 min (100%)
Example 327.
1-[3-Methylindole-6-carbonyl-D,L-(3-pyridinyl)glycinyl]-1'-
methyl-4,4'-bispiperidine
Prepared from 3-methylindole-6-carboxylic acid (40%).
1H-NMR
IS-MS, m/e 474.3(M+1)
Analysis for C28H35N502~1.6H20:
Calcd: C, 66.93; H, 7.66; N, 13.94;
Found: C, 66.63; H, 6.99; N, 13.52.
Analytical RPHPLC, Method 1, RT = 16.98 min (98%)
Example 328.
1-[3-Chloroindole-6-carbonyl-D,L-(3-pyridinyl)glycinyl]-1'-
methyl-4,4'-bispiperidine
Prepared from 3-chloroindole-6-carboxylic acid (46%).
1H-NMR
IS-MS, m/e 494.2 (M+1)
Analysis for C27H32C1N502~1.1H20:
Calcd: C, 63.11; H, 6.71; N, 13.63;
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Found: C, 62.84; H, 6.32; N, 13.26.
Analytical RPHPLC, Method 1, RT = 19.63 min (100x)
Examples 329 to 330
Preparation of Starting Materials
Boc-D-[3-(ethanesulfonylamino)phenyl]glycine
To a stirring solution of D-3- (ethanesulfonylamino)-
phenylglycine (20 g, 77.43 mmol) and sodium carbonate
(8.2 g, 77.43 mmol) in 3:1 THF/water (200 mL) at 0 °C, was
added di-tert-butyl dicarbonate (18.5 g, 85.17 mmol). After
stirring for 30 min, the cold bath was removed; and after an
additional 30 min at room temperature, the solvent was
removed and the residue was partitioned between ethyl
acetate and water. The aqueous layer was acidified to pH 2
with KHS04 and extracted twice with ethyl acetate. The
combined ethyl acetate extracts were washed with water,
dried with Na2S04, filtered and concentrated in vacuo to
give 17.51 g (63%) of a white solid.
1H-NMR
IS-MS, m/e 357.0 (M-1)
1- [Boc-D- [3- (ethanesulfonylamino) phenyl] glycinyl] -1' -methyl-
4,4'-bispiperidine
To a stirring solution of Boc-D-[3-(ethanesulfonylamino)-
phenyl]glycine (5 g, 13.95 mmol) in dichloromethane at 0 °C,
diethyl cyanophosphonate (2.12 mL, 13.95 mmol) and
diisopropylethylamine (4.86 mL, 27.91 mmol) and then
N-methylbispiperidine dihydrobromide (4.32 g, 12.56 mmol)
were added; and the mixture was stirred at 0 °C for 3 h.
The reaction mixture was then stirred at room temperature
overnight, filtered, washed with saturated aqueous sodium
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bicarbonate and water, dried over sodium sulfate, filtered
and concentrated in vacuo to give 5 g (76%) of a tan foam.
1H-NMR
IS-MS, m/e (M+1)
1- [D- [3- (Ethanesulfonylamino) phenyl] glycinyl] -1' -methyl-
4,4'-bispiperidine
Using Deprotection Method E, the title compound was prepared
from 1- [Boc-D- [3- (ethanesulfonylamino) phenyl] glycinyl] -1' -
methyl-4,4'-bispiperidine (74%).
1H-NMR
IS-MS, m/e 423.1(M+1)
Analysis for C21H34N4~3S'1.3H20:
Calcd: C, 56.55; H, 8.27; N, 12.56;
Found: C, 56.68; H, 7.87; N, 11.97.
General Procedure: The product of Examples 329-330 was
prepared from 1- [D- [3- (ethanesulfonylamino) phenyl] glycinyl] -
1'-methyl-4,4'-bispiperidine and the indicated acid using
the procedure described for Example 321 (Coupling Method D).
Example 329.
1-[4-Methoxybenzoyl-D-[3-(ethanesulfonylamino)-
phenyl]glycinyl]-1'-methyl-4,4'-bispiperidine
Prepared from 4-methoxybenzoic acid (43%).
1H-NMR
IS-MS, m/e 557.3(M+1)
Analysis for C29H40N4~5SØ9H20:
Calcd: C, 60.79; H, 7.35; N, 9.78;
Found: C, 60.49; H, 7.08; N, 9.62.
Analytical RPHPLC, Method 1, RT = 22.68 min (98%)
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Example 330.
1-[Indole-6-carbonyl-D-[3-(ethanesulfonylamino)-
phenyl]glycinyl]-1'-methyl-4,4'-bispiperidine
Prepared from indole-6-carboxylic acid (58%).
1H-NMR
IS-MS, m/e (M+1)
Analysis for C3pH39N5~4S.2H20:
Calcd: C, 59.88; H, 7.20; N, 11.64;
Found: C, 59.97; H, 6.65; N, 11.43.
Analytical RPHPLC, Method 1, RT = 29.02 min (98%)
Example 331.
1-(3-Aminoindazole-5-carbonyl-D-phenylglycinyl)-1'-methyl-
4,4'-bispiperidine
To a stirring solution of 1-(3-cyano-4-fluorobenzoyl-D-
phenylglycinyl)-1'-methyl-4,4'-bispiperidine (120 mg, 0.259
mmol) in p-dioxane (6 mL) was added hydrazine hydrate
(26 mg, 0.518 mmol), and the solution was heated to reflux.
After 2 h, the heat was removed and the solvent was
evaporated in vacuo. The residue was dissolved in ethanol
and heated to reflux. After 12 h, the solution was cooled
and concentrated in vacuo. The residue was chromatographed
over silica gel, eluting with l00 (2 N ammonia in mthanol)
in dichloromethane. The product containing fractions were
combined and concentrated in vacuo to give 75 mg (620) of an
off white solid.
1H-NMR
IS-MS, m/e 475.3 (M+1)
Analytical RPHPLC, Method 1, RT = 14.72 min (1000)
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Example 332.
1-(1-Methyl-3-aminoindazole-5-carbonyl-D-phenylglycinyl)-1'-
methyl-4,4'-bispiperidine
Using methods substantially equivalent to those described in
Example 331, the title compound was prepared from
methylhydrazine and 1-(3-cyano-4-fluorobenzoyl-D-
phenylglycinyl)-1'-methyl-4,4'-bispiperidine (31%).
1H-NMR
IS-MS, m/e 489.2 (M+1)
Analytical RPHPLC [Vydac C18, linear gradient of 98/2 -
80/20 (0.1% TFA in water / 0.1% TFA in acetonitrile) over 40
min, 1 mL/min] RT = 38.99 min (100%).
Example 333.
1-(Imidazo[1,2-a]pyrimidine-2-carbonyl-D-phenylglycinyl)-1'-
methyl-4,4'-bispiperidine
Imidazo[1,2-a]pyrimidine-2-carboxylic acid
To a stirring solution of ethyl 1-(imidazo[1,2-a]pyrimidine-
2-carboxylate (1 g, 5.2 mmol) [Abignente, et al. Eur. J.
Med. Chem. (1994) 2~, 279] in ethanol (30 mL) was added 2 N
aqueous KOH (10 mL, 20 mmol). The solution was heated to
reflux; and after 2 h, the heating mantle was removed, the
solution was allowed to cool and the solvent was removed by
rotary evaporation. The residue was dissolved in water
(20 mL) and acidified to pH 3 with 5 N HC1. The resulting
precipitate was filtered, washed with water and dried in
vacuo to give 700 mg (83%) of a tan solid.
1H-NMR
FD-MS, m/e 163.2 (M+1)
Analysis for C7H5N302:
Calcd: C, 51.54; H, 3.09; N, 25.76;
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Found: C, 51.12; H, 3.25; N, 25.25.
1-(Imidazo[1,2-a]pyrimidine-2-carbonyl-D-phenylglycinyl)-1'-
methyl-4,4'-bispiperidine
Using Coupling Method B, the title compound was prepared
from imidazo[1,2-a]pyrimidine-2-carboxylic acid and 1-D-
phenylglycinyl-1'-methyl-4,4'-bispiperidine (56%).
1H-NMR
IS-MS, m/e 461.2 (M+1)
Analytical RPHPLC [Vydac C18, linear gradient of 98/2 -
80/20 (0.1% TFA in water / 0.1% TFA in acetonitrile) over 40
min, 1 mL/min] RT = 32.72 min (96%).
Example 334.
1-(5,6,7,8-Tetrahydro-imidazo[1,2-a]pyrimidine-2-carbonyl-D-
phenylglycinyl)-1'-methyl-4,4'-bispiperidine
To a stirring solution of 1-(imidazo[1,2-a]pyrimidine-2-
carbonyl-D-phenylglycinyl)-1'-methyl-4,4'-bispiperidine
(250 mg, 0.542 mmol) in ethanol (5 mL) was added sodium
borohydride (103 mg, 2.71 mmol). After 24 h, the mixture
was diluted with water and extracted 3 times with
dichloromethane. The organic phase was dried (MgS04),
filtered and concentrated in vacuo. The residue was
dissolved in dichloromethane and chromatographed over silica
gel, eluting with 5% through 10% (2 N NH3 in MeOH) in
dichloromethane. The product containing fractions were
combined and concentrated in vacuo to give 55 mg (20%) of
the title compound.
1H-NMR
IS-MS, m/e 465.2 (M+1)
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Analytical RPHPLC [Vydac C18, linear gradient of 98/2 -
80/20 (0.1% TFA in water / 0.1% TFA in acetonitrile) over 40
min, 1 mL/min] RT = 28.44 min (97%).
Examples 335 to 338
Preparation of Starting Materials
Ethyl hydroxyimino-pyridine-4-acetate
The oxime was prepared in 82% yield from ethyl pyridine-4-
acetate using a procedure similar to that described above
under Examples 321-324 for the preparation of ethyl
hydroxyimino-pyridine-2-acetate.
1H-NMR (DMSO)
IS-MS, m/e 194.9 (M+1)
Boc-D,L-(4-Pyridinyl)glycine ethyl ester
The protected amino ester is prepared from ethyl
hydroxyimino-pyridine-4-acetate using a procedure similar to
that described above under Examples 321-324 for the
preparation of Boc-D,L-(2-pyridinyl)glycine ethyl ester.
1-[Boc-D,L-(4-Pyridinyl)glycinyl]-1'-methyl-4,4'-
bispiperidine
The protected amide is prepared from Boc-D,L-(4-pyridinyl)-
glycine ethyl ester and 1-methyl-4,4'-bispiperidine
dihydrochloride using a procedure similar to that described
above under Examples 321-324 for the preparation of 1-[Boc-
D,L-(2-pyridinyl)glycinyl]-1'-methyl-4,4'-bispiperidine.
1-[D,L-(4-Pyridinyl)glycinyl]-1'-methyl-4,4'-bispiperidine
The amine is prepared from 1-[Boc-D,L-(4-pyridinyl)-
glycinyl]-1'-methyl-4,4'-bispiperidine using a procedure
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similar to that described above under Examples 321-324 for
the preparation of 1-[D,L-(2-pyridinyl)glycinyl]-1'-methyl-
4,4'-bispiperidine.
General Procedure: The product of Examples 335-338 is
prepared from 1-[D,L-(4-pyridinyl)glycinyl]-1'-methyl-4,4'-
bispiperidine and the indicated acid using Coupling
Method D.
Example 335.
1-[4-Methoxybenzoyl-D,L-(4-pyridinyl)glycinyl]-1'-methyl-
4,4'-bispiperidine
From 4-methoxybenzoic acid.
Example 336.
1-(Indole-6-carbonyl-D,L-(4-pyridinyl)glycinyl]-1'-methyl-
4,4'-bispiperidine
From indole-6-carboxylic acid.
Example 337.
1-[3-Methylindole-6-carbonyl-D,L-(4-pyridinyl)glycinyl]-1'-
methyl-4,4'-bispiperidine
From 3-methylindole-6-carboxylic acid.
Example 338.
1-[3-Chloroindole-6-carbonyl-D,L-(4-pyridinyl)glycinyl]-1'-
methyl-4,4'-bispiperidine
From 3-chloroindole-6-carboxylic acid.
Assay protocols
Enzyme Inhibition assays:
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The ability of a test compound to inhibit factor Xa may be
evaluated in one or more of the following Enzyme Inhibition
assays, or in other standard assays known to those skilled
in the art.
Enzyme Inhibition Assay 1
Enzyme assays were carried out at room temperature in O.1M
phosphate buffer, pH7.4 according to the method of
Tapparelli et al (J. Biol. Chem. 1993,268,4734-4741).
Purified human factor Xa, trypsin, thrombin and plasmin were
purchased from Alexis Corporation, Nottingham, UK. Urokinase
was purchased from Calbiochem, Nottingham, UK. Chromogenic
substrates for these enzymes; pefachrome-FXA, pefachrome-
TRY, pefachrome-TH, pefachrome-PL and pefachrome-UK were
purchased from Pentapharm AG, Basel, Switzerland. Product
(p-nitroaniline) was quantified by adsorption at 405nm in 96
well microplates using a Dynatech MR5000 reader (Dynex Ltd,
Billingshurst, UK). Km and Ki were calculated using SAS PROC
NLIN (SAS Institute, Cary, NC, USA, Release 6.11) Km values
were determined as 100.9~M for factor Xa/pefachrome-FXA and
81.6~M for trypsin/pefachrome-TRY. Inhibitor stock solutions
were prepared at 40mM in Me2S0 and tested at 500~M, 50~M and
S~M. Accuracy of Ki measurements was confirmed by
comparison with Ki values of known inhibitors of factor Xa
and trypsin.
In agreement with published data, benzamidine inhibited
factor Xa, trypsin, thrombin, plasmin and urokinase with Ki
values of 155~M, 21~M, 330nM, 200nM and 100nM respectively.
NAPAP inhibited thrombin with a Ki value of 3nM. Compounds
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of the invention were found to have activity in these
assays.
Enzyme Inhibition Assay 2
Human factor Xa and human thrombin were purchased from
Enzyme Research Laboratories (South Bend, Indiana, USA).
Other proteases were from other commercial sources.
Chromogenic para-nitroanilide peptide protease substrates
were purchased from Midwest Biotech (Fishers, Indiana, USA).
The binding affinities for human factor Xa were measured as
apparent association constants (Kass) derived from protease
inhibition kinetics as described previously.a.b,c,d The
apparent Kass values were obtained using automated (BioMek-
1000) dilutions of inhibitors (Kass determinations are
performed in triplicate at each of four-eight inhibitor
concentrations) into 96-well plates and chromogenic
substrate hydrolysis rates determined at 405 nm using a
Thermomax plate reader from Molecular Devices (San
Francisco). For factor Xa inhibition, the assay protocol
was: 50 ~l buffer (0.06 M tris, 0.3 M NaCl, pH 7.4); 25 ~1
inhibitor test solution (in MeOH); 25 ~1 human factor Xa (32
nM in 0.03 M tris, 0.15 M NaCl, 1 mg/ml HSA); finally, 150
~,1 BzIleGluGlyArgpNA (0.3 mM in water) added within 2 min to
start hydrolysis. Final factor Xa was 3.2 nM. Free [Xa]
and bound [Xa] were determined from linear standard curves
on the same plate by use of SoftmaxPro software for each
inhibitor concentration and apparent Kass calculated for
each inhibitor concentration which produced hydrolysis
inhibition between 20o and 800 of the control (3.2 nM factor
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Xa) : apparent Kass - [E:I] / [Ef] [I f] - [Eb] / [Ef] [Io-Ib] .
The apparent Kass values so obtained are approximately the
inverse of the Ki for the respective inhibitors [1/appKass =
app Ki]. The variability of mean apparent Kass values
determined at the single substrate concentration was +/-
15%. The assay system Km was measured as 0.347 +/- 0.031 mM
[n=4]; and Vmax was 13.11 +/- 0.76 ~.M/min.
Kass values were determined with thrombin and other
proteases using the same protocol with the following enzyme
and substrate concentrations: thrombin 5.9 nM with 0.2 mM
BzPheValArgpNA; XIa 1.2 nM with 0.4 mM pyroGluProArgpNA;
XIIa 10 nM with 0.2 mM HDProPheArgpNA; plasmin 3.4 nM with
0.5 mM HDVaILeuLyspNA; nt-PA 1.2 nM with 0.8 mM
HDIleProArgpNA; and urokinase 0.4 nM with 0.4 mM
pyroGluGlyArgpNA; aPC 3 nM with 0.174 mM pyroGluProArgpNA;
plasma kallikrein 1.9 nM with D-ProPheArgpNA; bovine trypsin
1.4 nM with 0.18 mM BzPheValArgpNA.
Citations
(a) Sall DJ, JA Bastian, SL Briggs, JA Buben, NY
Chirgadze, DK Clawson, ML Denny, DD Giera, DS Gifford-
Moore, RW Harper, KL Hauser, VJ Klimkowski, TJ Kohn, H-
S Lin, JR McCowan, AD Palkowitz, GF Smith, ME Richett,
K Takeuchi, KJ Thrasher, JM Tinsley, BG Utterback, S-CB
Yan, M Zhang. Dibasic Benzo[b]thiophenes Derivatives
as a Novel Class of Active Site Directed Thrombin
Inhibitors. 1. Determination of the Serine Protease
Selectivity, Structure-Activity Relationships and
Binding Orientation. J Med Chem 40 3489-3493 (1997).
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(b) Smith GF, TJ Craft, DS Gifford-Moore, VJJ Coffman, KD
Kurz, E Roberts, RT Shuman, GE Sandusky, ND Jones, N
Chirgadze, and CV Jackson. A Family of Arginal Thrombin
Inhibitors Related to Efegatran. Sem. Thrombos. Hemost. 22,
173-183 (1996).
(c) Smith GF, DS Gifford-Moore, TJ Craft, N Chirgadze, KJ
Ruterbories, TD Lindstrom, JH Satterwhite. Efegatran: A New
Cardiovascular Anticoagulant. In New Anticoagulants for the
Cardiovascular Patient. Ed. R Pifarre. Hanley & Belfus,
Inc., Philadelphia (1997) pp 265-300.
(d) Sall DJ, JA Bastian, NY Chirgadze, ML Denny, MJ
Fisher, DS Gifford-Moore, RW Harper, VJ Klimkowski, TJ
Kohn, HS Lin, JR McCowan, ME Richett, GF Smith, K
Takeuchi, JE Toth, M Zhang. Diamino Benzo[b]thiophene
Derivatives as a Novel Class of Active Site Directed
Thrombin Inhibitors: 5. Potency, Efficacy and
Pharmacokinetic Properties of Modified C-3 Side Chain
Derivatives. In press, J Med Chem (1999).
In general, the compounds of formula (I) exemplified in Part
1 of the Examples herein have been found to exhibit a Ki of
10 ~M or less in Assay 1 and/or a Kass of at least 0.1 x 106
L/mole in Assay 2.
The ability of a test compound to elongate Partial
Thromboplastin Time (Prothrombin Time) may be evaluated in
the following test protocols.
Partial Thromboplastin Time (Prothrombin) Test Protocol
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Venous blood was collected into 3.2% (0.109m) trisodium
citrate vacutainer tubes at 1 volume of anticoagulant to
nine volumes of blood. The blood cells were separated by
centrifugation at 700g for ten minutes to yield plasma,
which was frozen at 700C until required.
To perform the test, 1001 of plasma was pipetted into in a
glass test tube, 1~1 of test compound in DMSO was added, and
allowed to warm to 370 over two minutes. 1001 of warm (370)
Manchester (tissue thromboplasin) reagent (Helena
Biosciences, UK) was added, allowed to equilibrate for two
minutes. 1001 of warm (370) 25mM calcium chloride solution
was added to initiate clotting. The test tube was tilted
three times through a 900 angle every five seconds to mix
the reagents and the time to clot formation recorded. Data
from a series of observations and test compound
concentrations are analysed by a SAS statistical analysis
program and a CT2 (Concentration required to double clotting
time) for each compound is generated.
Compounds of the invention were found to significantly
elongate the partial thromboplastin time (Prothrombin time).
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Example No. Conc. necessary to double
the prothrombin time (~M)a
8 26
27 6.7
30 7.8
32 11
35 8.8
38 9.0
3 9 12
40 12
62 8.6
63 2.1
64 4.4
65 6.1
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66 2.1 (average of 3 tests)
68 3.6
69 5.8
70 4.0
a The concentration quoted is that of the solution which,
when added to the other reagents in the assay, doubles
prothrombin time. The final concentration in the assay
mixture is one third of this value.
By way of comparison with the result for the compound
of Example 66, the compound of Example 75 of W099/11657 was
found to double prothrombin time at a concentration of
11.4~M (average of 3 tests).
By way of comparison with the result for the compound
of Example 35, 1-aminoisoquinolin-7-oyl-D-phenylglycine-4-
(4-fluoro-2-methanesulfonylphenyl)-piperazinamide
ditrifluoroactetate salt (a compound within the scope of
W099/11657) was found to double prothrombin time at a
concentration of 45~,M (average of 3 tests).
Alternative Prothrombin Time and APTT Protocols
Coagulation Determinations. Prothrombin Times and APTT
values were determined in HUMAN PLASMA with a STA instrument
(Stago). BioPT is a special non-plasma clotting assay
triggered with human tissue factor (Innovin). Possible
binding to albumen or to lipid was assessed by comparing the
BioPT effects in the presence/absence of 30 mg/ml human
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albumen (HSA) and 1 mg/ml phosphatidyl choline (PC).
Inhibitors were delivered in 50% MeOH vehicle.
APTT ASSAY
75 ~.1 plasma Citrol Baxter-Dade Citrated Normal
Human Plasma
25 ~,1 test sol' n
75 ~l Actin Baxter-Dade Activated Cephaloplastin incubate 2
min min. c~ 37°
75 ~1 CaCl2 (0.02 M)
PT ASSAY
75 ~1 plasma
25 ~1 test sol'n
75 ~1 saline incubate 1 min. @ 37° C
75 ~1 Innovin Baxter-Dade Recombinant Human Tissue Factor
Compounds of the invention were found to be potent
inhibitors of factor Xa.
Examples Part 2
Experimental:
Abbreviations used follow IUPAC-IUB nomenclature. Additional
abbreviations are HPLC, high-performance liquid
chromatography; LC/MS, liquid chromatography / mass
spectrometry; rt, retention time; NMR, nuclear magnetic
resonance, TBTU, 2-(1H-(benzotriazol-1-yl)-1,1,3,3-
tetramethyluroniumtetrafluoroborate. Starting materials were
purchased from Aldrich (Gillingham, UK), Lancaster
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(Morecambe, UK), Avocado (Heysham, UK), Maybridge (Tintagel,
UK), Nova Biochem (Nottingham, UK) or Bachem.
Purification:
Flash column chromatography was carried out using Merck
silica gel Si60 (40-63 Vim, 230-400 mesh). Purification of
final products was by crystallisation, flash column
chromatography or gradient reverse phase HPLC on a Waters
Deltaprep 4000 at a flow rate of 50 mL/minute using a
Deltapak C18 radial compression column (40 mm x 210 mm, 10-
mm particle size). Eluant A consisted of aqueous
trifluoroacetic acid (0.1 %) and eluant B 90% acetonitrile
in aqueous trifluoroacetic acid (0.1 %) with gradient
elution (Gradient, 0 minutes 5 % B for 1 minutes, then 5 % B
15 to 20 % B over 4 minutes, then 20 % B to 60 % B over 32
minutes). Fractions were analysed by analytical HPLC and
LC/MS before pooling those with >95 % purity for
lyophilisation.
Analysis:
Proton nuclear magnetic resonance (1H NMR) spectra were
recorded on a Bruker DPX300 (300 MHz). Analytical HPLC's
were performed on a Shimadzu LC6 gradient system equipped
with an autosampler. Eluant A consisted of aqueous
trifluoroacetic acid (0.1 %) and eluant B consisted of 90
acetonitrile and 10 % water, containing trifluoroacetic acid
(0.1 %). Gradient 1 elution began at 5 % B and increased to
100 % B over seven minutes. Gradient 2 elution began at 5 %
B and increased to 100 % B over ten minutes. Gradient 3
elution began at 5 % B for one minute, increasing to 20 % B
after the fourth minute, 40 % B after~the 14"' minute and
then 100 % B after the 15t'' minute. The columns used were
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Luna 2 C18 (3 ~, 30 mm x 4.6 mm), Luna 2 C18 (5 ~, 150 mm x
2 mm) and a Symmetry Rp8 (3.5 ~, 50 x 2.1 mm).
LC/MS were performed on a PESCIEX single quadrupole API-
150EX instrument, equipped with a Luna 2 C18 column (3 ~,, 30
mm x 4.6 mm) eluting with 20 % to 100 °s acetonitrile in
water over five minutes.
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Example 1
3-(Aminomethyl)benzoyl-D-phenylglycine 2-
aminobenzothiazol-6-amide bis(trifluoroacetate) salt
2,6-Diaminobenzothiazole
2-Amino-6-nitrobenzothiazole (500 mg, 2.56 mmol) was
dissolved in methanol (20 mL) and 10 % palladium on carbon
(50 mg) was added as a slurry in methanol (1 mL). The
atmosphere was replaced with hydrogen and the suspension was
stirred overnight. The catalyst was removed by suction
filtration and the solvent evaporated to afford 2,6-
diaminobenzothiazole (420 mg, 99 %) as a pale yellow solid.
N-BOC-D-Phenylglycine 2-aminobenzothiazol-6-amide
N-BOC-D-Phenylglycine (250 mg, 1.0 mmol), 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (190
mg, 1.0 mmol) and 7-aza-1-hydroxybenzotriazole (140 mg, 1.0
mmol) were stirred in dimethylformamide (3 mL) for ten
minutes. 2,6-Diaminobenzothiazole (160 mg, 1.0 mmol) was
then added and the solution was stirred overnight at room
temperature. Ethyl acetate (15 mL) was added and the
solution was washed with water (5 mL), saturated citric acid
solution (5 mL), saturated NaHC03 (5 mL) and water (5 mL),
and dried over MgS04. The solvent was removed under reduced
pressure to afford N-BOC-D-phenylglycine 2-
aminobenzothiazol-6-amide.
1H NMR (CDC13) : 8.93 (1 br C(O)NHAr) ; 7.72 (1 H,
H, s, s,
benzothiazole C (7)H); 7.35(2 br s, Ph); 7.23 - 7.05
H, (3
H, m, Ph); 6.93 (1 H, d, Hz, benzothiazole C(4)H
J = 10 or
C(5)H); 6.72 (1 H, d, J 10 benzothiazole C(4)H or
= Hz,
C(5)H); 6.05 (1 H, d, J 7 Hz, CHPh); 5.92 (2 H, br s,
=
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NHz) ; 5.45 (1 H, br s, BOCNH) ; 1.27 (9 H, s, 'Bu) .
D-Phenylglycine 2-aminobenzothiazol-6-amide
A solution of N-BOC-D-phenylglycine 2-aminobenzothiazol-5-
amide in dichloromethane (5 mL) was treated with
trifluoroacetic acid (5 mL) and stirred for 30 minutes. The
dichloromethane and excess trifluoroacetic acid were removed
under reduced pressure and the residue was triturated with
diethyl ether to afford D-phenylglycine 2-aminobenzothiazol-
6-amide as its trifluoroacetate salt (350 mg, 89 0).
3-(Aminomethyl)benzoyl-D-phenylglycine 2-aminobenzothiazol-
6-amide trifluoroacetate salt
N-BOC-3-aminomethylbenzoic acid (250 mg, 1.0 mmol), 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (190
mg, 1.0 mmol) and 7-aza-1-hydroxybenzotriazole (140 mg, 1.0
mmol) were stirred in dimethylformamide (10 mL) for five
minutes. D-Phenylglycine 2-aminobenzothiazol-6-amide
trifluoroacetate salt (350 mg, 0.85 mmol) was then added and
the mixture was stirred overnight. The solution was poured
into ethyl acetate (20 mL) and washed with 5 o HC1 (5 mL),
saturated NaHC03 (5 mL) and water (5 mL), dried over MgS04
and the solvent removed under reduced pressure. The crude
product was purified by flash column chromatography on
silica gel (60 % ethyl acetate / 40 % hexane to 100 % ethyl
acetate) to afford N-BOC-3-(aminomethyl)benzoyl-D-
phenylglycine 2-aminobenzothiazol-6-amide. This was
dissolved in dichloromethane (5 mL) and trifluoroacetic acid
(5 mL) was added. The solution was stirred at room
temperature for 30 minutes before the dichloromethane and
excess trifluoroacetic acid were removed under reduced
pressure. The residue was triturated with diethyl ether to
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afford 3-(aminomethyl)benzoyl-D-phenylglycine 2-
aminobenzothiazol-6-amide as its trifluoroacetate salt (150
mg, 32 °s ) .
1H NMR (d4 MeOH) : 8 . 21 ppm ( 1 H, s, benzothiazole C ( 7 ) H) ;
7.97 (1 H, s, aminomethylbenzoyl C(2)H); 7.94 (1 H, d, J = 5
Hz, 3-(aminomethyl)benzoyl C(6)H); 7.80 - 7.48 (5 H, m, Ar);
7.47 - 7.32 (4 H, m, Ar); 5.81 (1 H, s, CHPh); 4.22 (2 H, s,
CHZNHZ ) .
HPLC (Luna 2, Gradient 1): rt = 2.80 minutes.
LC/MS (Lung 2, Gradient 4): rt = 1.40 minutes, 432 (MH)'.
Examples 2 - 34 were prepared in the same fashion as Example
1, starting with the indicated nitro-compound or amine.
Other functional groups present were protected
appropriately.
Example 2
3-(Aminomethyl)benzoyl-D-phenylglycine phenylamide
trifluoroacetate salt
Prepared from aniline.
1H NMR (d4 MeOH): 7.85 ppm (2 H, br s, Ar); 7.49 (6 H, m,
Ar); 7.27 (5 H, m, Ar) 7.01 (1 H, t, J = 9 Hz, Ar); 5.70 (1
H, s, CHPh) ; 4.12 (2 H, s, CHzNHz) .
HPLC (Luna 2, Gradient 1): rt = 3.59 minutes.
LC/MS (tuna 2, Gradient 4): rt = 1.99 minutes, 360 (MH)+.
Example 3
2-Amino-5-(aminomethyl)benzoyl-D-phenylglycine
(1S,2S,3S,5R)-isopinocamphamide dihydrochloride salt
Prepared from (1S,2S,3S,5R)-(+)-isopinocampheylamine.
1H NMR (d4 MeOH) : 7.52 ppm (1 H, s, Ar-C (6) H) ; 7.42 (2 H, d,
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J = 10, 2 x Ph-o-CH); 7.32 - 7.2 (3 H, m, 2 x Ph-m-CH, Ph-p-
CH) ; 7.12 (1 H, d, J = 11 Hz, Ar-C(4)H) ; 6.67 (1 H, d, J =
11 Hz, Ar-C(3)H); 5.53 (1 H, s, NCH(Ph)); 4.18 (1 H,
quintet, J = 8 Hz, ipc-C (1) H) ; 3 . 90 (2 H, s, CHzNHz) ; 2 .42 -
2.23 (2 H, m, ipc-C(3)H and ipc-(C(2)H); 1.91 (1 H, m, ipc-
(C)6H); 1.80 (1 H, br s, ipc-(C)5H); 1.74 (1 H, t, J = 5 Hz,
ipc- (C) 6H) ; 1.32 (1 H, dd, J = 14, 8 Hz, ipc-C(7)H) ; 1.14 (3
H, s, ipc-C(8)H3) ; 1.02 (3 H, d, J = 8 Hz, ipc-C(10)H3) ; 0.95
(3 H, s, ipc-C (9) H3) ; 0 . 87 (1 H, d, J = 11 Hz, ipc-C (7) H) .
HPLC (Luna 2, Gradient 1): rt = 4.21 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.10 minutes, 418 (MH-NH3)+.
Example 4
3-(Aminomethyl)benzoyl-D-phenylglycine quinolin-3-
ylamide trifluoroacetate salt
Prepared from 3-aminoquinoline.
1H NMR (d4 MeOH): 9.21 and 8.88 ppm (1 H each, s, quinoline
C(2)H and C(4)H) ; 8.10 - 7.90 (4 H, m, Ar) ; 7.81 (1H, t, J =
7 Hz, Ar); 7.77 - 7.55 (5 H, m, Ar); 7.53 - 7.25 (3 H, m,
Ar) ; 5.91 (1 H, s, CH_Ph) ; 4.20 (2 H, s, CHzNHZ) .
HPLC (Luna 2, Gradient 1): rt = 2.98 minutes.
LC/MS (Lung 2, Gradient 4): rt = 1.83 minutes, 411 (MH)'.
Example 5
3-(Aminomethyl)benzoyl-D-phenylglycine 4-(1-
piperidyl)phenylamide trifluoroacetate salt
Prepared from 4-(1-piperidyl)aniline.
1H NMR (d4 MeOH) : 7.97 ppm (2 H, m, Ar) ; 7.8 (2 H, d, J = 9
Hz, Ar); 7.7 - 7.35 (9 H, m, Ar); 5.8 (1 H, s, CHPh); 4.2 (2
H, s, CHZNHZ) ; 3 .55 (4 H, m, pip) ; 2. 0 (4 H, m, pip) ; 1.8 (2
H, m. pip).
HPLC (Luna 2, Gradient 1): rt = 2.81 minutes
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LC/MS (Lung 2, Gradient 4): rt = 0.59 minutes, 443 (MH)+
Example 6: 3-(Aminomethyl)benzoyl-D-phenylglycine 1-
oxoindan-5-amide trifluoroacetate salt
Prepared from 5-amino-1-oxoindane.
1H NMR (d4 MeOH): 7.98 ppm (1 H, s, (aminomethyl)benzoyl
C(2)H); 7.96 ppm (1 H, d, J = 10 Hz, (aminomethyl)benzoyl
C(6)H); 7.94 (1 H, s, indanone C(4)H); 7.70 - 7.52 (6 H, m,
Ar); 7.47 - 7.33 (3 H, m, Ar); 5.84 (1 H, s, CHPh); 4.22 (2
H, s, CH2NH2) ; 3 . 12 (2 H, t, J = 5 Hz, indanone C (3 ) HZ) ; 2 . 82
- 2 . 75 ( 2 H, m, indanone C ( 2 ) Hz ) .
HPLC (Lung 2, Gradient 1): rt = 3.35 minutes.
LC/MS (tuna 2, Gradient 4): rt = 1.78 minutes, 414 (MH)'.
Example 7
3-(Aminomethyl)benzoyl-D-phenylglycine 3-cyano-4-
methylphenyl-amide trifluoroacetate salt
Prepared from 3-cyano-4-methylaniline.
1H NMR (d4 MeOH): 8.01 ppm (1 H, s, 3-cyano-4-methylphenyl
C(2)H); 7.98 (1, s, 3-(aminomethyl)benzoyl C(2)H); 7.94 (1
H, d, J = 9 Hz, 3-(aminomethyl)benzoyl C(6)H); 7.72 - 7.52
(5 H, m, Ar); 7.48 - 7.28 (4 H, m, Ar); 5.82 (1 H, s, CHPh);
4 . 19 ( 2 H , s , CHZNHz ) ; 2 . 4 7 ( 3 H , s , CH3 ) .
HPLC (Lung 2, Gradient 1): rt = 3.72 minutes.
LC/MS (tuna 2, Gradient 4): rt = 2.05 minutes, 399 (MH)'.
Example 8
3-(Aminomethyl)benzoyl-D-phenylglycine 4-amido
phenylamide trifluoroacetate salt
Prepared from 4-nitrobenzamide.
1H NMR (d4 MeOH): 8.20 - 8.05 ppm (2 H, m, 3-
(aminomethyl)benzoyl C(2)H and C(6)H); 7.97 (2 H, d, J = 9
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Hz, 4-(amidocarbonyl)phenyl C(2)H and C(6)H); 7.86 (2 H, d,
J = 9 Hz, 4-(amidocarbonyl)phenyl C(3)H and C(5)H); 7.82 -
7.65 (4 H, m, Ar); 7.63 - 7.47 (3 H, m, Ar); 6.01, (1 H, s,
CH_Ph ) ; 4 . 3 2 ( 2 H , br s , CHZNHz ) .
HPLC (Symmetry C8, Gradient 2): rt = 4.84 minutes.
LC/MS (Lung 2, Gradient 4): rt = 1.51 minutes, 403 (MH)'.
Example 9
3-(Aminomethyl)benzoyl-D-phenylglycine 3-
amidophenylamide trifluoroacetate salt
Prepared from 3-nitrobenzamide.
1H NMR (d4 MeOH): 8.30 ppm (1, s, 3-(amidocarbonyl)phenyl
C(2)H); 8.17 (1 H, s, 3-(aminomethyl)benzoyl C(2)H); 8.12 (1
H, d, J = 8 Hz, 3-(aminomethyl)benzoyl C(6)H); 7.93 (1 H, d,
J = 7 Hz, 3-(amidocarbonyl)phenyl C(6)H); 7.85 - 7.68 (5 H,
m, Ar); 7.65 - 7.52 (4 H, m, Ar); 6.03 (1 H, s, CHPh); 4.37
( 2 H , br s , CH2NH2 ) .
HPLC (Luna 2, Gradient 1): rt = 2.95 minutes.
LC/MS (Luna 2, Gradient 4): rt = 1.78 minutes, 403 (MH)+.
Example 10
3-(Aminomethyl)benzoyl-D-phenylglycine 1,2,3,4-
tetrahydro-1-oxonaphthyl-6-amide trifluoroacetate salt.
Prepared from 6-amino-1,2,3,4-tetrahydro-1-oxonaphthalene.
1H NMR (d4 MeOH): 7.72 ppm (3 H, m, Ar); 7.40 (6 H, m, Ar);
7.20 (3 H, m, Ar); 5.65 (1 H, s, CH_Ph); 4.02 (2 H, s,
CHzNHz ) ; 2 . 78 ( 2 H, t , J = 6 Hz , tetrahydronaphthyl C ( 4 ) Hz ) ;
2.42 (2 H, t, J = 7 Hz, tetrahydronaphthyl C(2)Hz); 1.95
(2H, m, tetrahydronaphthyl C (3 ) Hz) .
HPLC (Lung 2, gradient 1): rt = 3.57 minutes.
LC/MS (Luna 2, gradient 4): rt = 1.88 minutes; 428 (MH)+.
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Example 11
3-(Aminomethyl)benzoyl-D-phenylglycine 1,2,3,4-
tetrahydro-1-oxonaphthyl-7-amide trifluoroacetate salt
Prepared from 7-nitro-1,2,3,4-tetrahydro-1-oxonaphthalene.
1H NMR (d4 MeOH): 8.04 ppm (1 H, s, tetrahydronaphthyl
C(8)H) ; 7.82 (2 H, dd, J = 1, 10 Hz, Ar) ; 7.60 (2 H, dd,
Ar); 7.45 (4 H, m, Ar); 7.28 (3 H, m, Ar); 7.16 (1 H, m,
Ar) ; 5.68 (1 H, br s; CHPh) ; 4.03 (2 H, s, CHZNHZ) , 2.83 (2
H, t, J = 7 Hz, tetrahydronaphthyl C(4)HZ); 2.40 (2 H, t, J
- 7 Hz, tetrahydronaphthyl C(2)H2); 2.00 (2 H, m,
tetrahydronaphthyl C(3)Hz).
HPLC (tuna 2, gradient 1): rt = 3.65 minutes.
LC/MS (tuna 2, Gradient 4): rt = 1.94 minutes, 428 (MH)+.
Example 12
3-(Aminomethyl)benzoyl-D-phenylglycine 1,2,3,4-
tetrahydro-naphthyl-6-amide trifluoroacetate salt
Prepared from 6-amino-1,2,3,4-tetrahydronaphthalene.
1H NMR (d4 MeOH): 7.72 ppm (1 H, s, 3-(aminomethyl)benzoyl
C(2)H); 7.70 (1 H, d, J = 7 Hz, 3-(aminomethyl)benzoyl
C (6) H) ; 7.40 (4 H, m, Ar) ; 7.22 (3 H, m, Ar) ; 7. 09 (1 H, m,
Ar); 6.82 (1 H, m, Ar); 5.62 (1 H, s, CHPh); 4.00 (2 H, s,
CHZNHz); 2.50 (4 H, s,); 1.58 (4 H, s, tetrahydronaphthyl
C(4)HZ and C(5)Hz) .
HPLC (tuna 2, Gradient 4): rt = 4.21 minutes.
LC/MS (tuna 2, Gradient 4): rt = 2.21 minutes, 414 (MH)'.
Example 13
3-(Aminomethyl)benzoyl-D-phenylglycine 4-(piperazin-1-
yl)phenyl-amide bis(trifluoroacetate) salt
Prepared from 4-(piperazin-1-yl)aniline.
1H NMR (d4 MeOH): 8.00 ppm (2 H, m, Ar); 7.70 - 7.35 (9 H, m,
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Ar); 7.02 (2 H, d, J = 10 Hz, Ar); 5.80 (1 H, s, CH_Ph); 4.21
(2 H, s, CHZNHz) ; 3.30 (8 H, m, pip) .
HPLC (Lung 2, Gradient 1): rt = 2.71 minutes.
LC/MS (Luna 2, Gradient 4): rt = 0.59 minutes, 444 (MH)+.
Example 14
3-(Aminomethyl)benzoyl-D-phenylglycine 2,3-dihydroindol
5-amide bis(trifluoroacetate) salt
Prepared from 2,3-dihydro-5-nitroindole.
1H NMR (d4 MeOH): 7.97 ppm (2 H, m, Ar); 7.82 (1 H, s, Ar);
7.65 (5 H, m, Ar); 7.45 (4 H, m, Ar); 5.80 (1 H, s, CHPh);
4.20 (2 H, s, CH2NH2) ; 3 .85 (2 H, t, J = 7.5 Hz,
dihydroindole C(2)Hz); 3.30 (2 H, t, J = 7.5 Hz,
dihydroindole C ( 3 ) Hz ) .
HPLC (tuna 2, Gradient 1): rt = 2.59 minutes.
LC/MS (Lung 2, Gradient 4): rt = 0.59 minutes, 401 (MH)'.
Example 15
3-(Aminomethyl)benzoyl-D-phenylglycine 4-chloro-3-
amidophenylamide trifluoroacetate salt
Prepared from 2-chloro-5-nitrobenzamide.
1H NMR (d4 MeOH): 7.98 ppm (l, s, 3-(aminomethyl)benzoyl
C(2)H); 7.94 (1 H, d, J = 9 Hz, 3-(aminomethyl)benzoyl
C(6)H); 7.83 (1 H, s, 2-chloro-3-(amidocarbonyl)-phenyl
C(6)H); 7.70 - 7.50 (5 H, m, Ar); 7.45 - 7.35 (4 H, m, Ar);
5.58 (1 H, s, CHPh) ; 4.21 (2 H, s, CHzNH2) .
HPLC (Luna 2, Gradient 1): rt = 3.09 minutes.
LC/MS (tuna 2, Gradient 4): rt = 1.62 minutes, 437/439
(MH)'.
Example 16
3-(Aminomethyl)benzoyl-D-phenylglycine 3,5-
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dichlorophenylamide trifluoroacetate salt
Prepared from 3,5-dichloroaniline.
1H NMR (d4 MeOH): 7.98 ppm (1, s, 3-(aminomethyl)benzoyl
C(2)H); 7.94 (1 H, d, J = 9 Hz, 3-(aminomethyl)benzoyl
C(6)H); 7.73 - 7.51 (4 H, m, Ar); 7.64 (2 H, s, 3,5-
dichlorophenyl C(2)H and C(6)H); 7.49 - 7.32 (3 H, m, Ar);
7.18 (1 H, s, 3,5-dichlorophenyl C(4)H); 5.80 (1 H, s,
CHPh ) ; 4 . 2 0 ( 2 H , s , CHzNHz ) .
HPLC (Luna 2, Gradient 1): rt = 4.31 minutes.
LC/MS (tuna 2, Gradient 4): rt = 2.29 minutes, 428/430/432
(MH)'.
Example 17
3-(Aminomethyl)benzoyl-D-phenylglycine 3-
(aminomethyl)phenyl-amide bis(trifluoroacetate) salt
Prepared from 3-nitrobenzylamine.
1H NMR (d4 MeOH) : 7.97 ppm (2 H, m Ar) ; 7.82 (1 H, s, Ar) ;
7.61 (5 H, m, Ar) ; 7.40 (4 H, m, Ar) ; 7.22 (1 H, d, J = 11
Hz, Ar) ; 5.81 (1 H, s, CHPh) ; 4.22 (2 H, s, CH_zNH2) ; 4.10 (2
2 0 H , s , CHzNHz ) .
HPLC (Lung 2, Gradient 1): rt = 2.67 minutes.
LC/MS (tuna 2, Gradient 4): rt = 0.59 minutes, 389 (MH)'.
Example 18
3-(Aminomethyl)benzoyl-D-phenylglycine 2,3-
dimethylindol-5-amide bis(trifluoroacetate) salt
Prepared from 2,3-dimethyl-5-nitroindole.
1H NMR (d3 acetonitrile): 9.12 ppm (1 H, br s, NH); 9.08
(1H, bs, NH); 8.40 (1 H, d, J = 7 Hz, Ar), 8.20 (1 H, s,
Ar); 8.0 (1 H, d, J = 7 Hz, Ar); 7.88-7.50 (7 H, m, Ar);
7.30 (2 H, m, Ar) ; 6.0 (1 H, d, J = 6.5 Hz, CHPh) ; 4.30 (2
H, s, CHzNH2) ; 2.71 (2 H, br s, CH2NH2) ; 2.50 (3 H, s, indole
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C(3)CH_3); 2.31 (3 H, s, indole C(2)CH_3).
HPLC (Luna 2, Gradient 1): rt = 3.76 minutes.
LC/MS (Lung 2, Gradient 4): rt = 1.99 minutes, 427 (MH)+
Example 19
3-(Aminomethyl)benzoyl-D-phenylglycine 4-
chlorophenylamide trifluoroacetate salt
Prepared from 4-chloroaniline.
1H NMR (d4 MeOH): 7.97 ppm (2 H, m, Ar); 7.70 - 7.50 (13 H,
m, Ar) ; 5.80 (1 H, s, CH_Ph) ; 4.21 (2 H, s, CHZNHZ) .
HPLC (tuna 2, Gradient 1): rt = 3.95 minutes.
LC/MS (tuna 2, Gradient 4): rt = 2.05 minutes, 394 (MH)+.
Example 20
1-[3-(Aminomethyl)benzoyl-D-phenylglycinyl]piperidine
trifluoroacetate salt
Prepared from piperidine.
1H NMR (d4 MeOH): 7.97 ppm (2 H, m Ar); 7.65 - 7.30 (7 H, m,
Ar) ; 6.10 (1 H, s, CHPh) ; 4.21 (2H, s, CHZNHz) ; 3.79 (1H, m,
pip); 3.50 (3H, m, pip); 1.70 - 1.21 (5 H, m, pip).
HPLC (Lung 2, Gradient 1): rt = 3.36 minutes.
LC/MS (Luna 2, Gradient 4): rt = 1.78 minutes, 394 (MH)+.
Example 21
1-[3-(Aminomethyl)benzoyl-D-phenylglycinyl]-3-[(N-ethyl-
N-methyl)amido]piperidine trifluoroacetate salt
Prepared from 3-((N-ethyl-N-methyl)amidocarbonyl]-
piperidine.
1H NMR (CD3CN): The compound contains two chiral centres and
is therefore a mixture of diastereomers, as well as
exhibiting rotamers due to the N-ethyl-N-methyl amide. 8.45
- 7.78 ppm (5 H, m, Ar and NH); 7.72 - 7.28 (5 H, m, Ph);
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6.10 - 5.90 (1 H, m, CHPh); 4.61 - 4.35 (1 H, m, piperidine
H); 4.14 (2 H, br s, CHZNHZ); 3.97 - 3.66 (1 H, m, piperidine
H); 3.50 - 2.35 (12 H, m) 1.90 - 0.75 (4 H, m).
HPLC (tuna 2, Gradient 1): rt = 3.13 minutes.
LC/MS (Lung 2, Gradient 4): rt = 1.72 minutes, 437 (MH)+.
Example 22
1-[3-(Aminomethyl)benzoyl-D-phenylglycinyl]
pyrrolidine trifluoroacetate salt
Prepared from pyrrolidine.
1H NMR (d4 MeOH): 7.95 ppm (2 H, m, Ar); 7.72-7.34 (7 H, m,
Ar) ; 5.91 (1 H, m, CHPh) ; 4.20 (2 H, s, CHzNH2) ; 3.80 (2 H,
m, pyr); 3.61 (2 H, m, pyr); 3.50 (2 H, m, pyr); 3.19 (2 H,
m, pyr) .
HPLC (Luna 2, Gradient 1): rt = 3.06 minutes.
LC/MS (tuna 2, Gradient 4): rt = 0.57 minutes, 338 (MH)+.
Example 23
2-[3-(Aminomethyl)benzoyl-D-phenylglycinyl]
decahydroisoquinoline trifluoroacetate salt
Prepared from decahydroisoquinoline.
1H NMR (d4 MeOH): 7.70 ppm (2 H, br s, Ar); 7.41 -7.09 (7 H,
m, Ar); 5.95-5.78 (1H, m, CHPh); 3.95 (2H, s, CHzNHz); 1.7 -
0.65 (16 H, m, decahydroisoquinoline C(H)s).
HPLC (Luna 2, Gradient 1): rt = 4.11 minutes.
LC/MS (Lung 2, Gradient 4): rt = 2.15 minutes, 406 (MH)+.
Example 24
3-(Aminomethyl)benzoyl-D-phenylglycine 2,3-dihydroindol-
6-amide trifluoroacetate salt
Prepared from 2,3-dihydro-6-nitroindole.
1H NMR (d4 MeOH): 7.91 ppm (2 H, m, Ar); 7.75 (1 H, s, Ar);
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7.57 (4 H, m, Ar); 7.34 (5 H, m, Ar); 5.75 (1 H, s, CHPh);
4.15 (2 H, s, CHZNHz) ; 3.75 (2 H, t, J = 7.5 Hz,
dihydroindole C(2)Hz); 3.20 (2 H, t, J = 7.5 Hz,
dihydroindole C ( 3 ) HZ ) .
HPLC (tuna 2, Gradient 1): rt = 2.54 minutes.
LC/MS (tuna 2, Gradient 4): rt = 1.24 minutes, 401 (MH)+.
Example 25
3-(Aminomethyl)benzoyl-D-phenylglycine 2,3-
dihydroindolamide trifluoroacetate salt
Prepared from 2,3-dihydroindole.
1H NMR (d4 MeOH) : 8.92 ppm (1 H, d, J = 7 Hz, NH) ; 8.22 (1
H, d, J = 9.5 Hz, dihydroindole C(7)H); 7.97 (2 H, m, Ar);
7.48 (3 H, m, Ar); 7.19 (2 H, m, Ar); 7.08 (1 H, m, Ar);
6.02 (1 H, m, CHPh); 4.41 (1 H, m, dihydroindole C(2)H);
4.19 (2H, s, CHZNHz); 3.78 (1H, m, dihydroindole C(2)H); 3.23
(1H, m, dihydroindole C(3)H); 3.07 (1H, m, dihydroindole
C(3)H) .
HPLC (Luna 2, Gradient 1): rt = 3.79 minutes.
LC/MS (Luna 2, gradient 4): rt = 2.21minutes, 386 (MH)+.
Example 26
3-(Aminomethyl)benzoyl-D-phenylglycine 1-methyl-2,3-
dihydro-indol-6-amide bis(trifluoracetate salt)
Prepared from 6-amino-2,3-dihydro-1-methylindole.
1H NMR (d4 MeOH) : 8.0 ppm (2 H, m, Ar) ; 7.65 (4 H, m, Ar) ;
7.40 (3 H, m, Ar); 7.15 (2 H, m, Ar); 6.95 (1 H, m, Ar);
5.83 (1 H, s, CHPh) ; 4.20 (2 H, s, CHZNHZ) ; 3.42 (2 H, m,
dihydroindole C(2)H); 2.98 (2H, m, dihydroindole C(3)H);
2.82 (3H, s, NCH3) .
HPLC (tuna 2, Gradient 1): rt = 2.80 minutes.
LC/MS (tuna 2, Gradient 4): rt = 1.88 minutes, 415 (MH)+.
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Example 27
3-(Aminomethyl)benzoyl-D-phenylglycine 3-acetylamino-4-
methylphenylamide trifluoroacetate salt
Prepared from 2-methyl-5-nitroacetanilide.
1H NMR (D20): 7.78 - 7.19 (12 H, m, Ar), 5.64 (1H, s, a-CH),
4.17 (2 H, s, CHZNHz) , 2.12 (6H, s, 2 x CH3)
HPLC (Lung 2, Gradient 1): rt = 3.10 minutes.
LC/MS (Luna 2, Gradient 4):rt = 1.56 minutes, 431 (MH+).
Example 28
3-(Aminomethyl)benzoyl-D-phenylglycine (R/S)-8-methyl-
5,6,7,8-tetrahydronaphth-2-ylamide trifluoroacetate salt
Prepared from (R/S)-8-methyl-5,6,7,8-tetrahydronaphth-2-
ylamine, synthesised as described below.
(R/S)-8-methyl-5,6,7,8-tetrahydronaphth-2-ylamine
A suspension of methyltriphenylphosphonium iodide (680 mg,
1.68 mmol) in tetrahydrofuran (7 mL) was cooled to -45°C. n-
Butyllithium (1.0 mL, 1.6 M in hexane, 1.60 mmol) was then
added dropwise, and the solution was stirred for 1 hour.
1,2,3,4-Tetrahydro-7-nitro-1-oxonaphthalene (200 mg, 1.05
mmol) in tetrahydrofuran (3 mL) was then added over 5
minutes. The reaction mixture was allowed to warm to room
temperature before being quenched with water (20 mL). The
solution was then extracted with dichloromethane (2 x 25
mL), the solvent was dried (MgS04) and concentrated under
reduced pressure to give a black oil. The crude product was
then purified by flash chromatography (ethyl acetate /
hexane; 1:40) to afford 5,6,7,8-tetrahydro-8-methylene-2-
nitro-naphthalene as a white solid (150 mg, 76%).
A solution of the olefin (100 mg, 0.53 mmol) in methanol (2
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mL) was stirred over 10% palladium on carbon (20 mg). The
mixture was purged with hydrogen and stirred for 18 hrs
under a balloon of hydrogen. The reaction mixture was then
filtered through celite, washing with additional methanol,
and concentrated under reduced pressure to afford (R/S)-8-
methyl-5,6,7,8-tetrahydronaphth-2-ylamine as a colourless
oil (75 mg, 82%).
1H NMR (CDC13) : 7.53 ppm (1 H, d, J = 8 Hz, C(4)H) ; 7.21 (1
H, d, J = 2 Hz, C(1)H) ; 7.18 (1 H, dd, J = 8, 2 Hz, C(3)H) ;
4.16 (2 H, br s, NH2) ; 3.52 (1 H, sextet, J = 7 Hz, CHCH3) ;
3.41-3.25 (2 H, m, C(5)HZ); 2.61-2.45 (2 H, m, tetrahydro-
naphthalene C(6)H and/or C(7)H); 2.43-2.32 (1 H, m,
tetrahydronaphthalene C(6) or C(7)H); 2.23-2.12 (1 H, m,
tetrahydronaphthalene C(6)H or C(7)H); 1.96 (3 H, d, J = 7
Hz, CH3) .
3-(Aminomethyl)benzoyl-D-phenylglycine (R/S)-8-methyl-
5,6,7,8-tetrahydro-naphth-2-ylamide trifluoroacetate salt.
1H NMR (MeOH): 7.95 ppm (2 H, br s, Ar); 7.76 - 7.60 (4 H,
m, Ar); 7.48 - 7.31 (4 H, m, Ar); 7.29 - 7.21 (1 H, m, Ar);
6.97 (1 H, d, J = 8 Hz, Ar) ; 5.80 (1 H, s, CHPh) ; 4.18 (2 H,
s, CHZNHZ); 2.90 - 2.69 (3 H, m, tetrahydronaphthalene C(5)H
and C(8)H2); 1.99-1.80 (2 H, m, tetrahydronaphthalene C(6)H
and/or C(7)H); 1.75 - 1.63 (1 H, m, tetrahydronaphthalene
C(6) or C(7)H); 1.58 - 1.40 (1 H, m, tetrahydro-naphthalene
C(6)H or C(7)H); 1.27 (3 H, d, J = 7 Hz, CH3) .
HPLC (Symmetry, Gradient 2): rt = 6.73 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.53 minutes, 428 (MH)'.
Example 29
3-(Aminomethyl)benzoyl-D-phenylglycine indan-5-ylamide
trifluoroacetate salt
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Prepared from 5-aminoindane.
1H NMR (d4 MeOH): 8.16 ppm (1 H, s, 3-(aminomethyl)benzoyl
C(2)H); 8.15 (1 H, m, 3-(aminomethyl)benzoyl C(6)H); 7.96 -
7.54 (8 H, m, Ar) ; 7.45 (1 H, d, J = 8 Hz, indane C(6)H or
C(7)H) ; 7.33 (1 H, d, J = 8 Hz, indane C(6)H or C(7)H) ; 6.0
(1 H, s, CHPh) ; 4.39 (2 H, s, CHZNHz) ; 3.06 (4 H, q, J = 7
Hz, indane C(1)Hz and C(3)Hz) ; 2.26 (2 H, quintet, J = 7 Hz,
indane C ( 2 ) Hz ) .
HPLC (Luna 2, Gradient 1): rt = 4.02 minutes.
LC/MS (Lung 2, Gradient 4): rt = 2.42 minutes, 400 (MH)+.
Example 30
3-(Aminomethyl)benzoyl-D-phenylglycine 4-
isopropylphenylamide trifluoroacetate salt
Prepared from 4-isopropylaniline.
1H NMR (d4 MeOH): 8.17 ppm (1 H, s, 3-(aminomethyl)benzoyl
C(2)H); 8.15 (1 H, m, 3-(aminomethyl)benzoyl C(6)H); 7.83 -
7.59 (9 H, m, Ar); 7.38 (2 H, d, J = 8.5 Hz, Ar); 6.0 (1 H,
s, CHPh) ; 4 .38 (2 H, s, CHzNHz) ; 3 .09 (1 H, septet, J = 7 Hz,
CH (CH3) z) ; 1 .42 (6 H, d, J = 7 Hz, CH (CH_3) z) .
HPLC (Luna 2, Gradient 1): rt = 4.21 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.48 minutes, 402 (MH)+.
Example 31
3-(Aminomethyl)benzoyl-D-phenylglycine (1S,2S,3S,SR)-
isopinocamphamide trifluoroacetate salt
Prepared from (1S,2S,3S,5R)-(+)-isopinocampheylamine.
1H NMR (d4 MeOH): 7.96 ppm (1 H, s, 3-(aminomethyl)benzoyl
C(2)H); 7.95 (1 H, m, 3-(aminomethyl)benzoyl C(6)H); 7.67 -
7.25 (7 H, m, Ar); 5.70 (1 H, s, CHPh); 4.28 (1 H, m,
isopinocampheyl C (1) H) ; 4 .20 (2 H, s, CHzNHz) ; 2 . 55 - 1 . 77 (5
H, m, isopinocampheyl H~s); 1.26 (3 H, s, CH3); 1.14 (3 H,
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d, J = 7Hz, isopinocampheyl C(10)H3) ; 1.08 (3 H, s, CH3) ;
1.04 - 0.94 (2 H, m, isopinocampheyl H's).
HPLC (Luna 2, Gradient 1): rt = 4.34 minutes.
LC/MS (tuna 2, Gradient 4): rt = 2.34 minutes, 420 (MH)+
Example 32
3-(Aminomethyl)benzoyl-D-phenylglycine 4-(1-
hydroxyethyl)phenylamide trifluoroacetate salt
Prepared from 1-(4-aminophenyl)ethanol.
1H NMR (d4 MeOH): 7.85 ppm (1 H, s, 3-(aminomethyl)benzoyl
C(2)H); 7.84 (1 H, m, 3-(aminomethyl)benzoyl C(6)H); 7.56 -
7 . 05 ( 11 H, m, Ar) ; 5 . 72 ( 1 H, s, CHPh) ; 4 . 69 ( 1 H, q, J =
6 .5 Hz, CH (OH) CH3) ; 4 . 08 (2 H, s, CHzNH2) ; 1 .31 (3 H, d, J =
6 . 5 Hz , CH3 ) .
HPLC (Luna 2, Gradient 1): rt = 3.0 minutes.
LC/MS (tuna 2, Gradient 4): rt = 1.83 minutes, 404 (MH)'.
Example 33
3-(Aminomethyl)benzoyl-D-phenylglycine cis-2-
aminocyclohexyl-amide bis(trifluoroacetate) salt
Prepared from cis-1,2-diaminocyclohexane.
1H NMR (d4 MeOH): 8.08 ppm (1 H, s, 3-(aminomethyl)benzoyl
C(2)H); 8.06 (1 H, m, 3-(aminomethyl)benzoyl C(6)H); 7.79 -
7.48 (7 H, m, Ar); 5.87 (1 H, s, CHPh); 4.46 (1 H, m,
cyclohexyl C(1)H) ; 4.30 (2 H, s, CH_ZNHz) ; 3.54 (1 H, m,
cyclohexyl C(2)H); 2.11 - 1.52 (8 H, m, cyclohexyl H's).
HPLC (tuna 2, Gradient 1); rt = 2.40 minutes.
LC/MS (Lung 2, Gradient 4): rt = 1.08 minutes, 381 (MH)+.
Example 34
1-[3-(Aminomethyl)benzoyl-D-phenylglycinyl] 4-
hydroxypiperidine hydrochloride salt
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Prepared from 4-hydroxypiperidine.
1H NMR (d4 MeOH): 7.84 ppm (1 H, s, 3-(aminomethyl)benzoyl
C(2)H); 7.80 (1 H, m, 3-(aminomethyl)benzoyl C(6)H); 7.59 -
7.17 (7 H, m, Ar); 6.03 (1 H, s, CHPh); 4.11 (2 H, s,
CHZNHz) ; 3.90 (1 H, ~m, piperidyl C(4)H) ; 3.62 (2 H, m,
piperidyl C(2)H and C(6)H); 3.14 - 2.94 (2 H, m, piperidyl
C(2)H and C(6)H) ; 1.93 - 1.16 (4 H, m, piperidyl C(3)Hz and
C(5)HZ) .
HPLC (Luna 2, Gradient 1): rt = 2.56 minutes.
LC/MS (tuna 2, Gradient 4): rt = 1.36 minutes, 368 (MH)'.
Example 35
3-(Aminomethyl)benzoyl-D-phenylglycine 1-acetyl-2,3-
dihydro-indol-6-amide trifluoroacetate salt
1-Benzyloxycarbonyl-2,3-dihydro-6-nitroindole
A solution of 6-nitroindoline (10.0 g, 0.061 mol),
triethylamine (22.7 mL, 0.16 mol) and dimethylaminopyridine
(50 mg, cat.) in dichloromethane (130 mL) was stirred at 0°C
and benzyl chloroformate (18 mL, 0.12 mol) was added slowly.
The mixture was allowed to warm to room temperature
overnight. The mixture was washed with water (50 mL), 5a
aqueous HCl (100 mL), saturated aqueous NaHC03 (50 mL) and
water (50 mL). The dichloromethane was dried (MgS04) and
evaporated under reduced pressure to give an orange solid.
This was triturated in diethyl ether (150 ml) to give a
yellow solid (12.34 g, 68%).
1H NMR (CDC13): 7.80 ppm (1 H, dd, J = 8, 2 Hz, C(7)H); 7.35
(5 H, m, Ph) ; 7.20 (2 H, m, C(4)H and C(5)H) ; 5.25 (2 H, br
s, CHzPh) ; 4 . 11 (2 H, t, J = 8 Hz, dihydroindole C (2) HZ) ;
3 . 15 (2 H, t, J = 8 Hz, dihydroindole C (3) Hz) .
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6-amino-1-benzyloxycarbonyl-2,3-dihydroindole
A mixture of 1-benzyloxycarbonyl-2,3-dihydro-6-nitroindole
(1.0 g, 3.36 mmol) and tin(II) chloride dehydrate (3.78 g,
16.75 mmol) in ethanol (70 mL) was heated at 70°C, under an
atmosphere of nitrogen, for 3 hours. The solution was cooled
and the solvent evaporated under reduced pressure to give an
off-white solid. The solid was partitioned between water (50
mL) and ethyl actate (100 mL) and the aqueous layer basified
(pH 11) with 1M sodium hydroxide solution. The mixture was
filtered to remove tin salts and the ethyl acetate was
separated, dried (MgS04) and evaporated under reduced
pressure to give the amine as a yellow oil (0.89 g, 99 %)
1H NMR (CDC13): 7.51 - 7.33 ppm (6 H, m, Ph + C(7)H); 6.93 (1
H, d, J = 8 Hz, C(4)H) ; 6.32 (1 H, dd, J = 8, 2 Hz, C(5)H) ;
5.28 (2 H, br s, CH2Ph) ; 4.01 (2 H, t, J = 7.5 Hz,
dihydroindole C (2 ) Hz) ; 3 . 66 (2 H, bs, NHZ) ; 3 . 05 (2 H, t, J =
7 . 5 Hz, dihydroindole C (3 ) Hz) .
N-BOC-D-phenylglycine 1-benzyloxycarbonyl-2,3-dihydroindol-
6-amide
A solution of N-BOC-D-phenylglycine (0.83 g, 3.28 mmol), 1-
[3-(dimethyl-amino)propyl]-3-ethylcarbodiimide hydrochloride
(0.75 g, 3.9 mmol), 1-hydroxy-7-azabenzotriazole (0.54 g,
3.9 mmol) and 4-(N,N-dimethylamino)pyridine (10 mg, cat.) in
dimethylformamide (20 mL) was stirred at room temperature
and a solution of the above amine (0.88 g, 3.28 mmol) in
dimethylformamide (20 mL) was added and the mixture allowed
to stir overnight. The dimethylformamide was evaporated
under reduced pressure and the resulting oil partitioned
between water (50 mL) and ethyl acetate (50 mL). The ethyl
acetate was washed with 5% aqueous HC1 (10 mL) and saturated
aqueous NaHC03 (10 mL), dried (MgS04) and evaporated under
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reduced pressure to give the amide as a golden foam (1.6 g,
97 %) .
1H NMR (CDC13) : 7.43 - 7.10 ppm (13 H, m, Ar) : 6.85 (1 H, d,
J = 6 Hz, NH); 5.61 (1 H, br s, NH); 5.03 (2 H, br s,
CHzPh) ; 3.85 (2 H, t, J = 7 Hz, dihydroindole C(2)Hz) ; 2.85
(2 H, t, J = 8 Hz, dihydroindole C(3)Hz) ; 1.19 (9 H, s, tBu) .
D-phenylglycine 1-benzyloxycarbonyl-2,3-dihydroindol-6-amide
trifluoroacetate salt
Trifluoroacetic acid (5 mL) was added to a solution of the
above foam in dichloromethane (20 mL) and the solution was
allowed to stir for 2 hours at room temperature. The solvent
was evaporated under reduced pressure to give the amine
trifluoracetate salt as a red foam (1.5 g, 91 %) which was
used without further purification.
3-(N-BOC-Aminomethyl)benzoyl-D-phenylglycine (1-
benzyloxycarbonyl-2,3-dihydro)-indol-6-amide
A solution of 3-(N-BOC-aminomethyl)benzoic acid (0.798 g,
3.2 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (0.73 g, 3.8 mmol), 1-hydroxy-7-
azabenzotriazole (0.52 g, 3.8 mmol) and triethylamine (1.0
mL, 7.2 mmol) in dimethylformamide (10 mL) was stirred at
room temperature and a solution of the above amine (1.5 g,
3.0 mmol) in dimethylformamide (5 mL) was added. The
mixture was stirred overnight before the dimethylformamide
was evaporated under reduced pressure, and the resulting oil
partitioned between water (50 mL) and ethyl acetate (50 mL).
The ethyl acetate layer was washed with 5% aqueous HC1 (10
mL) and saturated aqueous NaHC03 (10 mL), dried (MgS04) and
evaporated under reduced pressure to give a yellow solid.
1H NMR (CDC13): 7.75 - 7.22 ppm (17 H, m, Ar): 7.05 (1 H, d,
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J = 5.5 Hz, NH); 5.74 (1H, d, J = 6 Hz, CHPh); 5.21 (2 H, s,
OCHzPh); 4.89 (1 H, br s, NH); 4.32 (2 H, d, J = 6 Hz,
CHZNHBOC) ; 4 . 02 (2H, t, J = 8 Hz, dihydroindole C (2 ) H2) ; 3 . 05
(2H, t, J = 8 Hz, dihydroindole C(3)H2) ; 1.4 (9 H. s, tBu) .
3-(N-BOC-Aminomethyl)benzoyl-D-phenylglycine 2,3-
dihydroindol-6-amide
A solution of the above solid in methanol (50 mL) was
stirred over 10%Pd/C (500 mg) under an atmosphere of HZ and
heated under reflux for 2 hours. The mixture was cooled,
filtered and the solvent evaporated under reduced pressure
to provide the unprotected dihydroindole as a yellow foam
(1.4g, 88%) which was used without further purification.
3-(Aminomethyl)benzoyl-D-phenylglycine 1-acetyl-2,3-
dihydroindol-6-amide trifluoroacetate salt
A solution of the dihydroindole (500 mg, 1.0 mmol) and
triethylamine (0.28 mL, 2 mmol) in dichloromethane (20 mL)
was stirred at 0°C and acetyl chloride (86 mg, 1.1 mmol) was
added dropwise, then left to stir overnight. The mixture was
washed with 5% aqueous HC1 (10 mL) and the organic phase was
dried (MgS04) and evaporated. The residue was purified by
flash column chromatography (ethyl acetate / hexane, 1:1) to
give a yellow oil. The oil was dissolved in dichloromethane
(20 mL) and treated with trifluoroacetic aid (5 mL). After
stirring for 2 hours the solvent was evaporated under redued
pressure to an oil, which after triturating with diethyl
ether gave the amine as its trifluoroacetate salt as a white
solid (337 mg, 61 %).
1H NMR (d4 MeOH): 8.30 ppm (1 H, s, Ar); 7.97 (2 H, m, Ar);
7.60 (4 H, m, Ar); 7.39 (4 H, 3, m, Ar); 7.22 (1 H, d, J =
10 Hz, Ar) ; 5.82 (1 H, s, CHPh) ; 4.2 (2 H, s, CHZNHZ) ; 4.15
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(2 H, t, J = 7 Hz, dihydroindole C (2) Hz) ; 3 . 17 (2 H, t, J =
7 Hz, dihydroindole C (3) HZ) ; 2 .25 (3 H, s, CH3) .
HPLC (Luna 2, Gradient 1): rt = 3.39 minutes.
LC/MS (Lung 2, Gradient 4): rt = 1.72 minutes, 443 (MH)+.
Examples 36 - 60 were prepared from the intermediate 3-(N-
BOC-aminomethyl)-benzoyl-D-phenylglycine 2,3-dihydroindol-5-
amide, described for Example 29, and the appropriate
carboxylic acid or derivative, using standard chemical
methods and protecting other functionality where required.
Example 36
3-(Aminomethyl)benzoyl-D-phenylglycine 1-propanoyl-2,3-
dihydro-indol-6-amide trifluoroacetate salt
Prepared using propanoyl chloride.
1H NMR (d4 MeOH) : 8.58 ppm (1 H, d, J = 1.2 Hz,
dihydroindole C(7)H); 8.18 (2 H, m, Ar); 7.82 (4 H, m, Ar);
7.59 (4 H, m, Ar); 7.37 (1 H, m, Ar); 6.03 (1 H, s, CHPh);
4.39 (2 H, s, CH_ZNHz) ; 4.31 (2 H, t, J = 9 Hz, dihydroindole
C (2 ) H) ; 3 . 37 (2 H, t, J = 9 Hz, dihydroindole C (3 ) H) ; 2 . 73
(2 H, q, J = 7.5 Hz, CHzCH3) ; 1.47 (3 H, t, J = 7.5 Hz,
CHZCH3 ) .
HPLC (Luna 2, Gradient 1): rt = 3.55 minutes.
LC/MS (tuna 2, Gradient 4):rt = 1.94 minutes, 457 (MH)+.
Example 37
3-(Aminomethyl)benzoyl-D-phenylglycine 1-(2-methyl-
propanoyl)-2,3-dihydroindol-6-amide trifluoroacetate
salt
Prepared using 2-methylpropanoyl chloride.
1H NMR (d4 MeOH): 8.32 ppm (1 H, s, dihydroindole C(7)H);
7.98 (2 H, m, Ar); 7.60 (4 H, m, Ar); 7.43 (4 H, m, Ar);
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7.18 (1 H, m, Ar) ; 5.83 (1 H, s, CHPh) ; 4.21 (4 H, m, CHzNH2
and dihydroindole C(2)H); 3.18 (2 H, t, J = 9 Hz,
dihydroindole C (3) H) , 2 . 95 (1 H, m, CH (CH3) z) ; 1 .22 (6 H, d,
J = 8 Hz, CH (CH3) 2) .
HPLC (tuna 2, Gradient 1): rt = 3.74 minutes.
LC/MS (tuna 2, Gradient 4): rt = 2.05 minutes, 471 (MH)+.
Example 38
3-(Aminomethyl)benzoyl-D-phenylglycine 1-D-alaninoyl-
2,3-dihydroindol-6-amide bis(trifluoroacetate) salt
Prepared using D-alanine.
1H NMR (d4 MeOH): 8.40 ppm (1 H, s, Ar); 8.01 (2 H, m, Ar);
7.65 (4 H, m, Ar) ; 7.45 (4 H, m, Ar) ; 7.25 (1 H, d, J = 10
Hz, Ar); 5.85 (1 H, s, CHPh); 4.4 (1 H, q, J = 7 Hz,
alaninyl CHNHz) ; 4.25 (2 H, s, ArCH2NHz) ; 4.25 (2 H, t, J = 8
Hz, dihydroindole C(2)Hz); 3.28 (2 H, t, J = 8 Hz,
dihydroindole C ( 3 ) Hz ) ; 1 . 65 ( 3 H, d, J = 7 Hz , CH3 ) .
HPLC (Luna 2, Gradient 1): rt = 2.85 minutes.
LC/MS (tuna 2, Gradient 4): rt = 1.35 minutes, 472 (MH)+.
Example 39
3-(Aminomethyl)benzoyl-D-phenylglycine 1-L-alaninoyl-
2,3-dihydroindol-6-amide bis(trifluoroacetate) salt
Prepared using L-alanine.
1H NMR (d4 MeOH) : 8.43 ppm (1 H, s, Ar) ; 7.97 (2 H, m, Ar) ;
7.63 (4 H, m, Ar); 7.45 (4 H, m, Ar); 7.25 (1 H, d, J = 10
Hz, Ar); 5.85 (1 H, s, CHPh); 4.35 (1 H, q, J = 7 Hz,
alaninyl CHNHZ) ; 4 .25 (2H, t, J = 7.5 Hz, indoline C (2) HZ) ;
4.2 (2 H, s, CHZNHz) ; 3.25 (2H, t, J = 8 Hz, indoline
C (3) HZ) ; 1 . 6 (3 H, d, J = 7 Hz, CH3) .
HPLC (tuna 2, Gradient 1): rt = 2.84 minutes.
LC/MS (Luna 2, Gradient 4): rt = 0.59 minutes, 472 (MH)+.
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Example 40
3-(Aminomethyl)benzoyl-D-phenylglycine 1-(N-acetyl-D-
alaninoyl)-2,3-dihydroindol-6-amide trifluoroacetate
salt
Prepared using N-acetyl-D-alanine.
1H NMR (d4 MeOH): 8.33 ppm (1 H, s, Ar); 7.97 (2 H, m, Ar);
7.61 (4 H, m, Ar); 7.40 (4 H, m, Ar); 7.18 (1 H, d, J = 9
Hz, Ar); 5.83 (1 H, s, CHPh); 4.70 (1 H, br m, CHNHAc); 4.38
(1 H, m, indoline C(2)H) ; 4.21 (2H, s, CHZNHZ) ; 4.20 (1 H, t,
J = 8 Hz indoline C(2)H); 3.2 (2 H, t, J = 8 Hz, indoline
C (3) HZ) ; 2 . 01 (3 H, s, COCH3) ; 1 .4 (3 H, d, J = 7 Hz, CH3) .
HPLC (Luna 2, Gradient 1): rt = 3.24 minutes.
LC/MS (Luna 2, Gradient 4): rt = 0.59 minutes, 514 (MH)+.
Example 41
3-(Aminomethyl)benzoyl-D-phenylglycine 1-(N-acetyl-L-
alaninoyl)-2,3-dihydroindol-6-amide trifluoroacetate
salt
Prepared using N-acetyl-L-alanine.
1H NMR (d4 MeOH): 8.33 ppm (1 H, s, Ar); 7.97 (2 H, m, Ar);
7.62 (4 H, m, Ar) ; 7.38 (4 H, m, Ar) ; 7.18 (1 H, d, Ar) ;
5.83.(1 H, s, CH_Ph); 4.70 (1 H, m, CHNHAc); 4.35 (1 H, m,
dihydroindole C (2) H) ; 4 .2 (2H, s, CHZNHz) ; 4 .2 (1H, m,
dihydroindole C(2)H); 3.2 (2 H, t, J = 8 Hz, dihydroindole
C(3)HZ) ; 2.0 (3 H, s, COCH3) ; 1.4 (3 H, d, J = 7 Hz, CH3) .
HPLC (Luna 2, Gradient 1): rt = 3.19 minutes.
LC/MS (tuna 2, Gradient 4): rt = 1.67 minutes, 514 (MH)+.
Example 42
3-(Aminomethyl)benzoyl-D-phenylglycine 1-aminoacetyl-
2,3-dihydroindol-6-amide bis(trifluoroacetate) salt
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Prepared using glycine.
1H NMR (d4 MeOH): 8.41 (1 H, s, dihydroindole C(7)H); 7.97
(2 H, br s, Ar); 7.58 (4 H, m, Ar); 7.22 (1 H, d, J = 8 Hz,
Ar) ; 5.84 (1 H, s, CHPh) ; 4.20 (2 H, s, CHZNHZ) ; 4.15 (2 H,
t, J = 9 Hz, dihydroindole C (2) H) ; 4 . 04 (2 H, s, COCH_zNH2) ;
3.23 (2H, t, J = 9 Hz, dihydroindole C(3)H).
HPLC (Lung 2, Gradient 1): rt = 2.77 minutes.
LC/MS (Luna 2, Gradient 4): rt = 1.24 minutes, 458 (MH)+.
Example 43
3-(Aminomethyl)benzoyl-D-phenylglycine 1-(3-
methylbutanoyl)-2,3-dihydroindol-6-amide
trifluoroacetate salt
Prepared using 3-methylbutanoyl chloride.
1H NMR (d4 MeOH) : 8.40 ppm (1 H, s, Ar) ; 8.02 (2 H, m, Ar) ;
7.67 (4 H, m, Ar); 7.22 (1 H, d, J = 11 Hz, Ar); 5.90 (1 H,
s, CHPh) ; 4.27 (2 H, s, CH_zNHz) ; 4.22 (2 H, t, J = 8 Hz,
indoline C(2)Hz) ; 3.22 (2H, t, J = 8 Hz, indoline C(3)Hz) ;
2.45 (2 H, d, J = 7 Hz, COCHz) ; 2.28 (1 H, septet, J = 7 Hz,
CHMez) ; 1 . 1 (6 H, d, J = 7 Hz, CH (CH3) 2) .
HPLC (Luna 2, Gradient 1): rt = 4.18 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.15 minutes, 485 (MH)+.
Example 44
3-(Aminomethyl)benzoyl-D-phenylglycine 1-(benzyloxy)-
acetyl-2,3-dihydroindol-6-amide trifluoroacetate salt
Prepared using 2-benzyloxyacetyl chloride.
1H NMR (d4 MeOH) : 8.40 ppm (1 H, s, Ar) ; 8.02 (2 H, m, Ar) ;
7.65 (5 H, m, Ar) ; 7.45 (10 H, m, Ar) ; 7.22 (1 H, d, J = 10
Hz, Ar); 5.91 (1 H, s, CHPh); 4.73 (2 H, s, COCH); 4.35 (1
H, q, CHNH2) ; 4.37 (2 H, s, CHzPh) ; 4.25 (2 H, s, CHzNH2) ;
4 . 12 (2 H, t, J = 7.5 Hz, indoline C (2) Hz) ; 3 .2 (2 H, t, J =
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7.5 Hz, indoline C(3)Hz) .
HPLC (Luna 2, Gradient 1): rt = 4.25 minutes.
LC/MS (Lung 2, Gradient 4): rt = 2.15 minutes, 549 (MH)+.
Example 45
3-(Aminomethyl)benzoyl-D-phenylglycine 1-L-threoninoyl-
2,3-dihydroindol-6-amide bis(trifluoroacetate) salt
Prepared using L-threonine.
1H NMR (d4 MeOH): 8.31 ppm (1 H, s, Ar); 7.80 (2 H, m, Ar);
7.45 (4 H, m, Ar); 7.25 (4 H, m, Ar); 7.05 (1 H, d, Ar);
5.65 (1 H, s, CHPh); 4.10 (2 H, t, J = 8 Hz, indoline
C(2)H2) ; 4.02 (2 H, s, CHzNH2) ; 3.11 (2 H, t, J = 8 Hz,
indoline C(3)HZ); 1.21 (3H, d, CH3); other signals obscured
by solvent.
HPLC (tuna 2, Gradient 1): rt = 2.84 minutes.
LC/MS (Luna 2, Gradient 4): rt = 0.65 minutes, 502 (MH)+.
Example 46
3-(Aminomethyl)benzoyl-D-phenylglycine 1-L-prolinoyl-
2,3-dihydroindol-6-amide bis(trifluoroacetate) salt
Prepared using L-proline.
1H NMR (d4 MeOH): 8.47 ppm (1 H, s, Ar); 8.05 (2 H, m, Ar);
7.75 - 7.65 (4 H, m, Ar); 7.56 - 7.47 (4 H, m, Ar); 7.30 (1
H, d, J = 9 Hz, Ar); 5.91 (1 H, s, CHPh); 4.73 (1 H, t, J =
6.5 Hz, proline C (2) H) ; 4 .25 (4 H, m, CHZNHz and indoline
C(2)Hz) ; 3.65-3.32 (3 H, m, indoline C(3)HZ and proline
C(5)H); 2.70 (1 H, m, proline C(5)H); 2.33 - 2.15 (4 H, m,
prol ine C ( 3 ) Hz and C ( 4 ) Hz ) .
HPLC (Lung 2, Gradient 1): rt = 2.98 minutes.
LC/MS (Luna 2, Gradient 4): rt = 0.59 minutes, 498 (MH)+.
Example 47
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3-(Aminomethyl)benzoyl-D-phenylglycine 1-((S)-2-hydroxy-
propanoyl)-2,3-dihydroindol-6-amide trifluoroacetate
salt
Prepared using (S)-2-hydroxypropanoic acid.
1H NMR (d4 MeOH): 8.33 ppm (1 H, s, Ar); 7.97 (2 H, m, Ar);
7.66 - 7.56 (4 H, m, Ar); 7.45 - 7.37 (4 H, m, Ar); 7.18 (1
H, d, J = 9 Hz, Ar); 5.83 (1 H, s, CH_Ph); 4.58 (1H, m,
CHOH); 4.31 (1H, m, indoline C(2)H); 4.21 (2 H, s, CHZNHz);
4.15 (1 H, m, indoline C(2)H); 3.18 (2 H, t, J = 8 Hz,
indoline C (3 ) HZ) ; 1 .4 (3 H, d, J = 7 Hz, CH3) .
HPLC (tuna 2, Gradient 1): rt = 3.31 minutes.
LC/MS (Lung 2, Gradient 4): rt = 1.72 minutes, 473 (MH)+.
Example 48
3-(Aminomethyl)benzoyl-D-phenylglycine 1-D-prolinoyl-
2,3-dihydroindol-6-amide bis(trifluoroacetate) salt
Prepared using D-proline.
1H NMR (d4 MeOH) : 8.41 ppm (1 H, s, Ar) ; 7.97 (2 H, m, Ar) ;
7.64 - 7.57 (4 H, m, Ar); 7.48 - 7.39 (4 H, m, Ar); 7.23 (1
H, d, J = 11 Hz, Ar); 5.82 (1 H, s, CHPh); 4.63 (1 H, m,
proline C (2 ) H) ; 4 .24 (4 H, m, CHzNH2 and indoline C (2 ) Hz) ;
3.52-3.24 (3 H, m, indoline C(3)H2 and proline C(5)H); 2.63
(1 H, m, proline C(5)H); 2.23 - 2.08 (4 H, m, proline C(3)Hz
and C ( 4 ) HZ ) .
HPLC (tuna 2, Gradient 1): rt = 2.98 minutes.
HPLC (Symmetry, Gradient 2): rt = 4.87 minutes.
LC/MS (Lung 2, Gradient 4): rt = 0.59 minutes, 498 (MH)+.
Example 49
3-(Aminomethyl)benzoyl-D-phenylglycine 1-L-serinoyl-2,3-
dihydroindol-6-amide bis(trifluoroacetate) salt
Prepared using L-serine.
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1H NMR (d4 MeOH): 8.40 ppm (1 H, s, Ar); 7.95 (2 H, m, Ar);
7.64 - 7.57 (4 H, m, Ar); 7.47 - 7.39 (4 H, m, Ar); 7.23 (1
H, d, J = 10 Hz, Ar) ; 5.81 (1 H, s, CHPh) ; 4.4 (1 H, dd, J =
12 Hz, 4 Hz, serine CHaHbOH) ; 4.25 (2 H, t, J = 7 Hz,
indoline C(2)Hz) ; 4.20 (2 H, s, CHzNH2) ; 4.05 (1 H, dd, J =
12, 6 Hz, serine CHaHbOH) ; 3.91 (1 H, m, serine CHNHz) ; 3.25
(2 H, t, J = 7 Hz, indoline C(3)Hz) .
HPLC (Lung 2, Gradient 1): rt = 2.84 minutes.
LC/MS (tuna 2, Gradient 4): rt = 1.35 minutes, 488 (MH)+.
Example 50
3-(Aminomethyl)benzoyl-D-phenylglycine 1-D-serinoyl-2,3-
dihydroindol-6-amide bis(trifluoroacetate) salt
Prepared using D-serine.
1H NMR (d4 MeOH) : 8.42 ppm (1 H, s, Ar) ; 7.97 (2 H, m, Ar) ;
7.64 - 7.57 (4 H, m, Ar); 7.47 - 7.39 (4 H, m, Ar); 7.23
(1H, d, J = 9 Hz, Ar) ; 5.82 (1 H, s, CHPh) ; 4.41 (1 H, dd, J
- 12, 4 Hz, serine CHaHbOH) ; 4.25 (2 H, t, J = 7.5 Hz,
indoline C(2)HZ) ; 4.2 (2 H, s, CHZNHz) ; 4.05 (1 H, dd, J =
12, 6 Hz, serine CHaHbOH) ; 3.9 (1 H, mserine CHNHZ) ; 3.25 (2
H, t, J = 7. 5 Hz, indoline C (3 ) Hz) .
HPLC (Luna 2, Gradient 1): rt = 2.78 minutes.
HPLC (Symmetry, Gradient 2): rt = 4.61 minutes.
LC/MS (Lung 2, Gradient 4): rt = 0.65 minutes, 488 (MH)'.
Example 51
3-(Aminomethyl)benzoyl-D-phenylglycine 1-(3-pyridyl-
acetyl)-2,3-dihydroindol-6-amide bis(trifluoroacetate)
salt
Prepared using 3-pyridylacetic acid.
1H NMR (d3 acetonitrile): 8.91 ppm (1 H, br s, Ar), 8.73-8.55
(2 H, m, Ar), 8.35 (1 H, br s, Ar), 8.15 (1 H, d, J = 10 Hz,
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Ar), 8.05-7.95 (2 H, m, Ar), 7.80 (1H, d, J = 10 Hz, Ar),
7.74 - 7.15 (10 H, m, Ar & 2 x amide NH), 5.69 (1 H, d, J =
7 Hz, CHPh), 4.25 - 4.12 (4 H, m, ArCHzN & dihydroindole
C (2 ) H2) , 3 . 98 (2 H, s, C (O) CHzPy) , 3 . 17 (2 H, t, J = 8 Hz,
dihydroindole C (3 ) Hz) .
HPLC (tuna 2, Gradient 1): rt = 2.96 minutes.
LC/MS (Luna 2, Gradient 4): rt = 1.35 minutes, 520 (MH+).
Example 52
3-(Aminomethyl)benzoyl-D-phenylglycine 1-(N-acetyl)-
aminoacetyl-2,3-dihydroindol-6-amide trifluoroacetate
salt
Prepared using N-acetylglycine.
1H NMR (d4 MeOH): 8.31 ppm (1 H, s, Ar); 7.95 (2 H, m, Ar);
7.64 - 7.57 (4 H, m, Ar); 7.43 - 7.38 (4 H, m, Ar); 7.18
(1H, d, J = 10 Hz, Ar); 5.81 (1H, s, CHPh); 4.23 - 4.11 (6
H, m, ArCHzNH2, aminoacetyl CHz and dihydroindole C (2 ) HZ) ;
3.21 (2 H, t, J = 7 Hz, dihydroindole C(3)H2); 2.07 (3H, s,
COCH3 ) .
HPLC (Luna 2, Gradient 1): rt = 3.33 minutes.
HPLC (Symmetry, Gradient 2): rt = 5.20 minutes.
LC/MS (Luna 2, Gradient 4): rt = 0.59 minutes, 500 (MH)+.
Example 53
3-(Aminomethyl)benzoyl-D-phenylglycine 1-
(hydroxyacetyl)-2,3-dihydroindol-6-amide
trifluoroacetate salt
Prepared using 2-benzyloxyacetic acid.
1H NMR (d4 MeOH) : 8.25 ppm (1 H, s, Ar) ; 7.85 (2 H, m, Ar) ;
7.54 - 7.47 (4 H, m, Ar); 7.35 - 7.26 (4 H, m, Ar); 7.10 (1
H, d, J = 11 Hz, Ar) ; 4.21 (2 H, s, CHzOH ) ; 4. 10 (2 H, s,
CH2NH2) ; 3 . 95 (2 H, t, J = 7. 5 Hz, dihydroindole C (2) Hz) ;
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3.21 (2 H, t, J = 7.5 Hz, dihydroindole C(3)HZ).
HPLC (tuna 2, Gradient 1): rt = 3.23 minutes.
HPLC (Symmetry, Gradient 2): rt = 5.26 minutes.
LC/MS (tuna 2, Gradient 4): rt = 1.67 minutes, 500 (MH)+.
Example 54
3-(Aminomethyl)benzoyl-D-phenylglycine 1-phenylacetyl-
2,3-dihydroindol-6-amide trifluoroacetate salt
Prepared using phenylacetic acid.
1H NMR (d3 acetonitrile): 8.78 (1 H, br s, Ar), 8.23 (1 H, br
s, Ar), 7.90 (2 H, s, Ar), 7.73 (1H, d, J = 10 Hz, Ar), 7.60
- 7.01 (14 H, m, Ar & 2 x amide NH), 5.60 (1 H, d, J = 7 Hz,
CHPh) , 4 . 10 - 3 . 97 (4 H, m, ArCHzN & dihydroindole C (2) HZ) ,
3.71 (2 H, s, PhCHz), 2.99 (2 H, t, J = 8 Hz, dihydroindole
C(3)HZ) .
HPLC (tuna 2, Gradient 1): rt = 4.17 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.26 minutes, 519 (MH+).
Example 55
3-(Aminomethyl)benzoyl-D-phenylglycine 1-(methylamino)-
acetyl-2,3-dihydroindol-6-amide bis(trifluoroacetate)
salt
Prepared using sarcosine.
1H NMR (d4 MeOH): 8.39 ppm (1 H, s, indoline C(7)H); 7.95 (2
H, br s, 3-(aminomethyl)phenyl C(2)H and C(6)H); 7.72 - 7.53
(4 H, m, Ar); 7.47 - 7.31 (4 H, m, Ar); 7.24 (1 H, d, J = 10
Hz, indoline C(4)H or C(5)H); 5.82 (1 H, br s, CHPh); 4.20
( 2 H , s , CHzNHz or C ( 0 ) CHZNHMe ) ; 4 . 15 ( 2 H , s , CHZNH2 or
C (0) CHzNHMe) ; 4 . 10 (2 H, t, J = 9 Hz, indoline C (2 ) Hz) ; 3 .25
(2 H, t, J = 9 Hz, indoline C(3)H2); 2.81 (3 H, s, CH3).
HPLC (Symmetry C8, Gradient 2): rt = 4.75 min.
LCMS (Luna 2, Gradient 4): rt = 1.45 min, 472 (MH)+.
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Example 56
3-(Aminomethyl)benzoyl-D-phenylglycine 3-aminopropionyl-
2,3-dihydroindol-6-amide bis(trifluoracetate) salt
Prepared using ~i-alanine.
1H NMR (D20): 7.98 ppm (1 H, s, indoline C(7)H); 7.72 (2 H,
br s, 3-(aminomethyl)phenyl C(2)H and C(6)H); 7.60 - 7.30 (7
H, m, Ar); 7.08 (1 H, d, J = 10 Hz, indoline C(4)H or
C(5)H) ; 6.95 (1 H, d, J = 10 Hz, indoline C(4)H or C(5)H) ;
5.57 (1 H, s, CHPh) ; 4.09 (2 H, s, ArCHzNH2) ; 3.82 (2 H, t, J
- 7 Hz, indoline C (3 ) H2) ; 3 . 20 (2 H, t, J = 4 . 5 Hz,
C (O) CH2CHZNHz) ; 2 . 95 (2 H, t, J = 7 Hz, indoline C (3 ) Hz) ;
2 . 71 (2 H, t, J = 4 . 5 Hz, C (O) CHZCHZNHZ) .
HPLC (Symmetry C8, Gradient 2): rt = 4.80 minutes.
LCMS (Luna 2, Gradient 4): rt = 1.53 minutes, 472 (MH)+.
Example 57
3-(Aminomethyl)benzoyl-D-phenylglycine 1-(4-pyridyl-
acetyl)-2,3-dihydroindol-6-amide bis-trifluoroacetate
salt
Prepared using 4-pyridylacetic acid.
1H NMR (CD3CN): 8.91 (1 H, br s, Ar), 8.73-8.55 (2 H, m, Ar),
8.35 (1 H, br s, Ar), 8.15 (1 H, d, J = 10 Hz, Ar), 8.05-
7.95 (2 H, m, Ar), 7.80 (1H, d, J = 10 Hz, Ar), 7.74 - 7.15
(10 H, m, Ar & 2 x amide NH), 5.69 (1 H, d, J = 7 Hz, CHPh),
4.25 - 4.12 (4 H, m, PhCH2N & dihydroindole C(2)H~z), 3.98 (2
H, s, C (O) CHZPy) , 3 . 17 (2 H, t, J = 8 Hz, dihydroindole
C(3)HZ) .
HPLC (Symmetry, Gradient 2): rt = 5.43 minutes.
LC/MS (tuna 2, Gradient 4): rt = 1.56 minutes, 520 (MH)'.
Example 58
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3-(Aminomethyl)benzoyl-D-phenylglycine 1-(imidazol-4-
ylacetyl)-2,3-dihydroindol-6-amide bis(trifluoroacetate)
salt
Prepared using imidazol-4-ylacetic acid.
1H NMR (D20): 7.75 ppm (1 H, br s, NH); 7.49 (2 H, br s, Ar);
7.28 (1 H, d, J = 8 Hz, Ar); 7.24-7.12 (9 H, m, Ar); 6.92 (1
H, d, J = 8 Hz, Ar); 6.74 (1 H, d, J = 8 Hz, Ar); 6.28 (1H,
s, NH) ; 5.38 (1 H, s, CHPh) ; 3.87 (2 H, s, ArCHzNHz) ; 3.72 (2
H, d, J 8 - Hz, dihydroindole C(2)HZ); 3.52 (2 H, br s,
CHZIm) ; 2 . 70 (2 H, t, J = 8 Hz, dihydroindole C (3) Hz) .
HPLC (Symmetry, Gradient 2): rt = 4.89 minutes.
LC/MS (tuna 2, Gradient 4): rt = 1.45 minutes, 509 (MH)+.
Example 59
3-(Aminomethyl)benzoyl-D-phenylglycine 1-(2-
aminothiazol-4-yl)-acetyl-2,3-dihydroindol-6-amide
dihydrochloride.
Prepared using (2-formamidothiazol-4-yl)acetic acid.
1H NMR (D20): 7.77 ppm (1 H, br s, NH); 7.51 (2 H, br s, Ar);
7.29 (1 H, d, J = 8 Hz, Ar); 7.24-7.03 (9 H, m, Ar); 6.91 (1
H, d, J = 8 Hz, Ar); 6.72 (1 H, d, J = 8 Hz, Ar); 6.22 (1H,
s, NH) ; 5.32 (1 H, s, CH_Ph) ; 3.85 (2 H, s, ArCHzNH2) ; 3.73 (2
H, d, J = 8 Hz, dihydroindole C(2)HZ); 3.56 (2 H, br s,
CHzThz) ; 2 .76 (2 H, t, J = 8 Hz, dihydroindole C (3) HZ) .
HPLC (Symmetry, Gradient 2): rt = 5.03 minutes.
LC/MS (tuna 2, Gradient 4): rt = 1.51 minutes, 541 (MH)+.
Example 60
3-(Aminomethyl)benzoyl-D-phenylglycine 1-(2-
formylaminothiazol-4-yl)acetyl-2,3-dihydroindol-6-amide
trifluoroacetate salt
Prepared using (2-formylaminothiazol-4-yl)acetic acid.
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1H NMR (D20): 8.30 ppm (1 H, s, NCHO); 7.90 (1 H, br s,
ArNH); 7.64 (2 H, br s, Ar); 7.42 (1 H, d, J = 8 Hz, Ar);
7.38 - 7.26 (9 H, m, Ar & NH); 7.01 (1 H, d, J = 8 Hz, Ar);
6.96 (1 H, d, J = 8 Hz, Ar); 6.82 (1H, s, NH); 5.50 (1 H, s,
CHPh) ; 4.06 (2 H, s, ArCH2NH2) ; 3 . 90 (2 H, d, J = 8 Hz,
dihydroindole C (2) HZ) ; 3 . 64 (2 H, br s, CHZThz) ; 2 . 90 (2 H,
t , J = 8 Hz , dihydroindole C ( 3 ) Hz ) .
HPLC (Symmetry, Gradient 2): rt = 5.75 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.10 minutes, 569 (MH)~.
Example 61
3-(Aminomethyl)benzoyl-D/L-(4-aminomethyl)phenylglycine
indan-5-amide bis(trifluoroacetate) salt.
Methyl 4-bromophenylacetate
Thionyl chloride (18 mL, 0.25 mol) was added dropwise to a
solution of 4-bromo-phenylacetic acid (50 g; 0.23 mol) in
methanol (250 mL). The resulting mixture was stirred at room
temperature for 1 hour before the methanol was removed in
vacuo. Ethyl acetate (300 mL) was added and the resulting
solution was washed with water (3 x 150 mL) and 1M aqueous
NaHC03 (1 x 150 mL), dried (MgS04) and evaporated to give the
ester (52.8 g; 100 %) as an orange oil which was used
without further purification.
1H NMR (CDC13) : 7 . 38 ppm (2 H, d, J = 8 .4 Hz, C (2 ) H and
C(6)H); 7.09 (2 H, d, J = 8.4 Hz, C(3)H and C(5)H); 3.63 (3
H, s, OMe) ; 3 .51 (2 H, s, CHZ) .
Methyl 4-cyanophenylacetate
Zinc cyanide (10.4 g, 0.088 mol) and tetrakis-
(triphenylphosphine)palladium(0) (5 g, 4.4 mmol) were added
to a solution of methyl 4-bromophenylacetate (20 g, 0.088
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mol) in dimethylformamide (150 mL). The resulting mixture
was stirred at 80°C for 5 hours, then allowed to cool to
room temperature. Toluene (500 mL) and 1M aqueous ammonia
(500 mL) were added, the layers were separated and the
organic layer washed with brine (100 mL) and dried (MgS04).
Evaporation of the solvents afforded an off-white solid,
which was purified by silica gel chromatorgraphy to afford
the cyano-compound as a white solid (11.3 g; 73 %).
1H NMR (CDC13) : 7. 65 ppm (2 H, d, J = 8 .4 Hz, C (3 ) H and
C(5)H) ; 7.42 (2 H, d, J = 8.1 Hz, C(2)H and C(6)H) ; 3.74 (3H,
s, OMe) ; 3.72 (2H, s, CHZ) .
4-Cyanophenylacetic acid
A solution of methyl 4-cyanophenylacetate (23.9 g; 0.136
mol) in ethanol (250 mL) was stirred at room temperature and
a solution of sodium hydroxide (6.0 g; 0.15 mol) in water
(25 mL) was added. After 2 hours the ethanol was removed in
vacuo. Ethyl acetate (300 mL) and 5% aqueous HC1 (300 mL)
were added and the layers were separated. The aqueous layer
was extracted with ethyl acetate (300 mL) and the combined
organic layers were dried (MgS04) and evaporated in vacuo to
give the acid (21.6 g; 99 %) which was used without further
purification.
1H NMR (CDC13) : 7.57 ppm (2 H, d, J = 8.3 Hz, C(3)H and
C(5)H) ; 7.34 (2 H, d, J = 8.2 Hz, C(2)H and C(6)H) ; 3.64 (2
H , s , CHz ) .
4-(N-BOC-aminomethyl)phenylacetic acid
A solution of 4-cyanophenylacetic acid (12.11 g, 0.075 mol)
in water (163 mL) and concentrated aqueous ammonia (40 mL)
was stirred at room temperature and Raney nickel (6.3 g) was
added. The resulting suspension was stuirred under a
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hydrogen atmosphere for 24 hours before the reaction mixture
was filtered through celite and evaporated in vacuo to give
crude 4-(aminomethyl)-phenylacetic acid (12.57 g; 100 %) as
a pale blue solid.
A solution of the crude amino acid (12.57 g, 0.075 mol) in
water (50 mL) and 1,4-dioxane (50 mL) was stirred at room
temperature and sodium hydroxide (3 g, 0.075 mol) and di-
tbutyl dicarbonate (16.4 g, 0.075 mol) were added
simultaneously. After 24 hours the 1,4-dioxane was removed
in vacuo and the aqueous layer was acidified with saturated
aqueous citric acid (200 mL). The solution was extracted
with ethyl acetate (3 x 150 mL) and the combined organic
layers were dried (MgS04) and evaporated in vacuo to give
the N-BOC-amine (17.6 g, 88 %) as a white solid which was
used without further purification.
1H NMR (CDC13): 7.00 ppm (4 H, m, Ar); 4.65 (1 H, br s, N-H);
4.09 (2 H, d, J = 6 Hz, CHzNH) ; 3.43 (2H, s, CHZ) ; 1.25 (9H,
S , tBu ) .
Methyl 4-(N-BOC-aminomethyl)phenylacetate
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (34.8 g, 0.18 mol) and 4-(N,N-
dimethylamino)pyridine (220 mg, 1.8 mmol) were added to a
solution of 4-(N-BOC-aminomethyl)phenylacetic acid (47.8 g,
0.18 mol) in methanol (200 ml). After stirring for 18 hours
the methanol was removed in vacuo and the reaction mixture
partitioned between ethyl acetate (200 mL) and saturated
aqueous citric acid (200 mL). The organic phase was
separated and washed with saturated aqueous NaHC03 (200 mL)
and brine (200 mL), dried (MgS04) and evaporated to give the
methyl ester (49.8 g; 99 %).
1H NMR (CDC13) : 7.42 ppm (4 H, s, Ar) ; 5.02 (1 H, br s, N-H) ;
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4.48 (2 H, d, J = 5.7 Hz, CHZNH); 3.87 (3 H, s, OMe); 3.79
(2 H, s, CHz) ; 1.64 (9 H, s, 'Bu) .
Methyl [4-(N-BOC-aminomethyl)phenyl]-a-azidoacetate
A solution of methyl 4-(N-BOC-aminomethyl)phenylacetate
(9.34 g; 0.033 mol) in THF (100 mL) was stirred under argon
at -78°C and potassium bis(trimethylsilyl)amide (16.7 g,
0.084 mol) in THF (50 mL) was added. After stirring for 30
minutes, 2,4,6-triisopropylbenzene-sulfonyl azide (31.1 g,
0.101 mol) was added as a solid. After 5 minutes, acetic
acid (10 mL, 0.175 mol) was added and the reaction warmed to
room temperature. The reaction mixture was then partitioned
between ethyl acetate (500 mL) and water (500 mL), separated
and the organic layer dried (MgS04). Evaporation of the
solvent and purification of the residue by silica gel
chromatography afforded the azide (7.1 g, 67 %).
1H NMR (CDC13) : 7.28 ppm (4 H, s, Ar) ; 4.92 (1 H, s, CHN3) ;
4.25 (2 H, s, CHzNH) ; 3.69 (3 H, s, OMe) ; 1.38 (9 H, s, 'Bu) .
Methyl a-amino-[4-(N-BOC-aminomethyl)phenylacetate
A solution of methyl [4-(N-BOC-aminomethyl)phenyl]-a-
azidoacetate (7.1 g, 0.022 mol) in ethyl acetate (50 mL) was
stirred over palladium on carbon (5%). The reaction vessel
was taken up to 250 psi with hydrogen for 17 hours. The
reaction mixture was filtered through celite and evaporated
in vacuo to give the amine (6.47 g, 100 %) as a pale solid.
1H NMR (CDC13) : 7.20 ppm (2 H, m, Ar) ; 7.12 (2 H, m, Ar) ;
4.81 (1 H, br s, NH); 4.45 (1 H, s, CH); 4.18 (2 H, d, J = 6
Hz, CH2NH) ; 3 .54 (3 H, s, OMe) ; 2. 09 (2 H, br s, NHz) ; 1.30
(9 H, s, tBu) .
Methyl a-(N-benzyloxycarbonyl-amino)-[4-(N-BOC-
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aminomethyl)phenyl]acetate
A solution of the amine (530 mg, 1.8 mmol) in
tetrahydrofuran (15 mL) was treated with triethylamine (0.25
mL, 1.8 mmol) and benzyl chloroformate (0.26 mL, 1.8 mmol)
and allowed to stir at room temperature for 1 hour. The
reaction was diluted with ethyl acetate (40 mL), washed with
brine (2 x 25 mL), dried (MgS04) and concentrated under
reduced pressure to afford a yellow oil. The
benzyloxycarbonyl ester was purified by flash chromatography
on silica gel (ethyl acetate / hexane 1 . 1) to give a
yellow solid (312 mg, 66 %).
1H NMR (CDC13): 7.32 - 7.15 ppm (9 H, m, 9 Ar); 5.80 (1 H, br
s, NH) ; 5.30 (1 H, d, J = 9.6 Hz, CH) ; 5.01 (2 H, s, CHzPh) ;
4.22 (2 H, d, J = 7.2 Hz, C_HZNHBoc) ; 3.63 (3 H, s, OCH3) ;
1.39 (9 H, s, tBu) .
D/L-a,-(N-benzyloxycarbonyl)-[4-(N-BOC-aminomethyl)
phenyl ] glyc ine
A solution of the ester (356 mg, 0.83 mmol) in
tetrahydrofuran (15 mL) was treated with 1 M LiOH (1.7 mL,
1.7 mmol) and heated at reflux for 3 hours. The solvent was
removed under reduced pressure and the residue diluted with
water (20 mL). The pH was reduced to 4 using 5 o aqueous HC1
and the aqueous phase was extracted with ethyl acetate (3 x
20 mL). The combined organic extracts were dried (MgS04) and
concentrated under reduced pressure to afford the acid as a
yellow solid (273 mg, 79 0) which was carried forward
without further purification.
D/L-a-(N-benzyloxycarbonyl)-[4-(N-BOC-
aminomethyl)phenyl]glycine indan-5-amide.
A solution of the acid (173 mg, 0.42 mmol) in
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dimethylformamide (15 ml) was treated with 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80
mg, 0.42 mmol), 1-hydroxy-7-azabenzotriazole (57 mg, 0.42
mmol), 5-aminoindane (56 mg, 0.42 mmol) and 4-(N,N-
dimethylamino)pyridine (5 mg) and stirred overnight at room
temperature before being partitioned between ethyl acetate
(50 mL) and water (50 mL). The layers were separated and the
organic phase was washed with 5 % aqueous HC1 (25 mL),
saturated aqueous NaHC03 (25 mL) and water (25 mL), dried
(MgS04) and concentrated under reduced pressure to afford
the indanamide as a colourless solid (160 mg, 72 %) which
was used without further purification.
1H NMR (CDC13): 7.39 - 7.09 ppm (12 H, m, 10 Ar and 2 NH);
6.99 (2 H, s, Ar); 5.38 (1 H, br s, CHAr); 5.01 (2 H, s,
CHZPh); 4.81 (1 H, m, NH); 4.19 (2 H, s, CHzNHBOC); 2.85 -
2 .68 (4 H, m, indane C (1) HZ and C (3) HZ) ; 2 . 04 - 1 . 88 (2 H, m,
indane C ( 2 ) Hz ) ; 1 . 3 9 ( 9 H , s , tBu ) .
3-(N-BOC-Aminomethyl)benzoyl-D/L-4-(N-BOC-aminomethyl)-
phenylglycine indan-5-amide
10 % Palladium on carbon (50 mg), was added to a solution of
the indanamide (160 mg, 0.3 mmol) in ethanol (20 mL) and the
suspension was stirred under a hydrogen atmosphere overnight
. The mixture was filtered and the filter was washed with
ethanol (20 ml). The combined filtrates were concentrated
under reduced pressure to afford the amine as a colourless
solid (107 mg, 90 %) which was carried forward without
further purification.
A solution of the amine (107 mg, 0.27 mmol) in
dimethylformamide (15 mL) was treated with 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (52
mg, 0.27 mmol), 1-hydroxy-7-azabenzotriazole (37 mg, 0.27
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mmol), N-BOC-3-(aminomethyl)benzoic acid (68 mg, 0.27 mmol)
and 4-(N,N-dimethylamino)pyridine (5 mg) and stirred
overnight at room temperature. The solution was partitioned
between ethyl acetate (25 mL) and water (25 mL) and the
organic phase was separated and washed with 5 % aqueous HC1
(25 mL), saturated aqueous NaHC03 (25 mL) and water (25 mL)
before being dried (MgS04) and concentrated under reduced
pressure to afford a yellow solid. The residue was purified
by flash chromatography on silica gel (ethyl acetate /
hexane 1 . 1) to give the diprotected bis-amide as a
colourless solid (103 mg, 61 %).
1H NMR (CDC13): 9.25 ppm (1 H, s, NH); 7.94 (1 H, d, J = 7.2
Hz, Ar); 7.62 (2 H, s, Ar); 7.43 - 7.24 (5 H, m, 4 Ar, NH);
7.05 (3 H, d, J = 7.2 Hz, Ar); 6.94 (1 H, d, J = 7.2 Hz,
Ar); 6.14 (1 H, d, J = 7.2 Hz, CH); 5.07 (1 H, m, NH); 4.99
(1 H, m, NH); 4.16 (2 H, s, CHzNHBOC); 4.10 (2 H, s,
CHZNHBOC ) ; 2 . 7 7 - 2 . 61 ( 4 H , m, indane C ( 1 ) HZ and C ( 3 ) Hz ) ;
1.98 - 1.87 (2 H, m, indane C(2)Hz) ; 1.35 (9 H, s, tBu) .
3-(Aminomethyl)benzoyl-D/L-4-(aminomethyl)phenylglycine
indan-5-amide bis(trifluoroacetate) salt.
A solution of the diprotected bis-amide (103 mg, 0.16 mmol)
in dichloromethane (5 mL) was stirred at room temperature
and trifluoroacetic acid (3 mL) was added. Stirring was
continued for a further hour before the solvents were
removed under reduced pressure to afford the
bis(trifluoroacetate) salt as a colourless solid (92 mg, 88
%) .
1H NMR (d4 MeOH): 7.90 ppm (1 H, s, Ar); 7.84 (1 H, s, Ar);
7.65 - 7.54 (4 H, m, Ar); 7.49 - 7.32 (3 H, m, Ar); 7.12 (1
H, d, J = 7.2 Hz, Ar); 7.02 (1 H, d, J = 7.2 Hz, Ar); 5.78
( 1 H , s , CHAr ) ; 4 . 0 8 ( 2 H , s , CH2NHz ) ; 4 . 01 ( 2 H , s , CHzNH2
) ;
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2.79 - 2.70 (4 H, m, indane C(1)Hz and C(3)HZ) ; 2.03 - 1.90
( 2 H, m, indane C ( 2 ) HZ ) .
HPLC (Luna 2, Gradient 1): rt = 3.13 minutes.
LCMS (tuna 2, Gradient 4): rt = 1.45 minutes, 429 (MH)+.
Examples 62 - 64 were prepared in a similar fashion to
Example 61, using the specified amine in place of 5-
aminoindane.
Example 62
3-(Aminomethyl)benzoyl-D/L-4-(aminomethyl)phenylglycine
1-aminoacetyl-2,3-dihydroindol-6-amide
tris(trifluoroacetate salt)
Prepared from 6-amino-1-(N-BOC-aminoacetyl)-2,3-
dihydroindole.
1H NMR (d4 MeOH): 8.23 ppm (1 H, s, Ar); 7.84 - 7.74 (2 H, m,
Ar); 7.56 - 7.30 (6 H, m, Ar); 7.17 (1 H, d, J = 7.2 Hz,
Ar); 7.02 (1 H, d, J = 7.2 Hz, Ar); 5.68 (1 H, s, CHAr);
4.02 (2 H, s, CHzNH2) ; 3.99 - 3.79 (6 H, m, CH2NH2,
dihydroindole C (2 ) Hz, CHZNHz glycine) ; 3 . 06 - 2 . 97 (2 H, m,
dihydroindole C (3 ) H2) .
HPLC (Luna 2, Gradient 1): rt = 2.13 minutes.
LCMS (Luna 2, Gradient 4): rt = 0.51 minutes, 487 (MH)+.
Example 63
3-(Aminomethyl)benzoyl-D/L-4-(aminomethyl)phenylglycine 1-
acetyl-2,3-dihydroindole bis(trifluoroacetate) salt
Prepared from 1-acetyl-6-amino-2,3-dihydroindole.
1H NMR (d4 MeOH): 8.21 ppm (1 H, s, Ar); 7.97 - 7.86 (2 H, m,
Ar); 7.72 - 7.43 (6 H, m, Ar); 7.32 (1 H, d, J = 7.2 Hz,
Ar) ; 7.12 (1 H, d, J = 7.2 Hz, Ar) ; 5.81 (1 H, s, CHAr) ;
4.17 (1 H, s, CHZNH2) ; 4.15 - 4.04 (4 H, m, CH_zNH2,
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dihydroindole C(2)HZ); 3.19 - 3.07 (2 H, m, dihydroindole
C ( 3 ) HZ ) ; 2 . 2 0 ( 3 H , s , NCOCH3 ) .
HPLC (Luna 2, Gradient 1): rt = 2.72 minutes.
LCMS (Luna 2, Gradient 4): rt = 1.18 minutes, 472 (MH)+.
Example 64
3-(Aminomethyl)benzoyl-D/L-4-(aminomethyl)phenylglycine
4-(isopropyl)phenylamide bis(trifluoroacetate salt)
Prepared from 4-isopropylaniline.
1H NMR (d4 MeOH): 8.01 - 7.92 ppm (2 H, m, Ar); 7.75 - 7.43
(8 H, m, Ar); 7.18 (2 H, d, J = 9.6 Hz, Ar); 5.87 (1 H, s,
CHAr ) ; 4 . 21 ( 2 H , s , CHzNH2 ) ; 4 . 14 ( 2 H , s , CH_zNHz ) ; 2 . 9 6 -
2.81 (1 H, m, CH(CH3)z) ; 1.24 (6 H, d, J = 7 Hz, CH(CH3)2) .
HPLC (Luna 2, Gradient 1): rt = 3.39 minutes.
LCMS (Luna 2, Gradient 4): rt = 1.59 minutes, 431 (MH)+.
Examples 65 - 68 were prepared in a similar manner to
Example 61 except that the indicated protected amino acid
was used in the place of D/L-4-(N-BOC-aminomethyl)-a-(N-
benzyloxycarbonyl)phenylglycine.
Example 65
3-(Aminomethyl)benzoyl-D-cyclohexylglycine indan-5-amide
trifluoroacetate salt
Prepared from N-BOC-D-cyclohexylglycine.
1H NMR (d4 MeOH): 7.88 - 7.02 ppm (7 H, m, Ar); 4.43 (1 H, d,
J = 9 Hz, CH(cHex) ) ; 4.04 (2 H, s, CHZNHZ) ; 2.78 - 2.68 (4 H,
m, indane C ( 1 ) Hz and C ( 3 ) HZ ) ; 2 . 04 - 1. 82 ( 4 H, m, indane
C (2 ) H2, cHex CHz) ; 1 . 77 - 1 . 56 (4 H, m, 2 x cHex CHz) ; 1 . 36 -
0.95 (5 H, m, 2 x cHex CHz and CH).
HPLC (tuna 2, Gradient 1): rt = 4.27 minutes.
LCMS (tuna 2, Gradient 4): rt = 2.21 minutes, 406 (MH)'.
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Example 66
3-(Aminomethyl)benzoyl-D/L-1-naphthylglycine indan-5-
amide trifluoroacetate salt
Prepared from N-BOC-D/L-1-naphthylglycine.
1H NMR (d4 MeOH) : 8.25 ppm (1 H, d, J = 7.2 Hz, Ar) ; 8.04 -
7.84 (4 H, m Ar); 7.75 - 7.44 (7 H, m, Ar); 7.33 (1 H, d, J
- 7.25 Hz, Ar); 7.16 (1 H, d, J = 7.25 Hz, Ar); 6.72 (1 H,
s, CHAr); 4.15 (2 H, s, CHZNH2); 2.94 - 2.78 (4 H, m, indane
C(1)Hz C(3)HZ) ; 2.17 - 1.98 (2 H, m, indane C(2)Hz) .
HPLC (tuna 2, Gradient 1): rt = 4.37 minutes.
LCMS (Luna 2, Gradient 4): rt = 2.37 minutes, 450 (MH)+.
Example 67
3-(Aminomethyl)benzoyl-D/L-(4-phenyl)phenylglycine
indan-5-amide trifluoroacetate salt
Prepared from N-Fmoc-D/L-(4-phenyl)phenylglycine.
1H NMR (d4 MeOH): 7.94 - 7.83 ppm (2 H, m, Ar); 7.64 - 7.15
(13 H, m, Ar); 7.02 (1 H, d, J = 7.2 Hz, Ar); 5.80 (1 H, s,
CH); 4.08 (2 H, s, CH_ZNH2); 2.81 - 2.77 (4 H, m, indane
C ( 1 ) Hz and C ( 3 ) HZ ) ; 2 . O 1 - 1 . 8 8 ( 2 H , m, indane C ( 2 ) Hz )
.
HPLC (Luna 2, Gradient 1): rt = 4.87 minutes.
LCMS (Luna 2, Gradient 4): rt = 2.56 minutes, 476 (MH)+.
Example 68
3-(Aminomethyl)benzoyl-D-(4-aminophenyl)glycine indan-5-
amide bis(trifluoroacetate) salt
Prepared from N-BOC-D-(4-Benzyloxycarbonylaminophenyl)-
glycine (prepared as described below).
D-(4-Hydroxyphenyl)glycine methyl ester hydrochloride
D-4-Hydroxyphenylglycine (12.5 g, 74.8 mmol) and dry
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methanol (24 mL) were stirred in a dry 250 mL three necked
round bottom flask, equipped with a low temperature
thermometer. The mixture was stirred under nitrogen and
cooled to an internal temperature of below -20°C. Using a
syringe, thionyl chloride (6 mL, 9,78 g, 82.2 mmol) was
added dropwise to the cooled mixture over a period of 10
minutes at such a rate that the internal temperature did not
exceed -20°C. Once the addition was complete the mixture
was allowed to warm to room temperature and stirred
overnight. Dry ether (150 mL) was added and the white
precipitate that formed was collected by suction filtration,
washed with a little more ether and dried (15.5g, 950).
N-BOC-D-(4-Hydroxyphenyl)glycine methyl ester
Di-t-butyl dicarbonate (15.9 g, 72.8 mmol) was added to a
stirred mixture of D-4-hydroxyphenylglycine methyl ester
hydrochloride (14 g, 64.3 mmol) and NaHC03 (11.7 g, 0.14
mol) in tetrahydrofuran (150 mL) and water (50 mL), in one
portion. The mixture was stirred rapidly for 4h. Hexane
(75 mL) was added and the organic layer separated and washed
with saturated aqueous NaHC03 (20 mL) and brine (20 mL) and
dried (MgS04). Evaporation of the solvent afforded the N-
BOC-protected amine (19.78, 96%).
N-BOC-D-(4-Trifluoromethylsulphonyloxyphenyl)glycine methyl
ester
2,6-Lutidine (9.44 ml, 8.68 g, 81.0 mmol) and 4-
dimethylaminopyridine (1.65 g, 13.5 mmol) were added to a
stirred solution of N-BOC-D-(4-hydroxyphenyl)glycine methyl
ester (19 g, 67.5 mmol) in dichloromethane (400 mL) and the
mixture cooled in an ice bath. Trifluoromethananesulphonic
anhydride (13.7 mL, 23.0 g, 81.4 mmol) was added over a
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period of five minutes and then the mixture was allowed to
warm to room temperature over four hours. The solution was
washed with water (2 x 150 mL), 1N HC1 (2 x 150 mL) and
saturated aqueous NaHC03 (150 mL) and dried (MgS04).
Evaporation of the solvent afforded an oil which was
purified by flash chromatography on silica gel (hexane /
dichloromethane 1:1 and then neat dichloromethane)
affording the triflate as a white solid (19 g, 77%).
N-BOC-D-(4-benzyloxycarbonylphenyl)glycine methyl ester
N-BOC-D-(4-trifluoromethylsulphonyloxyphenyl)glycine methyl
ester (27.6 g, 77.0 mmol), benzyl alcohol (32.6 mL, 34.1 g,
315 mmol), palladium (II) acetate (255 mg, 1.13 mmol), bis-
1,3-diphenylphosphinylpropane (448 mg, 1.09 mmol) and
triethylamine (10.2 mL, 7.40 g, 73.2 mmol) in
dimethylformamide (72 mL) were placed in a Parr reactor and
the reactor assembled. The vessel was pressurised to ~10 psi
with nitrogen and the gas released (repeated five times to
remove all oxygen from the system). Carbon monoxide gas was
then carefully introduced to -20 psi and released three
times. Carbon monoxide was then added to 100 psi and the
stirrer started. The vessel was slowly heated to 65 °C
internal temperature and then stirred, monitoring by tlc.
When complete (after -- 18 hours) the reaction was cooled to
30°C, the gas released and the vessel flushed five times
with nitrogen as before. The reaction mixture was
partitioned between ethyl acetate (250 mL) and water (100
mL) and the organic layer washed with 1M hydrochloric acid
(30 mL) and saturated aqueous NaHC03 (30 mL) and dried
(MgS04) and evaporated. Purification of the resulting oil by
column chromatography (ethyl acetate / hexane; 1:4) gave the
benzyl ester (18.7 g, 70%).
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N-BOC-D-(4-hydroxycarbonylphenyl)glycine methyl aster
% Palladium on carbon (100 mg) was added to a solution of
the benzyl ester (500 mg, 1.25 mmol) in ethanol (15 mL) and
5 the suspension was stirred under a hydrogen atmosphere
overnight. The mixture was filtered and the residue was
washed with ethanol (20 mL) and the combined organic
solvents were evaporated under reduced pressure to afford
the acid as a colourless solid (363 mg, 94 %).
10 1H NMR (CDC13): 8.08 ppm (2 H, br s, Ar); 7.49 (2 H, d, J =
7.2 Hz, Ar); 5.87 (1 H, d, J = 9 Hz, NHCH); 3.73 (3 H, s,
OCH3 ) ; 1 . 41 ( 9 H , s , tBu ) .
N-BOC-D-(4-Benzyloxycarbonylaminophenyl)glycine methyl
ester.
The acid (218 mg, 0.7 mmol) in tetrahydrofuran (20 mL) was
treated with triethylamine (108 ~1, 0.78 mmol) and
diphenylphosphonic azide (161 ~1, 0.78 mmol) and stirred at
room temperature for 1.5 hours. Benzyl alcohol (116 ~1,
1.12 mmol) was then added and the mixture was heated at
reflux for 18 hours. The solvent was evaporated under
reduced pressure and the residue was purified by flash
chromatography (ethyl acetate / hexane, 1:1) to give the N-
benzyloxycarbonylaniline as a brown solid (87 mg, 30 %).
1H NMR (CDC13): 7.35 - 7.23 ppm (7 H, m, Ar); 7.16 (2 H, d, J
- 9 Hz, Ar); 7.06 (1 H, s, NH); 5.53 (1 H, d, J = 9 Hz,
CHAr); 5.18 (1 H, d, J = 9 Hz, NH); 5.10 (2 H, s, CHZPh);
3.59 (3 H, s, OCH3) ; 1.31 (9 H, s, tBu) .
N-BOC-D-(4-Benzyloxycarbonylaminophenyl)glycine
A solution of the ester (87 mg, 0.21 mmol) in
tetrahydrofuran (5 mL) was treated with 1 M LiOH (0.84 ml,
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0.84 mmol) and heated at reflux for four hours. The solvent
was removed under reduced pressure and the residue was
diluted with water (10 mL). The aqueous solution was
acidified to pH 4 using 5 % aqueous HC1 and extracted with
ethyl acetate (3 x 10 mL). The combined extracts were dried
(MgS04) and evaporated under reduced pressure to afford the
crude acid (80 mg, 95 %) as a colourless solid which was
carried forward without further purification.
3-(Aminomethyl)benzoyl-D-(4-aminophenyl)glycine indan-5-
amide bis(trifluoroacetate) salt.
1H NMR (d4 MeOH): 7.92 - 7.80 ppm (2 H, m, Ar); 7.69 (2 H, d,
J = 7.3 Hz, Ar); 7.60 - 7.40 (2 H, m, Ar); 7.34 (3 H, d, J =
12 Hz, Ar); 7.15 (1 H, d, J = 7.2 Hz, Ar); 7.02 (1 H, d, J =
7.2 Hz, Ar); 5.79 (1 H, s, CHAr); 4.07 (2 H, s, CHzNHz); 2.80
- 2.69 (4 H, m, indane C(1)Hz and C(3)Hz) ; 2.01 - 1.88 (2 H,
m, indane C ( 2 ) HZ ) .
HPLC (tuna 2, Gradient 1): rt = 3.17 minutes.
LCMS (Luna 2, Gradient 4): rt = 1.59 minutes, 415 (MH)'.
Example 69
3-(Aminomethyl)benzoyl-D/L-piperidin-4-ylglycine indan-
5-amide bis(trifluoroacetate) salt
(N-BOC-Piperidin-4-ylidene)-(N-benzyloxycarbonyl)glycine
methyl ester
N-BOC-4-Piperidone (2.0 g, 10 mmol), N-(benzyloxy-carbonyl)-
a-phosphonoglycine trimethyl ester (3.64 g, 2.20 mmol) and
1,8-diazabicyclo[5.4.0]undec-7-ene (1.57 mL, 2.10 mmol) were
stirred in acetonitrile overnight. The solvent was removed
and the residue taken up in ethyl acetate (50 mL) and washed
with water (2 x 10 mL), dried (MgS04) and evaporated under
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reduced pressure. The residual oil was purified by
chromatography on silica gel (ethyl acetate / hexane, 40 % /
60 %) to afford the unsaturated ester (3.63 g, 90 %).
1H NMR (CDC13): 7.36 ppm (5 H, br s, Ph); 6.05 (1 H, br s,
NH); 5.12 (2 H, s, CHZPh); 3.73 (3 H, br s, OMe); 3.50 (4 H,
br s, piperidine C (2) Hz and C (6) Hz) ; 2 . 86 (2 H, br s,
piperidine C(3) Hz or C(5) Hz) ; 2.45 - 2.36 (2 H, m,
piperidine C(3) HZ or C(5) H2) ; 1.47 (9 H, s, tBu) .
(N-BOC-Piperidin-4-ylidene)-(N-benzyloxycarbonyl)glycine
A solution of the methyl ester (391 mg, 1 mmol) in
tetrahydrofuran (10 mL) was treated with 1 M LiOH (2 mL, 2
mmol) and heated at reflux for 4 hours. The solvent was
removed under reduced pressure and the residue diluted with
water (20 mL). The aqueous solution was acidified to pH 4
with 5 % aqueous HC1 and extracted with ethyl acetate (3 x
mL). The combined organic extracts were dried (MgS04) and
concentrated under reduced pressure to afford the acid as a
brown solid (305 mg, 78 %) which was carried forward without
20 further purification.
(N-BOC-Piperidin-4-ylidene)-(N-benzyloxycarbonyl)glycine
indan-5-amide
A solution of the acid (253 mg, 0.65 mmol) in
dimethylformamide (20 mL) was treated with 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (124
mg, 0.65 mmol), 1-hydroxy-7-azabenzotriazole (88 mg, 0.65
mmol), 5-aminoindane (86 mg, 0.65 mmol) and 4-(N,N-
dimethylamino)pyridine (10 mg) and stirred overnight at room
temperature. The solution was partitioned between ethyl
acetate (30 mL) and water (30 mL), separated, and~the
organic phase was washed with 5 % aqueous HC1 (30 mL),
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saturated aqueous NaHC03 (30 mL) and water (30 mL), dried
(MgS04) and concentrated under reduced pressure to afford a
colourless solid. The crude product was purified by flash
chromatography (ethyl acetate / hexane 1 . 1) to afford the
indanamide as a colourless solid (215 mg, 65 %).
1H NMR (CDC13): 8.31 (1 H, br s, NH); 7.43 (9 H, m, 8 Ar,
NH) ; 5 . O1 (2 H, s, CHzPh) ; 3 . 34 (4 H, br s, piperidine C (2 ) Hz
and C ( 6 ) Hz ) ; 2 . 8 3 - 2 . 71 ( 4 H , m, indane C ( 1 ) Hz and C ( 3 )
Hz ) ;
2 . 54 ( 2 H, br s , piperidine C ( 3 ) H2 or C ( 5 ) H2 ) ; 2 . 23 - 2 . 14 (
2
H, m, piperidine C(3)HZ or C(5)HZ); 2.05 - 1.92 (2 H, m,
indane C(2)Hz) ; 1.38 (9 H, s, tBu) .
D/L-(N-BOC-Piperidin-4-yl)glycine indan-5-amide
10 % Palladium on carbon (50 mg) was added to a solution of
the alkene (215 mg, 0.43 mmol) in ethanol (20 mL) and the
suspension was stirred under a hydrogen atmosphere
overnight. The mixture was filtered and the filtrand was
washed with ethanol (20 ml) before the combined solvents
were concentrated under reduced pressure to afford the
deprotected saturated amine as a colourless oil (97 mg, 60
%). The crude amine was carried forward without further
purification.
The remaining steps of the synthesis are identical to those
of Example 61.
3-(Aminomethyl)benzoyl-D/L-piperidin-4-ylglycine indan-5-
amide bis(trifluoroacetate) salt.
1H NMR (d4 MeOH): 8.04 - 7.92 ppm (2 H, m, Ar); 7.73 - 7.55
(2 H, m, Ar) ; 7.49 (1 H, s, Ar) ; 7.32 (1 H, d, J = 7.2 Hz,
Ar) ; 7.18 (1 H, d, J = 7.2 Hz, Ar) ; 4.68 (1 H, d, J = 9 Hz,
CH (Pip) ) ; 4 .21 (2 H, s, CHZNHZ) ; 3 . 54 - 3 .40 (2 H, m,
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piperidine C(2)H and C(6)H); 3.13 - 2.96 (2 H, m, piperidine
C ( 2 ) H and C ( 6 ) H) ; 2 . 94 - 2 . 81 ( 4 H, m, indane C ( 1 ) Hz and
C(3)Hz); 2.41 - 2.23 (1 H, m, piperidine C(4)H); 2.20 - 1.95
(4 H, m, indane C (2 ) H2, piperidine C (3 ) H and C (4 ) H) ; 1 . 84 -
1.60 (2 H, m, piperidine C(3)H and C(4)H).
HPLC (tuna 2, Gradient 1): rt = 3.08 minutes.
LCMS (tuna 2, Gradient 4): rt = 1.27 minutes, 407 (MH)+.
Example 70
2-Amino-5-(aminomethyl)benzoyl-D-phenylglycine indan-5-
ylamide bis(trifluoroacetate) salt
2-Amino-5-cyanobenzoic acid
A solution of 2-amino-5-bromobenzoic acid (6.9 g, 31.9 mmol)
in N-methyl-2-pyrrolidinone (100 mL) was treated with copper
cyanide (4.14 g, 46 mmol) and the mixture was heated at
190°C for 4.5 hours before being cooled to room temperature
and allowed to stand overnight. The mixture was diluted
with water (500 mL), acidified with 6N aqueous HC1 (100 mL)
and extracted with ethyl acetate (6 x 40 mL). The organic
extracts were dried (MgS04) and concentrated under reduced
pressure to yield the crude nitrile (4.35 g, 84 %).
2-Amino-5-cyanobenzoyl-D-phenylglycine methyl ester
A solution of 2-amino-5-cyanobenzoic acid (1.0 g, 6.17 mmol)
in dimethylformamide (50 mL) was treated with 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.18
g, 6.17 mmol) and 1-hydroxy-7-azabenzotriazole (0.84 g, 6.17
mmol). After stirring for 10 minutes, D-phenylglycine methyl
ester (1.24 g, 6.17 mmol) was added and the resulting
solution was stirred overnight at room temperature. The
mixture was partitioned between ethyl acetate (50 mL) and
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water (50 mL) and the organic solution was washed with
saturated aqueous citric acid (50 mL), saturated aqueous
NaHC03 (50 mL) and water (50 mL), dried (MgS04) and
concentrated under reduced pressure. The crude product was
purified by flash column chromatography (ethyl acetate /
hexane, 1:1) to yield 2-amino-5-cyanobenzoyl-D-phenylglycine
methyl ester (1.3 g, 68 %).
LC/MS (tuna 2, Gradient 4): rt = 3.28 minutes, 310 (MH)+.
2-(Di-t-butoxycarbonyl)amino-5-cyanobenzoyl-D-phenylglycine
methyl ester
A solution of 2-amino-5-cyanobenzoyl-D-phenylglycine methyl
ester (800 mg, 2.6 mmol) in dimethylformamide (20 mL) was
treated with 4-dimethylaminopyridine (30 mg; 0.3 mmol), 1-
(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(500 mg; 2.6 mmol) and di-t-butyldicarbonate (570 mg; 2.6
mmol). The mixture was stirred overnight at room
temperature and then partitioned between ethyl acetate (25
mL) and water (25 mL). The organic extracts were dried
(MgS04), concentrated under reduced pressure and the residue
was purified by flash column chromatography (ethyl acetate /
hexane 3:7) to yield the bis-protected amine (150 mg, 11 %).
2-(Di-t-butoxycarbonyl)amino-5-cyanobenzoyl-D-phenylglycine
The ester (150 mg, 0.29 mmol) was dissolved in
tetrahydrofuran (20 mL) and treated with 1 M lithium
hydroxide (0.6 mL, 0.6 mmol). The mixture was heated at
reflux for 3 hours, cooled to room temperature and
concentrated under reduced pressure. The residue was diluted
with water (10 mL), acidified with 5% aqueous HCl (10 mL)
and the product extracted into ethyl acetate (25 mL). The
organic extracts were then dried (MgS04) and concentrated
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under reduced pressure and the crude acid (110 mg, 75 %) was
carried forward without further purification.
2-(Di-t-butoxycarbonyl)amino-5-cyanobenzoyl-D-phenylglycine
indan-5-ylamide
A solution of the acid (110 mg, 0.20 mmol) in
dimethylformamide (10 mL) was treated with 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30
mg, 0.2 mmol) and 1-hydroxy-7-azabenzo-triazole (30 mg, 0.2
mmol). After stirring for 10 minutes, 5-aminoindane (30 mg,
0.2 mmol) was added and the resulting solution stirred
overnight at room temperature. The mixture was partitioned
between ethyl acetate (25 mL) and water (25 mL) and the
organic solution was washed with saturated aqueous citric
acid (25 mL), saturated aqueous NaHC03 (25 mL) and water
(25m1), dried (MgS04) and concentrated under reduced
pressure. The crude product was purified by flash column
chromatography (ethyl acetate / hexane, 3:7) to yield 2-(di-
t-butoxycarbonyl)amino-5-cyanobenzoyl-D-phenylglycine indan-
5-ylamide as an off-white solid (50 mg, 40 %).
2-Amino-5-(aminomethyl)benzoyl-D-phenylglycine indan-5-
ylamide bis(trifluoroacetate) salt.
A solution of the nitrile (50 mg, 0.08 mmol) in methanol (10
mL) and 36% aqueous HCl (0.5m1) was stirred over 10%
palladium on carbon (20 mg) under a hydrogen atmosphere for
16 hours. The mixture was filtered and the residue was
washed with methanol (10 mL) before concentrating the
extracts under reduced pressure.
The residue was dissolved in a mixture of trifluoroacetic
acid (5 ml) and dichloromethane (5m1) and stirred for one
hour. The mixture was concentrated under reduced pressure
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and the residue purified by preparative HPLC to afford 2-
amino-5-(aminomethyl)benzoyl-D-phenylglycine indan-5-ylamide
ditrifluoroacetate salt (2 mg, 6 %).
1H NMR (d4 MeOH): 7.98-7.37 ppm (10 H, m, Ar); 7.02 (1H, d, J
- 7.5 Hz, Ar) ; 6.03 (1H, s, CH_Ph) ; 3.92 (2 H, s, CHZNHZ) ;
3.09 (4H, q, J = 7.5Hz, indane C(1)Hz and C(3)HZ) ; 2.29 (2H,
quintet, J = 7 . 5 Hz, indane C (2 ) HZ) .
HPLC (Lung 2, Gradient 1): rt = 4.04 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.10 minutes, 398 (MH-NH3)+.
Example 71
1-(2-Amino-5-(aminomethyl)benzoyl-D-phenylglycinyl) 4-
hydroxypiperidine dihydrochloride salt
D-Phenylglycine 4-hydroxypiperidinamide trifluoroacetate
salt
A solution of 4-hydroxypiperidine (330 mg, 1.4 mmol) in
dimethylformamide (10 mL) was treated with 2-(1H-
benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate (450 mg; 1.4 mmol) and N-
ethyldiisopropylamine (0.74 mL, 4.2 mmol). After stirring
for 10 minutes, N-butoxycarbonyl-D-phenylglycine (330 mg,
1.4 mmol) was added and the resulting solution stirred
overnight at room temperature. The mixture was partitioned
between ethyl acetate (25 mL) and water (25 mL) and the
organic solution was washed with saturated aqueous citric
acid (25 mL), saturated aqueous NaHC03 (25 mL) and water (25
mL), dried (MgS04) and concentrated under reduced pressure.
The residue was dissolved in dichloromethane (5 mL) and
trifluoroacetic acid (5 mL) and stirred for one hour before
the solvents were removed under reduced pressure, giving D-
phenylglycine-4-hydroxypiperidinamide as its trifluoracetate
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salt (150 mg, 43 °s) .
LC/MS (Luna 2, Gradient 4): rt = 2.64 min, 235 (MH)+.
2-amino-5-cyanobenzoyl-D-phenylglycine 4-
hydroxypiperidinamide
A solution of 2-amino-5-cyanobenzoic acid (170 mg, 1.0 mmol)
in dimethylformamide (10 mL) was treated with 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (210
mg, 1.1 mmol) and 1-hydroxy-7-azabenzotriazole (150 mg, 1.1
mmol). After stirring for 10 minutes, D-phenylglycine 4-
hydroxypiperidinamide trifluoroacetate salt (250 mg; 1.1
mmol) was added and the resulting solution stirred overnight
at room temperature. The mixture was partitioned between
ethyl acetate (25 mL) and water (25 mL) and the organic
solution was washed with saturated aqueous citric acid (25
mL), saturated aqueous NaHC03 (25 mL) and water (25 mL),
dried (MgS04) and concentrated under reduced pressure. The
crude product was purified by column chromatography (ethyl
acetate) to yield 2-amino-5-cyanobenzoyl-D-phenylglycine 4-
hydroxypiperidinamide (90 mg, 23 %).
1-(2-amino-5-(aminomethyl)benzoyl-D-phenylglycinyl 4-
hydroxypiperidine dihydrochloride salt
A solution of the nitrile in methanol (10 mL) and 36%
hydrochloric acid (0.5 mL) was stirred over 10 % palladium
on carbon (20 mg) under an atmosphere of hydrogen for 16
hours. The mixture was filtered and the residue washed with
methanol (10 mL) before concentrating the filtrate under
reduced pressure. Purification by preparative HPLC afforded
2-amino-5-(aminomethyl)benzoyl-D-phenylglycine 4-hydroxy-
piperidinamide dihydrochloride salt (30 mg, 33 %).
1H NMR (d4 MeOH): 7.84 ppm (1 H, s, Ar); 7.61-7.17 (7 H, m,
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Ar); 6.85 (1 H, d, J = 8 Hz, Ar); 6.12 (1 H, s, CHPh); 4.26
(1 H, m, piperidine C(4)H) ; 3.99 (2 H, s, CHzNHz) ; 3.79 (2 H,
m, piperidine C(2)H and C(6)H); 3.42-3.08 (2H, m, piperidine
C(2)H and C(6)H) ; 1.86-0.72 (4H, m, piperidine C(3)H2 and
C (5) Hz) .
HPLC (tuna 2, Gradient 1): rt = 2.49 minutes.
LC/MS (Luna 2, Gradient 4): rt = 1.35 minutes, 366 (MH-NH3)+.
Examples 72 and 73
The compounds of Examples 72 and 73 were prepared by the
method described below, but using the appropriate starting
materials.
Boc D-phenylglycine (251 mg, 1 mmol.) was dissolved in
dimethylformamdide (3m1) with HATU [O-(7-azabenzotriazol-1-
yl)-1,1,3,3-tetramethyluronium hexafluorophosphate] (380
mg., 1 mmol.) and diisopropylethylamine (350,1., 2 mmol.).
To this mixture was added 4-methylbenzylamine (121mg., 1
mmol.) and diisopropylethylamine (1701., 1 mmol.). The
mixture was stirred overnight. The mixture was then taken up
into ethylacetate and washed with water, sodium carbonate
solution, water, 10°s hydrochloric acid solution and water.
The ethylacetate was evaporated without drying and treated
immediately with trifluoroacetic acid (TFA) for 30 min. The
TFA was then evaporated to dryness and the product
triturated with diethylether. Triethylamine (1m1) was added
and evaporated to dryness. A solution of 3-
hydroxymethylbenzoic acid (76m9, 0.5mmole) in dry
dimethylformamide (DMF) was treated with TBTU (161mg.,
0.5mmol.) and diisopropylethylamine (1.5 mmol.). The mixture
was then added to the D-phenylglycine-4-methylbenzylamide
(0.5mmol.) and stirred overnight. The crude product was
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dissolved in water/acetonitrile (20m1), filtered and
purified by preparative Hplc to yield pure product.
1H nmr (CD3CN) 7.75 (1H, m); 7.65 (2H, m); 7.30 (7H, broad
m) ; 6.80 (3H, m) ; 5.40 (1H, s) ; 4.45 (2H, s) ; 4 .10 (2H, m) ;
2.10 (3H, s). MS TOF 389 (M+1+). Hplc (Magellan C8,
Gradient 3, water/acetonitrile/TFA) rt 13.51 min.
Compounds made by the above method:-
Example 72.
3-Aminomethylbenzoyl-D-phenylglycine-4-aminomethylcyclohexyl
methylamide
1H nmr (CD3CN) 7. 95 (2H, m) ; 7.80 (2H, m) ; 7.50 (5H, m) ; 5.65
(1H, s); 4.45 (2H, s); 3.30 (2H, m); 3.00 (2H,m); 2.00-1.00
(lOH,m). MS TOF 409 (M+1+). Hplc (Magellan C8, Gradient 3,
water/acetonitrile/TFA) rt 12.68 min.
Example 73.
3-Aminomethylbenzoyl-D-phenylglycine-1-adamantylamide
1H nmr (CD3CN) 7.95 (1H, s); 7.85 (2H, d); 7.60 (1H, m); 7.50
(2H,m); 7.40 (3H,m); 5.65 (1H, s); 4.20 (2H, s); 2.50-1.50
(l5H,m). MS TOF 418 (M+1+). Hplc (Magellan C8, Gradient 1,
water/acetonitrile/TFA) rt 18.36 min.
Example 74
3-(Aminomethyl)benzoyl-D-phenylglycine 1-(2-
hydroxyphenyl)acetyl-2,3-dihydroindol-6-amide
trifluoroacetate salt.
Prepared in a similar manner to Example 35, using (2-
hydroxyphenyl)acetic acid.
1H NMR (CD3CN) : 8.91 ppm (1 H, s, OH) , 8.30 (1 H, s, NH) ,
7.94 (2 H, br s, Ar), 7.73 (1 H, d, J = 10 Hz, Ar), 7.54-
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7.06 (12 H, m, Ar & NH), 7.01 (1 H, d, J = 8 Hz, Ar), 6.74
(2 H, m, Ar), 5.61 (1 H, d, J = 8 Hz, ArCH), 4.21 (2 H, t, J
- 8 Hz, dihydroindole C(2)HZ), 4.10 (2 H, s, ArCH2N), 3.73
(2H, s, ArCH2C0), 3.10 (2 H, d, J = 8 Hz, dihydroindole
C(3)HZ) .
HPLC (Symmetry, Gradient 2): rt = 6.24 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.10 minutes, 535 (MH)'.
Example 75
3-(Aminomethyl)benzoyl-D-phenylglycine 1-(3-
hydroxyphenyl)acetyl-2,3-dihydroindol-6-amide
trifluoroacetate salt.
Prepared in a similar manner to Example 35, using (3-
hydroxyphenyl)acetic acid.
1H NMR (d4 MeOH): 8.21 ppm (1 H, s, Ar), 7.71 (2 H, br s,
Ar), 7.50-7.16 (8 H, m, Ar), 7.05-6.95 (2 H, m, Ar), 6.64-
6.50 (3 H, m, Ar), 5.62 (1 H, s, ArCH_), 4.09 (2 H, s,
ArCH2N) , 4 . 04 (2 H, t, J = 8 Hz, dihydroindole C (2) Hz) , 3 . 68
(2H, s, ArCH2C0), 2.91 (2 H, d, J = 8 Hz, dihydroindole
C(3)Hz) .
HPLC (Symmetry, Gradient 2): rt = 5.95 minutes.
LC/MS (Lung 2, Gradient 4): rt = 2.05 minutes, 535 (MH+).
Example 76
3-(Aminomethyl)benzoyl-D-phenylglycine 1-(4-
hydroxyphenyl)acetyl-2,3-dihydroindol-6-amide
trifluoroacetate salt.
Prepared in a similar manner to Example 35, using (4-
hydroxyphenyl)acetic acid.
1H NMR (d4 MeOH): 8.32 ppm (1 H, s, Ar), 8.04 (2 H, br s,
Ar) , 7.66-7.34 (8 H, m, Ar) , 7.22-7.11 (3 H, m, Ar) , 6.80 (2
H, d, J = 10 Hz, Ar), 5.85 (1 H, s, ArCH), 4.21 (2 H, s,
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ArCH2N) , 4 . 15 (2 H, t, J = 8 Hz, dihydroindole C (2) HZ) , 3 . 81
(2 H, s, ArCHzCO), 3.20 (2 H, d, J = 8 Hz, dihydroindole
C(3)HZ) .
HPLC (Symmetry, Gradient 2): rt = 5.97 minutes.
LC/MS (Lung 2, Gradient 4): rt = 2.02 minutes, 535 (MH+).
Example 77
3-(Aminomethyl)benzoyl-D-phenylglycine 1-benzyl-3-
acetylindol-5-amide trifluoroacetate salt.
Prepared in a similar fashion to Example 1, starting from
3-acetyl-5-amino-1-benzylindole, which was prepared as
described below.
3-Acetyl-5-nitroindole and 3-acetyl-7-nitroindole
Prepared by the method described by Ottoni, Cruz and Kramer
in Tetrahedron Letters, 40, 1999, 1117-1120, as a mixture of
isomers.
3-Acetyl-1-benzyl-5-nitroindole and 3-acetyl-1-benzyl-7-
nitroindole
Potassium carbonate (940 mg, 6.8 mmol) was added to a
stirred solution of the above indoles (695 mg, 3.4 mmol) in
dimethylformamide (30 mL). Benzyl bromide (0.61 mL, 5.1
mmol) was then added dropwise and the mixture left to stir
over the weekend. The dimethylformamide was removed under
reduced pressure and the residue partitioned between ethyl
acetate (30 mL) and water (20 mL). The ethyl acetate layer
was dried (MgS04) and evaporated to give the benzylamines as
a golden oil.
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3-Acetyl-5-amino-1-benzylindole and 3-acetyl-7-amino-1-
benzylindole
A mixture of the indoles (1.0 g, 3.4 mmol), tin(II) chloride
dehydrate (3.48 g, 15.4 mmol) and ethanol (20 mL) was heated
at reflux, under an atmosphere of nitrogen, for 3 hours. The
mixture was cooled and the solvent evaporated to give a
brown oil. To this was added water (50 mL), which was then
made basic with 1 N aqueous sodium hydroxide. The aqueous
solution was then extracted with ethyl acetate (2 x 30 mL).
The whole biphasic mixture was filtered through celite to
remove tin salts, separated and the organic solvent dried
(MgS04). The solvent was removed under reduced pressure to
give a brown oil which was purified by flash chromatography
on silica gel (hexane / ethyl acetate; 3:1)to afford, in
order of elution,
3-acetyl-7-amino-1-benzylindole
1H NMR (CDC13) : 7.67 ppm (1 H, s, indole C (2) H) ; 7.39 - 7. 13
(3 H, m, Ph); 7.15 (2 H, m, Ph); 7.05 (1 H, t, J = 6 Hz,
indole C (5) H) ; 6 . 57 (1 H, d, J = 6 . 5 Hz, indole C (4) H) ; 6 .41
(1 H, d, J = 6 Hz, indole C(6)H); 5.95 (2 H, br s, NHZ);
5.27 (2 H, s, PhCH2) ; 2.50 (3 H, s, CH3)
and 3-acetyl-5-amino-1-benzylindole
1H NMR (CDC13) : 8.08 ppm (1 H, d, J = 6 Hz, indole C(7)H) ;
7.50 (1 H, s, indole C(2)H); 7.31 - 7.22 (3 H, m, Ph); 7.05
(2 H, m, Ph); 6.63 (1 H, dd, J = 6, 2 Hz, indole C(6)H);
6.45 (1 H, s, indole 4-H); 5.25 (2 H, s, PhCH2); 3.62 (2 H,
br s, NHz) ; 2.5 (3 H, s, CH3) .
3-(Aminomethyl)benzoyl-D-phenylglycine 1-benzyl-3-
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acetylindol-5-amide trifluoroacetate salt.
1H NMR (d4 MeOH) : 8.28 ppm (1 H, s, Ar) ; 8.20 (1 H, d, J = 5
Hz, Ar); 7.97 (3 H, m, Ar); 7.71 - 7.56 (4 H, m, Ar); 7.47 -
7.19 (9 H, m, Ar); 5.85 (1 H, s, CHPh); 5.45 (2 H, s,
CHzPh) ; 4.21 (2 H, CH_zNH2) ; 2.53 (3 H, s, CH3) .
HPLC (Lung 2, Gradient 1): rt = 4.15 minutes.
HPLC (Symmetry, Gradient 2): rt = 6.77 minutes.
LC/MS (tuna 2, Gradient 4): rt = 2.48 minutes, 531 (MH)+.
Example 78
3-(Aminomethyl)benzoyl-D-phenylglycine 1-benzyl-3-
acetylindol-7-amide trifluoroacetate salt.
Prepared in a similar fashion to Example 1, starting from 3-
acetyl-7-amino-1-benzylindole, which was prepared as
described above.
1H NMR (d4 MeOH) : 8.46 ppm (1 H, s, Ar) ; 8.34 (1 H, d, J = 6
Hz, Ar); 8.11 - 7.95 (3 H, m, Ar); 7.75 - 7.48 (4 H, m, Ar);
7.46 - 7.12 (9 H, m, Ar) ; 5.85 (1 H, s, CHPh) ; 5.48 (2 H, s,
CHzPh) ; 4.21 (2 H, s, CHzNH2) ; 2.62 (3 H, s, CH_3) .
HPLC (Luna 2, Gradient 1): rt = 4.58 minutes.
HPLC (Symmetry, Gradient 2): rt = 6.80 minutes.
LC/MS (Lung 2, Gradient 4): rt = 2.80 minutes, 531 (MH)+.
Example 79
3-(Aminomethyl)benzoyl-D-(4-hydroxyphenyl)glycine indan-5-
amide trifluoroacetate salt.
Prepared in a similar fashion to Example 61, using (4-
hydroxyphenyl)glycine and protecting as appropriate.
1H NMR (d4 MeOH): 8.00 ppm (2 H, s, Ar); 7.72 - 7.55 (2 H, m,
Ar); 7.47 (3 H, t, J = 8.6 Hz, Ar); 7.31 (1 H, d, J = 7.5
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Hz, Ar); 7.18 (1 H, d, J = 8 Hz, Ar); 6.86 (2 H, d, J = 8.6
Hz, Ar) ; 5.75 (1 H, s, CHPh) ; 4.23 (2 H, s, CHZNH2) ; 2.94 (4
H, m, indane C ( 1 ) HZ and C ( 3 ) H_2 ) ; 2 . 12 ( 2 H, m, indane
C(2)Hz) .
HPLC (Luna 2, Gradient 1): rt = 3.78 minutes.
HPLC (Symmetry, Gradient 2): rt = 5.80 minutes.
LC/MS (Luna 2, Gradient 4): rt = 1.83 minutes, 416 (MH)+.
Example 80
3-(Aminomethyl)benzoyl-D/L-2-(N-formylamino)thiazol-4-
yl]glycine 5-indanamide trifluoroacetate salt
Prepared using the same method as described for Example 61
from D/L-a-(N-tbutyloxycarbonyl)-[2-(N-formylamino)thiaz-4-
yl]glycine (synthesised as described below).
Ethyl a-azido-[2-(N-formylamino)thiaz-4-yl]acetate
A solution of ethyl [2-(N-formylamino)thiaz-4-yl]acetate (1
g, 0.0047 mol) in THF (10 mL) was stirred under argon at -
78°C and potassium bis(trimethylsilyl)amide (2.8 g, 0.014
mol) in THF (10 mL) was added. After stirring for 30
minutes, 2,4,6-triisopropylbenzenesulfonyl azide (3.6 g,
0.012 mol) was added as a solid in one portion. After 5
minutes, acetic acid (1.4 mL, 0.018 mol) was added and the
mixture warmed to room temperature. The reaction mixture was
then partitioned between ethyl acetate (100 mL) and water
(100 mL), separated and the organic layer dried (MgS04).
Evaporation of the solvent and purification of the residue
by silica gel chromotography afforded the azide (0.95 g, 80
%) .
1H NMR (CDC13): 8.78 ppm (1 H, s, NHCHO); 6.98 (1 H, s,
C(5)H) ; 5.95 (1 H, s, CHN3) ; 4.18 (2 H, m, CH2CH3) ; 1.20 (3
H, m, CHZCH3 ) .
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Ethyl a,- (N-'butyloxycarbonylamino) - [2- (N-formylamino) thiaz-
4-yl] acetate
Di-tbutyl dicarbonate (0.9 g, 0.004 mol) and 5% palladium on
carbon (catalytic amount) were added to a solution of the
azide (0.95 g, 0.0037 mol) in methanol (25 mL). The mixture
was stirred at room temperature under an atmosphere of
hydrogen for 8 hours. After this time the mixture was
filtered through celite, washing through with methanol (25
mL). Evaporation of the solvent and purification of the
residue by silica gel chromotography afforded the
tbutyloxycarbonyl amine as a pale oily solid (1.1 g, 90 %)
1H NMR (CDC13): 8.53 ppm (1 H, s, NHCHO); 6.89 (1 H, s,
C(5)H) ; 6.18 (1 H, d, J = 8 Hz, NHBoc) ; 5.38 (1 H, d, J = 8
Hz, CH_N) ; 4.06 (2 H, m, CHzCH3) ; 1.28 (9 H, s, tBu) ; 1.12 (3
H, m, CHzCH3 ) .
D/L-a-N-'butyloxycarbonyl-[2-(N-formylamino)thiaz-4-
yl] glycine
A solution of the ester (1.1 g, 0.0031 g) in THF (25 mL) was
treated with 1 M aqueous LiOH (5 ml, 0.005 mol) and heated
at reflux for 1 hour. The solvent was removed under reduced
pressure and the residue diluted with water (100 mL). The
pH was reduced to 2 using 5% aqueous HC1 and the aqueous
phase was extracted with ethyl acetate (3 x 50 mL). The
combined organic extracts were dried (MgS04) and
concentrated under reduced pressure to afford the acid as a
white solid (0.8 g, 84 %).
1H NMR (d4 MeOH): 8.38 ppm (1 H, s, NHCHO); 7.01(1 H, s,
C(5)H) ; 5.21 (1 H, s, CHN) ; 1.39 (9 H, s, tBu) .
3-(Aminomethyl)benzoyl-D/L-[2-(formylamino)thiazol-4-
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yl]glycine 5-indanamide trifluoroacetate salt
1H NMR (d4 MeOH) : 10.10 ppm (1 H, s, NHCHO) ; 8.80 (1 H, d, J
- 8 Hz, NH); 8.48 (1 H, s, NHCH_O); 7.97 (2 H, br s, Ar);
7.58 (2 H, m, Ar); 7.42 (1 H, s, aminothiazole C(5)H); 7.37
(1 H, d, J = 7 Hz, indane C(6)H); 7.18 (1 H, s, indane
C(4)H); 7.10 (1 H, d, J = 7Hz, indane C(7)H); 5.92 (1 H, m,
CH_Ar ) ; 4 . 18 ( 2 H , s , CHZNH Z ) ; 2 . 8 3 ( 4 H , m, i ndane C ( 1 ) HZ
and
C(3)Hz) ; 2.02 (2 H, m, indane C(2)HZ)
HPLC (tuna 2, gradient 1): rt = 3.71 minutes.
LC/MS (Luna 2, gradient 4): rt = 2.05 minutes; 450 (MH)+.
Example 81
3-(Aminomethyl)benzoyl-D/L-2-aminothiazol-4-ylglycine-5-
indanamide bis(hydrochloride) salt.
Prepared from D/L-a-N-tbutyloxycarbonyl-[2-(N-
formylamino)thiaz-4-yl]glycine and synthesised using the
method of Example 80 except that the final deprotection was
effected using 3 M aqueous HC1 in THF, in order to remove
both the tbutyloxycarbonyl and formyl protecting groups.
1H NMR (d4 MeOH): 7.87 ppm (2 H, m, Ar); 7.51 (1 H, m, Ar);
7.48 (1 H, t, J = 7 Hz, (aminomethyl)benzoyl C(3)H) ; 7.40 (1
H, s, aminothiazole C(5)H); 7.20 (1 H, d, J = 8 Hz, indane
C(6)H) ; 7.05 (1 H, d, J = 8 Hz, indane C(7)H) ; 6.73 (1 H, s,
i ndane C ( 4 ) H ) ; 5 . 7 8 ( 1 H , s , CHAr ) ; 4 . 12 ( 2 H , s , CHZNHZ )
;
2 5 2 . 7 9 ( 4 H , m, indane C ( 1 ) Hz and C ( 3 ) H2 ) ; 2 . 0 0 ( 2 H , m,
indane
C(2)Hz) .
HPLC (tuna 2, gradient 1): rt = 3.21 minutes.
LC/MS (Luna 2, gradient 4): rt = 1.78 minutes; 422 (MH)+.
The compounds of formula (I) exemplified in the Examples -
Part 2 have been found to be inhibitors of tryptase by the
method of Tapparelli et al (J. Biol. Chem. 1993,268,4734-
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