Note: Descriptions are shown in the official language in which they were submitted.
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FORMAMIDE DERIVATIVES USEFUL AS ADRENOCEPTOR
This invention relates to R2 agonists of gerreral formula:
OH
H
CH- Q1
HO R1 R2 ( 2)n (1)
HN O
O~H
in which R1, R2, n and Q1 have the meanings indicated below, and to processes
for the preparation of, compositions containing and the uses of such
derivatives. -
Adrenoceptors are members of the large G-protein coupled receptor
super-family. The adrenoceptor subfamily is itself divided into the a and R
subfamilies with the R sub-family being composed of at least 3 receptor sub-
types: X31, R2 and R3. These receptors exhibit differential expression
patterns in
tissues of various systems and organs of mammals. (32 adrenergic (R2)
receptors are mainly expressed in smooth muscle cells (e.g. vascular,
bronchial, uterine or intestinal smooth muscles), whereas R3 adrenergic
receptors are mainly expressed in fat tissues (therefore P3 agonists could
potentially be useful in the treatment of obesity and diabetes) and 01
adrenergic receptors are mainly expressed in cardiac tissues (therefore R1
agonists are mainly used as cardiac stimulants).
The pathophysiology and treatments of airway diseases have been
extensively reviewed in the literature (for reference see Barnes, P.J. Chest,
1997, 111:2, pp 17S-26S and Bryan, S.A. et al, Expert Opinion on
investigational drugs, 2000, 9:1, pp25-42) and therefore only a brief summary
will be included here to provide some background information.
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2
Glucocorticosteroids, anti-leukotrienes, theophylline, . cromones, anti,
cholinergics and (32 agonists constitute drug classes that are currently used
to
treat allergic and non-allergic airways diseases such as asthma and chronic
obstructive airways disease (COPD). Treatment guidelines for these diseases
include both short and long acting inhaled R2 agonists. Short acting, rapid
onset
R2 agonists are used for "rescue" bronchodilation, whereas, long-acting forms
provide sustained relief and are used as maintenance therapy.
Bronchodilation is mediated via agonism of the (32 adrenoceptor
expressed on airway smooth muscle cells, which results in relaxation and
hence bronchodilation. Thus, as functional antagonists, (32 agonists can
prevent and reverse the effects of all bronchoconstrictor substances,
including
leukotriene D4 (LTD4), acetylcholine, bradykinin, prostaglandins, histamine
and
endothelins. Because 132 receptors are so widely distributed in the airway,
132
agonists may also affect other types of cells that play a role in asthma. For
example, it has been reported that R2 agonists may stabilize mast cells. The
inhibition of the release of bronchoconstrictor substances may be how R2
agonists block the bronchoconstriction induced by allergens, exercise and cold
air. Furthermore, (32 agonists inhibit cholinergic neurotransmission in the
human
airway, which can result in reduced cholinergic-reflex bronchoconstriction.
In addition to the airways, it has also been established that (32
adrenoceptors are also expressed in other organs and tissues and thus R2
agonists, such as those described in the present invention, may have
application in the treatment of other diseases such as, but not limited to
those
of the nervous system, premature labor, congestive heart failure, depression,
- inflammatory and allergic skin diseases, psoriasis, proliferative skin
diseases,
glaucoma and in conditions where there is an advantage in lowering gastric
acidity, particularly in gastric and peptic ulceration.
However, numerous 132 agonists are limited in their use due to their low
selectivity or adverse side-effects driven by high systemic exposure and
mainly
mediated through action at 132 adrenoreceptors expressed outside the airways
CA 02560547 2009-03-17
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3
(muscle tremor, tachycardia, palpitations, restlessness). Therefore there is a
need for improved agents in this class.
Accordingly, there is still a need for novel i2 agonists that would have an
appropriate pharmacological profile, for example in terms of potency,
selectivity,
pharmacokinetics or duration of action. In this context, the present invention
relates to novel X32 agonists.
Various formamide derivatives have already been disclosed. For
example, US200410006102 discloses compounds active as (32 agonist, of
formula:
OH
N / R5
HO R2 O R4
R' (I) R6 R3
US2003/0229058 discloses selective P2 agonists of formula :
R13
R1 OH
R N lR9)w
R6 cOZ
R3 R5 Rao
R4 ~l )
However, none of the above formamide derivative have shown a
pharmacological profile allowing them to be used as efficient drugs in the
treatment of 02-mediated diseases and/or conditions, such as allergic and non-
allergic airways diseases; in particular by the inhalation route.
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4
The invention relates to the compounds of -general formula (1.):
OH
H
N
1
R1 R2 = (CH2n Q (1)
HO
HN O
~-H
O
wherein the (CH2)n-C(=O)Q1 group is in the meta or para position,
- R1 and R2 are independently selected from H and C1-C4 alkyl;
- n is 0, 1 or 2;
- Q1 is a group selected from,
R3 R4
(CHOP \ / R5
N'(CH2)q R6
wherein p is 1 or 2 and q is 1 or 2, said group being optionally bridged by
one
carbon atom,
R3
R8 R4
R5 -N
R6
and a group *-NR 8.Q2-A, wherein Q2 is a C1-C4 alkylene, R8 is H or C1-C4
alkyl
and A is pyridyl, C3-CIO cycloalkyl, said cycloalkyl being optionally bridged
by
one or more, preferably 1, 2, 3 or 4, carbon atoms, tetrahydropyranyl,
piperidinyl, tetrahydrothiopyranyl or a group
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R3 R4
R3
R5
CQ-R4
R5 or R7 R6
- R3, R4, R5, R6 and R7 are the same or different and are selected from H, C1-
C4
alkyl, OR9, SR9, SOR9, S02R9, halo, CN, C02R9, CF3, OCF3, SO2NR9R10,
CONR9R10, NR9R10, NHCOR10 and phenyl optionally substituted with I to 3
5 groups selected from OR9, halo and C1-C4 alkyl
- R9 and R10 are the same or different and are selected from H or C1-C4 alkyl
and the * represent the attachment point to the carbonyl group;
or, if appropriate, their pharmaceutically acceptable salts and/or isomers,
tautomers, solvates or isotopic variations thereof.
The compounds of formula (1) are agonists of the 02 receptors, that are
particularly useful for the treatment of [i2-mediated diseases and/or
conditions,
by showing excellent potency, in particular when administered via the
inhalation
route.
In the here above general formula (1), C1-C4 alkyl and C1-C4 alkylene
denote a straight-chain or branched group containing 1, 2, 3 or 4 carbon
atoms.
This also applies if they carry substituents or occur as substituents of other
radicals, for example in O-(C1-C4)alkyl radicals, S-(C1-C4)alkyl radicals
etc...
Examples of suitable P-C4)alkyl radicals are methyl, ethyl, n-propyl, iso-
propyl,
n-butyl, iso-butyl, sec-butyl, tent-butyl.... Examples of suitable O-(C1-
C4)alkyl
radicals are methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, iso-
butyloxy,
sec-butyloxy and tert-butyloxy....
The C3-C10 cycloalkyl wherein 2 carbon atoms or more are optionally bridged by
one or more carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and cycloheptyl, adamantyl, bicyclo[3.1.1]heptane,
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6
bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane. Preferred cycloalkyl groups are.
cyclohexyl and adamantyl.
Finally, halo denotes a halogen atom selected from the group consisting
of fluoro, chioro, bromo and iodo in particular fluoro or chioro.
In the following, the free bond on the phenyl group such as in the structure
below,
means that the phenyl can be substituted in the meta or para position.
The compounds of the formula (1)
OH
H
N
R1 R2 (CH2)õ Q1
(1)
HO
HN
O~- H
can be prepared using conventional procedures such as by the following
illustrative methods in which Q1, Q2, R1, R2, A and n are as previously
defined
for the compounds of the formula (1) unless otherwise stated.
The amide derivatives of the formula (1) may be prepared by coupling an
acid of formula (2):
OH
H
N \ (2)
(CHA OH
R1 R2 /
/
HO Y
NHCHO
with an amine of formula NHR8-Q2-A (3),
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7
R3
R3 R4
R8 ,R4
(CH )P / R5 N H
HN
HN~(CH2)q R6 (3,), or R6 (3õ) (3,.,).
The coupling is generally carried out in an excoss of said amine as an acid
receptor, with a conventional coupling agent (e.4: 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride , N, N'-dicycleohexylcarbodiimide or O-(1 H-
benzotriazol-1-yl)-N,N,M,M-tetramethyluronium hexafluorophosphate),
optionally in the presence of a catalyst (e.g. 1-h;droxybenzotriazole hydrate
or
1-hydroxy-7-azabenzotriazole), and optionally h the presence of a tertiary
amine base (e.g. N-methylmorpholine, triethylamine or diisopropylethylamine).
The reaction may be undertaken in a suitable solvent such as pyridine,
dimethylformamide, tetrahydrofuran, dimethylsulfoxide, dichioromethane or
ethyl acetate, and at temperature comprised between 10 C and 40 C (room
temperature) for a period of 1-24 hours.
Said amine (3), (3'), (3") or (3"') is either commercially available or may
be prepared by conventional methods well known to the one skilled in the art
(e.g. reduction, oxidation, alkylation, transition metal-mediated coupling,
protection, deprotection etc...) from commercially available material.
The acid of formula (2) may be prepared from the corresponding ester of
formula (4):
OH
N \ (4)
(CHA ORa
HO R1 R2
O
NHCHO
wherein Ra is a suitable acid protecting group, preferably a benzyl group or a
(C1-C4) alkyl group, which includes, but is not limited to, methyl and ethyl,
according to any method well-known to the one skilled in the art to prepare an
acid from an ester, without modifying the rest of the molecule. For example,
the
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8
ester may be hydrolysed by treatment with aqueous acid or base (e.g. hydrogen.
chloride, potassium hydroxide, sodium hydroxide or lithium hydroxide),
optionally in the presence of a solvent or mixture of solvents (e.g. water,
1,4-
dioxan, tetrahydrofuran/water), at a temperature comprised between 20 C and
100 C, for a period of 1 to 40 hours. Alternatively, if the ester is a benzyl
group,
the ester may be hydrogenated in the presence of a suitable catalyst (e.g.
palladium-on-carbon, or palladium hydroxide-on-carbon) in a suitable solvent
such (methanol, ethanol, 2M ammonia in methanol) at a temperature
comprised between 20 C and 50 C for 1-48 h at 1-4 atmospheres of
hydrogen.
The ester of formula (4) may be prepared by reaction of an amine of
formula (5) :
H2N (5)
/(CH2)n ~ORa
R1 R2
0
wherein Ra and n are as previously defined, with a bromide of formula (6) :
OH
Br
i (6)
HO
NHCHO
In a typical procedure, the amine of formula (5) is reacted with a bromide
of formula (6) optionally in the presence of a solvent or mixture of solvents
(e.g.
dimethylsuifoxide, toluene, N, N-dimethylformamide, acetonitrile), optionally
in
the presence of a suitable base (e.g. triethylamine, diisopropylethylamine,
potassium carbonate) at a temperature comprised between 80 C and 120 C,
for 12. to 48 hours.
The bromide of formula (6) may be prepared according to the method
disclosed in "Organic Process Research and Development 1998, 2, 96-99".
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9
The amine of formula (5), where R1 is Me _and R2 is H, may be prepared.
as either the (R) or (S) enantiomer from the corresponding protected amine of
formula (7) :
Rc
Rb"N (7)
/ 2 I (CH2)n ORa
R R
O
wherein Ra and n are as previously defined and Rb and Rc represent any
suitable substituents so that HNRbRc is a chiral amine (for example, Rb may be
hydrogen and Rc may be a-methylbenzyl), provided that the bonds between N
and Rb and N and Rc can be easily cleaved to give the free amine of formula
(5) using standard methodology for cleaving nitrogen protecting groups, such
as those found in the text book Protective Groups in Organic Synthesis Third
Edition by T. W. Greene and P. G. M. Wuts, John Wiley and Sons Inc., 1999.
The amine of formula (7) may be prepared as a single diastereomer by
reaction of an amine of formula HNRbRc with a ketone of formula (8):
H3C (8)
O (CH2)n ORa
O
wherein Ra, Rb, Rc and n are as previously defined.
In a typical procedure, the reaction of the ketone of formula (8) with the
amine of formula HNRbRc leads to a chiral intermediate which is in turn
reduced by a suitable reducing agent (e.g. sodium cyanoborohydride of formula
NaCNBH3 or sodium triacetoxyborohydride of formula Na(OAc)3BH) optionally
in the presence of a drying agent (e.g. molecular sieves, magnesium sulfate)
and optionally in the presence of an acid catalyst (e.g. acetic acid) to give
the
amine of formula (7) as a mixture of diastereomers. The reaction is generally
done in a solvent such as tetrahydrofuran or dichloromethane at a temperature
comprised between 20 C and 80 C for 3 to 72 hours. The resulting product is
then converted to the hydrochloride or nitrate salt and selectively
crystallised
from a suitable solvent or mixture of solvents (e.g. isopropanol, ethyl
acetate,
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ethanol, methanol, diisopropyl ether or diisopropyl ether/methanol) to give
(7)
as a single diastereomer.
The ketone of formula (8) where n=1 may be prepared by palladium
mediated coupling of an aryl halide of formula (9):
Hal
ORa (9)
5 O
wherein Ra is as previously defined and Hal represents an halogen atom, which
includes, but is not limited to bromo and iodo, with an enolate or enolate
equivalent.
In a typical procedure, the aryl halide of formula (9) is reacted with a tin
10 enolate generated in-situ by treatment of isopropenyl acetate with tri-n-
butyltin
methoxide of formula Bu3SnOMe in the presence of a suitable palladium
catalyst (palladium acetate/ tri-ortho-tolylphosphine of formula Pd(OAc)2/P(o-
Tol)3) in a non-polar solvent (e.g. toluene, benzene, hexane). Preferably, the
reaction is carried out at a temperature comprised between 80 C and 110 C for
6 to 16 hours.
The aryl halide of formula (9) may be obtained by esterification of the
corresponding acid of formula (10):
Hal
OH (10)
O
wherein Hal is as previously defined, according to any method well-known to
the one skilled in the art to prepare an ester from an acid, without modifying
the
rest of the molecule.
In a typical procedure, the acid of formula (10) is reacted with an
alcoholic solvent of formula RaOH, wherein Ra is as previously defined, in the
presence of an acid such as hydrogen chloride at a temperature between 10 C
and 40 C (room temperature) for 8 to 16 hours. Alternatively, the acid of
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11
formula (10) is reacted with a base (for example cesium or potassium.
carbonate) and treated with an alkyl halide (for example methyl iodide, benzyl
bromide) in an appropriate solvent such as N, N-diemthylformamide at a
temperature between 10 C and 40 C (room temperature) for I to 20 h.
The acid of formula (10) is a commercial product.
The amine of formula (5), where R1 and R2 are both Cl-C4 alkyl, may be
prepared according to the following scheme:
Scheme I
0
O HO
RaO (CH2n OH
0 ( (CH2n OH R1 R2
(~ ~) (12)
0
H2N a R1 R2 (CH2n ORa
(5)
wherein R1, R2 and Ra are as previously defined.
In a typical procedure, the ester of formula (11) is reacted with an
"activated" alkyl (organometallic alkyl such as R2MgBr, R2MgCI or R2Li) to
give
the corresponding tertiary alcohol of formula (12) using the method described
above.
Said tertiary alcohol of formula (12) is then treated with an alkyl nitrile
(e.g. acetonitrile, chloroacetonitrile) in the presence of an acid (e.g.
sulphuric
acid, acetic acid) to give a protected intermediate which is in turn cleaved
using
standard methodology for cleaving nitrogen protecting group such as those
. mentioned in textbooks. The resulting amino acid is then esterified using
the
method described herein to give the amine of formula (5).
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12
Alternatively, the amine of formula (5), where R1 are- R2 both CI-C4 alkyl
and n=0, may be prepared according to the following scheme:
Scheme 2
RaO HO
---~ R1 R2
0 Br Br
(13) (14)
HN HN O
R1 R2 Br --~ R1 R2
ORa
(15) (5)
wherein R1, R2 and Ra are as previously defined.
In a typical procedure, the ester of formula (13) is reacted with an
"activated" alkyl (organometallic alkyl such as R2MgBr, R2MgCI or R2Li) to
give
the corresponding tertiary alcohol of formula (14) using the method described
above.
Said tertiary alcohol of formula (14) is then treated with an alkyl nitrile
(e.g. acetonitrile, chloroacetonitrile) in the presence of an acid (e.g.
sulphuric
acid, acetic acid) to give a protected intermediate which is in turn cleaved
using
standard methodology for cleaving nitrogen protecting group such as those
mentioned in textbooks to give the bromo amine (15).
The resulting bromo amine (15) is treated with a suitable palladium
catalyst ' (e.g. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
palladium(II) acetate 1,1'-bis(diphenylphosphino)ferrocene],
tris(dibenzylideneacetone)dipalladium(0), 2,2'-bis(diphenylphosphino)-1,1'-
binaphthyldichloropalladium(ll)) under an atmosphere of carbon monoxide
using RaOH as solvent (e.g. MeOH, EtOH, benzyl alcohol), or alternatively
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13
using a co-solvent such as DMF, at elevated temperature (100 C) and pressure
(100psi) to give the ester of formula (5).
The ketone of formula (8) where n=2 may ~e prepared by reduction of an
alkene of formula (16) :
H3C O
O ~DRa (16)
In a typical procedure, a solution of the oldiin of formula (16) in a suitable
solvent (e.g. methanol, ethanol, ethyl acetate; is treated with a palladium
catalyst (e.g. 10% palladium on charcoal) and stirred under an atmosphere of
hydrogen, optionally at elevated pressure (e.g. 60 psi), at temperature
between
room temperature and 60 C for 8-24 hours.
The alkene of formula (16) may be prepared by a palladium mediated
coupling of an activated olefin with an aryl halide of formula (17):
H3C
Hal (17)
O
In a typical procedure, the aryl halide (17) is coupled with a vinyl ester
(e.g. methyl acrylate) in the presence of a suitable palladium catalyst (e.g.
tetrakis(triphenylphosphine)palladium(0) of formula Pd(PPh3)4, palladium
acetate/tri-oitho-tolylphosphine of formula Pd(OAc)2/P(o-Tol)3 or
(diphenylphosphino)ferrocenyl palladium chloride of formula dppfPdC12) in a
suitable solvent (e.g. acetonitrile, N, N-dimethylformamide, toluene),
optionally
in the* presence of a base such as triethylamine at a temperature between 40 C
and 110 C for 8 to 24 hours.
The ketone of formula (17) is a commercial product.
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14
Alternatively a compound of formula (1) may be prepared by reaction of a
bromide of formula (6) and an amine of formula (18):
H2N
R1 R2 (CH2)n Q1 (18)
X
O
where R1, R2, Q1and n are as previously defined for the compounds of the
formula (1) unless otherwise stated.
In a typical procedure, the amine of formula (18) is reacted with a
bromide of formula (6) optionally in the presence of a solvent or mixture of
solvents (e.g. dimethylsulfoxide, toluene, N, N-dimethylformarnide,
acetonitrile),
optionally in the presence of a suitable base (e.g. triethylamine,
diisopropylethylamine, potassium carbonate) at a temperature comprised
between 80 C and 120 C, for 12 to 48 hours.
The amide of formula (18) may be prepared by coupling an acid of formula (19)
incorporating a suitable amine protecting group P1:
H
PAN (19) Y RRUJ(CH2)noH
O
with an amine of formula NHR8-Q2-A (3),
R3 R4 R3
R8 R4
(CHOP R5 H 1 /
R5 HN
HN~(CH2)q R6 (3,), R6 (3"), (3,,,),
The coupling is generally carried out in an excess of said amine as an acid
receptor, with a conventional coupling agent (e.g. 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride or N, W-dicyclohexylcarbodiirnide), optionally
in
the presence of a catalyst (e.g. 1-hydroxybenzotriazole hydrate or 1-hydroxy-7-
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azabenzotriazole), and optionally in the presence of a tertiary amine base
(e.g..
N-methylmorpholine, triethylamine or diisopropylethylamine). The reaction may
be-undertaken in a suitable solvent such as pyridine, NN-dimethylformamide,
tetrahydrofuran, dimethylsulfoxide, dichioromethane or ethyl acetate, and at
5 temperature comprised between 10 C and 40 C (room temperature) for a
period of 1-24 hours.
Said amine (3), (3'), (3") and (3"') is either commercially available or may
be
prepared by conventional methods well known to the one skilled in the art
(e.g.
reduction, oxidation, alkylation, transition metal-mediated coupling,
protection,
10 deprotection etc...) from commercially available material.
The acid of formula (19) may be prepared from the corresponding ester
of formula (5).
The acid of formula (19), where R1 and R2 are both C1-C4 alkyl, may be
prepared from the ester (5) incorporating a suitable amine protecting group P1
15 either before or after the acid formation:
H2N (5)
/(CH
R1 R2 On _r ORa
0
wherein Ra is a suitable acid protecting group, preferably a P-C4)alkyl group,
which includes, but is not limited to, methyl and ethyl, according to any
method
well-known to the one skilled in the art to prepare an acid from an ester,
without
modifying the rest of the molecule. For example, the ester may be hydrolysed
by treatment with aqueous acid or base (e.g. hydrogen chloride, potassium
hydroxide, sodium hydroxide or lithium hydroxide), optionally in the presence
of
a solvent or mixture of solvents (e.g. water, 1,4-dioxan,
tetrahydrofuran/water),
at a temperature comprised between 20 C and 100 C, for a period of I to 40
hours.
The amine of formula (5), where R1 and R2 are both H, may be prepared
according to the following scheme:
Scheme 3
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16
ORa
HO O Y"'~O HO CH
(CHA ORa ( A
O
(20) (21)
O
H2N
-~ / (CHZ~, ORa
(5)
wherein R1, R2 and Ra are as previously defined.
In a typical procedure, the acid of formula (20) is preferentially reduced
to the corresponding alcohol (21) in the presence of the ester. This may be
performed by formation of the acyl imidazole or mixed anhydride and
subsequent reduction with sodium borohydride or another suitable reducing
agent.
Said primary alcohol of formula (21) is then converted into a leaving
group such as mesylate, tosylate, bromide or iodide and displaced with an
appropriate amine nucleophile. The preferred nucleophile is an azide ion which
can then be reduced to the primary amine via hydrogenation or
triphenylphosphine. Alternative nucleophiles could include ammonia or
alkylamines such as benzylamine or allylamine and subsequent cleavage of the
alkyl group to furnish the amine.
0
~ ~ o
(CH2). Q1 N
/ O (CH2)n Q1
(22) (23)
O
O :2NCH2)õ 1(25)
(24)
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17
Alternatively, the amide of formula 22, can be prepared as outlined earlier
using.
standard amide bond forming reactions. The compound of formula 22 can then
be reacted with a protected vinylamine (e.g. N-vinylphthalimide) in the
presence
of a suitable catalyst (e.g. palladium(II)acetate) and a phosphine (e.g.
triphenylphosphine, tri-ortho-tolylphosphine) in the presence of a base (e.g.
N,
N-diisopropylethylamine) in a solvent (e.g. N,N-dimethylformamide,
acetonitrile)
at a temperature comprised between 20 C and 120 C and for 1 to 48 hours.
The alkene of formula 23 can then be reduced to an alkane of formula 24 using
standard hydrogenation conditions and the protecting phthalimide group
removed using standard protecting group removal. The amine of formula 25
can be reacted with a bromide of formula 6 to give a compound of formula 1
using conditions outlined earlier.
For some of the steps of the here above described process of preparation of
the compounds of formula (1), it may be necessary to protect potential
reactive
functions that are not wished to react, and to cleave said protecting groups
in
consequence. In such a case, any compatible protecting radical can be used. In
particular methods of protection and deprotection such as those described by
T. W. Greene and P. G. M. Wuts (Protective Groups in Organic Synthesis,
John Wiley and Sons Inc., 1999) or by P. J. Kocienski (Protecting groups,
Georg Thieme Verlag, 1994), can be used.
All of the above reactions and the preparations of novel starting
materials used in the preceding methods are conventional and appropriate
reagents and reaction conditions for their performance or preparation as well
as
procedures for isolating the desired products will be well-known to those
skilled
in the art with reference to literature precedents and the examples and
preparations hereto.
Also, the compounds of formula (1) as well as intermediate for the
preparation thereof can be purified according to various well-known methods,
such as for example crystallization or chromatography.
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18
Subgroups of compounds of formula (1) containing the following substituents.
are preferred:
Preferably Q1 is a group *-NH-Q2-A, wherein A is cyclohexyl or adamantyl.
Preferably, Q1 is
R3 R4 R3
R4
- I \
R5 N
H
-N R5 *-N
R6 R6 or
*-N
wherein R3, R4, R5 and R6 are H.
Preferably Q1 is
R3 R4 R3
R4
N
*-N R5 H / R
5
R6 R6 wherein one of R3 to R6 is
OH and the others are H.
Preferably,-Q1 is a group *-NH-Q2-A, wherein A is a group
R3 R4
R5
R7 R6
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wherein R3, R4, R5, R6 and R7 are the same or different and-are selected from
H, C1-C4 alkyl, OR9, SR9, SOR9, S02R9, halo, CN, C02R9, CF3, OCF3,
S02NR9R10, CONR9R10, NR9R10, NHCOR10 and phenyl optionally substituted
with 1 to 3 groups selected from OR9, halo and C1-C4 alkyl provided at least 2
of R3 to R7 are equal to H; wherein R9 and R10 are the same or different and
are
selected from H or C1-C4 alkyl.
More preferably, Q1 is a group *-NH-Q2-A, wherein A is a group
R3 R4
R5
R7 R6
wherein R3, R4, R5, R6 and R7 are the same or dcifferent and are selected from
H, OH, CH3, OCH3, OCF3, OCH2-CH3, SCH3, N(CH3)2, N(C=O)CH3, C(=O)NH2,
COOCH3, SO2CH3, SO2NH2, halo, CN, CF3 and phenyl optionally substituted
with OH provided at least 2 of R3 to R7 are equal to H.
In a preferred embodiment, A is a group
R3 R4
R5
R7 R6
wherein one of R3 to R7 is OH or phenyl substituted with OH.
In a preferred embodiment, A is a group
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R3 R4
R5
R7 R6
wherein one of R3 to R7 is OH or phenyl substituted with OH and the other are
selected from H, Cl or CH3 provided at least 2 of R3 to R7 are H.
Preferably A is naphthyl optionally substituted with OR
5 Preferably, A is naphthyl substituted with OR
In the above groups of compounds, the following substituents are particularly
preferred:
Q2 is -CH2-, -(CH2)2-, -(CH2)3-, -CH2-C(CH3)2- or -C(CH3)2-, preferably -CH2-
or -
(CH2)2.
10 R1 is H or CI-C4 alkyl and R2 is Cl-C4 alkyl. More preferably, R1 is H or
CH3 and
R2 is H or CH3.
n is 0 or 1.
R' is H and R2 is CH3 and n is 0 or 1.
R1 is CH3, R2 is CH3 and n is 0 or 1.
Particularly preferred are the compounds of the formula (1) as described
in the Examples section hereafter, i.e. :
N-Benzyl-2-(3-{2-[(2R)-2-(3-formylamino-4-hyd roxyphenyl)-2-
hydroxyethylamino]-2-methylpropyl}phenyl)acetamide;
N-(3,4-Di methyl benzyl)-2-(3-{2-[(2R)-2-(3-formylamino-4-hyd roxyphenyl)-2-
hydroxyethyl amino]-2-methylpropyl}phenyl)acetamide;
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N-[2-(4-Chlorophenyl)ethyl]-3-{2-[(2R)-2-(3-formyl.amino-4-hydroxyphenyl)-2-
hydroxyethylamino]-2-methylpropyl}benzamide;
N-[2-(2-Chlorophenyl)ethyl]-3-{2-[(2R)-2-(3-formylamino-4-hyd roxyphenyl)-2-
hyd roxyethylamino]-2-methylpropyl}benzamide;
3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]-2-
methylpropyl}-N-(2-naphthalen-1-ylethyl)benzamide;
3-{2-[(2R)-2-(3-Formylamino-4-hyd roxyphenyl)-2-hyd roxyethylamino]-2-
methyl propyl}-N-[2-(4-methylphenyl)ethyl]benzamide;
N-[2-(2, 6-Dimethyl phenyl)ethyl]-3-{2-[(2R)-2-(3-formylamino-4-hyd roxyphenyl
)-
2-hydroxyethylamino]-2-methylpropyl}benzamide;
N-[2-(2,3-Dimethyl phenyl)ethyl]-3-{2-[(2R)-2-(3-formylamino-4-hyd roxyphenyl
)-
2-hyd roxyethylamino]-2-methylpropylbenzamide;
3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]-2-
methyl propyl}-N-[2-(4-hyd roxy-2, 3-d i methyl phenyl )ethyl] benza m ide;
3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]-2-
methyl propyl}-N-[2-(4-methoxyphenyl)ethyl]benzamide;
3-{2-[(2R)-2-(3-Formylamino-4-hyd roxyphenyl)-2-hyd roxyethylamino]-2-
methylpropyl}-N-phenethyl-benzamide;
N-Cyclohexylmethyl-3-{2-[(2R)-2-(3-formylamino-4-hyd roxyphenyl)-2-
hydroxyethylamino]-2-methylpropyl}benzamide;
N-[5-((1 R)-2-{1,1-Dimethyl-2-[3-(piperidine-1-carbonyl)phenyl]ethylamino}-1-
hyd roxyethyl)-2-hydroxyphenyl]formamide;
3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]-2-
methylpropyl}-N-[2-(3-trifluoromethylphenyl)ethyl] benzamide;
3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]-2-
methyl propyl}-N-(3-phenylpropyl)benzamide;
3-{2-[(2R)-2-(3-Formylamino-4-hyd roxyphenyl)-2-hyd roxyethylamino]-2-
methylpropyl}-N-indan-2-ylbenzamide;
3-{2-[(2R)-2-(3-Formylamino-4-hyd roxyphenyl)-2-hyd roxyethylamino]-2-
methyl propyl}-N-(2-pyridin-2-ylethyl)benzamide;
3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hyd roxyethylamino]-2-
methylpropyl}-N-[2-(4-sulfamoylphenyl)ethyl] benzamide;
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N-(4-Dimethylaminobenzyl)-2-(3-{(2R)-2-[(2R)-2-(3-formylamino-4-
hyd roxyphenyl)-2-hydroxyethylamino] propyl}phenyl )acetamid e;
N-[5-(2-{(1 R)-2-[3-(3,4-Dihydro-1 H-isoquinoline-2-carbonyl)-phenyl]-1,1-
dimethyl-ethylamino}-1-hydroxyethyl)-2-hyd roxyphenyl]formamide;
3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]-2-
methylpropyl}-N-(4'-hydroxybiphenyl-3-ylmethyl)benzamide
3-{2-[(2R)-2-(3-Formylamino-4-hyd roxyphenyl)-2-hyd roxyethylami no]-2-
methylpropyl}-N-[2-(4-hyd roxy-2,5-d imethylphenyl)ethyl]benzamide;
3-{2-[(2R)-2-(3-Formylamino-4-hyd roxyphenyl)-2-hydroxyethylamino]-2-
methylpropyl}-N-[2-(4-hydroxy-3-methylphenyl)ethyl]benzamide;
N-(4-Acetylaminobenzyl)-2-(3-{(2R)-2-[(2R)-2-(3-formylamino-4-hyd roxyphenyl)-
2-hydroxyethylamino]propyl}phenyl)acetamide;
4-{[2-(3-{(2R)-2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-
hydroxyethylamino]propyl}phenyl)acetylamino]methyl}benzamide;
N-Adamantan-1-yI-3-{2-[(2R)-2-(3-formylamino-4-hydroxyphenyl)-2-
hydroxyethylamino]-2-methylpropyl}benzamide;
3-{2-[(2R)-2-(3-Formylamino-4-hyd roxyphenyl)-2-hyd roxyethylamino]-2-
methylpropyl}-N-(2-hydroxy-naphthalen-1-ylmethyl)benzamide;
3-{2-[(2R)-2-(3-Formylamino-4-hyd roxyphenyl)-2-hydroxyethylamino]-2-
methylpropyl}-N-(4-hydroxy-3,5-d imethylbenzyl)benzamide;
3-{2-[(2R)-2-(3-Formylamino-4-hyd roxyphenyl)-2-hydroxyethylamino]-2-
methylpropyl}-N-(6-hydroxy-naphthaleN-2-ylmethyl)benzamide;
N-(3,6-Dichloro-2-hyd roxybenzyl)-3-{2-[(2R)-2-(3-formylamino-4-
hydroxyphenyl)-2-hyd roxyethylamino]-2-methyl propyl}benzamide;
N.-(3,4-Dimethylbenzyl)-2-(3-{2-[(2R)-2-(3-formylamino-4-hydroxyphenyl)-2-
hydroxyethylamino]ethyl}phenyl)acetamide;
3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hyd roxyethylamino]-2-
methylpropyl}-N-[2-(4-hydroxyphenyl)-2-methylpropyl]benzamide;
3-{2-[(2R)-2-(3-Formylamino-4-hyd roxyphenyl)-2-hyd roxyethylamino]-2-
methylpropyl}-N-(4'-hyd roxybiphenyl-4-ylmethyl)benzamide;
NAdamantan-1-yI-2-(3-{(2R)-2-[(2R)-2-(3-formylamino-4-hydroxyphenyl)-2-
hydroxyethylamino]propyl}phenyl)acetamide;
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N-[5-(2-{2-[3-(10-Aza-tricyclo[6.3.1.0' 2'7]dodeca-2(7), 3, 5-triene-10-
carbonyl)phenyl]-1,1-dimethylethylamino}-1-hydroxyethyl)-2-hydroxyphenyl]-
formamide;
2-(3-{(2R)-2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-
hydroxyethylamino]propyl}phenyl)-N-(4'-hyd roxybiphenyl-3-ylmethyl)acetamide;
4-{[2-(3-{2-[(2R)-2-(3-Formylam ino-4-hyd roxyp he nyl)-2-hyd roxyethylamino]-
2-
methylpropyl}phenyl)-acetylamino]methyl}benzoic acid methyl ester;
2-(3-{(2R)-2-[(2R)-2-(3-Formylamino-4-hyd roxyphenyl)-2-hydroxyethylamino]-2-
methylpropyl}phenyl)-N-(4-trifluoromethoxy-benzyl )acetamide;
N-(2-Chloro-4-hydroxybenzyl)-N-ethyl-2-(3-{(2R)-2-[(2R)-2-(3-formylamino-4-
hydroxyphenyl)-2-hydroxyethylamino]-2-methylpropyl}phenyl)-cetamide;
N-(2-Chloro-4-hyd roxybenzyl)-2-(3-{(2R)-2-[(2R)-2-(3-formyla mino-4-
hydroxyphenyl)-2-hydroxyethylamino]-2-methylpropyl}-phenyl)acetamide;
2-(3-{(2R)-2-[(2R)-2-(3-Formylam ino-4-hyd roxyphenyl)-2-
hydroxyethylamino]propyl}phenyl)-N-(4-hydroxy-3,5-dimethylbenzyl)acetamide;
2-(3-{(2R)-2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-
hydroxyethylamino]propyl}phenyl)-N-(2-hydroxynaphthalen-1-
ylmethyl)acetamide;
N-(5-Chloro-2-hyd roxybenzyl)-2-(3-{(2R)-2-[(2R)-2-(3-formylamino-4-
hydroxyphenyl)-2-hydroxyethylamino]propyl}phenyl)acetamide;
N-(3, 5-Dichloro-2-hyd roxybenzyl)-2-(3-{(2R)-2-[(2R)-2-(3-formylamino-4-
hydroxyphenyl)-2-hyd roxyethylamino]propyl}phenyl)acetamide;
2-(3-{(2 R)-2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-
hyd roxyethylamino] propyl}phenyl)-N-(6-hyd roxynaphthalen-2-
ylmethyl)acetamide;
2-(3-{(2R)-2-[(2R)-2-(3-Formylamino-4-hyd roxyphenyl)-2-
hydroxyethylamino]propyl}phenyl)-N-(4'-hyd roxybiphenyl-4-ylmethyl)acetamide;
N-(4-Cyano-benzyl)-2-(3-{2-[(2R)-2-(3-formylamino-4-hydroxyphenyl)-2-
hydroxyethylamino]-2-methylpropyl}-phenyl)-acetamide;
2-(3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]-2-
methylpropyl}-phenyl)-N-(4-methanesulfonyl-benzyl)-acetamide;
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2-(3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]-2-
methylpropyl}-phenyl)-N-(4-methylsulfanyl-benzyl)-acetamide;
2-(3-{2-[(2R)-2-(3-Formylamino-4-hyd roxyphenyl)-2-hyd roxyethylamino]-2-
methylpropyl}-phenyl)-N-(4-trifluoromethyl-benzyl)-acetamide;
2-(3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]-2-
methylpropyl}phenyl)-N-(4'-hydroxy-biphenyl-4-ylmethyl)acetamide;
N-[2-(5-Ch loro-2-hyd roxyphenyl)-ethyl]-3-{2-[(2R)-2-(3-formylamino-4-
hyd roxyphenyl)-2-hyd roxyethylamino]-2-methylpropyl}-benzamide;
2-(3-{2-[(2R)-2-(3-Formylam ino-4-hydroxyphenyl)-2-hyd roxyethylamino]-2-
methylpropyl}phenyl)-N-(4'-hydroxybiphenyl-3-ylmethyl)-acetamide;
3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]-propyl}-N-
[2-(4-hyd roxyphenyl)-2-methyl propyl]-benzamide;
N-(2-Chloro-4-hyd roxybenzyl)-2-(3-{(2R)-2-[(2R)-(2R)-2-(3-formylamino-4-
hyd roxyphenyl)-2-hyd roxyethylamino]propyl}phenyl)acetamide;
N-[2-(5-Chloro-2-hydroxyphenyl)-ethyl]-3-{2-[(2R)-2-(3-formylamino-4-
hydroxyphenyl)-2-hydroxyethylamino]-2-methylpropyl}benzamide;
3-{2-[(2R)-2-(3-Formylamino-4-hyd roxyphenyl)-2-hydroxyethylamino]-propyl}-N-
[2-(4-hyd roxyphenyl)-2-methyl propyl]benzamide;
2-(3-{2-[(2R)-2-(3-Formylam ino-4-hyd roxyphenyl)-2-hydroxyethylamino]-2-
methyl pro pyl}phenyl)-N-(tetrahyd ro-th iopyran-4-yl)acetam ide;
N-(5-Chloro-2-hyd roxybenzyl)-2-(3-{2-[(2R)-2-(3-formylamino-4-hyd roxyphenyl)-
2-hydroxyethylamino]-2-methylpropyl}phenyl)acetamide; and,
N-{5-[(1 R)-2-((1 R)-2-{3-[3-(3,4-Dihydro-1 H-isoquinolin-2-yl)-3-
oxopropyl]phenyl}-1-methylethylamino)-1-hydroxyethyl]-2-
hydroxyphenyl}formamide.
According to one aspect of the present invention, the compounds of formula (1)
wherein the (CH2)õ-C(=O)Q' group is in the meta position are generally
preferred.
Pharmaceutically acceptable salts of the compounds of formula - (1)
include the acid addition and base salts thereof.
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Suitable acid addition salts are formed from acids which form non-toxic salts.
Examples include the acetate, adipate, aspartate, benzoate, besylate,
bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate,
5 cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate,
glucuronate, hexafluorophosphate, hibenz#te, hydrochloride/chloride,
hydrobromide/bromide, hydroiodide/iodide, hydrogen phosphate, isethionate,
D- and L-lactate, malate, maleate, malonate, Tnesylate, methylsulphate, 2-
napsylate, nicotinate, nitrate, orotate, oxialate, palmitate, pamoate,
10 phosphate/hydrogen, phosphate/phosphate dihydrogen, pyroglutamate,
saccharate, stearate, succinate, tannate, D- and L-tartrate, 1-hydroxy-2-
naphthoate tosylate and xinafoate salts.
Suitable base salts are formed from bases which form non-toxic salts.
Examples include the aluminium, arginine, benzathine, calcium, choline,
15 diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine,
potassium, sodium, tromethamine and zinc salts.
Hemisalts of acids and bases may also be formed, for example, hemisulphate
and hemicalcium salts.
20 For a review on suitable salts, see "Handbook of Pharmaceutical Salts:
Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim,
Germany, 2002).
Pharmaceutically acceptable salts of compounds of formula (1) may be
25 prepared by one or more-of three methods:
(i) by reacting the compound of formula (1) with the desired acid or base;
(ii) by removing an acid- or base-labile protecting group from a suitable
precursor of the compound of formula (1) or by ring-opening a suitable
cyclic precursor, for example, a lactone or lactam, using the desired acid
or base; or
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(iii) by converting one salt of the compound. of formula (1) to. another by
reaction with an appropriate acid or base or by means of a suitable ion
exchange column.
All three reactions are typically carried out in solution. The resulting salt
may
precipitate out and be collected by filtration or may be recovered by
evaporation
of the solvent. The degree of ionisation in the resulting salt may vary from
completely ionised to almost non-ionised.
The compounds of the invention may exist in both unsolvated and solvated
forms. The term `solvate' is used herein to describe a molecular complex
comprising the compound of the invention and a stoichiometric amount of one
or more pharmaceutically acceptable solvent molecules, for example, ethanol.
The term `hydrate' is employed when said solvent is water.
Included within the scope of the invention are complexes such as clathrates,
drug-host inclusion complexes wherein, in contrast to the aforementioned
solvates, the drug and host are present in stoichiometric or non-
stoichiometric
amounts. Also included are complexes of the drug containing two or more
organic and/or inorganic components which may be in stoichiometric or non-
stoichiometric amounts. The resulting complexes may be ionised, partially
ionised, or non-ionised. For a review of such complexes, see J Pharm Sci, 64
(8), 1269-1288 by Haleblian (August 1975).
Hereinafter all references to compounds of formula (1) include references to
salts, solvates and complexes thereof and to solvates and complexes of salts
thereof.
The compounds of the invention include compounds of formula (1) as
hereinbefore defined, including all polymorphs and crystal habits thereof,
prodrugs and isomers thereof (including optical, geometric and tautomeric
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isomers) as hereinafter defined and isotopically-labeled compounds of formula
(1).
As indicated, so-called 'pro-drugs'_of the compounds of formula (1) are also
within the scope of the invention. Thus certain derivatives of compounds of
formula (1) which may have little or no pharmacological activity themselves
can,
when administered into or onto the body, be converted into compounds of
formula (1) having the desired activity, for example, by hydrolytic cleavage.
Such derivatives are referred to as 'prodrugs'. Further information on the use
of
prodrugs may be found in `Pro-drugs as Novel Delivery Systems, Vol. 14, ACS
Symposium Series (T. Higuchi and W. Stella) and `Bioreversible Carriers in
Drug Design', Pergamon Press, 1987 (ed. E. B Roche, American
Pharmaceutical Association).
Prodrugs in accordance with the invention can, for example, be produced by
replacing appropriate functionalities present in the compounds of formula (1)
with certain moieties known to those skilled in the art as 'pro-moieties' as
described, for example, in "Design of Prodrugs" by H. Bundgaard (Elsevier,
1985).
Some examples of prodrugs in accordance with the invention include:
(i) where the compound of formula (1) contains a carboxylic acid
functionality (-COOH), an ester thereof, for example, a compound wherein the
hydrogen of the carboxylic acid functionality of the compound of formula (1)
is
replaced by (Cl-C$)alkyl;
(ii) where the compound of formula (1) contains an alcohol functionality (-
OH), an ether thereof, for example, a compound wherein the hydrogen
of the alcohol functionality of the compound of formula (1) is replaced by
(Ci-C6)alkanoyloxymethyl; and
(iii) where the compound of formula (1) contains a primary or secondary
amino functionality (-NH2 or -NHR where R F,-,H), an amide thereof, for
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28
example, a compound wherein, as the. case may -be, one or both
hydrogens of the amino functionality of the compound of formula (1)
is/are replaced by (Ci-C1o)alkanoyl.
Further examples of replacement groups in accordance with the foregoing
examples and examples of other prodrug types may be found in the
aforementioned references.
Moreover, certain compounds of formula (1) may themselves act as prodrugs of
other compounds of formula (1).
Also included within the scope of the invention are metabolites of compounds
of
formula (1), that is, compounds formed in vivo upon administration of the
drug.
Some examples of metabolites in accordance with the invention include
(i) where the compound of formula (1) contains a methyl group, an
hydroxymethyl derivative thereof (-CH3 -> -CH2OH):
(ii) where the compound of formula (1) contains an alkoxy group, an
hydroxy derivative thereof (-OR - -OH);
(iii) where the compound of formula (1) contains a tertiary amino group, a
secondary amino derivative thereof (-NR1R2 - -NHR" or -NHR2);
(iv) where the compound of formula (1) contains a secondary amino group, a
primary derivative thereof (-NHR1 - -NH2);
(v) where the compound of formula (1) contains a phenyl moiety, a phenol
derivative thereof (-Ph - -PhOH); and
(vi) where the compound of formula (1) contains an amide group, a
carboxylic acid derivative thereof (-CONH2 - COOH).
Compounds of formula (1) containing one or more asymmetric carbon atoms
can exist as two or more stereoisomers. Where a compound of formula (1)
contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers
are possible. Where structural isomers are interconvertible via a low energy
barrier, tautomeric isomerism ('tautornerism') can occur. This can take the
form
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of proton tautomerism in compounds of formula (1) containing, for example, an,
imino, keto, or oxime group, or so-called valence tautomerism in compounds
which contain an aromatic moiety. It follows that a single compound may
exhibit
more than one type of isomerism.
Included within the scope of the present invention are all stereoisomers,
geometric isomers and tautomeric forms of the compounds of formula (1),
including compounds exhibiting more than one type of isomerism, and mixtures
of one or more thereof. Also included are acid addition or base salts wherein
the counterion is optically active, for example, d-lactate or /-lysine, or
racemic,
for example, d/-tartrate or d/-arginine.
Cis/trans isomers may be separated by conventional techniques well known to
those skilled in the art, for example, chromatography and fractional
crystallisation.
Conventional techniques for the preparation/isolation of individual
enantiomers
include chiral synthesis from a suitable optically pure precursor or
resolution of
the racemate (or the racemate of a salt or derivative) using, for example,
chiral
high pressure liquid chromatography (HPLC).
Alternatively, the racemate (or a racemic precursor) may be reacted with a
suitable optically active compound, for example, an alcohol, or, in the case
where the compound of formula (1) contains an acidic or basic moiety, an acid
or base such as tartaric acid or 1-phenylethylamine. The resulting
diastereomeric mixture may be separated by chromatography and/or fractional
crystallization and one or both of the diastereoisomers converted to the
corresponding pure enantiomer(s) by means well known to a skilled person.
Chiral compounds of the invention (and chiral precursors thereof) may be
obtained in enantiomerically-enriched form using chromatography, typically
HPLC, on an asymmetric resin with a mobile phase consisting of a
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hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume.
of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an
alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords
the
enriched mixture.
5
Stereoisomeric conglomerates may be separated by conventional techniques
known to those skilled in the art - see, for example, "Stereochemistry of
Organic
Compounds" by E. L. Eliel (Wiley, New York, 1994).
10 According to one aspect of the present invention, the (R,R)-stereoisomer of
the
formula below, wherein R1 is hydrogen and R2 is C1-C4 alkyl, preferably
methyl,
and n and Q1 are as defined above, is generally preferred:
OH
H
RI R2 (CH2)n Q1
HO
?
I""~ "~r
HN 0
~r-H
O
The present invention includes all pharmaceutically acceptable isotopically-
15 labelled compounds of formula (1) wherein one or more atoms are replaced by
atoms having the same atomic number, but an atomic mass or mass number
different from the atomic mass or mass number which predominates in nature.
Examples of isotopes suitable for inclusion in the compounds of the invention
20 include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C
and
14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 9231 and
1251,
nitrogen, such as 13N and 15N, oxygen, such as 150, 170 and 180, phosphorus,
such as 32P, and sulphur, such as 35S.
25 Certain isotopically-labelled compounds of formula (1), for example, those
incorporating a radioactive isotope, are useful in drug and/or substrate
tissue
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31
distribution studies. The radioactive isotopes tritium, i.e. 3H,. and carbon-
14, i.e..
14C, are particularly useful for this purpose in view of their ease of
incorporation
and ready means of detection.
Substitution with heavier isotopes such as deuterium, Le. 2H, may afford
certain
therapeutic advantages resulting from greater metabolic stability, for
example,
increased in vivo half-life or reduced dosage requirements, and hence may be
preferred in some circumstances.
Substitution with positron emitting isotopes, such as 11C, 18F, 150 and 13N,
can
be useful in Positron Emission Topography (PET) studies for examining
substrate receptor occupancy.
Isotopically-labeled compounds of formula (1) ;can generally be prepared by
conventional techniques known to those skilled in the art or by processes
analogous to those described in the accompanying Examples and Preparations
using an appropriate isotopically-labeled reagents in place of the non-labeled
reagent previously employed.
Pharmaceutically acceptable solvates in accordance with the invention include
those wherein the solvent of crystallization may be isotopically substituted,
e.g.
D20, d6-acetone, d6-DMSO.
The compounds of formula (1), their pharmaceutically acceptable salts
and/or derived forms, are valuable pharmaceutically active compounds, which
are suitable for the therapy and prophylaxis of numerous disorders in which
the
(32 receptor is involved or in which agonism of this receptor may induce
benefit,
in particular the allergic and non-allergic airways diseases but also in the
treatment of other diseases such as, but not limited to those of the nervous
system, premature labor, congestive heart failure, depression, inflammatory
and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma
and
in conditions where there is an advantage in lowering gastric acidity,
particularly
in gastric and peptic ulceration.
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Compounds of the invention intended for pharmaceutical use may be
administered as crystalline or amorphous products. They may be obtained, for
example, as solid plugs, powders, or films by methods such as precipitation,
crystallization, freeze drying, spray drying, or evaporative drying. Microwave
or
radio frequency drying may be used for this purpose.
They may be administered alone or in combination with one or more other
compounds of the invention or in combination with one or more other drugs (or
as any combination thereof). Generally, they will be administered as a
formulation in association with one or more pharmaceutically acceptable
excipients. The term "excipient" is used herein to describe any ingredient
other
than the compound(s) of the invention. The choice of excipient will to a large
extent depend on factors such as the particular mode of administration, the
effect of the excipient on solubility and stability, and the nature of the
dosage
form.
Pharmaceutical compositions suitable for the delivery of compounds of the
present invention and methods for their preparation will be readily apparent
to
those skilled in the art. Such compositions and methods for their preparation
may be found, for example, in 'Remington's Pharmaceutical Sciences', 19th
Edition (Mack Publishing Company, 1995).
The compounds of the invention may be administered orally. Oral
administration may involve swallowing, so that the compound enters the
gastrointestinal tract, or-buccal or sublingual administration may be employed
by which the compound enters the blood stream directly from the mouth.
Formulations suitable for oral administration include solid formulations such
as
tablets, capsules containing particulates, liquids, or powders,- lozenges
(including liquid-filled), chews, multi- and nano-particulates, gels, solid
solution,
liposome, films, ovules, sprays and liquid formulations.
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33
Liquid formulations include suspensions, solutions, syrups _ and elixirs,
Such.
formulations may be employed as fit lers in soft or hard capsules and
typically
comprise a carrier, for example, water, ethanol, polyethylene glycol,
propylene
glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents
and/or suspending agents. Liquid formulations may also be prepared by the
reconstitution of a solid, for example, from a sachet.
The compounds of the invention nay also be used in fast-dissolving, fast-
disintegrating dosage forms such as those described in Expert Opinion in
Therapeutic Patents, 11 (6), 981-986,, by Liang and Chen (2001).
For tablet dosage forms, depending on dose, the drug may make up from 1
weight % to 80 weight % of the dosage form, more typically from 5 weight % to
60 weight % of the dosage form. I n addition to the drug, tablets generally
contain a disintegrant. Examples of disintegrants include sodium starch
glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose,
croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose,
microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose,
starch, pregelatinised starch and sodium alginate. Generally, the disintegrant
will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20
weight % of the dosage form.
Binders are generally used to impart cohesive qualities to a tablet
formulation.
Suitable binders include microcrystall ine cellulose, gelatin, sugars,
polyethylene
glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised
starch,
hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also
contain diluents, such as lactose (monohydrate, spray-dried monohydrate,
anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol,
microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
Tablets may also optionally comprise surface active agents, such as sodium
lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and
talc.
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When present, surface active agents may comprise from-0.2- weight % to 5
weight % of the tablet, and glidants may comprise from 0.2 weight % to 1
weight % of the tablet.
Tablets also generally contain lubricants such as magnesium stearate, calcium
stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium
stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25
weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the
tablet.
Other possible ingredients include anti-oxidants, colourants, flavouring
agents,
preservatives and taste-masking agents.
Exemplary tablets contain up to about 80% drug, from about 10 weight % to
about 90 weight % binder, from about 0 weight % to about 85 weight % diluent,
from about 2 weight % to about 10 weight % disintegrant, and from about 0.25
weight % to about 10 weight % lubricant.
Tablet blends may be compressed directly or by roller to form tablets. Tablet
blends or portions of blends may alternatively be wet-, dry-, or melt-
granulated,
melt congealed, or extruded before tabletting. The final formulation may
comprise one or more layers and may be coated or uncoated; it may even be
encapsulated.
The formulation of tablets is discussed in Pharmaceutical Dosage Forms:
Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York,
1980).
Consumable oral films for human or veterinary use are typically pliable water-
soluble or water-swellable thin film dosage forms which may be rapidly
dissolving or mucoadhesive and typically comprise a compound of formula .(1),
a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a
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stabiliser or emulsifier, a viscosity-modifying agent and -a solvent. _ Some.
components of the formulation may perform more*than one function-
The compound of formula (1) may be water-soluble or insoluble. A water-
5 soluble compound typically comprises from 1 weight % to 80 weight %, more
typically from 20 weight % to 50 weight %, of the solutes. Less soluble
compounds may comprise a greater proportion of the composition, typically up
to 88 weight % of the solutes. Alternatively, the compound of formula (1) may
be in the form of multiparticulate beads.
The film-forming polymer may be selected from natural polysaccharides,
proteins, or synthetic hydrocolloids and is typically present in the ra nge
0.01 to
99 weight %, more typically in the range 30 to 80 weight %.
Other possible ingredients include anti-oxidants, colorants, flavourings and
flavour enhancers, preservatives, salivary stimulating agents, cool ing
agents,
co-solvents (including oils), emollients, bulking agents, anti-foaming agents,
surfactants and taste-masking agents.
Films in accordance with the invention are typically prepared by evaporative
drying of thin aqueous films coated onto a peelable backing suppo rt or paper.
This may be done in a drying oven or tunnel, typically a combined cater dryer,
or by freeze-drying or vacuuming.
Solid formulations for oral administration may be formulated to be immediate
and/or modified release. Modified release formulations include delayed-,
sustained-, pulsed-, controlled-, targeted and programmed release.
Suitable modified release formulations for the purposes of the invention are
described in US Patent No. 6,106,864. Details of other suitable release
technologies such as high energy dispersions and osmotic and coated particles
are to be found in Pharmaceutical Technology On-line, 25(2), 1-14, by Verma
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36
et a/ (2001). The use of chewing gum to achieve controlled release.is
described
in WO 00/35298.
The compounds of the invention may also be administered directly into the
blood stream, into muscle, or into an internal organ. Suitable means for
parenteral administration include intravenous, intraarterial, intraperitoneal,
intrathecal, intraventricular, intraurethral, intrasternal, intracranial,
intramuscular
and subcutaneous. Suitable devices for parenteral administration include
needle (including microneedle) injectors, needle-free injectors and infusion
techniques.
Parenteral formulations are typically aqueous solutions which may contain
excipients such as salts, carbohydrates and buffering agents (preferably to a
pH of from 3 to 9), but, for some applications, they may be more suitably
formulated as a sterile non-aqueous solution or as a dried form to be used in
conjunction with a suitable vehicle such as sterile, pyrogen-free water.
The preparation of parenteral formulations under sterile conditions, for
example, by lyophilisation, may readily be accomplished using standard
pharmaceutical techniques well known to those skilled in the art.
The solubility of compounds of formula (1) used in the preparation of
parenteral
solutions may be increased by the use of appropriate formulation techniques,
such as the incorporation of solubility-enhancing agents.
Formulations for parenteral administration may be formulated to be immediate
and/or modified release. Modified release formulations include delayed-,
sustained-, pulsed-, controlled-, targeted and programmed release. Thus
compounds of the invention may be formulated as a solid, semi-solid, or
thixotropic liquid for administration as an implanted depot providing modified
release of the active compound. Examples of such formulations include drug-
coated stents and poly(d/-lactic-coglycolic)acid (PGLA) microspheres.
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The compounds of the invention may also be administered topically to the skin
or mucosa, that is, dermally or transdermally. Typical formulations for this
purpose include gels, hydrogels, lotions, solutions, creams, ointments,
dusting
powders, dressings, foams, films, skin patches, wafers, implants, sponges,
fibres, bandages and microemulsions. Liposomes may also be used. Typical
carriers include alcohol, water, mineral oil, liquid petrolatum, white
petrolatum,
glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may
be incorporated - see, for example, J Pharm SOi, 88 (10), 955-958 by Finnin
and Morgan (October 1999).
Other means of topical administration include delivery by electroporation,
iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free
(e.g. PowderjectTM, BiojectTM, etc.) injection.
Formulations for topical administration may be formulated to be immediate
and/or modified release. Modified release formulations include delayed-,
sustained-, pulsed-, controlled-, targeted and programmed release.
The compounds of the invention can also be administered intranasally or by
inhalation, typically in the form of a dry powder (either alone, as a mixture,
for
example, in a dry blend with lactose, or as a mixed component particle, for
example, mixed with phospholipids, such as phosphatidylcholine) from a dry
powder inhaler or as an aerosol spray from a pressurised container, -pump,
spray, atomiser (preferably an atomiser using electrohydrodynamics to produce
a fine mist), or nebuliser, with or without the use of a suitable propellant,
such
as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For
intranasal
use, the powder may comprise a bioadhesive agent, for example, chitosan or
cyclodextrin.
The pressurised container, pump, spray, atomizer, or nebuliser contains a
solution or suspension of the compound(s) of the invention comprising, for
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38
example, ethanol, aqueous ethanol, or a suitable alternative agent for
dispersing, solubilising, or extending release of the active, a propellant(s)
as
solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or
an
oligolactic acid.
Prior to use in a dry powder or suspension formulation, the drug product is
micronised to a size suitable for delivery by inhalation (typically less than
5
microns). This may be achieved by any appropriate comminuting method, such
as spiral jet milling, fluid bed jet milling, supercritical fluid processing
to form
nanoparticles, high pressure homogenisation, or spray drying.
Capsules (made, for example, from gelatin or hydroxyprc pyl methyl eel I u
lose),
blisters and cartridges for use in an inhaler or insufflator may be formulated
to
contain a powder mix of the compound of the invention, a suitable powder base
such as lactose or starch and a performance modifier such as /-leucine,
mannitol, or magnesium stearate. The lactose may be anhydrous or in the form
of the monohydrate, preferably the latter. Other suitable excipients include
dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
A suitable solution formulation for use in an atomiser using
electrohydrodynamics to produce a fine mist may contain from 1,ug to 20mg of
the compound of the invention per actuation and the actuation volume may vary
from lpl to 100pl. A typical formulation may comprise a compound of formula
(1), propylene glycol, sterile water, ethanol and sodium chloride. Alternative
solvents. which may be used instead of propylene glycol include glycerol and
polyethylene glycol.
Suitable flavours, such as menthol and levomenthol, or sweeteners, such as
saccharin or saccharin sodium, may be added to those formulations of the
invention intended for inhaled/intranasal administration.
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Formulations for inhaled/intranasal administration may be .formulated. to be
immediate and/or modified release using, for example, PGLA. Modified release
formulations include delayed-, sustained-,
pulsed-, controlled-, targeted and programmed release.
In the case of dry powder inhalers and aerosols, the dosage unit is determined
by means of a valve which delivers a metered amount. Units in accordance with
the invention are typically arranged to administer a metered dose or "puff"
containing from 0.001 mg to 10mg of the compound of formula (1). The overall
daily dose will typically be in the range 0.001 mg to 40mg which may be
administered in a single dose or, more usually, as divided doses throughout
the
day.
The compounds of formula (1) are particularly suitable for an administration
by
inhalation
The compounds of the invention may be administered rectally or vaginally, for
example, in the form of a suppository, pessary, or enema. Cocoa butter is a
traditional suppository base, but various alternatives may be used as
appropriate.
Formulations for rectal/vaginal administration may be formulated to be
immediate and/or modified release. Modified release formulations include
delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
The compounds of the invention may also be administered directly to the eye or
ear, typically in the form of drops of a micronised suspension or solution in
isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular
and
aural administration include ointments, biodegradable (e.g. absorbable gel
sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers,
lenses and particulate or vesicular systems, such as niosomes or liposomes. A
polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic
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acid, a cellulosic polymer, for example, _hydroxypropylmethylcellulose,.
hyd roxyethylcell u lose, or methyl cellulose, or a heteropolysaccharide
polymer,
for example, gelan gum, may be incorporated together with a preservative,
such as benzalkonium chloride. Such formulations may also be delivered by
5 iontophoresis.
Formulations for ocular/aural administration may be formulated to be immediate
and/or modified release. Modified release formulations include delayed-,
sustained-, pulsed-, controlled-, targeted, or programmed release.
The compounds of the invention may be combined with soluble
macromolecular entities, such as cyclodextrin and suitable derivatives thereof
or polyethylene glycol-containing polymers, in order to improve their
solubility,
dissolution rate, taste-masking, bioavailability and/or stability for use in
any of
the aforementioned modes of administration.
Drug-cyclodextrin complexes, for example, are found to be generally useful for
most dosage forms and administration routes. Both inclusion and non-inclusion
complexes may be used. As an alternative to direct complexation with the drug,
the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier,
diluent,
or solubiliser. Most commonly used for these purposes are alpha-, beta- and
gamma-cyclodextrins, examples of which may be found in International Patent
Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.
Inasmuch as it may desirable to administer a combination of active compounds,
for example, for the purpose of treating a particular disease or condition, it
is
within the scope of the present invention that two or more pharmaceutical
compositions, at least one of which contains a compound in accordance with
the invention, may conveniently be combined in the form of a kit suitable for
coadministration of the compositions.
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Thus the kit of the invention comprises two or more separate pharmaceutical.
compositions, at least one of which contains a' compound of formula (1) in
accordance with the invention, and means for separately retaining said
compositions, such as a container, divided bottle, or divided foil packet. An
example of such a kit is the familiar blister pack used for the packaging of
tablets, capsules and the like.
The kit of the invention is particularly suitable for administering different
dosage
forms, for example parenteral, for administering the separate compositions at
different dosage intervals, or for titrating the separate compositions against
one
another. To assist compliance, the kit typically comprises directions for
administration and may be provided with a so-called memory aid.
For administration to human patients, the total daily dose of the compounds of
the invention is typically in the range 0.001 mg to 5000mg depending, of
course,
on the mode of administration. For example, an intravenous daily dose may
only require from 0.001 mg to 40mg. The total daily dose may be administered
in single or divided doses and may, at the physician's discretion, fall
outside of
the typical range given herein.
These dosages are based on an average human subject having a weight of
about 65kg to 70kg. The physician will readily be able to determine doses for
subjects whose weight falls outside this range, such as infants and the
elderly.
For the avoidance of doubt, references herein to "treatment" include
references
to curative, palliative and prophylactic treatment.
According to another embodiment of the present invention, the
compounds of the formula (1), or pharmaceutically acceptable salts, derived
forms or compositions thereof, can also be used as a combination with one or
more additional therapeutic agents to be co-administered to a patient to
obtain
some particularly desired therapeutic end result such as the treatment of
pathophysiologically-relevant disease processes including, but not limited to
(i)
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bronchoconstriction, (ii) inflammation, (iii) allergy, (iv) tissue
destruction, (v).
signs and symptoms such as breathlessness, cough. The second ' and more
additional therapeutic agents may also be a compound of the formula (1), or a
pharmaceutically acceptable salt, derived forms or compositions thereof, or
one
or more p2 agonists known in the art. More typically, the second and more
therapeutic agents will be selected from a different class of therapeutic
agents.
As used herein, the terms "co-administration", "co-administered" and "in
combination with", referring to the compounds of formula (1) and one or more
other therapeutic agents, is intended to mean, and does refer to and include
the following:
= simultaneous administration of such combination of compound(s) of
formula (1) and therapeutic agent(s) to a patient in need of treatment,
when such components are formulated together into a single dosage
form which releases said components at substantially the same time to
said patient,
= substantially simultaneous administration of such combination of
compound(s) of formula (1) and therapeutic agent(s) to a patient in need
of treatment, when such components are formulated apart from each
other into separate dosage forms which are taken at substantially the
same time by said patient, whereupon said components are released at
substantially the same time to said patient,
= sequential administration of such combination compound(s) of formula
(1) and therapeutic agent(s) to a patient in need of treatment, when such
components are formulated apart from each other into separate dosage
forms which are taken at consecutive times by said patient with a
significant time interval between each administration, whereupon said
components are released at substantially different times to said patient;
and
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= sequential administration of such combination of compound(s) of formula.
(1) and therapeutic agent(s) to a patient in need of treatment, when such
components are formulated together into a single dosage form which
releases said components in a controlled manner whereupon they are
concurrently, consecutively, and/or overlapingly administered at the
same and/or different times by said patient,
where each part may be administered by either the same or different route.
Suitable examples of other therapeutic agents which may be used in
combination with the compound(s) of formula (1), or pharmaceutically
acceptable salts, derived forms or compositions thereof, include, but are by
no
means limited to :
(a) 5-Lipoxygenase (5-LO) inhibitors or 5-lipi'xygenase activating protein
(FLAP) antagonists,
(b) Leukotriene antagonists (LTRAs) including antagonists of LTB4, LTC4, LTD4,
and LTE4,
(c) Histamine receptor antagonists including H1 and H3 antagonists,
(d) a,- and a2-adrenoceptor agonist vasoconstrictor sympathomimetic agents
for decongestant use,
(e) muscarinic M3 receptor antagonists or anticholinergic agents,
(f) PDE inhibitors, e.g. PDE3, PDE4 and PDE5 inhibitors,
(g) Theophylline,
(h) Sodium cromoglycate,
(i) COX inhibitors both non-selective and selective COX-1 or COX-2 inhibitors
(NSAIDs),
(j) Oral and inhaled glucocorticosteroids,
(k) Monoclonal antibodies active against endogenous inflammatory entities,
(I) Anti-tumor necrosis factor (anti-TNF-a) agents,
(m)Adhesion molecule inhibitors including VLA-4 antagonists,
(n) Kinin-B1 - and B2 -receptor antagonists,
(o) Immunosuppressive agents,
(p) Inhibitors of matrix metalloproteases (MMPs),
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(q) Tachykinin NK1, NK2 and NK3 receptor antagonists,
(r) Elastase inhibitors,
(s) Adenosine A2a receptor agonists,
(t) Inhibitors of urokinase,
(u) Compounds that act on dopamine receptors, e.g. D2 agonists,
(v) Modulators of the NF-KO pathway, e.g. IKK inhibitors,
(w) modulators of cytokine signalling pathyways such as p38 MAP kinase or syk
kinase,
(x) Agents that can be classed as mucolytics or anti-tussive,
(y) Antibiotics,
(z) HDAC inhibitors, and,
(aa) P13 kinase inhibitors.
According to the present invention, combination of the compounds of
formula (1) with :
- H3 antagonists,
- Muscarinic M3 receptor antagonists,
- PDE4 inhibitors,
- glucocorticosteroids,
- Adenosine A2a receptor agonists,
- Modulators of cytokine signalling pathyways such as p38 MAP kinase or syk
kinase, or,
- Leukotriene antagonists (LTRAs) including antagonists of LTB4, LTC4, LTD4,
and LTE4,
are preferred.
.25 According to the present invention, combination of the compounds of
formula (1) with :
- glucocorticosteroids, in particular inhaled glucocorticosteroids with
reduced systemic side effects, including prednisone, prednisolone,
flunisolide, triamcinolone acetonide, beclomethasone dipropionate,
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budesonide, fluticasone propionate, ciclesonide; and mometasone.
furoate, or
- muscarinic M3 receptor antagonists or anticholinergic agents
including in particular ipratropium salts, namely bromide, tiotropium
5 salts, namely bromide, oxitropium salts, namely bromide,
perenzepine, and telenzepine,
are further preferred.
It is to be appreciated that all references herein to treatment include
curative, palliative and prophylactic treatment. The description, which
follows,
10 concerns the therapeutic applications to which the compounds of formula (1)
may be put.
The compounds of formula (1) have the ability to interact with the R2
receptor and thereby have a wide range of therapeutic applications, as
described further below, because of the essential role which the R2 receptor
15 plays in the physiology of all mammals.
Therefore, a further aspect of the present invention relates to the
compounds of formula (1), or pharmaceutically acceptable salts, derived forms
or compositions thereof, for use in the treatment of diseases, disorders, and
conditions in which the R2 receptor is involved. More specifically, the
present
20 invention also concerns the compounds of formula (1), or pharmaceutically
acceptable salts, derived forms or compositions thereof, for use in the
treatment of diseases, -disorders, and conditions selected from the group
consisting of :
= asthma of whatever type, etiology, or pathogenesis, in particular asthma
25 that is a member selected from the group consisting of atopic- asthma,
non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated
asthma, bronchial asthma, essential asthma, true asthma, intrinsic
asthma caused by pathophysiologic disturbances, extrinsic asthma
caused by environmental factors, essential asthma of unknown or
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inapparent cause, non-atopic asthma, bronchitic asthma,.
emphysematous asthma, exercise-induced asthma, allergen induced
asthma, cold air induced asthma, occupational asthma, infective asthma
caused by bacterial, fungal, protozoal, or viral infection, non-allergic
asthma, incipient asthma, wheezy infant syndrome and bronchiolytis,
= chronic or acute bronchoconstriction, chronic bronchitis, small airways
obstruction, and emphysema,
= obstructive or inflammatory airways diseases of whatever type, etiology,
or pathogenesis, in particular an obstructive or inflammatory airways
disease that is a member selected from the group consisting of chronic
eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD),
COPD that includes chronic bronchitis, pulmonary emphysema or
dyspnea associated or not associated with COPD, COPD that is
characterized by irreversible, progressive airways obstruction, adult
respiratory distress syndrome (ARDS), exacerbation of airways hyper-
reactivity consequent to other drug therapy and airways disease that is
associated with pulmonary hypertension,
= bronchitis of whatever type, etiology, or pathogenesis, in particular
bronchitis that is a member selected from the group consisting of acute
bronchitis, acute laryngotracheal bronchitis, arachidic bronchitis,
catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious
asthmatic bronchitis, productive bronchitis, staphylococcus or
streptococcal bronchitis and vesicular bronchitis,
= acute lung injury,
= bronchiectasis of whatever type, etiology, or pathogenesis, in particular
bronchiectasis that is a member selected from the group consisting of
cylindric bronchiectasis, sacculated bronchiectasis, fusiform
bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry
bronchiectasis and follicular bronchiectasis.
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A still further aspect of the present invention also relates to the use of
the compounds of formula (1), or pharmaceutically acceptable salts, derived
forms or compositions thereof, for the manufacture of a drug having a 02
agonist activity. In particular, the present inventions concerns the use of
the
compounds of formula (1), or pharmaceutically acceptable salts, derived forms
or compositions thereof, for the manufacture of a drug for the treatment of P2-
mediated diseases and/or conditions, in particular the diseases and/or
conditions listed above.
As a consequence, the present invention provides a particularly
interesting method to treat a mammal, including a human being, with an
effective amount of a compound of formula (1), or a pharmaceutically
acceptable salt, derived form or composition thereof. More precisely, the
present invention provides a particularly interesting method for the treatment
of
a 02-mediated diseases and/or conditions in a mammal, including a human
being, in particular the diseases and/or conditions listed above, comprising
administering said mammal with an effective amount of a compound of formula
(1), its pharmaceutically acceptable salts and/or derived forms.
The following examples illustrate the preparation of the compounds of
the formula (1):
Preparation 1 : (3-Ethoxycarbonylmethylphenyl)acetic acid ethyl ester
OCH3
H3C0
C I / O
Y
2,2'-(1,3-Phenylene)diacetic acid (10.0 g, 51 mmol) was dissolved in ethanol
(100 mL-) and the solution treated dropwise with acetyl chloride (2.5 mL). The
reaction mixture was stirred at reflux for 18 hours before being allowed to
cool
and concentrated in vacuo. The residue was taken up in ethyl acetate (100 ml-)
and extracted with sodium bicarbonate solution (3x 50 ml-) and brine (3x 50
mL). The organic phase was dried (MgSO4), concentrated in vacuo and the
residue triturated with pentane to yield the product (11.8 g).
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48
1HNMR (CDCI3, 400 MHz) 8: 1.31 (6H, t), 3.65 (4H, s), 4.20.(4H, q), 7.24-7.36.
(4H, m); LRMS ESI m/z 251 [M+H]+
Preparation 2 (3-Ethoxycarbonylmethylphenyl)acetic acid
HO Y-~' O~CH3
O O
A solution of preparation 1 (44.3 g, 177 mmol) and 2,2'-(1,3-
phenylene)diacetic
acid (59.2 g, 308 mmol) in ethanol (24 mL) and dioxan (290 mL) was treated
dropwise with hydrochloric acid (12 M, 4.9 mL, 58.8 mmol). The reaction
mixture was stirred at reflux for 18 hours before being allowed to cool and
concentrated to low volume. The reaction mixture was diluted with toluene (125
mL) and the resulting slurry filtered. The filtrate was concentrated in vacuo
and
the residue taken up in water and basified with sodium bicarbonate until pH
neutral. The mixture was diluted with ethyl acetate (200 mL) and the organic
layer was separated and washed with sodium bicarbonate solution (5x 30 ml)
and brine (50 mL). The combined aqueous extracts were acidified to pH 3 with
6M hydrochloric acid and extracted with diethylether (3x 30 mL). The organics
were combined, dried (MgSO4) and concentrated in vacuo. The residue was
triturated with pentane to yield a colourless solid (10.8 g).
1HNMR (CD3OD, 400 MHz) 8: 1.25 (3H, t), 3.60 (2H, m), 3.63 (2H, m), 4.15
(2H, q), 7.18-7.32 (4H, m); LRMS ESI m/z 245 [M+Na]+
Preparation 3 : [3-(2-Hydroxy-2-methylpropyl)phenyl]acetic acid
HO OH
0 H3C CH3
Methyl magnesium chloride (51 mL of a 3M solution in tetrahydrofuran; 153
mmol) was added dropwise to a stirred solution of the preparation 2 (11.6 g,
51
mmol) (International Journal of Peptide and Protein Research, 1987, 29(3),
331) in tetrahydrofuran (300 ml-) at 0 C under nitrogen. The reaction was
allowed to warm to room temperature overnight with the formation of a thick
white precipitate and then water (50 mL) and 2N hydrochloric acid (80 ml-)
were
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49
cautiously added. The aqueous was extracted with ethyl acetate (2x 300 mL).
and the combined organics washed with brine ( 0 mL), dried (sodium sulfate),
and the solvent removed in vacuo to furnish the title compound as a golden oil
(11.2 g).
'HNMR (CDCI3, 400 MHz) b: 1.22 (6H, s), 2.75 (2H, s), 3.63 (2H, s), 7.12-7.30
(4H, m); LRMS ESI mlz 209 [M+H] +
Preparation 4 : (3-{2-[(Chloroacetyl)amino]-2imethylpropyl}phenyl) acetic
acid
H
HO N
O H3C CH3 O
2-Chloroacetonitrile (8.8 mL, 140 mmol) was added to a solution of preparation
3 (16.0 g, 70 mmol) in acetic acid (33 mL) and pooled to 0 C. The resulting
solution was treated with concentrated sulphuric acid (33 mL) and allowed to
warm gradually to room temperature. After 4 hours the reaction mixture was
poured onto ice and basified with solid sodium carbonate. The solution was
extracted with ethyl acetate (2x 500 mL) and the combined organic extracts
dried (MgSO4) and concentrated in vacuo to give the title product as a
colourless solid (19.0 g).
1HNMR (CDCI3, 400 MHz) 8: 1.36 (6H, s), 3.02 (2H, s), 3.62 (2H, s), 3.95 (2H,
s), 6.19 (1 H, m), 7.06-7.31 (4H, m);
LRMS ESI m/z 282 [M-H]-
Preparation 5 : [3-(2=Amino-2-methylpropyl)phenyl]acetic acid methyl
ester
H2N O`CH
3
H3C CH3 0
A solution of preparation 4 (5.1 g, 18 mmol), thiourea (1.6 g, 21 mmol) and
acetic acid (18 ml-) in ethanol (80 mL) was heated to reflux under a nitrogen
atmosphere for 16 hours. The reaction mixture was allowed to cool to room
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temperature and filtered and the filtrate concentrated in vacuo. The residue.
was dissolved in ethanol (150 mL), saturated with hydrogen chloride gas and
the resulting solution heated to reflux for 16 hours. The mixture was
concentrated in vacuo and ethyl acetate (200 ml-) and 5% aqueous sodium
5 carbonate solution (200 mL) added. The organic phase was washed with brine
(100 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified
by strong cation exchange resin (methanol and then a 2M solution of ammonia
in methanol) to give a yellow oil (2.68 g).
1HNMR (CDCI3, 400 MHz) 8:1.14 (6H, s), 2.68 (2H, s), 3.62 (2H, s), 3.69 (3H,
10 s), 7.08-7.16 (3H, m), 7.23-7.27 (1 H, m); LRMS ESI m/z 222 [M+H]+
Preparation 6 : [3-(2-tert-Butoxycarbonylamino-2-methylpropyl)phenyl]
acetic acid methyl ester
~/ H
H3C' I CyN 01, CH3
CH3 0 H3C CH3 0
15 A solution of di-tent-butyldicarboxylate (8.19 g, 38.0 mmol) in
dichloromethane
(40 mL) was added to a solution of preparation 5 (8.4 g, 38.0 mmol) and
triethylamine (5.2 mL, 38.0 mmol) in dichloromethane (60 mL) at 0-5 C. The
mixture was allowed to warm to RT and stirred overnight. The solvent was
removed and the residue treated with sodium carbonate solution and extracted
20 with ethyl acetate (3 x 30 mL). The combined organic layers were washed
with
brine (3x 20 mL) and dried (Na2SO4). The product was purified by
chromatography (0-80 % ethyl acetate in hexane) to yield a colourless oil-
which
was dissolved in diethylether (x3) and evaporated (10.1 g)
1HNMR (CDCI3, 400 MHz) 8: 1.26 (6H, s), 1.46 (9H, s), 2.97 (2H, s), 3.60 (2H,
25 s), 3.68 (3H, s), 4.26 (1 H, bs), 7.05-7.07 (2H, m), 7.13-7.17 (1 H, m),
7.22-7.26
(1 H, m); LRMS ESI m/z 344 [M+Na]+
Preparation 7 : [3-(2-tent-Butoxycarbonylamino-2-methylpropyl)phenyl]
acetic acid
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51
H
H3C H3C>(OyN OH
O H
CH3C CH3 O
3
Preparation 6 (7.45 g, 23.0 mmol), sodium hydroxide solution (5M, 4.6 mL, 115
mmol), dioxane (30 mL) and water (8 mL) were stirred at RT for 18 h. The
solvent was removed and the material dissolved in water, cooled and acidified
to pH 3 with hydrochloric acid (2M). The product was extracted with ethyl
acetate (3 x 30 mL), and the organics washed with brine (3x 30 mL) and dried
(Na2SO4). The resulting oil was dissolved in diethylether and evaporated to
yield a colourless gum (7.0 g).
1HNMR (CD3OD, 400 MHz) S: 1.23 (6H, s), 1.48 (9H, s), 2.96 (2H, s), 3.57 (2H,
s), 7.04-7.06 (2H, m), 7.11-7.13 (1 H, m), 7.18-7.22 (1 H, m); .
LRMS APCI m/z 308 [M+H]+
Preparation 8 : (2-{3-[(3,4-Dichlorobenzylcarbamoyl)methyl]phenyl}-1,1-
dimethyl-ethyl)carbamic acid tert-butyl ester
a
H3C O N N
CI
H3~' CH3 0 H3C CH3 O
3, 4-Dichlorobenzylamine (1.30 mL, 9.76 mmol) was added to a solution of
preparation 7 (3.00 g, 9.76 mmol), hydroxybenzotriazole hydrate (1.50 g, 9.76
mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.87 g,
9.76 mmol) and triethylamine (4.07 mL, 11.2 mmol) and the resulting solution
was stirred at RT for 18 h. The solvent was removed and the crude material
taken up in .ethyl acetate (50 ml-) and washed with water (30 rnL), sodium
carbonate solution (2x 30 mL), brine (30 ml), hydrochloric acid (0.5 M, 2x 30
ml)
and brine (30 ml-) and then dried (Na2SO4). The resulting white solid was
triturated with diethylether (3.1 g).
1HNMR (CDCI3, 400 MHz) 5: 1.25 (6H, s), 1.45 (9H, s), 2.97 (2H, s), 3.62 (2H,
s), 4.22 (1 H, bs), 4.34 (2H, d), 5.78 (1 H, bs), 6.99-7.01 (1 H, dd), 7.04 (1
H, s),
7.07-7.09 (1 H, d), 7.12-7.14 (1 H, d), 7.22 (1 H, d), 7.27 (1 H, d), 7.32 (1
H, d); :
LRMS APCI m/z 465 [M+H]+
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Preparation 9 : (2-{3-[(3,4-Dimethylbenzylcarbamoyl)methyl]phenyl}-1,1-
dimethyl-ethyl)carbamic acid tent-butyl ester
CH3
H3C O H H
\
GH3
H3C H C CH
CH3 O 3 3
Prepared using the acid from Preparation 7 and the method described for
Preparation 8 and 3,4-dimethylbenzylamine.
1HNMR (CDCI3, 400 MHz) 8: 1.19 (6H, s), 1.46 (9H, s), 2.20 (6H, d), 2.95 (2H,
s), 3.59 (2H, s), 4.15 (1H, bs), 4.32 (2H, d), 5.59 (1H, bs), 6.86-6.93 (2H,
m),
7.02-7.06 (3H, m), 7.13-7.15 (1 H, d), 7.23-7.27 (1 H, m); .
LRMS APCI m/z 425 [M+H]+
Preparation 10: 2-[3-(2-Amino-2-methylpropyl)phenyl]-N-(3,4-dichloro
benzyl)acetamide
ci
H2N N \
CI
H3C CH3 O
Preparation 8 (3.0 g, 6.50 mmol) in dioxane (5 mL) was treated with hydrogen
chloride (4M in dioxane, 20 mL) and the resulting solution left to stir at RT
for
18 h. The solvent was removed and the compound re-dissolved in methanol
(x2) and evaporated, then the resulting gum suspended in diethylether (x2) and
evaporated to yield a white solid (2.7 g). mp (ethyl acetate-methanol) 214-216
(dec) C.
1HNMR (CD3OD, 400 MHz) 8: 1.33 (6H, s), 2.90 (2H, s), 3.59 (2H, s), 4.35 (2H,
s), 7.13-7.19 (3H, m), 7.24-7.27 (1 H, m), 7.31-7.38 (2H, m), 7.42 (1 H, d); .
LRMS ESI m/z 365 [M+H]+
Preparation 11: 2-[3-(2-Amino-2-methylpropyl)phenyl]-N-(3,4-dimethyl
benzyl)acetamide
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/ CH3
HZN N
CH3
H3C CH3 o
Prepared using the amide from Preparation 9 and the method described for
Preparation 10.
1HNMR (CD3OD, 400 MHz) 8: 1.32 (6H, s), 2.21 (6H, s), 2.89 (2H, s), 3.56 (2H,
s), 4.29 (2H, s), 6.95-7.05 (3H, m), 7.14-7.16 (2H, m), 7.24-7.26 (1 H, m),
7.31 -
7.35 (1 H, m); .
LRMS ESI m/z 325 [M+H]+
Preparation 12: N-(2-Benzyloxy-5-[(1R)-2-bromo-1-(tert-butyldimethyl
silanyloxy)ethyl]phenyl}formamide
H3C~ H3
H3 H CO
3
Br
C0r
HN
0
To a solution of N-[2-benzyloxy-5-(2-bromo-1-hydroxyethyl)phenyl]formami de
(Organic Process Research and Development 1998, 2, 96-99) (4.12 g, 11.8
mmol) in N,N-dimethylformamide (25 mL) at RT under N2 was added tert-
butyldimethylsilyl chloride (3.50 g, 23.2 mmol), imidazole (1.90 g, 27.9 mmol)
and 4-(dimethylamino)pyridine (40 mg, 330 mol). The resulting solution was
stirred at RT overnight, the solvent was removed and the product taken up in
ethyl acetate (70 mL). The organics were washed with water (100 mL), and the
aqueous extracted with ethyl acetate (20 mlmLThe combined organics were
washed with hydrochloric acid (2M, 50 ml), brine (100 ml-) and dried (MgSO4).
The crude material was purified by chromatography (5-25 % ethyl acetate in
pentane) to yield a colourless oil (5.7 g).
1HNMR (CDCI3, 400 MHz) 8: -0.08 to -0.05 (3H, m), 0.09-0.11 (3H, s), 0.39-
0.90 (9H, m), 3.38-3.55 (2H, m), 3.78-3.84 (1H, m), 5.06-5.11 (2H, m), 6.90-
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54
6.97 (1 H, m), 7.03-7.12 (1 H, m), 7.24 (m), 7.36-7.43 (5H, 7.67-7.78 (m),.
7.88 (d), 8.74 (d);
LRMS APCI m/z 464/466 [M+H]+
Preparation 13 : 2-(3-{2-[(2R)-2-(4-Benzyloxy-3 formylaminophenyl)-2-(tert-
butyl-dimethylsilanyloxy)ethylamino]-2-methylpropyl}phenyl)-N-(3,4-
dichlorobenzyl)acetamide
H3C`CI H~H3
H3 H CC'Si'O CI
3
N / N I CI
O H3C CH3 I O
HN
0
Preparation 12 (500 mg, 1.08 mmol) and preparation 10 (780 mg, 216 mmol)
were heated and stirred at 90 C for 24 h. After cooling the material was
dissolved in methanol and evaporated, the material was suspended in
diethylether and the precipitate filtered off. The filtrate was evaporated and
the
material purified by chromatography (0-5 % methanol in dichloromethane) and
then suspended in diethylether (x3) and evaporated to yield a foam (425 mg).
1HNMR (CD3OD, 400 MHz) S: -0.20 to -0.18 (3H, m), -0.04 to 0.00 (3H, m),
0.78-0.81 (9H, m), 1.01-1.03 (3H, m), 1.05 (3H, bs), 2.62-2.74 (3H, m), 2.83-
2.88 (1H, m), 3.52 (2H, d), 4.31 (2H, s), 4.68-4.71 (1H, m), 5.17-5.19 (2H,
m),
7.00-7.23 (7H, m), 7.29-7.41 (5H, m), 7.44-7.49 (2H, m), 8.57 (s); LRMS ESI
m/z 748 [M+H]+;
HRMS C41H51Cl2N3O4Si 748.3099 [M+H]+ found 748.3066.
Preparation 14 : 2-(3-{2-[(2R)-2-(4-Benzyloxy-3-lormylaminophenyl)-2-(tert-
butyl-dimethylsilanyloxy)ethylamino]-2-methylpropyl}phenyl)-N-(3,4-
dimethylbenzyl)acetamide
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H3C~ f bH3
H3 H~C\'Si,o / CH3
3
N~ N \ ` CH3
O H3C CH3 0
\ / \ ~
HN
II
O
Prepared using the amide from Preparation 13, the bromide from Preparation
12 and the method described for Preparation 11.
1HNMR (CDCI3, 400 MHz) 8: -0.17, -0.16 (3H, ~x s), -0.05 to -0.01 (3H, m),
5 0.78-0.82 (9H, m), 0.97-1.01 (6H, m), 2.19 (3H, ), 2.20 (3H, s), 2.56-2.90
(4H,
m), 3.54-3.63_(2H, m), 4.28-4.35 (2H, m), 4.67-4.74 (1 H, m), 5.06-5.09 (2H,
m),
5.58-5.62 and 5.99-6.03 (1 H, m), 6.87-7.25 (9H, m), 7.35-7.44 (5H, m), 7.68-
7.79 (1 H, m), 8.30 (d), 8.43 (d), 8.71 (s), 8.74 (s); LRMS ESI m/z 748
[M+H]+;
HRMS C43H57N3O4Si 708.4191 [M+H]+ found 706.4156.
Preparation 15 : N-Benzyl-2-(3-{2-[(2R)-2-(tent-butyldimethylsilanyloxy)-2-
(3-formylamino-4-hydroxyphenyl)ethylamino]-2-
methylpropyl)phenyl)acetamide
H3C~H3
H3 H C'Si,O
4rj'~ N N
H CH3 \ O
HO
HN\
0
Preparation 13 (100 mg;'134 gmol) and palladium-on-carbon (10 %, 20 mg) in
methanol (10 mL) were hydrogenated at 50 psi/RT for 6 h. The mixture was
filtered through a `filter-aid' and the solvent removed. The material was
suspended in sodium hydrogen carbonate solution and extracted with ethyl
acetate (30 mL). The organic layer was washed with sodium hydrogen
carbonate solution, brine (2x mL) and dried (Na2SO4). The resulting material
was suspended in diethylether (x3) and evaporated to yield a film (24 mg).
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56
1HNMR (CD3OD, 400 MHz) 8: -0.19 (3H, s), -0.02 (3H, s); 0.79 (9H, s), 1.04.
(3H, s), 1.07 (3H, s), 2.62-2.89 (4H, m), 3.48-3.56 (2H, dd), 4.35 (2H, s),
4.61
(1 H, bs), 4.69-4.72 (1 H, m), 5.17-5.19 (2H, m), 6.79-6.85 (1H, m), 6.91-6.94
(1 H, m), 7.04-7.06 (1 H, m), 7.11-7.28 (7H, m), 8.12 (1 H, d), 8.27, 8.59 (1
H, 2x
s); .
LRMS ESI m/z 590 [M+H]+;
HRMS C34H47N3O4Si 590.3402 [M+H]+ found 590.3409.
Preparation 16 2-(3-{2-[(2R)-2-(tert-Butyldimethylsilanyloxy)-2-(3-
formylamino-4-hydroxyphenyl)ethylamino]-2-methylpropyl}phenyl)-N-(3,4-
dimethylbenzyl)acetamide
H3C> H3
H3 H c'Si.o / CH3
3
N\ / N \ CH3
H3 CH3 O
HO
HN\
0
Prepared using the amide from Preparation 14 and the method described for
Preparation 15. The product was purified by chromatography (0-3.5 %
methanol in dichloromethane + 0.3 % ammonia) to yield a foam (85 mg).
1HNMR (CD3OD, 400 MHz) 8: -0.20 to -18 (3H, m), -0.03-0.00 (3H, m), 0.79-
0.81 (9H, m), 1.02-1.05 (6H, m), 2.19 (3H, s), 2.20 (3H, s), 2.61-2.73 (3H,
m),
2.83-2.88 (1 H, m), 3.46 (2H, dd), 4.27 (21-1, s), 4.65 (1 H, dd), 6.78-7.22
(8H, m),
8.12 (d), 8.27 (s), 8.59 (s); .
LRMS ESI m/z 618 [M+H]+;
1HRMS C36H51N3O4Si 618.3722 [M+H]+ found 618.3701.
Preparation 17: Methyl (3-bromophenyl)acetate
B r " . ~CH3
/ O
Acetyl chloride (0.7 mL, 9.3 mmol) was slowly-added to a solution of (3-bromo-
phenyl)acetic acid (20.0 g, 93 mmol) in methanol (500 mL) at 0 C under
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57
nitrogen and the reaction was allowed to warm gradually to room temperature.
over a period of 5 hours. The solvent was removed in vacuo and the residual
oil
was re-dissolved in dichloromethane, dried over sodium sulfate and
concentrated in vacuo to give the title compound as a colourless oil (20.6 g).
'H NMR (400MHz, CDCI3): S: 3.59 (2H, s), 3.70 (3H, s), 7.17-7.24 (2H, m),
7.37-7.45 (2H, m); LRMS ESI m/z 253 [M+Na]+
Preparation 18: Methyl [3-(2-oxopropyl)phenyl]acetate
C'jf" O"~CH3
O o
Tributyltin methoxide (28.3 mL, 98 mmol), the product of preparation 17 (15.0
g,
65mmol), isopropenyl acetate (10.8 mL, 98 mmol), palladium([ [)acetate (750
mg, 3.30 mmol) and tri-ortho-tolylphosphine (2.0 g, 6.5 mmol) were stirred
together in toluene (75 mL) at 100 C for 5 hours. After cooling, the reaction
was diluted with ethyl acetate (150 mL) and 4M aqueous potassium fluoride
solution (90 mL), and stirred for 15 minutes. The mixture was filtered through
Arbocel and the organic phase was separated and concentrated in vacuo. The
residue was then purified by column chromatography on silica gel eluting with
diethyl ether:pentane, 0:100 to 25:75, followed by dichioromethane to give the
title compound as a pale yellow oil in 94% yield (12.6 g).
1H NMR (400MHz, CDCI3): 8: 2.15 (3H, s), 3.61 (2H, s), 3.69 (5H, s), 7.10-7.13
(2H, m), 7.19 (1 H, d), 7.30 (1 H, t); LRMS ESI: m/z 229 [M+Na]+
Preparation 19: Methyl [3-((2R)-2-{[(1 R)-1-phenylethyl]amino}propyl)=
phenyl]acetate hydrochloride
H HCI
N I C~1
CH3
CH3 CH3 O
A solution of the product of preparation 18 (8.5 g, 41.2 mmol), (R)-a-methyl
benzylamine (4.8 mL, 37.2 mmol), sodium triacetoxyborohydride (11.6 g, 56
mmol) and acetic acid (2.2 mL, 38 mmol) in dichloromethane (400 mL) was
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58
stirred at room temperature for 48 hours. The reaction mixture- was quenched.
by addition of saturated sodium hydrogen carbonate solution (200 ml-) and
allowed to stir until effervescence ceased. The aqueous phase was separated
and extracted with dichloromethane (100 mL). The combined organic solution
was then dried over magnesium sulfate and concentrated in vacuo. Purification
by column chromatography on silica gel, eluting with
dichloromethane:methanol: ammonia, 99:1:0.1 to 95:5:0.5, gave a 4:1 mixture
of diastereomers (R,R major) as a pale yellow oil (8.71 g). Treatment with
hydrogen chloride (40 mL of a 1M solution in methanol, 40 mmol) followed by
three successive crystallisations (diisopropylether/methanol) gave the title
compound as a white crystalline solid in 50% yield, 5.68 g.
1H NMR (400MHz, CD3OD): 8: 1.18 (3H, d), 1.68 (3H, d), 2.60-2.66 (11-1, m),
3.15-3.26 (11-1, m), 3.25-3.30 (11-1, m), 3.31 (3H, s), 3.62 (2H, s), 4.59 (11-
1, q),
6.99-7.02 (2H, m), 7.17 (11-1, m), 7.25-7.28 (11-1, m), 7.48-7.52 (5H, m) LRMS
ESI m/z 312 [M+H]+
Preparation 20: Methyl {3-[(2R)-2-aminopropyl]phenyl}acetate
HZN 0`1 CH3 Y*'~ Y CH3 I O
A solution of the product of preparation 19 (7.69 g, 22 mmol) and ammonium
formate (6.94 g, 110 mmol) was heated to 75 C in the presence of 20%
palladium hydroxide-on-charcoal (2.00 g). After 90 minutes the reaction
mixture
was cooled to room temperature, filtered through Arbocel and the filtrate
concentrated in vacuo. The residue was partitioned between dichloromethane
(100 mL) and 0.88 ammonia (100 ml-) and the phases were separated. The
aqueous phase was extracted with dichloromethane (100 mL) and the
combined organic solution was dried over magnesium sulfate and concentrated
in vacuo to afford the title compound as a colourless oil in quantitative
yield
(4.78 g).
1H NMR (400MHz, CD3OD): 8: 1.06 (3H, d), 2.57-2.67 (2H, m), 3.05-3.12 (11-1,
m), 3.63 (2H, s), 3.67 (31-1, s), 7.09-7.13 (3H, m), 7.23-7.27 (1 H, t); LRMS
ESI
m/z 208 [M+H]+
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Preparation 21: Methyl (3-{(2R)-2-[(tert-butoxycarbonyl)amino]propy1}
phenyl)acetate
O\ /NH OUCH
~I I( 3
O CH3 O
The title compound was prepared from the product of preparation 20 and cli-
tertbutyl dicarboxylate, using a method similar to that of preparation 6, as a
yellow oil in 97% yield.
1H NMR (400MHz, CD3CI3): 8: 1.07 (3H, d), 1.43 (91-1, s), 2.61 (1 H, dd), 23 1
(1 H, dd), 3.60 (2H, s), 3.69 (3H, s), 3.89 (1 H, bs), 4.36 (1 H, bs), 7.06-
7.19 (3H,
m), 7.22-7.27 (1 H, m); LRMS APCI m/z 306 [M-H]-
Preparation 22: (3-{(2r)-2-[(tert-butoxycarbonyl)amino]propyl} phenyl)
acetic acid
~O` /NH OH
O cH3 0
A mixture of preparation 21 (8.31 g, 27.1 mmol) and lithium hydroxide solution
(1 M in water, 54 mL, 54 mmol) in tetrahydrofuran (100 ml-) was stirred at
room
temperature for 20 hours. The reaction mixture was then concentrated in vacuo
and the aqueous residue was acidified to pH 2 with 2M hydrochloric acid. The
mixture was then extracted with ethyl acetate (3x 75 ml-) and the combined
organic solution was washed with brine (100 mL), dried over magnesium sulfate
and concentrated in vacuo to afford the title compound as a yellow oil in 82%
yield (6.50 g)
1H NMR (400MHz, CD3CI3): 8: 1.07 (3H, d), 1.40 (9H, s), 2.61 (1 H, dd), 2.77-
2.88 (11-1, bs), 3.62 (2H, s), 3.89 (11-1, bs), 4.39 (11-1, bs), 7.07-7.16
(3H, m),
7.22-7.27 (1 H, m); LRMS APCI m/z 292 [M-H]"
Preparation 23: Benzyl (3-{(2R)-2-[(tert-butoxycarbonyl)amino]propy[}
phenyl)acetate
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\ /OyNH
I O
O cH3 / O
/XI
The product of preparation 22 (6.30 g, 21.5 mmol), 1-(3-dimethylaminopropyl)-
3-ethylcarbodiimide hydrochloride (4.14 g, 21.5 mmol), 1-hydroxybenzotriazole
hydrate (3.30 g, 21.5 mmol) and triethylamine (4.85 mL, 43 mmol) were stirred
5 together in dichloromethane (100 mL) for 10 minutes at room temperature.
Benzyl alcohol (2.2 mL, 21.5 mmol) was then added and the mixture was stirred
at room temperature for 18 hours. The reaction mixture was then diluted with
dichloromethane (50 mL), washed with sodium hydrogen carbonate solution
(100 mL) and brine (100 mL), dried over magnesium sulfate and concentrated
10 in vacuo to afford the title compound as a clear oil in 50% yield, 4.16 g.
1H NMR (400MHz, CD3CI3): 8: 1.04 (3H, d), 1.44 (9H, s), 2.59 (1 H, dd), 2.81
(1 H, dd), 3.64 (2H, s), 3.87 (1 H, bs), 4.34 (1 H, bs), 5.13 (2H, s), 7.07-
7.11 (2H,
m), 7.13 (1 H, bd), 7.22-7.27 (1 H, m), 7.29-7.38 (5H, m); LRMS APCI m/z 382
[M-H]-
Preparation 24: Benzyl {3-[(2R)-2-aminopropyl]phenyl}acetate
HZN O y
CH3 O
Hydrogen chloride (4M in dioxane, 5.43 mL, 21.72 mmol) was added to a
solution of the product of preparation 23 (4.16 g, 10.86 mmol) in dioxane (50
mL) and the resulting solution stirred at room temperature for 72 hours. The
solvent -was removed in vacuo and the residue was dissolved in
dichloromethane and washed with sodium hydrogen carbonate solution (50mL)
and brine (50mL). The organic solution was then dried over magnesium sulfate
and concentrated in vacuo to afford the title compound as a yellow oil in 93%
yield (2.85 g).
1H NMR (400MHz, CD3CI3): 8: 1.09 (3H, d), 1.55 (2H, bs), 2.48 (1H, dd), 2.66
(1 H, dd), 3.10-3.18 (1 H, m), 3.65 (2H, s), 5.17 (2H, s), 7.09-7.13 (2H, m),
7.14-
7.18 (1 H, bd), 7.24-7.38 (6H, m); LRMS APCI m/z 284 [M-H]"
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Preparation 25: Benzyl (3-{(2/)-2-[((2R)-2-[4-(berizyloxy)-3-
(formylamino)phenyl]-2-{[tent-butyl(dimethyl)silyl]oxy}ethyl)amino]-
propyl}phenyl)acetate
H CH3
IH3
H3 H3C~_SI\0
N O
/ H3 O
O
HN\ /H
0
The title compound was prepared from the pr9ducts of preparation 12 and
preparation 24, using a similar method to that of preparation 13, as a brown
oil
in 25% yield
LRMS APCI m/z 667 [M+H]+
Preparation 26: {3-[(2R)-2-({(2R)-2-{[tent Butyl(dimethyl)silyl]oxy}-2-[3-
(formylamino)-4-hydroxyphenyl]ethyl}ami no)propyl]phenyl}acetic acid
CH3
H3C i H3
H3C llSl~
H3co
H
N \ OH
HO CH3 I / O
HNyH
0
The product. of preparation 25 (851 mg, 1.27 mmol) and 10% Pd/C (50 mg)
were suspended in methanol and the mixture was stirred under 60psi of
hydrogen gas, at room temperature for 72 hours. The reaction mixture was then
filtered through Filter aid and the filtrate was concentrated in vacuo to
afford
the title product as a brown foam in 94% yield, 580mg.
'H NMR (400MHz, CDCI3): S: -0.09 (3H, s), 0.08 (3H, s), 0.88 (9H, s),
1.12,1.24
(3H, 2xd), 2.07-2.82 (2H, m), 2.99 (1 H, dd), 3.18 (1 H, dd), 3.60 (2H, s),
4.16-
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4.22 (1 H, m), 4.97-5.07 (1 H, m), 6.87 (1 H, d), 6.99-7.32 (6H,_m), 7.93 (s),
8.17.
(d), 8.33 (s); LRMS APCI m/z 487 [M+H]"
Preparation 27: 2-{3-[(2R)-2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[3-
(formylamino)-4-hydroxyphenyl]ethyl}amino)propyl]phenyl}-N-[4-(dimethyl
amino)benzyl]acetamide
H3C CH3
H3C(.(H3 CH3
H3C -Si\ N~
O CH3
\ N I \ N \
CH3 0
HO HN\ /H
0
A mixture of the product of preparation 26 (100 mg, 206 mol),
hydroxybenzotriazole hydrate (32 mg, 206 mol), 1-(3-d imethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (40 mg, 206 mol) and triethylamine (58 L,
412 mol) in N,N-dimethylformamide (2 mL) was stirred at room temperature
for 10 minutes. 4-(Dimethylamino)benzylamine (31 mg, 206 gmol) was then
added and the mixture was stirred at room temperature for 20 hours. The
solvent was then removed in vacuo and the residue was diluted with
dichloromethane, washed with sodium hydrogen carbonate solution (20 ml-)
and brine (20 mL), dried over magnesium sulfate and concentrated in vacuo to
afford the title compound as a brown gum in 10% yield, 131 mg.
~H NMR (400MHz, CD3CI3): 0.17 (3H, s), 0.00 (3H, s), 0.83 (9H, s), 1.08 (3H,
m), 2.80-3.00 (1 OH, m), 3.47 (1 H, m), 3.66 (2H, m), 4.23 (2H, m), 5.48 (1 H,
m),
6:66 (1 H, d), 6.70-7.23 (1 OH, m), 7.97 (m), 8.27 (s); LRMS APCI m/z 504
[M+H]
Preparations 28 to 29
The following compounds, of the general formula shown below were prepared
from the product of preparation 26 and the appropriate amine, using a method
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similar to that described for preparation 27. The reactions were monitored by
tic.
analysis and were stirred at room temperature for 18-72hours.
CH3
H3C>CH3
H3C Sip
H3C ""A
O
H
N Q,
HO I / CH3 I /
HNyH
0
No. Q1 Data Yield
28 HNYCH3 LRMS APCI m/z 632 [M-H]- 99%
~iN \ 0
29 LRMS APCI m/z 6618 [M-H]" 99%
NH2
~IN \
Preparation 28: N-[4-(aminomethyl)phenyl]acetamide may be prepared as
described in J. Med. Chem, 46, 3116; 2003
Preparation 29: 4-(aminomethyl)benzamide may be prepared as described in
WO 02085860 p239
Preparation 30: [3-((2R)-2-([(1 R)-1-Phenylethyl]amino}propyl)phenyl]acetic
acid
\ I N OH
CH3 CH3 O
Lithium hydroxide solution (1M in water, 90 mL, 90 mmol) was added to a
solution of the product of preparation 19 (13.50 g, 43.5 mmol) in methanol
(200
ml-) and the mixture was stirred at room temperature for 18 hours. 1M
Hydrochloric acid (90 mL) was then added to the reaction mixture and the
methanol removed in vacuo. The resulting precipitate was filtered off and
washed with water (20 ml-) and a mixture of ethanol/diethyl ether, 20:80, to
afford the title compound as a solid in 91% yield, 11.8 g
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1H NMR (400MHz, CD3OD) 6: 1.16 (3H, d), 1.62 (31-1, d), =2.66-2.62 (1H, m),.
3.13- 3.26 (2H, m), 3.46 (2H, s), 4.48-4.56 (1 H, q), 6.92 (1 H, d), 7.19 (1
H, s),
7.18-7.22 (2H, m), 7.45-7.52 (5H, m); LRMS ESI m/z 298 [M+H] +
Preparation 31: N-1-Adamantyl-2-[3-((2R)-2-{[(1R)-1-phenylethyl]amino}
propyl)phenyl]acetamide
/
\ N N
CH3 CH3 I / O
1-Adamantylamine (5.44 g, 36.0 mmol) and triethylamine (15 mL, 108 mmol)
were added to a solution of the product of preparation 30 (10.7 g, 36.0 mmol)
in
dichloromethane (200 mL). 2-Chloro-1,3-dimethylimidazolidinum
hexafluorophosphate (10.0 g, 36.0 mmol) was then added and the mixture was
stirred at room temperature for 2 hours. The reaction mixture was washed with
water and the organic solution was dried over magnesium sulfate and
concentrated in vacuo. Purification of the residue by column chromatography
on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 95:5:0.5,
afforded the product as a foam in quantitative yield, 17.6g.
1H NMR (400MHz, CD3OD) b: 0.89 (3H, d), 1.35 (31-1, d), 1.65-1.75 (6H, m),
1.98 (6H, m), 2.04 (31-1, m), 2.37-2.42 (1 H, dd), 2.65-2.74 (1 H, m), 2.95-
3.00
(1 H, dd), 3.36 (21-1, s), 3.98 (1 H, q), 6.89 (1 H, d), 6.98 (1 H, s), 7.09
(1 H, d), 7.17
(1 H, t), 7.22-7.27 (1 H, m), 7.30-7.38 (4H, m); LRMS ESI m/z 431 [M+H]+
Preparation 32: N-1-Adamantyl-2-{3-[(2R)-2-aminopropyl]phenyl}- _
acetamide_
H
HZN
Y\
""~
CH3 I / O
The title compound was prepared from preparation 31, using a similar method
to that of preparation 20, as a solid in 92% yield.
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'H NMR (400MHz, CD3OD) S: 1.09 (3H, d), 1.66-1.72 (61-1; m); 2.00 (6H, m),.
2.03 (3H, m), 2.58-2.70 (2H, m), 3.10-3.16 (1 H, q), 3.40 (2H, s), 7.05-7.28
(4H,
m); LRMS ESI m/z 327 [M+H]+
5 Preparation 33: 2-(3-{(2R)-2-[((2R)-2-[3-(Acetylamino)-4-(benzyloxy)phenyl]-
2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]propyl}-phenyl)-N-1-
adamantylacetamide
H3C CH3
CH
H3C 3/ 3
H3C C H H
~ N I ~ N
CH3 O
O
HN\ /H
0
A mixture of the products of preparation 12 (696 mg, 1.5 mmol) and preparation
10 32 (978 mg, 3.0 mmol) in dichloromethane (0.5 ml-) was heated at 90 C for
5
minutes allowing the dichloromethane to evaporate. The reaction mixture was
then heated as a melt at 90 C for 18 hours before cooling to room
temperature.
The crude product was then purified by column chromatography on silica gel,
eluting with dichloromethane:methanol:0.88 ammonia, 98:2:0.2, to afford the
15 title compound as a pale foam in 59% yield, 630 mg.
1H NMR (400MHz, CD3OD) S: -0.18 (3H, s), 0.00 (3H, s), 0.83 (91-1, s), 1.05-
1.08 (d, 3H), 1.66-1.72 (6H, m), 2.00 (6H, m), 2.02 (3H, m), 2.52-2.71 (3H,
m),
2.84-2.96 (2H, m), 3.36-3.41 (2H, m), 4.68-4.72 (1 H, m), 5.20 (2H, s), 6.92-
7.18
(6H, m), 7.30-7.50 (5H, m), 8.22 (m), 8.36 (s), 8.54 (s); LRMS ESI m/z 710
20 [M+H]+
Preparation 34: N Adamantan-1-yl-2-(3-{2-[(2R)-2-({(2R)-2-(tert-
butyi(limethylsilanyloxy)-2-(3-formylamino-4-
hydroxyphenyl)ethylamino]propyl}phenyl)acetamide
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NC CH3
H3C_ ,CH3
.S=
H3C o
~ H H
HO I / CH3 O
HN(H
0
The title compound was prepared from the product of 33, using a similar
method to that of preparation 20, as a clear foam in quantitative yield.
1H NMR (400MHz, CD30D) 8: -0.17 (3H, s), 0.00 (3H, s), 0.83 (9H, s), 1.04-
1.06 (d, 3H), 1.69-1.70 (6H, m), 2.00 (6H, m), 2.03 (3H, m), 2.52-2.70 (3H,
m),
2.88-2.94 (2H, m), 3.37-3.38 (2H, m), 4.64-4.69 (1 H, m), 6.92-7.18 (6H, m),
8.00 (1 H, d), 8.30 (s), 8.56 (s); LRMS ESI m/z 620 [M+H]+
Preparation 35: 1-(3-Bromophenyl)-2-methylpropan-2-ol)
Br OH
/ H3C CH3
Methylmagnesium bromide (3M solution in diethyl ether, 51.6 mL, 155 mmol)
was slowly added to a solution of 1-(3-bromo-phenyl)propan-2-one (15.0 g, 70
mmol) in dry diethyl ether (200 ml-) at 0 C and the mixture was stirred for 3
hours. The reaction mixture was then re-cooled to 0 C and slowly quenched
with saturated aqueous ammonium chloride solution. The organic solution was
washed with brine, dried over sodium sulfate and concentrated in vacuo. The
residual yellow oil was then purified by column chromatography on silica gel
eluting with dichloromethane:pentane:methanol, 90:5:5, to afford a pale-yellow
oil in 83% yield, 13.26 g:
1H NMR (400MHz, CDCI3) 8:1.22 (6H, s), 1.42 (1H, bs), 2.74 (2H, s), 7.15 (2H,
m), 7.40 (2H, m)
Preparation 36: N-[2-(3-Bromophenyl)-1, I -dimethylethyl]-2-
chloroacetamide
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H
Br / N ~ CI
H3C CH)r _
3 O
Chloroacetonitrile (6.63 mL, 105 mmol) was added to a stirred solution of the
product of preparation 35 (12.0 g, 52.0 mmol) in acetic acid (25 ml-) at room
temperature. The resulting solution was cooled to 0 C and concentrated
sulfuric acid (25 ml-) was added whilst the temperature was maintained below
C. The resulting solution was left to stir for 1 hour and was then poured
onto ice and basified by the addition of solid potassium carbonate. The
product
was extracted with ethyl acetate (2x 500 ml) and the combined organic
solution was washed with water (50mL), dried over sodium sulfate and the
10 concentrated in vacuo to afford the title compound as an orange solid in
quantitative yield, 16.08 g.
'H NMR (400MHz, CDCI3) S: 1.37 (6H, s), 3.02 ;(2H, s), 3.94 (2H, s), 6.17 (1
H,
bs), 7.08-7.03 (1H, d), 7.10-7.13 (11-1, t), 7.26 (1H, s), 7.39-7.32 (11-1
d,); LRMS
ESI m/z 306 [M+H]+; Microanalysis: C12H15BrCINO requires: C 47.32; H 4.96; N
4.60; found C 47.26; H 4.87; N 4.65
Preparation 37: 2-(3-Bromophenyl)-1,1-dimethylethylamine
Br O :1-1 NH2
CH3
C C H
A solution of the product of preparation 36 (32.0 g, 105 mmol), thiourea (9.60
g,
126 mmol) and acetic acid (50 ml-) in ethanol (250 ml-) was heated to reflux
overnight. The reaction mixture was cooled to room temperature and filtered.
The filtrate was concentrated in vacuo, basified using aqueous sodium
hydroxide solution (1M, 450 ml-) and extracted with dichloromethane (2x 500
mL). The combined organic solution was washed with brine (50 mL), dried over
sodium sulfate and concentrated in vacuo to afford the title compound as a
black oil in 96% yield, 23 g.
'H NMR (400MHz, CDC13) 8:1.12 (6H, s), 1.84 (2H, bs), 2.62 (2H, s), 7.16-7.08
(2H, m), 7.36-7.32 (2H, m); LRMS ESI m/z 228 [M+H]+
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Preparation 38: [2-(3-Bromophenyl)-1,1-dimethylethyl]carbamic acid tert-.
butyl ester
H
Br N 0 CH3
)<CH
H3C CH3 0 CH3 3
The product of preparation 37 (5.0g, 22mmol) was treated with di-tert-butyl
dicarbonate (5.26g, 24mmol) in dichloromethane (50mL) and stirred for 20
hours. The reaction mixture was washed with water (50mL) and the combined
organic solution was dried over sodium sulfate and concentrated in vacuo. The
crude material was purified using a cation exchange column (methanol followed
by 2M ammonia in methanol), followed by purification by flash column
chromatography on silica gel eluting with dichloromethane to afford the title
compound as a brown oil in quantitative yield, 7.23g.
'H NMR (400MHz, CDCI3) 8: 1.27 (6H, s) 1.50 (9H, s), 2.97 (2H, s), 4.24 (1 H,
bs), 7.05 (11-1, d), 7.15-7.11 (11-1, t), 7.30 (11-1, s), 7.35 (11-1, d); LRMS
ESI m/z
350 [M+NH4]+
Preparation 39: Benzyl 3-{2-[(tert-butoxycarbonyl)amino]-2-
methylpropyl}benzoate
0
H
0 N 0 CH3
CH
"'~
H3C' CH3 0 CH3 3
cr'~
A solution of the product of preparation 38 (3.9 g, 12 mmol), [1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.00 g, 1.3 mrnol) and
triethylamine (3.3 mL, 24 mmol) in benzyl alcohol (60 mL) was heated to 100 C
_
under 100psi carbon monoxide for 5 hours. The cooled reaction mixture was
then filtered through Arbocel and the filtrate concentrated in vacuo. The
residue was dissolved in ethyl acetate and washed with sodium hydrogen
carbonate solution (50 mL) and brine (2x 50 mL). The organic solution was then
dried over sodium sulfate and concentrated in vacuo to give a dark oil. This
oil
was purified by column chromatography on silica gel, eluting with hexane:ethyl
acetate 100:0 to 84:16, to afford the title compound as a pale yellow oil in
61%
yield, 2.81 g.
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1H NMR (400MHz, CDCI3) 8: 1.25 (6H, s), 1.45 (9H, s), 3.05.(2H, s), 4.22 (1H,-
bs), 5.35 (2H, s), 7.32-7.48 (7H, m), 7.86 (1 H, s), 7.93-7.97 (1 H, m)
Preparation 40: Benzyl 3-(2-amino-2-methyl propyl)benzoate hydrochloride
0
J0)Ei<HCI
3C C H3
The title compound was prepared from the product of preparation 39, using a
method similar to that of preparation 24, as a white solid in 91 % yield.
1H NMR (400MHz, CD3OD) 8: 1.33 (6H, s), 2.98 (2H, s), 5.37 (2H, s), 7.31-7.53
(7H, m), 7.93 (1 H, s), 8.00-8.04 (1 H, m); LRMS APCI m/z 284 [M+H]+
Preparation 41: Benzyl 3-{2-[((2R)-2-[4-(benzyloxy)-3-
(formylamino)phenyl]-2-{[tent-butyl(dimethyl)silyl]oxy}ethyl)amino]-2-
methylpropyl}benzoate
CH3
H3C 1 3
H3C BSI,
H3C 0 0
H
N \ 0~
H3C CH3
HNYH
0
A mixture of the product of preparation 40 (1.81 g, 6.38 mmol), preparation 12
(2.96 g, 6.38 mmol) and potassium carbonate (1.76 g, 12.8 mmol) in
dimethylsulfoxide (10 ml-) was heated at 95 C for 40 hours. The cooled
reaction mixture was then diluted with water (250 ml-) and extracted with
ethyl
acetate (3x 50 mL). The combined organic solution was washed with sodium
hydrogen carbonate solution (50 ml-) and brine (2x 50 mL), dried over sodium
sulfate and concentrated in vacuo to give an orange oil. This oil was purified
by
column chromatography on silica gel, eluting with dichloromethane:hexane,
50:50, followed by dichloromethane:methanol, 100:0 to 98:2. The appropriate
fractions were evaporated under reduced pressure and the residue was further
purified by column chromatography on silica gel, eluting with
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dichloromethane:methanol, 100:0 to 98:2, to give a yellow gum: The gum was.
azeotroped with diethyl ether (x3) to afford the title compound as a yellow
gum
in 20% yield, 0.83 g.
1H NMR (400MHz, CDCI3): 8: -0.15 to -0.17 (3H, m), -0.03 (3H, s), 0.79-0.82
5 (91-1, s), 1.01 (3H, s), 1.04 (3H, s), 2.62-2.86 (4H, m), 4.66-4.74 (11-1,
m), 5.06-
5.07 (21-1, m), 5.36 (2H, s), 6.88 (1 H, d), 7.01-7.05 (1 H, m), 7.27-7.50
(12H, m),
7.74 (1 H, m), 7.87-7.96 (2H, m), 8.39 (s), 8.40 (s), 8.76 (s), 8.78 (s); LRMS
APCI m/z 667 [M+H]-
10 Preparation 42: 3-[2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[3-
(formylamino)-4-hydroxyphenyl]ethyl}amino)-2-methylpropyl]benzoic acid
H C`'CH3
H3 H3C~_Si`
O O
H
N OH
/ H3C CH3
HO
HN` /H
0
The title compound was prepared from the product of preparation 41, using a
method similar to that of 26. The crude product was then azeotroped with
15 diethyl ether (x3) to afford the title compound as a pale yellow solid in
97%
yield.
1H NMR (400MHz, CD3OD): 8: -0.12 (3H, s), 0.05 (3H, s), 0.81 (9H, s), 1.24
(61-1, s), 2.98 (2H, dd), 3.26-3.30 (2H, m), 4.91 (1 H, t), 6.89 (1 H, d),
7.02 (1 H,
m), 7.37-7.49 (2H, m), 7.85 (1 H, bs), 7.93-7.96 (1 H, d), 8.11 (s, 1 H), 8.32
(s),
20 8.61 (s); LRMS ESI mlz 487 [M+H]-
Preparation 43: (4-Hydroxy-2,5-dimethylphenyl)acetonitrile
CH3
LOH
CH3
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A solution of (4-methoxy-2,5-dimethylphenyl)acetonitrile (0.5 g; 2.9 mmol) in.
dichloromethane (10 ml-) was cooled to -80 C and treated with
borontribromide (IM in dichloromethane, 14.3 mL, 14.3 mmol). The reaction
mixture was stirred at -80 C for a further 30 minutes and then was allowed to
warm to room temperature over a period of 2 hours. The reaction mixture was
quenched with saturated sodium hydrogen carbonate solution (20 mL) and the
organic layer was separated. The organic solution was washed with brine
(20mL), dried over sodium sulfate and the concentrated in vacuo to afford a
pale brown solid. Purification by column chromatography on silica gel, eluting
with ethyl acetate:pentane 20:80 to 33:67, afforded the title compound as a
colourless solid in 60% dispersion in mineral oil yield, 0.28 g.
1H NMR (400MHz, CD3OD) 8: 2.13 (3H, s), 2.23 (3H, s), 3.66 (2H, s), 6.60 (1 H,
s), 6.98 (1 H, s); LRMS ESI m/z 160 [M-H]-
Preparation 44: (4-Hydroxy-2,3-dimethyl-phenyl)acetonitrile
CH3
\\ CH3
OH
The title compound was prepared from (4-methoxy-2,3-dimethyl-
phenyl)acetonitrile using a similar method to that of preparation 43, as a
colourless solid in 94% yield.
1H NMR (400MHz, CDCI3) S: 2.20 (3H, s), 2.24 (3H, s), 3.62 (2H, s), 6.64 (1 H,
d), 7.03 (1 H, d); LRMS APCI m/z 160 [M-H]-
Preparation .45: (4-Hydroxy-3-methylphenyl)acetonitrile
CH3
OH
The title compound was prepared from (4-methoxy-3-methylphenyl)acetonitrile
using a similar method to that of preparation 43, as a pale yellow solid.
1H NMR (400MHz, CDCI3) 8: 2.25 (3H, s), 3.65 (2H, s), 4.98 (1 H, bs), 6.76 (1
H,
d), 7.01 (1 H, d), 7.07 (1 H, s); LRMS ESI m/z 146 [M-H]-
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Preparation 46: 4-(2-Aminoethyl)-2,5-dimethylphenol
CH,
OH
HZN
CH3
A solution of the product of preparation 43 (0.28 g, 1.74 mmol) in ethanol (15
mL) was hydrogenated at 60psi over Raney Nickel (0.1 g, 50% w/w) for 16
hours. The reaction mixture was then filtered and the solvent was removed in
vacuo. The residue was purified using a cation exchange resin, eluting with
methanol and then 1 M ammonia in methanol to afford the title compound as a
colourless oil.
'HNMR(400MHz, CD3OD) 8: 2.11 (3H, s), 2.19 (3H, s), 2.63-2.67 (2H, m), 2.72-
2.76 (2H, m), 6.54 (1 H, s), 6.81 (1 H, s); LRMS ESI m/z 166 [M+H]+
Preparation 47: 4-(2-Amino-ethyl)-2,3-dimethyl-phenol
CH3
HZN CH3
OH
The title compound was prepared from the product of preparation 44 using a
similar method to that of preparation 46, as a colourless solid in 95% yield.
' H NMR (400MHz, CDCI3) 8: 6.78 (1 H, d), 6.55 (1 H, d), 2.75-2.68 (4H, m),
2.19
(3H, s), 2.12 (3H, s); LRMS APCI m/z 166 [M+H]+
Preparation 48: 4-(2-Aminoethyl)-2-methylphenol
CH3
OH
HZN
The title compound was prepared from the product of preparation 45, using a
similar method to that of preparation 46, as a colourless oil.
'HNMR(400MHz, CD3OD) 8:2.15 (3H, s), 2.60-2.64 (2H, m), 2.79-2.83 (2H, m),
6.66 (d, 1 H), 6.82 (1 H, d), 6.90 (1 H, s); LRMS ESI m/z 152 [M+H]+
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Preparation 49: tert-Butyl (3-iodobenzyl)carbarate
CH3 O
H3C H3C>~ OIk H
A suspension of 3-iodobenzylamine hydrochloride (4.95 g, 18.4 mrnol) in
dichloromethane (100 ml-) was treated with triehylamine (3.1 mL, 22 mmol)
and di-tent-butyl dicarbonate (4.40 g, 20 mmol) acid the resulting solution
stirred
at room temperature for 1.5 hours. The reaction (mixture was then washed with
2M hydrochloric acid (30 mL), water (30 mL), dried over sodium sulfate and
concentrated in vacuo to afford the title compound as a colourless solid in
quantitative yield, 6.43 g.
1HNMR (400MHz, CDCI3) 8:1.46 (9H, s), 4.21-4.30 (2H, m), 4.79-4.89 (1 H, bs),
7.06 (1 H, dd), 7.25 (1 H, d), 7.60 (1 H, d), 7.63 (1 s); LRMS ESI m/z 332 [M-
H]-
Preparation 50: tert-Butyl [(4'-hydroxybiphenyl-3-yl)methyl]carbamate
CH3 0 - OH
Hac
H3C>~O'J~ H
A solution of the product of preparation 49 (0.75 g, 2.25 mmol), 4-hydroxy
phenylboronic acid (0.62 g, 4.50 mmol) and 1,1'-
bis(diphenylphosphino)ferrocenyl palladium(II)chloride (0.11 g, 0.14 mrnol) in
N,N-dimethylformamide (14 ml-) was treated with 2M aqueous sodium
carbonate solution (4 ml-) and the resulting mixture was heated at 80 C-for
16
hours. The solvent was removed in vacuo and the residue was purified by
column chromatography on silica gel, eluting with ethyl acetate: pentane,
25:75,
to afford the title compound as a pale pink crystalline solid in quantitative
yield,
0.73 g.
'H NMR (400MHz, CDCI3) 8: 1.47 (9H, s), 4.33-4.41 (2H, m), 4.87-4.94 (11-1,
bs), 6.89 (2H, d), 7.21 (1 H, d), 7.37 (1 H, dd), 7.43-7.45 (4H, m); LRMS ESI
m/z
298 [M-H]"
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Preparation 51: 3'-(Aminomethyl)biphenyl-4-ol -hydrochloride
/ OH
HZN
HCI
The product of preparation 50 (0.73 g, 2.43 mmol) was treated with 4M
hydrochloric acid in dioxan (6.1 mL, 24.3 mmol) and the resulting solution
allowed to stir at room temperature for 3 hours. The reaction mixture was then
concentrated in vacuo to afford the title compound as a colourless solid.
'H NMR (400MHz, CD3OD) 8: 4.17 (2H, s), 6.87 (2H, d), 7.34 (1H, d), 7.45-7.50
(3H, m), 7.61 (1 H, d), 7.65 (1 h, s); LRMS ESI m/z 198 [M-H]-
Preparation 52: 2-Hydroxy-1-naphthamide
HO
HaN
0 I /
A solution of 2-hydroxy-1-napthoic acid (5.0 g, 26.6 mmol), 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.6 g, 29.2 mmol),
and 1-hydroxybenzotriazole (3.95 g, 29.2 mmol) in tetrahydrofuran (70 mL) was
stirred at room temperature for 30 minutes prior to the addition of 0.88
ammonia (6 mL). The resulting suspension was stirred at room temperature for
2 hours. The reaction mixture was then filtered, and the filtrate was diluted
with
water (80mL) and extracted with ethyl acetate (4x 80 mL). The combined
organic extracts were washed with water (2x 50mL) and brine (50 mL), dried
over sodium sulfate and concentrated in vacuo to give an orange oil:
Purification- of the oil by column chromatography on silica gel, eluting with
dichloromethane:methanol:0.880 ammonia, 95:5:0.5, afforded the title
compound as a pink solid in 37% yield, 1.83 g.
'HNMR (400MHz, CDCI3) S: 6.11-6.35 (2H, bs), 7.17 (1H, d), 7.36 (1H, dd),
7.54 (1H, dd), 7.79 (1H, d), 7.84 (1H, d), 8.22 (1H, d), 11.70-11.88 (1 H,
bs);
LRMS ESI m/z 186 [M-H]"
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Preparation 53: 3,5-Dichloro-N-ethyl-2-hydroxybenzamide.
H
O NI___'CH3
HO L
cl CI
The title compound was prepared from 3,5-dichloro-2-hydroxybenzoic acid and
ethylamine, using a similar method to that of preparation 52, to afford the
title
5 compound as a pale yellow solid.
'HNMR (400MHz, CDCI3) 8: 1.28 (3H, t), 3.47-3.54 (2H , m), 6.29-6.36 (1 H,
bs),
7.27 (1 H, d), 7.48 (1 H, d); LRMS ESI m/z 232 [M-H]-
Preparation 54: 4-(Aminomethyl)-2,6-dimethylphenol hydrochloride
H3C NHS HCI
HO
10 CH3
A solution of borane in tetrahydrofuran (1 M in tetrahydrofuran, 27.1 mL, 27.1
mmol) was added dropwise to a solution of 3,5-dimethyl-4-hydroxybenzonitrile
(1.0 g, 6.79 mmol) in tetrahydrofuran (70 mL) and the resulting solution was
heated under reflux for 16 hours. The reaction mixture was cooled to room
15 temperature, treated with 6N hydrochloric acid (20mL) and heated under
reflux
for a further 30 minutes. The reaction mixture was then cooled to room
temperature and the solvent was removed in vacuo. The residue was purified
using a strong cation exchange resin eluting with methanol followed by 2M
ammonia in methanol, to give an orange oil. This oil was then treated with 1M
20 hydrogen chloride in methanol (20mL) and the reaction mixture was
concentrated in vacuo to afford the title compound as a pale yellow solid in
quantitative yield, 1.12 g.
1HNMR (400MHz, CDCI3) S: 2.22 (6H, s), 3.75 (211, s), 6.90 (2H, s).
25 Preparation 55: 2-(Aminomethyl)-4-chlorophenol hydrochloride
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CI NHZ
HCI
OH
The title compound was prepared from 5-chloro-2-hydroxybenzonitrile, using a
method similar to that described for preparation 54.
'HNMR (400MHz, CDCI3) 6: 4.08 (2H, s), 6.87 (1 H, d), 7.27 (1 H, d), 7.35 (1
H,
s); LRMS APCI m/z 156 [M-H]-
Preparation 56: 4'-(Aminomethyl)biphenyl-4-ol hydrochloride
OH
HZN
HCI
The title compound was prepared from 4'-hydroxybiphenyl-4-carbonitrile, using
a method similar to that of preparation 54.
'HNMR (400MHz, CD3OD) 6: 4.10 (s, 2H), 6.83 (d, 2H), 7.44-7.46 (m, 4H),
7.60 (d, 2H).
Preparation 57: 1-(Aminomethyl)-2-naphthol
HO
H2N 15
A solution of borane in tetrahydrofuran (19.23 mL of a 1M solution, 19.23
mmol) was added dropwise to a solution of the amide from preparation 52 (0.90
g, 4.81 mmol) in tetrahydrofuran (10 ml-) and the reaction. was then heated
under reflux for 2 hours. The solution was cooled, treated with 6M
hydrochloric
acid (10_ ml-) and heated under reflux for a further 2 hours. The resulting
suspension was cooled to room temperature and the pH was adjusted to pH 9
by addition of 0.88 ammonia and extracted with ethyl acetate (3x 50 rL). The
combined organic solution was washed with brine (20 mL), dried over sodium
sulfate and concentrated in vacuo. Purification of the residue by column
chromatography on silica gel, eluting with dichloromethane:methanol:0.88
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ammonia, 95:5:0.5 to 90:10:1, afforded the title. compound as a pink solid in.
23% yield, 0.19 g.
1H NMR (400MHz, CD3OD) 8: 4.41 (2H, s), 7.07 (1 H, d), 7.23 (dd, 1H), 7.43
(1 H, dd), 7.66 (1 H, d), 7.72 (1 H, d), 7.87 (1 H, d); LRMS ESI m/z 174
[M+H]+
Preparation 58: 2,4-Dichloro-6-[(ethylamino)methyl]phenol
H
N..CH3
HO
CI CI
A solution of the product of preparation 53 (0.77 g, 3.29 mmol) in
tetrahydrofuran (10 ml-) was cooled to 0 C and treatecil with borane-
tetrahydrofuran complex (1M in tetrahydrofuran, 9.9 mL, 9.9 mmol). The
resulting solution was allowed to warm to room temperature over 20 minutes
and was then heated under reflux for 16 hours. The reaction mixture was
cooled to 0 C and quenched by addition of methanol. The resulting solution
was allowed to warm to room temperature over 2 hours and was then
concentrated in vacuo. The residue was dissolved in dichloromethane (40 ml-)
and washed with water (2x 10 mL), brine (10 mL), dried over sodium sulfate
and reduced in vacuo to give a colourless oil. Purification of the oil by
column
chromatography on silica gel, eluting with methanol:dichloromethane, 2:98 to
5:95 afforded the title compound as a colourless solid in 74% yield, 0.53 g.
1HNMR (400MHz, CDCI3) 8: 1.17 (3H, t), 2.72 (2H, q), 3.98 (2H, s), 6.86 (1H,
d), 7.23 (1 H, d).
Preparations 59 to 68
. The following compounds, of the general formula shown below were prepared
from the product of preparation 42 and the appropriate amine, using a method
similar to that described for preparation 27. The reactions were monitored by
TLC analysis and were stirred at room temperature for 18-72 hours.
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CH3
H3C> i H3
H3C
H3C /Si O O
H
N Q~
H3C CH3 1
HO
HN\ /H
O
No. Q1 Data Yield
59 Ci H NMR (400MHz, CD30D) b: -0.19 21
(3H, s), -0.04 (3H, s), 0.78 (9H, s),
H~
1.08 (3H, s), 1.10 (3H, s), 2.65-2.85
(4H, m), 2.89 (2H, t), 3.57 (2H, t), 4.67
(1 H, dd), 6.79 (1 H, d), 6.93 (1 H, dd),
7.21-7.37 (6H, m), 7.59-7.65 (2H, m),
8.08 (1H, d), 8.29 (s); LRMS ESI m/z
624 [M+H]+
60 CH3 1H NMR (400MHz, CDCI3) 5: -0.23 569/6
H3C OH
(3H, s), -0.09 (3H, s), 0.71 (9H, s),
H 1.06 (3H, s), 1.08 (3H, s), 2.18 (3H,
s), 2.26 (3H, s), 2.60-2.82 (4H, m),
2.90-2.94 (2H, m), 3.61-3.71 (2H, m),
4.61-4.65 (1H, m), 6.29-6.33 (1H, m),
6.62-6.64 (1 H, m), 6.85-6.89 (2H, m),
6.96 (1H, d), 7.18 (1H, s), 7.27-7.32
(2H, m), 7.40-7.42 (1H, m), 7.78 (1 H,
s), 8.23 (1 H, s), 9.62 (1 H, bs)
LRMS APCI m/z 634 [M-H]-
6.1 / LRMS APCI m/z 668 [M+H] 88 'o
.-HN
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62 HN ` i LRMS APCI m/z 668 [M+H] 48%
\ / OH
63 H3C I OH LRMS APCI m/z 634 [M+H] 77%
HN CH3
64 CH3 LRMS APCI m/z 620 [M+H]+ 96%
HN OH
65 / LRMS APCI m/z 642[M+H] 91%
H \ I -
/
HO
66 CH3 LRMS APCI m/z 620 [M+H] 95%
OH
HN
CH3
67 CI LRMS APCI m/z 660 [M+H] 89%
HO
C4
68 OH LRMS APCI m/z 642 [M+H] 91%
Preparation, 60: purified by column chromatography using a 12g Redisep
cartridge, eluting with dichloromethane:methanol:0.88 ammonia, 96:4:0.3
Preparation 62: was further azeotroped with diethyl ether (x3) to afford the
desired product
Preparation 68: 6-(aminomethyl)-2-naphthalenol may be prepared as
described in US20040204455, p19
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Preparation 69: 3-[2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[3-(formyi
amino)-4-hydroxyphenyl]ethyl}ami no)-2-methylpropyl]-N-[2-(4-
hydroxyphenyl)-2-methylpropyl]benzamide
CH3
H3C~1 CH,
H3C /Sip
H3C O O / OH
H
N N \
HO H3C CH, H
H3C CH3
HNC, .H
5 0
4-(2-Amino-1,l-dimethylethyl)phenol hydrochloride (Acta Chem. Scand. 8,
1203, 1207; 1954), (41 mg, 0.21 mmol) was added to a mixture of the product
of preparation 42 (100 mg, 0.21 mmol), O-(1 H-benzotriazol-1-yl)-N,N,N',N'-
tetramethyluronium hexafluorophosphate (78 mg, 0.21 mmol) and triethylamine
10 (35 pL, 0.4 mmol) in N,N-dimethylformamide (3 ml-) and the mixture was
stirred for 18 hours at room temperature. The solvent was then removed in
vacuo and the residue was taken up in ethyl acetate and washed with saturated
sodium hydrogen carbonate solution (3x 20 ml-) and brine (3x 20 mL). The
organic solution was then dried over sodium sulfate and concentrated in vacuo
15 to afford the title compound as a brown foam in 54% yield.
LRMS APCI m/z 634 [M+H]+
Preparations 70 to 76
20 The following compounds, of the general formula shown below were prepared
from the product of preparation 42 and the appropriate amine, using a method
similar to that described for preparation 69. The reactions were monitored by
TLC analysis and were stirred at room temperature for 18-72hours.
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CH3
H3C> CIH3
H3C /SIB
H3C 0
H
N Q1
HO CH3 O
HN\ /H
O
No. Q1 Data Yield
70 \ off LRMS APCI m/z 668 [M+H] 96%
71 CH3 LRMS APCI m/z 620 [M+H] 89%
OH
~IN I /
CH3
72 / I LRMS APCI m/z 642[M+H] 84%
HI
HO
73 H ci LRMS APCI m/z 626 [M+H]+ 96%
HO
74 c' LRMS APCI m/z 660 [M+H] 83%
HO ~
JAN I /
CI
75 OH LRMS APCI m/z 642 [M+H] 99%
76 HN/~-- OH LRMS APCI m/z 668 [M+H] 80%
\ /
Preparation 77: Diethyl 2,2'-(1,3-phenylene)diacetate
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O"-,'-CH3
H3C1-1/0
0 ( 0
Y'^~ Y
Acetyl chloride (12.5 mL, 175 mmol) was added to a suspension of 2,2'-(1,3-
phenylene)diacetic acid (50.0 g, 260 mmol) in ethanol (500 ml-) and the
resulting solution was heated under reflux for 16 hours. The reaction was then
cooled to room temperature and the solvent was removed in vacuo. The
residue was partitioned between saturated aqueous sodium hydrogen
carbonate solution (300 ml-) and ethyl acetate (500 mL). The organic phase
was separated and washed with water (200 ml-) and brine (300 mL), dried over
sodium sulfate and the concentrated in vacuo to afford the title compound as a
pale yellow oil in quantitative yield, 63.5 g.
1HNMR (CDCI3, 400MHz) S: 1.31 (6H, t), 3.65 (4H, s), 4.20 (4H, q), 7.24-7.36
(4H, m); LRMS ESI m/z 251 [M+H]+
Preparation 78: [3-(2-Oxo-propyl)-phenyl]-acetic acid ethyl ester
HO OCH3
0 0
A solution of the diester from preparation 77 (44.3 g, 177 mmol) and 2,2'-(1,3-
phenylene)diacetic acid (59.2 g, 308 mmol) in ethanol (24 ml-) and dioxan
(290mL) was treated dropwise with 12M hydrochloric acid (4.9 mL, 58.8 mmol).
The reaction mixture was stirred under reflux for 18 hours, cooled to room
temperature and concentrated in vacuo. The reaction mixture was then diluted
with toluene (125 ml-) and the resulting slurry was filtered. The filtrate was
concentrated in vacuo and the residue was taken up in water and basified with
sodium bicarbonate until pH neutral. The mixture was diluted with ethyl
acetate
(200 mL) and the organic layer was separated and washed with sodium
hydrogen carbonate solution (5x 30 mL) and brine (50 mL). The combined
aqueous extracts were acidified to pH 3 with 6M hydrochloric acid and
extracted
with diethyl ether (3x 30 mL). The combined organic solution was dried over
magnesium sulphate and concentrated in vacuo. Trituration of the residue with
pentane afforded the title compound as a colourless solid in 27% yield, 10.8
g.
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1HNMR (CD3OD, 400MHz) 6:1.25 (3H, t), 3.60 (2H, m), 3.63 (2H, m), 4.15 (2H,.
q), 7.18-7.32 (4H, m); LRMS ESI: m/z 245 [M+Na1+
Preparation 79: [3-(2-Hydroxy-2-methyl-propyl)-phenyl]-acetic acid
HO OH
0 I / HC CH3
Methyl magnesium chloride (51 mL of a 3M solution in tetrahydrofuran, 153
mmol) was added dropwise to a stirred solution of the product of preparation
78
(11.6 g, 51 mmol) (International Journal of Peptide and Protein Research,
1987, 29(3), 331) in tetrahydrofuran (300 ml-) at 0 C. The reaction was then
allowed to warm to room temperature overnight with the formation of a thick
white precipitate and then water (50 mL) and 2N hydrochloric acid (80mL) were
cautiously added. The aqueous layer was separated and extracted with ethyl
acetate (2x 300 mL). The combined organic solution was washed with brine (50
mL), dried over sodium sulfate and concentrated in vacuo to afford the title
compound as a golden oil in quantitative yield, 11.2 g.
1HNMR (CDCI3, 400 MHz) 8: 1.22 (6H, s), 2.75 (2H, s), 3.63 (2H, s), 7.12-7.30
(4H, m); LRMS ESI m/z 209 [M+H]+
Preparation 80: {3-[2-(2-Chloro-acetylamino)-2-methyl-propyl]-phenyl}-
acetic acid
H
HO ~ N
~CI
0 H3C CH3 O
2-Chioroacetonitrile (8.8-mL, 140-mmol) was added to a solution of the product
-
of preparation 79 (16.0 g, 70 mmol) in acetic acid (33 mL). The resulting
solution was cooled to 0 C, treated with concentrated sulphuric acid (33 mL),
and the reaction mixture allowed to warm gradually to room temperature. After
4 hours, the reaction mixture was poured onto ice and basified- with solid
sodium carbonate. The solution was extracted with ethyl acetate (2x 500 ml-)
and the combined organic extract solution was dried over magnesium sulphate
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and concentrated in vacuo to afford the title product as a. colourless solid
in.
96% yield 19.0 g.
'HNMR (CDCI3, 400MHz) 8: 1.36 (6H, s), 3.02 (2H, s), 3.62 (2H, s), 3.95 (2H,
s),
6.19 (1 H, m), 7.06-7.31 (4H, m); LRMS ESI m/z 282 [M-H]-
Preparation 81: [3-(2Amino-2-methyl-propyl)-phenyl]-acetic acid methyl
ester
HzN 011 CH3
H3C CH3
A solution of the product of preparation 80 (5.1 g, 18 mmol), thiourea (1.6 g,
21
mmol) and acetic acid (18 ml-) in ethanol (80 ml-) was heated under reflux 16
hours. The reaction mixture was then allowed to cool to room temperature and
was filtered. The filtrate was concentrated in vacuo and the residue was
dissolved in methanol (150 ml-) and saturated with hydrogen chloride gas. The
resulting solution was heated to reflux for 16 hours. The mixture was
concentrated in vacuo and the residue partitioned between ethyl acetate (200
ml-) and 5% aqueous sodium carbonate solution (200 mL). The organic phase
was washed with brine (100mL), dried over magnesium sulphate and
concentrated in vacuo. The residue was purified by strong cation exchange
resin, eluting with methanol followed by 2M solution of ammonia in methanol to
afford the title compound as a yellow oil in 67% yield, 2.68 g.
'HNMR (CDCI3,400MHz) 8: 1.14 (6H, s), 2.68 (2H, s), 3.62 (2H, s), 3.69 (3H,
s),
7.08-7.16 (3H, m), 7.23-7.27 (1 H, m); LRMS ESI m/z 222 [M+H]+
Preparation- 82: Methyl (3-(2-[(tert-butoxycarbonyl)amino]-2-methyl
propyl}phenyl) acetate
H
H3c
H3c>0YN Ol~ CH3
CH3 0 H3C CH3 ( 0
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The title compound was prepared form the product of preparation.81, using a.
method similar to that of preparation 49, to afford the title compound as a
colourless oil in 81 % yield.
1HNMR (CDCI3, 400MHz) 6:1.25 (6H, s), 1.45 (9N, s), 2.95 (2H, s), 3.60 (2H,
s),
5 3.70 (3H, s), 4.25 (1 H, bs), 7.02-7.06 (2H, m), 7.15 (1 H, d), 7.25 (1 H,
m); LRMS
ESI m/z 344 [M+Na]+
Preparation 83: (3-{2-[(tert-Butoxycarbonyl)amino]-2-methylpropyl}
phenyl)acetic acid
H
H,C; /YN OH
H3G O
10 CH3 0 H3C CH3 0
5M Sodium hydroxide solution (4.6 mL 23 mmol) was added to a solution of the
product of preparation 82 (7.45 g, 23 mmol) in di xan (30 mL) and water (8 ml-
)
and the mixture was stirred at room temperature for 18 hours. The reaction
mixture was then concentrated in vacuo and the residue was dissolved in water
15 and acidified to pH3 with 2M hydrochloric acid. The mixture was then
extracted
with ethyl acetate (3x 30 ml-) and the combined organic solution was washed
with brine (3x 30 mL), dried over sodium sulfate and concentrated in vacuo to
give an oil. This oil was then azeotroped with diethyl ether to afford the
title
compound as a colourless gum in 99% yield, 7.0 g.
20 1HNMR (CDCI3, 400MHz) 6: 1.25 (6H, s), 1.50 (9H, s), 2.95 (2H, s), 3.55
(2H, s),
3.65 (s, 1 H), 7.05 (2H, m), 7.10 (1 H, d), 7.20 (1 H, m), 7.25 (1 H, m)
Preparation 84: Benzyl (3-{2-[(tert-Butoxycarbonyl)amino]-2--
methylpropyl}phenyl)acetate
H3CO~N 0~0
O H3C CI H 101 H3C CH3 25
Caesium carbonate (6.03 g, 18.6 mmol) was added to a solution of the product
of preparation 83 (5.7 g, 18.6 mmol) in N,N-dimethylformamide (40 mL)`and the
mixture was stirred for 1 hour at room temperature. The reaction mixture was
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86
then concentrated in vacuo and the residue was dissolved in. N,N-.
dimethylformamide (80 mL), treated with benzylbromide (3.18 g, 1'8.6 mmol)
and stirred for 3 hours at room temperature. The mixture was then filtered and
concentrated in vacuo and the residue was dissolved in ethyl acetate (60 mL),
washed with brine (60 mL), dried over magnesium sulfate and concentrated in
vacuo to afford the title compound as a pale yellow oil in 76% yield, 5.6 g.
1HNMR (CDCI3, 400MHz) 5: 1.25 (6H, s), 1.49 (9H, s), 2.98 (2H, s), 3.65 (2H,
s),
4.30 (s, 1 H), 5.14 (2H, s), 7.06 -7.10 (2H, d), 7.15-7.20 (1 H, m), 7.22-7.39
(6H,
m); LRMS ESI m/z 396 [M-H]-
Preparation 85: Benzyl [3-(2-amino-2-methylpropyl)phenyl]acetate
HZN / O \
H3nCH3
I
O
Trifluoroacetic acid (30 ml-) was added to the product of preparation 84 (5.6
g,
14.1 mmol) and the mixture was stirred at room temperature for 18 hours. The
reaction mixture was then concentrated in vacuo and the residue was diluted
with dichloromethane (100 ml-) and basified with saturated sodium hydrogen
carbonate solution (300 mL). The organic layer was separated, washed with
brine, dried over magnesium sulfate and concentrated in vacuo to afford the
title compound as a yellow oil in 76 % yield.
1HNMR (CDCI3,400MHz) S: 1.10 (6H, s), 1.50 (9H, s), 2.64 (2H, s), 3.66 (2H,
s),
5.13 (2H, s), 7.07 -7.12 (2H, d), 7.14-7.18 (11-1, m), 7.22-7.38 (6H, m); LRMS
ESI m/z 298 [M+H]+
Preparation 86: Benzyl (3-{2-(((2R)-2-[4-(benzyloxy)-3-
(formylamino)phenyl]-2-{[tent-butyl(dimethyl)silyl]oxy}ethyl)amino]-2-
methylpropyl}phenyl) acetate
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CH3
H3C>CH3
H3C
-i3C O
N\
HC/ C4:)""Yo
0 HN H
Y
O
The title compound was prepared from the products of preparation 12 and
preparation 85, using a similar method to that of preparation 13, in 55%
yield.
1H NMR (400MHz, CDCI3) 8: -0.20 (3H, m), -0.06 (3H, s), 0.78 (9H, s), 0.92
(3H, s), 0.95 (3H, s), 2.53-2.77 (4H, m), 3.57 (2H, s), 4.61-4.68 (1H, m),
5.01-
5.02 (2H, m), 5.06 (2H, s), 6.84-6.87 (1 H, rn), 6.97-7.36 (14H, m), 7.62-7.70
(1H, m), 8.33-8.35 (1H, m), 8.34 (s), 8.67 (s), 8.70 (s); LRMS ESI m/z 681
[M+H]
Preparation 87: {3-[2-({(2R)-2-{[tent-Butyl(dimethyl)silyl]oxy}-2-[3-
(formylamino)-4-hydroxyphenyl]ethyl}amino)-2-methylpropyl]phenyl}acetic
acid
CH3
H3C> CH3
H3C
H3C 0
H
N OH
H3C CHJ
HO ? O
HN\ /H
O
The title compound was prepared from the product of preparation 86, using a
similar method to that of-preparation 26, in 93% yield.
'H NMR (400MHz, CDCI3) 8: -0.06 (3H, s), 0.05 (3H, s), 0.88 (9H, s), 1.00 (3H,
s), 1.04 "(3H, s), 2.58-2.88 (4H, m), 3.58 (2H, s), 4.64-4.67 (1 H, m), 6.88-
6.90
(1 H, m), 6.95-6.98 (1 H, m), 7.07-7.27 (5H, m), 8.04-8.05 (d), 8.25 (s), 9.55
(bs);
LRMS ESI m/z 501 [M+H]-
Preparation 88: 2-Chloro-N-ethyl-5-hydroxybenzamide
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88
H
0 Nl-/CH,
CI
OH
The title compound was prepared from 2-chloro-5-hydroxybenzoic acid and
ethylamine, using a method similar to that used for preparation 52, as a
colourless solid.
'HNMR (400MHz, CDCI3) 8: 1.22 (3H, t), 3.42-3.49 (2H, rn), 6.48-6.52 (1 H, m),
6.80 (1 H, dd), 7.13 (1 H, d), 7.38 (1 H, d); LRMS ESI m/z 200 [M+H]+
Preparation 89: 4-Chloro-3-[(ethylamino)methyl]phenol
H
N.. CH3
CI
OH
The title compound was prepared from the product of preparation 88 using the
method of preparation 57, as a colourless solid.
1HNMR (400MHz, CD30D) 8: 1.15 (3H, t), 2.68 (2H, q), 3.79 (2H, s), 6.67-6.70
(1 H, m), 6.84 (1 H, d), 7.16 (1 H, d).
Preparation 90: 4-{[tert-Butyl(dimethyl)silyl]oxy}-2-chlorobenzaldehyde
0\ _ CH CH3
0-S\~CH3
CH3 CH3
CI
A solution of 2-chloro-4-hydroxybenzaldehyde (5.0 g, 32 mmol), tert-
butyl(dimethyl)silyl chloride (5.3 g, 35 mmol), imidazole (2.9 g, 45 mmol) and
N,N-dimethylaminopyridine (10 mg) in N,N-dimethylformamide (40 mL) was
stirred at room temperature for 16 hours. The solvent was removed in vacuo
and the residue was partitioned between ethyl acetate (1O0mL) and water (100
mL). The organic phase was separated, washed with brine (50mL), dried over
sodium sulfate and concentrated in vacuo. Purification by column
chromatography on silica gel, eluting with pentane:ethyl acetate, 75:25 to
67:33, afforded the title compound as a colourless oil in 75% yield, 6.50 g.
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'HNMR (40OMHz, CDCI3) 8: 0.25 (6H, s), 0.97 (9H, s), 6.80. (_1 H, dd), 6.87 (1
H,.
d), 7.84 (1 H, d), 10.32 (1 H, s)
Preparation 91: N-(4-{[tert-Butyl(dimethyl)silyl]oxy}-2-chlorobenzyl) prop-
2-en-1-amine
H2C-~
N - CH3 CH3
-S'CH3
CH3 CH3
A solution of the aldehyde from preparation 90 (6.50 g, 24.0 mmol) and
allylamine (1.51 g, 26.4 mmol) in dichloromethane (60 mL) was treated with
sodium triacetoxyborohydride (7.6 g, 35.6 mmol) and the resulting suspension
stirred at room temperature for 16 hours. Saturated sodium bicarbonate
solution (50 mL) was added and the organic layer separated. The organic
solution was washed with brine (50 mL), dried (sodium sulfate) and
concentrated in vacuo to give a yellow oil. Purification of the oil by column
chromatography on silica gel, eluting with pentane:ethyl acetate 75:25 to
67:33,
afforded the title compound as a colourless oil in 38% yield, 2.80 g.
'HNMR (400MHz, CDCI3) 8: 0.19 (6H, s), 0.97 (9H, s), 1.84 (1H, bs), 3.26 (2H,
d), 3.81 (2H, s), 5.12 (11-1, dd), 5.20 (1H, dd), 5.88-5.98 (1H, m), 6.71 (11-
1, dd),
6.85-6.86 (1 H, d), 7.24 (1 H, d); LRMS ESI m/z 312 [M+H]+
Preparation 92: (4-{[tent-Butyl(dimethyl)silyl]oxy}-2-chlorobenzyl)amine
H2N CH3CH3
C-S; +CH3
CH3 CH3
C'
A solution of the product of preparation 91 (2.8 g, 9.0 mmol),
dimethylbarbituric
acid (7.0 g, 45 mmol) and tetrakis(triphenylphosphine)palladium(O) (0.10 g,
0.08mmol) in dichloromethane (80 ml-) was heated under reflux for 4 hours.
The cooled solution was then concentrated in vacuo and the residue was
partitioned between ethyl acetate (50 mL) and IN aqueous sodium hydroxide
solution (50 mL). The organic layer was separated, washed with brine (50mL),
dried over sodium sulfate and concentrated in vacuo. Purification of the
residue
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by column chromatography on silica gel, eluting . with.
dichloromethane:methanol:0.880 ammonia, 98:2:0 to 95:5:0.5, afforded the title
compound as a colourless oil 70% yield, 1.70 g.
1HNMR (400MHz, CDCI3) 8: 0.19 (6H, s), 0.97 (9H, s), 1.89 (2H, s), 3.85 (2H,
5 s), 6.70 (1 H, dd), 6.85-6.86 (1 H, dd), 7.21 (1 H, d)
Preparations 93 to 95
The following compounds, of the general formula shown below were prepared
10 from the product of preparation 87 and the appropriate amine, using a
method
similar to that described for preparation 27. The reactions were monitored by
tic
analysis and were stirred at room temperature for 18-72 hours.
CH3
H3C CH 3
H3C /sly
H3C O
H
\ N C:r O,
H3C CH3
HO ~ O
HN\ /H
0
No. Q1 Data Yield
93 O-cH 1H NMR (400MHz, CD3OD) 8: -0.18 41%
HN 0 (3H, s), -0.07 (3H, s), 0.75 (9H, s), 1.01
(3H, s), 1.04 (3H, s), 2.59-2.83 (4H, m),
3.56-3.58 (2H, m), 3.89 (3H, s), 4.41-
4.53 (2H, m), 4.63-4.66 (11-1, m), 6.80-
6.82 (11-1, m), 6.95-6.98 (11-1, m), 7.03-
7.05 (11-1, m), 7.09-7.11 (21-1, m), 7.21-
7.26 (4H, m),7.93-7.69 (2H, d); LRMS
ESI m/z 648 [M+H]+ -
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94 HO 1H NMR (400MHz, CO3OD) 8: -0.21 to - 43%
0.16 (3H, m), -0.04-0.01 (3H, m), 0.76-
H3C- / 0.83 (9H, m), 1.02-1.09 (9H, m), 2.61-
ci 2.77 (3H, m), 2.84-2.92 (1 H, m), 3.32-
3.38 (2H, m), 3.70= 181 (2H, 2xs), 4.55,
4.63 (2H, 2xs), 4.6C,,4.72 (1 H, m), 6.62-
6.69 (1H, m), 6.78-6.87 (2H, m), 6.90-
6.96 (1H, m), 6.99-7.26 (5H, m), 8.07-
8.10 (1H, s), 8.29 (), 8.60 (s); LRMS
APCI m/z 668 [M+H]i
95 / - 1H NMR (400MHz, CD3OD) 8: -0.25 54%
HN - \ / O (3H, s), -0.09 (3H, s), 0.73 (9H, m), 0.97
(3H, s), 0.99 (3H, s),.2.56-2.83 (4H, m),
3.47-3.48 (2H, m), 4.31 (2H, s), 4.59-
4.63 (1H, m), 6.73.-7.41 (15H, m), 8.08
(s), 8.21 (s), 8.57 (s); LRMS ESI m/z
682 [M+H]+
Preparation 96: 2-{3-[2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[3-
(formylam i no)-4-hydroxypeenyl]ethyl}ami nod-2-methylpropyl]phenyl}-N-(2-
chloro-4-hydroxybenzyl) acetamide
CH3
H3C 1 3
H 3C /SIB
H3C O OH
H H
~.. N N
H3C CH3I
HO O CI
HNYH
0
The title compound was prepared from the products of preparations_87 and 92
using a method similar to that of preparation 27, as brown foam in 62% yield.
1H NMR (400MHz, CD3OD) 8: -0.19 (3H, s), -0.03 (3H, s), 0.79 (9H, s), 1.01-
1.10 (6H, m), 2.62-2.76 (3H, m), 2.85 (1H, m), 3.37-3.92 (2H, m), 4.34 (2H,
s),
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4.66 (1 H, m), 6.62 (1 H, m), 6.78-6.82 (2H, m), 6.91 (1 H, m), 7.02-7.23 (5H,
m),.
8.09-8.11 (1 H, m), 8.27 (s), 8.59 (s); LRMS APCI m/z 640 [M+H] +
Preparation 97: 2-(3-Bromophenyl)-N-(3,4-dimethylbenzyl)acetamide
CH3
CH3
Br 0-", N
O
The title compound was prepared from 3,4-dimethylbenzylamine and 3-
bromophenylacetic acid, using a method similar to that of preparation 27, as a
white solid in 93% yield.
IH NMR (400MHz, CDCI3) 8: 2.20 (6H, s), 3.50 (2H, s), 4.30 (2H, d), 5.80 (1 H,
brs), 7.60-7.80 (7H, m); LRMS ESI 332 [M]+
Preparation 98: N-(3,4-Dimethylbenzyl)-2-{3-[(E)-2-(1,3-dioxo-1,3-dihydro-
2H-isoindol-2-yl)vinyl]phenyl}acetamide
CH3
0 CH3
N N
O CY""'YO
The product of preparation 97 (5.0 g, 15 mmol), N-vinylphthalimide (2.62 g,
15.1 mmol), tri-ortho-tolylphosphine (473 mg, 1.55 mmol), palladium(II)acetate
(98 mg, 0.4 mmol) and N,N-diisopropylethylamine (30 mL, 172 mmol) in
acetonitrile (35 ml-) was heated under reflux for 16 hours. The reaction
mixture
was then cooled to room temperature and the precipitate was filtered off. The
solid was then dissolved in dichloromethane, activated charcoal was added,
and the solution was filtered through Celite . The filtrate was concentrated
in
vacuo and the residue was re-crystallised from hot dichloromethane/methanol
to afford the title compound as a yellow solid in 55% yield, 3.5 g.
1 H NMR (400MHz, CDCI3) 8: 2.20 (6H, s), 3.80 (2H, s), 4.30 (2H, d), 6.0 (1 H,
brs), 6.90 (2H, m), 7.01 (1 H, m), 7.18 (1 H, m), 7.26-7.40 (4H, m), 7..56-
7.61
(1 H, m), 7.75 (2H, m), 7.88 (2H, m)
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Preparation 99: N-(3,4-Dimethylbenzyl)-2-{3-[2-(1,3-dioxo-1,3-dihydro-2H-
isoindol-2-yl)ethyl]phenyl}acetamide
CH3
O CH3
yN N
O l / O
The product of preparation 98 (3.3 g, 7.7 mmol) and I D% palladium-on-carbon
(1 g) were suspended in ethanol and the mixture was stirred under 50 psi of
hydrogen gas, at room temperature for 16 hours. The reaction mixture was then
filtered through Arbocel , washing through with ethanol, and the filtrate was
concentrated in vacuo to afford the title product as a yellow solid in 52%
yield,
1.7 g.
1H NMR (400MHz, CDCI3) 8: 2.20 (6H, s), 2.95 (2H, t), 3-60 (2H, s), 3.90 (2H,
t),
4.39 (2H, d), 5.95 (1 H, brs), 6.90-7.20 (8H, m), 7.60-7.70 (3H, m)
Preparation 100: 2-[3-(2 Aminoethyl)phenyl]-M-(3,4-dimethylbenzyl)-
acetamide
CH3
CH3
H 2 N N
Hydrazine monohydrate (6 mL, 123.6 mmol) was added to a suspension of the
product of preparation 99 (3.5 g, 8.2 mmol) in ethanol (125 ml-) and the
mixture
was heated under reflux for 4 hours. The reaction mixture was then cooled to
.20 room temperature and filtered. The filtrate was concentrated in vacuo and
the
residue was purified by column chromatography on silica gel, eluting with
dichloromethane:methanol:0.88 ammonia, 95:5:1 to afford the title compound
the title compound in 57% yield, 1.4 g.
1H NMR (400MHz, CD3OD) 8: 2.18 (6H, s), 2.73 (2H, m), 2.86 (2H, m), 3.50
(2H, s), 4.25 (2H, s), 6.87-7.25 (7H, m); LRMS ESI 297 [[M+H]+
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Preparation 101: 2-(3-{2-[((2R)-2-[4-(Benzyloxy)-3-(formylamino)phenyl]-2-
{[tent-butyl(dimethyl)silyl]oxy}ethyl)amino]ethyl}phenyl)-N-(3,4-
dimethylbenzyl)acetamide
H3C CH f 3 i H3 CH3
H3C CH3
H3C 0
\ N I \ N \
O
HN\ /H
0
The title compound was prepared from products of preparation 12 and
preparation 100, using a method similar to that of preparation 33, as a yellow
oil
in 37% yield.
hH NMR (400MHz, CD3OD) 8: -0.18 (3H, s), -0.03 (3H, s), 0.80 (9H, s), 2.20
(6H, m), 2.80 (4H, m), 3.40 (2H, m), 3.50 (2H, s), 4.25 (2H, s), 4.76 (1 H,
nun),
5.18 (2H, s), 6.85-7.45 (15H, m), 8.23 (s), 8.30 (s); LRMS ESI 680 [M+H]+
Preparation 102: 2-{3-[2-({(2R)-2-{[tent-butyl(dimethyl)silyl]oxy}-2-[3-
(formylamino)-4-hydroxyphenyl]ethyl}amino)ethyl]phenyl}-N-(3,4-
dimethyl benzyl)acetamide
CH
H3C>CH3 CH3
H3C H3C"SimO CH3
N I N v
I O
/ /
HO
HN\ /H
O.
The title compound was prepared from the product of preparation 101, using a
method similar to that of preparation 20, as a white foam in 83% yield.
1H NMR (400MHz, CD3OD) 8: -0.18 (3H, s), -0.05 (3H, s), 0.81 (9H, s), 2.18
(6H, m), 2.80 (4H, m), 3.29 (2H, m), 3.51 (2H, s), 4.25 (2H, s), 4.70 (11-1,
nn),
6.80 (1H, d), 6.91-7.20 (9H, m), 8.03 (s), 8.25 (s); LRMS ESI 590 [M+H]+
Preparations 103 to 110
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The following compounds, of the general formula shown below were prepared
from the product of preparation 87 and the appropriate amine, using a method
similar to that described for preparation 27. The reactions were monitored by
tic
5 analysis and were stirred at room temperature for 18-72 hours.
CH3
H3C> i H3
H3C /Sip
H3C 0
J"H
\ N \ Q1
HC CH3
HO / O
HN\ /H
O
No. Q1 Data Yield
103 I S~ H NMR (400MHz, CD3OD) b: -0.25 66%
~HN / (3H, s), -0.08 (3H, s), 0.73 (9H, s),
0.97 (3H, s), 0.99 (3H, s), 2.37 (3H,
s), 2.56-2.83 (4H, m), 3.39-3.45 (2H,
m), 4.24 (2H, s), 4.60-4.63 (1H, m),
6.73-6.79 (1 H, m), 6.85 (1 H, dd), 6.97
(11-1, d), 7.03 (1H, s), 6.97-7.16 (6H,
m), 8.04 (d), 8.21 (s), 8.53 (s); LRMS
ESI m/z 658 [M+H]"
104 F 1H NMR (400MHz, CDCI3) 8: -0.24 55%
.~N F F (3H, s), -0.08 (3H, s), 0.74 (9H, s), -
0.98 (3H, s), 1.00 (3H, s), 2.57-2.83
(4H, m), 3.48 (2H, m), 4.37 (2H, s),
4.60-4.63 (11-1, m), 6.73 (11-1, d), 6.85
(11-1, dd), 6.99-7.17 (5H, m), 7.32 (2H,
d), 7.49 (2H, d), 8.04 (d), 8.22 (s),
8.52 (s); LRMS APCI m/z 658 [M+H]+
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105 CN 1H NMR (400MHz, CDC13) S:. -0.17 19%
N I /
(3H, s), -0.06 (3H, s), 0.76 (9H, s),
1.01 (3H, s), 1.03 (3H, s), 2.59-2.83
(4H, m), 3.56-3.68 (2H, dd), 4.45-4.49
(2H, m), 4.64-4.67 (1H, m), 6.84-6.86
(1 H, m), 6.95 (8H, m), 7.55-7.57 (2H,
m), 8.17 (d), 8.63 (s); LRMS ESI m/z
615 [M+H]+
106 O F H NMR (400MHz, CDCI3) 8: -0.16 52%
-
F (3H, s), -0.06 (3H, s), 0.77 (9H, s),
1.00 (3H, s), 1.04 (3H, s), 2.57-2.85
(4H, m), 2.53-3.67 (2H, dd), 4.40 (2H,
m), 4.64-4.67 (1 H, m), 6.80 (1 H,m),
6.96 (1H, m), 7.02 (7H, m), 7.32-7.34
(2H, m), 8.17 (d), 8.74 (s); LRMS
APCI m/z 674 [M+H]+
107 H NMR (400MHz, CD3OD) 8: -0.26 72% tlN (3H, s), -0.10 (3H, s), 0.72 (9H,
s),
OH 0.93 (3H, s), 0.95 (3H, s), 2.49-2.79
(4H, m), 3.46-3.47 (2H, m), 4.33 (2H,
s), 4.58-4.61 (1H, m), 6.72-7.48 (15H,
m), 8.04 (1 H, d), 8.21 (s), 8.52 (s)
LRMS APCI m/z 682 [M+H]+
108 HO H NMR (400MHz, CD3OD) 8: -.024 43%
ci (3H, s), -0.08 (3h, s), 0.74 (9H, s),
0.99 (3H, s), 1.02 (3H, s), 2.59-2.87
(4H, m), 3.47 (2H, m), 4.23 (2H, s),
4.62-4.65 (1 H, m), 6.65 (1H, d), 6.74
(1H, d), 6.90-6.95 (1H, m), 7.01-7.07
(3H, m), 7.10 (1H, s), 7.14-7.24 (2H,
m), 8.05 (1 H, d), 8.22 (s), 8.53 (s);
LRMS APCI m/z 640 [M+H]+
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109 H NMR (400MHz, CD3OD) & -0.24 83%
S (3H, s), -0.08 (3H, s), 0.73 (9H, s),
1.00 (3H, s), 1.02 (31-1, s), 1.45-1.56
(2H, m), 2.01-2.04 (2H, m), 2.53-2.84
(8H, m), 3.38 (2H, s), 3.58 (1 H, s),
4.60-4.63 (1 H, m), 6.73 (1 H, d), 6.85
(1 H, dd), 6.97 (1 H, d), 7.05-7.14 (3H,
m), 8.04 (1 H, d), 8.24 (s), 8.53 (s);
LRMS APCI m/z 598 [M+H]+
110 \ .Z'Sti H NMR (400MHz, CD3OD) 6: -0.18
(311, s), -0.02 (31-x, s), 0.80 (9H, s),
1.05 (3H, s), 1.07 (3H, s), 2.61-2.91
(4H, m), 3.08 (3E, s), 3.55 (2H, d),
4.45 (2H, s), 4.66,(2H, dd), 6.79 (1H,
d), 6.91 (1H, dd), '7.05 (1H, d), 7.13
(1 H, s), 7.15-7.25 (3H, m), 7.45 (2H,
d), 7.85 (2H, d), 8.10 (1 H, d), 8.28 (s),
8.60 (s); LRMS APCI m/z 668 [M+H]+
Preparations 111 to 119
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (40 mg, 205
gmol) was added to a solution of preparation 42 (100 mg, 206 -gmol),
hydroxybenzotriazole hydrate (32 mg, 205 mol) and triethylamine (0.55 L,
412 mol) in dichloromethane (2 mL) followed by the amine (205 mol) and the
mixture was stirred at room temperature for 18 hours. The solvent was then
removed in vacuo and the residue was diluted with ethyl acetate, washed with
sodium hydrogencarbonate solution (20 ml-) and brine (20 mL), dried (Na2SO4)
and concentrated in vacuo to leave a film which was suspended in diethylether
(x3) to afford a foam.
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CH3
H3C i H3
H3C Si
H3C O O
H
N
C CH-1
HO
f
HN\ /H
I00
No. Q1 Data Yield
111 LRMS ESI m/z 590 [M+H] 81%
112 LRMS APCI m/z 582 [M+H]+ 74%
..,~N
113 LRMS APCI m/z 554 [M+H] 94%
N
114 LRMS APCI m/z 658 [M+H] 87%
HN I / F
F F
115 I LRMS APCI mlz 604 [M+H] 83%
HN
116 LRMS APCI m/z 602 [M+H] 89%
"w--HN
117 LRMS APCI m/z 591 [M+H] 74%
RHN N
118 0 'CH3 LRMS APCI m/z 620 [M+H] 90%
N
119 SONH2 LRMS APCI m/z 669 [M+H] 80%
120* nl~ LRMS APCI m/z 602 [M+H] 92%
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69387-701
99
121 * HNL~ LRMS APCI mlz 620 [M+H] 38%
* no evaporation from diethylether
Preparation 122 : N-{5-[(2R)-2-{2-[3-(10-Aza-tricyclo[6.3.1.0 2'7]dodeca-
2(7),3,5-triene-10-carbonyl)phenyl]-1,1-dimethylethylamino}-1-(tert-
butyldimethylsilanyloxy)ethyl]-2-hydroxyphenyl}formamide
H
H3C 3TH3
H3C 'Si,
H3C O O
N
\ H3C CH ( ~ N
HO
HNyH
O
The title compound was prepared with 10-aza-tricyclo[6.3.1.02,7 jdodeca-
-2(7),3,5-triene, using a method similar to that of preparation 69.
LRMS APCI m/z 628 [M+H]+
Preparation 123 : 3-{2-[(2R)-2-(tert-B utyldimethylsilanyloxy)-2-(3-
formylamino-4-hydroxyphenyl)ethylamino]-2-methylpropyl}-N-[2-(5-chloro-
2-hyd roxyph a nyl)ethyl] be nzam ide
H
H3C 3CH3
H3C _St.
H3C q HO N CI
HC CHI / H
HO
HNyH
O
The title compound was prepared with 2-(2-aminoethyl)-4-chlorophenol, using a
method similar to that of preparation 69.
LRMS APCI mlz 640 [M+H]+
Preparations 124 to 128
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100
The amine (412 mol) was added to a mixture of preparation 42 (200 mg, 412.
mol), hydroxybenzotriazole hydrate (63 mg, 412 mol), 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (79 mg, 412 mol) and
triethylamine (0.11 mL, 824 mol) in dichloromethane (2 ml-) and the mixture
was stirred at room temperature for 18 hours. The solvent was then removed in
vacuo and the residue was diluted with ethyl acetate, washed with sodium
hydrogencarbonate solution (3x 20 ml-) and brine (3x 20 mL), dried (MgSO4).
The crude material was purified by chromatography on silica gel, eluting with
dichloromethane:0.88 ammonia, 99.7:0.3. The appropriate fractions were
evaporated under reduced pressure and the residue and concentrated in
vacuo, the resulting white foam was suspended in diethylether (x3) and
evaporated.
OH 0
H
N ~ Qa
H3C CH3I /
HO
HNyH
O
No. Q1 Data Yield
124 H NMR (400MHz, CDCI3) S: -0.23 63%
HN CH3 (3H, s), -0.09 (3H, s), 0.69 (9H, s),
CH3 1.07 (3H, s), 1.08 (31-1, s), 2.27 (31-1,
s), 2.29 (3H, s), 2.60-2.82 (4H, m),
2.98 (2H, t), 3.64-3.73 (2H, m), 4.61-
4.65 (11-1, m), 6.39 (11-1, m), 6.84-7.42
(1 OH, m), 7.80 (1 H, s), 8.24 (1 H, s),
9.70-9.80 (m); LRMS APCI m/z 619
[M+H]+
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125 'H NMR (400MHz, CDCI3) 6:. -0.23 70%
RHN (3H, s), -0.09 (3H, s), 0.70 (9H, s),
ci 1.02 (3H, s), 1.04 (3H, s), 2.60-2.79
(4H, m), 3.09-3.12 (2H, t), 3.74-3.79
(2H, m), 4.58-4.60 (1H, m), 6.35-6.39
(1 H, m), 6.88 (1 H, d), 6.94 (1 H, d),
7.10 (1 H, s), 7.20-7.34 (4H, m), 7.38-
7.42 (2H, m), 7.76 (1 H, s), 8.24 (1 H,
s), 9.76 (1 H, s); LRMS APCI m/z 624
[M+H]+
126 H3C H NMR (400MHz, CDCI3) 8: -0.22 96%
RHN (3H, s), -0.09 (3H, s), 0.71 (9H, s),
CH 3 1.20 (3H, s), 1.22 (3H, s), 2.34 (6H,
s), 2.61-2.78 (4H, m), 3.00 (2H, t),
3.56-3.60 (2H, m), 4.59-4.62 (1H, m),
6.39-6.43 (1H, m), 6.86 (1H, d), 6.96-
7.07 (3H, m), 7.16 (1H, s), 7.28-7.33
(2H, m), 7.42 (1 H, d), 7.77 (1 H, s),
8.24 (1 H, s), 9.65 (1 H, s); LRMS APCI
m/z 618 [M+H]+
127 CH3 H NMR (400MHz, CDCI3) 8: -0.23 73%
RHN
14, (3H, s), -0.09 (3H, s), 0.70 (9H, s),
1.04 (3H, s), 1.05 (3H, s), 2.33 (3H,
s), 2.61-2.76 (4H, m), 2.88-2.92 (2H,
t), 3.67-3.74 (2H, m), 4.57-4.60 (1H,
m), 6.25-6.29 (1H, m), 6.88 (1H, d),
6.98 (1H, d), 7.09-7.33 (7H, m), 7.75
(1 H, s), 8.23 (1 H, s), 9.82 (1 H, s);
LRMS APCI m/z 604 [M+H]+
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128 H NMR (400MHz, CDCI3) S:. -0.23 19%
RHN (3H, s), -0.10 (3H, s), 0.68 (9H, s),
1.03 (3H, s), 1.04 (3H, s), 2.59-2.76
(4H, m), 3.42-3.48 (2H, m), 3.80-3.94
(2H, m), 4.58-4.61 (11-1, m), 6.30-6.34
(1 H, m), 6.89 (1 H, d), 6.98 (1 H, d),
7.10 (1 H, s), 7.23-7.60 (6H, m), 7.75
(1 H, s), 7.77 (1 H, d), 8.15 (1 H, d),
8.18 (1 H, d), 9.77 (1 H, s); LRMS APCI
m/z 640 [M+H]}
Preparation 129 3-(2-Oxo-propyl)benzoic acid methyl ester
0
H3C 0 CH3
/
o v
Tributyltin methoxide (80.3 mL, 279 mmol), methyl 3-bromobenzoate (53.5 g,
249 mmol), isopropenyl acetate (39.4 ml, 358 mmol), palladium(II)acetate (2.6
g, 11.6 mmol) and tri-ortho-tolylphosphine (7.1 g, 23.2 mmol) were stirred
together in toluene (350 mL) at 100 C under nitrogen for 18 hours. After
cooling, the reaction was treated with potassium fluoride solution (4M, 560
ml)
and stirred for 2 hours. The resulting mixture was diluted with further
toluene
(200 ml-) and filtered through Celite , washing the filter pad with ethyl
acetate.
The organic phase was separated, dried (sodium sulfate) and reduced in
vacuo. The residue was purified by chromatography eluting with
ethylacetate:pentane 10:90 to 20:80 to give the title compound (45.3 g) as an
orange oil.
'H NMR-(400MHz, CDCI3) S: 2.18 (3H, s), 3.75 (2H, s), 3.91 (3H, s), 7.43-7.37
(2H, m), 7.87 (1 H, s), 7.95-7.93 (1 H, d); LRMS ESI m/z 215 [M+Na]+, 191 [M-
H]-.
Preparation 130 : 3-[(2R)-2-((1 R)-1-Phenylethylamino)propyl]benzoic acid
methyl ester hydrochloride
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O
O""N CH3
CH3 CH3
The title compound was prepared with preparatidn 129, using a method similar
to that of preparation 19, to give the title compound (27.3 g) as a colourless
crystalline solid.
1H NMR (400MHz, CD3OD) 8: 1.17-1.16, (3H, d, 1.71-1.69 (3H, d), 2.71-2.65
(1 H, dd), 3.25-3.19 (1 H, m), 3.43-3.38 (1 H, dd), ;x.90 (3H, s), 4.68-4.63
(1 H, q),
7.35-7.33 (1 H, d), 7.45-7.42 (1 H, dd), 7.55-7.49 (~H, m), 7.75 (1 H, s),
7.92-7.90
(1 H, d).
Preparation 131 : Methyl {3-[(2R)-2-aminopropyl]phenyl}acetate
0
0 CH3
H2N
Y
CH3 /
The title compound was prepared with preparation 130, using a method similar
to that of preparation 20, to give the title compound (8.48g) as a pale yellow
oil.
1H NMR (400MHz, CDCI3) 8: 1.14-1.12 (3H, d), 2.64-2.59 (1H, dd), 2.78-2.73
(1 H, dd), 3.26-3.17 (1 H, m), 3.90 (3H, s), 7.38-7.34 (2H, m), 7.90-7.87 (2H,
m);
LRMS ESI m/z 194 [M+H]}.
Preparation 132: 3-((2R)-2-tert-Butoxycarbonylaminopropyl)benzoic acid
methyl ester
H 0
H3C = H3C~ Y
0 II N CH3
CH3
CH3 0
A mixture of preparation 131 (5.00 g, 26.0 mmol), di-tent-butyldicarboxylate
(6.22 g, 28.5 mmol) and sodium hydrogencarbonate (4.35 g, 52 mmol) were
stirred in a mixture of 1,4-dioxane (100 ml-) and water (10 ml-) for 20 h. The
solvent was removed and the material partitioned between ethyl acetate (200
ml-) and hydrochloric acid (2M, 100 mL), the organics were washed with brine
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(100 mL) and dried (MgSO4). Removal of the solvent left a -white solid (7.12
g,.
93 %).
'H NMR (400MHz, CD3OD) 8: 1.09 (3H, d), 1.35 (9H, s), 2.73-2.79 (2H, m),
3.76-3.83 (1 H, m), 3.89 (3H, s), 6.54 (1 H, d), 7.26-7.46 (2H, m), 7.84-7.87
(2H,
m); LCMS Rt 4.53 min m/z 294 [M+H]+
Preparation 133 : 3-((2R)-2-tent-Butoxycarbonylaminopropyl)benzoic acid
0
H
H3C
OH
H3C>(OyN
CH3 O CH3
A mixture of preparation 132 (7.10 g, 24.3 mmol) and lithium hydroxide (1.00
M,
50.0 mL, 50.0 mmol) in tetrahydrofuran (100 mL) were stirred for 20 h. The
reaction mixture was diluted with ethyl acetate (250 mL) and acidified to pH 2
with hydrochloric acid (2M). The aqueous phase was re-extracted with ethyl
acetate (150 mL) and the combined organics washed with brine (300 mL) and
dried (MgSO4). Filtration and removal of the solvent gave 5.53 g (82 %) of the
title compound.
'H NMR (400MHz, CD3OD) 8: 1.10 (3H, d), 1.36 (9H, s), 2.82-2.81 (2H, m),
3.77-3.84 (1 H, m), 7.35-7.45 (2H, m), 7.84-7.89 (2H, m); LRMS APCI m/z 278
[M-H]-
Preparation 134 3-((2R)-2-tert-Butoxycarbonylaminopropyl)benzoic acid
benzyl ester
0
H
H C oyN 0
H3C II
CH3 O CH3
Caesium carbonate (6.50 g, 19.8 mmol) in water (10 mL) was added to a
solution of preparation 133 (5.50 g, 19.8 mmol) in N,N-dimethylformamide (50
mL) and the resulting mixture stirred at room temperature for 1 h.
Benzylbromide (3.42 g, 19.8 mmol) was then added and the mixture stirred for
20 h. Ethyl acetate (50 mL) was added and the suspension filtered, the
filtrate
was washed with saturated brine (100 mL) and dried (MgSO4). Filtration and
removal of the solvent left 7.20 g of the title compound.
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~H NMR (400MHz, CD3OD) 8:1.09 (3H, d), 1.32 (9H, s), 2.74_(2H, d), 2.75-2.83.
(1H, m), 5.34 (2H, s), 7.29-7.40 (4H, m), 7.43-7.47 (3H, m), 7.85-7.90 (2H,
m);
LRMS APCI m/z 270 [M-BOC]+
Preparation 135: 3-((2R)-2-Aminopropyl)benzoic acid benzyl ester
0
HZN \ O \
CH3
Preparation 134 (7.20 g, 19.0 mmol) was treated with trifluoroacetic acid (35
ml-) and the mixture left to stir for 20 h. The trifluoroacetic acid was
removed in
vacuo and dichloromethane (175 ml-) added. The mixture was basified with
sat. sodium hydrogen carbonate (150 ml-) and washed with sodium hydroxide
(1M, 50 mL). The combined organics were washed with brine (150 ml-) and
dried (MgSO4) to leave a brown oil (3.70 g, 72 %).
1H NMR (400MHz, CD3OD) 6: 1.04 (3H, d), 2.66 (2H, d), 3.05 (11-1, dt), 5.33
(2H, s), 7.28-7.44 (71-I, m), 7.86-7.90 (2H, m); LRMS APCI m/z 270 [M+H]+
Preparation 136 : 3-{(2R)-2-[(2R)-2-(4-Benzyloxy-3-formylaminophenyl)-2-
(tert-butyldimethylsilanyloxy)ethylamino]propyl}benzoic acid benzyl ester
CHI
H3C`H3
HH3CCISi 00iri}ix:oioc
HNI
I I
O
Preparation 135 (3.70 g, 13.8 mmol) and preparation 12 (3.20 g, 6.9 mmol)
were heated to 90 C for 26 h. The mixture was allowed to cool and diluted
with dichloromethane (100 mL). The organics were washed with sat. sodium
hydrogencarbonate (200 ml-) and concentrated in vacuo. The crude material
was purified by chromatography (x2), eluting with ethyl acetate:heptane 0:100
to 40:60 to yield 2.0 g (52 %) of the title compound.
LRMS APCI m/z 270 [M+H]+
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Preparation 137 3-{(2R)-2-[(2R)-2-(tert-B.utyldimethylsilanyloxy)-2-(3-.
formylamino-4-hydroxyphenyl)ethylamino]propyl}benzoic acid
H3C~k H3
H3 H C'Si.O H O
3
\ N \ OH
HO I / CH3 I /
HN\
0
Preparation 136 (2.0 g, 3.1 mmol) and palladium-on-carbon (10 %, 205 mg) in
methanol (100 ml-) were hydrogenated at 60 psi/RT for 20 h. A solution of
ammonia in methanol (2M, 50 ml-) was added and the mixture allowed to stir
for 2 min. The mixture was then filtered through a filter-aid, which was
washed
with the ammonia in methanol solution (2M, 250 mL), and the resulting organics
concentrated to yield a dark green solid. The crude material was purified by
chromatography, eluting with dichloromethane:methanol: 0.88 ammonia 100:0:0
to 75:20:5 to yield the title compound as a dark green solid (131 mg).
'H NMR (400MHz, DMSO-d6) 6: -0.18 (3H, s), -0.06 (3H, s), 0.77 (9H, s), 0.89
(3H, d), 2.61-2.68 (2H, m), 2.65-2.73 (2H, m), 2.80-2.86 (1 H, m), 4.56-4.60
(1 H,
m), 6.75 (1 H, d), 6.81 (1 H, dd), 7.83 (2H, d), 7.70-7.75 (2H, m), 8.00 (d),
8.25
(s), 9.53 (s); LRMS APCI m/z 473 [M+H]+
Preparation 138 : 3-{(2R)-2-[(2R)-2-(tert-Butyldimethylsilanyloxy)-2-(3-
formylam i no-4-hydroxyphenyl)ethylam ino]propyl}-N-[2-(4-hyd roxyphenyl)-
2-methylpropyl]benzamide
H3C H3
H3C H3C'Si,O N O / OH
Cf __X
N \
/ H H3C CH3
HO
HN\
10
The title compound was prepared with 4-(2-amino-1,1-dimethylethyl)phenol
hydrochloride (Acta Chem. Scand. 8, 1203, 1207; 1954), using a method similar
to that of preparation 27.
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1H NMR (400MHz, CD30D) 6: -0.24 (3H, s), -0.08 (3H, s); 0.76 (9H, s), 0.99.
(3H, d), 1.28 (6H, s), 2.54-2.92 (5H, m), 3.46 (2H, s), 4.60-4.63 (114, m),
6.66-
6.70 (3H, m), 6.77-6.80 (1 H, dd), 7.20-7.34 (4H, m), 7.45 (1 H, s), 7.50 (1
H, d),
7.92-7.93 (1 H, d), 8.21 (s), 8.55 (s); LRMS APCI m/z 620 [M+H]+
Preparation 139: Methyl (2E)-3-[3-(2-oxopropyl)phenyl]acrylate
0
H3C \ \ OCH3
O I /
A solution of 3-bromophenylacetone (50.0 g, 235 mmol), methyl acrylate (40.4
g, 469 mmol), palladium(II)acetate (7.9 g, 35.2 mmol), tri-ortho-
tolylphosphine
(21.4 g, 70.4 mmol) and triethylamine (82 ml-) in acetonitrile (900 ml-) was
heated at reflux under a nitrogen atmosphere for 16 hours. The reaction
mixture was cooled to room temperature and the solvent removed in vacuo.
Purification by flash column chromatography eluting with pentane:ethyl acetate
90:10 to 70:30 gave the title compound as an orange oil (54.3 g).
1H NMR (400MHz, CD3OD) b: 2.15 (3H, s), 3.70 (2H, s), 3.77 (3H, s), 6.43-6.39
(1 H, d), 7.20-7.18 (1 H, d), 7.34-7.31 (2H, t), 7.41-7.39 (1 H, d), 7.66-7.62
(1 H,
d); LRMS ESI : m/z 241 [M+Na]+, 217 [M-H]".
Preparation 140 : Methyl 3-[3-(2-oxopropyl)phenyl]propanoate
0
H3C 0 CH3
0
Prepared according to the procedure used for preparation 26 using preparation
139 to give the title compound as an orange oil.
1H NMR (400MHz, CD3OD) S: 2.14 (3H, s), 2.64-2.60 (2H, t), 2.96-2.92 (2H, t),
3:66 (5H, s), 7.05-7.04 (2H, d), 7.11-7.09 (1 H, d), 7.27-7.23 (1 H, q); LRMS
ESI
m/z 243 [M+Na]+, 219 [M-H]".
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Preparation 141: Methyl _ [3-((2R)-2-{[(1 R)-1 -phenyl-.
ethyl]amino}propyl)phenyl]propanoate hydrochloride
0
_ N I ~ .CH3
CH3 CH3
Prepared according to the procedure used for preparation 19, using preparation
140 to give the title compound as a white crystalline solid.
1H NMR (400MHz, CD3OD) 8: 1.18-1.16 (3H, d), 1.71-1.69 (3H, d), 2.62-2.56
(3H, m), 2.89-2.85 (2H, t), 3.20-3.12 (1 H, m), 3.34-3.29 (1 H, m), 3.61 (3H,
s),
4.64-4.59 (1 H, q), 6.92-6.91 (2H, d), 7.12-7.10 (1 H, d), 7.23-7.19 (1 H, t),
7.54-
7.47 (5H, m); LRMS ESI m/z 326 [M+H]+.
Preparation 142 : 3-{3-[(2R)-2-((1 R)-1-Phenylethylamino)propyl]phenyl}-
propionic acid
OH
CH3 CH3
Preparation 141 (3.25 g, 8.98 mmol) and sodium hydroxide (5M, 9.0 mL, 45.0
mmol) were stirred in 1,4-dioxane (40 mL) and water (40 mL) for 18 h. The
solvent was removed in vacuo and the material dissolved in water, acidified to
pH 6 with hydrochloric acid (2M) which solidified over 18 h. The solid was
filtered off and dried in vacuo (1.0 g, 36 %). The filtrate was concentrated
and
tetrahydrofuran added and the mixture filtered. The filtrate was evaporated to
leave a foam which was suspended in diethylether (x3) to yield a colourless
foam (1.96 g, 70 %). = .
1H NMR (400MHz, CD3OD) 8: 1.13 (3H, d), 1.62 (3H, d), 2.42 (2H, t), 2.55-2.64
(1H, m),"2.84 (2H, t), 3.08-3.42 (2H, m), 4.46-4.52 (1H, m), 6.86 (1H, d),
6.98
(1 H, s), 7.11-7.22 (2H, m), 7.45-7.52 (5H, m); LCMS APCI m/z 312 [M+H]+
Preparation 143: 1-(3,4-Dihydro-1H-isoquinolin-2 yl)-3-{3-[(2R)-2-((1R)-1-
phenylethylamino)propyl]phenyl}propan-1-one
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0
N \ IN I~\
CH3 CH3 / \.X
Preparation 142 (1.95 g, 6.27 mmol), triethylamine (2.62 mL, 19.0 mmol) in
dichloromethane (80 mLO were treated with 2-chloro-1,3-dimethylimidazoline
hexafluorophosphate (1.75 g, 6.27 mmol) and the resulting solution left to
stir
for 3 h. The solvent was removed and the residue taken up in ethyl acetate
and washed with sat. sodium hydrogencarbonatd (3x 20 mL), brine (3x 20 mL)
and dried (Na2SO4). After filtration and removal of the solvent the material
was
purified by chromatography, eluting with drehloromethane:methanol:0.88
ammonia 99.7:0:0.3 to 96.7:3:0.3. The prrduct was evaporated from
diethylether (x3) to yield a semi-solid (2.3 g, 86 %).
~H NMR (400MHz, CDCI3) 8: 0.88 (3H, d), 1.30 (3H, d), 2.42-2.50 (1H, m), 2.64-
2.98 (8H, m), 3.55-3.62 (1 H, m), 3.78-3.96 (2H, '-m), 4.51 (1 H, s), 4.72 (1
H, s),
6.88-7.38 (13H, m); LCMS APCI m/z 427 [M+H].
Preparation 144: 3-[3-((2R)-2 Aminopropyl)phenyl]-1-(3,4-dihydro-1 H -
isoquinolin-2 yl)propan-1-one
0
HZN ~ N ~
CH3 ` / ' /
Preparation 143 (2.20 g, 5.16 mmol), ammonium formate (1.63 g, 26.0 mmol)
and palladium hydroxide (500 mg) in ethanol (40 mL) were heated and stirred
at 70 C for 4 h. The mixture was filtered through a filter-aid and the
solvent
removed. The material was purified by chromatography, eluting with
dichloromethane:methanol:0.88 ammonia 99.7:0:0.3 to 94.7:5:0.3 to yield a
colourless oil which was evaporated from diethylether (x3) (1.26 g, 76 %).
1H NMR (400MHz, CDCI3) 8: rotamers 1.10/1.11 (3H, 2x d), 2.43-2.48 (1 H, m),
2.62-2.76 (3H, m), 2.78-2.86 (2H, m), 2.96-3.02 (2H, m), 3.08-3.18 (1H, m),
3.58 (1 H, t), 3.81 (1 H, t), 4.53/4.73 (2H, 2x s), 6.98-7.24 (8H, m); LCMS
APCI
m/z 323 [M+H]+
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Preparation 145 : N-{2-Benzyloxy-5-[(1 R)-1-(tent-butyidimethylsilanyloxy)-.
2-((1 R)-2-{3-[3-(3,4-dihydro-1 H-isoquinolin-2-yl)-3-oxo-propyl]phenyl}-1-
methylethylamino)ethyl]phenyl}formamide
H3C~bH3
H3 H C'SI'O H 0
3
O CH3
N \ N`~
HNC
I I
O
The title compound was prepared with preparation 144 and preparation 12,
using a method similar to that of preparation 136 (216 mg, 67 %).
1H NMR (400MHz, CD3OD) b: rotamers -0.19 (3H, s), -0.01 (3H, s), 0.82 (9H,
s), 0.98-1.04 (3H, s), 2.48-2.96 (11H, m), 3.57-3.62/3.72-3.76 (2H, rn), 4.53-
4.70 (3H, m), 5.18 (21H, m), 6.87-6.97 (3H, m), 6.99-7.18 (7H, m), 7.28-7.39
(3H, m), 7.45-7.60 (2H, m), 8.20 (d), 8.31 (d); LCMS APCI m/z 707 [M+H]+
.Preparation 146: N-{5-[(1 R)-1-(tert-Butyldimethylsilanyloxy)-2-((1 R)-2-{3-
[3-
(3,4-dihydro-1 H-isoqu inolin-2-yl)-3-oxo-propyl]phenyl}-1-
methylethylamino)ethyl]-2-hydroxyphenyl}formamide
H3C?c l H3
\~SI.O 0
3 H
~ N ~ NI \
HO I / CH3
HN\
0
Prepared using the amide from preparation 145 and the method described for
preparation 15 to yield a brown foam (280 mg, 100 %).
1H NMR (400MHz, CD3OD) b: rotamers -0.14 (3H, s), -0.03 (3H, s), 0.84 (9H,
s), 1.08-1.12 (3H, m), 2.54-3.20 (11 H, m), 3.60-3.65/3.74-3.77 (2H, 2x t),
4.56-
4.66 (2H, 2x s), 4.78-4.84 (1 H, m), 6.80-7.24 (1 H, m), 8.10 (s), 8.31 (s);
LCMS
APCI m/z 617 [M+H]+
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Example I : N-Benzyl-2-(3-{2-[(2R)-2-(3 formylamino-4-hydroxyphenyl)-2-
hydroxyethylamino]-2-methylpropyl}phenyl)acetamide
OH
I \ Nro___yH
HO H0
HN)
O
Preparation 15 (24 mg, 40 pmol), formic acid (0.5 mL), tetrahydrofuran (5 m L)
and water (0.5 mL) were heated to 90 C for 18 h. A further aliquot of formic
acid (0.5 mL) and tetrahydrofuran (5 mL) were added and heating continued for
a further 18 h. The solvent was removed and the product purified by
chromatography (0-10 % methanol in dichioromethane + 0.3 %-ammonia). The
product was dissolved in methanol (x3) and evaporated (10 mg).
'HNMR (CD3OD, 400 MHz) S: 1.05-1.09 (6H, m), 2.69-2.78 (2H, m), 2.78-2.83
(1 H, m), 2.87-2.93 (1 H, m), 3.53 (2H, s), 4.35 (2H, s), 4.65 (1 H, dd), 6.82-
6.86
(1 H, m), 6.99 (1 H, dd), 7.03-7.06 (1 H, m), 7.13-7.28 (7H, m), 8.08 (d),
8.28 (s),
8.55 (s), 8.61 (s); MS (APCI) m/z 476 [M+H]+; HRMS C28H33N304 476.2544
[M+H]+ found 476.2533.
Example 2 N-(3,4-Dimethylbenzyl)-2-(3-{2-[(2R)-2-(3 formylamino-4-
hydroxy-phenyl)-2-hydroxyethylamino]-2-methylpropyl}phenyl)acetamide
CH3
OH
\ N / I N CH3
H3C CH3 0
HO
HN\
0
Prepared using the amide from Preparation 16 and the method described for
Example 1.
'HNMR (CD3OD, 400 MHz) 8: 1.05-1.08 (6H, m), 2.18 (3H, s), 2.19 (3H, s),
2.67-2.94 (4H, m), 3.52 (2H, s), 4.27 (2H, s), 4.62 (1 H, dd), 4.65 (1 H, dd),
6.81-
7.06 (6H, m), 7.12-7.24 (3H, m), 8.07 (d), 8.27 (s), 8.55 (s), 8.61 (s).
MS (APCI) M/Z 504 [M+H]+; HRMS C30H37N304 504.2857 [M+H]+ FOUND
504.2842.
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Example 3: N-[4-(dimethylamin o)benzyl]-2-{3-[(2R)-2-({(2R)-2-[3-
(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl}amino)propyl]phenyl}
acetamide
~H3
OH NCH3
N I N
CH3 / 0
HO
HN` /H
0
A mixture of the product of preparation 27, (131 mg, 0.21 mmol) and
triethylamine trihydrofluoride (16 NL, 0.10 mrmol) in tetrahydrofuran (2 ml-)
was
stirred at room temperature for 3 days. The: mixture was then concentrated in
vacuo and the residue was purified by column chromatography on silica gel,
eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 90:10:1 to
afford the title compound as a brown foam in 36% yield, 18 mg.
1H NMR (400MHz, CD3CI3) S: 1.07 (3H, m), 2.57 (11-1, dd), 2.67-2.76 (2H, m),
2.85-2.99 (2H, m), 2.87 (6H, s), 3.47 (1 H, m), 4.23 (2H, s), 4.68 (1 H, dd),
6.67-
6.71 (2H, m), 6.77-6.79 (2H, d), 6.90 (1H, m), 6.97-7.70 (m, 6H), 7.97 (d),
8.27
(s), 8.35 (s); LRMS APCI m/z 619 [M+H]"
Examples 4 to 12
The following compounds, of the general formula shown below were prepared
using a method similar to that described for example 3. The appropriate
starting
material.was treated with 1-1.1eq of triethylamine trihydrofluoride at room
temperature for 18-72hours.
OH
H
N r
HO CH3 0
HN. ,H
0
No. Q1 Data Yield
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4 N\ /CH3 H NMR (40OMHz, CD3CI3)- 8: 1.00 17.%
N o (3H, d), 2.09 (3H,* s), 2.55 (1 H, dd),
2.64-2.71 (2H, m), 2.83-2.93 (2H,
m), 3.13 (m, 1 H), 3.49 (2H, s), 4.30
(2H, s), 4.64-4.69 (1 H, m), 6.76 (1 H,
d), 6.89 (1 H, dd), 6.98 (1 H, d), 7.06
(1 H, m), 7.09-7.19 (4H, m), 7.45
(2H, d), 7.99 (d), 8.03 (s), 8.28 (s),
8.35 (s); LRM S APCI m/z 517 [M-H]-
1H NMR (40OMHz, CD3CI3) 8: 1.09 12%
NH2 (3H, d), 2.60 (1 H, dd), 2.74-2.82
N I (2H, m), 2.90-2.96 (1 H, m), 3.00-
3.08 (1H, m), 3.53 (2H, s), 4.40 (2H,
s), 4.61 (1 H, dd), 6.78 (1 H, d), 6.91
(1 H, dd), 7.02 (1 H, d), 7.08-7.10
(1 H, m), 7.1 2-7.25 (3H, m), 7.29
(2H, d), 7.78 (2H, d), 7.99 (d), 8.28
(s), 8.56 (s) LRMS APCI m/z 503
[M-H]-
*6 / \ - OH H NMR (400MHz, CD3OD) 8: 1.05, 10%
1.07 (3H, d), 2.54-3.06 (5H, m), 3.53
HN
(2H, s), 4.40 (2H, s), 4.60-4.65 (1H,
m), 6.80-7.42 (14H, m), 8.00 (1 H, s),
8.27 (s), 8.59 (s); LRMS APCI m/z
554 [M+H]
*7 CH3 1H NMR (400MHz, CD3OD) 8: 31%
OH 1.07,1.08 (34, d), 2.14 (6H, s), 2.54-
,~N CH, 3.02 (5H, m), 3.47 (2H, s), 4.18 (2H,
m), 4.56-4.64- (1 H, m) 6.76-7.22 (8H,
m), 7.97 (1 H, s), 8.27 (s), 8.56 (s);
LRMS APCI rr/z 506 [M+H]+
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*8 H NMR (400MHz, CD3OD) -8: 0:96, 38%
0.97 (3H, d), 2.42-2.84 (5H, m), 3.46
H{J
WI / (2H, s), 4.54-4.60 (1 H, m), 4.78 (2H,
HO s), 6.76-7.40 (8H, m), 7.66-7.74 (3H,
m), 7.85-7.91 (1H, m), 7.96 (1H, s),
8.27 (s), 8.54 (s); LRMS APCI m/z
528 [M+H]+
*9 H Ci H NMR (400MHz, CD3OD) 8: 1.07, 25%
1.08 (3H, d), 2.58-3.00 (5H, m), 3.51
HO
(2H, s), 4.29 (2H, s), 4.58-4.64 (1 H,
m), 6.71-7.23 (9H, m), 7.96 (1 H, s),
8.28 (s), 8.56 (s); LRMS APCI m/z
512 [M+H]+
*10 ci H NMR (400MHz, CD3OD) 8: 1.09, 24%
HO I 1.10 (3H, d), 2.58-3.04 (5H, m), 3.52
W-IIN / ci (2H, s), 4.32 (2H, s), 4.60-4.64 (1 H,
m), 7.05-7.24 (8H, m), 7.97 (1 H, s),
8.29 (s), 8.57 (s); LRMS APCI m/z
546 [M+H]+
*11 I OH H NMR (400MHz, CD3OD) 8: 1.02, 30%
1.04 (3H, d), 2.54-2.94 (5H, s), 3.52
(2H, s), 4.45 (2H, s), 4.55-4.60 (1 H,
m), 6.76-7.29 (9H, m), 7.53-7.61
(3H, m), 7.96 (1 H, s), 8.28 (s), 8.55
(s); LRMS APCI m/z 528 [M+H]+
*12 \ off H NMR (400MHz, CD3OD) 8: 1.05, 35%
HI 1.06 (3H, d), 2.46-2.98 (5H, m), 3.51
(2H, s), 4.36 (2H, s), 4.52-4.60 (1 H,
m), 6.75-7.25 (10H, m), 7.39-7.47
(4H, m), 7.96 (1 H, s), 8.27 (s), 8.54
(s); LRMS APCI m/z 554 [M+H]+
* crude compounds were azeotroped with 2M methanolic ammonia before
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purification by column chromatography on silica gel, - eluting. with.
dichloromethane:methanol:0.88 ammonia 90:10:1. This was followed by further
azeotropes in methanol (x3) and diethyl ether (x3) to afford desired products
as
white solids
Examples 13 to 23
The following compounds, of the general formulo shown below were prepared
using a method similar to that described for example 3. The appropriate
starting
material was treated with 1-1.1 eq of triethylainine trihydrofluoride at room
temperature for 18-72hours.
OH O
H
N Q1
I y
I ~ H3C CH3
HO
HN\ /H
~I If
O
No. Q1 Data Yield
0
13 Ci H NMR (400MHz, CD3OD) 8: 1-09, 65%
1.10 (3H, 2xs), 1.14, 1.16 (3H, 23(s),
N~
2.76-3.04 (6H, m), 3.56 (2H, m),
4.67 (1 H, dd), 6.84 (1 H, d), T.02
(11-1, m), 7.20-7.28 (4H, m), 7-33-
7.40 (2H, m), 7.60-7.67 (2H, m),
8.12 (1 H, d), 8.29 (s), 8.64 (s);
LRMS ESI m/z 534 [M+Na]+
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14 C'H3 1H NMR (400MHz, CD3OD)- 6: 1.06 90%
H3C OH
(3H, s), 1.13 (3H, s), 2.10 (3H, s),
H Y 2.21 (3H, s), 2.70-3.02 (6H, m), 3.51
(2H, t), 4.62-4.68 (1 H, m), 6.79-6.81
(1H, m), 6.82-6.87 (2H, m), 7.01-
7.07 (1 H, m), 7.31-7.39 (2H, m),
7.69 (2H, m), 8.09 (1 H, s), 8.29 (s),
8.63 (s); LRMS APCI m/z 520
[M+H]+
*15 / \ - OH H NMR (400MHz, CD3OD) 6: 1.06 39%
- \ /
(3H, s), 1.12 (3H, s), 2.72-2.98 (4H,
~HN
m), 4.58-4.67 (3H, m), 6.77-7.00
(4H, m), 7.16-7.73 (10H, m), 8.04
(1 H, s), 8.27 (s), 8.59 (s); LRMS
APCI m/z 554 [M+H]+
16 / \ - off H NMR (400MHz, CD3OD) 5: 1.06 41%
\ /
Hi - (3H, s), 1.13 (3H, s), 2.72-3.00 (4H,
m), 4.54-4.70 (3H, m), 6.78-6.86
(3H, m), 6.97-6.99 (1 H, d), 7.34-7.58
(8H, m), 7.71-7.76 (2H, m), 8.05
(1 H, s), 8.27 (s), 8.59 (s); LRMS
APCI m/z 554 [M+H]+
*17 H3c OH H NMR (400MHz, CD3OD) 8: 1.09 40%
Htv cH (3H, s), 1.16 (3H, s), 2.08 (3H, s),
3 2.21 (3H, s), 2.75-3.06 (6H, m),
3.45-3.51 (2H, m), 4.66-4.71 (1H,
m), 6.53 (1 H, s), 6.83-6.88 (3H, m),
7.02-7.04 (1H, m), 7.32-7.41 (2H,
m), 7.63-7.68 (2H, m), 8.11 (s), 8.29
(s), 8.63 (s); LRMS APCI m/z 520
[M+H]
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*18 H 1H NMR (400MHz, CD3OD)- 8: 1.06 43%
HN CH3 (3H, s), 1.13 (3H, s), 2.13 (3H, s),
2.71-3.00 (6H, m), 3.47-3.56 (2H,
m), 4.64-4.69 (1H, m), 6.63-6.65
(1 H, m), 6.83-7.39 (6H, m), 7.60-
7.69 (2H, m), 8.09 (1 H, s), 8.29 (s),
8.63 (s); LRMS APCI m/z 506
[M+H]+ -
*19 H NMR (400MHz, CD3OD) 8: 1.09 33%
H~ (3H, s), 1.14 (3H, s), 2.77-3.00 (4H,
HO I m), 4.63-4.67 (1 H, m), 4.98 (2H, s),
6.38-6.40 (1H, m), 6.81-6.83 (1 H,
m), 7.12-7.14 (1 H, d), 7.26-7.48 (5H,
m), 7.70-7.78 (4H, m), 8.06 (1H, s),
8.28 (s), 8.60 (s); LRMS APCI m/z
528 [M+H]+
*20 CH3 1H NMR (400MHz, CD3OD) S: 1.09 48%
OH (3H, s), 1.15 (3H, s), 2.17 (6H, s),
CH3 2.75-3.00 (4H, m), 4.37-4.46 (2H,
m), 4.64-4.82 (1H, m), 6.79-6.82
(1 H, m), 6.91 (2H, s), 6.97-7.01 (1 H,
m), 7.33-7.40 (2H, m), 7.68-7.74
(2H, m), 8.05 (1 H, s), 8.28 (s), 8.61
(s); LRMS APCI m/z 506 [M+H]+
*21 Cl 1H NMR (400MHz, CD3OD) 5: 1.13 20%
HO (3H, s), 1.18 (3H, s), 2.80-3.06 (4H,
~N I m), 4.52 (2H, m), 4.64-4.77 (1 H, m),
Cl 6.82-6.84 (1H, m), 7.00-7.25 (3H,
m), 7.39-7.44 (2H, m), 7.73-7.78
(2H, m), 8.08 (1 H, s), 8.29 (s), 8.62
(s); LRMS APCI m/z 546 [M+H] +
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*22 H NMR (400MHz, CD3OD)- 8: 1.07 62%
'PN I Off (3H, s), 1.13 (3H, s), 2.73-2.98 (4H,
m), 4.63-4.76 (3H, m), 6.75-6.78
(11-1, m), 6.95-7.05 (3H, m), 7.33-
7.40 (3H, m), 7.60-7.80 (5H, m),
8.04 (1 H, s), 8.26 (s), 8.60 (s);
LRMS APCI m/z 528 [M+H]+
23 OH 1H NMR (400MHz, CD3OD) 8: 1.07 35%
HN (3H, s), 1.11 (3H, s), 1.33 (6H, s),
HC CH3 2.74-2.96 (4H, m), 3.52 (2H, s),
4.56-4.70 (2H, m), 6.72-6.74 (1 H, d),
6.82-6.84 (11-1, d), 7.04 (111-1, m),
7.20-7.36 (4H, m), 7.49-7.57 (2H, m)
8.06 (1 H, s), 8.29 (s), 8.63 (s);
LRMS APCI m/z 520 [M+H]+
Example 14: was azeotroped with 2M methanolic ammonia before purification.
* crude compounds were azeotroped with 2M methanolic ammonia before
purification by column chromatography on silica gel, eluting with
dichloromethane:methanol:0.88 ammonia 90:10:1. This was followed by further
azeotropes in methanol (x3) and diethyl ether (x3) to afford desired products
as
white solids
Examples 24 to 27
The following compounds, of the general formula shown below were prepared
using a method similar to that described for example 3. The appropriate
starting
material was treated with 1-1.1eq of triethylamine trihydrofluoride at room
temperature for 18-72 hours.
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OH
H
N Q,
H3C CH3I
HO O
HNyH
O
No. Qi Data Yield
24 O-CH3 H NMR (400MHz, CD3OD) 8: 1.01 75%
HN Q (3H, s), 1.03 (3H, s), 2.63-2.87 (4H,
m), 3.52 (2H, s), 3.84 (3H, s), 4.38
(2H, s), 4.56-4.60 (11-1, m), 6.78-6.80
(11-1, m), 6.94-6.97 (11-1, m), 7.00-7.02
(11-1, m), 7.11-7.20 (4H, m), 7.26-7.29
(2H, m), 7.87-7.89 (2H, d), 7.98-7.99
(d), 8.21 (s), 8.54 (s); LRMS ESI m/z
534 [M+H]-
25 HO 1H NMR (400MHz, CDCI3) 6: 0.96- 41%
1.04 (9H, m), 2.60-2.88 (4H, m), 3.16-
H3c~ 3.33 (2H, m), 3.66, 3.79 (2H, 2xs),
4.61, 4.66 (2H, 2xs), 4.64, 4.79 (11-1,
m), 6.56 (11-1, m), 6.73-6.79 (2H, m),
6.92-7.19 (6H, m), 7.98 (11-1, m), 8.23
(s), 8.65 (s); LRMS APCI m/z 554
[M+H]+
r__ - H NMR (400MHz, CDCI3) 8:0.98 (3H, 93%
26 OH
HN . - ~ ~ -
s), 1.00 (3H, s), 2.61-2.84 (4H, m),
3.48 (2H, s), 4.30 (2H, s), 4.54-4.57
(1H, m), 6.75-6.77 (3H, m), 6.91-6.94
(11-1, m), 6.96-6.99 (11-1, m), 7.08-7.18
(6H, m), 7.33-7.40 (4H, m), 7.98 (s),
8.21 (s), 8.56 (s); LRMS ESI m/z 568
[M+H]+
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27 off H NMR (400MHz, CD3OD) =8, 1.05 44%
(3H, s), 1.08 (3H, s), 2.66-2.93 (4H,
CI m), 3.52 (2H, m), 4.34 (2H, s), 4.61
(1 H, m), 6.81 (1 H, m), 6.79 (1 H, d),
6.81 (11-1, d), 6.99-7.22 (6H, m), 8.06
(1 H, d), 8.28 (s), 8.61 (s); LRMS APCI
m/z 526 [M+H]+
Example 28: N-1 Adamantyl-2-{3-[(2R)-2-({(2R)-2-[3-(formylamino)phenyl]-
2-hydroxyethyl}am ino)propyl]phenyl}acetamide
OH
H
HO CiH3 O
HN\ /H
O
A mixture of the product of preparation 34 (500 mg, 0.81 mmol) and ammonium
fluoride (200 mg, 5.4 mmol) in methanol (5 ml-) and water (1.5 ml-) was heated
at 40 C for 18 hours. The reaction mixture was then concentrated in vacuo and
the residue was purified by column chromatography on silica gel, eluting with
dichloromethane:methanol:0.88 ammonia, 90:10:0.1, to afford the title
compound as a foam in 84% yield, 347 mg.
1H NMR (400MHz, CD3OD) 8: 1.05-1.10 (m, 3H), 1.64-1.74 (6H, m), 1.98-2.03
(9H, m), 2.36-2.98 (5H, m), 3.36 (2H, s), 4.46-4.60 (11-1, m), 6.46-7.20 (6H,
m),
7.96 (1 H, s), 8.28 (s), 8.56 (s); LRMS ESI m/z 506 [M+H]+
.15 Example 29: N-(3,4-Dimethylbenzyl)-2-{3-[2-({(2R)-2-[3-(formylamino)-4-
hydroxy phenyl]-2-hydroxyethyl}amino)ethyl]phenyl}acetamide
OH H3
/ CH,
? N I ~ N \
HO O
HN` /H
0
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The title compound was prepared from the product of preparation 102, using a
similar method to that of examples 4-12, as solid.
1H NMR (400MHz, CD30D) 2.20 (6H, m), 3.00 (2k, m), 3.18 (2H, m), 3.28 (2H,
m), 3.56 (2H, s), 4.28 (2H, s), 4.81 (1 H, m), 6.81 (1 H, d), 6.98(2H, m),
7.05 (2H,
m), 7.20 (4H, m), 7.30 (1 H, t), 8.10 (s), 8.30 (s); LPMS ESI 476 [M+H]+
Examples 30 to 37
The following compounds, of the general formula shown below were prepared
using a method similar to that described for example 3. The appropriate
starting
material was treated with 1-1.1eq of triethylaiine trihydrofluoride at room
temperature for 18-72hours.
OH
H
\ N / H3C CH3) O
HO
HNyH
O
No. Q1 Data Yield
30 I \ S\ H NMR (400MHz, CD30D) 8: 0.94 26%
N i (3H, s), 0.97 (3H, s), 2.33 (3H, s),
2.56-2.81 (4H, m), 3.43 (2H, s), 4.21
(2H, s), 4.52-4.55 (11-1, m), 6.73 (11-1,
m), 6.89-6.95 (2H, m), 7.03-7.13 (7H,
m), 7.98 (d), 8.19 (s), 8.52 (s); LRMS
ESI m/z 522 [M+H]"
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31 F 1H NMR (400MHz, CD3OD) -&: 0.99 27.%
F (3H, s), 1.01 (3H, s), 2.60-2.85 (4H,
~N I F
m), 3.49 (2H, s), 4.36 (2H, s), 4.54-
4.59 (1 H, m), 6.75 (1 H, d), 6.92 (1 H,
dd), 6.98 (1H, d), 7.08-7.18 (3H, m),
7.31 (2H, d), 7.48 (2H, d), 8.00 (d),
8.22 (s), 8.64 (s); LRMS APCI m/z
544 [M+H]+
32 CN 1H NMR (400MHz, CD3OD) 5: 0.97 38%
N I (3H, s), 1.00 3H s), 2.59-2.86 (4H,
m), 3.48 (2H, s), 4.34 (2H, s), 4.53-
4.56 (1 H, m), 6.74 (1 H, d), 6.92 (1 H,
d), 6.98 (1H, bd), 7.08-7.17 (3H, m),
7.29 (2H, d), 7.55 (2H, d), 8.00 (1 H,
d), 8.22 (s), 8.64 (s); LRMS ESI m/z
501 [M+H]+
33 0 F H NMR (400MHz, CD3OD) 8: 1.00 49%
F (3H, s), 1.02 (3H, s), 2.62-2.86 (4H,
m), 3.47 (2H, s), 4.30 (2H, s), 4.55-
4.58 (1 H, m), 6.82 (1 H, d), 6.99 (1 H,
dd), 7.04 (1H, d), 7.14-7.23 (5H, m),
7.29 (1 H, s), 7.31 (1 H, s), 8.07 (1 H,
d0, 8.29 (s), 8.64 (s); LRMS APCI m/z
560 [M+H]+ -
34 H NMR (400MHz, CD3OD) 8: 0.93 82 %
(3H, s), 0.96 (3H, s), 2.51-2.83 (4H,
OH m), 3.47 (2H, s), 4.34 (2H, s), 4.52-
4.55 (1 H, m), 6.73-6.76 (3H, m), 6.90-
6.97 (2H, m), 7.04-7.06 (2H, m), 7.12-
7.14 (2H, m), 7.20-7.33 (5H, m), 7.99
(1 H, bs), 8.21 (s), 8.54 (s); LRMS
APCI m/z 568 [M+H]+
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35 HO I H NMR (400MHz, CD30D) -8: 0.99 50%
CI (3H, s), 1.01 (3H, s), 2.61-2.86 (4H,
m), 3.47 (2H, s), 4.23 (2H, s), 4.55-
4.58 (1 H, m), 6.64-6.66 (1 H, m), 6.75-
6.79 (11-1, m), 6.92-7.16 (8H, m), 7.99
(1 H, d), 8.22 (s), 8.54 (s); LRMS APCI
m/z 526 [M+H]+
36 1H NMR (400MHz, CD3OD) 8: 1.02 40%
S (3H, s), 1.04 (3H, s), 1.44-1.55 (2H,
m), 2.00-2.04 (2H, m), 2.52-2.87 (8H,
m), 2.39 (2H, s), 3.55-3.61 (1H, m),
4.56-4.59 (1 H, m), 6.76 (1 H, d), 6.93-
6.98 (2H, m), 7.07-7.16 (3H, m), 8.00
(1 H, d), 8.23 (s), 8.55 (s); LRMS APCI
m/z 486 [M+H]+
37 1H NMR (400MHz, CD3OD) 8: 1.06
\ ,\ (3H, s), 1.08 (3H, s), 2.67-2.95 (4H,
m), 3.07 (3H, s), 3.56 (2H, s), 4.45
(2H, s), 4.60 (1 H, dd), 6.81 (1 H, d),
6.98 (11-1, dd), 7.04 (11-1, d), 7.14-7.25
(4H, m), 7.44 (2H, d), 7.84 (2H, d),
8.06 (1 H, d), 8.28 (s), 8.61 (s); LRMS
APCI m/z 554 [M+H]+
Examples 38 to 46
The appropriate amides, triethylamine trihydrofluoride (1 equivalent) in
tetrahydrofuran (5 mL) was stirred at room temperature for 2 days. The mixture
was then concentrated in vacuo and the residue treated with methanolic
ammonia and evaporated (x3) to leave a foam which was taken up in
dichloromethane:methanol:0.88 ammonia, 90:10:1 filtered, then purified ' by
column chromatography on silica gel, eluting with
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dichloromethane:methanol:0.88 ammonia, 90:10:1 to afford- the -title compound.
as a film which was dissolved in methanol - and evaporated -(x3), then
suspended in diethylether and evaporated (x3) to yield a white solid.
OH O
H
N ~ Ql
/ H3c CH3 /
HO
HN.H
O
No. Q1 Data Yield
38 H NMR (400MHz, CD3OD) 8: 1.07 52%
(3H, s), 1.14 (3H, s), 2.73-3.00 (6H,
m), 3.57-3.62 (2H, m), 4.65-4.70 (1 H,
m), 6.83 (1H, d), 7.01-7.05 (1H, m),
7.16-7.40 (7H, m), 7.61-7.67 (2H, m),
8.09 (1H, d), 8.29 (s), 8.63 (s); LRMS
APCI m/z 476 [M+H]+
39 1H NMR (400MHz, CD3OD) 8: 0.94- 65%
~N 1.34 (11 H, m), 1.58-1.80 (6H, m),
2.74-3.00 (4H, m), 3.14-3.30 (2H, m),
4.65-4.69 (1 H, m), 6.83 (1 H, d), 7.02-
7.06 (1H, m), 7.32-7.31 (2H, m), 7.37-
7.73 (2H, m), 8.07 (1 H, d), 8.30 (s),
8.63 (s); LRMS APCI m/z 468 [M+H]+
40 H NMR (400MHz, CD3OD) 8: 1.09 69%
N (3H, s), 1.11 (3H, s), 1.46-1.80 (6H,
AVII m), 2.76-2.95 (4H, m), 3.35 (2H, bs),
3.69 (2H, bs), 4.62-4.65 (1 H, m), 6.82
(1H, d), 6.99-7.02 (1H, m), 7.18-7.30
(3H, m), 7.33-7.37 (1 H, m), 8.04 (1H,
s), 8.29 (s), 8.63 (s); LRMS APCI m/z
438 [M+H]+
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41 1H NMR (400MHz, CD3OD) -&: 1.04 52%
~HN F (3H, s), 1.11 (3H, s), 2.69-3.03 (6H,
F F
m), 3.47-3.67 (2H, m), 4.63-4.67 (1 H,
m), 6.82 (1H, d), 7.00-7.06 (1H, m),
7.30-7.64 (8H, m), 8.08 (1H, s), 8.29
(s), 8.63 (s); LRMS APCI m/z 542
[M+H]+
42 H NMR (400MHz, CD3OD) 8: 1.05 59%
HN i (3H, s), 1.13 (3H, s), 1.88-1.98 (2H,
m), 2.64-2.80 (4H, m), 2.89-3.00 (2H,
m), 3.38-3.46 (2H, m), 4.63-4.67 (1 H,
m), 6.81 (1 H, d), 6.98-7.08 (1H, m),
7.10-7.30 (5H, m), 7.30-7.40 (2H, m),
7.62-7.70 (2H, m), 8.08 (1H, s), 8.27
(s), 8.61 (s); LRMS APCI m/z 488
[M+Hl+
43 - H NMR (400MHz, CD3OD) 8: 1.06 56%
(3H, s), 1.13 (3H, s), 2.71-3.04 (8H,
~HN s), 4.50-4.80 (2H, m), 6.80 (1H, d),
6.96-7.06 (1 H, m), 7.11-7.20 (4H, m),
7.31-7.42 (2H, m), 7.68-7.71 (2H, m),
8.06 (1 H, d), 8.27 (s), 8.61 (s); LRMS
APCI m/z 488 [M+H]+
44 / H NMR (400MHz, CD3OD) 8: 1.04 62%
HN ~N I (3H, s), 1.11 (3H, s), 2.70-2.97 (4H,
m), 3.06 (2H, t), 3.71 (2H, t), 4.64-
4.68 (1 H, m), 6.82-6.86 (1 H, m), 7.00-
7.06 (1 H, m), 7.19-7.38 (4H, m), 7.61-
7.64 (2H, m), 7.72 (1 H, t), 8.08 (1 H,
s), 8.28 (s), 8.45 (1 H, d), 8.63 (s);
LRMS APCI m/z 477 [M+H]+
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45 0 H NMR (400MHz, CD3OD) -&: 1.05 28%
HN (3H, s), 1.12 (3H, s), 2.70-3.00 (6H,
m), 3.50-3.60 (2H, m), 3.74 (3H, s),
4.63-4.66 (1 H, m), 6.80-6.86 (3H, m),
7.00-7.06 (1 H, m), 7.12 (2H, d), 7.30-
7.39 (2H, rn), 7.60-7.65 (2H, m), 8.09
(1 H, s), 8.29 (s), 8.63 (s); LRMS APCI
m/z 506 [M-}-H]+
46 ` S02NH2 H NMR (400MHz, CD3OD) 8: 1.13 27%
*,,HN (3H, s), 1.18 (3H, s), 2.75-3.06 (6H,
m), 3.62 (2H, t), 4.68-4.75 (1H, m),
6.85 (1H, d), 7.03 (1H, d), 7.37-7.45
(4H, m), 7.62-7.70 (2H, m), 7.80 (2H,
d), 8.12 (1 H, s), 8.30 (s), 8.64 (s);
LRMS APCI m/z 555 [M+H]+
47 H NMR (400MHz, CD3OD) 6: 1.14- 57%
N I
1.24 (6H, m), 2.80-3.06 (7H, m), 3.80-
3.84 (1 H, bs), 3.93-3.97 (1 H, bs),
4.55-4.59 (1 H, bs), 4.68-4.73 (1 H, m),
6.87 (1 H, dd), 7.00-7.15 (3H, m),
7.20-7.30 (2 H, m), 7.82-7.87 (1 H, m),
8.09 (1H, s), 8.28 (s), 8.63 (s); LRMS
APCI m/z 488 [M+H]+
48 1H NMR (400MHz, CD3OD) 6: 1.14 8-0/0
~HN
(3H, s), 1.19 (3H, s), 1.74 (6H, s),
2.07 (3H, s), 2.15 (6H, s), 2.76-3.10
(4H, m), 4.56 (1 H, bs), 4.64-4.72 (1 H,
m), 6.84 (1 H, d), 7.03 (1 H, d), 7.31-
7.39 (2H, m), 7.58-7.62 (2H, m), 8.11
(1 H, s), 8.30 (s), 8.63 (s); LRMS APCI
m/z 506 [M+H]+
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49 1H NMR (400MHz., CD30D) & 1-.00- 19%
FN \ 1.08 (6H, m), 2.00 (1H, d), 2.26-2.38
(11-1, m), 2.63-3.30 (7H, m), 3.40-3.58
(2H, m), 4.46-4.56 (1H, d), 4.60-4.68
(11-1, m), 6.58-6.68 (2H, m), 6.80-6.90
(1H, m), 6.96-7.34 (7H, m), 8.08 (1H,
s), 8.30 (s), 8.63 (:i); LRMS APCI m/z
514 [M+H]+
50 HO acl H NMR (400MH7?, CD3OD) 6: 1.10 17%
(3H, s), 1.14 (3H, s), 2.27-3.00 (6H,
HN
m), 3.57-3.60 (214, t), 4.63-4.71 (1H,
m), 6.71 (11-1, d),,:6.82 (11-1, d), 6.99-
7.09 (3H, m), 7.32-7.39 (2H, m), 7.61-
7.67 (2H, m), 8.Q8 (1 H, s), 8.29 (s),
8.63 (s); LRMS APCI m/z 526 [M+H]+
Examples 51 to 55
The following compounds, of the general formula shown below were prepared
using a method similar to that described for example 3. The appropriate
starting
material was treated with 1-1.1eq of triethylamine trihydrofluoride at room
temperature for 18-72hours.
OH O
H
Q~
N CH3
HF '
/
HO
HN\ /H
O
No. Qi Data Yield
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51 H NMR (400MHz, CD3OD) -S: 1.04 81%
i (3H, s), 1.12 (3H, s), 2.24 (6H, s),
RHN
2.69-3.01 (6H, m), 3.52-3.55 (2H, m),
4.62-4.66 (1H, m), 6.82-6.84 (1 H, m),
6.95-7.10 (4H, m), 7.31-7.37 (2H, m),
7.60-7.70 (2H, m), 8.09 (1 H, s), 8.28
(s), 8.63 (s); LRMS APCI m/z 504
[M+H]+
52 I H NMR (400MHz, CD3OD) 8: 1.04 79%
RHN (3H, s), 1.11 (3H, s), 2.69-2.96 (4H,
c- m), 3.01-3.08 (2H, m), 3.61-3.66 (2H,
m), 4.62-4.65 (1 H, m), 6.82 (1 H, d),
7.00-7.03 (1 H, m), 7.16-7.21 (2H, m),
7.28-7.40 (4H, m), 7.61-7.65 (2H, m),
8.08 (1 H, s), 8.28 (s), 8.63 (s); LRMS
APCI m/z 510 [M+H]+
53 1H NMR (400MHz, CD3OD) 8: 1.05 96%
RHN (3H, s), 1.13 (3H, s), 2.34 (6H, s),
2.71-2.79 (2H, m), 2.95-3.01 (4h, m),
3.43-3.49 (2H, m), 4.64-4.67 91 H, m),
6.83 (1 H, d), 6.95-6.97 (3H, m), 7.02-
7.08 (1 H, m), 7.33-7.41 (2H, m), 7.67-
7.73 (2H, m), 8.12 (1 H, s), 8.29 (s),
8.63 (s); LRMS APCI m/z 504 [M+H]+
54 1H NMR (400MHz, CD3OD) 8: 1.04 86%
"-HN (3H, s), 1.11 (3H, s), 2.27 (3H, s),
2.69-2.98 (6H, m), 3.54-3.60 (2H, m),
4.62-4.65 (1 H, m), 6.82 (1 H, d), 7.00-
7.14 (5H, m), 7.30-7.38 (2H, m), 7.59-
7.67 (2H, m), 8.08 (1 H, s), 8.29 (s),
8.62 (s); LRMS APCI m/z 504 [M+H]+
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55 H NMR (400MHz, CD3OD) -&: 1.04 76%
(3H, s), 1.12 (3H, s), 2.68-3.02 (4H,
RHN - m 3.62-3.97 2H, m), 3.70-3.74 2H,
m), 4.64-4.68 (11-1, m), 6.83 (11-1, d),
7.02 (11-1, d), 7.34-7.48 (6H, m), 7.62
(11-1, s), 7.65-7.67 (11-1, m), 7.72-7.76
(11-1, m), 7.80-7.84 (11-1, m), 8.18 (11-1,
s), 8.20 (1 H, d), 8.29 (s), 8.62 (s);
LRMS APCI m/z 526 [M+H]+
Example 56: 3-{(2R)-2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-
hydroxyethylamino] propyl}-N-[2-(4-hydroxyphenyl)-2-
methytpropyl]benzamide
OH
OH O
H
\ N N
/ CH, / H H3C CH3
HO
HNC
I I
0
The title compound was prepared from the product of preparation 138, using a
method similar to that of examples 38-50, as a brown glass (35 mg, 31 %)
'H NMR (400MHz, CD3OD) 8: 1.03 (3H, d), 1.27 (6H, s), 2.56-2.90 (4H, m),
3.45 (2H, s), 4.55-4.58 (1 H, m), 6.67-6.72 (3H, m), 6.85-6.87 (1 H, m), 7.19-
7.26
(5H, m), 7.38 (1 H, s), 7.43 (1 H, d), 7.91 (d), 8.21 (s), 8.51 (s); LRMS APCI
m/z
506 [M+H]+
Example 57: N-{5-[(1 R)-2-((1 R)-2-{3-[3-(3,4-Dihydro-1 H-isoquinolin-2-yl)-3-
oxopropyl]phenyl}-1-methylethylamino)-1-hydroxyethyl]-2-
hydroxyphenyl)formamide
OH O
N N
HO CH,
HN\
O
The title compound was prepared from the product of preparation 138, using a
method similar to that of examples 38-50, as a brown glass (35 mg, 31 %)
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1H NMR (400MHz, CD3OD) 6: 1.00-1.05 (3H, m),-2.48-2.92-(11H, m), 3.59 (1H,.
t), 3.73 (1 H, t), 4.54-4.65 (3H, m), 6.75-7.18 (1 OH, m), 7.97 (s), 8.28 (d),
8.56
(d); LRMS APCI m/z 502 [M+H]**
The ability of the compounds of the formula (1) to act as potent (32
agonists therefore mediating smooth muscle relaxation may be determined by
the measure of the effect of beta-2 adrenergic receptor stimulation on
electrical
field stimulated-contraction of guinea pig trachea strips.
Guinea-pig trachea
Male, Dunkin-Hartley guinea pigs (475-525g) are killed by CO2 asphyxiation
and exsanguination from the femoral artery and the trachea is isolated. Four
preparations are obtained from each animal, starting the dissection
immediately
below the larynx and taking 2.5 cm length of trachea. The piece of trachea is
opened by cutting the cartilage opposite the trachealis muscle, then
transverse
sections, 3-4 cartilage rings wide, are cut. The resulting strip preparations
are
suspended in 5 ml organ baths using cotton threads tied through the upper and
lower cartilage bands. The strips are equilibrated, un-tensioned, for 20
minutes
in a modified Krebs Ringer buffer (Sigma K0507) containing 3 M Indomethacin
(Sigma 17378), 10 4M Guanethidine (Sigma G8520) and 10 M Atenolol (Sigma
A7655), heated at 37 C and gassed with 95% 02/5% C02, before applying an
initial tension of 1 g. The preparations are allowed to equilibrate for a
further 30-
45 minutes, during which time they are re-tensioned (to 1 g) twice at 15-
minute
intervals. Changes in tension are recorded and monitored via standard
isometric transducers coupled to a data-collection system (custom-designed at
Pfizer). Following the tensioning equilibration, the tissues are subjected to
electrical field stimulation (EFS) using the following parameters : 10 s
trains
every 2 minutes, 0.1 ms pulse width, 10 Hz and just-maximal voltage (25 Volts)
continuously throughout the length of the experiment. EFS of post-ganglionic
cholinergic nerves in the trachea results in monophasic contractions of the
smooth muscle and twitch height is recorded. The organ baths are constantly
perfused with the above-described Krebs Ringer buffer by means of a
peristaltic pump system (pump flow rate 7.5 ml / minute) throughout the
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experiment, with the exception of when a beta-2 agonist . according to the.
present invention is added, the pump is then stopped for the time of the
cumulative dosing to the bath and started again after maximal response is
reached for the wash-out period.
Experimental protocol for assessment of potency and efficacy
Following equilibration to EFS, the peristaltic pump is stopped and the
preparations `primed' with a single dose of 300 nM isoprenaline (Sigma 15627)
to establish a maximal response in terms of inhibition of the contractile EFS
response. The isoprenaline is then washed out over a period of 40 minutes.
Following the priming and wash-out recovery, a standard curve to isoprenaline
is carried out on all tissues (isoprenaline Curve 1) by means of cumulative,
bolus addition to the bath using half log increments in concentration. The
concentration range used is 1 e"9 to 1 e/3e-6 M. At the end of the
isoprenaline
curve the preparations are washed again for 40 minutes before commencing a
second curve, either to isoprenaline (as internal control) or a beta-2 agonist
according to the present invention. Beta-2 agonist responses are expressed as
percentage inhibition of the EFS response. Data for beta-2 agonist are
normalised by expressing inhibition as a percentage of the maximal inhibition
induced by isoprenaline in Curve 1. The EC50 value for beta-2 agonist
according to the present invention refers to the concentration of compound
required to produce half rnaximal effect. Data for beta-2 agonists according
to
the present invention are then expressed as relative potency to isoprenaline
defined by the ratio (EC5o beta-2 agonist)/(EC50 Isoprenaline).
Confirmation of beta-2 mediated functional activity
Beta-2 agonist activity of test compounds is confirmed using the protocol
above, however, prior to constructing the curve to beta-2 agonist according to
the present invention, the preparations are pre-incubated (for a minimum of
45 minutes) with 300 nM ICI 118551 (a selective P2 antagonist) which results
in
the case of a beta-2 mediated effect in a rightward-shift of the test compound
dose response curve.
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According to another alternative, the agonist potency for the. (32 receptor.
of the compounds of the formula (1) may also be determined by the measure of
the concentration of compound according to the present invention required to
produce half maximal effect (EC50) for the X32 receptor.
Compound Preparation
mM/100% DMSO (dimethylsulfoxide) stock of compound is diluted to
required top dose in 4 % DMSO. This top dose is used to construct a 10-point
semi-log dilution curve, all in 4 % DMSO. Isoprenaline (Sigma, 1-5627) was
used as a standard in every experiment and for control wells on each plate.
10 Data was expressed as % Isoprenaline response.
Cell Culture
CHO (Chinese Hamster Ovary) cells recombinantly expressing the human P2
adrenergic receptor (from Kobilka et al., PNAS 84: 46-50, 1987 and Bouvier et
al., Mol Pharmacol 33: 133-139 1988 CHOh(32) were grown in Dulbeccos MEM/
NUT MIX F12 (Gibco, 21331-020) supplemented with 10 % foetal bovine serum
(Sigma, F4135, Lot 90K8404 Exp 09/04), 2 mM glutamine (Sigma, G7513),
500 pg/ml geneticin (Sigma, G7034) and 10 pg/ml puromycin (Sigma, P8833).
Cells were seeded to give about 90 % confluency for testing.
Assay Method
25 pl / well each dose of compound was transferred into a cAMP- Flashplate
(NEN, SMP004B), with 1% DMSO as basal controls and 100 nM Isoprenaline
as max controls. This was diluted 1:2 by the addition of 25 pl / well PBS.
Cells
were trypsinised (0.25% Sigma, T4049), washed with PBS (Gibco, 14040-174)
and resuspended in stimulation buffer (NEN, SMP004B) to give 1x106 cells / ml
CHOhB2. Compounds were incubated with 50 pl / well cells for 1 hour. Cells
were then lysed by the addition of 100 pl / well detection buffer (NEN,
SMP004B) containing 0.18 pCi / ml 1251-CAMP (NEN, NEX-130) and plates were
incubated at room temperature for a further 2 hours. The amount of 1251-CAMP
bound to the Flashplate was quantified using a Topcount NXT (Packard),
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normal counting efficiency for 1 minute. Dose-redponse data was expressed as.
% Isoprenaline activity and fitted using a four parSimeter sigmoid fit.
It has thus been found that the compounds of formula (1) according to the
present invention that are illustrated in examples 1 to 57 above show a 02
cAMP EC50 below 5nM.
