Note: Descriptions are shown in the official language in which they were submitted.
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COMPOUNDS USEFUL FOR THE TREATMENT OF DISEASES
This invention relates to ~i2 agonists of general formula:
H O
N
(CH )
R~ R2 ~~ 2 n
HO (1)
HV
in which R', R2, n and Q' have the meanings indicated below,
and to processes for the preparation of, intermediates used in 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 ~i
_ subfamilies with the a sub-family being composed of at least 3 receptor sub-
types: ~i1, ~2 and ~i3. These receptors exhibit differential expression
patterns in
tissues of various systems and organs of mammals. ~i2 adrenergic (~32)
receptors are mainly expressed in smooth muscle cells (e.g. vascular,
bronchial, uterine or intestinal smooth muscles), whereas X33 adrenergic
receptors are mainly expressed in fat tissues (therefore ~i3 agonists could
potentially be useful in the treatment of obesity and diabetes) and (i1
adrenergic receptors are mainly expressed in cardiac tissues (therefore X31
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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Glucocorticosteroids, anti-leukotrienes, theophylline, cromones, anti-
cholinergics and X32 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 ~2 agonists. Short acting, rapid
onset
X32 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 X32 adrenoceptor
expressed on airway smooth muscle cells, which results in relaxation and
hence bronchodilation. Thus, as functional antagonists, ~i2 agonists can
prevent and reverse the effects of all bronchoconstrictor substances,
including
leukotriene D4 (LTD4), acetylcholine, bradykinin, prostaglandins, histamine
and
endothelins. Because ~i2 receptors are so widely distributed in the airway,
~i2
agonists may also affect other types of cells that play a role in asthma. For
example, it has been reported that X32 agonists may stabilize mast cells. The
inhibition of the release of bronchoconstrictor substances may be how ~2
agonists block the bronchoconstriction induced by allergens, exercise and cold
air. Furthermore, ~i2 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 X32
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 X32 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 ~i2 adrenoreceptors expressed outside the airways
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(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,
duration of action and/or pharmacodynamic properties. In this context, the
present invention relates to novel X32 agonists.
EP 0654534 B1 and EP0939134 B1 disclose a process for the preparation of
compounds of formula (XI):
s
R' OZ R
R2 ~ N R~
R" ~ /
R3 ~R5 Rio ~ 'Rs
Ra Rs
These compounds are disclosed as anti-obesity and anti-diabetic agents having
specific X33 activity.
US5,561,142 discloses selective ~i3 agonists of formula
OH Ra
R2
A CHCH2~(X)m \ / N-S02(CH2)~-R~
(R~) ERs Rs
R5
EP0236624 discloses compounds of formula
OH R~ R2 _
R R
Ro-X-CHCH2 N~(CH2)~-Y \ / 4- 5
~R3
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having anti-obesity and/or anti-hyperglycaemic activity coupled with good
selectivity from cardiac side-effects.
The invention relates to compounds of general formula (1 ):
H O
N
(CH )
R~ R2 I~ z r, Q
HO (1)
HO
wherein the (CHz)~-C(=O)Q' group is in meta or para position,
- R' and R2 are independently selected from H and C~-C4 alkyl,
- n is 0, 1 or 2, and,
- Q' is a group selected from:
R3 R4 R3 R3
8
R \ Ra Ra Ra
*-N I / *-N-C \
R5
\R5 H2 ~ s
N R
* ~ Rs Rs Rs
*-NH-C~-C4alkyl, and a group *-N(R$)-Qz-A, wherein
Qz is a single bond or a C~-C4 alkylene,
- R8 is H or C~-C4 alkyl,
- p is 1 or 2, and
- A is a C3-Coo cycloalkyl, 2 carbon atoms or more of said cycloalkyl
being optionally bridged by one or more carbon atoms, preferably by
1, 2, 3 or 4 carbon atoms, O-phenyl-pyrazolyl, 5 to 10 membered
heterocyclic group, optionally aromatic, comprising one, two, three or
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four heteroatoms selected from O, S or N, optionally substituted with
C~-Ca alkyl or O-C~-C4 alkyl, or a group of formula
R3 Ra
R3
R5
R
R~ R6
R or
- R3, R4, R5, R6 and R' are the same or different and are selected from H, C~-
C4
5 alkyl, ORS, SRS, SOR9, S02R9, halo, CN, CF3, OCF3, phenyl, O-phenyl, S-
phenyl, S02-morpholinyl, O-(CH2)3-pyrrolidinyl, COORS, S02NR9R'o,
CONR9R'°, NR9R'° and NHCOR'°;
- R9 and R'° are the same or different and are selected from H or C~-C4
alkyl
and the * represents the attachment point to the carbonyl group;
or, if appropriate, their pharmaceutically acceptable salts and/or isomers,
tautomers, solvates or isotopic variations thereof,
with the proviso that when n is 0, then Q' is not -NHCH3, and, when n is 1 or
2,
then:
1 ) Q' is *-NH-C~-C4alkyl, or *-N(R$)-Q2-A where A is
- C3-C~° cycloalkyl, 2 carbon atoms or more of said cycloalkyl being
optionally bridged by one or more carbon atoms,
- O-phenyl-pyrazolyl,
- 5 to 10 membered heterocyclic group, optionally aromatic,
comprinsing one, two, three or four heteroatoms selected from O, S
or N optionally substituted with C~-C4 alkyl or O-C~-C4 alkyl, said
heterocyclic group being other than pyridyl,
- a group of formula
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R3 Ra
R3
R5
R
s
R5 or R' R wherein one of R3 to R' is
CN, SOR9, S02R9, phenyl, O-phenyl, S-phenyl, S02-morpholinyl or O-(CH2)s-
pyrrolidinyl and/or,
2) when one of R' and R2 is H, the other is not CH3.
It has now been found that the compounds of formula (1 ) are agonists of the
X32
receptors, that are particularly useful for the treatment of X32-mediated
diseases
and/or conditions, and show good potency, in particular when administered via
the inhalation route.
In the present invention, the term "potent" means that the compounds of
formula (1 ) show an agonist potency for the ~i2 receptor, which is less than
10 nM
as measured by the cell-based assay described herein.
Preferably, the compounds of the invention are selective agonists of the ~i2
receptor. Preferably, the compounds of the invention show an agonist potency
for
the a2 receptor, which is at least about 100-fold higher as for the X33
receptor and
at least about 500-fold higher as for the ~1 receptor.
In the here above general formula (1 ), C~-C4 alkyl and C~-Ca 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-(C~-Ca)alkyl radicals, S-(C~-Ca)alkyl radicals
etc... .
Examples of suitable (C~-Ca)alkyl radicals are methyl, ethyl, n-propyl, iso-
propyl,
n-butyl, iso-butyl, sec-butyl, Pert-butyl.... Examples of suitable O-(C~-
Ca)alkyl
radicals are methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, iso-
butyloxy,
sec-butyloxy and tent-butyloxy....
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The C3-Coo cycloalkyl wherein 2 carbon atoms or more are optionally bridged by
one or more carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, adamantyl, bicyclo[3.1.1]heptane,
bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane. Preferred cycloalkyl groups are
cyclohexyl and adamantyl.
Examples of 5 to 10 membered heterocyclic group, optionally aromatic,
comprinsing one, two, three or four heteroatoms independently selected from
O, S or N are morpholinyl, pyrrolidinyl, piperidyl, piperazinyl, thienyl,
isothiazolyl,
oxazolyl, pyridyl, pyrimidyl oxazolyl, isoxazolyl, thiazolyl, furanyl,
imidazolyl,
pyrazolyl, pyrrolyl, pyridazinyl, pyrazinyl, triazolyl, tetrazolyl,
oxadiazolyl,
triazinyl, indolyl, quinolyl, isoquinolyl, benzofuranyl, quinazolyl,
quinoxalyl,
phthalazinyl, benzothiazolyl, benzoxazolyl, benzisothiazolyl, benzisoxazolyl,
benzimidazolyl, indazolyl and benzotriazolyl.
Preferred heterocyclic groups are pyrrolidinyl, pyridyl, pyrimidyl, quinolyl,
isoquinolyl, benzoimidazolyl and benzofuranyl.
Preferably said heterocyclic group contains 1 or 2 heteroatoms selected from
O, S or N. More preferably said heterocyclic group contains one or two
nitrogen
atoms.
Finally, halo denotes a halogen atom selected from the group consisting
of fluoro, chloro, bromo and iodo in particular fluoro or chloro.
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 )
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H O
N
(CH )
z~ Q
HO (1 )
11U
can be prepared using conventional procedures such as by the following
illustrative methods in which Q', Qz, 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):
H
N \ (2)
\ ~(CH2)~ OH
HO R R
O
11U
with an amine of formula NHz-C~-C4alkyl, -NH(R$)-Qz-A,
3
R3 Ra R Ra
s
R \ Ra Ra Ra
N
R5 H I ~ H H2
HN R ~R5
R6 , or R6 , Rs
wherein R8, Qz, A, p and R3 to R6 are as previously defined for compounds of
formula (1 ).
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, N'-dicyclohexylcarbodiimide), optionally
in
the presence of a catalyst (e.g. 1-hydroxybenzotriazole hydrate or 1-hydroxy-7-
azabenzotriazole), and optionally in the presence of a tertiary amine base
(e.g.
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N-methylmorpholine, triethylamine or diisopropylethylamine). The reaction may
be undertaken in a suitable solvent such as pyridine, dimethylformamide,
tetrahydrofuran, dimethylsulfoxide, dichloromethane or ethyl acetate, and at
temperature comprised between 10°C and 40°C (room temperature)
for a
period of 1-24 hours.
Said amine 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, protection, deprotection etc...) from commercially
available
material.
The acid of formula (2) may be prepared from the corresponding ester of
formula (4):
H
N ~ (4)
R' R2 ~(CH2)~ ORa
HO
O
11U
wherein Ra is a suitable acid protecting group, preferably a (C~-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 1 to 40
hours.
The ester of formula (4) may be prepared by reaction of an amine of
formula (5)
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H2N ~ (5)
~(CH2)~~ORa
R~ R2 I /
O
wherein Ra and n are as previously defined, with a bromide of formula (6)
Br
HO ( )
HD
In a typical procedure, the amine of formula (5) is reacted with a bromide
5 of formula (6) optionally in the presence of a solvent or mixture of
solvents (e.g.
dimethyl sulphoxide, 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.
10 The bromide of formula (6) may be prepared from the ester of formula
(7)
Br
HO (7)
V V
I
CH3
according to any method well-known to the one skilled in the art to prepare an
alcohol from an ester, without modifying the rest of the molecule.
In a typical procedure, the ester of formula (7) is reduced with borane
dimethylsulfide complex in tetrahydrofuran at a reflux for a period of 2
hours.
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The alcohol of formula (7) may be prepared as either the (R) or (S)
enantiomer according to methods well described in the literature (Tetrahedron
Letters 1994, 35(50), 9375).
The amine of formula (5) may be prepared as either the (R) or (S)
enantiomer from the corresponding protected amine of formula (8)
Rc
I
Rb~N ~ (8)
R~ R2 ~(CH2)~ ORa
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 T.W. GREENE, Protective Groups in Organic
Synthesis , A. Wiley-Interscience Publication, 1981.
The amine of formula (8) may be prepared as a single diastereomer by
reaction of an amine of formula HNRbRc with a ketone of formula (9):
H3C ~ (9)
~(CI"12)n ORa
O
wherein Ra, Rb, Rc and n are as previously defined.
In a typical procedure, the reaction of the ketone of formula (9) 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
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amine of formula (8) 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 salt and selectively crystallised from a
suitable solvent or mixture of solvents (e.g. isopropanol, ethanol, methanol,
diisopropyl ether or diisopropyl ether/methanol) to give (8) as a single
diastereomer.
The ketone of formula (9) where n=1 may be prepared by palladium
mediated coupling of an aryl halide of formula (10):
Hal
ORa (10)
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 (10) is reacted with a tin
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 (10) may be obtained by esterification of the
corresponding acid of formula (11 ):
Hal
OH (11)
O
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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 (11 ) 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.
The acid of formula (11 ) is a commercial product.
The amine of formula (5), where R' and R2 are both the same C~-C4 alkyl, may
be prepared according to the following scheme:
Scheme 1
O
Ra0 O HO ~
--~ ~ (CH2)~~OH
0 ~(CHz)~ OH R' RZ
x(12) (13)
O
HZN
(CH2)~~ORe
R~ R2
(5)
wherein R', R2 and Ra are as previously defined.
In a typical procedure, the ester of formula (12) is reacted with an
"activated" alkyl (organometallic alkyl such as R2MgBr, R2MgCl or R2Li) to
give
the corresponding tertiary alcohol of formula (13) using the method described
above.
Said tertiary alcohol of formula (13) is then treated with an alkyl nitrite
(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
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14
mentioned in textbooks. The resulting amino acid is then esterified using the
method described herein to give the amine of formula (5).
Alternatively, the amine of formula (5), where R' are R2 both the same
C~-C4 alkyl and n=0, may be prepared according to the following scheme:
Scheme 2
Ra0 ~ HO
Br --~ Br
O R~ R2 ~ /
(14) (15)
H2N ~ H2N ~ O
R~ R2 I / Br ----~ R~ R2
ORa
(16) (5)
wherein R', R2 and Ra are as previously defined.
In a typical procedure, the ester of formula (14) is reacted with an
"activated" alkyl (organometallic alkyl such as R2MgBr, R2MgCl or R2Li) to
give
the corresponding tertiary alcohol of formula (15) using the method described
above.
Said tertiary alcohol of formula (15) is then treated with an alkyl nitrite
(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 (16).
The resulting bromo amine (16) is treated with a suitable palladium
catalyst (e.g. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II))
under
an atmosphere of carbon monoxide using RaOH as solvent (e.g. MeOH, EtOH)
at elevated temperature (100°C) and pressure (100psi) to give the ester
of
formula (5).
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The ketone of formula (9) where n=2 may be prepared by reduction of an
alkene of formula (17)
H3C ~ O
(17)
O / ORa
In a typical procedure, a solution of the olefin of formula (17) in a suitable
5 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 (17) may be prepared by a palladium mediated
10 coupling of an activated olefin with an aryl halide of formula (18):
H3C
OI ~Hal (18)
In a typical procedure, the aryl halide (18) 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
15 acetate/tri-ortho-tolylphosphine of formula Pd(OAc)2/P(o-tol)3 or
(diphenylphosphino)ferrocenyl palladium chloride of formula dppfPdCl2) in a
sutiable 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 (18) is a commercial product.
The amine of formula (5), where R' and R2 are both H and n is 1, may be
prepared according to the following scheme:
Scheme 3
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16
O O
HO ~
HO ~~ ~ I ~ CH "ORa
~(CHz)n ORa ~( z)n
O ~ /
(19) (20)
O
HZN
CH ~pRa
/ ( 2)n
wherein R', R2 and Ra are as previously defined.
1n a typical procedure, the acid of formula (19) is preferentially reduced
to the corresponding alcohol (20) 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 (20) is then converted into _a leaving
group such as mesylate, tosylate, bromide or iodide and displaced with
appropriate amine nucleophile. The preferred nucleophile is azide ion which
can then be reduced to the primary amine via hydrogenation or
triphenylphosphine. Alternative nucleophiles could include ammonia or
alkyfamines such as benzylamine or allylamine and subsequent cleavage of the
alkyl group to furnish the amine.
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 (Protective Groups in Organic Synthesis, A. Wiley-Interscience
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17
Publication, 1981 ) or by P. J. Kocienski (Protecting groups, Georg Thieme
Verlag, 1994), can be used.
Alternatively, compounds of general formula (1 ) can also be prepared
according
to the following scheme:
Where in R', R2, Ra, Rb, Rc, n and Q~ are as previously defined.
Scheme 4
Rc
I Rc
,N \ I
Rb R~ Rz I (C~..~z)~ ORa ~ Rb'N \
R' Rz I (CHz)n OH
(8) (21) O
Rc
I
HzN \ ~--- ~N \
R~ Rz ~(CHz)~~Q~ Rb R~ Rz~(CHz)~ Q
t
(23) O
(22) O
PG
1
Br
PG'~O I ~ C
HO
H H
N
R~ \Rz ~(CHz)n~Qt
H ~O
(1 ) O
HO~
PG is a suitable bulky hydroxyl-protecting group and is preferably TBDMS
PG' is a suitable hydroxyl-protecting group such as benzyl
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In a typical procedure, the acid of formula (21 ) is obtained by hydrolysis of
the
ester of formula (8). This is achieved 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
befinreen
20°C and 100°C, for a period of 1 to 40 hours.
Amide of formula (22) is prepared by coupling of acid (21 ) with a suitable
amine of formula (3), (3') or (3"). The coupling is generally carried out in
an
excess of said amine as an acid receptor, with a conventional coupling agent
(e.g. 2-chloro-1,3-dimethylimidazolidinum hexafluorophosphate, 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or N, N'-
dicycfohexylcarbodiimide), optionally in the presence of a catalyst (e.g. 1-
hydroxybenzotriazole hydrate or 1-hydroxy-7-azabenzotriazole), and optionally
in the presence of a tertiary amine base (e.g. N-methylmorpholine,
triethylamine
or N,N-diisopropylethylamine). The reaction may be undertaken in a suitable
solvent such as pyridine, N,N-dimethylformamide, tetrahydrofuran,
dimethylsulfoxide, dichloromethane 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') 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, protection, deprotection etc) from commercially
available
material.
The amine of formula (23) can be prepared using standard methodology for
cleaving nitrogen protecting groups, such as those found in the text book T.W.
GREENE, Protective Groups in Organic Synthesis, A. Wiley-Interscience
Publication, 1981.
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When Rb or Rc=a-methylbenzyl, a typical deprotection procedure involves
treatment of a solution of the protected amine of formula (22), in a suitable
solvent (e.g. methanol, ethanol, ethyl acetate), with a suitable hydrogen
donor
such as ammonium formate or formic acid in the presence of a suitable
palladium catalyst (e.g. 20% palladium hydroxide on charcoal), at a
temperature between 25°C and elevated temperature, for 1-4 hours.
Compounds of formula (1 ) can be obtained by reaction of said amine (23) with
a bromide of formula (6). In a typical procedure amine (23) and bromide (6)
can
be heated together, optionally in the presence of a suitable solvent (e.g.
toluene
or xylene) and a suitable tertiary amine base (e.g. N-methylmorpholine,
triethylamine or N,N-diisopropylethylamine) at elevated temperature, for 18-48
hours.
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
hydroxyl 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 (Protective Groups in Organic Synthesis, A. Wiley-
Interscience Publication, 1981 ) 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.
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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.
5 Compounds of formula (I) wherein,
- R' and R2 are independently selected from H and C~-C4 alkyl,
- n is 0, 1 or 2 and,
- Q' is a group selected from:
R3
R3 Ra
R8 Ra
I I\
R5 * N /
1 ~ ~Rs
N
* ~ Rs Rs
10 *-NH-C~-C4alkyl, and a group *-N(R$)-Q2-A, wherein
- Q2 is a single bond or a C~-C4 alkylene,
- R8 is H or C,-C4 alkyl,
- p is 1 or 2, and
- A is a C3-Coo cycloalkyl, 2 carbon atoms or more of said cycloalkyl
15 being optionally bridged by one or more carbon atoms, pyridyl, or a
group of formula
R3 Ra
R3
\ ~ ~ Rs
R
R5 or R~ Rs
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21
- R3, R4 R5, R6 and R' are the same or different and are selected from H, C~-
C4
alkyl, ORS, SRS, SOR9, S02R9, halo, CN, CF3, OCF3, COORS, S02NR9R'°,
CONR9R'°, NR9R'°, NHCOR'°;
- R9 and R'° are the same or different and are selected from H or C~-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,
with the proviso that when n is 0, then Q' is not -NHCH3, and, when n is 1 or
2,
then:
1 ) Q' is *-NH-C~-C4alkyl, or *-N(R$)-Q2-A where A is C3-C~°
cycloalkyl, 2 carbon
atoms or more of said cycloalkyl being optionally bridged by one or more
carbon atoms, and/or,
2) when one of R' and R2 is H, the other is not CH3
are preferred
A preferred *-NH-C~-C4alkyl is NH-isopropyl.
Preferred compounds of formula 1 are those wherein Q' is *-N(R$)-Q2-A where
A is C3-C~° cycloalkyl, 2 carbon atoms or more of said cycloalkyl
being
optionally bridged by one or more carbon atoms, preferably cyclohexyl, or
adamantyl.
More preferably, n is 1, Q2 is CH2 or a bond and A is C3-C~°
cycloalkyl, 2 carbon
atoms or more of said cycloalkyl being optionally bridged by one or more
carbon atoms, preferably cyclohexyl, or adamantyl.
Other preferred compounds of formula (I) are those wherein n is 0.
Preferably n is 0 and Q' is a group of formula
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22
Rs Ra Rs
R$ Ra
_I I \
R5 * N /
N R
* ~ Rs Rs
or *-N(R$)-Q2-A, wherein Q2 is a single bond or a C~-Ca alkylene, R$ is H and
A
is naphthyl or
R3 Ra
R5
wherein R3, Ra, R5, Rs and R' are the same or different and are selected from
H, C~-Ca alkyl, ORS, SRS, SOR9, S02R9, halo, CF3, OCF3, COORS,
S02NR9R'°,
CONR9R'°, NR9R'°, NHCOR'°, wherein at least 2 of R3
to R' are equal to H;
wherein R9 and R'° are the same or different and are selected from H or
C~-Ca
alkyl and the * represent the attachment point to the carbonyl group.
Preferably Q' is
* *-
-N ~ ~ N I \
H
or
a group *-N(R8)-Q2-A, wherein Q2 is a single bond or a C~-Ca alkylene, R8 is H
or C~-Ca alkyl, and A is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, adamantyl, naphthyl or a group of formula
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23
R3 Ra
R5
R~ Rs
wherein R3, Ra, R5, Rs and R' are as defined above.
Preferably, A is a group of formula
R3 Ra
Rs
R~ Rs
wherein R3, Ra, R5, Rs and R' are selected from H, C~-Ca alkyl, ORS, SRS, CI,
F,
CF3, OCF3, COORS, S02NR9R'°, and at least 2 of R3 to R' represent
H,
wherein R9 and R'° are the same or different and are selected from H or
C~-Ca
alkyl.
Preferably, R3, Ra, R5, Rs and R' are the same or different and are selected
from H, CH3, OH, OCH3, SCH3, OCH2CH3, CI, F, CF3, OCF3, COOH, S02NH2,
and at least 2 of R3 to R' represent H.
Preferably, R3, Ra, R5, Rs and R' are the same or different and are selected
from H, CH3, OH, OCH3, OCH2CH3, CI, F, CF3, OCF3, COOH, S02NH2, and at
least 3 of R3 to R' are represent H.
Preferably, R8 is H, methyl or ethyl, more preferably H.
Preferably, Q2 is selected from a bond, -CH2-, -(CH2)2-, -(CHZ)3-, -C(CH3)2-
CH2-, -CH2-C(CHs)2-, and -CH(CH3)-.
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24
Preferably n is 0 or 1.
In the above groups of compounds" the following substituents are preferred:
R' and R2 are both CH3 or,
R' is H and R2 is CH3 or CH2-CH3 or,
R' and R2 are both H.
Particularly preferred are the compounds of the formula (1 ) as described
in the Examples section hereafter, i.e.
N-cycloheptyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;
N-(cyclohexylmethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-methylacetamide;
N-[(1 S)-1-cyclohexylethyl]-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;
2-{3-[(2 R)-2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-isopropylacetamide;
N-cyclopentyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;
N-(cyclobutylmethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;
N-(cyclopentylmethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;
N-cyclohexyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;
N-cyclobutyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;
N-(cyclohexylmethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;
N-(cyclopropylmethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;
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N-(cycloheptylmethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;
N-1-adamantyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;
5 N (1-adamantylmethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;
N-2-ad a m a ntyl-2-{3-[(2 R)-2-({(2 R)-2-hyd roxy-2-[4-h yd roxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;
N-(2-cycl oh exyl ethyl )-2-{3-[(2 R)-2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3-
10 (hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-methylacetamide;
N-cycloheptyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-methylacetamide;
N-cyclohexyl-N-ethyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;
15 N-(2-cyclohexyfethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;
N-(4-chlorobenzyl)-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide;
N-(2,6-dimethoxybenzyl)-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
20 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide;
N-benzyl-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide;
4-{(1 R)-2-[(2-{3-[2-(3,4-dihydroisoquinolin-2(1 H)-yl)-2-oxoethyl]phenyl}-1,1-
dimethylethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;
25 N-[2-fluoro-5-(trifluoromethyl)benzyl]-2-{3-[2-({(2R)-2-hydroxy-2-[4-
hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide;
N-(2,6-d ich to ro be n zyl )-2-{3-[2-( {(2 R)-2-hyd roxy-2-[4-h yd roxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide;
2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]phenyl}-N-[2-(methylthio)benzyl]acetamide;
N-(2,3-dimethylbenzyl)-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide;
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26
2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]phenyl}-N-[3-(trifluoromethyl)benzylJacetamide;
N-[4-chloro-3-(trifluoromethyl)benzyl]-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide;
N-[2-chloro-5-(trifluoromethyl)benzylJ-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropylJphenyl}acetamide;
N-[3,5-bis(trifluoromethyl)benzyl]-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide;
N-[3-fluoro-5-(trifluoromethyl)benzyl]-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide;
N-[2-(4-chlorophenyl)ethyl]-3-{2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxy-
methylphenyl)ethylamino]-2-methylpropyl}benzamide;
3-{2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-2-
methylpropyl}-N-[2-(4-methylphenyl)ethyl]benzamide;
3-{2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-2-
methyl-propyl}-N-[2-(4-trifluoromethylphenyl)ethyl]benzamide;
N-[2-(3,4-dichlorophenyl)ethyl]-3-{2-[(2R)-2-hydroxy-2-(4-hydroxy-3-
hydroxymethylphenyl)ethylamino]-2-methyl-propyl}-benzamide;
N-[2-(3,4-dimethylphenyl)ethyl]-3-{2-[(2R)-2-hydroxy-2-(4-hydroxy-3-
hydroxymethylphenyl)-ethylaminoJ-2-methylpropyl}benzamide;
3-{2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-
methyl-propyl}-N-(2-naphthalen-2-yl-ethyl)benzamide;
N-( 1,1-dimethyl-2-phenylethyl)-3-{2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxy-
methylphenyl)-ethylamino]-2-methylpropyl}benzamide;
3-{2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylaminoJ-2-
methylpropyl}-N-(2-methyl-2-phenylpropyl)benzamide;
N-(4-chlorobenzyl)-3-{2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxy-
methylphenyl)ethylaminoJ-2-methylpropyl}benzamide;
N-(2,6-dimethoxybenzyl)-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetamide;
N-(3,4-dichlorobenzyl)-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetamide;
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27
N-benzyl-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetamide;
N (2,3-dihydro-1 H-inden-2-yl)-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetamide;
2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}-N-(2-phenylethyl)acetamide;
2-{3-(2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}-N-(3-phenylpropyl)acetamide;
N-benzyl-3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide;
N-(3,4-d ich lorobenzyl )-3-[(2R)-2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide;
N-[2-fluoro-5-(trifluoromethyl)benzyl]-3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-
3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide;
N-(2,6-dimethoxybenzyl)-3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide;
- N-[2-(4-chlorophenyl)ethyl]-3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide;
N-(2,3-dihydro-1 H-inden-2-yl)-3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide;
3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]-N-(2-phenylethyl)benzamide;
3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]-N-[(1 R)-1-phenylethyl]benzamide;
3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]-N-(3-phenylpropyl)benzamide;
4-[(1 R)-2-({(1 R)-2-[3-(3,4-dihydroisoquinolin-2(1 H)-ylcarbonyl)phenyl]-1-
methylethyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol;
N-(2,3-dimethylbenzyl)-3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide;
N-(5,6-diethyl-2,3-dihydro-1 H-inden-2-yl)-3-[(2R)-2-({(2R)-2-hydroxy-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide;
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28
N-(4-chlorobenzyl)-3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide;
3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]-N-phenylbenzamide;
N-[4-(aminosulfonyl)benzyl]-3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide;
N-[2-(3-Fluorophenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]-N-(2-pyrrolidin-1-ylethyl)benzamide;
N-[2-(2,6-dichlorophenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-(4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
N-(2,3-dihydro-1 H-inden-2-ylmethyl)-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
N-(2-{4-[(butylamino)carbonyl]phenyl}ethyl)-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-
3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]-N-{2-[2-(phenylthio)phenyl]ethyl}benzamide;
N-(2-cyclohexylethyl)-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]-N-(3-phenylpropyl)benzamide;
3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]-N-(2-phenylethyl)benzamide;
N-[2-(3,6-dichloro-2-methylphenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
N-[2-(5-chloro-2-methoxyphenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]-N-[2-(3-methoxyphenyl)ethyl]benzamide;
N-[2-(3-ethoxyphenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
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29
3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]-N-{2-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]ethyl}benzamide;
3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]-N-{2-[2-(3-pyrrolidin-1-ylpropoxy)phenyl]ethyl}benzamide;
3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2
methylpropyl]-N-{2-[3-(3-pyrrolidin-1-ylpropoxy)phenyl]ethyl}benzamide;
N-[2-(4-Chlorophenyl)ethyl]-N-ethyl-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl] ethyl}amino)-2-
methylpropyl]phenyl}-N-(3-pyrrolidin-1-ylpropyl)acetamide;
N-(Cycloheptylmethyl)-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide;
N-1-Ada ma ntyl-2-{3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide;
N-Benzyl-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)
phenyl]ethyl}amino)-2-methylpropyl]phenyl}-N-methylacetamide;
N-[2-(4-Fluorophenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]-N-[2-(4-phenoxyphenyl)ethyl]benzamide;
N-[2-(4-ethoxyphenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
N-[2-(4-ethylphenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropylJ-N-[2-(6-methylpyridin-2-yl)ethyl]benzamide;
3-(2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenylJethyl}amino)-2-
methylpropyl]-N-[2-(2-methoxyphenyl)ethyl]benzamide;
methyl 4-[({3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}
amino)-2-methylpropyl]benzoyl}amino)methyl]benzoate;
N-[4-(dimethylamino)benzylJ-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
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N-{2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl}-3-[2-({(2R)-2-hydroxy-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
N-[2-(3-fluoro-4-methylphenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
N-[2-(2,3-difluoro-4-methylphenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]-N-(2-mesitylethyl)benzamide;
N-[2-(2,6-difluoro-3-methylphenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
10 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropylJbenzamide;
N-[2-(6-chloro-2-fluoro-3-methylphenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropylJbenzamide;
N-[2-(2-chloro-6-fluoro-3-methylphenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
15 N-[2-(5-fluoro-2-methylphenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
- N-{2-[3-fluoro-5-(trifluoromethyl)phenyl]ethyl}-3-[2-({(2R)-2-hydroxy-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
20 methylpropyl]-N-{2-[2-(trifluoromethyl)phenyl]ethyl}benzamide;
3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]-N-[2-(2,4,5-trimethylphenyl)ethyl]benzamide;
3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]-N-(2-pyridin-2-ylethyl)benzamide;
25 N-[2-(1 H-benzimidazol-2-yl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]-N-{2-[4-(morpholin-4-ylsulfonyl)phenyl]ethyl}benzamide;
N-[2-(3-chloro-2-hydroxyphenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
30 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
N-[4-fluoro-2-(trifluoromethyl)benzyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
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N-(3-chlorobenzyl)-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
N-(2-chlorobenzyl)-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
N-[2-(4,6-dimethylpyrimidin-2-yl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]-N-[2-(3-methylpyridin-2-yl)ethyl]benzamide;
N-[2-(2-chlorophenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
N-[2-( 1-ad a ma ntyl )ethyl]-3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]-N-[2-(1-naphthyl)ethyl]benzamide;
N-(2-(2,6-dimethylphenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
3-[2-({(2R)-2-hydroxy-2-(4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]-N-{2-[4-(methylthio)phenyl]ethyl}benzamide;
N-[2-(5-chloro-2-fluorophenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
N-[2-(2-chloro-4-fluorophenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]-N-[2-(4-methoxy-2,5-dimethylphenyl)ethyl]benzamide;
N-[2-(2,3-dichlorophenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]-N-[2-(4-methoxy-2,3-dimethylphenyl)ethyl]benzamide;
N-(2-biphenyl-4-ylethyl)-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
N-[2-(2,4-dimethylphenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
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N-[2-(2,3-dimethylphenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethy!)phenyl]ethyl}amino)-2-
methylpropyl]-N-{2-[3-(trifluoromethy!)phenyl]ethyl}benzamide;
N-[2-(4-chloro-2-fluorophenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
N-(2,5-dimethylbenzyl)-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
N-(3,4-Dichlorobenzyl)-3-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}propanamide;
3-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethy!)phenyl]ethyl}amino)-2-
methylpropyl]-N-{2-[4-(trifluoromethoxy)phenyl]ethyl}benzamide;
3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl)ethyl}amino)-2-
methylpropyl]-N-[2-(4-hydroxyphenyl)-2-methylpropyl]benzamide;
3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethy!)phenyl]ethyl}amino)-2-
methylpropyl]-N-[2-(4-hydroxy-3-methylphenyl)ethyl]benzamide;
N-[2-(4-hydroxy-2,3-dimethylphenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
N-[2-(4-hydroxy-2, 5-d imethyl phenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-
hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
N-(3,4-dichlorobenzyl)-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide;
N-(3,5-dichlorobenzyl)-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide;
2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethy!)phenyl]ethyl}amino)-2-
methylpropyl]phenyl}-N-(pyridin-2-ylmethyl)acetamide;
N-ethyl-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}
amino)-2-methylpropyl]-N-(3-phenylpropyl)benzamide;
3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethy!)phenyl]ethyl}amino)-2-
methylpropyl]-N-[3-(4-hydroxyphenyl)propyl]benzamide;
3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethy!)phenyl]ethyl}amino)-2-
methylpropyl]-N-[2-(3-methylphenyl)ethyl]benzamide;
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3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]-N-[2-(6-methoxypyridin-3-yl)ethyl]benzamide;
3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]-N-[3-(3-methoxyphenyl)propyl]benzamide;
N-[3-(4-Chlorophenyl)propyl]-3-{2-[(2R)-2-hydroxy-2-(4-hydroxy-3-
hydroxymethylphenyl)ethylamino]-2-methylpropyl}benzamide;
3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]-N-{2-[4-(1 H-pyrazol-1-yl)phenoxy]ethyl}benzamide;
N-[2-(3,4-difluorophenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide;
3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]-N-(2-quinolin-5-ylethyl)benzamide; and,
N-[3-(2-ethyl-2,3-dihydro-1-benzofuran-5-yl)propyl]-3-[2-({(2R)-2-hyd roxy-2-
[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide.
According to one aspect of the present invention, the compounds of formula (1
)
wherein the (CHZ)~-C(=O)Q' group is in position meta are generally preferred.
The compounds of formula (1 ) may also be optionally transformed into
pharmaceutically acceptable salts. In particular, these pharmaceutically
acceptable salts of the compounds of the formula (1 ) include the acid
addition
and the base salts (including disalts) thereof.
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,
cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate,
glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride,
hydrobromide/bromide, hydroiodide/iodide, hydrogen phosphate, isethionate,
D- and L-lactate, malate, maleate, malonate, mesylate, methylsulphate, 2-
napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,
phosphate/hydrogen, phosphate/phosphate dihydrogen, pyroglutamate,
saccharate, stearate, succinate, tannate, D- and L-tartrate, 1-hydroxy-2-
naphthoate tosylate and xinafoate salts.
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Suitable base salts are formed from bases which form non-toxic salts.
Examples include the aluminium, arginine, benzathine, calcium, choline,
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.
For a review on suitable salts, see Stahl and Wermuth, Handbook of
Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH, Weinheim,
Germany (2002).
Pharmaceutically acceptable salts of compounds of formula (1 ) may be
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
(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
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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,
5 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
10 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
15 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
20 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
25 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
30 Symposium Series (T. Higuchi and W. Stella) and 'Bioreversible Carriers in
Drug Design', Pergamon Press, 1987 (ed. E. B Roche, American
Pharmaceutical Association).
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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 (C~-C8)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
(C~-C6)alkanoyloxymethyl; and
(iii) where the compound of formula (1 ) contains a primary or secondary
amino functionality (-NH2 or -NHR where R ~H), an amide thereof, for
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 (C~-C~o)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 ).
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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 -~ -CH20H):
(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 (-NR'R2 ~ -NHR' or -NHR2);
(iv) where the compound of formula (1 ) contains a secondary amino group, a
primary derivative thereof (-NHR' -> -NH2);
(v) where the compound of formula (1 ) contains a phenyl moiety, a phenol
derivative thereof (-Ph -~ -PhOH); and
(I).(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 cisitrans (or ZJE) isomers
are possible. Where the compound contains, for example, a keto orstructural
isomers are interconvertible via a low oxime group or an aromatic
moiety,energy barrier, tautomeric isomerism ('tautomerism') can occur. This
can take the form 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.
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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 I-lysine, or
racemic,
for example, dl tartrate or dl-arginine..
Cisltrans 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
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.
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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).
According to one aspect of the present invention, the (R,R)-stereoisomer
of the formula below wherein R' is hydrogen and R2 is C~-C4 alkyl, preferably
methyl, and n and Q' are as defined above, is generally preferred: is
generally
preferred:
H
N
R~ R2 I~(CHZ)n Qi
HO
O
HU
wherein n and Q' are as defined above for compounds of formula (1 ).
The present invention includes all pharmaceutically acceptable isotopically-
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
include isotopes of hydrogen, such as 2H and 3H, carbon, such as "C, '3C and
14C~ chlorine, such as 36CI, fluorine, such as '8F, iodine, such as '231 and
'251,
nitrogen, such as '3N and 'SN, oxygen, such as 'S0, "O and '$O, phosphorus,
such as 32P, and sulphur, such as 35S.
Certain isotopically-labelled compounds of formula (1 ), for example, those
incorporating a radioactive isotope, are useful in drug and/or substrate
'tissue
distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-
14, i.e.
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'4C, 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, i.e. 2H, may afford
certain
5 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 "C, '8F,'S0 and '3N, can
10 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
15 analogous to those described in the accompanying Examples and Preparations
using an appropriate isotopically-labeled reagente in place of the non-labeled
reagent previously employed.
Pharmaceutically acceptable solvates in accordance with the invention include
20 those wherein the solvent of crystallization may be isotopically
substituted, e.g.
D20, ds-acetone, ds-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
25 (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
30 in conditions where there is an advantage in lowering gastric acidity,
particularly
in gastric and peptic ulceration.
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The compounds of formula (1 ) and their pharmaceutically acceptable
salts and derived forms as mentioned above can be administered according to
the invention to animals, preferably to mammals, and in particular to humans,
as pharmaceuticals for therapy and/or prophylaxis. They can be administered
per se, in mixtures with one another or in the form of pharmaceutical
preparations which as active constituent contain an efficacious dose of at
least
one compounds of formula (1 ), its pharmaceutically acceptable salts and/or
derived forms,, in addition to customary pharmaceutically innocuous excipients
and/or additives.
The compounds of formula (1 ), their pharmaceutically acceptable salts and/or
derived forms may be freeze-dried, spray-dried, or evaporatively dried to
provide a solid plug, powder, or film of crystalline or amorphous material.
Microwave or radio frequency drying may be used for this purpose.
The compounds of formula (1 ), their pharmaceutically acceptable salts and/or
derived forms may be administered alone or in combination with other drugs
and will generally 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 of the invention.
The
choice of excipient will to a large extent depend on the particular mode of
administration.
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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Liquid formulations include suspensions, solutions, syrups and elixirs. Such
formulations may be employed as fillers 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 may 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. In 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 microcrystalline 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.
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Tablets may also optionally comprise surface active agents, such as sodium
lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and
talc.
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
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44
dissolving or mucoadhesive and typically comprise a compound of formula (1 ),
a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a
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-
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 range
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, cooling 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 support or paper.
This may be done in a drying oven or tunnel, typically a combined coater
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
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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
et al (2001 ). The use of chewing gum to achieve controlled release is
described
in WO 00/35298.
5
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
10 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
15 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.
20 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
25 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-,
30 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
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46
release of the active compound. Examples of such formulations include drug-
coated stents and PGLApoly(dl lactic-coglycolic)acid (PGLA) microspheres.
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 Sci, 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. PowderjectT"", BiojectT"", 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.
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47
The pressurised container, pump, spray, atomizer, or nebuliser contains a
solution or suspension of the compounds) of the invention comprising, for
example, ethanol, aqueous ethanol, or a suitable alternative agent for
dispersing, solubilising, or extending release of the active, a propellants)
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 hydroxypropylmethylcellulose),
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 I-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 1Ng to 20mg of
the compound of the invention per actuation and the actuation volume may vary
from 1,u1 to 100,u1. 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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48
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 1 Omg 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
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49
polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic
acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose,
hydroxyethylcellulose, 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
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
5 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
10 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
15 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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51
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 formula (1 ), or a
pharmaceutically acceptable salt, derived forms or compositions thereof, or
one
or more X32 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 compounds) of
formula (1 ) and therapeutic agents) 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
compounds) of formula (1 ) and therapeutic agents) 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 compounds) of formula
(1 ) and therapeutic agents) 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 compounds) of formula
(1 ) and therapeutic agents) 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 compounds) 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-lipoxygenase 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 PDES 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, such as DAGR (dissociated agonists
of the corticoid receptor)
(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-B~ - and B2-receptor antagonists,
(o) Immunosuppressive agents,
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53
(p) Inhibitors of matrix metalloproteases (MMPs),
(q) Tachykinin NK~, 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 NFx~i pathway, e.g. IKK inhibitors,
(w) modulators of cytokine signalling pathways such as p38 MAP kinase, syk
kinase or JAK kinase inhibitor,
(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.
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
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,
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 (i2
receptor and thereby have a wide range of therapeutic applications, as
described further below, because of the essential role which the (32 receptor
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 (i2 receptor is involved. More specifically, the
present
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
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
5 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
10 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
15 respiratory distress syndrome CARDS), 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
20 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,
25 ~ 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 X32
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
~i2-
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 ~i2-mediated diseases and/or conditions in a mammal, including a human
being, in particular the diseases and/or conditions listed above, comprising
admidministering 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 ):
Example 1: N-cycloheptyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide
OH
N
HO CH3 ~ O
~U
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Ammonium fluoride (98mg, 2.64mmol) was added in one portion to a stirred
solution of 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-
hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N cycloheptylacetamide
(Preparation 1 ) (150mg, 0.26mmol) in methanol (3ml) and water (1.5m1) at
room temperature. The reaction was heated at 40°C for 18 hours and then
allowed to cool to room temperature. The solvent was removed in vacuo and
the residue dissolved in ethyl acetate (30m1) and water (20m1), the organic
layer
was separated, washed with brine (10m1), dried (magnesium sulfate) and the
solvent removed in vacuo to yield a clear oil. This was purified by flash
column
chromatography on silica gel eluting with dichloromethane:methanol: ammonia
(90:10:1 by volume) to furnish the title compound as a white foam (87mg).
'H NMR (400MHz, CD30D): 8 = 7.25-7.00 (6H, m), 6.85 (1H, d), 4.58 (3H, m),
3.80 (1 H, m), 3.40 (2H, s), 2.95 (2H, m), 2.75 (2H, m), 2.58 (1 H, m), 1.83
(2H,
m), 1.70-1.40 (10H, m), 1.05 (3H, d) ppm.
LRMS (electrospray) : m/z [M+Na]+ 477, [M-H]- 453.
- Example 2: N-(cyclohexylmethyl)-2-~3-[(2R)-2-({(2R)-2-hydroxy-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-
methylacetamide
H CH3
N ~ N
CH3 ~ OI
HO
HO
Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-
hydroxy-
3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(cyclohexylmethyl)-N-
methylacetamide (Preparation 2) using the method for example 1 to give the
title compound as a white foam.
'H NMR (400MHz, CD30D): 8 = 7.21 (2H, m), 7.00 (4H, m), 6.68 (1 H, d), 4.61
(3H, m), 3.71 (2H, s), 3.31 (2H, m), 3.20 (2H, m), 2.91 (5H, m), 2.71 (2H, m),
2.60 (1 H, m), 1.70 (5H, m), 1.22 (4H, m), 1.04 (3H, d), 0.95 (2H, m) ppm.
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58
LRMS (electrospray) : m/z [M+H]+ 469, [M+Na]+ 491.
Example 3: N-[(1S)-1-cyclohexylethyl]-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide
N ~ N CH3
CH3
HO
HU
Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl)oxy}-2-[4-
hydroxy-
3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-[(1 S)-1-
cyclohexylethyl]acetamide (Preparation 3) using the method for example 1 to
give the title compound as a white foam.
'H NMR (400MHz, CD30D): 8 = 7.20 (4H, m), 7.01 (2H, dd), 6.71 (1H, d), 4.60
(3H, m), 3.62 (1 H, m), 3.48 (1 H, d), 3.41 (1 H, d), 2.85 (2H, m), 2.63 (2H,
m),
2.58 (1 H, dd), 1.60 (5H, m), 1.40-1.02 (10H, m), 0.93 (2H, m) ppm.
LRMS (electrospray) : m/z [M+H]+ 469, [M+Na]+ 491.
Example 4: 2-{3-[(2R)-2-(f(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-isopropylacetamide
N ~ N CH3
HO CHs ~ O CH3
t1U
Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-
hydroxy-
3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-isopropylacetamide
(Preparation 4) using the method for example 1 to give the title compound as a
white foam.
'H NMR (400MHz, CD30D): 8 = 7.22 (1 H, d), 7.18-7.16 (1 H, d), 7.12-7.10 (1 H,
d), 7.07 (1 H, s), 7.04-6.99 (2H, t), 6.71-6.69 (1 H, d), 4.63-4.60 (3H, m),
3.97-
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59
3.90 (1 H, m), 3.41 (2H, s), 2.98-2.93 (1 H, q), 2.91-2.86 (1 H, dd), 2.74-
2.70 (2H,
dd), 2.60-2.55 (1 H, dd), 1.13-1.11 (6H, d), 1.08-1.07 (3H, d) ppm.
LRMS (electrospray) : m/z [M+H]+ 401, [M-H]- 399.
Example 5: N-cyclopentyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide
N N
HO CHa ~ O
NU
Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-
hydroxy-
3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-cyclopentylacetamide
(Preparation 5) using the method for example 3 to give the title compound as a
white foam.
'H NMR (400MHz, CD30D): b = 7.22 (1 H, d), 7.18-7.16 (1 H, d), 7.11-7.09 (1 H,
d), 7.06 (1 H, s), 7.04-6.98 (2H, t), 6.71-6.69 (1 H, d), 4.63-4.60 (3H, m),
4.10-
4.04 (1 H, m), 3.42 (2H, s), 2.98-2.93 (1 H, q), 2.90-2.85 (1 H, dd), 2.74-
2.69 (2H,
dd), 2.60-2.55 (1 H, dd), 1.94-1.86 (2H, m), 1.73-1.65 (2H, m), 1.62-1.54 (2H,
m), 1.47-1.39 (2H, m), 1.08-1.07 (3H, d), ppm.
LRMS (electrospray) : m/z [M+H]+ 427, [M-H]- 425.
CHN analysis : found C 68.48%, H 8.20%, N 6.35%; C25H~N204+0.66H20
requires C 68.49%, H 8.12%, N 6.39%.
Example 6: N-(cyclobutylmethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide
OH
N N
HO CHs / O
I-iU
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Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl)oxy}-2-[4-
hydroxy-
3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-
(cyclobutylmethyl)acetamide (Preparation 6) using the method for example 1 to
give the title compound as a white foam.
5 'H NMR (400MHz, CD30D): b = 7.22 (1 H, d), 7.18-7.16 (1 H, d), 7.12-7.10 (1
H,
d), 7.07 (1 H, s), 7.04-6.99 (2H, t), 6.71-6.69 (1 H, d), 4.62-4.59 (3H, m),
3.44
(2H, s), 3.18-3.17 (2H, d), 2.97-2.92 (1 H, q), 2.90-2.85 (1 H, dd), 2.73-2.69
(2H,
dd), 2.60-2.55 (1 H, dd), 2.50-2.43 (1 H, m), 2.04-1.97 (2H, m), 1.92-1.78
(2H,
m), 1.72-1.63 (2H, m), 1.08-1.06 (3H, d), ppm.
10 LRMS (electrospray) : m/z [M+H]+ 427, [M-H]- 425.
CHN analysis : found C 68.24%, H 8.09%, N 6.39%; C25H~N204+0.75H20
requires C 68.23%, H 8.13%, N 6.37%.
Example 7: N-(cyclopentylmethyl)-2-~3-[(2R)-2-({(2R)-2-hydroxy-2-[4-
15 hydroxy-3-(hydroxymethyl)phenyl)ethyl}amino)propyl]phenyl}acetamide
H H
N ~ N
CH3 ~ O
HO
HU
Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-
hydroxy-
3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-
(cyclopentylmethyl)acetamide (Preparation 7) using the method for example 1
20 to give the title compound as a white foam.
'H NMR (400MHz, CD30D): b = 7.22 (1 H, d), 7.19-7.17 (1 H, d), 7.12-7.11 (1 H,
d), 7.08 (1 H, s), 7.04-7.00 (2H, t), 6.71-6.69 (1 H, d), 4.63-4.60 (3H, m),
3.44
(2H, s), 3.10-3.08 (2H, d), 2.98-2.94 (1 H, q), 2.90-2.85 (1 H, dd), 2.74-2.70
(2H,
dd), 2.60-2.55 (1 H, dd), 2.07-2.00 (1 H, m), 1.73-1.66 (2H, m), 1.62-1.46
(4H,
25 m), 1.22-1.12 (2H, m), 1.08-1.07 (3H, d), ppm.
LRMS (electrospray) : m/z [M+H]+ 441, [M-H]- 439.
CHN analysis : found C 69.12%, H 8.19%, N 6.26%; C26HssN20a+0.62H20
requires C 69.13%, H 8.31 %, N 6.20%.
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Example 8: N-cyclohexyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide
N ~ N
CH3
HO
HO
Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-
hydroxy-
3-(hydroxymethyl)phenyl]ethyl}amino)propylJphenyl}-N-cyclohexylacetamide
(Preparation 8) using the method for example 1 to give the title compound as a
white. foam.
'H NMR (400MHz, CD30D): 8 = 7.22 (1 H, d), 7.19-7.17 (1 H, d), 7.12-7.10 (1 H,
1.0 d), 7.07 (1 H, s), 7.04-6.99 (2H, t), 6.71-6.69 (1 H, d), 4.64-4.60 (3H,
m), 3.64-
3.56 (1 H, m), 3.42 (2H, s), 3.00-2.94 (1 H, q), 2.91-2.86 (1 H, dd), 2.76-
2.72 (2H,
dd), 2.61-2.56 (1 H, dd), 1.86-1.80 (2H, m), 1.75-1.70 (2H, m), 1.65-1.59 (1
H,
m), 1.38-1.28 (2H, m), 1.25-1.15 (3H, m), 1.09-1.07 (3H, d), ppm.
LRMS (electrospray) : m/z [M+HJ+ 441, [M-H]- 439.
CHN analysis : found C 68.49%, H 8.27%, N 6.14%; C26HssN20a+0.85H20
requires C 68.50%, H 8.34%, N 6.14%.
Example 9: N-cyclobutyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide
N ~ N
CH3 / O
HO
Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tent-butyl(dimethyl)silyl]oxy}-2-[4-
hydroxy-
3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-cyclobutylacetamide
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(Preparation 9) using the method for example 1 to give the title compound as a
white foam.
'H NMR (400MHz, CD30D): 8 = 7.21 (1 H, d), 7.18-7.16 (1 H, d), 7.11-7.09 (1 H,
d), 7.06 (1 H, s), 7.03-6.98 (2H, t), 6.70-6.68 (1 H, d), 4.62-4.59 (3H, m),
4.29-
4.21 (1 H, m), 3.40 (2H, s), 2.88-2.43 (1 H, q), 2.90-2.85 (1 H, dd), 2.73-
2.68 (2H,
m), 2.61-2.56 (1 H, dd), 2.29-2.21 (2H, m), 1.98-1.89 (2H, m), 1.76-1.66 (2H,
m), 1.08-1.07 (3H, d), ppm.
LRMS (electrospray) : m/z [M+H]+ 413, [M-H]- 411.
CHN analysis : found C 67.18%, H 7.75%, N 6.51 %; C24Hs2N20a+0.93H20
requires C 67.15%, H 7.95%, N 6.53%.
Example 10: N-(cyclohexylmethyl)-2-~3-[(2R)-2-({(2R)-2-hydroxy-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide
N ~ N
CH3 ~ OI .
HO
HO
Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-
hydroxy-
3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-
(cyclohexylmethyl)acetamide (Preparation 10) using the method for example 1
to give the title compound as a yellow foam.
'H NMR (400MHz, CD30D): 8 = 7.21-7.20 (1 H, m), 7.18-7.16 (1 H, d), 7.11-7.09
(1 H, d), 7.06 (1 H, s), 7.02-6.98 (2H, t), 6.70-6.68 (1 H, d), 4.61-4.58 (3H,
m),
3.44 (2H, s), 2.99-2.98 (2H, d), 2.94-2.83 (2H, m), 2.71-2.67 (2H, q), 2.58-
2.53
(1 H, dd), 1.70-1.60 (5H, m), 1.49-1.40 (1 H, m), 1.26-1.12 (3H, m), 1.06-1.05
(3H, d), 0.93-0.83 (2H, m) ppm.
LRMS (electrospray) : m/z [M+H]+ 455, [M+Na]+ 477, [M-H]- 453.
CHN analysis : found C 70.07%, H 8.50%, N 6.17%; C2~H38N204+0.45H20
requires C 70.09%, H 8.47%, N 6.05%.
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Example 11: N-(cyclopropylmethyl)-2-{3-[(2R)-2-( f (2R)-2-hydroxy-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide
N \ N
CH3
HO
HU
Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tent-butyl(dimethyl)silyl]oxy}-2-[4-
hydroxy-
3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-
(cyclopropylmethyl)acetamide (Preparation 11 ) using the method for example 1
to give the title compound as a white foam.
' H NMR (400MHz, CD30D): 8 = 7.21-7.16 (2H, m), 7.12-7.10 (1 H, d), 7.07 (1 H,
s), 7.02-6.98 (2H, m), 6.70-6.68 (1 H, d), 4.61-4.58 (3H, m), 3.45 (2H, s),
3.03-
3.01 (2H, d), 2.95-2.83 (2H, m), 2.71-2.67 (2H, m), 2.59-2.54 (1 H, m), 1.07-
1.06
(3H, d), 0.97-0.90 (1 H, m), 0.48-0.43 (2H, q), 0.19-0.15 (2H, q) ppm.
LRMS (electrospray) : m/z [M+H]+ 413, [M+Na]+ 435, [M-H]~ 411.
CHN analysis : found C 67.85%, H 7.82%, N 6.48%; C24Hs2N20a+0.70H20
requires C 67.80%, H 7.92%, N 6.59%.
Example 12: N-(cycloheptylmethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide
N N
CH3 / O
HO
HO
Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tent-butyl(dimethyl)silyl]oxy}-2-[4-
hydroxy-
3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-
(cycloheptylmethyl)acetamide (Preparation 12) using the method for example 1
to give the title compound as a white foam.
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'H NMR (400MHz, CD30D): d = 7.24-6.95 (6H, m), 6.72-6.69 (1 H, d), 4.62 (2H,
s), 4.62-4.59 (1 H, m), 3.26 (2H, s), 3.00-2.97 (2H, d), 2.98-2.54 (m, 5H),
1.70-
1.02 (m, 13H), 1.05 (3H, d) ppm.
LRMS (electrospray) : m/z [M+H]+ 469.
Example 13: N-1-adamantyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide
N ~ N
CH3 ~ IOI
HO
HU
Prepared from N-1-adamantyl-2-{3-[(2R)-2-({(2R)-2-{[tert-
butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide (Preparation 13)
using the method for example 1 to give the title compound as a white foam.
'H NMR (400MHz, CD30D): d = 7.22-6.96 (6H, m), 6.68-6.65 (1 H, d),-4.63-4.59
(3H, m), 3.38 (2H, s), 2.98-2.92 (1 H, q), 2.88-2.54 (4H, m), 2.02 (3H, s),
2.00
(6H, s), 1.68 (6H, s), 1.05-1.03 (3H, d) ppm.
LRMS (electrospray) : m/z [M-H]- 491.
Example 14: N-(1-adamantylmethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide
N ~ N
CH3 ~ O
HO
HU
Prepared from N-(1-adamantylmethyl)-2-{3-[(2R)-2-({(2R)-2-{[tert-
butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-
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(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide (Preparation 14)
using the method for example 1 to give the title compound as a white foam.
'H NMR (400MHz, CD30D): d = 7.22-7.12 (5H, m), 7.06-7.00 (1H, t), 6.72-6.70
(1 H, d), 4.62-4.59 (1 H, m), 4.61 (2H, s), 3.46 (2H, s), 2.98-2.92 (1 H, q),
2.91-
5 2.54 (6H, m), 2.90 (3H, s), 1.68-1.56 (6H, m), 1.42 (6H, s), 1.06-1.04 (3H,
d)
ppm.
LRMS (electrospray) : m/z [M+H]+ 507, [M+Na]+ 529.
Example 15: N-2-adamantyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
10 (hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide
N N
HO CH3 ~ O
11U
Prepared from N-2-adamantyl-2-{3-[(2R)-2-({(2R)-2-{[tert-butyl
(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)
propyl]phenyl}acetamide (Preparation 15) using the method for example 1 to
15 give the title compound as a white foam.
'H NMR (400MHz, CD30D): d = 7.24-7.10 (5H, m), 7.05-6.98 (1 H, t), 6.70-6.68
(2H, d), 4.61 (2H, s), 4.62-4.58 (1 H, m), 3.94 (1 H, s), 3.54 (2H, s), 2.96-
2.52
(5H, m), 1.96-1.75 (12H, m), 1.62-1.56 (2H, d), 1.05-1.03 (3H, d) ppm.
LRMS (electrospray) : m/z [M-H]- 491.
Example 16: N-(2-cyclohexylethyl)-2-~3-((2R)-2-({(2R)-2-hydroxy-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-
methylacetamide
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H CHs
N ~ N
CH3
HO
HU
Prepared from 2-(3-[(2R)-2-({(2R)-2-{[tent-butyl(dimethyl)silyl]oxy}-2-[4-
hydroxy-
3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2-cyclohexylethyl)-N-
methylacetamide (Preparation 16) using the method for example 1 to give the
title compound as a white foam.
'H NMR (400MHz, CD30D): d = 7.23-7.00 (6H, m), 6.71-6.68 (1 H, d), 4.61 (2H,
s), 4.61-4.57 (1 H, m), 3.71-3.68 (2H, m), 4.61-4.57 (1 H, m), 3.71-3.68 (2H,
m),
3.43-3.26 (2H, m), 2.97-2.52 (8H, m), 1.78-0.82 (13H, m), 1.08-1.06 (3H, d)
ppm.
LRMS (electrospray) : m/z [M+Na]+ 505, [M-H]- 491.
Example 17: N-cycloheptyl-2-(3-[(2R)-2-(~(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-methylacetamide
OH H CH3
N ~ N
CH3 ~ IOI
HO
HO
Prepared from 2-(3-[(2R)-2-(((2R)-2-([tent-butyl(dimethyl)silyl]oxy}-2-[4-
hydroxy-
3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-cycloheptyl-N-
methylacetamide (Preparation 17) using the method for example 1 to give the
title compound as a white foam.
'H NMR (400MHz, CD30D): d = 7.23-6.96 (6H, m), 6.72-6.64 (1 H, dd), 4.62-
4.60 (2H, d), 4.61-4.58 (1 H, m), 4.58-4.51 (0.5H, m), 3.70-3.63 (0.5H, m),
3.75-
3.67 (2H, d), 2.95-2.50 (5H, m), 2.82-2.78 (3H, d), 1.72-1.20 (12H, m), 1.02-
1.00 (3H, 2d) ppm.
LRMS (electrospray) : m/z [M+Na]+ 491.
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Example 18: N-cyclohexyl-N-ethyl-2-{3-[(2R)-2-( f(2R)-2-hydroxy-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide
~CH3
N ~ N
CH3
HO
HO
Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tent-butyl(dimethyl)silyl]oxy}-2-[4-
hydroxy-
3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-cyclohexyl-N-
ethylacetamide (Preparation 18) using the method for example 1 to give the
title
compound as a white foam.
'H NMR (400MHz, CD30D): d = 7.25-6.98 (6H, m), 6.70-6.67 (1 H, d), 4.61 (2H,
s), 4.60-4.57 (1 H, m), 3.72 (2H, s), 3.65-3.61 (1 H, m), 3.30-3.24 (2H, q),
2.95
2.50 (5H, m), 1.84-1.08 (10H, m), 1.12-1.08 (3H, t), 1.04-1.02 (3H, d) ppm.
LRMS (electrospray) : m/z [M+Na]+ 491.
Example 19: N-(2-cyclohexylethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide
N ~ N
CH3
HO
HU
Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tent-butyl(dimethyl)silyl]oxy}-2-[4-
hydroxy-
3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2-
cyclohexylethyl)acetamide (Preparation 19) using the method for example 1 to
give the title compound as a white foam.
'H NMR (400MHz, CD30D): a = 7.22-6.98 (6H, m), 6.68-6.66 (1 H, d), 4.61 (2H,
s), 4.60-4.58 (1 H, m), 3.42 (2H, s), 3.20-3.16 (2H, t), 2.96-2.56 (5H, m),
1.73-
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1.60 (5H, m), 1.40-1.35 (2H, q), 1.30-1.12 (4H, m), 1.07-1.05 (3H, d), 0.92-
0.81
(2H, m) ppm.
LRMS (electrospray) : m/z [M+Na]+ 491.
Example 20: N-(4-chlorobenzyl)-2-{3-[2-(f(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide
OH / CI
N \ N \ I
sC CH3 I / O
HO
11U
Prepared according to the procedure used for preparation 1 using (3-[2-(((2R)-
2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to
give the title compound as a white foam.
'H NMR (400MHz, CD30D): d = 7.37-7.36 (1 H, d), 7.32-7.17 (8H, m), 7.13-7.11
(1 H, d), 6.82-6.80 (1 H, d), 4.75-4.71 (1 H, m), 4.70 (2H, s), 4.37 (2H, s),
3.58
(2H, s), 3.02-2.96 (1 H, m), 2.93-2.89 (1 H, m), 2.86-2.78 (2H, m), 1.16 (3H,
s),
1.14 (3H, s) ppm.
LRMS (electrospray) : m/z [M+H]+ 497, [M+Na]+ 519, [M-H]- 495.
Example 21: N-(2,6-dimethoxybenzyl)-2-{3-[2-(~(2R)-2-hydroxy-2-[4-hydroxy-
3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide
CH3
O /
\
HO 3C CH3 I ~ O O
CH3
~U
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Prepared according to the procedure used for preparation 1 using {3-[2-({(2R)-
2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to
give the title compound as a white foam.
'H NMR (400MHz, CD30D): d = 7.39-7.38 (1 H, d), 7.32-7.13 (6H, m), 6.83-6.81
(1 H, d), 6.66 (1 H, s), 6.64 (1 H, s), 4.80-4.77 (1 H, m), 4.70 (2H, s), 4.46
(2H, s),
3.80 (6H, s), 3.52 (2H, s), 3.15-3.00 (2H, m), 2.88 (2H, m), 1.21 (3H, s),
1.20
(3H, s) ppm.
LRMS (electrospray) : m/z [M+H]+ 523, [M+Na]+ 545, [M-H]- 521.
Example 22: N-benzyl-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide
N \ N \
sC CH3 ~ O
HO
HO
Prepared according to the procedure used for preparation 1 using {3-[2-({(2R)-
2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to
give the title compound as a white foam.
'H NMR (400MHz, CD30D): a = 7.38-7.37 (1 H, d), 7.33-7.17 (9H, m), 7.12-7.11
(1 H, m), 6.82-6.80 (1 H, d), 4.75-4.72 (1 H, dd), 4.70 (2H, s), 4.40 (2H, s),
3.58
(2H, s), 3.02-2.96 (1 H, m), 2.93-2.89 (1 H, m), 2.86-2.78 (2H, m), 1.16 (3H,
s),
1.15 (3H, s) ppm.
LRMS (electrospray) : m/z [M+H]+ 463, [M+Na]+ 485, [M-H]- 461.
Example 23: 4-{(1R)-2-[(2-{3-[2-(3,4-dihydroisoquinolin-2(11-x-yl)-2-
oxoethyl]phenyl}-1,1-dimethylethyl)amino]-1-hydroxyethyl}-2-
(hydroxymethyl)phenol
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N \ N
H 3C CHa ~ O
O
NU
Prepared according to the procedure used for preparation 1 using {3-[2-({(2R)-
2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to
5 give the title compound as a white foam.
'H NMR (400MHz, CD30D): d = 7.36-7.35 (1 H, d), 7.29-7.24 (1 H, m), 7.22-7.13
(5H, m), 7.12-7.09 (2H, m), 7.04-7.02 (1 H, d), 6.80-6.78 (1 H, m), 4.74 (1 H,
s),
4.71-4.66 (4H, m), 3.90-3.89 (2H, m), 3.86-3.82 (1 H, m), 3.78-3.75 (1 H, m),
2.94-2.86 (2H, m), 2.81-2.66 (4H, m), 1.08-1.01 (6H, m) ppm.
10 LRMS (electrospray) : m/z [M+H]+ 489, [M+Na]+ 511, [M-H]- 487.
Example 24: N-[2-fluoro-5-(trifluoromethyl)benzyl]-2-~3-[2-({(2R)-2-hydroxy-
2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]phenyl}acetamide
F /
N \ N \ ~ F
HO 3C CH3 ~ O F F
Prepared according to the procedure used for preparation 1 using {3-[2-({(2R)-
2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to
give the title compound as a white foam.
'H NMR (400MHz, CD30D): d = 7.62-7.58 (1 H, m), 7.56-7.54 (1 H, m), 7.33-
7.32 (1 H, d), 7.28-7.12 (5H, m), 7.08-7.06 (1 H, d), 6.78-6.76 (1 H, d), 4.70-
4.67
(1 H, m), 4.65 (2H, s), 4.46 (2H, s), 3.55 (2H, s), 2.96-2.91 (1 H, m), 2.86-
2.81
(1 H, m), 2.80-2.72 (2H, m), 1.10 (3H, s), 1.09 (3H, s) ppm.
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LRMS (electrospray) : m/z [M+H]+ 549, [M+Na]+ 571, [M-H]~ 547.
Example 25: N-(2,6-dichlorobenzyl)-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide
CI /
N \ N
sC CH3 I / O CI
HO
11U
Prepared according to the procedure used for preparation 1 using {3-[2-({(2R)-
2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to
give the title compound as a white foam.
'H NMR (400MHz, CD30D): d = 7.45-7.43 (2H, m), 7.39-7.38 (1H, d), 7.34-7.27
(2H, m), 7.23-7.19 (3H, m), 7.14-7.12 (1 H, m), 6.83-6.81 (1 H, d), 4.79-4.76
(1 H,
_ m), 4.71 (2H, s), 4.70 (2H, s), 3.55 (2H, s), 3.09-2.97 (2H, m), 2.88 (2H,
s), 1.22
(3H, s), 1.21 (3H, s) ppm.
LRMS (electrospray) : m/z [M+H]+ 531, [M+Na]+ 553, [M-H]- 529.
Example 26: 2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}-N-[2-
(methylthio)benzyl]acetamide
N \ N
H 3C CHs I / O ,S
O HaC
I1U
Prepared according to the procedure used for preparation 1 using {3-[2-({(2R)-
2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
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methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to
give the title compound as a white foam.
'H NMR (400MHz, CD30D): d = 7.36-7.10 (10H, m), 6.81-6.79 (1 H, d), 4.73-
4.69 (1 H, m), 4.69 (2H, s), 4.47 (2H, s), 3.59 (2H, s), 2.99-2.94 (1 H, m),
2.89-
2.84 (1 H, m), 2.81-2.76 (2H, m), 2.48 (3H,s), 1.15 (3H, s), 1.13 (3H, s) ppm.
LRMS (electrospray) : m/z [M+H]+ 509, [M+Na]+ 531, [M-H]- 507.
Example 27: N-(2,3-dimethylbenzyl)-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide
N \ N \
CH3
aC CH3 I / O CH3
HO
Prepared according to the procedure used for preparation 1 using {3-[2-({(2R)-
2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to
give the title compound as a white foam.
'H NMR (400MHz, CD30D): d = 7.37-7.36 (1H, m), 7.30-7.16 (4H, m), 7.12-
7.01 (4H, m), 6.82-6.80 (1 H, d), 4.74-4.71 (1 H, m), 4.69 (2H, s), 4.40 (2H,
s),
3.56 (2H, s), 3.01-2.96 (1 H, m), 2.92-2.88 (1 H, m), 2.86-2.77 (2H, m), 2.29
(3H,
s), 2.18 (3H, s), 1.16 (3H, s), 1.14 (3H, s) ppm.
LRMS (electrospray) : m/z [M+H]+ 491, [M+Na]+ 513, [M-H]- 489.
Example 28: 2-{3-[2-({(2R)-2-hydroxy-2-(4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}-N-[3-
(trifluoromethyl)benzyl]acetamide
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N ~ N \ F
CH3 ~ O F F
HO
HO
Prepared according to the procedure used for preparation 1 using {3-[2-({(2R)-
2-hyd.roxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl)amino)-2-
methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to
give the title compound as a white foam.
'H NMR (400MHz, CD30D): d = 7.56-7.47 (4H, m), 7.36-7.35 (1H, m), 7.28-
7.15 (4H, m), 7.11-7.09 (1 H, d), 6.80-6.78 (1 H, d), 4.73-4.69 (1 H, m), 4.69
(2H,
s), 4.47 (2H, s), 3.59 (2H, s), 2.99-2.94 (1 H, m), 2.89-2.85 (1 H, m), 2.84-
2.75
(2H, m), 1.14 (3H, s), 1.13 (3H, s) ppm.
LRMS (electrospray) : m/z [M+H]+ 531, [M+Na]+ 553, [M-H]- 529.
Example 29: N-[4-chloro-3-(trifluoromethyl)benzyl]-2-{3-[2-({(2R) ~-hydroxy-
2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]phenyl}acetamide
OH / CI
N ~ N \ ~ F
sC CH ~ ~ F
HO 3 ~ O F
Prepared according to the procedure used for preparation 1 using {3-[2-({(2R)-
2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to
give the title compound as a white foam.
'H NMR (400MHz, CD30D): d = 7.64-7.63 (1 H, m), 7.54-7.52 (1 H, m), 7.47-
7.45 (1 H, m), 7.34-7.33 (1 H, m), 7.27-7.14 (4H, m), 7.09-7.08 (1 H, d), 6.80-
6.78
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(1 H, d), 4.71-4.67 (1 H, m), 4.69 (2H, s), 4.43 (2H, s), 3.58 (2H, s), 2.96-
2.91
(1 H, m), 2.84-2.80 (1 H, m), 2.81-2.72 (2H, m), 1.12 (3H, s), 1.09 (3H, s)
ppm.
LRMS (electrospray) : m/z [M+H]+ 565, [M+Na]+ 587, [M-H]- 563.
Example 30: N-[2-chloro-5-(trifluoromethyl)benzyl]-2-~3-[2-(f(2R)-2-hydroxy-
2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]phenyl}acetamide
CI
N \ N \ I F
CH I ~ F
HO 3 ~ O F
HU
Prepared according to the procedure used for preparation 1 using {3-[2-({(2R)-
2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to
give the title compound as a white foam.
'H NMR (400MHz, CD30D): d = 7.63-7.56 (3H, m), 7.36-7.35 (1 H, d), 7.30-
7.21 (3H, m), 7.18-7.16 (1 H, dd), 7.12-7.11 (1 H, d), 6.81-6.79 (1 H, d),
4.73-4.69
(1 H, m), 4.69 (2H, s), 4.54 (2H, s), 3.62 (2H, s), 3.03-2.91 (1 H, m), 2.89-
2.84
(1 H, m), 2.86-2.75 (2H, m), 1.14 (3H, s), 1.12 (3H, s) ppm.
LRMS (electrospray) : m/z [M+H]+ 565, [M+Na]+ 587, [M-H]- 563.
Example 31: N-[3,5-bis(trifluoromethyl)benzyl]-2-{3-[2-(~(2R)-2-hydroxy-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]phenyl}acetamide
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F
OH
N ~ N F
C CHs ~ O r
HO
HO
Prepared according to the procedure used for preparation 1 using {3-[2-({(2R)-
2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to
5 give the title compound as a white foam.
'H NMR (400MHz, CD30D): d = 7.86-7.84 (3H, m), 7.35 (1H, s), 7.28-7.15 (4H,
m), 7.11-7.09 (1 H, d), 6.81-6.79 (1 H, d), 4.71-4.68 (1 H, m), 4.69 (2H, s),
4.54
(2H, s), 3.60 (2H, s), 2.96-2.91 (1 H, m), 2.83-2.79 (1 H, m), 2.80-2.71 (2H,
m),
1.10 (3H, s), 1.08 (3H, s) ppm.
10 LRMS (electrospray) : m/z [M+H]+ 599, [M+Na]+ 621, [M-H]- 597.
Example 32: N-[3-fluoro-5-(trifluoromethyl)benzyl]-2-{3-[2-({(2R)-2-hydroxy-
2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]phenyl}acetamide
N ~ N F
C CH3 ~ 0 r
HO
15 ~U
Prepared according to the procedure used for preparation 1 using {3-[2-({(2R)-
2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to
give the title compound as a white foam.
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'H NMR (400MHz, CD30D): a = 7.40 (1 H, s), 7.36-7.16 (7H, m), 7.13-7.11 (1 H,
d), 6.82-6.80 (1 H, d), 4.74-4.69 (1 H, m), 4.69 (2H, s), 4.47 (2H, s), 3.60
(2H, s),
3.01-2.94 (1 H, m), 2.91-2.87 (1 H, m), 2.85-2.77 (2H, m), 1.15 (3H, s), 1.13
(3H,
s) ppm.
LRMS (electrospray) : m/z [M+H]+ 549, [M+Na]+ 571, [M-H]~ 547.
Example 33: N-[2-(4-chlorophenyl)ethyl]-3-{2-[(2R)-2-hydroxy-2-(4-hydroxy-
3-hydroxy-methylphenyl)ethylamino]-2-methylpropyl}benzamide
OH ~ / CI
H
N
~N
I
sC CH3 I / H
HO
HU
3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-
phenyl)ethylamino]-2-methylpropyl}-N-[2-(4-chlorophenyl)ethyl]benzamide
(Preparation 38) (470mg, 0.77mmol) and ammonium fluoride (280mg,
7.70mmol) in methanol (3ml) and water (1.7m1) were heated to 43°C for
18
hours. The solvent was removed in vacuo and the product purified by flash
column chromatography on silica gel eluting with
dichloromethane:methanol:ammonia (95:5:0.5 by volume). The resulting
compound was taken up in methanol and evaporated (x3) to yield a white foam
(320 mg). A small sample was recrystallised (hexane:ethyl acetate) to give a
white solid (mp 139-140 °C).
'H NMR (400MHz, CD30D) 8 = 7.64-7.60 (2H, m), 7.37-7.20 (7H, m), 7.11 (1 H,
dd), 6.74 (1 H, d), 4.68-4.65 (3H, m), 3.57 (2H, m), 2.98-2.87 (4H, m), 2.77-
2.70
(2H, m), 1.12 (3H, s), 1.05 (3H, s).
LRMS (electrospray) m/z 497 [M+H]+, 519 [M+Na]+
Analysis for C28Hs3CIN204Ø5 H20 0.3 C4H~o0 Calc. (Found) C 66.63 (66.39),
H 6.95 (7.06), N 5.31 (5.30) %.
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Example 34: 3-~2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-
ethylamino]-2-methylpropyl}-N-[2-(4-methylphenyl)ethyl]benzamide
O / CH3
H
N
~N
I
H 3C CHs I / H
O
HU
Prepared from 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-
hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}-N-[2-(4-
methylphenyl)ethyl]benzamide (Preparation 39) using the method for example
33 to give the title compound as a white foam.
'H NMR (400MHz, CD30D) 8 = 7.69-7.65 (2H, m), 7.37-7.30 (3H, m), 7.14-7.06
(5H, m), 6.75 (1 H, d), 4.67-4.64 (3H, m), 3.59-3.54 (2H, m), 2.96-2.84 (4H,
m),
2.77-2.69.(2H, m), 2.28 (3H, s), 1.11 (3H, s), 1.04 (3H, s).
LRMS (electrospray) m/z 477 [M+H]+, 499 [M+Na]+
Analysis for C29HasN20aØ5 H20 0.3 C4H~o0 Calc. (Found) C 71.42 (71.62), H
7.94 (7.88), N 5.52 (5.57) %.
Example 35: 3-f2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-
ethylamino]-2-methyl-propyl}-N-[2-(4-
trifluoromethylphenyl)ethyl]benzamide
O / CF3
H
N
~N
I
HO 3C CH3 I / H
HU
Prepared from 3-(2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-
hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl}-N-[2-(4-
trifluoromethylphenyl)ethyl]benzamide (Preparation 40) using the method for
example 33 to give the title compound as a white foam.
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'H NMR (400MHz, CD30D) 8 = 7.68-7.62 (1 H, m), 7.61 (1 H, bs), 7.66 (2H, d),
7.42 (2H, d), 7.38-7.30 (3H, m), 7.12 (1 H, dd), 6.75 (1 H, dd), 4.68-4.65 (1
H),
4.65 (2H, s), 3.61 (2H, m), 3.00 (2H, t), 2.92 (1 H, dd), 2.86 (1 H, d), 2.73
(1 H,
dd), 2.69 (1 H, d), 1.11 (3H, s), 1.04 (3H, s).
LRMS (electrospray) m/z 531 [M+H]+
HRMS for C2gH34F3N2O4 531.2447 [M+H]+ found 531.2465.
Example 36: N-[2-(3,4-dichlorophenyl)ethyl]-3-{2-[(2R)-2-hydroxy-2-(4-
hydroxy-3-hydroxymethylphenyl)ethylamino]-2-methyl-propyl}-benzamide
H
N
CI
sC CH3 ~ H
HO
Prepared from 3-{2-[(2R)-2-(tent-butyldimethylsilanyloxy)-2-(4-hydroxy-3-
hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl}-N-[2-(3,4-
dichlorophenyl)ethyl]benzamide (Preparation 41 ) using the method for example
33 to give the title compound as a white foam.
'H NMR (400MHz, CD30D) S = 7.62 (1 H, d), 7.60 (1 H, s), 7.42-7.40 (2H, m),
7.38-7.31 (3H, m), 7.18-7.11 (2H, m), 6.75 (1 H, d), 4.68-4.66 (1 H), 4.65
(2H, s),
3.56 (2H, m), 2.86-2.97 (4H, m), 2.69-2.77 (2H, m), 1.11 (3H, s), 1.04 (3H,
s).
LRMS (electrospray) m/z 531 [M+H]+
HRMS for C28H33C12N2O4 531.1801 [M+H]+ found 531.1812.
Example 37: N-[2-(3,4-dimethylphenyl)ethyl]-3-{2-[(2R)-2-hydroxy-2-(4-
hydroxy-3-hydroxymethylphenyl)-ethylamino]-2-methylpropyl}benzamide
H
N
CH3
HO 3C CH3 ~ H
NU
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Prepared from 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-
hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl)-N-[2-(3,4-
dimethylphenyl)ethyl]benzamide (Preparation 42) using the method for example
33 to give the title compound as a white foam.
'H NMR (400MHz, CD30D) 8 = 7.63 (1 H, m), 7.61 (1 H, bs), 7.38-7.31 (3H, m),
7.12 (1 H, dd), 7.02-6.99 (2H, m), 6.92 (1 H, dd), 6.75 (1 H, d), 4.67-4.64 (1
H, m),
4.65 (2H, s), 3.53 (2H, t), 2.92 (1 H, dd), 2.86 (1 H, d), 2.82 (2H, t), 2.72
(1 H, dd),.
2.69 (1 H, d), 2.20 (6H, s), 1.11 (3H, s), 1.04 (3H, s).
LRMS (electrospray) m/z 491 [M+H]+
HRMS for C3oH39N2O4 491.2905 [M+H]+ found 491.2892.
Example 38: 3-(2-((2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-
phenyl)ethylamino)-2-methyl-propyl}-N-(2-naphthalen-2-yl-ethyl)benzamide
H O /
N
~N
I
3C CHs I / H
HO
HU
Prepared from 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-
hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl}-N-(2-naphthalen-2-yl-
ethyl)benzamide (Preparation 43) using the method for example 33 to give the
title compound as a white foam.
'H NMR (400MHz, CD30D) 8 7.80-7.75 (3H, m), 7.68 (1 H, bs), 7.62 (1 H, m),
7.57 (1 H, bs), 7.44-7.29 (6H, m), 7.12 (1 H, dd), 6.75 (1 H, d), 4.67-4.63 (1
H, m),
4.66 (2H, s), 3.67 (2H, m), 3.06 (2H, t), 2.90 (1 H, dd), 2.82 (1 h, d), 2.71
(1 H,
dd), 2.66 (1 H, d), 1.08 (3H, s), 1.01 (3H, s).
LRMS (electrospray) m/z 513 [M+H]+
HRMS for C32H37N204 513.2748 [M+H]+ found 513.2726.
Example 39: N-(1,1-dimethyl-2-phenylethyl)-3-{2-[(2R)-2-hydroxy-2-(4-
hydroxy-3-hydroxy-methylphenyl)-ethylamino)-2-methylpropyl}benzamide
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O CH3
H
N
~N
C CH3 ~ / H CH3
HO
HU
Prepared from 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-
hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl}-N-(1,1-dimethyl-2-phenyl-
ethyl)benzamide (Preparation 44) using the method for example 33 to give the
5 title compound as a white foam.
'H NMR (400MHz, CD30D) 8 = 7.64 (1 H, m), 7.60 (1 H, bs), 7.35-7.27 (3H, m),
7.24-7.15 (5H, m), 7.06 (1 H, dd), 6.72 (1 H, d), 4.64 (2H, s), 4.64-4.61 (1
H, m),
3.20 (1 H, d), 3.12 (1 H, d), 2.86 (1 H, dd), 2.81 (1 H, d), 2.73-2.69 (2H,
m), 1.42
(3H, s), 1.39 (3H, s), 1.09 (3H, s), 1.05 (3H, s).
10 LRMS (electrospray) m/z 491 [M+H]+
HRMS for C32H3~N204 491.2905 [M+H]+ found 491.2885.
Example 40: 3-~2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-
ethylamino]-2-methylpropyl}-N-(2-methyl-2-phenylpropyl)benzamide
H O
N
~N
sC CH3 ~ / H H3C CH3
HO
15 HU
Prepared from 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-
hydroxymethylphenyl)ethylamino]-2-methylpropyl}-N-(2-methyl-2-phenylpropyl)-
benzamide (Preparation 45) using the method for example 33 to give the title
compound as a white foam.
20 'H NMR (400MHz, CD30D) 8 7.53 (1 H, m), 7.60 (1 H, bs), 7.43 (1 H, dd),
7.34-
7.28 (5H, m), 7.20-7.16 (1 H, m), 7.10 (1 H, dd), 6.74 (1 H, d), 4.65 (2H, s),
4.65-
4.61 (1 H, dd), 3.57 (2H, s), 2.87 (1 H, dd), 2.79 (1 H, d), 2.75-2.69 (2H,
m), 1.38
(6H, s), 1.07 (3H, s), 1.03 (3H, s).
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LRMS (electrospray) m/z 491 [M+H]+
HRMS for C3pH39N2~4 491.2905 [M+H]+ found 491.2897.
Example 41: N-(4-chlorobenzyl)-3-{2-[(2R)-2-hydroxy-2-(4-hydroxy-3-
hydroxy-methylphenyl)ethylamino]-2-methylpropyl}benzamide
H O
N
~N
I
sC CH3 I / H I /
HO CI
HO
Prepared from 3-{(2R)-2-[2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-
hydroxymethyl-phenyl)ethylamino]-2-methylpropyl)-N-(4-
chlorobenzyl)benzamide (Preparation 46) using the method for example 33 to
give the title compound as a white foam.
'H NMR (400MHz, CD30D) 8 = 7.74-7.70 (3H, m), 7.40-7.29 (7H, m), 7.07 (1 H,
dd), 6.71 (1 H, d), 4.67-4.63 (1 H, dd), 4.63 (2H, s), 4.60 (2H, dd), 2.96-
2.88 (2H,
m), 2.76-2.70 (2H, m), 1.12 (3H, s), 1.04 (3H, s).
LRMS (electrospray) m/z 481 /483 [M+H]+
HRMS for C3oH32CIN2O4 483.2045 [M+H]+ found 483.2038.
Example 42: N-(2,6-dimethoxybenzyl)-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-
3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetamide
CH3
O /
I / OI ~O
HO
H3C
11U
Prepared according to the procedure used for Preparation 1 using {3-[2-({(2R)-
2-hyd roxy-2-[4-hyd roxy-3-
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(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetic acid (Preparation 51 )
and the appropriate amine to give the title compound as a white foam.
'H NMR (400MHz, CD30D): d = 7.26-7.19 (3H, m), 7.11-7.07 (4H, m), 6.74-
6.72 (1 H, d), 6.61-6.59 (2H, d), 4.70-4.67 (1 H, m), 4.63 (2H, s), 4.41 (2H,
s),
3.75 (6H, s), 3.45 (2H, s), 2.91-2.75 (6H, m) ppm.
LRMS (electrospray) : m/z [M+H]+ 495, [M+Na]+ 517, [M-H]- 493.
CHN analysis : found C 66.15%, H 6.89%, N 5.53%; C28H34N206+0.75H20
requires C 66.19%, H 7.04%, N 5.51 %.
Example 43: N-(3,4-dichlorobenzyl)-2-~3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl)ethyl}amino)ethyl]phenyl}acetamide
OH / CI
N \ N
CI
HO ~ O
NU
Prepared according to the procedure used for Preparation 1 using {3-[2-({(2R)-
2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetic acid (Preparation 51 )
and the appropriate amine to give the title compound as a white foam.
'H NMR (400MHz, CD30D): d = 7.43-7.41 (1 H, d), 7.36-7.35 (1 H, d), 7.26-7.23
(2H, m), 7.15-7.06 (5H, m), 6.74-6.72 (1 H, d), 4.70-4.66 (1 H, m), 4.63 (2H,
s),
4.32 (2H, s), 3.53 (2H, s), 2.94-2.75 (6H, m) ppm.
LRMS (electrospray) : m/z [M+H]+ 503, [M+Na]+ 525, [M-H]- 501.
CHN analysis : found C 59.26%, H 5.52%, N 5.20%; C26HZeN20aC12+1.35H20
requires C 59.17%, H 5.86%, N 5.31 %.
Example 44: N-benzyl-2-f 3-[2-( f (2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetamide
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H H /
N N \
I
HO ~ O
11U
Prepared according to the procedure used for Preparation 1 using {3-[2-(f(2R)-
2-hyd roxy-2-[4-hyd roxy-3-
(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetic acid (Preparation 51 )
and the appropriate amine to give the title compound as a white foam.
'H NMR (400MHz, CD30D): d = 7.30-7.19 (7H, m), 7.15-7.14 (2H, m), 7.11-
7.06 (2H, m), 6.74-6.72 (1 H, d), 4.70-4.67 (1 H, m), 4.63 (2H, s), 4.35 (2H,
s),
3.52 (2H, s), 2.95-2.77 (6H, m) ppm.
LRMS (electrospray) : m/z [M+H]+ 435, [M+Na]+ 457, [M-H]- 433.
CHN analysis : found C 67.21 %, H 6.70%, N 5.99%; C26HsoNzOa+0.45CH2CI2
requires C 67.20%, H 6.59%, N 5.93%.
Example 45: N-(2,3-dihydro-1H-inden-2-yl)-2-{3-[2-({(2R)-2-hydroxy-2-(4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetamide
N N
I
HO ~ O
HU
Prepared according to the procedure used for Preparation 1 using {3-[2-({(2R)-
2-hyd roxy-2-[4-hyd roxy-3-
(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetic acid (Preparation 51 )
and the appropriate amine to give the title compound as a white foam.
'H NMR (400MHz, CD30D): d = 7.26 (1H, s), 7.24-7.17 (3H, m), 7.13-7.07 (6H,
m), 6.74-6.72 (1 H, d), 4.72-4.68 (1 H, m), 4.63 (2H, s), 4.59-4.52 (1 H, m),
3.45
(2H, s), 3.26-3.24 (1 H, d), 3.22-3.20 (1 H, d), 2.97-2.79 (8H, m) ppm.
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LRMS (electrospray) : m/z [M+H]+ 461, [M+Na]+ 483, [M-H]- 459.
CHN analysis : found C 65.30%, H 6.57%, N 5.57%;
C28H32Nz04+0.80CH2CI2+0.10H20 requires C 65.23%, H 6.42%, N 5.28%.
Example 46: 2-{3-[2-(~(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}-N-(2-
phenylethyl)acetamide
OH
N \ N \
O~ ~ /
HO
HO
Prepared according to the procedure used for Preparation 1 using {3-[2-({(2R)-
2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl)acetic acid (Preparation 51 )
and the appropriate amine to give the title compound as a white foam.
'H NMR (400MHz, CD30D): d = 7.27-7.26 (1 H, d), 7.24-7.06 (10H, m), 6.74
6.72 (1 H, d), 4.72-4.69 (1 H, m), 4.64 (2H, s), 3.44-3.39 (4H, m), 3.00-2.92
(2H,
m), 2.89-2.82 (4H, m), 2.79-2.75 (2H, t) ppm.
LRMS (electrospray) : m/z [M+H]+ 449, [M+Na]+ 471, [M-H]- 447.
.
CHN analysis : found C 64.80%, H 6.70%, N 5.52%; C2~H32N204+0.75CH2CI2
requires C 65.07%, H 6.59%, N 5.47%.
Example 47: 2-(3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}-N-(3-
phenylpropyl)acetamide
N \ N \
HO
HU
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Prepared according to the procedure used for Preparation 1 using {3-[2-({(2R)-
2-hyd roxy-2-[4-hyd roxy-3-
(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetic acid (Preparation 51 )
and the appropriate amine to give the title compound as a white foam.
5 'H NMR (400MHz, CD30D): d = 7.25-7.19 (4H, m), 7.15-7.05 (7H, m), 6.74-
6.72 (1 H, d), 4.69-4.64 (3H, m), 3.47 (2H, s), 3.21-3.17 (2H, t), 2.96-2.74
(6H,
m), 2.60-2.56 (2H, t), 1.75-1.73 (2H, m) ppm.
LRMS (electrospray) : m/z [M+H]+ 463, [M+Na]+ 485, [M-H]- 461.
CHN analysis : found C 68.54%, H 7.17%, N 5.80%;
10 C28H~N204+0.40CH2CI2+0.10 H20 requires C 68.45%, H 7.08%, N 5.62%.
Example 48: N-benzyl-3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide
OH O
H
N
\ ~H ~ \
CH3 / /
HO
HO
15 To a solution of 3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59)
(116mg, 0.22mmol) in DMF (2ml) was added triethylamine (62p,1, 0.45mmol),
benzylamine (29.1, 0.27mmol), HOBt (33mg, 0.25mmol) and WSCDI (47mg,
0.25mmol) and the resulting solution stirred at room temperature for 18 hours.
20 The solvent was removed in vacuo and the residue partitioned between
saturated aqueous sodium hydrogen carbonate solution (5ml) and
dichloromethane/methanol (95/5) (10m1). The aqueous layer was separated
and extracted with further dichloromethane/methanol (95/5) (4x10m1). The
combined organic layers were dried (sodium sulfate), filtered and evaporated
in
25 vacuo. The resulting oil was purified by flash column chromatography on
silica
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gel eluting with dichloromethane:methano1:880 ammonia (90:10:1, by volume)
to give the title compound as a white foam (70mg).
'H NMR (400MHz, CD30D): 8 = 7.70-7.68 (1 H, d), 7.66 (1 H, s), 7.38-7.29 (6H,
m), 7.26-7.21 (1 H, m), 7.21 (1 H, s), 7.03-7.01 (1 H, d), 6.69-6.67 (1 H, d),
4.64-
4.61 (1 H, m), 4.61 (2H, s), 4.58 (2H, s), 3.05-2.98 (1 H, m), 2.92-2.86 (1 H,
dd),
2.84-2.79 (1 H, dd), 2.75-2.71 (1 H, dd), 2.68-2.63 (1 H, dd), 1.10-1.08 (3H,
d)
ppm.
LRMS (electrospray) : m/z [M+H]+ 435, [M+Na]+ 457, [M-H]~ 433.
CHN analysis : found C 69.79, H 6.96, N 6.37; C26HsoN20a+0.7H20 requires C
69.84, H 7.08, N 6.26.
Example 49: N-(3,4-dichlorobenzyl)-3-[(2R)-2-({(2R)-2-hydroxy-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide
OH O
H
N ~ CI
HO CH3
CI
HU
Prepared according to the procedure used for example 49 using 3-[(2R)-2-
({(2R)-2-hyd roxy-2-[4-hyd roxy-3-
(hydroxymethyl)phenyl]ethyl)amino)propyl]benzoic acid (Preparation 59) and
the appropriate amine to give the title compound as a white foam.
'H NMR (400MHz, CD30D): 8 = 7.69-7.67 (1 H, d), 7.65 (1 H, s), 7.51 (1 H, s ),
7.48-7.46 (1 H, d), 7.36-7.27 (3H, m), 7.21 (1 H, s), 7.03-7.02 (1 H, d), 6.69-
6.66
(1 H, d), 4.65-4.61 (1 H, m), 4.61 (2H, s), 4.54 (2H, s), 3.02-2.97 (1 H, m),
2.91
2.86 (1 H, dd), 2.83-2.77 (1 H, dd), 2.74-2.69 (1 H, dd), 2.68-2.63 (1 H, dd),
1.09
1.08 (3H, d) ppm.
LRMS (electrospray) : m/z [M+H]+ 503, [M+Na]+ 525, [M-H]- 501.
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Example 50: N-[2-fluoro-5-(trifluoromethyl)benzyl]-3-[(2R)-2-({(2R)-2-
hyd roxy-2-[4-hyd roxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide
H O F
N \
FF
CH3 / /
HO F
HO
Prepared according to the procedure used for example 49 using 3-[(2R)-2-
({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and
the appropriate amine to give the title compound as a white foam.
'H NMR (400MHz, CD30D): 8 = 7.74-7.60 (4H, m), 7.38-7.29 (3H, m), 7.22 (1H,
s), 7.04-7.02 (1 H, d), 6.69-6.67 (1 H, d), 4.67 (2H, s), 4.67-4.61 (1 H, m)
4.61
_ (2H, s), 3.04-2.99 (1 H, m), 2.93-2.80 (2H, m), 2.76-2.71 (1 H, m), 2.68-
2.63 (1 H,
m), 1.09-1.08 (3H, d) ppm.
LRMS (electrospray) : m/z [M+H]+ 521, [M+Na]+ 543, [M-H]- 519.
CHN analysis : found C 60.88, H 5.58, N 5.58; C2~H28F4N204+0.7H20 requires
C 60.83, H 5.56, N 5.25.
Example 51: N-(2,6-dimethoxybenzyl)-3-[(2R)-2-({(2R)-2-hydroxy-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide
O O~CH3
H
N
\ ~H ~ \
HO CH3 ~ O
I
NO CH3
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Prepared according to the procedure used for example 49 using 3-[(2R)-2-
({(2 R)-2-h yd roxy-2-[4-h yd roxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and
the appropriate amine to give the title compound as a white foam.
'H NMR (400MHz, CD30D): 8 = 7.58-7.55 (2H, m), 7.31-7.24 (3H, m), 7.19 (1H,
s), 7.00-6.98 (1 H, dd), 6.68-6.64 (3H, m), 4.63 (2H, s), 4.63-4.58 (1 H, m)
4.60
(2H, s), 3.84 (6H, s), 3.00-2.94 (1 H, m), 2.90-2.85 (1 H, m), 2.78-2.61 (3H,
m),
1.08-1.06 (3H, d) ppm.
LRMS (electrospray) : m/z [M+H]+ 495, [M+Na]+ 517, [M-H]- 493.
CHN analysis : found C 65.52, H 6.89, N 5.43; CZ$H34Nz06+1.OH20 requires C
65.61, H 7.08, N 5.46.
Example 52: N-[2-(4-chlorophenyl)ethylj-3-[(2R)-2-(f(2R)-2-hydroxy-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyljbenzamide
CI
H O
N
-N
HO CH3 ~ / H
HU
Prepared according to the procedure used for example 49 using 3-[(2R)-2-
({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and
the appropriate amine to give the title compound as a white foam.
'H NMR (400MHz, CD30D): 8 = 7.60-7.58 (1H, d), 7.54 (1H, s), 7.35-7.23 (7H,
m), 7.04-7.01 (1 H, dd), 6.70-6.68 (1 H, d), 4.64-4.61 (1 H, m), 4.61 (2H, s),
3.60-
3.57 (2H, t), 3.02-2.96 (1 H, m), 2.92-2.87 (3H, m), 2.83-2.78 (1 H, m), 2.75-
2.71
(1 H, dd), 2.66-2.61 (1 H, dd), 1.09-1.08 (3H, d) ppm.
LRMS (electrospray) : m/z [M+H]+ 483, [M+Na]+ 505, [M-H]- 481.
CHN analysis : found C 65.90, H 6.68, N 5.55; C2~H3~CIN204+0.5H20 requires
C 65.91, H 6.56, N 5.69 .
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Example 53: N-(2,3-dihydro-1 H-inden-2-yl)-3-[(2R)-2-(((2R)-2-hydroxy-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide
H O
N
N
CH3 I / H
HO
f1 U
Prepared according to the procedure used for example 49 using 3-[(2R)-2-
(((2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and
the appropriate amine to give the title compound as a white foam.
'H NMR (400MHz, CD30D): 8 = 7.66-7.63 (2H, m), 7.35-7.28 (2H, m), 7.22
7.21 (3H, m), 7.15-7.13 (2H, m), 7.03-7.02 (1 H, dd), 6.70-6.68 (1 H, d), 4.84
4.79 (1 H, m), 4.64-4.60 (1 H, m), 4.61 (2H, s), 3.37-3.30 (2H, dd), 3.03-2.97
(3H, m), 2.92-2.87 (1 H, m), 2.84-2.78 (1 H, m), 2.76-2.71 (1 H, m), 2.68-2.63
(1 H, dd), 1.09-1.08 (3H, d) ppm.
LRMS (electrospray) : m/z [M+H]+ 461, [M+Na]+ 483, [M-H]- 459.
CHN analysis : found C 70.42, H 6.87, N 5.91; C28H32N204+0.9H20 requires C
70.54, H 7.15, N 5.88 .
Example 54: 3-[(2R)-2-(~(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]-N-(2-phenylethyl)benzamide
OH O
H
N \ _ \
CH I / H
HO
HU
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Prepared according to the procedure used for example 49 using 3-[(2R)-2-
({(2 R)-2-hyd roxy-2-(4-h yd roxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and
the appropriate amine to give the title compound as a white foam.
5 'H NMR (400MHz, CD30D): 8 = 7.60-7.58 (1 H, d), 7.56 (1 H, s), 7.35-7.17
(8H,
m), 7.05-7.02 (1 H, dd), 6.70-6.68 (1 H, d), 4.64-4.60 (1 H, m), 4.62 (2H, s),
3.61-
3.57 (2H, t), 3.03-2.97 (1 H, m), 2.93-2.87 (3H, m), 2.84-2.78 (1 H, m), 2.77-
2.71
(1 H, m), 2.66-2.61 (1 H, dd), 1.09-1.08 (3H, d) ppm.
LRMS (electrospray) : m/z [M+H]+ 449, [M+Na]+ 471, [M-H]- 447.
10 CHN analysis : found C 70.10, H 7.16, N 6.09; C2~H32N204+0.75H2O requires C
70.18,H7.31,N6.06
Example 55: 3-((2R)-2-({(2R)-2-hydroxy-2-(4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]-N-((1 R)-1-
15 phenylethyl]benzamide
O CH3
H
N \ N \.
CH3 ~ H
HO
11U
Prepared according to the procedure used for example 49 using 3-[(2R)-2-
({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and
20 the appropriate amine to give the title compound as a white foam.
'H NMR (400MHz, CD30D): 8 = 7.67-7.64 (2H, m), 7.41-7.39 (2H, d), 7.34-7.28
(4H, m), 7.24-7.21 (2H, m), 7.02-7.00 (1 H, dd), 6.68-6.66 (1 H, d), 5.26-5.21
(1 H, q), 4.63-4.60 (1 H, m), 4.60 (2H, s), 3.03-2.99 (1 H, m), 2.91-2.86 (1
H, dd),
2.83-2.78 (1 H, dd), 2.74-2.70 (1 H, dd), 2.69-2.63 (1 H, dd), 1.57-1.55 (3H,
d),
25 1.09-1.08 (3H, d) ppm.
LRMS (electrospray) : m/z [M+H]+ 449, [M+Na]+ 471, [M-H]- 447.
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CHN analysis : found C 68.96, H 7.07, N 5.91; C2~H32N204+1.2H20 requires C
68.97, H 7.37, N 5.96
Example 56: 3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]-N-(3-phenylpropyl)benzamide
H O
N
\ ~N ~ ~ \
CH3 / H /
HO
HU
Prepared according to the procedure used for example 49 using 3-[(2R)-2-
({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and
the appropriate amine to give the title compound as a white foam.
'H NMR (400MHz, CD30D): 8 = 7.63-7.61 (1 H, d), 7.59 (1 H, s), 7.35-7.21 (7H,
m), 7.16-7.13 (1 H, m), 7.03-7.01 (1 H, dd), 6.69-6.67 (1 H, d), 4.61 (3H, m),
3.42-3.39 (2H, t), 3.00-2.96 (1 H, q), 2.91-2.86 (1 H, dd), 2.81-2.76 (1 H,
dd),
2.74-2.61 (4H, m), 1.98-1.91 (2H, quin), 1.09-1.07 (3H, d) ppm.
LRMS (electrospray) : m/z [M+H]+ 463, [M+Na]+ 485, [M-H]- 461.
Example 57: 4-[(1R)-2-({(1R)-2-[3-(3,4-dihydroisoquinolin-2(1I-~-
ylcarbonyl)phenyl]-1-methylethyl}amino)-1-hydroxyethyl]-2-
(hydroxymethyl)phenol
H O
N
\ ,N ( \
HO CHs / /
NU
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Prepared according to the procedure used for example 49 using 3-[(2R)-2-
({(2R)-2-hyd roxy-2-[4-hyd roxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and
the appropriate amine to give the title compound as a white foam.
'H NMR (400MHz, CD30D): 8 = 7.39-7.36 (1 H, m), 7.29-7.17 (6H, m), 7.12-
7.01 (3H, m), 6.71-6.69 (1 H, d), 4.62 (2H, s), 4.62-4.55 (2H, m), 3.96 (2H,
s),
3.60-3.56 (1 H, m), 3.11-2.64 (7H, m), 1.10-1.08 (3H, d) ppm.
LRMS (electrospray) : m/z [M+H]+ 461, [M+Na]+ 483, [M-H]- 459.
CHN analysis : found C 71.65, H 7.12, N 6.39; C2$H32N204+0.41 H20 requires C
71.87, H 7.07, N 5.99.
Example 58: N-(2,3-dimethylbenzyl)-3-[(2R)-2-({(2R)-2-hydroxy-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide
O CH3
H
N CH
s
HO CH3
11U
Prepared according to the procedure used for example 49 using 3-[(2R)-2-
({(2R)-2-hyd roxy-2-[4-hyd roxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and
the appropriate amine to give the title compound as a white foam.
'H NMR (400MHz,' CD30D): 8 = 7.68-7.66 (1 H, d), 7.64 (1 H, s), 7.36-7.28 (2H,
m), 7.21 (1 H, d), 7.14-7.12 (1 H, d), 7.08-6.99 (3H, m), 6.68-6.68 (1 H, d),
4.63
4.59 (1 H, m), 4.61 (2H, s), 4.59 (2H, s), 3.04-2.99 (1 H, q), 2.92-2.89 (1 H,
dd),
2.83-2.79 (1 H, dd), 2.75-2.71 (1 H, dd), 2.69-2.64 (1 H, dd), 2.30 (3H, s),
2.28
(3H, s), 1.11-1.09 (3H, d) ppm.
LRMS (electrospray) : m/z [M+H]+ 463, [M+Na]+ 485, [M-H]- 461.
CHN analysis : found C 70.17, H 7.33, N 5.90; C28H~N204+0.90H20 requires C
70.24, H 7.54, N 5.85.
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Example 59: N-(5,6-diethyl-2,3-dihydro-1 H-inden-2-yl)-3-((2R)-2-({(2R)-2-
hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide
CH3
O
N CHs
N
CH3 ~ / H
HO
HU
Prepared according to the procedure used for example 49 using 3-[(2R)-2-
({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl)amino)propyl]benzoic acid (Preparation 59) and
the appropriate amine to give the title compound as a white foam.
'H NMR (400MHz, CD30D): 8 = 7.65-7.63 (1 H, d), 7.61 (1 H, s), 7.34-7.26 (2H,
m), 7.21 (1 H, s), 7.03-7.01 (1 H, m), 7.01 (2H, s), 6.69-6.67 (1 H, d), 4.81-
4.77
(1 H, dd), 4.63-4.60 (1 H, m), 4.61 (2H, s), 3.31-3.26 (2H, dd), 3.03-2.99 (1
H, q),
2.97-2.92 (2H, dd), 2.92-2.87 (1 H, dd), 2.83-2.78 (1 H, dd), 2.75-2.71 (1 H,
dd),
2.68-2.61 (5H, m), 1.22-1.18 (6H, t), 1.10-1.09 (3H, d) ppm.
LRMS (electrospray) : m/z [M+H]+ 517, [M+Na]+ 539, [M-H]- 515.
CHN analysis : found C 72.58, H 7.80, N 5.34; C32H4oN204+0.7H20 requires C
72.62, H 7.88, N 5.29.
Example 60: N-(4-chlorobenzyl)-3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide
H O
N
\ ~H
HO CH3 / /
CI
~U
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To a solution of 3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59)
(120mg, 0.27mmol) in DMF (3ml) was added triethylamine (111 ~I, 0.79mmol),
4-chlorobenzylamine (391, 0.32mmol), and HBTU (110mg, 0.29mmol) and the
resulting solution stirred at room temperature for 18 hours. The solvent was
removed in vacuo and the residue purified by flash column chromatography on
silica gel eluting with dichloromethane:methano1:880 ammonia (93:7:0.7
changing to 90:10:1, by volume) to give the title compound as a white foam
(97mg).
'H NMR (400MHz, CD30D): 8 = 7.70-7.68 (1 H, d), 7.66 (1 H, s), 7.38-7.30 (6H,
m), 7.23 (1 H, d), 7.05-7.03 (1 H, dd), 6.70-6.68 (1 H, d), 4.67-4.64 (1 H,
dd), 4.62
(2H, s), 4.55 (2H, s), 3.15-3.07 (1 H, m), 3.00-2.86 (2H, m), 2.82-2.78 (1 H,
dd),
2.72-2.67 (1 H, dd), 1.13-1.12 (3H, d) ppm.
LRMS (electrospray) : m/z [M+H]+ 469, [M+Na]+ 491, [M-H]- 467.
Example 61: 3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]-N-phenylbenzamide
OH O
H
N
-N
H
CH3 I /
HO
HO
Prepared according to the procedure used for example 60 using 3-[(2R)-2-
({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and
the appropriate amine to give the title compound as a white foam.
'H NMR (400MHz, CD30D): 8 = 7.77-7.74 (2H, m), 7.69-7.67 (2H, d), 7.41-7.33
(4H, m), 7.22 (1 H, d), 7.16-7.12 (1 H, t), 7.05-7.03 (1 H, dd), 6.70-6.68 (1
H, d),
4.66-4.61 (1 H, m), 4.62 (2H, s), 3.09-3.04 (1 H, m), 2.96-2.84 (2H, m), 2.79-
2.69
(2H, m), 1.14-1.12 (3H, d) ppm.
LRMS (electrospray) : m/z [M+H]+ 421, [M+Na]+ 443, [M-H]- 419
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CHN analysis : found C 67.98, H 6.64, N 6.48; C25H28N204+0.06CH2C12+0.95
H20 requires C 67.99, H 6.83, N 6.33.
Example 62: N-[4-(aminosulfonyl)benzyl]-3-[(2R)-2-({(2R)-2-hydroxy-2-[4-
5 hydroxy-3-(hydroxymethyl)phenyl]ethyl)amino)propyl]benzamide
O
H
N \ N \
CH3 ~ H
HO S02NH2
11U
Prepared according to the procedure used for example 60 using 3-[(2R)-2-
({(2 R)-2-hyd roxy-2-[4-hyd roxy-3-
10 (hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and
the appropriate amine, substituting with dichloromethane :methano1:880
ammonia (85:15:2, by volume) as eluent to give the title compound as a white
foam.
'H NMR (400MHz, CD30D): 8 = 7.87-7.85 (2H, d), 7.71-7.69 (1 H, d), 7.67 (1 H,
15 s), 7.53-7.50 (2H, d), 7.39-7.32 (2H, m), 7.23 (1 H, d), 7.05-7.03 (1 H,
dd), 6.70-
6.68 (1 H, d), 4.67-4.65 (1 H, m), 4.65 (2H, s), 4.62 (2H, s), 3.14-3.07 (1 H,
m),
2.97-2.92 (1 H, dd), 2.91-2.86 (1 H, dd), 2.82-2.78 (1 H, dd), 2.72-2.67 (1 H,
dd),
1.13-1.12 (3H, d) ppm.
LRMS (electrospray) : m/z [M+H]+ 514, [M+Na]+ 536, [M-H]- 512.
20 CHN analysis : found C 56.26, H 6.01, N 7.45; C26H3~N306S+2.1 H20 requires
C
56.63, H 6.43, N 7.62.
Example 63
N-[2-(3-Fluorophenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
25 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide
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F
O /
H
N \ N \
H
C \CH3
HO
HO
3-[2-({(2R)-2-{[terf-Butyl(dimethyl)sifyl]oxy}-2-[4-hydroxy-3-(hydroxylmethyl)
phenyl]ethyl}amino)-2-methylpropyl]-N-[2-(3-fluorophenyl)ethyl]benzamide
(preparation 157), (343mg, 0.58mmol) and ammonium fluoride (213mg,
5.76mmol) in methanol (12mL) and water (2mL) were stirred at room
temperature for 42 hours. The solvent was removed in vacuo and the residue
was purified by column chromatography on silica gel, eluting with
dichloromethane:methano1:0.88 ammonia, 100:0:0 to 90:10:1. The appropriate
fractions were concentrated in vacuo and the residue was azeotroped (x2) in
ethanol tv give a white solid. This solid was then re-crystallised with
ethanol/water and dried under vacuum to afford the title compound as very pale
yellow crystals in 52% yield, 144mg.
'H NMR (400MHz, CD30D) 8: 7.63 (2H, m) 7.38-7.23 (4H, m), 7.13 (1H, m),
7.05 (1 H, m), 7.00 (1 H, m), 6.91 (1 H, m), 6.85 (1 H, d), 4.65 (3H, m), 3.59
(2H,
m), 2.96-2.84 (2H, m), 2.78-2.68 (2H, m), 1.10 (3H, s), 1.04 (3H, s) ppm;
LRMS ESI m/z 481 [M+H]+
Examples 64 to 78
The following compounds, of the general formula shown below were prepared
by a similar method to that described for example 63, using the appropriate
starting material and ammonium fluoride. The reaction mixtures were warmed
to 40°C until thin layer chromatography analysis indicated that all of
the starting
materials had been consumed.
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H O
N
I3C CH3 ~ _Q1
HO
NU
No. Q1 Data Yield
64 H NMR (400MHz, CD30D) 8: 7.78-
~N 7.71 (2H, m) 7.40-7.31 (3H,
m), 7.15
N
(1 H, m), 6.76 (1 H, m), 4.70-4.64
(3H, m), 3.62-3.50 (2H, m),
3.01-
2.94 (2H, m), 2.76-2.63 (4H,
m),
2.59-2.46 (4H, m), 1.78-1.65
(4H,
m), 1.13 (3H, s), 1.01 (3H,
s) ppm;
LRMS APCI m/z 456 [M+H]+
65 CI / 'H NMR (400MHz, CD30D) 8: 81
7.65
(2H, m) 7.37-7.29 (5H, m),
7.21-7.11
N v ~ (2H, m), 6.77 (1 H, m), 4.70-4.63
CI (3H, m), 3.66 (2H, m), 3.30
(2H, m),
2.96-2.69 (4H, m), 1.10 (3H,
s), 1.05
(3H, s) ppm; LRMS APCI mlz
531
[M+H]+
66 N 'H NMR (400MHz, CD30D) 8: 35%
7.64
(m, 2H), 7.40-7.30 (3H, m),
7.19-
7.05 (5H, m), 6.75 (1 H, m),
4.65
(3H, m), 3.42 (2H, m), 2.69-3.10
(9H, m), 1.14 (3H, s), 1.05
(3H, s)
ppm
LRMS APCI m/z 489 [M+H]+
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67 ~ 'H NMR (400MHz, CD30D) S: 31%
7.74
~NH (2H, m), 7.66-7.59 (2H, m),
7.37-
7.25 (5H, m), 7.13 (1 H, m),
6.75
CH3
(1 H, d), 4.65 (3H, m), 3.62
(2H, m),
3.32 (2H, m), 3.00-2.68 (6H,
m),
1.59 (2H, m), 1.39 (2H, m),
1.12
(3H, s), 1.04 (3H, s), 0.97
(3H, t)
ppm
LRMS APCI m/z 562 [M+H]+
68 / ~ 'H NMR (400MHz, CD30D) b: 34%
7.68-
7.56 (2H, m), 7.40-7.07 (13H,
brm),
6.74 (1 H, m), 4.86-4.74 (3H,
m),
3.70-3.58 (2H, m), 3.11 (2H,
m),
N ~ ~ 2.68-2.95 (4H, m), 1.12 (3H,
s), 1.06
(3H, s) ppm; LRMS APCI m/z
571
[M+H]+
69 'H NMR (400MHz, CD30D) 8: 69%
7.66
(2H, m), 7.34 (3H, m), 7.13
(1 H, m),
6.74 (1 H, d), 4.67 (1 H,
d), 4.65 (2H,
s), 3.42-3.34 (2H, m), 2.87-2.97
(2H,
m), 2.70-2.77 (2H, m), 1.80-1.59
(5H, m), 1.47 (2H, q), 1.15-1.30
(4H,
m), 1.12 (3H, s), 1.05 (3H,
s), 1.00-
0.90 (2H, m) ppm
LRMS ESI m/z 469 [M+H]+
70 ~ 'H NMR (400MHz, CD30D) 8: 89%
7.67
(2H, m), 7.39-7.32 (3H, m),
7.26-
7.12 (6H, m), 6.75 (1 H, d),
4.68-4.63
(3H, t), 3.43-3.38 (2H, m),
2.98-2.88
(2H, m), 2.76-2.64 (4H, m),
1.97-
1.89 (2H, m), 1.12 (3H, s),
1.05 (3H,
s) ppm; LRMS APCI m/z 477
[M+H]+
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71 N 'H NMR (400MHz, CD30D) 8: 72%
7.64
\ ~ (2H, m), 7.38-7.13 (9H, m),
6.76
(1 H, d), 4.65 (3H, m), 3.60
(2H, m),
2.97-2.86 (4H, m), 2.76-2.70
(2H,
m), 1.11 (3H, s), 1.05 (3H,
s) ppm;
LRMS APCI m/z 463 [M+H)+
72 c~ 'H NMR (400MHz, CD30D) 8: 16%
7.68-
Hsc ~ 7.63 (2H, m), 7.39-7.31 (3H,
m),
/ 7.25 (2H, m), 7.26-7.19 (1
H, m),
6.76 (1 H, d), 4.69-4.64 (3H,
m),
C~ 3.58-3.53 (2H, t), 3.23-3.18
(2H, m),
3.00-2.80 (2H, m), 2.71-2.69
(2H, t),
2.47 (3H, s), 1.12 (3H, s),
1.06 (3H,
s) ppm; LRMS ESI m/z 545 [M+H]+
73 CHs 'H NMR (400MHz, CD30D) 8: 48%
7.61
(2H, m), 7.40-7.30 (3H, m),
7.20-
N
7.10 (3H, m), 6.90 (1 H, d),
6.77 (1 H;
\ ~ d 4.75-4.60 3H m
), ( , ), 3.80 (3H, s),
3.60-3.50 (2H, m), 3.00-2.80
(4H,
m), 2.80-2.70 (2H, m), 1.95-1.15
(3H, m), 1.10 (3H, s) ppm
74 N 'H NMR (400MHz, CD30D) 8: 10%
7.75-
\ ~ 7.65 (2H, m), 7.40-7.10 (6H,
m),
0 6.80-6.70 (3H, m), 4.70-4.60
(3H,
H3~ m), 3.67 (3H, s), 3.60-3.50
(2H, m),
3.00-2.70 (6H, brm), 1.15
(3H, s),
1.05 (3H, s) ppm; LRMS APCI
493
[M+Hl+
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75 N 'H NMR (400MHz, CD30D) b: 5%
\ ~ 7.67-
0 7.60 (2H, m), 7.40-7.25 (3H,
m),
7.20-7.10 (2H, m), 6.80-6.70
(4H,
m), 4.70-4.60 (3H, m), 4.00-3.90
(2H, m), 3.63-3.53 (2H, m),
2.96-
2.60 (6H, m), 1.40-1.30 (3H,
m),
1.20-1.00 (6H, m) ppm; LRMS
APCI
507 [MH]+
76 ,~" ~ ~ 'H NMR (400MHz, CD30D) 8:
7.70-
7.60 (2H, m) 7.40-7.35 (3H,
~/ m),
7.20-7.10 (3H, m), 6.90-6.70
(3H,
m), 4.65-4.60 (3H, m), 4.10-4.00
(2H, m), 3.60-3.50 (2H, m),
3.00-
2.80 (12H, m), 2.10 (2H, m),
1.95
(4H, m), 1.20 (3H, s), 1.17
(3H, s)
ppm; LRMS APCI m/z 590 [M+H]+
77 ~ - 'H NMR (400MHz, CD30D) 8: 62%
7.62
(2H, m), 7.36-7.29 (3H, m)
7.18-7.11
o (3H, m), 6.90 (1 H, m), 6.84
(1 H, m),
~ 6.74 (1 H, m), 4.66-4.62 (3H,
N m),
,
4.05-3.97(2H, m), 3.61-3.57
(2H, m),
2.95-2.83 (4H, m), 2.65-2.76
(4H,
m), 2.60 (4H, m), 2.04-1.92
(2H, m),
1.84-1.76 (4H, m), 1.09 (3H,
s), 1.03
(3H, m) ppm; LRMS APCI m/z
590
[M+Hl+
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78 / 'H NMR (400MHz, CD30D) 8: 56%
7.65-
7.61 (2H, m) 7.37-7.30 (3H,
m),
0
7.18-7.12 (2H, m), 6.81-6.72
(4H,
m), 4.68-4.64 (3H, m), 3.96
(2H, m),
3.64-3.54 (2H, m), 2.96-2.85
(4H,
N m), 2.75-2.56 (8H, m), 2.00-1.93
2H, m , 1.84-1.79 4H m 1.10
( ) (
(3H, s), 1.03 (3H, s) ppm;
LRMS ESI
m/z 590 [M+H]+
Example 65: Compound was further purified by trituration with diethyl ether.
Example 72: Purified by column chromatography using an ISCO~ silica
cartridge, eluting with dichloromethane:methano1:0.88 ammonia, 100:0 to
90:10:1
Example 75: Purified by column chromatography using a 4g RediSep°
silica
cartridge, eluting with, dichloromethane:methano1:0.88 ammonia, 100:0:0 to
90:10:1, followed by ethyl acetate:methano1:0.88 ammonia, 100:0:0 to 80:20:2
Example 78: Crude compound was further purified by trituration with diethyl
ether
Example 79
N-[2-(4-Chlorophenyl)ethyl]-N-ethyl-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide
O
H
N
~N
isC CHs ~ \
HO
CH3
CI
11U
The title compound was prepared from 3-[2-({(2R)-2-{[tert-
butyl(dimethyl)silyl]oxy)-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl)amino)-2-
methylpropyl]-N-[2-(4-chlorophenyl)ethyl]-N-ethylbenzamide (preparation 110),
using a similar method to example 33, as a colourless solid in 61 % yield.
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'H NMR (400MHz, CD30D) 7.30-7.10 (8H, m), 6.87 (2H, m), 6.73 (1H, d), 4.63
(3H, m), 3.71 (1 H, m), 3.61 (1 H, m), 3.50 (1 H, m), 3.16 (1 H, m), 3.01-2.69
(6H,
m), 1.29-1.26, 1.07-1.01 (9H, 2xm) ppm; LRMS APCI m/z 525 [M+H]+
Example 80
2-{3-[2-( f (2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]
ethyl}amino)-2-methylpropyl]phenyl}-N-(3-pyrrolidin-1-ylpropyl)acetamide
0
\ N ~~/~/ N
HO
11U
The title compound was prepared from 2-{3-[2-({(2R)-2-{[tert-
butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]phenyl}-N-(3-pyrrolidin-1-ylpropyl)acetamide (preparation 109),
using a similar method to that of example 33. The crude residue was further
purified by column chromatography on Biotage° amino silica gel, eluting
with
dichloromethane:methanol, 80:20, to afford the title compound as a colourless
gum in 54% yield.
'H NMR (400MHz, CD30D) 7.70-7.64 (2H, m), 7.40-7.30 (3H, m), 7.13 (1H, m),
6.75 (m, 1 H), 4.69-4.64 (3H, m), 3.42 (2H, m), 3.00-2.90 (2H, m), 2.77-2.64
(2H, m), 2.60-2.50 (6H, m), 1.88-1.75 (6H, m), 1.12 (3H, s), 1.03 (s, 3H) ppm;
LRMS APCI m/z 470 [M+H]+
Example 81
N-(Cycloheptylmethyl)-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide
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H H
N N
\
3C CH3 / O
HO
HO
The title compound was prepared from 2-{3-[2-({(2R)-2-{[tert-
butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]phenyl}-N-(cycloheptylmethyl)acetamide (preparation 151 ), using
a similar method to that of example 33 as a white foam in 69% yield.
'H NMR (400MHz, CD30D) 8: 7.65 (1 H, m), 7.38 (1 H, s), 7.18-7.07 (4H, m),
- 6.90 (1 H, d), 4.93-4.78 (1 H, m), 4.04 (2H, m), 3.51 (2H, d), 3.18-3.07
(2H, m),
3.02-2.93 (4H, m), 1.72-1.36 (10H, m), 1.28 (6H, m), 1.19-1.07 (3H, m) ppm;
LRMS ESI m/z 483 [M+H]+
Example 82
N-1-Adamantyl-2-{3-[2-( f (2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide
OH
N N
isC CH3 ~ / O
HO
HU
The title compound was prepared from N-1-adamantyl-2-{3-[2-({(2R)-2-{[tert-
butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]phenyl}acetamide (preparation 152), using a method similar to
that of example 33, as a white foam in 41 % yield.
'H NMR (400MHz, CD30D) 8: 7.19-7.12 (5H, m), 7.02 (1 H, dd), 6.78 (1 H, d),
4.65 (3H, m), 3.40 (2H, d), 2.97 (1 H, m), 2.82 (1 H, m), 2.78 (2H, dd), 2.03
(9H,
m), 1.64 (6H, m), 1.05 (6H, dd) ppm; LRMS ESI m/z 507 [M+H]+
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Example 83
N-Benzyl-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)
phenyl]ethyl}amino)-2-methylpropyl]phenyl}-N-methylacetamide
CH3
N ~ N
3C \CH3
O
HO
ti U
The title compound was prepared from N-benzyl-2-{3-[2-({(2R)-2-{[tert-
butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]phenyl}-N-methylacetamide (preparation 156), using a similar
method to example 33, as a colourless solid in 75% yield.
'H NMR (400MHz, CD30D) 8: 7.18 (11 H, m), 6.75 (1 H, m), 4.61 (5H, m), 3.80
(2H, m), 2.60-2.95 (7H, m), 1.01 (6H, m) ppm; LRMS APCI m/z 477 [M+H]+
_ Example 84
N-[2-(4-Fluorophenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenylJethyl}amino)-2-methylpropyl]benzamide
o
H
N H
~N
~3Cr CHg
HO /
F
Ho
Solutions of 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-
hydroxy
methyl-phenyl)ethylamino]-2-methylpropyl}benzoic acid (preparation 37) (90mg,
0.19mmol) in N,N-dimethylacetamide (1 mL) and O-(1 H-benzotriazol-1-yl)-
N,N,N',N'-tetramethyluronium hexafluorophosphate (61 mg, 0.16mmol) in N,N-
dimethylacetamide (0.5mL) were added to a solution of 4-fluorophenethylamine
(33mg, 0.19mmol) in N,N-dimethylacetamide (0.5mL). The resulting riiixture
was stirred for 72 hours at room temperature. The solvent was removed in
vacuo and the residue was partitioned between dichloromethane (4mL) and
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saturated sodium hydrogen carbonate solution (1 mL). The mixture was then
filtered through a phase separation tube and the organic solution was
concentrated in vacuo. Ammonium fluoride (70mg, 1.9mmol) was added to a
suspension of the residue in methanol (2mL) and water (1 mL) and the mixture
was stirred at room temperature for 72 hours. The reaction mixture was then
concentrated in vacuo and the residue was purified by column chromatography
on silica gel, eluting with dichloromethane:methano1:0.88 ammonia, 100:0:0 to
91:9:1, followed by trituration with diethyl ether, to afford the title
compound in
50% yield, 45mg.
'H NMR (400MHz, CD30D) 8: 7.63 (2H, m), 7.40-7.30 (3H, m), 7.23 (2H, m),
7.14 (1 H, m), 7.00 (2H, m), 6.75 (1 H, d), 4.65 (3H, m), 3.58 (2H, m), 2.98-
2.64
(6H, m), 1.11 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m/z 481 [M+H]+
Examples 85 to 91
The following compounds, of the general formula shown below were prepared
by a similar method to that described for example 84, using 3-{2-[(2R)-2-(tert-
butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl) ethylamino]-2-
methylpropyl}benzoic acid (preparation 37) and the appropriate amine starting
material. The amines were either commercially available or prepared as
described in preparations 69-108
H O
N
\CH3
HO
11U
No. ~ Q' I Data Yield
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85 ( ~ o I ~ 'H NMR (400MHz, CD30D) b: 58%
N 7.63 (2H, m), 7.39-7.27 (5H, m),
7.22 (2H, m), 7.13 (1 H, m), 7.06
(1 H, m), 6.98-6.85 (4H, m), 6.75
(1 H, d), 4.65 (3H, m), 3.59 (2H,
m), 2.96-2.66 (6H, m), 1.10 (3H,
s), 1.03 (3H, s) ppm; LRMS APCI
m/z 555 [M+H]+
86 'H NMR (400MHz, CD30D) 8: 45%
H3c~o ~ 7.63 (2H, m), 7.39-7.27 (3H, m),
7.16-7.09 (3H, m), 6.84-6.72 (3H,
m), 4.65 (3H, m), 3.99 (2H, q),
3.56 (2H, m), 2.96-2.80 (4H, m),
2.78-2.66 (2H, m), 1.35 (3H, t),
1.10 (3H, s), 1.05 (3H, s) ppm;
LRMS APCI m/z 507 [M+H]+
87 H C ~ 'H NMR (400MHz, CD30D) 8: 45%
3
7.63 (2H, m), 7.39-7.27 (3H, m),
7.16-7.07 (5H, m), 6.76 (1 H, d),
4.65 (3H, m), 3.58 (2H, m), 2.96-
2.83 (4H, m), 2.78-2.66 (2H, m),
2.59 (2H, q), 1.19 (3H, t), 1.11 (3H,
s), 1.05 (3H, s) ppm; LRMS APCI
m/z 491 [M+H]+
88 ~ 'H NMR (400MHz, CD30D) 8: 22%
7.66-7.59 (3H, m), 7.39-7.29 (3H,
H3C N N m), 7.15-7.08 (3H, m), 6.75 (1 H,
d), 4.65 (3H, m), 3.70 (2H, t), 3.04
(2H, t), 2.99-2.83 (2H, m), 2.80-
2.68 (2H, m), 2.49 (3H, s), 1.10
(3H, s), 1.03 (3H, s) ppm; LRMS
APCI m/z 478 [M+H]+
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89 / 'H NMR (400MHz, CD30D) 8: 25%
I 7.60 (2H, m), 7.42-7.10
(6H, m),
H C'~ 6.90-6.70 (3H, d), 4.65
3 (3H, m),
3.75 (3H, s), 3.50-3.60
(2H, m),
2.95-2.60 (6H, m), 1.15
(3H, s),
1.05 (3H, s) ppm; LRMS APCI
m/z
493 [M+H]+
90 ~ 'H NMR (400MHz, CD30D) b: 32%
0 8.00-7.90 (2H, m), 7.80-7.70
(2H,
I m), 7.50-7.10 (6H, m), 6.80-6.70
3
(1 H, m), 4.65 (3H, m),
3.90 (2H, s),
3.32 (3H, s), 2.80-3.00
(2H, m),
2.80-2.70 (2H, m), 1.17
(3H, s),
1.07 (3H, s) ppm; LRMS APCI
m/z
507 [M+H]+
91 ~ Hs 'H NMR (400MHz, CD30D) 8: 52%
N~ 7.80-7.60 (2H, m), 7.40-7.10
(6H,
~H
3
~I
m), 6.80-6.60 (3H, m), 5.00-4.80
(3H, m), 4.60-4.40 (2H,
m), 2.80-
3.00 (6H, m), 2.80-2.60
(4H, m),
1.15 (3H, s), 1.05 (3H,
s) ppm;
LRMS APCI m/z 492 [M+H]+
Upon addition of ammonium fluoride, examples: 89, 90 and 91 were warmed at
50°C for 18 hours.
Example 92
N-[2-(4-Ethoxy-3-methoxyphenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-
3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide
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108
O
H
N ~ H
-N
~3C CH3
HO
O~CH3
11U O
H3C~
Solutions of 3-{2-[(2R)-2-(tent-butyldimethylsilanyloxy)-2-(4-hydroxy-3-
hydroxy
methyl-phenyl)ethylamino]-2-methylpropyl}benzoic acid (preparation 37) (90mg,
0.19mmol) in N,N-dimethylacetamide (1 mL) and O-(1 H-benzotriazol-1-yl)-
N,N,N',N'-tetramethyluronium hexafluorophosphate (61 mg, 0.16mmol) in N,N-
dimethylacetamide (0.5mL) were added to a solution of 4-ethoxy-3-
methoxyphenethylamine (37mg, 0.19mmol) in N,N-dimethylacetamide (0.5mL).
The resulting mixture was stirred for 72 hours at room temperature. The
solvent
was removed in vacuo and the residue was partitioned between
dichloromethane (4mL) and saturated sodium hydrogen carbonate solution
(1 mL). The mixture was then filtered through a phase separation tube and the
organic solution was concentrated in vacuo. The residue was dissolved in
dimethylsulfoxide (700~L), triethylamine trihydrofluoride (30p.L, 0.19mmol)
was
added and the mixture was stirred at room temperature for 72 hours. The
reaction mixture was then purified directly by HPLC using a Phenomenex Luna
C18 system, eluting with water/0.05% diethylamine:acetonitrile, 5:95 to 95:5,
to
afford the title compound in 30% yield (30.9mg).
'H NMR (400MHz, CD30D) b: 7.60-7.68 (2H, m), 7.39-7.29 (3H, m), 7.13 (1H,
m), 6.85-6.81 (2H, m), 6.78-6.72 (2H, m), 4.67-4.62 (3H, m), 4.00 (2H, q),
3.75
(3H, s), 3.58 (2H, m), 2.98-2.64 (6H, m), 1.37 (3H, t), 1.10 (3H, s), 1.03
(3H, s)
ppm; LCMS m/z 537.28 [M+H]+
Examples 93 to 112
The following compounds, of the general formula shown below were prepared
by a similar method to that described for example 92, using 3-{2-[(2R)-2-(tert-
butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl) ethylamino]-2-
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-- 109
methylpropyl}benzoic acid (preparation 37) and the appropriate amine as
starting material. The amines were either commercially available or prepared
as
described in preparations 69-108
O
H
N \ Q'
~3C \CH3
HO
HO
No. Q Data Yield
g3 F F 'H NMR (400MHz, CD30D) b: 11%
F
W 7.60 (3H, m), 7.35 (3H, m),
7.22
i (2H, m), 7.13 (1 H, m), 6.76
(1 H,
N
m), 4.64 (3H, m), 3.62 (2H,
m)
2.92 (4H, m), 2.75 (2H, m),
1.10
(3H, s), 1.03 (3H, s) ppm;
LRMS
ESI m/z 549 [M+H]+
94 F 'H NMR (400MHz, CD30D) 8: 36%
7.62 (2H, m), 7.35 (3H, m),
7.10
/ (2H, m), 6.90 (2H, m), 6.75
(1 H,
m), 4.65 (3H, m), 3.58 (2H,
m),
2.90 (3H, m) 2.70 (3H, m),
2.20
(3H, s) 1.10 (3H, s), 1.03
(3H, s)
ppm; LRMS APCI m/z 495 [M+H]+
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110
95 F 'H NMR (400MHz, CD30D) b: 63%
H3C ~ F 7.62 (2H, m), 7.32 (3H,
m), 7.13
(1 H, m), 6.90 (2H, m),
6.75 (1 H,
m), 4.65 (3H, m), 3.60 (2H,
m)
2.80 (6H, m), 2.22 (3H,
s) 1.10
(3H, s), 1.05 (3H, s) ppm;
LRMS
APCI m/z 513 [M+H]+
g6 H3C ~ CH3 'H NMR (400MHz, CD30D) 8: 80%
7.69 (2H, m), 7.37 (3H,
m), 7.15
(1 H, m), 6.78 (3H, m),
4.63 (3H,
CH3 ~, m), 3.42 (2H, m), 2.95 (4H,
m),
2.74 (2H, m), 2.32 (6H,
s), 2.20
(3H, s) 1.12 (3H, s), 1.05
(3H, s)
ppm; LRMS APCI m/z 505 [M+H]+
97 CH3 'H NMR (400MHz, CD30D) b: 44%
7.60 (2H, m), 7.32 (3H,
m), 7.10
(2H, m), 6.78 (2H, m), 4.63
(3W,
m), 3.60 (2H, m), 2.66 (6H,
m),
2.19 (3H, s) 1.10 (3H, s),
1.05 (3H,
s) ppm; LRMS APCI m/z 513
[M+H]+
gg CHs 'H NMR (400MHz, CD30D) 8: 28%
7.62 (2H, m), 7.35 (3H,
m), 7.10
(3H, m), 6.76 (1 H, m),
4.65 (3H,
m), 3.62 (2H, m) 3.14 (2H,
m),
2.81 (4H, m), 2.19 (3H,
s) 1.10
(3H, s), 1.05 (3H, s) ppm;
LRMS
APCI m/z 529 [M+H]+
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111
99 CHs 'H NMR (400MHz, CD30D) 8: 64%
7.61 (2H, m), 7.32 (3H,
m), 7.17
(2H, m), 6.93 (1 H, m),
6.76 (1 H,
m), 4.65 (3H, m), 3.62 (2H,
m)
3.17 (2H, m), 2.81 (4H,
m), 2.32
(3H, s) 1.10 (3H, s), 1.05
(3H, s)
ppm; LRMS APCI m/z 529 [M+H]+
100 F 'H NMR (400MHz, CD30D) 8: 46%
7.67-7.61 (2H, m), 7.40-7.32
(3H,
m), 7.17 (2H, m), 6.93 (1
H, m),
6.82 (1 H, m), 6.76 (1 H,
m), 4.65
CH3
(3H, m), 3.62 (2H, m) 3.17
(2H,
m), 3.00-2.64 (4H, m), 2.32
(3H, s)
1.10 (3H, s), 1.05 (3H,
s) ppm;
LRMS APCI m/z 529 [M+H]+
101 F 'H NMR (400MHz, CD30D) 8: 35%
W 7.60 (4H, m), 7.34 (4H,
m), 7.25
(1 H, m), 7.13 (1 H, m),
-N 6.75 (1 H,
m), 4.65 (3H, m), 3.63 (2H,
m),
3.04 (2H, m), 2.81 (4H,
m), 1.10
(3H, s), 1.05 (3H, s) ppm;
LRMS
APCI m/z 549 [M+H]+
102 F F 'H NMR (400MHz, CD30D) 8: 50%
7.66 (3H, m), 7.50 (2H,
m), 7.37
(4H, m), 7.13 (1 H, m),
6.75 (1 H,
NH m), 4.65 (3H, m), 3.63 (2H,
m),
3.11 (2H, m), 2.90 (2H,
m), 2.75
(2H, m), 1.10 (3H, s), 1.05
(3H, s)
ppm; LRMS APCI m/z 531 [M+H]+
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112
103 cH3 'H NMR (400MHz, CD30D) b: 38%
7.66 (2H, m), 7.36 (3H, m),
7.15
/ (1 H, m), 6.88 (2H, m), 6.76
(1 H,
N m), 4.65 (3H, m), 3.83 (6H,
m),
3.50 (2H, m), 2.25 (3H, s),
2.14
(6H, m), 1.10 (3H, s), 1.05
(3H, s)
ppm; LRMS APCI m/z 505 [M+H]+
104 ~ 'H NMR (400MHz, CD30D) b: 52%
8.44 (m, 1 H), 7.75 (m, 1
H), 7.64-
N N 7.60 (2H, m), 7.38-7.23 (5H,
m),
7.12 (1 H, m), 6.76 (1 H,
m), 4.69-
4.60 (3H, m), 3.73 (2H, m),
3.09
(2H, m), 2.98-2.65 (4H, m),
1.11
(3H, s), 1.04 (3H, s) ppm;
LCMS
m/z 464.29 [M+H]+
105 ~~~N 'H NMR (400MHz, CD30D) 8: 19%
N
7.67-7.61 (m, 2H), 7.50-7.43
(2H,
m), 7.38-7.27 (3H, m), 7.20-7.10
(3H, m), 6.76 (1 H, m), 4.69-4.64
(3H, m), 3.83 (2H, t), 3.20
(2H, t),
2.97-2.61 (4H, m), 1.08 (3H,
s),
1.01 (3H, s) ppm; LCMS m/z
503.23 [M+H]+
106 ~ 'H NMR (400MHz, CD30D) 8: 25%
7.68-7.46 (6H, m), 7.28-7.38
(3H,
m), 7.11 (1 H, m), 6.76 (1
H, m),
- 4.67-4.62 (3H, m), 3.60-3.70
(6H,
/o
o%SVN m), 3.03 (2H, t), 2.98-2.66
(8H, m),
1.10 (3H, s), 1.04 (3H, s)
ppm;
LCMS m/z 612.23 [M+H]+
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113
107 ~~ LCMS m/z 513.17 [M+H] 46%
OH
N
108 F F 'H NMR (400MHz, CD30D) 8: 33%
F ~ 7.81 (m, 2H), 7.60 (1 H,
m), 7.49
F
/ (3H, m), 7.36 (2H, m), 7.20
(1 H,
m), 6.80 (1 H, m), 4.84 (1
H, m),
4.76 (2H, s), 4.65 (2H, m),
3.20
(2H, m), 3.08 (2H, s), 1.34
(6H, m)
ppm; LRMS APCI m/z 535 [M+H]+
109 C~ 'H NMR (400MHz, CD30D) b: 45%
7.83-7.78 (m, 2H), 7.50-7.20
(8H,
/ m), 6.90-6.80 (1 H, d), 4.65
(2H, s),
4.58-4.50 (3H, m), 3.22-3.05
(4H,
m), 1.40-1.25 (6H, m) ppm;
LCMS
m/z 483.2045 [M+H]+
110 ~ C~ 'H NMR (400MHz, CD30D) 8: 21%
7.82-7.78 (2H, m), 7.45-7.20
(8H,
m), 6.82-6.78 (1 H, d), 4.90-4.80
(1 H, s), 4.75-4.60 (4H,
m), 3.25-
3.05 (4H, m), 1.30-1.22 (6H,
m)
ppm; LCMS m/z 483.2045 [M+H]+
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114
111 'H NMR (400MHz, CD30D) b: 33%
cHs 7.65-7.61 (2H, m), 7.38-7.27 (3H,
N m), 7.13 (1 H, m), 7.09 (1 H, s),
H C N~N~ 676 (1 H, m), 4.68-4.62 (3H, m),
3
3.82 (2H, t), 3.13 (2H, t), 2.98-2.64
(4H, m), 1.11 (3H, s), 1.04 (3H, s)
ppm; LRMS APCI m/z 493.29
[M+H]+
112 ~ N LRMS APCI m/z 478.28 [M+H]+ 25%
N~
CH3
txamp~e lUZ: fz-[z-(tntluoromethyl)phenyl]ethyl}amine can be prepared as
described in WO 2003093231
Example 106: 4-[[4-(2-aminoethyl)phenyl]sulfonyl]- morpholine is commercially
available from Scientific Exchange Product List (K-046583)
Example 107: amine precursor (2-(2-aminoethyl)-6-chlorophenol) can be
prepared as described in DE1959898
Example 108: crude compound was purified by HPLC using a Phenomenex
Luna C18 system, eluting with water/acetonitrile/trifluoroacetic acid
(5:95:0.1 ):acetonitrile, 95:5 to 5:95, to isolate the trifluoroacetic acid
salt of the
desired product.
Example 109 and 110: crude compound was purified by HPLC using a
Phenomenex Luna C18 system, eluting with water/0.1 % formic
acid:acetonitrile/0.1 % formic acid, 85:15 to 15:85
Example 113
N-[2-(2-Chlorophenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide
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115
CI
O
H
N
~N
IsC CHs ( ~ H
HO
t1U
A mixture of 3-[2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]-N-[2-(2-chlorophenyl)
ethyl]benzamide (preparation 118), (147mg, 0.24mmol) and triethylamine
trihydrofluoride (39,uL, 0.24mmol) 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:methano1:0.88 ammonia, 100:0:0 to 95:5:0.5 . The appropriate
fractions were evaporated under reduced pressure and the residue was
azeotroped with methanolic ammonia to afford the title compound as a
colourless solid in 77% yield, 75mg.
'H NMR (400MHz, CD30D) 8: 7.61 (2H, m), 7.37-7.29 (5H, m), 7.23-7.16 (2H,
m), 7.12 (1 H, dd), 6.74 (1 H, d), 4.66 (1 H, m), 4.64 (2H, s), 3.63 (2H, m),
3.05
(2H, t), 2.96-2.84 (2H, t), 2.76-2.69 (2H, m), 1.10 (3H, s), 1.04 (3H, s) ppm;
LRMS ESI m/z 497 [M+H]+
Examples 114 to 128
The following compounds, of the general formula shown below were prepared
by a similar method to that described for example 113, using the appropriate
starting material and triethylamine trihydrofluoride. The reactions were
monitored by tlc analysis and were stirred at room temperature for 18-72hours.
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116
O
H
N
\CH3
HO
HU
No. Q Data Yield
114 ~ 'H NMR (400MHz, CD30D) 8: 67%
7.66
N (2H, m), 7.38-7.31 (3H, m),
7.13
(1 H, m), 6.75 (1 H, d), 4.67
(1 H, m),
4.65 (2H, d), 3.44-3.36 (2H,
m),
H,,,, 2.99-2.88 (2H, m), 2.78-2.69
(2H,
m), 1.94 (3H, s), 1.67-1.77
(6H, m),
H 1.58 (6H, m), 1.37 (2H, m),
1.12
(3H, s), 1.05 (3H, s) ppm;
LRMS
APCI m/z 521 [M+H]+
115 / \ ~H NMR (400MHz, CD30D) 8: 50%
8.21
(1 H, m), 7.85 (1 H, m), 7.74
(1 H, m),
7.65 (2H, m), 7.47 (2H, m),
7.39-
N
7.31 (5H, m), 7.14 (1 H, dd),
6.75
(1 H, m), 4.68 (1 H, m), 4.64
(2H, d),
3.71 (2H, m), 3.39 (2H, m),
2.99-
2.87 (2H, m), 2.79-2.70 (2H,
m),
1.12 (3H, s), 1.05 (3H, s)
ppm;
LRMS APCI m/z 513 [M+H]+
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117
116 H3c 'H NMR (400MHz, CD30D) 8: 75%
7.68-
7.61 (2H, m), 7.36 (2H, m),
7.33
(1 H, m), 7.14 (1 H, dd),
6.96 (3H, m),
H c 6.75 (1 H, m), 4.67 (1 H,
3 m), 4.63
(2H, m), 3.47 (2H, m), 3.00-2.89
(4H, m), 2.77-2.71 (2H, m),
2.35
(6H, s), 1.13 (3H, s), 1.05
(3H, s)
ppm; LRMS APCI m/z 491 [M+Hj+
117 ~ ~ 'H NMR (400MHz, CD30D) 8: 30%
7.63
N
s (2H, m), 7.37-7.31 (3H, m),
cH 7.20-
3
7.12 (5H, m), 6.74 (1 H,
m), 4.67
(1 H, m), 4.65 (2H, d), 3.55-3.59
(2H,
m), 2.97-2.85 (4H, m), 2.70-2.77
(2H, m), 2.42 (3H, s), 1.11
(3H, s),
1.05 (3H, s) ppm
LRMS APCI m/z 509 [M+Hj+
118 F 'H NMR (400MHz, CD30D) 8: 23%
7.61-
(2H, m), 7.36-7.28 (4H, m),
7.21
(1 H, m), 7.11 (1 H, m),
7.02 (1 H, m),
ci 6.74 (1 H, d), 4.65 (3H,
m), 3.60 (2H,
m), 2.96-2.84 (4H, m), 2.77-2.69
(2H, m), 1.10 (3H, s), 1.04
(3H, s)
ppm; LCMS m/z 515 [M]+
119 c~ 'H NMR (400MHz, CD30D) 8: 45%
7.62
(2H, m), 7.30-7.37 (4H, m),
7.17
F
(1 H, m), 7.11 (1 H, dd),
6.96 (1 H, m),
6.74 (1 H, d), 4.67 (1 H,
m), 4.64 (2H,
m), 3.61 (2H, m), 3.02 (2H,
t), 2.96-
2.85 (2H, m), 2.78-2.70 (2H,
m),
1.11 (3H, s), 1.04 (3H, s)
ppm;
LRMS APCI m/z 515 [M+Hj+
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118
120 cHs 'H NMR (400MHz, CD30D) 8: 52%
7.65
(2H, m), 7.38-7.31 (3H, m),
cH3 cH3 7.12
(1 H, dd), 6.88 (1 H, s),
6.75 (1 H, d),
6.66 (1 H, s), 4.67 (1 H,
m), 4.65 (2H,
m), 3.77 (3H, s), 3.49 (2H,
m), 2.98-
2.87 (2H, m), 2.84-2.70 (4H,
m),
2.30 (3H, s), 2.08 (3H, s),
1.12 (3H,
s), 1.05 (3H, s) ppm; LRMS
ESI m/z
521 [M+H]+
121 c~ 'H NMR (400MHz, CD30D) 8: 67%
7.62
N
(2H, m), 7.38 (1 H, dd), 7.32
(3H, m),
/ 7.25 (1 H, m), 7.19 (1 H,
m), 7.12
(1 H, d), 6.74 (1 H, d), 4.68
(1 H, m),
4.65 (2H, m), 3.68 (2H, m),
3.10
(2H, m), 2.96 (2H, m), 2.73
(2H, m),
1.11 (3H, s), 1.05 (3H, s)
ppm;
LRMS APCI m/z 531 [M+H]+
122 cHs 'H NMR (400MHz, CD30D) 8: 83%
7.65
N
(1 H, m) 7.63 (1 H, m), 7.38-7.31
(3H,
m), 7.13 (1 H, dd), 6.95 (1
H, s), 6.75
(1 H, d), 6.67 (1 H, d), 4.67
(1 H, m),
CH3 4.65 (2H, m), 3.76 (3H, s),
3.49 (2H,
m), 2.98-2.87 (4H, m), 2.79-2.70
(2H, m), 2.25 (3H, s), 2.12
(3H, s),
1.12 (3H, s), 1.05 (3H, s)
ppm
LRMS ESI m/z 521 [M+H]+
Microanalysis: C3~H4pN2Og.
0.1 H20
requires (%): C 71.27; H 7.76;
N
5.36; found (%) C 70.87; H
7.36, N
5.36.
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119
123 ~ / I 'H NMR (400MHz, CD30D) 8: 74%
7.63
(1 H, m), 7.60 (1 H, bs),
7.57-7.50
(4H, m), 7.41-7.26 (8H, m),
7.11
(1 H, m), 6.73 (1 H, dd),
4.66-4.62
(3H, m), 3.69 (2H, t), 2.96-2.83
(4H,
m), 2.75-2.67 (2H, m), 1.09
(3H, s),
1.02 (3H, s) ppm
LRMS ESI m/z 539 [M+Na]+
124 ~ 'H NMR (400MHz, CD30D) 8: 79%
7.65
(2H, m) 7.63 (2H, m), 7.39-7.30
(1 H,
d), 7.12 (1 H, dd), 7.01
(1 H, d), 6.95
\ (1 H, bs), 6.88 (1 H, d),
CH 6.74 (1 H, d),
H3c 3 4.69-4.63 (3H, m), 3.60 (2H,
m),
2.98-2.85 (4H, m), 2.78-2.68
(2H,
m), 2.29 (3H, s), 2.24 (3H,
s), 1.11
(3H, s), 1.04 (3H, s) ppm;
LRMS ESI
m/z 513 (M+Na]+
125 \ 'H NMR (400MHz, CD30D) 8: 58%
7.65
(2H, m), 7.39-7.31 (3H, m),
7.13
\ (1 H, dd), 7.02-6.94 (3H,
m), 6.75
cH
3
~"~3Cr (1 H, d), 4.65 (3H, m), 3.64-3.60
(2H,
m), 2.99-2.93 (3H, m), 2.88
(1 H, m),
2.74 (1 H, dd), 2.71 (1 H,
m), 2.26
(3H, s), 2.25 (3H, s), 1.12
(3H, s),
1.06 (3H, s) ppm
LRMS APCI m/z 491 [M+H]+
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126 F F 'H NMR (400MHz, CD30D) 8: 79%
7.66-
F 7.46 (6H, m), 7.33 (3H, m),
7.13
(1 H, d), 6.75 (1 H, d), 4.67
(3H, m),
\ ~ 3.66-3.60 2 H m 3.04-2.85
4 H
( , )~ ( ,
m), 2.89-2.76 (2H, m), 1.11
(3H, s),
1.04 (3H, s) ppm
LRMS APCI m/z 531 [M+H]+
127 N 'H NMR (400MHz, CDCI3) 8: 85%
7.60
\ ~ C~ (2H, m), 7.36-7.26 (4H, m),
7.16-
7.09 (3H, m), 6.75 (1 H, d),
4.66 (3H,
F
m), 3.83-3.57 (2H, m), 2.98-2.69
(6H, m), 1.10 (3H, s), 1.04
(3H, s)
ppm; LRMS APCI m/z 515 [M+H]+
128 H3C 'H NMR (400MHz, CD30D) 8: 44%
7.72
(2H, m) 7.39-7.32 (2H, m),
7.26 (1 H,
\ ~ d), 7.11 (1 H, bs), 7.09-7.03
(2H, dd),
CH3 6.95 (1 H, d), 6.68 (1 H,
d), 4.63 (3H;
m), 4.49 (2H, dd), 2.94-2.86
(2H, m),
2.73 (2H, dd), 2.29 (3H, s),
2.24 (3H,
s), 1.11 (3H, s), 1.04 (3H,
s) ppm;
LRMS ESI m/z 499 [M+Na]+
Example 129
N-(3,4-Dichlorobenzyl)-3-(3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl~amino)-2-methylpropyl]phenyl}propanamide
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O
N CHs
\ ~ ~N ( \
H
HO CH3 / /
-CI
CI
HO
The title compound was prepared from 3-{3-[2-({(2R)-2-{[tert-
butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl) phenyl]ethyl}amino)-2-
methylpropyl]phenyl}-N-(3,4-dichlorobenzyl) propanamide (preparation 145),
using a method similar to that of example 113, as a white foam in 71 % yield.
'H NMR (400MHz, CD30D) 8: 7.38 (1 H, d), 7.35 (2H, d), 7.08 (6H, m), 6.78
(1 H, d), 5.61 (3H, m), 4.23 (2H, s), 2.95 (3H, m), 2.68 (3H, m), 2.58 (2H,
t), 1.01
(6H, s) ppm; LRMS ESI m/z 545 [M+H]+
Example 130
3-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-
2-methylpropyl]-N-{2-[4-(trifluoromethoxy)phenyl]ethyl}benzamide
0
H
N \ H
N
i3C CHs ~ \
HO /
O
HU
F~F
F
A mixture of 3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]
ethyl}amino)-2-methylpropyl)benzoic acid (preparation 140) (100mg,
0.28mmol), 2-(4-trifluoromethoxyphenyl)ethylamine (US20020082454A1, p2),
(46mg, 0.28mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (43mg, 0.28mmol), 1-hydroxybenzotriazloe hydrate (35mg,
0.28mmol) and triethylamine (60~L, 0.45mmol) in N,N-dimethylformamide
(5mL) was stirred at room temperature for 20 hours. The reaction mixture was
then concentrated in vacuo and the residue was dissolved in dichloromethane.
The solution was then washed with saturated sodium carbonate solution and
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brine, dried over magnesium sulfate and concentrated in vacuo. Purification of
the residue by column chromatography on silica gel, eluting with
dichloromethane:methano1:0.88 ammonia, 100:0:0 to 95:5:1, afforded the title
compound as a white powder in 51 % yield, 79mg.
'H NMR (400MHz, CD30D) 8: 7.63 (2H, m), 7.38-7.30 (5H, m), 7.17 (2H, m),
7.12 (1 H, dd), 6.75 (1 H, d), 4.66 (3H, m), 3.57 (2H, d), 2.99-2.85 (4H, m),
2.79-
2.69 (2H, m), 1.12 (3H, s), 1.06 (3H, s) ppm; LRMS APCI m/z 547 [M+H]+
Examples 131 to 137
The following compounds, of the general formula shown below were prepared
by a similar method to that described for example 130, using the appropriate
acid and amine starting materials. The amines were either commercially
available or prepared as described in preparations 69-108
H
N \ Q~
~ ~n
~3C \CH3 ~ / ' O
HO
11U
OH O
H
\ N
v \ ~Q~
H3C CH3
HO
HO~
No. ~ Q' ~ Data ~ Yield
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131 ~ off 'H NMR (400MHz, CD30D) 8: 6%
7.54
H3C CH3 (1 H, m), 7.50 (1 H, m), 7.34-7.28
(3H, m), 7.25 (2H, m), 7.10
(1 H, dd),
6.73 (3H, m), 4.62 (3H, m),
3.51
(2H, s), 2.92-2.87 (1 H, m),
2.81 (1 H,
m), 2.76-2.70 (2H, m), 1.33
(6H, s),
1.08 (3H, s), 1.04 (3H, s)
ppm;
LRMS APCI m/z 507 [M+H]+
132 ~ off 'H NMR (400MHz, CD30D) 8: 22%
7.88-
7.80 (3H, m), 7.63 (2H, m),
7.12
N CH3 (1 H, dd), 6.92 (1 H, m),
6.84 (1 H,
dd), 6.75 (1 H, d), 6.63 (1
H, d), 4.67
(1 H, m), 4.65 (2H, m), 3.51
(2H, m),
2.99-2.86 (2H, m), 2.78-2.70
(4H,
m), 2.13 (3H, s), 1.12 (3H,
s), 1.05
(3H, s) ppm; LRMS APCI m/z
493
[M+H]+
133 ~ ~H ~H NMR (400MHz, CD30D) 8: 6%
7.98
(2H, m), 7.43-7.36 (3H, m),
7.16
N v ~ -CH3 (1 H, dd), 6.82-6.77 (2H,
m), 6.52
cH3 (1 H, d), 4.75 (1 H, m), 4.66
(2H, m),
3.47 (2H, m), 3.07 (1 H, m),
2.98
(2H, m), 2.92 (1 H, m), 2.85
(2H, m),
2.24 (3H, s), 2.11 (3H, s),
1.23 (3H,
s), 1.19 (3H, s) ppm; LRMS
APCI
m/z 507 [M+H]+
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134 cHs 'H 16%
NMR
(400MHz,
CD30D)
8:
7.66
(2H,
m),
7.40-7.34
(3H,
m),
7.14
(1
H,
dd),
6.83(1
H,
s),
6.76
(1
H,
m),
N v ~ 6.50
(1
H,
d),
4.69
(1
H,
m),
4.66
(2H,
CH3 s),
3.49
(2H,
m),
3.04-2.98
(2H,
m),
2.87
(1
H,
m),
2.82-2.77
(3H,
m),
2.22
(3H,
s),
2.08
(3H,
s),
1.17
(3H,
s),
1.12
(3H,
s)
ppm;
LRMS
APCI
m/z
507
[M+H]+
OH
H
\
N
\
Q,
/
O
/
H3C
CH3
HO
HO
135 ~ c~ 'H NMR (400MHz, CD30D) 41%
8:
/ 7.41-7.05 (9H, m), 6.78
(1 H, d),
4.65 (3H, m), 4.36 (2H,
s), 3.55
(2H, s), 2.87 (2H, m),
2.81-2.69
(2H, m), 1.12 (3H, s),
1.05 (3H,
s) ppm; LRMS ESI m/z 531
[M+H]+
136 C~ 'H NMR (400MHz, CD30D) 24%
b:
7.34-7.03 (9H, m), 6.79
(1 H, d),
/ 4.63 (3H, m), 4.37 (2H,
s), 3.54
c~ (2H, s), 2.90 (2H, m),
2.81-2.64
(2H, m), 1.12 (3H, s),
1.05 (3H,
s) ppm; LRMS ESI m/z 531
[M+H]+
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137 ~ 'H NMR (400MHz, CD30D) 66%
8:
8.42 (1 H, d), 7.77 (1
H, t), 7.31-
7.04 (8H, m), 6.76 (1 H,
d), 4.62
(3H, m), 4.44 (2H, s),
3.59 (2H,
s), 2.92-2.65 (4H, m),
1.06 (3H,
s), 1.04 (3H, s) ppm; LRMS
ESI
m/z 464 [M+H]+
txample 131: amine precursor (4-(2-amino-1,1-dimethylethyl)phenol) can be
prepared as described in Acta Chem.Scand. 8, 1203, 1207; 1954
Examples 138 to 147
OH H O
N ~ _
13C CH3 Q
HO
t1 U
A mixture of 3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl) phenyl]
ethyl}amino)-2-methylpropyl]benzoic acid (preparation 140), (0.2M in
dimethylacetamide/3.75% triethylamine, 225,uL, 45,umol), the appropriate
amine (0.2M in dimethylacetamide/3.75% triethylamine, 150,uL, 30,umol) and
O-(1 H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
(0.2M in dimethylacetamide, 225,uL, 45,umol) was stirred at 60°C for 3
days.
The reaction mixture was then concentrated in vacuo, re-dissolved in
dimethylsulfoxide (300,uL) and stirred for 30 minutes at room temperature. The
mixture was diluted with further dimethylsulfoxide (50,uL) and water (100NL),
stirred for one minute at room temperature and then purified by HPLC using a
Phenomenex Luna C18 system, eluting with water/acetonitrile/diethylamine
(5:95:0.05):acetonitrile, 95:5 to 5:95, to afford the desired compound.
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126
No. Q' Data
138 /CHs /
\ ~ LRMS ESI m/z 504.30 [M]+
139 / off
LRMS ESI m/z 492.26 [MJ+
140 \
/ LRMS ESI m/z 476.26 [M]+
CH3
141 \ o~CH
3
N
LRMS ESI m/z 493.26 (M]+
142 \
E- N ~ / ~ LRMS ESI m/z 506.28 [M]+
O
143 ~ CI
N ~ /
LRMS ESI m/z 510.23 [M-H]~
144 N
N
LRMS ESI m/z 544.27 (M]+
N ~ /
~~O
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145 F
F
LRMS ESI m/z 498.23 [M]+
146 /
LRMS ESI m/z 513.26 [M]+
147
O
LRMS ESI m/z 546.31 [M]+
txampie ~ 3~: N-ethy-3-phenylpropylamine can be prepared as described in J.
Med. Chem. 34, 248; 1991
Example 141: 6-methoxy-3-pyridineethanamine can be prepared as described
in Drug Design and Discovery, 10, 35; 1993
Example 143: 2-[4-(Pyrazol-1-yl)phenoxy]ethylamine can be prepared as
described in W02002032897, p55
Example 146: 5-Quinolineethanamine can be prepared as described in J. Med.
Chem., 28, 1803-10; 1985
Preparation 1: 2-{3-[(2R)-2-(~(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-
cycloheptylacetamide
MS
N
CH3 ~ O
HO
HU
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A solution of (3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-
3-
hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20)
(250mg, 0.45mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (94mg, 0.49mmol), hydroxybenzotriazole monohydrate (66mg,
0.49mmol) in N,N-dimethylformamide (4ml) was treated with triethylamine
(0.12m1, 0.89mmol) and cycloheptylamine (56mg, 0.49mmol) and the resulting
suspension left to stir at room temperature under a nitrogen atmosphere for 18
hours. The solvent was removed in vacuo and the residue partitioned between
ethyl acetate (10m1) and saturated aqueous sodium bicarbonate (10m1). The
organic phase was separated, and the aqueous phase extracted with further
ethyl acetate (2x10m1). The combined organic extracts were washed with water
(5ml), brine (5ml), dried (sodium sulfate) and the solvent removed in vacuo.
The residue was purified by flash column chromatography on silica gel eluting
with dichloromethane:methanol: 880 ammonia (95:5:0.5 by volume) to give the
title compound as a pale yellow oil (150mg).
'H NMR (400MHz, CD30D): 8 = 7.20-6.98 (6H, m), 6.68 (1H, d), 4.60 (3H, m),
3.80 (1 H, m), 3.40 (2H, s), 2.85 (2H, m), 2.63 (2H, m), 2.58 (1 H, m),-1.80
(2H,
m), 1.75-1.40 (10H, m), 1.03 (3H, d), 0.83 (9H, s), 0.00 (3H, s), -0.20 (3H,
s)
ppm.
LRMS (electrospray) : m/z [M+H]+ 569.
Preparation 2: 2-{3-[(2R)-2-({(2R)-2-([tent-butyl(dimethyl)silyl]oxy}-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-
(cyclohexylmethyl)-N-methylacetamide
OTBD HS CH3
\ N \ N
CH3 ~ / O
HO Y
HO
Prepared according to the procedure used for preparation 1 using (3-{(2R)-2-
[(2R)-2-{[tent-butyl(dimethyl)silyl]oxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)-
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129
ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate
amine to give the title compound as a colourless oil.
'H NMR (400MHz, CD30D): b = 7.20-6.95 (6H, m), 6.63 (1 H, d), 4.60 (3H, m),
3.68 (2H, s), 3.20 (2H, m), 2.85 (5H, m), 2.63 (2H, m), 2.57 (1 H, m), 1.60
(5H,
m), 1.20 (4H, m), 1.03 (3H, d), 0.81 (11 H, m), 0.00 (3H, s), -0.21 (3H, s)
ppm.
LRMS (electrospray) : m/z [M+H]+ 583.
Preparation 3: 2-{3-[(2R)-2-(f(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-[(1 S)-1-
cyclohexylethyl]acetamide
MS
N CH3 ~ OH
CH3 ~ OI
HO
tiU
Prepared according to the procedure used for preparation 1 using (3-{(2R)-2-
[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-
ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate
amine to give the title compound as a colourless oil.
'H NMR (400MHz, CD30D): 8 = 7.20 (3H, m), 7.03 (1 H, s), 6.98 (2H, dd), 6.68
(1 H, d), 4.60 (3H, m), 3.68 (1 H, m), 3.42 (1 H, d), 3.38 (1 H, d), 2.85 (2H,
m),
2.63 (2H, m), 2.58 (1 H, dd), 1.65 (4H, m), 1.40-0.83 (13H, m), ppm.
LRMS (electrospray) : m/z [M+H]+ 583, [M+Na]+ 605, [M-H]- 582.
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Preparation 4: 2-{3-[(2R)-2-( f (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-
isopropylacetamide
OTBDMS
\ N \ N CH3
I
HO / CH3 / O CH3
HO
Prepared according to the procedure used for preparation 1 using (3-{(2R)-2-
[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-
ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate
amine to give the title compound as a colourless oil.
'H NMR (400MHz, CD30D): 8 = 7.19-7.15 (2H, m), 7.11-7.10 (1H, d), 7.04 (1H,
s), 6.99-6.96 (2H, t), 6.69-6.67 (1 H, d), 4.71-4.67 (1 H, dd), 4.65-4.58 (2H,
m),
3.96-3.90 (1 H, m), 3.39 (2H, s), 2.93-2.84 (2H, m), 2.70-2.62 (2H, m), 2.56-
2.52
- (1 H, m), 1.12-1.11 (6H, d), 1.05-1.03 (3H, d), 0.83 (9H, s), -0.01 (3H, s),
-0.20
(3H, s) ppm.
LRMS (electrospray) : m/z [M+H]+ 515, [M-H]- 513.
Preparation 5: 2-~3-[(2R)-2-({(2R)-2-([tert-butyl(dimethyl)silyl]oxy}-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-
cyclopentylacetamide
OTBDMS
\ N \ N
( / CH3 I / O
HO Y
HO
Prepared according to the procedure used for preparation 1 using (3-{(2R)-2
[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)
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131
ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate
amine to give the title compound as a colourless oil.
'H NMR (400MHz, CD30D): s = 7.19 (1 H, d), 7.17-7.15 (1 H, d), 7.11-7.09 (1 H,
d), 7.04 (1 H, s), 6.99-6.95 (2H, t), 6.69-6.67 (1 H, d), 4.71-4.67 (1 H, dd),
4.65
4.58 (2H, m), 4.10-4.04 (1 H, m), 3.40 (2H, s), 2.92-2.84 (2H, m), 2.69-2.62
(2H,
m), 2.56-2.51 (1 H, m), 1.94-1.86 (2H, m), 1.73-1.65 (2H, m), 1.62-1.53 (2H,
m),
1.47-1.39 (2H, m), 1.05-1.03 (3H, d), 0.83 (9H, s), -0.01 (3H, s), -0.20 (3H,
s)
ppm.
LRMS (electrospray) : m/z [M+H]+ 541, [M-H]- 539.
Preparation 6: 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyljoxy}-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-
(cyclobutylmethyl)acetamide
OTBDMS
H H
N ~ N
HO CH
11U
Prepared according to the procedure used for preparation 1 using (3-{(2R)-2-
[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-
ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate
amine to give the title compound as a colourless oil.
'H NMR (400MHz, CD30D): 8 = 7.19-7.15 (2H, m), 7.12-7.10 (1 H, m), 7.04 (1 H,
s), 7.00-6.96 (2H, m), 6.69-6.67 (1 H, d), 4.71-4.67 (1 H, dd), 4.65-4.58 (2H,
m),
3.43 (2H, s), 3.19-3.17 (2H, d), 2.93-2.85 (2H, m), 2.70-2.62 (2H, m), 2.56-
2.51
(1 H, m), 2.48-2.43 (1 H, m), 2.04-1.96 (2H, m), 1.90-1.78 (2H, m), 1.72-1.65
(2H, m), 1.05-1.03 (3H, d), 0.83 (9H, s), 0.00 (3H, s), -0.20 (3H, s) ppm.
LRMS (electrospray) : m/z [M+HJ+ 541, [M-H]- 539.
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Preparation 7: 2-{3-[(2R)-2-( f (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-
(cyclopentylmethyl)acetamide
MS
N ~ N
H CH IO~
O
HO
Prepared according to the procedure used for preparation 1 using (3-{(2R)-2-
[(2R)-2-{[tent-butyl(dimethyl)silyl]oxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)-
ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate
amine to give the title compound as a colourless oil.
'H NMR (400MHz, CD30D): 8 = 7.18 (1 H, s), 7.16-7.14 (1 H, d), 7.11-7.09 (1 H,
d), 7.04 (1 H, s), 6.99-6.95 (2H, m), 6.68-6.66 (1 H, d), 4.70-4.67 (1 H, dd),
4.65-
4.57 (2H, m), 3.43 (2H, s), 3.10-3.08 (2H, d), 2.93-2.85 (2H, m), 2.70-2.63
(2H,
m), 2.56-2.51 (1 H, m), 2.08-2.00 (1 H, m), 1.74-1.67 (2H, m), 1.64-1.50 (4H,
m),
1.22-1.14 (2H, m), 1.06-1.04 (3H, d), 0.84 (9H, s), 0.01 (3H, s), -0.18 (3H,
s)
ppm.
LRMS (electrospray) : m/z [M+H]+ 555, [M-H]- 554.
Preparation 8: 2-~3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-
cyclohexylacetamide
OTBDMS
N ~ N
CH3 ~ O
HO
HO
Prepared according to the procedure used for preparation 1 using (3-{(2R)-2-
[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)-
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ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate
amine to give the title compound as a colourless oil.
'H NMR (400MHz, CD30D): 8 = 7.19 (1 H, d), 7.17-7.15 (1 H, d), 7.11-7.09 (1 H,
d), 7.04 (1 H, s), 6.99-6.95 (2H, t), 6.69-6.67 (1 H, d), 4.70-4.67 (1 H, dd),
4.65-
4.58 (2H, m), 3.65-3.57 (1 H, m), 3.40 (2H, s), 2.92-2.84 (2H, m), 2.69-2.61
(2H,
m), 2.56-2.51 (1 H, m), 1.86-1.80 (2H, m), 1.75-1.70 (2H, m), 1.64-1.59 (1 H,
m),
1.39-1.28 (2H, m), 1.24-1.15 (3H, m), 1.05-1.03 (3H, d), 0.83 (9H, s), -0.01
(3H,
s), -0.20 (3H, s) ppm.
LRMS (electrospray) : m/z [M+H]+ 555, [M-H]- 554.
Preparation 9: 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-
cyclobutylacetamide
MS
N N
CH3 / O
HO
HO
Prepared according to the procedure used for preparation 1 using (3-f(2R)-2-
[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-
ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate
amine to give the title compound as a colourless oil.
'H NMR (400MHz, CD30D): 8 = 7.19 (1 H, d), 7.17-7.15 (1 H, d), 7.11-7.09 (1 H,
d), 7.03 (1 H, s), 6.99-6.95 (2H, m), 6.68-6.66 (1 H, d), 4.70-4.65 (1 H, dd),
4.62-
4.61 (2H, d), 4.29-4.21 (1 H, m), 3.39 (2H, s), 2.92-2.84 (2H, m), 2.68-2.61
(2H,
m), 2.57-2.52 (1 H, m), 2.29- 2.21 (2H, m), 1.98-1.87 (2H, m), 1.74-1.66 (2H,
m), 1.05-1.03 (3H, d), 0.82 (9H, s), -0.01 (3H, s), -0.20 (3H, s) ppm.
LRMS (electrospray) : m/z [M+H]+ 527, [M-H]- 525.
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Preparation 10: 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-
(cyclohexylmethyl)acetamide
OTBDMS
N \ N
CH3
HO
HO
Prepared according to the procedure used for preparation 1 using (3-{(2R)-2-
[(2R)-2-{[tent-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-
ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate
amine to give the title compound as a white foam.
'H NMR (400MHz, CD30D): 8 = 7.18-7.14 (2H, m), 7.11-7.09 (1 H, m), 7.03 (1 H,
s), 6.98-6.95 (2H, m), 6.68-6.66 (1 H, d), 4.70-4.67 (1 H, dd), 4.62-4.61 (2H,
d),
3.43 (2H, s), 3.00-2.99 (2H, d), 2.91-2.84 (2H, m), 2.70-2.62 (2H, m), 2.55-
2.50
(1 H, m), 1.69-1.67 (5H, m), 1.49-1.43 (1 H, m), 1.27-1.14 (3H, m), 1.05-1.03
(2H, m), 0.84 (9H, s), 0.01 (3H, s), -0.18 (3H, s) ppm.
LRMS (electrospray) : m/z [M+H]+ 569, [M+Na]+ 591, [M-H]- 567.
Preparation 11: 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-
(cyclopropylmethyl)acetamide
MS
N \ N
CH3
HO
HO
Prepared according to the procedure used for preparation 1 using (3-{(2R)-2
[(2R)-2-{[tert butyl(dimethyl)silyl]oxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)
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ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate
amine to give the title compound as a white foam.
'H NMR (400MHz, CD30D): 8 = 7.15-7.07 (3H, m), 7.01 (1 H, s), 6.95-6.92 (2H,
m), 6.65-6.63 (1 H, d), 4.66-4.63 (1 H, m), 4.58-4.57 (2H, d), 3.40 (2H, s),
3.00-
2.98 (2H, d), 2.89-2.80 (2H, m), 2.65-2.57 (2H, m), 2.53-2.48 (1 H, dd), 1.01-
1.00 (3H, d), 0.93-0.87 (1 H, m), 0.79 (9H, s), 0.44-0.40 (2H, q), 0.15-0.12
(2H,
q), -0.04 (3H, s), -0.24 (3H, s) ppm.
LRMS (electrospray) : m/z [M+H]+ 527, [M+Na]+ 549, [M-H]~ 525.
Preparation 12: 2-{3-[(2R)-2-(~(2R)-2-((tert-butyl(dimethyl)silyl]oxy~-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-
(cycloheptylmethyl)acetamide
H
N
CH3 ~ OI
HO
HU
Prepared according to the procedure used for preparation 1 using (3-{(2R)-2-
[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-
ethylamino]-propyl)-phenyl)-acetic acid (Preparation 20) and the appropriate
amine to give the title compound as a white foam.
'H NMR (400MHz, CD30D): b = 7.24-6.95 (6H, m), 6.70-6.67 (1H, d), 4.72-4.68
(1 H, m), 4.67-4.58 (2H, m), 3.24 (2H, s), 3.02-2.99 (2H, d), 2.92-2.50 (5H,
m),
1.72-1.08 (13H, m ), 1.06-1.04 (3H, d), 0.92 (9H, s), 0.00 (3H, s), -0.19 (3H,
s)
ppm.
LRMS (electrospray) : m/z [M+H]+ 583, [M+Na]+ 605.
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Preparation 13: N-1-adamantyl-2-~3-[(2R)-2-(~(2R)-2-{[tert-
butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide
OTBDMS
H H
N ~ N
HO CH3
t1 U
Prepared according to the procedure used for preparation 1 using (3-{(2R)-2-
[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)-
ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate
amine to give the title compound as a white foam.
'H NMR (400MHz, CD30D): 8 = 7.20-6.93 (6H, m), 6.68-6.65 (1 H, d), 4.74-4.68
(1 H, m), 4.65-4.58 (2H, m), 3.40 (s, 2H), 2.96-2.85 (m, 2H), 2.72-2.54 (3H,
m),
2.04 (3H, s), 2.01 (6H, s), 1.70 (6H, s), 1.07-1.05 (3H, d), 0.85 (9H, s),
0.02
(3H, s), -0.19 (3H, s) ppm.
LRMS (electrospray) : m/z [M-HJ- 605.
Alternative method
The title compound was prepared from N-1-adamantyl-2-{3-[(2R)-2-({(2R)-2-[4-
(benzyloxy)-3-(hydroxymethyl)phenyl]-2-hydroxyethyl)amino)propylJphenyl}
acetamide (preparation 164) using a similar method to that of preparation 25,
as a colourless foam in 91 % yield
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Preparation 14: N-(1-adamantylmethyl)-2-{3-[(2R)-2-(~(2R)-2-{[tert-
butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide
OTBDMS
N ~ N
CH3
HO
NU
Prepared according to the procedure used for preparation 1 using (3-{(2R)-2-
[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-
ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate
amine to give the title compound as a white foam.
'H NMR (400MHz, CD30D): 8 = 7.22-6.96 (6H, m), 6.71-6.68 (1 H, d), 4.75-4.67
(1 H, m), 4.66-4.58 (2H, m), 3.26 (2H, s), 2.88-2.50 (5H, m), 2.84 (2H, s),
1.90
(3H, s), 1.74-1.58 (6H, m), 1.44 (6H, s), 1.08-1.06 (3H, d), 0.84 (9H, s),
0.01
(3H, s), -0.19 (3H, s) ppm.
LRMS (electrospray) : m/z [M-H]- 619.
Preparation 15: N-2-adamantyl-2-{3-[(2R)-2-({(2R)-2-{[tert-butyl
(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)
propyl]phenyl}acetamide
OTBDMS
N ~ N
CH3
HO
HO
Prepared according to the procedure used for preparation 1 using (3-{(2R)-2-
[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-
ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate
amine to give the title compound as a white foam.
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'H NMR (400MHz, CD30D): b = 7.22-6.96 (6H, m), 6.70-6.68 (1 H, d), 4.72-4.68
(1 H, m), 4.67-4.58 (2H, m), 3.95 (1 H, s), 3.52 (2H, s), 2.94-2.50 (5H, m),
1.96-
1.78 (12H, m), 1.62-1.56 (2H, d), 1.05-1.03 (3H, d), 0.83 (9H, s), 0.00 (3H,
s), -
0.19 (3H, s) ppm.
LRMS (electrospray) : m/z [M-H]- 605.
Preparation 16: 2-~3-[(2R)-2-(f(2R)-2-~[tert-butyl(dimethyl)silyl)oxy}-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2-
cyclohexylethyl)-N-methylacetamide
OTBDMS CH
H
\ N \ N
CH3 I / O
Ho Y
HO
Prepared according to the procedure used for preparation 1 using (3-{(2R)-2-
[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-
ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate
amine to give the title compound as a white foam.
'H NMR (400MHz, CD30D): 8 = 7.22-6.98 (6H, m), 6.70-6.68 (1 H, d), 4.75-4.71
(1 H, m), 4.70-4.58 (2H, m), 3.70-3.64 (2H, m), 3.45-3.37 (2H, m), 2.98-2.52
(8H, m), 1.80-0.80 (25H, m), 0.04 (3H, s), -0.19 (3H, s) ppm.
LRMS (electrospray) : m/z [M+H]+ 619.
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Preparation 17: 2-{3-[(2R)-2-({(2R)-2-{[tent-butyl(dimethyl)silyl]oxy}-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-
cycloheptyl-N-methylacetamide
OTBD HS CH3
\ N \ N
CH3 ~ / OI
HO
HO
Prepared according to the procedure used for preparation 1 using (3-{(2R)-2-
[(2R)-2-{[tent-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-
ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate
amine to give the title compound as a white foam.
'H NMR (400MHz, CD30D): 8 = 7.22-6.96 (6H, m), 6.72-6.64 (1H, dd), 4.72-
4.65 (1 H, m), 4.62-4.60 (2H, m), 4.58-4.51 (0.5H, m), 3.90-3.83 (0.5H, m),
3.77
(1 H, s), 3.66 (1 H, s), 2.96-2.50 (5H, m), 2.82-2.78 (3H, d), 1.76-1.20 (12H,
m),
1.06-1.04 (3H, dd), 0.82-0.80 (9H, 2s), 0.01-0.00 (3H, 2s), -0.18- --0.19 (3H,
2s) ppm.
LRMS (electrospray) : m/z [M+H]+ 583, [M+Na]+ 605.
Preparation 18: 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-
cyclohexyl-N-ethylacetamide
OTBDMS CH3
H
N \ N
CH3 ~ O
HO
NU
Prepared according to the procedure used for preparation 1 using (3-{(2R)-2
[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)
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ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate
amine to give the title compound as a white foam.
'H NMR (400MHz, CD30D): 8 = 7.25-6.94 (6H, m), 6.70-6.66 (1 H, d), 4.72-4.68
(1 H, m), 4.64-4.58 (2H, m), 3.73 (2H, s), 3.70-3.60 (1 H, m), 3.73 (2H, s),
3.70
3.60 (1 H, m), 3.30-3.24 (2H, q), 2.95-2.48 (5H, m), 1.85-1.10 (10H, m), 1.12
1.08 (3H, t), 1.04-1.02 (3H, d), 0.92 (9H, s), 0.01 (3H, s), -0.20 (3H, s)
ppm.
LRMS (electrospray) : m/z [M+H]+ 605.
Preparation 19: 2-{3-[(2R)-2-(~(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-
hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2-
cyclohexylethyl)acetamide
MS
H H
N ~ N
HO CH3
HU
Prepared according to the procedure used for preparation 1 using (3-{(2R)-2-
[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-
ethylamino)-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate
amine to give the title compound as a white foam.
'H NMR (400MHz, CD30D): 8 = 7.22-6.96 (6H, m), 6.68-6.66 (1H, d), 4.70-4.65
(1 H, m), 4.64-4.58 (2H, m), 3.42 (2H, s), 3.21-3.17 (2H, t), 2.93-2.50 (5H,
m),
1.74-1.60 (5H, m), 1.39-1.34 (2H, q), 1.30-1.12 (4H, m), 1.04-1.02 (3H, d),
0.96-0.91 (2H, m), 0.90 (9H, s), 0.00 (3H, s), -0.19 (3H, s)ppm.
LRMS (electrospray) : m/z [M+Na]+ 605.
Preparation 20: (3-{(2R)-2-[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4-
hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetic acid
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OTBDMS
H
N ~ OH
CH3
HO
HO
A solution of methyl (3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-
hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl)-phenyl)-acetate
(Preparation 21 ) (7.04g, 14.43mmol) in tetrahydrofuran (40m1) was treated
with
lithium hydroxide (28.9m1 of a 1 M aqueous solution, 28.9mmol) and the
reaction left to stir at room temperature for 16 hours. Hydrochloric acid
(28.9m1
of a 1 M aqueous solution, 28.9mmol) was added and then the tetrahydrofuran
was removed in vacuo. The remaining aqueous layer was decanted and the
residue washed with further water (10m1). The residue was redisolved in
methanol (30m1) and the solvent removed in vacuo to give the title compound
as a colorless foam (5.95g) which was used without further purification.
'H NMR (400MHz, CD30D): 8 = 7.32 (1 H, s), 7.25-7.18 (2H, m), 7.13 (1 H, s),
7.12-7.10 (1 H, d), 7.02-7.01 (1 H, d), 6.79-6.77 (1 H, d), 4.98-4.95 (1 H,
m), 4.65-
4.64 (2H, d), 3.48 (2H, s), 3.48-3.43 (1 H, m), 3.28-3.23 (1 H, dd), 3.13-3.09
(1 H,
dd), 2.98-2.93 (1 H, dd), 2.77-2.72 (1 H, dd), 1.23-1.21 (3H, d), 0.86 (9H,
s), 0.06
(3H, s), -0.13 (3H, s) ppm.
LRMS (electrospray) : m/z [M+H]+ 474, [M+Na]+ 496, [M-H]~ 472.
CHN analysis : found C 64.15%, H 8.25%, N 2.84%; C26H39N05Si+0.7H20
requires C 64.22%, H 8.37%, N 2.88%.
Preparation 21: methyl (3-{(2R)-2-[(2R)-2-~[fert-butyl(dimethyl)silyl)oxy}-2-
(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetate
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MS
H
N ~ O~CH3
CH3
HO
HO
A suspension of methyl (3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-
(4-
[benzyloxy]-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetate
(Preparation 22) (5.27g, 9.12mmol) and 10% palladium on carbon (1.OOg) in
ethanol (50m1) was stirred under an atmosphere of hydrogen (60psi) at room
temperature for 16 hours. The catalyst was filtered off through arbocel and
the
filtrate concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel eluting with dichloromethane:methano1:880
ammonia (96:4:0.4 changing to 95:5:0.5, by volume) to give the title compound
as a pale yellow oil (1.99g) which was used without further purification.
'H NMR (400MHz, CD30D): 8 = 7.21-7.17 (2H, m), 7.11-7.09 (1H, d), 7.03-6.98
(3H, m), 6.69-6.67 (1 H, d), 4.71-4.68 (1 H, t), 4.62-4.61 (2H, d), 3.67 (3H,
s),
3.59 (2H, s), 2.96-2.86 (2H, m), 2.69-2.55 (3H, m), 1.07-1.05 (3H, d), 0.82
(9H,
s), -0.01 (3H, s), -0.20 (3H, s) ppm.
LRMS (electrospray) : m/z [M+H]+ 488, [M+Na]+ 510, [M-H]- 486
Preparation 22: methyl (3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-
(4-[benzyloxy]-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-
acetate
MS
H
N ~ O
~CH3
CH3 / 0
~O
HO
A solution of [2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)
silyl]oxy}ethyl) phenyl]methanol (Preparation 23) (12.58, 27.7mmol) and methyl
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{3-[(2R)-2-aminopropyl]phenyl}acetate (Preparation 25) (11.58, 55.4mmol) in
dichloromethane (130m1) was heated to 90°C, allowing the
dichforomethane to
evaporate. The resulting melt was left at 90°C for a further 16 hours.
The
reaction mixture was cooled to room temperature and purified by flash column
chromatography on silica gel eluting with dichloromethane:methano1:880
ammonia (98:2:0.2 changing to 97:3:0.3, by volume) to give the title compound
(12.1 g) as a white oil.
'H NMR (400MHz, CD30D): 8 = 7.47-7.45 (2H, m), 7.39-7.29 (4H, m), 7.19
7.15 (1 H, t), 7.13-7.07 (2H, m), 7.03 (1 H, s), 7.01-6.99 (1 H, d), 6.93-6.91
(1 H,
d), 5.12 (2H, s), 4.76-4.73 (1 H, t), 4.67-4.66 (2H, d), 3.66 (3H, s), 3.58
(2H, s),
2.95-2.80 (2H, m), 2.68-2.55 (3H, m), 1.06-1.05 (3H, d), 0.83 (9H, s), 0.00
(3H,
s), -0.19 (3H, s) ppm.
L_RMS (electrospray) : m/z [M+H]~ 578, [M+Na]+ 600.
Preparation 23: (2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)
silyl]oxy}ethyl) phenyl]methanol
MS
Br
~O
NU
Borane dimethylsulfide complex (42.4m1 of 10M solution in tetrahydrofuran,
424mmol) was added dropwise to a solution of methyl 2-(benzyloxy)-5-((1 R)-2-
bromo-1-{[tert-butyl(dimethyl)silyl]oxy)ethyl)benzoate (Preparation 24),
(91.Og,
189mmol) in tetrahydrofuran (1600m1). The resulting mixture was then heated
to reflux for 2 hours and then cooled to 0°C before quenching With
methanol
(270m1). The mixture was left to stir at room temperature for 16 hours and
then
the solvent removed in vacuo. The residue was partitioned between
dichloromethane (500m1) and water (500m1). The aqueous phase was
separated and extracted with dichloromethane (500m1) and the combined
organic extracts washed with saturated aqueous sodium chloride (500m1), dried
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(magnesium sulfate) and the solvent removed in vacuo. The residue was
purified by flash column chromatography on silica gel eluting with
cyclohexane:ethyl acetate (100:0 changing to 80:20, by volume) to give the
title
compound (68.7g) as a colourless oil.
'H NMR (400MHz, CDC13): 8 = 7.42-7.36 (5H, m), 7.29-7.25 (3H, m), 6.94 (1H,
d), 5.12 (2H, s), 4.84-4.81 (1 H, m), 4.74 (2H, s), 3.48-3.40 (2H, m), 0.90
(9H, s),
0.11 (3H, s), -0.07 (3H, s) ppm.
LRMS (electrospray) : m/z [M+Na]+ 473 / 475.
Preparation 24: methyl 2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl
(dimethyl)silyl]oxy}ethyl)benzoate
TBDMS
Br
~O
/
O O
I
CH3
A solution of methyl 2-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]benzoate
(71.05g, 195mmol), imidazole (18.52g, 272mmol), tert-butyldimethylsilyl
chloride (32.23g, 214mmol) and 4-(N,N-dimethylamino)pyridine (0.44g,
3.6mmol) in N,N-dimethylformamide (270m1) was left to stir at room
temperature under a nitrogen atmosphere for a period of 24 hours. The solvent
was removed in vacuo and the residue partitioned between ethyl acetate
(500m1) and water (500m1). The organic phase was separated and washed with
2N hydrochloric acid (2-fold 500m1), saturated aqueous sodium bicarbonate (2-
fold 500m1) saturated sodium chloride (500m1), dried (magnesium sulfate) and
the solvent removed in vacuo to give the title compound as a colourless oil
(91.Og).
'H NMR (400MHz, CDCI3): 8 = 7.81 (1 H, bs), 7.51-7.30 (6H, m), 7.01 (1 H, d),
5.19 (2H, s), 4.85-4.82 (1 H, m), 3.91 (3H, s), 3.48-3.39 (2H, m), 0.90 (9H,
s),
0.11 (3H, s), -0.08 (3H, s) ppm.
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LRMS (electrospray) : m/z [M+Na]+ 501 / 503.
Preparation 25: methyl {3-[(2R)-2-aminopropyl]phenyl}acetate
H2N \ O~CH
3
CH3 ~ O
A solution of methyl [3-((2R)-2-{[(1 R)-1-phenyl-ethyl]-amino}-propyl)-phenyl]-
acetate hydrochloride (Preparation 26) (7.698, 22mmol) and ammonium
formate (6.94g, 110mmol) was heated to 75°C in the presence of 20%
palladium hydroxide-on-charcoal (Pd(OH)2/C, 2.OOg). 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 (100m1) and 880 ammonia (100m1) and the organic phase
separated. The aqueous phase was extracted dichloromethane (100m1) and the
combined organic extracts dried (magnesium sulfate) and reduced in vacuo to
give the title compound as a colourless oil (4.78g).
'H NMR (400MHz, CD30D): 8 = 7.27-7.23 (1H, t), 7.13-7.09 (3H, m),-3.67 (3H,
s), 3.63 (2H, s), 3.12-3.05 (1 H, m), 2.67-2.57 (2H, m), 1.06 (3H, d) ppm.
LRMS (electrospray) : m/z [M+H]+ 208, [M+Na]+ 230.
Preparation 26: methyl [3-((2R)-2-{[(1R)-1-phenyl-ethyl]-amino}-propyl)-
phenyl]-acetate hydrochloride
H
\ I N O
\ ~ CHs
CH3 CH3 / O
A solution of methyl [3-(2-oxopropyl)phenyl]acetate (Preparation 27) (8.5g,
41.2mmol), (R)-a-methyl benzylamine (4.8m1, 37.2mmol), sodium
triacetoxyborohydride (11.6g, 56mmol) and acetic acid (2.2m1, 38mmol) in
dichloromethane (400m1) was stirred at room temperature for 48 hours. The
reaction mixture was quenched by addition of saturated aqueous sodium
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bicarbonate (200m1) and allowed to stir until effervescence ceased. The
organic
phase was separated and the aqueous phase extracted with dichloromethane
(100m1). The combined organic extracts were dried (magnesium sulfate) and
reduced in vacuo. Purification by flash column chromatography eluting with
dichloromethane:methanol: ammonia (99:1:0.1 to 95:5:0.5 by volume) gave a
4:1 mixture of diastereomers (R,R major) as a pale yellow oil (8.71g).
Treatment with hydrogen chloride (40m1 of a 1 M solution in methanol, 40mmol)
followed by three successive crystallisations (diisopropylether/ methanol)
gave
the title compound as a white crystalline solid (5.68g).
'H NMR (400MHz, CD30D): 8 = 7.52-7.48 (5H, m), 7.28-7.25 (1H, m), 7.18-
- 7.16 (1 H, m), 7.02-6.99 (2H, m), 4.59 (1 H, q), 3.62 (2H, s), 3.30 (3H, s),
3.30-
3.25 (1 H, m), 3:26-3.15 (1 H, m), 2.66-2.60 (1 H, m), 1.68 (3H, d), 1.18,
(3H, d)
ppm.
LRMS (electrospray): m/z [M+H]+ 312, [M+Na]+ 334.
Preparation 27: methyl [3-(2-oxopropyl)phenyl]acetate
H3C ~ O~CH
O ~ O
Tributyltin methoxide (28.3 ml, 98mmol), preparation 28 (15.Og, 65mmol),
isopropenyl acetate (10.8m1, 98mmol), palladium(II)acetate (750mg, 3.30mmol)
and tri-ortho-tolylphosphine (2.Og, 6.5mmo1) were stirred together in toluene
(75m1) at 100°C under nitrogen for 5 hours. After cooling the reaction
was
diluted with ethyl acetate (150m1) and 4M aqueous potassium fluoride solution
(90m1) and stirred for 15 minutes. The mixture was filtered through arbocel
and
the organic phase separated and reduced in vacuo. The residue was purified
by flash column chromatography silica gel eluting with a solvent gradient of
diethyl ether:pentane (0:100 to 25:75, by volume) changing to dichloromethane
to give the title compound as a pale yellow oil (12.6g).
'H NMR (400MHz, CDC13): 8 = 7.30 (1 H, t), 7.19 (1 H, d), 7.13-7.10 (2H, m),
3.69 (5H, s), 3.61 (2H, s), 2.15 (3H, s) ppm.
LRMS (electrospray) : m/z [M+NH4]+ 224, [M+Na]+ 229.
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Preparation 28: Methyl (3-bromophenyl)acetate
Br ~ O~CH
s
Acetyl chloride (0.7m1, 9.3mmol) was slowly added to a solution of (3-bromo-
phenyl)-acetic acid (20.Og, 93mmol) in methanol (500m1) at 0°C under
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
redissolved in dichloromethane, dried (sodium sulfate) and concentrated in
vacuo to give the title compound as a colourless oil (20.6g).
'H NMR (400MHz, CDCI3): 8 = 7.37-7.45 (2H, m), 7.24-7.17 (2H, m), 3.70 (3H,
s), 3.59 (2H, s) ppm.
LRMS (electrospray) : m/z [M+Na]+ 253.
Preparation 29 : 1-(3-bromophenyl)-2-methylpropan-2-ol)
CH3
HO ~ Br
CH3
Methylmagnesium bromide (3M solution in diethylether, 51.6m1, 155mmol) was
slowly added to a solution of 1-(3-bromo-phenyl)propan-2-one (15.Og, 70mmol)
in dry diethylether (200m1) at 0°C. The resulting mixture was left for
3 hours,
then cooled to 0°C and slowly quenched with saturated aqueous ammonium
chloride solution. The organic phase was washed with brine, dried (sodium
sulfate). The yellow oil was then purified by column chromatography on silica
gel eluting with dichloromethane:pentane:methanol (90:5:5 by volume to afford
a pale yellow oil (13.26 g).
'H NMR (400MHz, CDC13) 8 = 7.40 (2H, m), 7.15 (2H, m), 2.74 (2H, s), 1.42
(1 H, bs), 1.22 (6H, s).
Preparation 30: N-[2-(3-bromophenyl)-1,1-dimethylethyl]-2-
chloroacetamide
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H CHs
CI~N ~ Br
IOI CH3
Chloroacetonitrile (6.63m1, 105mmol) was added to a stirred solution of 1-(3-
bromophenyl)-2-methylpropan-2-ol) (Preparation 29) (12.Og, 52.Ommol) in
acetic acid (25m1) at room temperature. The resulting solution was cooled to
0°C and concentrated sulfuric acid (25m1) was added keeping the
temperature
<10°C. The resulting solution was left to stir for 1 hour and then
poured onto ice
and basified by the addition of ~ solid potassium carbonate. The product was
extracted with ethyl acetate (2x500m1), the organics combined and washed with
water (50m1), dried (sodium sulfate) and the solvent removed in vacuo to
afford
the title compound as an orange solid (16.08 g).
'H NMR (400MHz, CDC13) 8 = 7.39-7.32 (1 H, d), 7.26 (1 H, s), 7.1-7.13 (1 H,
t),
7.08-7.03 (1 H, d), 6.17 (1 H, bs), 3.94 (2H, s), 3.02 (2H, s), 1.37 (6H, s).
CHN for C~2H~5BrCINO calc. (found): C 47.32 (47.26), H 4.96 (4.87), N 4.60
(4.65).
LRMS (electrospray) m/z 306 [M+H]+
Preparation 31 : 2-(3-bromophenyl)-1,1-dimethylethylamine
CH3
H2N ~ Br
CH3
A solution of N-[2-(3-bromophenyl)-1,1-dimethylethyl]-2-chloroacetamide
(Preparation 30) (32.Og, 105mmol), thiourea (9.60g, 126mmol) and acetic acid
(50m1) in ethanol (250m1) was heated to reflux overnight. The reaction mixture
was cooled to room temperature and filtered, the filtrate was concentrated in
vacuo and basified using aqueous sodium hydroxide solution (1 M, 450m1). The
product was extracted with dichloromethane (2x500m1) and the combined
organics washed with brine (50m1), dried (sodium sulfate) and the solvent
removed in vacuo to afford the title compound as a black oil (23g).
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'H NMR (400MHz, CDC13) b = 7.36-7.32 (2H, m), 7.16-7.08 (2H, m), 2.62 (2H,
s), 1.84 (2H, bs), 1.12 ( 6H, s).
LRMS (electrospray) m/z 228 [M+H]+
Preparation 32: (2-(3-bromophenyl)-1,1-dimethylethyl]carbamic acid tert-
butyl ester
CH
H3C O N 3 ~ Br
H3C
CH3 O CH3
2-(3-bromophenyl)-1,1-dimethylethylamine (Preparation 31) (S.Og, 22mmol)
was treated with di-tert-butyl Bicarbonate (5.26g, 24mmol) in dichloromethane
(50m1) and stirred for 20 hours. The reaction mixture was washed with water
(50m1) and the combined organics dried (sodium sulfate) and the solvent
removed 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 (7.23g).
'H NMR (400MHz, CDCI3) 8 = 7.35 (1 H, d), 7.30 (1 H, s), 7.15-7.11 (1 H, t),
7.05
(1 H, d), 4.24 (1 H, bs), 2.97 ( 2H, s), 1.50 (9H, s), 1.27 (6H, s).
LRMS (electrospray) m/z 350 [M+NH4]+
Preparation 33: 3-(2-tent-butoxycarbonylamino-2-methylpropyl)benzoic
acid methyl ester
H C O CH3 O
H3C~ ~ ~ O
ICH3 O CH3 ~ CH3
A solution of [2-(3-bromophenyl)-1,1-dimethylethyl]carbamic acid Pert-butyl
ester
(Preparation 32) (7.Og, 21 mmol), [1,1 -
bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.74g, 2.1 mmol) and
triethylamine (5.94m1, 43mmol) in methanol (250m1) was heated to 100°C
under
100psi carbon monoxide for 12 hours. The reaction mixture was filtered through
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arbocel and the filtrate concentrated in vacuo and purified by flash column
chromatography on silica gel eluting with dichloromethane:pentane (50:50 by
volume) to afford the title compound as a yellow solid (3.76g).
'H NMR (400MHz, CDCI3) 8 = 7.92-7.90 (1 H, m), 7.82 (1 H, s), 7.35-7.34 (2H,
m), 4.24 (1 H, bs), 3.90 (3H, s), 3.05 (2H, s), 1.48 (9H, s), 1.26 (6H, s).
LRMS (electrospray) m/z 208 [M+H-BOC]+
Preparation 34: 3-(2-amino-2-methylpropyl)benzoic acid methyl ester
CH3 O
H2N
-O
CH3 I / CH3
A solution of 3-(2-tent-butoxycarbonylamino-2-methylpropyl)benzoic acid methyl
ester (Preparation 33) (1.6g, 5.2mmol) in dichloromethane (160m1) at
0°C was
treated with trifluoroacetic acid (13.6m1) and left to warm to room
temperature
over 2 hours. The solvent was removed in vacuo and the product purified by
ration exchange chromatography (methanol followed by 2M ammonia in
methanol) to yield the title compound as an amber oil (1.06g).
'H NMR (400MHz, CDCI3) 8 = 7.90-7.88 (1 H, m), 7.84 (1 H, s), 7.36-7.35 (2H,
m), 3.90 (3H, s), 2.71 (2H, s), 1.67 (2H, bs), 1.12 (6H, s).
LRMS (electrospray) m/z 208 [M+H]+
Preparation 35: 3-{2-[(2R)-2-(4-benzyloxy-3-hydroxymethylphenyl)-2-(tert-
butyldimethyl-silanyloxy)ethylaminoJ-2-methylpropyl}benzoic acid methyl
ester
MS O
H
N ~ O
13C \CH3 ~ I
O / CH3
HO
3-(2-amino-2-methylpropyl)benzoic acid methyl ester (Preparation 34) (1.36g,
6.60mmol), [2-(benzyloxy)-5-((1R)-2-bromo-1-~[tert-butyl(dimethyl)
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silyl]oxy}ethyl) phenyl]methanol (Preparation 23) (2.96g, 6.60mmol), sodium
iodide (980mg, 6.60mmol) and diisopropylethylamine (3.44m1, 19.7mmol) in
acetonitrile (10m1) were heated to reflux for 48 hours under a nitrogen
atmosphere. The solvent was then removed in vacuo and saturated aqueous
sodium hydrogen carbonate solution (20m1) added and the product extracted
with ethyl acetate (3x30m1). The combined organics were washed with brine
(3x20 ml), dried (sodium sulfate) and the solvent removed in vacuo. The
residue was purified by flash column chromatography on silica gel eluting with
dichloromethane:methanol:ammonia (95:5:0.5 by volume) to furnish the title
compound, the purified product was dissolved in diethylether and evaporated
(x3) to yield a white foam (1.70 g).
'H NMR (400MHz, CDCI3) 8 = 7.89-7.84 (2H, m), 7.44-7.21 (9H, m), 6.88 (1H,
d), 5.10 (2H, s), 4.73-4.69 (3H, m), 3.91 (3H, s), 2.83-2.62 (4H, m), 2.86 (1
H, t),
1.05 (3H, s), 1.02 (3H, s), 0.79 (9H, s), -0.04 (3H, s), -0.19 (3H, s).
LRMS (electrospray) m/z 578 [M+H]+, 600 [M+Na]+
Preparation 36 : 3-f2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-
hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}benzoic acid methyl
ester
OTBDMS O
H
N ~ O
~3C \CH3 ~ I
HO ~ CH3
HO
3-{2-[(2R)-2-(4-benzyloxy-3-hydroxymethylphenyl)-2-(tert-butyldimethyl-
silanyloxy)ethylamino]-2-methylpropyl}benzoic acid methyl ester (Preparation
35) (2.12g, 3.70mmol) and palladium-on-carbon (10%, 300mg) in methanol
(50m1) were hydrogenated at room temperature and 60 psi for 18 hours. The
reaction mixture was filtered through arbocel and the filtrate concentrated in
vacuo, the residue was purified by flash column chromatography on silica gel
eluting with dichloromethane:methanol:ammonia (95:5:0.5 by volume) to furnish
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the title compound, this material was taken up in diethylether and evaporated
(x3) to yield a white foam (1.50 g).
'H NMR (400MHz, CDCI3) 8 = 7.89-7.86 (1 H, m), 7.82 (1 H, bs), 7.33-7.31 (2H,
m), 7.13 (1 H, dd), 6.96 (1 H, d), 6.79 (1 H, d), 4.81 (2H, dd), 4.66 (1 H,
dd), 3.91
(3H, s), 2.81-2.76 (1 H, m), 2.67 (2H, dd), 2.58 (1 H, dd), 1.06 (3H, s), 1.03
(3H,
s), 0.79 (9H, s), -0.03 (3H, s), -0.19 (3H, s).
LRMS (electrospray) m/z 488 [M+H]+, 510 [M+Na]+
Preparation 37: 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-
hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}benzoic acid
OTBDMS O
H
N ~ OH
H3C \CH3
HO
HO
3-f2-[(2R)-2-(tent-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-
phenyl)ethylamino]-2-methylpropyl}benzoic acid methyl ester (Preparation 36)
(1.50g, 3.08mmol), aqueous sodium hydroxide solution (5M, 3.07m1,
15.Ommol), water (2ml) and dioxane (20m1) were stirred at room temperature
for 18 hours. The solvent was removed in vacuo and the residue dissolved in
water (30m1) and acidified with aqueous hydrochloric acid (1 N, 15.38m1). The
resulting white precipitate was filtered off and dried in vacuo for 72 hours
to
furnish the title compound as a white solid (1.28g).
'H NMR (400MHz, CD30D) b = 7.88 (1 H, d), 7.81 (1 H, bs), 7.38-7.28 (3H, m),
7.10 (1 H, dd), 6.77 (1 H, d), 4.92 (1 H, m, partially under solvent peak),
4.61 (2H,
dd), 3.23-3.12 (2H, m), 2.95 (2H, dd), 1.08 (6H, s), 0.81 (9H, s), -0.04 (3H,
s),
0.15 (3H, s).
LRMS (electrospray) m/z 474 [M+H]+
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Preparation 38: 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-
hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}-N-[2-(4-
chlorophenyl)ethyl]benzamide
MS O / CI
H
N
-N
CH3 I . / H
HO
HO
2-(4-Chlorophenyl)ethylamine (164mg, 1.06mmol) was added to a mixture of 1-
(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (203mg, 1.06mmol),
3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-
phenyl)ethylamino]-2-methylpropyl}benzoic acid
(Preparation 37) (500mg, 1.06mmol),1-hydroxybenzotriazole hydrate (160mg,
1.06mmol) and triethylamine (4401, 3.20mmol) in dichloromethane (30m1). The
resulting solution was stirred for 48 hours under nitrogen. The solvent was
removed in vacuo and the residue taken up in ethyl acetate (30m1), washed
with water (20m1), sodium hydrogen carbonate (0.5 M, 2x20 ml), brine (2x20
ml), dried (sodium sulfate) and the solvent removed in vacuo. The residue was
purified by flash column chromatography on silica gel eluting with
dichloromethane:methanol:ammonia (95:5:0.5 by volume) to furnish the title
compound, the resulting material was taken up in methanol and evaporated,
then taken up in diethylether and evaporated to yield a white foam (480 mg).
'H NMR (400MHz, CD30D) 8 = 7.64-7.60 (2H, m), 7.36-7.19 (7H, m), 7.05 (1 H,
dd), 6.72 (1 H, d), 4.71-4.67 (1 H, m), 4.60 (2H, dd), 3.57 (2H, t), 2.93-2.61
(6H,
m), 1.09 (3H, s), 1.06 (3H, s), 0.78 (9H, s), -0.04 (3H, s), -0.22 (3H, s).
LRMS (electrospray) m/z 611 [M+H]+, 633 [M+Na]+
Preparation 39: 3-{2-[(2R)-2-(Pert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-
hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}-N-[2-(4-
methylphenyl)ethyl]benzamide
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OTBDMS O / CH3
H
N \ N \
H3C \CH3 ~ / H
HO Y
HO
Prepared according to the procedure used for preparation 38 using 3-{2-[(2R)-
2-(tent-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-
phenyl)ethylaminoJ-2-methylpropyl}benzoic acid (Preparation 37) and the
appropriate amine to give the title compound as a white foam.
'H NMR (400MHz, CD30D) 8 = 7.65-7.61 (2H, m), 7.36-7.30 (2H, m), 7.27 (1 H,
d), 7.14-7.06 (5H, m), 6.72 (1 H, d), 4.71-4.68 (1 H, m), 4.60 (2H, dd), 3.54
(2H,
t), 2.90-2.83 (3H, m), 2.70 (2H, dd), 2.61 (1 H, dd), 2.28 (3H, s), 1.09 (3H,
s),
1.05 (3H, s), 0.78 (9H, s), -0.04 (3H, s), -0.22 (1 H, s).
LRMS (electrospray) m/z 591 [M+H]+, 613 [M+Na]+
Preparation. 40: 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-
hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl}-N-[2-(4-
trifluoromethylphenyl)ethyl]benzamide
OTBDMS O / CF3
H
N \ \
-N
I3C CH3 ~ I
HO ~ H
Prepared according to the procedure used for preparation 38 using 3-f2-[(2R)-
2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-
phenyl)ethylamino]-2-methylpropyl}benzoic acid (Preparation 37) and the
appropriate amine to give the title compound as a white foam.
'H NMR (400MHz, CDCI3) 8 = 7.66 (2H, d), 7.45 (1 H, m), 7.38 (1 H, s), 7.33
(2H, d), 7.29-7.22 (2H, m), 7.07 (1 H, dd), 6.88 (1 H, dd), 6.75 (1 H, dd),
6.15
(1 H, t), 4.75 (1 H, dd), 4.57 (1 H, t), 3.73-3.68 (2H, m), 2.99 (2H, t), 2.76
(1 H,
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dd), 2.65 (2H, s), 2.58 (1 H, dd), 1.03 (3H, s), 1.00 (3H, s), 0.79 (9H, s), -
0.05
(3H, s), -0.20 (3H, s).
LRMS (electrospray) m/z 646 [M+HJ+
Preparation 41: 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-
hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl}-N-[2-(3, 4-
dichlorophenyl)ethyl]benzamide
MS O / CI
H I
N \
\ CI
/ H
HO 13C \CH3
HO
Prepared according to the procedure used for preparation 38 using 3-{2-[(2R)-
2-(Pert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-
phenyl)ethylaminoJ-2-methylpropyl}benzoic acid (Preparation 37) and the
appropriate amine to give the title compound as a white foam.
'H NMR (400MHz, CDC13) 8 = 7.45 (1 H, d), 7.40-7.36 (2H, m), 7.33 (1 H, d),
7.30-7.22 (2H, m), 7.05 (2H, m), 6.88 (1 H, dd), 6.75 (1 H, d), 6.17 (1 H, t),
4.75
(1 H, dd), 4.69 (1 H, t), 3.63 (2H, m), 2.89 (1 H, t), 2.76 (1 H, dd), 2.66
(2H, s),
2.59 (1 H, dd), 1.04 (3H, s), 1.00 (3H, s), 0.79 (9H, s), -0.05 (3H, s), -0.20
(3H,
s).
LRMS (electrospray) m/z 646 [M+HJ+
Preparation 42: 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-
hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl}-N-[2-(3, 4-
dimethylphenyl)ethyl]benzamide
OTBDMS O / CH3
H
\ N \ N \ CHs
I / H3C \CH3
HO ~ H
HO
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Prepared according to the procedure used for preparation 38 using 3-{2-[(2R)-
2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-
phenyl)ethylamino]-2-methylpropyl}benzoic acid (Preparation 37) and the
appropriate amine to give the title compound as a white foam.
'H NMR (400MHz, CDC13) 8 = 7.43 (1 H, d), 7.37 (1 H, s), 7.20-7.27 (2H, m),
7.06-7.09 (2H, m), 7.01 (1 H, s), 6.94 (1 H, d), 6.88 (1 H, dd), 6.74 (1 H,
dd), 6.13
(1 H, t), 4.75 (1 H, dd), 4.59 (1 H, t), 3.64 (1 H, dd), 2.85 (1 H, t), 2.77
(1 H, dd),
2.65 (2H, s), 2.59 (1 H, dd), 2.24 (3H, s), 2.23 (3H, s), 1.03 (3H, s), 1.00
(3H, s),
0.79 (9H, s), -0.05 (3H, s), -0.20 (3H, s).
LRMS (APCI) m/z 606 [M+H]+
Preparation 43: 3-(2-[(2R)-2-(tent-butyldimethylsilanyloxy)-2-(4-hydroxy-3-
hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl}-N-(2-naphthalen-2-yl-
ethyl)benzamide
MS O /
H
N
~N
13C CH3) i _
HO / H
Prepared according to the procedure used for preparation 38 using 3-f2-[(2R)-
2-(tent-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-
phenyl)ethylamino]-2-methylpropyl}benzoic acid (Preparation 37) and the
appropriate amine to give the title compound as a white foam.
'H NMR (400MHz, CDC13) b 7.77 (3H, m), 7.67 (1 H, s), 7.48-7.35 (5H, m), 7.23-
7.19 (2H, m), 7.06 (1 H, dd), 7.37 (1 H, dd), 6.74 (1 H, d), 6.17 (1 H, t),
4.74 (2H,
dd), 4.67 (1 H, t), 3.76 (2H, dd), 3.09 (2H, t), 2.75 (1 H, dd), 2.62 (2H, s),
2.57
(1 H, dd), 1.00 (3H, s), 0.97 (3H, s), 0.78 (9H, s), -0.05 (3H, s), -0.21 (3H,
s).
LRMS (electrospray) m/z 628 [M+H]+
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Preparation 44: 3-(2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-
hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl}-N-(1,1-dimethyl-2-
phenyl-ethyl)benzamide
HS O H3C CH3 ~
N
C CH3 ~ ~N
I
HO ~ H
HU
Prepared according to the procedure used for preparation 38 using 3-(2-[(2R)-
2-(tent-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-
phenyl)ethylamino]-2-methylpropyl}benzoic acid (Preparation 37) and the
appropriate amine to give the title compound as a white foam.
'H NMR (400MHz, CDCI3) 8 = 7.43 (1 H, m), 7.36 (1 H, s), 7.31-7.13 (7H, m),
7.08 (1 H, dd), 6.84 (1 H, dd), 6.75 (1 H, d), 5.70 (1 H, s), 4.73 (2H, dd),
4.68 (1 H,
t), 3.10 (2H, dd), 2.77 (1 H, dd), 2.65 (2H, s), 2.68 (1 H, dd), 1.45 (3H, s),
1.44
_ (3H, s), 1.06, (3H, s), 1.01 (3H, s), 0.79 (9H, s), -0.04 (3H, s), -0.21
(3H, s).
LRMS (electrospray) m/z 605 [M+H]+
Preparation 45: 3-{2-[(2R)-2-(tent-butyldimethylsilanyloxy)-2-(4-hydroxy-3-
hydroxymethylphenyl)ethylamino]-2-methylpropyl}-N-(2-methyl-2-
phenylpropyl)-benzamide
MS O
H
N
~N
13C CH3 ( / H H3C CH3
HO
HO
Prepared according to the procedure used for preparation 38 using 3-{2-[(2R)-
2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-
phenyl)ethylamino]-2-methylpropyl}benzoic acid (Preparation 37) and the
appropriate amine to give the title compound as a white foam.
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'H NMR (400MHz, CDC13) 8 = 7.42-7.34 (4H, m), 7.29-7.15 (5H, m), 7.05 (1 H,
dd), 6.87 (1 H, dd), 6.74 (1 H, d), 5.73 (1 H, t), 4.74 (2H, dd), 4.64 (1 H,
dd), 3.62
(2H, dd), 2.75 (1 H, dd), 2.61 (2H, dd), 2.66 (1 H, dd), 1.40 (6H, s), 1.00
(3H, s),
0.97 (3H, s), 0.79 (9H, s), -.05 (3H, s), -0.20 (3H, s).
LRMS (electrospray) m/z 605 [M+H]+
Preparation 46: 3-{(2R)-2-[2-(Pert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-
hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}-N-(4-
chlorobenzyl)benzamide
OTBDMS O
H
\ N \ N \
/ H3C CH3 ~ ~ H ~ /
HO ~ SCI
HO
Prepared according to the procedure used for preparation 38 using 3-{2-[(2R)-
2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-
phenyl)ethylamino]-2-methylpropyl}benzoic acid (Preparation 37) and the
appropriate amine to give the title compound as a white foam.
'H NMR (400MHz, CDCI3) 8 7.55 = (1 H, m), 7.49 (1 H, m), 7.33-7.24 (4H, m),
7.06 (1 H, dd), 6.88 (1 H, dd), 6.74 (1 H, d), 6.49 (1 H, t), 4.73 (1 H, dd),
4.57 (2H,
dd), 2.75 (1 H, dd), 2.66 (2H, s), 2.66 (1 H, dd), 1.04 (3H, s), 1.00 (3H, s),
0.78
(9H, s), -0.06 (3H, s), -0.21 (3H, s).
LRMS (electrospray) m/z 597/599 [M+H]+
Preparation 47: [3-(2-amino-2-methyl-propyl)-phenyl]-acetic acid ethyl
ester
H3C~0 ~ NH2
p ~ H3C' CH3
A solution of {3-[2-(2-chloro-acetylamino)-2-methyl-propyl]-phenyl}-acetic
acid
(Preparation 48) (5.1g, 18mmol), thiourea (1.6g, 21mmol) and acetic acid
(18m1) in ethanol (80m1) was heated to reflux under a nitrogen atmosphere for
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16 hours. The reaction mixture was cooled and filtered. The filtrate was
reduced in vacuo, the residue dissolved in ethanol (150m1), saturated with
hydrogen chloride gas and the resulting solution heated to reflux for 16
hours.
The solvent was reduced in vacuo and the residue partitioned between ethyl
acetate (200m1) and 5% aqueous sodium carbonate (200m1). The organic
extract was washed with saturated sodium chloride (100m1), dried (sodium
sulfate) and reduced in vacuo. The residue was purified by strong cation
exchange resin, eluting with methanol and then 2N ammonia in methanol to
elute the product. The eluent was concentrated in vacuo giving the title
compound as a yellow oil (2.68g, 63%).
'H NMR (400MHz, CDCI3): 8 = 7.29-7.04 (4H, m), 4.08 (2H, q), 3.64 (2H, s),
2.57 (2H, s), 1.18 (3H, t), 0.99 (6H, s) ppm.
LRMS (electrospray) : m/z [M+H]+ 236, [M+NH4]+ 258.
Preparation 48: {3-[2-(2-chloro-acetylamino)-2-methyl-propyl]-phenyl}-
acetic acid
H -
HO ~ N
~CI
p ~ H3C CH3 O
Concentrated sulphuric acid (21 ml) was added dropwise to a solution of [3-(2-
hydroxy-2-methyl-propyl)-phenyl]-acetic acid (Preparation 49) (10.6g,
51.Ommol) and chloroacetonitrile (4.8m1, 76.Ommol) in glacial acetic acid
(16m1)
at 0°C. The reaction was allowed to warm to room temperature and after
2
hours was poured onto iced water (500m1). The aqueous was extracted with
ethyl acetate (2x250m1) and the combined organics washed with brine (50m1),
dried (sodium sulfate), and the solvent removed in vacuo to furnish the title
compound as a golden oil (14.Og).
'H NMR (400MHz, CDC13): 8 = 7.31-7.06 (4H, m), 6.19 (1 H, bs), 3.95 (2H, s),
3.62 (2H, s), 3.02 (2H, s), 1.36 (6H, s) ppm.
LRMS (electrospray) : m/z [M-H]- 282 / 284.
Preparation 49: [3-(2-hydroxy-2-methyl-propyl)-phenyl]-acetic acid
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HO ~ OH
p ~ H3C CH3
Methyl magnesium chloride (51 ml of a 3M solution in tetrahydrofuran,
153mmol) was added dropwise to a stirred solution of the ester (11.6g,
51 mmol) (International Journal of Peptide and Protein Research, 1987, 29(3),
331 ) in tetrahydrofuran (300m1) 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 (50m1) and 2N hydrochloric acid (80m1) were
cautiously added. The aqueous was extracted with ethyl acetate (2x300m1) and
the combined organics washed with brine (50m1), dried (sodium sulfate), and
the solvent removed in vacuo to furnish the title compound as a golden oil
(11.2g).
'H NMR (400MHz, CDCI3): 8 = 7.30-7.12 (4H, m), 3.63 (2H, s), 2.75 (2H, s),
1.22 (6H, s) ppm.
LRMS (electrospray) : m/z [M+H]+ 209.
- 15 Ester needs to be named?
Preparation 50: ~3-[2-(~(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetic acid
H
N ~ OH
IsC CHs ~ O
HO
HO
Prepared according to the procedure used for preparation 20 using ethyl {3-[2-
({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyl]phenyl}acetate (Preparation 68) to give the title compound as a
cream solid.
'H NMR (400MHz, CD30D): d = 7.43-7.42 (1 H, d), 7.37-7.22 (4H, m), 7.15-7.13
(1 H, m), 6.85-6.83 (1 H, d), 4.90-4.86 (1 H, m), 4.71 (2H, s), 3.56-3.55 (2H,
m),
3.25-3.13 (2H, m), 3.05-2.98 (2H, m), 1.40 (3H, s), 1.38 (3H, s) ppm.
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LRMS (electrospray) : m/z [M+H]+ 374, [M-H]- 372.
Preparation 51: {3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl~ethyl}amino)ethyl]phenyl}acetic acid
H
N ~ OH
H I / OI
O
HU
Prepared according to the procedure used for preparation 20 using ethyl {3-[2-
({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl)ethyl}amino)ethyl]phenyl}acetate (Preparation 52) to
give the title compound as a white solid.
'H NMR (400MHz, CD30D): d 7.26 (1 H, d), 7.20-7.16 (1 H, t), 7.09-6.97 (5H,
m), 6.74-6.72 (1 H, d), 4.68-4.65 (1 H, m), 4.44 (2H, s), 3.42 (2H, s), 2.95-
2.71
(6H, m) ppm.
LRMS (electrospray) : m/z [M-H]- 344.
Preparation 52: ethyl {3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)ethyl)phenyl}acetate
H
N ~ O~CH3
/ O
HO
HU
Prepared according to the procedure used for preparation 21 using ethyl {3-[2-
({(2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-
hydroxyethyl}amino)ethyl]phenyl}acetate (Preparation 53) to give the title
compound as an orange oil.
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'H NMR (400MHz, CD30D): d 7.25-7.20 (2H, m), 7.11-7.05 (4H, m), 6.73-6.71
(1 H, d), 4.68-4.63 (3H, m), 4.15-4.09 (2H, m), 3.59 (2H, s), 2.89-2.71 (6H,
m),
1.24-1.21 (3H, t) ppm.
LRMS (electrospray) : m/z [M+H]+ 374, [M-H]- 372.
Preparation 53: ethyl {3-[2-({(2R)-2-[4-(benzyloxy)-3-
(hydroxymethyl)phenyl]-2-hydroxyethyl}amino)ethyl]phenyl}acetate
H
N ~ O~CH3
/ OI
~O
HU
A solution of ethyl (3-{2-[((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-
{[Pert-butyl(dimethyl)silyl]oxy}ethyl)amino]ethyl)phenyl)acetate (Preparation
54)
(2.39g, 4.14mmol) in methanol (15m1) and water (10m1) was treated with
ammonium fluoride (1.53g, 41.4mmol) and the reaction heated to 40°C for
16
hours. The methanol was removed in vacuo and the aqueous residue extracted
with dichloromethane (3x50m1). The combined organics were dried (sodium
sulfate) and the sovent removed in vacuo and the residue purified by flash
column chromatography on silica gel eluting with
dichloromethane:methano1:880 ammonia (97:3:0.3 changing to 95:5:0.5, by
volume) to give the title compound as an orange gum (1.90g).
'H NMR (400MHz, CD30D): 8 = 7.45-7.34 (5H, m), 7.31-7.27 (1 H, m), 7.24-716
(2H, m), 7.11-7.09 (3H, m), 2.96-2.94 (1 H, d), 5.12 (2H, s), 4.72-4.68 (3h,
M),
4.15-4.09 (2H, m), 3.59 (2H, s), 2.91-2.74 (6H, m), 1.24-1.20 (3H, t) ppm.
LRMS (electrospray) : m/z [M+H]+ 464, [M-H]- 462.
Preparation 54: ethyl(3-{2-[((2R)-2-[4-(benzyloxy)-3-
(hydroxymethyl)phenyl]-2-{[tert-
butyl(dimethyl)silyl]oxy}ethyl)amino]ethyl}phenyl)acetate
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OTBDMS
H
\ N \ O\~CH3
/ O
\ ~O
HO
Prepared according to the procedure used for preparation 22 using [2-
(benzyloxy)-5-((1 R)-2-bromo-1-{[tert-butyl(dimethyl) silyl]oxy}ethyl)
phenyl]methanol (Preparation 23) and ethyl [3-(2-aminoethyl)phenyl]acetate
(Preparation 58) to give the title compound as a yellow oil.
'H NMR (400MHz, CD30D): 8 = 7.44-7.43 (2H, d), 7.37-7.33 (3H, m), 7.30-7.27
(1 H, t), 7.24-7.20 (1 H, t), 7.15-7.08 (4H, m), 6.94-6.92 (1 H, d), 5.10 (2H,
s),
4.77-4.74 (1 H, m), 4.67-4.66 (2H, d), 4.14-4.09 (2H, m), 3.58 (2H, s), 2.90-
2.75
(5H, m), 2.66-2.62 (1 H, m), 1.24-1.21 (3H, t), 0.78 (9H, s), -0.05 (3H, s), -
0.22
(3H, s) ppm.
LRMS (electrospray) : m/z [M+H]+ 578, [M-H]- 576.
Preparation 55: ethyl [3-(2-hydroxyethyl)phenyl]acetate
HO \ O\,CH3
/
Carbonyl diimidazole (5.11 g, 31.5mmol) was added in one portion to a stirred
solution of the ester (International Journal of Peptide and Protein Research,
1987, 29(3), 331 ) (7.OOg, 31.5mmol) in tetrahydrofuran (100m1) at room
temperature under nitrogen. The reaction was stirred for 2 hours and water
(26m1) was added and the reaction cooled to 0°C. Sodium borohydride
(6.OOg,
0.15mmol) was then added portionwise and the reaction allowed to warm to
room temperature with continued stirring over 2 hours. Ethyl acetate (300m1)
was added followed by dropwise addition of 2N aqueous hydrochloric acid
(20m1). The organic layer was separated and the aqueous extracted with ethyl
acetate (2x75m1), the combined organics were dried (sodium sulfate) and the
solvent removed in vacuo to furnish a white solid which was purified by flash
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column chromatography on silica gel eluting with ethyl acetate:penatane
(50:50,
by volume) to give the title compound as a colourless oil (4.60g).
'H NMR (400MHz, CDCI3): 8 = 7.28-7.24 (1 H, m), 7.15-7.11 (3H, m), 4.17-4.08
(2H, m), 3.84-3.81 (2H, t), 3.59 (2H, s), 2.86-2.82 (2H, t), 1.29-1.23 (3H, t)
ppm.
LRMS (electrospray) : m/z [M+Na]+ 231, [M-H]- 207.
Preparation 56: ethyl (3-{2-[(methylsulfonyl)oxy]ethyl}phenyl)acetate
O
O~CH3
O I / OI
Methane sulfonyl chloride (2.78g, 24.3mmol) was added dropwise to a solution
of ethyl [3-(2-hydroxyethyl)phenyl]acetate (Preparation 55) (4.60g, 22.1 mmol)
and triethylamine (3.40m1, 24.3mmol) in dichloromethane (250m1) at 0°C
under
nitrogen. The reaction was allowed to warm to room temperature over 1 hour
and washed with saturated aqueous sodium hydrogen carbonate (75m1). The
aqueous was washed with dichloromethane (2x100m1) and the .combined
organics washed with water (25m1), dried (sodium sulfate) and the solvent
removed in vacuo to furnish the title compound as a colourless oil (6.2g).
'H NMR (400MHz, CDCI3): 8 = 7.29-7.25 (1 H, t), 7.17-7.12 (3H, t), 4.41-4.38
(2H, t), 4.16-4.10 (2H, m), 3.58 (2H, s), 3.04-3.00 (2H, t), 2.81 (3H, s),
1.26-
1.22 (3H, t) ppm.
LRMS (electrospray) : m/z [M+H]+ 578, [M-H]- 576.
Preparation 57: ethyl [3-(2-azidoethyl)phenyl]acetate
N3 ~ O~CH3
/
Sodium azide (2.82g, 43.3mmol) was added in one portion to a stirred solution
of ethyl(3-(2-[(methylsulfonyl)oxy]ethyl)phenyl)acetate (Preparation 56)
(6.20g,
21.7mmol) in N,N-dimethylformamide (400m1) at room temperature. The
reaction was heated at 60°C for 1 hour and then allowed to cool to room
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temperature and the solvent removed in vacuo. Ethyl acetate (200m1) and water
(75m1) was added and the organics separated, the aqueous was washed with
ethyl acetate (2x100m1) and the combined organics evaporated in vacuo to
yield an oil that was purified by flash column chromatography on silica gel
eluting with ethyl acetate:penatane (5:95, by volume) to give the title
compound
as a colourless oil (4.65g).
'H NMR (400MHz, CDC13): 8 = 7.27-7.23 (1H, t), 7.17-7.12 (3H, m), 4.15-4.06
(2H, m), 3.60 (2H, s), 3.51-3.47 (2H, t), 2.87-2.84 (2H, t), 1.24-1.20 (3H, t)
ppm.
LRMS (electrospray) : m/z [M+Na]+256, [M-H]~ 232.
Preparation 58: ethyl [3-(2-aminoethyl)phenyl]acetate
H2N ~ O~CH3
Triphenylphosphine (3.88g, 23.3mmol) was added in one portion to a stirred
solution of ethyl [3-(2-azidoethyl)phenyl]acetate (Preparation 57) (3.88g,
16.6mmol) in tetrahydrofuran (100m1) at room temperature under nitrogen. The
reaction was stirred for 18 hours and water (5ml) added and the reaction
heated at 50°C for 4 hours, the reaction was cooled to room temperature
and
the solvent removed in vacuo. The residue was dissolved in saturated aqueous
sodium hydrogen carbonate (40m1) and the aqueous extracted with
dichloromethane (3x50m1). The combined organics were dried (sodium sulfate),
the solvent removed in vacuo and the residue purified by flash column
chromatography on silica gel eluting with dichlromethane:methanol (95:5, by
volume) to give the title compound as a colourless oil (3.11 g).
'H NMR (400MHz, CDC13): 8 = 7.26-7.22 (1H, t), 7.13-7.08 (3H, t), 4.16-4.11
(2H, m), 3.58 (2H, s), 2.96-2.93 (2H, t), 2.74-2.71 (2H, t), 1.25-1.22 (3H, t)
ppm.
LRMS (electrospray) : m/z [M+H]+ 208, [M+Na]+ 230, [M-H]- 206.
Preparation 59: 3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid
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O
H
N
~OH
CH3 /
HO
HU
To a solution of methyl 3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoate (Preparation 60) (5.12g,
14.24mmol) in tetrahydrofuran (35m1), was added aqueous lithium hydroxide
solution (1 M, 29m1, 29mmol) and the solution left to stir at room temperature
for
18 hours. Aqueous hydrochloric acid (1 M, 29m1, 29mmol) was added and the
tetrahydrofuran/water removed in vacuo to give the title compound as an off-
white solid (5.87g) that was used without further purification.
H NMR (400MHz, CD30D): 8 = 7.86-7.84 (1 H, d), 7.82 (1 H, s), 7.37-7.30 (3H,
m), 7.17-7.15 (1 H, dd), 6.79-6.77 (1 H, d), 4.89-4.85 (1 H, m), 4.65 (2H, s),
3.60-
3.50 (1 H, m), 3.21-3.15 (3H, m), 2.84-2.78 (1 H, dd), 1.25-1.23 (3H, d) ppm.
LRMS (electrospray) : m/z [M+H]+ 346, [M+Na]+ 368, [M-H]- 344.
CHN analysis : found C 50.29, H 6.07, N 3.07; C~9H23N05+2.OLiCI+1.3H20
requires C 50.31, H 5.69, N 3.09.
Preparation 60: methyl 3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoate
OH O
H
N ~ O~CH3
CH3
HO
HO
A suspension of methyl 3-[(2R)-2-({(2R)-2-[4-(benzyloxy)-3-
(hydroxymethyl)phenyl]-2-hydroxyethyl}amino)propyl]benzoate (Preparation 61 )
(6.83g, 15.2mmol) and 10% palladium on carbon (683mg) in ethanol (100m1)
was stirred under an atmosphere of hydrogen (60psi) at room temperature for
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18 hours. The catalyst was filtered off through arbocel and the filtrate
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel eluting with dichloromethane:methano1:880
ammonia (95:5:0.5 changing to 90:10:1, by volume) to give the title compound
as a pale yellow gum (5.12g).
'H NMR (400MHz, CD30D): 8 = 7.85-7.83 (1 H, m), 7.79 (1 H, s), 7.36-7.35 (2H,
m), 7.20 (1 H, s), 7.02-6.99 (1 H, dd), 6.68-6.65 (1 H, d), 4.61-4.58 (1 H,
m), 4.60
(2H, s), 3.90 (3H, s), 2.97-2.87 (2H, m), 2.80-2.62 (3H, m), 1.08-1.07 (3H, d)
ppm.
LRMS (electrospray) : m/z [M+H]+ 360, [M+Na]+ 382, [M-H]- 358
Preparation 61: methyl 3-[(2R)-2-(~(2R)-2-[4-(benzyloxy)-3-
(hydroxymethyl)phenyl]-2-hydroxyethyl}amino)propyl]benzoate
H O
N ~ O~CH3
CHs
_O
Nc~
A solution of methyl 3-{(2R)-2-[((2R)-2-[4-(benzyloxy)-3-
(hydroxymethyl)phenylJ-
2-{[tert butyl(dimethyl)slyl]oxy}ethyl)amino]propyl}benzoate (Preparation 62)
(10g, 17.74mmol) and ammonium fluoride (6.57g, 177mmol) in methanol
(180m1) and water (60m1) was heated at 40°C for 18hrs. The methanol was
removed in vacuo and the remaining aqueous layer extracted with
dichloromethane (2x100m1). The combined organic layers were dried (sodium
sulfate), filtered and evaporated in vacuo. The resulting oil was purified by
flash
column chromatography on silica gel eluting with
dichloromethane:methano1:880 ammonia (95:5:0.5, by volume) to give the title
compound (6.83g) as a pale yellow gum.
'H NMR (400MHz, CD30D): b = 7.83-7.82 (1 H, d), 7.78 (1 H, s), 7.47-7.45 (2H,
m), 7.39-7.28 (6H, m), 7.11-7.10 (1 H, d), 6.89-6.87 (1 H, d), 5.11 (2H, s),
4.65
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(2H, s), 4.65-4.62 (1 H, m), 3.88 (3H, s), 2.98-2.89 (2H, m), 2.79-2.64 (3H,
m),
1.09-1.08 (3H, d) ppm.
LRMS (electrospray) : m/z [M+H]+ 450, [M+Na]+ 472, [M-H]~ 448.
Preparation 62: methyl 3-{(2R)-2-[((2R)-2-[4-(benzyloxy)-3-
(hydroxymethyl)phenyl]-2-{[tert-
butyl(dimethyl)silyl]oxy}ethyl)amino]propyl}benzoate
MS O
H
N \ O~CH3
\ CHs
~O
NU
A solution of [2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)
silyl]oxy}ethyl) phenyl]methanol (Preparation 23) (9.23g, 20.5mmol) and methyl
{3-[(2R)-2-aminopropyl]phenyl}acetate (Preparation 63) (8.48g, 40.9mmol) in
dichloromethane (70m1) was heated to 90°C, allowing the dichloromethane
to
evaporate. The resulting melt was left at 90°C for a further 18 hours.
The
reaction mixture was cooled to room temperature and purified by flash column
chromatography on silica gel eluting with dichloromethane:methano1:880
ammonia (98:2:0.2 changing to 97.5:2.5:0.25, by volume) to give the title
compound (10g) as an orange oil.
'H NMR (400MHz, CD30D): 8 = 7.84-7.82 (1 H, m), 7.79 (1 H, s), 7.47-7.43 (2H,
m), 7.39-7.30 (6H, m), 7.08-7.06 (1 H, d), 6.89-6.86 (1 H, d), 5.10 (2H, s),
4.74-
4.71 (1 H, t), 4.65-4.64 (2H, d), 3.88 (3H, s), 2.97-2.87 (2H, m), 2.69-2.68
(2H,
d), 2.65-2.61 (1 H, dd), 1.08-1.07 (3H, d), 0.80 (9H, s), -0.03 (3H, s), -0.21
(3H,
s) ppm.
LRMS (electrospray) : m/z [M+H]+ 564, [M+Na]+ 586.
Preparation 63: methyl {3-[(2R)-2-aminopropyl]phenyl}acetate
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169
O
H2N ~ O~CH3
CH3
A solution of methyl [3-((2R)-2-{[(1 R)-1-phenyl-ethyl]-amino}-propyl)-phenyl]-
acetate (Preparation 64) (13.65g, 40.9mmol) and ammonium formate (12.98,
204mmol) in ethanol (200m1) was heated at reflux in the presence of 20% of
palladium hydroxide on charcoal (Pd(OH)2/C, 1.36g). After 3 hours the reaction
mixture was cooled to room temperature, filtered through arbocel and the
filtrate concentrated in vacuo. The residue was partitioned between
dichloromethane (200m1) and 880 ammonia (100m1) and the organic phase
separated. The aqueous phase was extracted with further dichlorormethane
(3x100m1) and the combined organic extracts washed with brine (100m1), dried
(sodium sulfate) and reduced in vacuo to give the title compound (8.48g) as a
pale yellow oil.
'H NMR (400MHz, CDC13): 8 = 7.90-7.87 (2H, m), 7.38-7.34 (2H, m), 3.90 (3H,
s), 3.26-3.17 (1 H, m), 2.78-2.73 (1 H, dd), 2.64-2.59 (1 H, dd), 1.14-1.12
(3H, d)
ppm.
LRMS (electrospray) : m/z [M+H]+ 194.
Preparation 64: methyl [3-((2R)-2-{[(1R)-1-phenyl-ethyl]-amino}-propyl)-
phenyl]-acetate hyrdrochloride
O
\ _ N ~ O~CH3
CH3 CH3
A solution of methyl [3-(2-oxopropyl)phenyl]acetate (Preparation 65) (45.3g,
236mmol), (R)-a-methyl benzylamine (27.6m1, 214mmol), sodium
triacetoxyborohydride (68.1g, 321mmol) and acetic acid (14.7m1, 257mmol) in
dichloromethane (1500m1) was stirred at room temperature for 18 hours. The
reaction mixture was quenched by addition of saturated aqueous sodium
bicarbonate (600m1) and allowed to stir until effervescence ceased. The
organic
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phase was separated and the aqueous phase extracted with further
dichloromethane (2x100m1). The combined organic extracts were washed with
brine (100m1), dried (sodium sulfate), filtered through celite and reduced in
vacuo. The oil was dissolved in methanol (200m1), treated with 1 M hydrogen
chloride in methanol (300m1) and reduced in vacuo to give a 4:1 mixture of
diastereomers (R,R major) as an off-white, hydrochloride salt. Two successive
crystallisations (diisopropylether/methanol) gave the title compound (27.3g)
as
a colourless crystalline solid.
'H NMR (400MHz, CD30D): b = 7.92-7.90 (1 H, d), 7.75 (1 H, s), 7.55-7.49 (5H,
m), 7.45-7.42 (1 H, dd), 7.35-7.33 (1 H, d), 4.68-4.63 (1 H, q), 3.90 (3H, s),
3.43-
3.38 (1 H, dd), 3.25-3.19 (1 H, m), 2.71-2.65 (1 H, dd), 1.71-1.69 (3H, d),
1.17-
1.16, (3H, d) ppm.
Preparation 65: methyl [3-(2-oxopropyl)phenyl]acetate
O
H3C ~ O~CH3
O
Tributyltin methoxide (80.3m1, 279mmol), methyl 3-bromobenzoate (53.5g,
249mmol), isopropenyl acetate (39.4m1, 358mmol), palladium(II)acetate (2.6g,
11.6mmol) and tri-o-tolylphosphine (7.1 g, 23.2mmol) were stirred together in
toluene (350m1) at 100°C under nitrogen for 18 hours. After cooling,
the
reaction was treated with 4M aqueous potassium fluoride solution (560m1) and
stirred for 2 hours. The resulting mixture was diluted with further toluene
(200m1) 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 flash column chromatography on silica gel eluting
with ethylacetate:pentane (10:90, changing to 20:80, by volume) to give the
title
compound (45.3g) as an orange oil.
'H NMR (400MHz, CDC13): 8 = 7.95-7.93 (1 H, d), 7.87 (1 H, s), 7.43-7.37 (2H,
m), 3.91 (3H, s), 3.75 (2H, s), 2.18 (3H, s) ppm.
LRMS (electrospray) : m/z [M+Na]+ 215, [M-H]- 191.
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Preparation 66: ethyl (3-{2-[((2R)-2-[4-(benzyloxy)-3-
(hydroxymethyl)phenyl)-2-~[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-2-
methylpropyl}phenyl)acetate
MS
H
N ~ O~CH3
_ sC CHs ~ O
O
/
HU
Prepared according to the procedure used for preparation 22 using [2-
(benzyloxy)-5-((1 R)-2-bromo-1-{[tert-butyl(dimethyl) silyl]oxy}ethyl)
phenyl]methanol (Preparation 23) and [3-(2-amino-2-methyl-propyl)-phenyl]-
acetic acid ethyl ester (Preparation 47) to give the title compound as a
yellow
oil.
_ 'H NMR (400MHz, CD30D): 8 = 7.48-7.05 (11 H, m), 7.04-6.96 (1 H, d), 5.10
(2H, s), 4.80-4.74 (1 H, m), 4.78-4.63 (2H, q), 4.16-4.05 (2H, q), 3.60 (2H,
s),
2.89-2.63 (2H, m), 2.70-2.62 (2H, m), 1.24-1.20 (3H, t), 1.07-1.04 (6H, d),
0.81
(9H, s), 0.00 (3H, s), -0.18 (3H, s) ppm.
LRMS (electrospray) : m/z [M+H]+ 606, [M-H]- 604.
Preparation 67: ethyl {3-[2-( f (2R)-2-[4-(benzyloxy)-3-
(hydroxymethyl)phenyl]-2-hydroxyethyl}amino)-2-
methylpropyl]phenyl}acetate
OH
H
N ~ O~CH3
_ 3C CHs ~ O
O
HO
Prepared according to the procedure used for preparation 53 using ethyl (3-{2-
[((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert-
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butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methylpropyl}phenyl)acetate
(Preparation
66) to give the title compound as an oil.
'H NMR (400MHz, CD30D): 8 = 7.47-7.03 (11 H, m), 6.98-6.95 (1 H, d), 5.14
(2H, s), 4.68 (2H, s), 4.68-4.66 (1 H, m), 4.15-4.10 (2H, q), 3.60 (2H, s),
2.90-
2.64 (4H, m), 1.26-1.22 (3H, t), 1.08-1.05 (6H, d) ppm.
LRMS (electrospray) : m/z [M+H]+ 492, [M-H]- 490.
Preparation 68: ethyl {3-(2-({(2R)-2-hydroxy-2-(4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropylJphenyl}acetate
H
N ~ O~CH3
sC CH3 ~ O
HO
Prepared according to the procedure used for preparation 21 using ethyl {3-[2-
({(2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-hydroxyethyl}amino)-2-
methylpropyl]phenyl}acetate (Preparation 67) to give the title compound as a
colourless oil.
'H NMR (400MHz, CD30D): 8 = 7.30-7.02 (6H, m), 6.77-6.75 (1H, d), 4.62 (2H,
s), 4.62-4.60 (1 H, m), 4.17-4.09 (2H, q), 3.65-3.50 (2H, m), 2.90-2.63 (4H,
m),
1.14-1.10 (3H, t), 1.08-1.05 (6H, d) ppm.
LRMS (electrospray) : m/z [M+H]+ 402, [M-H]- 400.
Preparation 69
2-(3-Fluoro-4-trifluoromethyl-phenyl)-ethylamine
NHz
F
F
F F
Chlorotrimethylsilane (2mL, 16mmol) was added dropwise to lithium
borohydride (2M in tetrahydrofuran, 4mL, 8mmol). A solution of 3-fluoro-4-
(trifluoromethyl)phenylacetonitrile (312mg, 4mmol) in tetrahydrofuran (2mL)
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was then added at 0°C and the mixture was allowed to stir for 24 hours,
whilst
warming to room temperature. The mixture was then diluted with methanol
(20mL) and concentrated in vacuo. The residue was taken up in 20%
potassium hydroxide solution (20mL), extracted with dichloromethane (3x20mL)
and the combined organic solution was dried over magnesium sulfate and
concentrated in vacuo. The residue was purified by column chromatography
using an Isolute~ SCX-2 cartridge, eluting with methanol followed by 1 M
ammonia in methanol, to give an oily residue. The oil was triturated with
diethyl
ether to afford the title compound in 59% yield, 485mg.
'H NMR (400MHz, CDCI3) 8: 7.53 (1 H, m), 7.08 (2H, m), 3.02 (2H, t) 2.82 (2H,
t) ppm; LRMS APCI m/z 208 [M+H]+
Preparation 70
2-(5-Chloro-2-methoxy-phenyl)-ethylamine
~CH~
HZN
The title compound was prepared from (5-chloro-2-methoxy-phenyl)acetonitrile
(W02004039377, p40), using a similar method to that of preparation 69, in
52% yield.
'H NMR (400MHz, CDCI3) b: 7.11-7.00 (2H, m), 6.75-6.65 (1H, m) 3.72 (3H, s),
2.90-2.80 (2H, m), 2.70-2.60 (2H, m) ppm
Preparations 71 to 79
The following compounds, of the general formula shown below were prepared
by a similar method to that described for preparation 69 using the appropriate
phenylacetonitrile starting material. Unless otherwise stated R3 to R' are
hydrogen.
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NHZ
R
No. Data Yield
71 R=H; R"= F; R=CH3 95%
'H NMR (400MHz, CDCI3) 8: 7.12 (1 H, m), 6.90
(2H, m),
2.95 (2H, t) 2.70 (2H, t) 2.25 (3H, s) ppm;
LRMS APCI m/z
154 [M+H]+
72 R=F; R"= F; R~=CH3 61
'H NMR (400MHz, CDC13) 8: 6.83 (2H, m), 2.94
(2H, t) 2.78
(2H, t) 2.25 (3H, s) ppm; LRMS APCI m/z 172
[M+H]+
73 R=CH3; R=CH3; R'=CH3CH3 80%
'H NMR (400MHz, CDC13) 8: 6.84 (2H, m), 2.88-2.69
(4H,
m) 2.30 (6H, s) 2.24 (3H, s) ppm; LRMS APCI
m/z 163
[M+H]+
74 R=F; R"= CH3; R'=F 66%
'H NMR (400MHz, CDCI3) 8: 6.97 (1 H, m), 6.75
(1 H, m),
2.92 (2H, t) 2.82 (2H, t) 2.24 (3H, s) ppm;
LRMS APCI m/z
172 [M+H]+
75 R=F; R"= CH3; R'=CI 58%
'H NMR (400MHz, CDC13) 8: 7.05 (1 H, m), 6.97
(1 H, m),
2.96 (4H, m) 2.23 (3H, s) ppm; LRMS APCI m/z
228
[M+CH3CN]+
76 R=CI; R"=CH3; R'=F 63%
'H NMR (400MHz, CDC13) 8: 7.14-6.99 (1 H, m),
6.97-6.73
(1 H, m), 3.07-2.83 (4H, m) 2.35 (3H, s) ppm;
LRMS APCI
m/z 228 [M+CH3CN]+
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77 R =H; R4=F; R'=CH3 62%
'H NMR (400MHz, CDC13) 8: 7.07 (1 H, m), 6.83
(2H, m),
2.97 (2H, t), 2.78 (2H, m) 2.27 (3H, s) ppm;
LRMS APCI m/z
154 [M+H]+
78 R"=F; R''=H; R"=CF3 53%
'H NMR (400MHz, CDC13) ~: 7.44-7.26 (1 H, m),
7.09-6.86
(2H, m), 2.98-2.84 (2H, t) 2.72-2.84 (2H, t)
ppm; LRMS
APCI m/z 208 [M+H]+
79 R=CH3; R"= CH3; R'= CH3 62%
'H NMR (400MHz, CDC13) 8: 6.98 (2H, m), 2.95
(2H, m),
2.77 (2H, m), 2.25 (3H, s), 2.19 (6H, s) ppm;
LRMS APCI
m/z 164 [M+H]+
Preparation 79: compound was purified by use of sulfonic acid functionalised
lanterns.
Preparation 80
2-(4-Chloro-phenyl)-N-ethyl-acetamide
H
N~CH3
CI
A mixture of 4-chlorophenyl acetic acid (1g, 5.88mmol), ethylamine (2M in
tetrahydrofuran, 5.88mL, 11.76mmol), 1-hydroxybenzotriazole hydrate (90mg,
5.88mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(1.13g, 5.88mmol), and triethylamine (1.78g, 17.64mmol) in dichloromethane
(30mL) was stirred at room temperature for 18 hours. The mixture was then
diluted with 1 M sodium hydroxide solution (30mL) and the aqueous layer was
extracted with dichloromethane (30mL). The combined organic solution was
washed with 1 M hydrochloric acid and brine, dried over magnesium sulfate and
concentrated in vacuo. The residue was purified by column chromatography on
silica gel, eluting with dichloromethane:methanol, 100:0 to 90:10, to afford
the
title compound as a colourless solid in 37% yield, 443mg.
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'H NMR (400MHz, CDC13) 8: 7.31-7.28 (2H, m), 7.27-7.24 (2H, m), 3.45 (2H,
s), 3.18 (2H, m), 1.08 (3H, t) ppm; LRMS APCI m/z 198 [M+H]+
Preparation 81
[2-(4-Chloro-phenyl)-ethyl]-ethyl-amine hydrochloride
H
N~CH3
/ HCI
CI
A mixture of 2-(4-chloro-phenyl)-N-ethyl-acetamide (preparation 80), (437mg,
2.22mmol) and borane tetrahydrofuran complex (1 M, 8.88mL, 8.88mmol) in
tetrahydrofuran was heated under reflux for 18 hours. The cooled reaction
mixture was then diluted with methanol (5mL) and 12M hydrochloric acid (2mL)
and the re-heated to reflux for a further hour. The mixture was cooled to room
temperature and concentrated in vacuo. Trituration of the residue with ethyl
acetate afforded the title compound as a colourless solid in 99% yield, 403mg.
'H NMR (400MHz, CDCI3) b: 7.35 (2H, m), 7.27 (2H, m), 3.22 (2H, m), 3.05
(2H, q), 2.97 (2H, m), 1.29 (3H, t) ppm; LRMS APCI m/z 184 [M+H]+
Preparation 82
2-(4-Methylsulfanyl-phenyl)-ethylamine
NHZ
S
H3~~
A solution of 4-(methylthio)phenylacetonitrile (828mg, 5.08mmol) in
tetrahydrofuran (10mL) was added dropwise to lithium aluminium hydride (1 M
in tetrahydrofuran, 5.6mL, 5.6mmol) and the mixture was stirred for 1 hour at
0°C. Further lithium aluminium hydride (1 M in tetrahydrofuran, 5.6mL,
5.6mmol)
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was added and the mixture was stirred at room temperature for 18 hours then
heated under reflux for 1 hour. The reaction mixture was cooled to 0°C,
1 M
sodium hydroxide solution (3mL) was added dropwise, and stirring continued
for a further hour. The mixture was then filtered through Celite~, washing
through with ethyl acetate, and the filtrate was washed with 1 M sodium
hydroxide solution. The organic solution was then loaded onto an Isolute~ SCX
cartridge, washed with methanol and eluted with 1 M ammonia in methanol. The
relevant fractions were concentrated in vacuo and the residue was purified by
column chromatography on silica gel, eluting with
dichloromethane:methano1:0.88 ammonia, 100:0:0 to 95:5:0.5, to afford the
title
compound as a yellow oil in 18% yield, 154mg.
'H NMR (400MHz, CDCI3) S: 7.20 (2H, m), 7.14 (2H, m), 2.84 (2H, m), 2.71
(2H, m), 2.43 (3H, s) ppm; LRMS APCI m/z 168 [M+H]+
Preparation 83
(4-Hydroxy-3-methyl-phenyl)-acetonitrile
_ N\~ \ CH3 _ .
OH
Boron tribromide (1 M in dichloromethane, 6.2mL, 6.2mmol) was added to a
solution of 4-methoxy-3-methylphenylacetonitrile (0.2g, 1.24mmol) in
dichloromethane (10mL), cooled to -78°C. The reaction mixture was
stirred at
this temperature for 1 hour and then at room temperature for 2 hours. The
mixture was then re-cooled to -78°C, diluted with sodium hydrogen
carbonate
solution and allowed to warm to room temperature. The organic layer was
separated, washed with brine, dried over sodium sulfate and concentrated in
vacuo to afford the title compound as a white solid in 87% yield, 0.16g.
'H NMR (400MHz, CDC13) 8: 7.07 (1 H, s), 7.00 (1 H, d), 6.76 (1 H, d), 3.65
(2H,
s), 2.25 (3H, s) ppm; LRMS APCI m/z 146 [M-H]-
Preparation 84
(4-Hydroxy-2,5-dimethyl-phenyl)-acetonitrile
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N
OH
CH3
The title compound was prepared from (4-methoxy-2,5-dimethylphenyl)
acetonitrile using a similar method to that of preparation 83, as a colourless
solid in 60% yield.
'H NMR (400MHz, CDC13) 8: 6.98 (1 H, s), 6.60 (1 H, s), 3.66 (2H, s), 2.25
(3H,
s), 2.13 (3H, s) ppm; LRMS APCI m/z 160 [M-H]-
Preparation 85
(4-Hydroxy-2,3-dimethyl-phenyl)-acetonitrile
CH3
\\ \ CHs
OH
The title compound was prepared from (4-methoxy-2,3-dimethyl-phenyl)-
acetonitrile using a similar method to that of preparation 83, as a colourless
solid in 94% yield.
'H NMR (400MHz, CDC13) 8: 7.03 (1 H, d), 6.64 (1 H, d), 3.62 (2H, s), 2.24
(3H,
s), 2.20 (3H, s) ppm; LRMS APCI m/z 160 [M-H]-
Preparation 86
2-(4-Methoxy-2,5-dimethyl-phenyl)-ethylamine
~CH3
CH3
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A mixture of (4-methoxy-2,5-dimethyl-phenyl)-acetonitrile (200mg, 1.14mmol)
and Raney° nickel (50mg) in 2M methanolic ammonia (10mL) was stirred
under
60psi of hydrogen gas at room temperature for 18 hours. Tlc analysis showed
that not all of the starting material had been consumed and so further
Raney°
nickel (50mg) in 2M methanolic ammonia (10mL) was added. The reaction
mixture was stirred under 60psi of hydrogen gas for an additional 18 hours at
room temperature and was then filtered through Arbocel°. The filtrate
was
concentrated in vacuo and the residue was purified by column chromatography
on silica gel, eluting with dichloromethane:methano1:0.88 ammonia, 100:0:0 to
90:10:1 to afford the title product as a pale brown solid in 38% yield, 98mg.
'H NMR (400MHz, CDCI3) 8: 6.87 (1 H, s), 6.68 (1 H, s), 3.77 (3H, s), 2.80
(2H,
m), 2.69 (2H, m), 2.28 (3H, s), 2.10 (3H, s) ppm; LRMS APCI m/z 180 [M+H]+
Preparation 87
2-(4-Methoxy-2,3-dimethyl-phenyl)-ethylamine
HZN
._
H C / O~CH3
3
CH3
The title compound was prepared from (4-methoxy-2,3-dimethyl-phenyl)-
acetonitrile, using a similar method to that of preparation 86, as a clear oil
in
93% yield.
' H NMR (400MHz, CDCI3) 8: 6.96 (1 H, d), 6.66 (1 H, d), 3.80 (3H, s), 2.96-
2.84
(2H, m), 2.81-2.73 (2H, m), 2.22 (3H, s), 2.17 (3H, s), 1.63 (2H, s) ppm; LRMS
APCI m/z 180 [M+H]+
Preparation 88
4-(2-Amino-ethyl)-2-methyl-phenol
H2N
-OH
CH3
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The title compound was prepared from (4-hydroxy-3-methylphenyl)acetonitrile
(preparation 83), using a similar method to that of preparation 86, as a clear
oil
in 85% yield.
'H NMR (400MHz, CDC13) 8: 6.90 (1 H, s), 6.82 (1 H, d), 6.65 (1 H, d), 2.83-
2.79
(2H, m), 2.61 (2H, m), 2.15 (3H, s) ppm; LRMS APCI m/z 152 [M+H]+
Preparation 89
4-(2-Amino-ethyl)-2,5-dimethyl-phenol
OH
CH3
The title compound was prepared from (4-hydroxy-2,5-dimethyl-phenyl)-
acetonitrile (preparation 84), using a similar method to that of preparation
86,
as a solid in 73% yield.
'H NMR (400MHz, CDCI3) 8: 6.81 (1 H, s), 6.54 (1 H, s), 2.79-2.64 (4H, m),
2.19
(3H, s), 2.11 (3H, s) ppm; LRMS APCI m/z 166 [M+H]+
Preparation 90
4-(2-Amino-ethyl)-2,3-dimethyl-phenol
CH3
HZN ~ CH3
OH
The title compound was prepared from (4-hydroxy-2,3-dimethyl-phenyl)
acetonitrile (preparation 85) using a similar method to that of preparation
86, as
a colourless solid in 95% yield.
'H NMR (400MHz, CDCI3) b: 6.78 (1 H, d), 6.55 (1 H, d), 2.75-2.68 (4H, m),
2.19
(3H, s), 2.12 (3H, s) ppm; LRMS APCI m/z 166 [M+H]+
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Preparation 91
2-(2,3-Dimethyl-phenyl)-ethylamine
HZN
i
CH3
H3C
A mixture of 2,3-dimethylphenylacetonitrile (J. Org Chem, 51 (26), 5157-60;
1986), (190mg, 1.31 mmol) and Raney° nickel (100mg) in 2M methanolic
ammonia (5mL) was stirred under 50psi of hydrogen gas for 4 days. The
mixture was then filtered through Arbocel° and concentrated in vacuo to
afford
the title compound as a solid in 66% yield, 130mg.
'H NMR (400MHz, CDC13) 8: 7.02-6.94 (3H, m), 2.26-2.13 (10H, m) ppm; LRMS
ESI m/z 150 [M+H]+
Preparation 92
2-(2,3-Dichloro-phenyl)-ethylamine
HzN
CI
CI
A solution of 2,3-dichlorophenylacetonitrile (0.5g, 2.7mmol) in diethyl ether
(5mL) was added to an ice-cold solution of lithium aluminium hydride (1 M in
diethyl ether, 2.7mL, 2.7mmol) and aluminium trichloride (359mg, 2.7mmol).
The mixture was stirred at room temperature 2.5 hours and was then quenched
with 1 M sodium hydroxide solution (5mL). The mixture was stirred for a
further
30 minutes and filtered through Celite°. The layers of the filtrate
were
separated and the organic solution was concentrated in vacuo. Purification of
the residue by column chromatography on silica gel, eluting with
dichloromethane:methano1:0.88 ammonia, 100:0:0 to 95:5:0.5 afforded the title
compound as a clear oil in 26% yield, 135mg.
'H NMR (400MHz, CDC13) 8: 7.38 (1 H, dd), 7.27-7.19 (2H, m), 2.95 (2H, m),
2.87 (2H, m) ppm; LRMS APCI m/z 190 [M+H]+
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Preparation 93
2-(5-Chloro-2-fluoro-phenyl)-ethylamine
HzN ~ CI
F
Sodium borohydride (1.73g, 45.51 mmol) was added portionwise to a solution of
5-chloro-2-fluorophenylacetonitrile (1.04g, 6.15mmol) and cobalt (II) chloride
hexahydrate (2.18g, 9.22mmol) in methanol (30mL) and the mixture was stirred
at room temperature for 3 hours. The suspension was then filtered though
Celite°, concentrated in vacuo and the residue was partitioned
between 1 M
.hydrochloric acid (40mL) and dichloromethane (40mL). The aqueous phase
was separated, basified to pH 11 with 1 M ammonia solution and extracted with
dichloromethane (2x40mL). The combined organic solution was washed with
brine (30mL), dried over magnesium sulfate and concentrated in vacuo. The
residue was purified by column chromatography on silica gel, eluting with
dichloromethane:methano1:0.88 ammonia, 100:0:0 to 98:2:0.2, to afford the
title
compound as a yellow oil in 33% yield, 350mg.
'H NMR (400MHz, CDCI3) 8: 7.28 (1 H, m), 7.22 (1 H, m), 7.05 (1 H, m), 2.85
(2H, m), 2.77 (2H, m) ppm; LRMS APCI m/z 174 [M+H]+
Preparation 94
2-(2-Chloro-4-fluoro-phenyl)-ethylamine
HZN
CI F
The title compound was prepared from 2-chloro-4-fluorophenylacetonitrile,
using a similar method to that of preparation 93, as a light brown oil in 46%
yield.
'H NMR (400MHz, CDCI3) b: 7.30 (1 H, dd), 7.17 (1 H, dd), 6.99 (1 H, m), 2.86
(4H, m) ppm; LRMS APCI m/z 174 [M+H]+
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Preparation 95
2-(4-Chloro-2-fluoro-phenyl)-ethylamine
HzN \
F CI
The title compound was prepared from 4-chloro-2-fluorophenylacetonitrile,
using a similar method to that of preparation 93. The crude compound was
purified using an Isco SCX° cartridge, eluting with methanol followed
by 1 M
methanolic ammonia. The appropriate fractions were concentrated in vacuo
and the residue was further purified by column chromatography on silica gel,
eluting with dichloromethane:methano1:0.88 ammonia, 95:5:0.3 to afford the
title compound as a pale yellow oil in 29% yield.
'H NMR (400MHz, CDCI3) 8: 7.30 (1 H, dd), 7.17 (1 H, dd), 6.99 (1 H, dt), 2.86
(4H, m) ppm; LRMS APCI m/z 174 [M+H]+
Preparation 96
(2,3-Dihydro-benzofuran-2-yl)-methanol
H
A solution of meta-chloroperbenzoic acid (96.48, 335mmol) in dichloromethane
(500mL) was added to an ice-cold solution of 2-allylphenol (30g, 224mmol) in
dichloromethane (1 L) and the mixture was stirred at 0°C for 30 minutes
and at
room temperature for 18 hours. The reaction mixture was then re-cooled to
0°C,
quenched with 2M sodium hydroxide solution (700mL) and stirred for 30
minutes. The organic layer was then separated, dried over magnesium sulfate
and concentrated in vacuo to give a yellow oil. The oil was
purified by HPLC using a Chiralpak AD 250*4.6mm column and
hexane:isopropanol (90:10) as the eluant, to afford the title compound.
' H NMR (400MHz, CDC13) 8: 7.20-7.10 (2H, m), 6.85 ( 1 H, m), 6.78 ( 1 H, m),
4.90 ( 1 H,
m), 3.86 (1H, m), 3.70 (1H, m), 3.30-3.20 (1H, m) 3.10 (1H, m) ppm
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Preparation 97
2,3-Dihydro-1-benzofuran-2-ylmethyl 4-methylbenzenesulfonate
0
-SI CH
0
p-Toluenesulphonyl chloride (26.7g, 140mmol) was added to a solution of (2,3-
dihydro-benzofuran-2-yl)-methanol (preparation 96) (21g, 140mmol) in pyridine
(400mL) and the mixture was stirred at room temperature for 4 days. The
reaction mixture was then concentrated in vacuo and the residue was
azeotroped with toluene, diluted with ethyl acetate (500mL) and washed with
2M hydrochloric acid (2x300mL). The organic solution was dried over
magnesium sulfate and concentrated in vacuo to give a brown oil. Trituration
of
the oil in cyclohexane then afforded the title compound as a white solid in
79%
yield, 33.5g.
LRMS APCI m/z 305 [M+H]+
Preparation 98
2-Ethyl-2,3-dihydro-benzofuran
CH3
Methyl lithium (1.6M in diethyl ether, 313mL, 500mmol) was added to a solution
of copper (I) iodide (47.6g, 250mmol) in diethyl ether (750mL) at
-70°C. The solution was then allowed to warm to -10°C and was
stirred for 30
minutes. The mixture was then added to a solution of 2,3-dihydro-1-
benzofuran-2-ylmethyl 4-methylbenzenesulfonate (preparation 97) (15.2g,
50mmol) in diethyl ether (500mL) and the reaction mixture was stirred at -
40°C
for 1 hour and at room temperature for 2 hours. The mixture was then cooled to
-70°C and quenched with 10% ammonium chloride solution (750mL) and 2M
hydrochloric acid (50mL), diluted with 0.88 ammonia (100mL) and then stirred
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for 18 hours. The reaction mixture was extracted with diethyl ether (3x500mL)
and the organic solution was dried over magnesium sulfate and concentrated in
vacuo to afford the title compound as a brown oil in 98% yield, 7.25g.
Preparation 99
(+) and (-) 5-Bromo-2-ethyl-2,3-dihydro-benzofuran
Bf
H
3
N-Bromosuccinimide (8.66g, 48.6mmol) was added to a solution of 2-ethyl-2,3-
dihydro-benzofuran (preparation 98) in dichloromethane (70mL) and the
mixture was stirred at room temperature for 18 hours. The mixture was then
diluted with dichloromethane (200mL) and washed with water (200mL) and
sodium meta-bisulphite (200mL). The organic solution was dried over
magnesium sulfate and concentrated in vacuo to give a yellow oil that was
purified by HPLC using a Chiralcel OJ 250*20mm column and
hexane:isopropanol (95:5) as the eluant to afford the first enantiomer of the
title
compound. Further elution provided the second isomer of the title compound,
2.95g.
~ H NMR (400MHz, CDC 13) ~: 7.24 ( 1 H, m), 7.18 ( 1 H, m), 6.62 ( 1 H, d),
4.75 ( 1 H, m),
3.30-3.20 (1H, m), 2.92-2.80 (1H, m), 1.77-1.88 (1H, m), 1.75-1.65 (1H, m)
1.00 (3H,
m) ppm
Preparation 100
di-tert-Butyl [3-(2-ethyl-2,3-dihydro-1-benzofuran-5-
yl)propyl]imidodicarbonate
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CH3 O
H3C~O~N \
3
H
O O
H C~CH
3 CH3 3
N,N-8is-Boc-N-allylamine (2.99g, 11.6mmol) was azeotroped with toluene
(2x50mL) then dissolved in tetrahydrofuran (12mL). The solution was cooled to
0°C, 9-borabicyclo[3.3.1]nonane dimer (0.5M in tetrahydrofuran, 46.5mL,
23.2mmol) was added and the mixture was stirred at 0°C for 3 hours. A
mixture
of 5-bromo-2-ethyl-2,3-dihydro-benzofuran (preparation 98, enantiomer 2),
(2.9g, 12.8mmol), tripotassium phosphate (7.7mL, 23.2mmol) and [1,1'-
bis(diphenylphosphino)ferrocene]palladium(II) chloride (4.74mg, 0.58mmol) in
N,N-dimethylformamide (12mL) was added and the reaction mixture was stirred
at room temperature for 18 hours. The reaction was then quenched with 2M
- sodium hydroxide solution (30mL) and water (10mL) and stirred for 1 hour at
__
room temperature. The mixture was then extracted with diethyl ether, dried
over
magnesium sulfate and concentrated in vacuo. The residue was suspended in
ethyl acetate:petroleum ether, 25:75, filtered and the filtrate was
concentrated
in vacuo. The residue was purified by column chromatography on silica gel,
eluting with ethyl acetate:petroleum ether, 7:93, to afford the title compound
as
a clear oil in 46% yield, 2.15g.
LRMS ESI m/z 428 [M+Na]+
Preparation 101
3-(2-Ethyl-2,3-dihydro-benzofuran-5-yl)-propylamine hydrochloride
HZN ~ \
O CH
. HCI
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A solution of di-tert-butyl [3-(2-ethyl-2,3-dihydro-1-benzofuran-5-
I)propylJimidodicarbonate (preparation 100), (2.198, 5.4mmol) in hydrochloric
acid (4M in dioxane, 20mL) was stirred at room temperature for 18 hours. The
reaction mixture was then concentrated in vacuo to afford the title compound
in
quantitative yield.
1H NMR (400MHz, CDC13) 8: 7.00-6.85 (2H, m), 6.60 ( 1 H, d), 4.75 ( 1 H, m),
3.20 ( 1 H,
m), 2.97 (2H, m), 2.80 (1H, m), 2.60 (2H, m), 2.10-1.95 (2H, m), 1.90-1.60
(2H, m)
1.00 (3H, m) ppm
Preparation 102
tert-Butyl (2-{4-((butylamino)carbonyl]phenyl}ethyl)carbamate
H
H3C- I O II N \ H
CH3 O ~ / N~~CH3
O
A mixture of 4-(2-[(tert-butoxycarbonyl)aminoJethyl}benzoic acid (22.2g,
83.6mmol) (EP0836839, p60) carbonyldiimidazole (21.36g, 131.7mmol), and
N,N-diisopropylethylamine (20mL, 115.1 mmol) in dichloromethane (600mL)
was stirred at room temperature for 2 hours. "Butylamine (10mL, 101.18mmol)
was then added and the mixture was stirred for a further 18 hours at room
temperature. The reaction mixture was concentrated in vacuo and the residue
was dissolved in ethyl acetate and washed with 10% citric acid (2x50mL),
saturated sodium hydrogen carbonate solution (200mL), water (200mL) and
brine (200mL). The organic solution was dried over sodium sulfate and
concentrated in vacuo to give a cream powder. The powder was purified by
column chromatography on silica gel, eluting with dichloromethane:methanol,
99:1, to afford the title compound in 65% yield, 17.5g.
LRMS CI m/z 338.3 [M+NH4J+, m.p.= 118°C
Preparation 103
4-(2-Aminoethyl)-N-butylbenzamide hydrochloride
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HzN
.HCI ~ / N~~CH3
O
The title compound was prepared from tert-butyl(2-{4-
[(butylamino)carbonyl]phenyl)ethyl)carbamate (preparation 102), using a
similar
method to preparation 101, as white powder in 84% yield.
'H NMR (400MHz, DMSO-ds) 8: 8.38 (1H, m), 8.04 (3H, m), 7.78 (2H, d), 7.34
(2H, d), 3.24 (2H, m), 3.06 (2H, m), 2.82 (2H, m), 1.46 (2H, m), 1.28 (2H, m),
0.86 (3H, t) ppm
LRMS CI m/z 221.2 [M+H]+
Preparation 104
[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-acetonitrile
/%
N~~O
A mixture of 1-(3-chloropropyl)pyrrolidine (J. Am. Chem. Soc., 77, 2270; 1955)
(1338, 0.9mo1), 4-hydroxybenzonitrile (100g, 0.75mo1) and caesium carbonate
(256g, 0.78mo1) in acetonitrile (1 L) was stirred at 45°C for 18 hours.
The
reaction mixture was then concentrated in vacuo and the residue was
partitioned between ethyl acetate (800mL) and water (800mL). The aqueous
layer was separated and extracted with ethyl acetate (800mL) and the
combined organic solution was washed with water (500mL) and extracted with
2M hydrochloric acid (2x600mL). The acidic solution was basified to pH8-9 with
40% potassium hydroxide solution and extracted with ethyl acetate (800mL).
The aqueous solution was then further basified to pH10-11 using 40%
potassium hydroxide solution and extracted with ethyl acetate (800mL). The
combined organic solution was dried over sodium sulfate, filtered through a
pad
of silica and concentrated in vacuo to afford the title compound as a red oil
in
79% yield, 150g.
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'H NMR (400MHz, CDC13) 8: 7.24 (2H, d), 6.85 (2H, d), 4.09-3.89 (2H, m), 3.75
(2H, s), 2.71-2.36 (6H, m), 2.14-1.93 (2H, m), 1.89-1.65 (4H, m) ppm;
LRMS APCI m/z 245 [M+H]+
Preparation 105
2-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-ethylamine
NHZ
N~~O
A mixture of [4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-acetonitrile (preparation
104),
(1g, 4.1mmol) and Raney~ nickel (100mg) in 2M methanolic ammonia (35mL)
was stirred under 60psi of hydrogen gas at 50°C for 6 hours. Tlc
analysis
showed that not all of the starting material had been consumed and so further
Raney° nickel (200mg) was added to the reaction mixture and heating
continued for 5 hours. Tlc analysis again showed that starting material was
still
present and so additional Raney~ nickel (200mg) was added and the mixture
was stirred at 50°C for 3 hours. The reaction mixture was then filtered
through
Arbocel° and was concentrated in vacuo to give a yellow oil. The oil
was
purified by column chromatography using a 4g RediSep° silica cartridge,
eluting
with dichloromethane:methano1:0.88 ammonia, 85:15:1.5 to 80:20:2, to afford
the title compound in 16% yield, 160mg.
'H NMR (400MHz, CDC13) 8: 7.10 (2H, d), 6.81 (2H, d), 4.10-4.00 (2H, m), 3.05-
2.65 (10H, m), 2.25-2.14 (2H, m), 2.05-1.95 (4H, m) ppm; LRMS APCI m/z 249
[M+H]+
Preparation 106
[2-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-acetonitrile
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//N
/
O~N
The title compound was prepared from 2-hydroxy-benzeneacetonitrile (J. Org.
Chem.; 66, 3435; 2001 ) and 1-(3-chloropropyl)pyrrolidine, using a method
similar to that of preparation 104, as a pale brown gum in 58% yield.
'H NMR (400MHz, CD30D) 8: 7.33-7.25 (2H, m), 7.02-6.90 (2H, m), 4.12-4.09
(2H, m), 3.75 (2H, s), 2.76-2.72 (2H, m), 2.62-2.57 (4H, m), 2.09-2.02 (2H,
m),
1.87-1.78 (4H, m); LRMS APCI m/z 245 [M+H]+
Preparation 107
2-[2-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-ethylamine
NHZ
O~~N
The title compound was prepared from the product of preparation 106, using a
method similar to that of preparation 69, in 48% yield.
'H NMR (400MHz, CD30D) 8: 7.19-7.16 (2H, m), 6.92 (1 H, m), 6.86 (1 H, m),
4.06-4.02 (2H, m), 2.87-2.83 (2H, m), 2.80-2.75 (2H, m), 2.71-2.67 (2H, m),
2.62-2.55 (4H, m), 2.07-2.00 (2H, m), 1.86-1.81 (4H, m); LRMS APCI m/z 249
[M+H]+
Preparation 108
{2-[3-(3-Pyrrolidin-1-ylpropoxy)phenyl]ethyl}amine
NHz
/ O~~N
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The title compound was prepared from [3-(3-pyrrolidin-1-
ylpropoxy)phenyl]acetonitrile (170mg, 0.70mmol), using a method similar to
that
of preparation 69. The crude compound was then further purified by column
chromatography using a 4g RediSep~ silica cartridge, eluting with
dichloromethane:methano1:0.88 ammonia, 100:0:0 to 80:20:2, to afford the
desired product in 30% yield.
'H NMR (400MHz, CD30D) s: 7.23-7.19 (1 H, m), 6.81-6.78 (3H, m), 4.04-3.98
(2H, m), 2.99-2.95 (2H, m), 2.81-2.77 (2H, m), 2.74-2.70 (2H, m), 2.66-2.62
(4H, m), 2.05-1.98 (2H, m), 1.87-1.82 (4H, m); LRMS APCI m/z 249 [M+H]+
_ Preparation 109
3-{2-[(2R)-(tert-Butyl-dimethyl-silanyloxy)-2-(4-hydroxy-3-hydroxymethyl-
phenyl)-ethylamino]-2-methyl-propyl}-N-(3-pyrrolidin-1-yl-propyl)
-benzamide
0
\ N ~~/
CH3
HO
H°
1-(3-Aminopropyl)pyrrolidine (38,uL, 0.30mmol) was added to a mixture of 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (79mg, 0.41 mmol), 3-
{2-((2R)-2-(tent-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxy methyl-
phenyl)ethylamino]-2-methylpropyl}benzoic acid (preparation 37) (130mg,
0.28mmol), 1-hydroxybenzotriazole hydrate (40mg, 0.29mmol) and N,N-
diisopropylethylamine (210~L, 1.49mmol) in N,N-dimethylformamide (4mL). The
resulting solution was stirred for 9 days at room temperature, after which
time,
tlc analysis showed that starting material still remained. Further 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (79mg, 0.41mmol), 1-
hydroxybenzotriazole hydrate (40mg, 0.29mmol) and N,N-diisopropylethylamine
(2101, 1.49mmol) were then added and stirring continued for 2 days at room
temperature. The solvent was removed in vacuo and the residue was
partitioned between ethyl acetate (25mL) and saturated sodium hydrogen
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carbonate solution (20mL). The organic solution was separated, dried (sodium
sulfate) and concentrated in vacuo to give an orange oil. The oil was purified
by
flash column chromatography on silica gel eluting with
dichloromethane:methano1:0.88 ammonia, 100:0:0 to 75:25:2 to afford the title
compound as a glass in 43% yield, 70mg
'H NMR (400MHz, CD30D) 8: 7.48 (2H, m) 7.40- 7.31 (2H, m), 7.27 (1 H, m),
7.07 (1 H, dd), 6.74 (1 H, d), 4.69 (1 H, m), 4.64 (2H, m), 3.43 (2H, m), 2.90-
2.50
(10H, m), 1.90-1.70 (6H, m), 1.11 (3H, s), 1.07 (3H, s), 0.79 (9H, s),
-0.02 (3H, s), -0.21 (3H, s) ppm; LRMS APCI m/z 584 [M+H]+
Preparation 110
3-[2-({(2R)-2-~[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]-N-[2-(4-
chlorophenyl)ethyl]-N-ethylbenzamide
OTBDMS O
H
N \ N
H3C CH3 ~ \
HO
CH3
CI
HO
The title compound was prepared from 3-{2-[(2R)-2-(tert-
butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxy methyl-phenyl)ethylamino]-2-
methylpropyl}benzoic acid (preparation 37) and [2-(4-chloro-phenyl)-ethyl]-
ethyl-amine hydrochloride (preparation 81 ), using a similar method to that of
preparation 109, as a white solid in 43% yield.
'H NMR (400MHz, CD30D) 7.90-6.90 (10H, m), 6.72 (1 H, d), 4.69 (1 H, m), 4.63
(2H, m), 3.70 (1 H, m), 3.61 (1 H, m), 3.49 (1 H, m), 3.10 (1 H, m), 3.03-2.58
(6H,
m), 1.29-1.26, 1.07-1.01 (9H, 2xm), 0.82 (9H, s), 0.01 (3H, s), -0.18 (3H, s)
ppm; LRMS APCI m/z 639 [M+H]+
Preparation 111
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3-[2-( f (2R)-2-{[tert-Butyl(dimethyl)silyljoxy}-2-[4-hydroxy-3-(hydroxyl
methyl)phenyljethyl}amino)-2-methylpropylj-N-(2-pyrrolidin-1-ylethyl)
benzamide
~S
H
N H
~N~
~3C CH3 ~ N
HO
NU
1-(2-Aminoethyl)pyrrolidine (83,uL, 0.63mmol) was added to a mixture of 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (122mg, 0.63mmol), 3-
{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxy methyl-
phenyl)ethylamino]-2-methylpropyl)benzoic acid (preparation 37) (200mg,
0.42mmol), 1-hydroxybenzotriazole hydrate (63mg, 0.47mmol) and N,N-
diisopropylethylamine (88p.L, 0.63mmol) in N,N-dimethylformamide (5mL). The
resulting solution was stirred for 18 hours at room temperature. The solvent
was removed in vacuo and the residue was partitioned between ethyl acetate
(50mL) and saturated sodium hydrogen carbonate solution (10mL). The
aqueous layer was separated and re-extracted with dichloromethane (30mL),
and the combined organic solution was dried (sodium sulfate) and concentrated
in vacuo to give a yellow oil. The oil was purified by flash column
chromatography on silica gel eluting with dichloromethane:methano1:0.88
ammonia, 100:0:0 to 75:25:2 to afford the title compound as a pale yellow
solid.
'H NMR (400MHz, CD30D) 8: 7.69 (2H, m) 7.40-7.31 (2H, m), 7.26 (1 H, m),
7.14-7.03 (1 H, dd), 6.85 (1 H, d), 4.69 (1 H, m), 4.62 (2H, m), 3.58 (2H, m),
2.89-
2.59 (10H, m), 1.82-1.79 (4H, m), 1.12 (3H, s), 1.07 (3H, s), 0.79 (9H, s),
-0.01 (3H, s), -0.21 (3H, s) ppm; LRMS APCI m/z 570 [M+H]+
Preparations 112 to 138
The following compounds, of the general formula shown below were prepared
by a similar method to that described for preparation 38, using 3-{2-[(2R)-2-
(tent-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)
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ethylamino]-2-methylpropyl}benzoic acid (preparation 37) and the appropriate
amine starting material. The reactions were monitored by tlc analysis and were
stirred at room temperature for 18-72hours.
0
HO
No. Q~ Data Yield
112 C~ /. 'H NMR (400MHz, CD30D) s: 44%
7.64
\ ~ (2H, m) 7.37-7.28 (5H, m),
7.20 (1 H,
m), 7.08 (1 H, m), 6.75 (1
H, d), 4.72
C~ (1 H, m), 4.65 (2H, m), 3.68
(2H, m),
3.30 (2H, m), 2.95-2.60 (4H,
m),
1.12 (3H, s), 1.08 (3H, s),
0.80 (9H,
s), -0.02 (3H, s), -0.19 (3H,
s) ppm;
LRMS APCI m/z 645 [M+H]+
113 N 'H NMR (400MHz, CD30D) b: 16%
7.65
(2H, m), 7.40-7.05 (8H, m),
6.75
(1 H, m), 4.78-4.63 (3H, m),
3.46
(2H, m), 3.15- 2.70 (9H, m),
1.15
(3H, s), 1.11 (3H, s), 0.79
(9H, s), -
0.01 (3H, s), -0.20 (3H, s)
ppm;
LRMS APCI m/z 603 [M+H]+
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114 ~ 'H NMR (400MHz, CD30D) b: 22%
7.75
~NH (2H, m), 7.65 (2H, m), 7.40-7.25
(5H, m), 7.09 (1 H, m), 6.73
(1 H, m),
4.75-4.62 (3H, m), 3.62 (2H,
m),
c"3 3.37 (2H, m), 3.02-2.62 (6H,
m),
1.59 (2H, m), 1.41 (2H, m),
1.14-
1.07 (6H, m), 0.97 (3H, t),
0.79 (9H,
s), -0.01 to -0.21 (6H, m)
ppm;
LRMS APCI m/z 676 [M+H]+
115 ~ ~ 'H NMR (400MHz, CD30D) 8: 34%
7.63
(2H, m), 7.25 (12H, m), 7.05
(1 H,
S m), 6.73 (1 H, m), 4.68 (3H,
m), 3.62
(2H, m), 3.13 (2H, m), 2.80
(4H,
brm), 1.08 (6H, m), 0.80
(9H, s),
-0.05 (3H, s). -0.21 (3H,
s) ppm
LRMS ESI m/z 685 [M+H]+
116 C~ 'H NMR (400MHz, CD30D) s: - 30%
7.63
(2H, m), 7.40-7.20 (5H, m),
7.10
/ (1 H, m), 6.75 (1 H, m),
4.62 (3H, m),
3.59 (2H, m), 3.22 (2H, m),
2.92-
C~ 2.64 (4H, brm), 2.51 (3H,
s), 1.10
(6H, m), 0.80 (9H, s), -0.02
(3H, s), -
0.21 (3H, s) ppm; LRMS ESI
m/z
659 [M+H]+
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117 'H NMR (400MHz, CD30D) 8: 34%
7.66
(2H, m), 7.34 (2H, m), 7.26
(1 H, d),
7.07 (1 H, m), 6.72 (1 H,
m), 4.69
(1 H, m), 4.63 (2H, d), 3.39
(2H, t),
2.75 (3H, brm), 2.63 (1 H,
m), 1.81
(2H, m), 1.75-1.63 (3H, m),
1.52
(2H, m), 1.36 (1 H, m), 1.28
(1 H, m),
1.17-1.24 (2H, m), 1.11 (3H,
s), 1.08
(3H, s), 1.03-0.92 (2H, m),
0.77 (9H,
s),
-0.05 (3H, s) -0.27 (3H, s)
ppm
LRMS ESI m/z 583 [M+HJ+
118 ~ 'H NMR (400MHz, CD30D) 8: 38%
7.65
/ (2H, m), 7.38-7.31 (4H, m),
7.27
(1 H, d), 7.20 (2H, m), 7.06
(1 H, dd),
C~ 6.72 (1 H, d), 4.69 (1 H,
m), 4.63 (2H,
d), 3.62 (2H, m), 3.07 (2H, -
t), 2.89-
2.82 (2H, t), 2.79-2.71 (1
H, m), 2.65
(1 H, m), 1.10 (3H, s), 1.07
(3H, s),
0.78 (9H, s), -0.04 (3H, s)
-0.21 (3H,
s) ppm; LRMS ESI m/z 611 [M+H]+
119 'H NMR (400MHz, CD30D) b: 37%
7.66
(2H, m), 7.37-7.30 (2H, m),
7.26
(1 H, m), 7.09-7.00 (1 H,
m), 6.72
(1 H, d), 4.69 (1 H, m), 4.63
(2H, d),
3.43-3.38 (2H, m), 2.83-2.89
(2H,
m), 2.80-2.71 (1 H, m), 2.61-2.65
(1 H, m), 1.96 (3H, s), 1.68
(6H, m),
1.61 (6H, d), 1.42 (2H, m),
1.10 (3H,
s), 1.07 (3H, s) 0.78 (9H,
s), -0.04
(3H, s) -0.22 (3H, s) ppm;
LRMS ESI
m/z 635 [M+HJ+
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120 / \ 'H NMR (400MHz, CD30D) 8: 8.26 24%
(1 H, m), 7.86 (1 H, m), 7.74 (1 H, m),
7.64 (2H, m), 7.53 (1 H, m), 7.46
N
(1 H, m), 7.41-7.31 (4H, m), 7.27
(1 H, m), 7.06 (1 H, dd), 6.73 (1 H, m),
4.70 (1 H, m), 4.63 (2H, d), 3.72 (2H,
m), 3.40 (2H, t), 2.90-2.70 (3H, m),
2.64 (1 H, m), 1.09 (3H, s), 1.07 (3H,
s), 0.78 (9H, s), -0.03 (3H, s), -0.21
(3H, s) ppm; LRMS ESI m/z 627
[M+HJ+
121 HsC ~H NMR (400MHz, CD30D) 8: 7.67 40%
(2H, m), 7.39-7.32 (2H, m), 7.27
N (1 H, m), 7.07 (1 H, dd), 6.98 (3H, m),
H C 6.72 (1 H, m), 4.70 (1 H, m), 4.63
3
(2H, d), 3.46 (2H, t), 2.99 (2H, m),
2.87 (2H, m), 2.73 (1 H, m), 2.66 -
(1 H, m), 2.39 (6H, s), 1.11 (3H, s),
1.09 (3H, s), 0.79 (9H, s), -0.03 (3H,
s), -0.21 (3H, s) ppm; LRMS ESI m/z
605 [M+H]+
122 N ~ ~ 'H NMR (400MHz, CD30D) b: 7.63 46%
s 7.27 1 H, m ,
cH (2H, m), 7.35 (2H, m), ( )
3
7.17 (4H, m), 7.06 (1 H, dd) 6.72
(1 H, m), 4.70 (1 H, m), 4.63 (2H, d),
3.56 (2H, t), 2.87 (3H, m), 2.71 (2H,
m), 2.64 (1 H, m), 2.43 (3H, s), 1.09
(3H, s), 1.07 (3H, s), 0.78 (9H, s), -
0.04 (3H, s), -0.22 (3H, s) ppm;
LRMS ESI m/z 623 [M+H]+
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123 F 'H NMR (400MHz, CD30D) 8: 61
7.62
(2H, m), 7.34-7.27 (3H, m),
7.22
(2H, m), 7.03-7.09 (2H, m),
6.72
(1 H, d), 4.69 (1 H, m), 4.63
(2H, m),
3.59 (2H, m), 2.96 (2H, m),
2.71
(2H, m), 2.63 (2H, m), 1.09
(3H, s),
1.06 (3H, s), 0.78 (9H, s),
-0.04 (3H,
s), -0.21 (3H, s) ppm; LRMS
APCI
m/z 629 [M+H]+
124 C~ 'H NMR (400MHz, CD30D) 8: 60%
7.62
(2H, m), 7.34 (3H, m), 7.27
(1 H, d),
F 7.18 (1 H, m), 7.06 (1 H,
dd), 6.97
(1 H, m), 6.72 (1 H, d), 4.69
(1 H, m),
4.63 (2H, m), 3.62 (2H, m),
3.04
(2H, t), 2:89-2.70 (3H, m),
2.61 (1 H,
m), 1.09 (3H, s), 1.07 (3H,
s), 0.78
(9H, s), -0.04 (3H, s), -0.21
(3H, s)
ppm; LRMS APCI m/z 629 [M+H]+
125 ~H3 'H NMR (400MHz, CD30D) 8: 19%
7.54-
V
7.75 (2H, m), 7.42-7.24 (3H,
m),
7.17-7.04 (1 H, m), 6.98-6.83
(1 H,
dd), 6.79-6.64 (2H, m), 4.70
(1 H, m),
cH3 cH3 4.63 (2H, d), 3.77 (3H, s),
3.51 (2H,
t), 2.89-2.82 (4H, m), 2.79-2.71
(1 H,
m), 2.64 (1 H, m), 2.33 (3H,
s), 2.09
(3H, s), 1.07 (6H, s), 0.78
(9H, s), -
0.03 (3H, s), -0.21 (3H, s)
ppm;
LRMS ESI m/z 635 [M+H]+
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126 cl ~H NMR (400MHz, CD30D) 8: 67%
N CI 7.62
/ (2H, m) 7.44-7.14 (6H, m),
7.08 (1 H,
d), 6.73 (1 H, d), 4.71 (1
H, m), 4.60
(2H, m), 3.68 (2H, m), 3.14
(2H, m),
2.93-2.58 (4H, m), 1.10 (3H,
s), 1.07
(3H, s), 0.78 (9H, s), -0.04
(3H, s), -
0.21 (3H, s) ppm; LRMS APCI
m/z
645 [M+H]+
127 cHs 'H NMR (400MHz, CD30D) 8: 39%
7.65
N
H3 (2H, m) 7.37-7.31 (2H, m),
7.27 (1 H,
d), 7.06 (1 H, dd), 6.97 (1
H, d), 6.73
(1 H, d), 6.68 (1 H, d), 4.73-4.68
(1 H,
CH3 m), 4.60 (2H, m), 3.76 (3H,
s), 3.49
(2H, m), 2.93-2.60 (6H, m),
2.28
(3H, s), 2.13 (3H, s), 1.10
(3H, s),
1.07 (3H, s), 0.78 (9H, s),
-0.04 (3H,
s), -0.21 (3H, s) ppm
LRMS APCI m/z 635 [M+H]+
128 ~ / 'H NMR (400MHz, CD30D) 8: 43%
7.67-
I 7.62 (2H, m), 7.59-7.52 (4H,
\ dd),
/ 7.42-7.36 (2H, dd), 7.35-7.26
(6H,
m), 7.05 (1 H, dd), 6.71 (1
H, dd),
4.67 (1 H, dd), 4.60 (2H,
dd), 3.61
(2H, t), 2.95 (2H, t), 2.83
(1 H, dd),
2.70 (2H, dd), 2.60-2.65 (1
H, m),
1.08 (3H, s), 1.06 (3H, s),
0.77 (9H,
s), -0.05 (3H, s), -0.23 (3H,
s) ppm;
LRMS APCI m/z 653 [M+H)+
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129 / ~ cH3 'H NMR (400MHz, CD30D) 8: 46%
7.65
(2H, m) 7.37-7.31 (2H, m),
7.27 (1 H,
d), 7.06 (1 H, dd), 7.03
(1 H, d), 6.96
H3C
(1 H, bs), 6.90 (1 H, d),
6.72 (1 H, d),
4.72-4.68 (1 H, m), 4.60
(2H, m),
3.51 (2H, m), 2.91-2.84 (3H,
m),
2.71 (2H, dd), 2.64 (1 H,
m), 2.33
(3H, s), 2.24 (3H, s), 1.10
(3H, s),
1.07 (3H, s), 0.78 (9H, s),
-0.04 (3H,
s), -0.22 (3H, s) ppm; LRMS
APCI
m/z 605 [M+H]+
130 \ 'H NMR (400MHz, CD30D) b: 35%
7.87-
7.80 (2H, m), 7.38-7.30 (2H,
m),
\~ 7.27 (1 H, d), 7.06 (1 H,
dd), 7.02-
6.94 (3H, m), 6.72 (1 H,
d), 4.68 (1 H,
m), 4.60 (2H, m), 3.51 (2H,
m), 2.94
(2H, m), 2.84 (1 H, m), 2.71
(2H, dd),
2.61 (1 H, m), 2.29 (3H,
s), 2.27 (3H,
s), 1.10 (3H, s), 1.07 (3H,
s), 0.78
(9H, s), -0.04 (3H, s), -0.21
(3H, s)
ppm; LRMS APCI m/z 605 [M+H]+
131 ~1 'H NMR (400MHz, CDCI3) 8: 45%
7.44-
7.38 (2H, m), 7.33-7.20 (7H,
m),
7.06 (1 H, d), 6.88 (1 H,
s), 6.75 (1 H,
d), 6.13-6.09 (1 H, m), 4.82-4.60
(2H,
m), 4.58 (1 H, t), 3.51-3.44
(2H, m),
2.84-2.55 (6H, m), 2.00-1.90
(2H,
m), 1.04 (3H, s), 1.00 (3H,
s), 0.79
(9H, s), -0.05 (3H, s),
-0.21 (3H, s) ppm; LRMS APCI
m/z
592 [M+H]+
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132 N H NMR (400MHz, CDC13) 8: 7.4445%
\ ~ (1 H, d), 7.38 (1 H, m), 7.32-7.22
(7H,
m), 7.08 (1 H, d), 6.88 (1
H, s), 6.75
(1 H, d), 6.14 (1 H, m), 4.83-4.75
(2H,
m), 4.59 (1 H, t), 3.72-3.68
(2H, q),
2.92 (2H, t), 2.82-2.75 (1
H, m), 2.65-
2.56 (3H, m), 1.03 (3H, s),
1.00 (3H,
s), 0.79 (9H, s), -0.05 (3H,
s), -0.20
(3H, s) ppm; LRMS APCI m/z
592
[M+H]+
133 F F 'H NMR (400MHz, CDCI3) 8: 53%
7.51-
F 7.39 (6H, m), 7.27-7.23 (2H,
m),
N
7.10 (1 H, d), 6.89 (1 H,
s), 6.77-6.65
\ ~ 1 H d 6.16 1 H m 4. 84-4 .
76 2 H
( , ), ( , ), ( ,
m), 4.62-4.58 (1 H, t), 3.72-3.68
(2H,
m), 2.99 (2H, t), 2.83-2.76
(1 H, m),
2.66-2.58 (3H, m), 1.03 (3H,
s), 1.00
(3H, s), 0.79 (9H, s), -0.04
(3H, s), -
0.20 (3H, s) ppm;
LRMS APCI m/z 645 [M+H]+
134 N 'H NMR (400MHz, CDCI3) 8: 46%
7.45
\ ~ c~ (1 H, d), 7.39 (1 H, m), 7.29-7.23
(2H,
m), 7.20-7.06 (4H, m), 6.90
(1 H, s),
6.76 (1 H, d), 6.19 (1 H,
m), 4.83-4.76
(2H, m), 4.59 (1 H, t), 3.69-3.63
(2H,
m), 2.99 (2H, m), 2.84-2.76
(1H, m),
2.66-2.60 (3H, m), 1.04 (3H,
s), 1.01
(3H, s), 0.80 (9H, s), -0.04
(3H, s), -
0.19 (3H, s) ppm; LRMS APCI
m/z
629 [M+H]+
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135 Hsc 'H NMR (400MHz, CD30D) 8: 44%
7.73
(2H, m) 7.40-7.33 (2H, m),
7.26 (1 H,
d), 7.11 (1 H, bs), 7.07-7.04
(2H, dd),
cH3 6.96 (1 H, d), 6.71 (1 H,
d), 4.66 (2H,
dd), 4.63 (2H, dd), 4.54 (2H,
s), 2.83
(1 H, t), 2.72 (2H, dd), 2.61
(1 H, dd),
2.32 (3H, s), 2.26 (3H, s),
1.11 (3H,
s), 1.08 (3H, s), 0.78 (9H,
s), -0.06
(3H, s), -0.23 (3H, s) ppm;
LRMS
APCI m/z 591 [M+H]+
136 ~ - 'H NMR (400MHz, CD30D) ~: 2%
7.69-
0
7.58 (2H, m) 7.39-7.03 (5H,
m),
6.90-6.68 (4H, m), 4.75-4.57
(3H,
m), 3.62-3.49 (2H, m), 3.18-3.07
2H
m
2
91
2
53
10H
2
05
(
,
),
.
-
.
(
, m),
.
-
1.90 (4H, m), 1.87-1.73 (2H,
m),
1.11-1.06 (6H, m), 0.78 (9H,
s),
0.05 (3H, s), -0.22 (3H, s)
ppm;
LRMS APCI m/z 691 [M+H]+
137 ~ - 'H NMR (400MHz, CD30D) 8: 78%
7.65-
7.61 (2H, m), 7.34-7.30 (2H,
m),
7.26 (2H, m), 7.17-7.15 (2H,
m) 7.06
(1 H, m), 6.93 (1 H, m), 6.85
(1 H, m),
6.73 (1 H, m), 4.71-4.63 (3H,
m),
4.06-4.02 (2H, m), 3.61-3.57
(2H,
m), 2.96-2.58 (15H, m), 2.07-2.02
(2H, m), 1.84-1.79 (4H, m),
1.09-
1.06 (6H, m), 0.79 (9H, s),
-0.03
(3H, s), -0.21 (3H, s) ppm;
LRMS
APCI m/z 705 [M+HJ+
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138 r 'H NMR (400MHz, CD30D) b: 56%
7.63
0
(2H, m) 7.34-7.21 (3H, m),
7.17 (1 H,
m), 7.07 (1 H, m), 6.79-6.65
(4H, m),
4.67-4.57 (3H, m), 3.95-3.92
(2H,
m), 3.57-3.53 (2H, m), 2.86-2.53
(12H, m), 1.98-1.85 (2H, m),
1.82-
1.70 (4H, m), 1.04-1.01 (6H,
m),
0.78 (9H, s), -0.02 (3H, s),
-0.20
(3H, s) ppm
Preparation 115: 2-(2-phenylsulfanyl-phenyl)-ethylamine can be prepared as
described in Collection of Czechoslovak Chemical Communications, 54(7),
1995-2008; 1989
Preparation 116: appropriate fractions were concentrated in vacuo and the
residue was further purified by column chromatography on amino silica gel,
eluting with ethyl acetate:pentane, 100:0 to 80:20, followed by
dichloromethane:methanol, 100:0 to 80:20.
Preparation 139
Methyl 3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}
amino)-2-methylpropyl]benzoate
O
H
N
~O
isC CHs
HO / CH3
HO
A mixture of 3-{2-[(2R)-2-(Pert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-
hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}benzoic acid methyl ester
(preparation 36), (4.Og, 8.21 mmol) and ammonium fluoride (3.04g, 82.Ommol)
in methanol (20mL) and water (5mL) 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
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dichloromethane:methanol: 0.88 ammonia, 100:0:0 to 90:10:0.1, to afford the
title compound as a white foam in 81 % yield, 2.428.
'H NMR (400MHz, CD30D) 8: 7.87 (2H, m), 7.40 (2H, m), 7.29 (1 H, m), 7.09
(1 H, dd), 6.72 (1 H, d), 4.69-4.61 (3H, m), 3.90 (3H, s), 2.90-2.73 (4H, m),
1.08
(3H, s), 1.06 (3H, s) ppm; LRMS ESI m/z 374 [M+H]+
Preparation 140
3-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-
2-methylpropyl]benzoic acid
0
H
N
OOH
~3Cr CrH3
HO
2LiCl
H~
A mixture of 3-(2-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-
2-methyl-propyl}-benzoic acid methyl ester (preparation 139) (2.358, 6.32mmol)
and lithium hydroxide (303mg, 12.64mmol) in tetrahydrofuran (20mL) and water
(20mL) was stirred at room temperature for 3 days. The reaction mixture was
then concentrated in vacuo and the residue was diluted with water and
acidified
with 1 M hydrochloric acid (12mL). The mixture was stirred for 2 hours at room
temperature and was then concentrated in vacuo. The crude residue was used
in subsequent reactions without further purification.
'H NMR (400MHz, CD30D) 8: 7.87 (1 H, m), 7.84 (1 H, bs), 7.39-7.31 (3H, m),
7.19 (1 H, dd), 6.79 (1 H, d), 4.86 (1 H, m), 4.66 (2H, s), 3.22-3.11 (2H, m),
3.02
(2H, m), 1.32 (6H, s) ppm; LRMS ESI m/z 360 [M+H]+
Preparation 141
3-[3-(2-tert-Butoxycarbonylamino-2-methyl-propyl)-phenyl]-acrylic acid
benzyl ester
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O
H3C O N CH3
H3C~ ~ I \ ~ \O ~ \
CH3 O CH3 / /
A mixture of [2-(3-bromophenyl)-1,1-dimethylethyl]carbamic acid tent-butyl
ester
(preparation 32), (2g, 6.09mmol), benzyl acrylate (2g, 12.19), palladium (II)
acetate (204mg, 0.91 mmol), tri-p-tolyl phosphite (556mg, 1.83mmol) and
triethylamine (2.12mL, 15.22mmol) in acetonitrile (100mL) was heated under
reflux for 48 hours. The reaction mixture was then concentrated in vacuo and
the residue was purified by column chromatography on silica gel, eluting with
ethyl acetate:pentane to afford the title compound as a pale yellow oil in 90%
yield, 2.238
'H NMR (400MHz, CD30D) 8: 7.75 (1 H, d), 7.35 (7H, m), 7.20 (1 H, d), 6.58
(1 H, d), 6.00 (1 H, brs), 5.20 (2H, s), 3.00 (2H, s), 1.43 (9H, s), 1.22 (6H,
s)
ppm; LRMS ESI m/z 310 [M+H]+
Preparation 142
3-[3-(2-Amino-2-methyl-propyl)-phenyl]-acrylic acid benzyl ester
O
CH3
HZN \ \
CH3 / /
A mixture of 3-[3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-phenyl]-acrylic
acid benzyl ester (preparation 141 ), (2.23g, 5.45mmol), and trifluoroacetic
acid
(5mL) in dichloromethane (10mL) was stirred for 1 hour at room temperature.
The mixture was then concentrated in vacuo and the residue was diluted with
sodium hydrogen carbonate solution (10mL) and extracted with ethyl acetate
(3x20mL). The combined organic solution was dried over magnesium sulfate
and concentrated in vacuo to afford the title compound as a yellow oil in
quantitative yield.
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'H NMR (400MHz, CD30D) 8: 7.78 (1 H, d), 7.60 (1 H, d), 7.48 (1 H, s), 7.38
(7H,
m), 6.60 (1 H, brs), 5.23 (2H, s), 2.91 (2H, s), 1.30 (6H, s) ppm; LRMS ESI
m/z
408 [M-H]-
Preparation 143
Benzyl-3-(3-{2-[((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert-
butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methylpropyl}phenyl)acrylate
1S p
N CHs
\ \~ w0 ~ \
\ O CH3 / /
HO
A mixture of [2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-
butyl(dimethyl)silyl]oxy}ethyl) phenyl]methanol (Preparation 23) (800mg,
1.77mmol) and 3-[3-(2-amino-2-methyl-propyl)-phenyl]-acrylic acid benzyl ester
(preparation 142), (1.10g, 3.55mmol) was stirred at 90°C for 18 hours.
The
reaction mixture was then cooled to room temperature, diluted with diethyl
ether
(40mL) and stirred for 4 hours. The resulting precipitate was filtered off,
washing though with diethyl ether, and the filtrate was concentrated in vacuo
to
give a brown oil. Purification of the oil by column chromatography on silica
gel,
eluting with dichloromethane:methano1:0.88 ammonia afforded the title
compound in 25% yield, 300mg.
'H NMR (400MHz, CD30D) b: 7.78 (1 H, d), 7.38 (16H, m), 6.95 (1 H, m), 6.58
(1 H, d), 5.25 (2H, s), 5.04 (2H, s), 4.78 (1 H, m), 4.64 (2H, m), 2.80 (2H,
m),
2.68 (2H, m), 1.14 (3H, s), 1.10 (3H, s), 0.78 (9H, s), -0.03 (3H, s), -0.21
(3H, s)
ppm; LRMS ESI m/z 680 [M+H]+
Preparation 144
3-{3-[2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}propanoic
acid
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OTBDMS O
N CHs
~ OOH
HO CH3 /
HO
Ammonium formate (139mg, 2.20mmol) and palladium (II) hydroxide (50mg)
was added to a solution of 3-(3-{2-[2-(4-benzyloxy-3-hydroxymethyl-phenyl)-2-
(tent-butyl-dimethyl-silanyloxy)-ethylamino]-2-methyl-propyl}-phenyl)-acrylic
acid
benzyl ester (preparation 143), (300mg, 0.44mmol) in ethanol (10mL) and the
mixture was heated under reflux for 30 minutes. The reaction mixture was then
cooled, filtered through Arbocel° and concentrated in vacuo to afford
the title
compound in 90% yield, 200mg.
'H NMR (400MHz, CD30D) b: 7.30 (1 H, s), 7.20 (1 H, m), 7.18 (1 H, d), 7.09
(2H,
m), 7.00 (1 H, d), 6.78 (1 H, d), 4.88 (1 H, m), 4.63 (2H, m), 3.11 (2H, m),
2.83
(4H, m), 2.48 (2H, m), 1.23 (6H, s), 0.81 (9H, s), -0.03 (3H, s), -0.18 (3H,
s)
ppm; LRMS ESI m/z 502 [M+H]+
Preparation 145
3-{3-[2-({(2R)-2-{[tent-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-
(hydroxymethyl) phenyl]ethyl}amino)-2-methylpropyl]phenyl}-N-(3,4-
dichlorobenzyl) propanamide
OTBDMS O
H
N ~ CI
v ~ ~N
H3C CH3 ~ / H
Ho Y cl
Ho
The title compound was prepared from 3-{3-[2-({(2R)-2-{[tert-
butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl)amino)-2-
methylpropyl]phenyl)propanoic acid (preparation 144) and 3,4-
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dichlorobenzylamine, using a method similar to that of preparation 38, as a
clear oil in 64% yield.
'H NMR (400MHz, CD30D) 8: 7.40 (3H, m), 7.18 (1H, m), 7.08 (5H, m), 6.78
(1 H, d), 4.61 (3H, m), 4.23 (2H, s), 2.90 (3H, m), 2.60 (5H, m), 1.08 (3H,
s),
1.04 (3H, s), 0.81 (9H, s), 0.00 (3H, s), -0.18 (3H, s) ppm; LRMS ESI m/z 659
[M+H]+
Preparation 146
[3-(2-Amino-2-methyl-propyl)-phenyl]-acetic acid methyl ester
O
HaC CHs
H3C~ /
~ NHz
Acetyl chloride (154.58, 1.97mo1) was added to a solution of {3-[2-(2-chloro-
acetylamino)-2-methyl-propyl]-phenyl}-acetic acid (preparation 48), (208,
0.66mo1) in methanol (350mL) and the mixture was heated under reflux for 18
hours. The reaction mixture was then concentrated in vacuo to afford the title
compound as a brown oil in 87% yield, 154.58.
'H NMR (300MHz, CDC13) 8: 7.22 (1H, m), 7.18-7.05 (3H, m), 3.71 (3H, s), 3.58
(2H, s), 2.62 (2H, s), 1.12 (6H, s) ppm; GCMS m/z 206 [M-H]-
Preparation 147
Methyl (3-{2-[((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert-
butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methylpropyl}phenyl)acetate
is
H
N \ O~
CH3
3C CH3 / 0
\ ~O
/
HO
A mixture of [2-(benzyloxy)-5-((1 R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]
oxy}ethyl) phenyl]methanol (preparation 23), (3.48, 7.5mmol), [3-(2-amino-2-
methylpropyl)phenyl]acetic acid (preparation 146), (1.78, 7.5mmol) and N,N-
diisopropylethylamine (1.4mL, 8mmol) in dimethylsulfoxide (7.5mL) was stirred
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at 90°C for 28 hours. The reaction mixture was then cooled, diluted
with ethyl
acetate and washed with water. The organic solution was then dried over
magnesium sulfate, concentrated in vacuo and the residue was purified by
column chromatography on silica gel, eluting with ethyl acetate:pentane,
66:33,
to afford the title compound as a colourless oil in 50% yield, 2.2g.
~H NMR (400MHz, CDC13) 8: 7.44-7.31 (6H, m), 7.30-7.19 (3H, m), 7.13-7.05
(2H, m), 6.80 (1 H, d), 4.75-4.66 (3H, m), 3.68 (3H, s), 3.59 (2H, s), 2.90-
2.72
(4H, m), 1.22-1.09 (6H, m), 0.70 (9H, s), -0.06 (3H, s), -0.28 (3H, s) ppm
Preparation 148
(3-{2-[((2R)-2-[4-(Benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert-
butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methylpropyl}phenyl)acetic acid
DMS
OH
H3C \CH3 ~ /
~O
HO
Lithium hydroxide solution (1 M in water, 16.2mL, 16.2mmol) was added to a
solution of methyl (3-{2-[((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-
{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methylpropyl}phenyl)acetate
(preparation 147), (4.80g, 8.1 mmol) in tetrahydrofuran (49mL) and methanol
(17mL) 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 water and acidified to pH 7 with 1 M hydrochloric acid. The resulting
precipitate was filtered off and washed with water to afford the title
compound
as a pale yellow solid in 94% yield, 4.37g
'H NMR (400MHz, DMSO-ds) 8: 7.45-7.38 (6H, m), 7.31 (2H, m), 7.13 (1H, m)
7.02 (3H, m), 5.04 (3H, m), 4.52 (2H, d), 3.52 (2H, d), 2.43 (2H, d), 3.37
(2H,
d), 1.24 (6H, m), 0.78 (9H, s), 0.02 (3H, s), -0.92 (3H, s) ppm; LRMS ESI m/z
659 [M+H]+
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Preparation 149
2-(3-{2-[((2R)-2-[4-(Benzyloxy)-3-(hydroxymethyl)phenylj-2-~[tert-
butyl(dimethyl)silyljoxy}ethyl)amino]-2-methylpropyl}phenyl)-N-
(cycloheptylmethyl)acetamide
OTBDMS
H H
N ~ N
3C CH3
O
Ho
The title compound was prepared from (3-{2-[((2R)-2-[4-(benzyloxy)-3-
(hydroxymethyl)phenyl]-2-{[Pert-butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methyl
propyl}phenyl)acetic acid (preparation 148) and cycloheptane methylamine,
using a similar method to that of preparation 38, as a white solid in 97%
yield.
'H NMR (400MHz, CD30D) 8: 7.72 (1 H, dd), 7.44 (1 H, d), 7.42 (2H, m), 7.38-
7.21 (5H, m), 7.19 (1 H, d), 7.07 (1 H, d), 7.02 (1 H, m), 5.08 (2H, d), 5.03
(1 H,
m), 4.71 (2H, d), 3.51 (2H, d), 3.03-2.96 (4H, m), 1.77-1.34 (13H, m), 1.28
(6H,
m), 1.07 (2H, m), 0.93 (9H, s), 0.07 (3H, s), -0.92 (3H, s) ppm; LRMS ESI m/z
688 [M+H]+
Preparation 150
N-1-Adamantyl-2-(3-~2-[((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenylj-2-
{[tert-butyl(dimethyl)silyljoxy}ethyl)amino]-2-
methylpropyl}phenyl)acetamide
9S
H H
N ~ N
.~3C CH3
O
HU
The title compound was prepared from (3-{2-[((2R)-2-[4-(benzyloxy)-3-
(hydroxymethyl)phenyl]-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methyl
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propyl}phenyl)acetic acid (preparation 148) and 1-adamantylamine, using a
similar method to that of preparation 38, as a yellow oil in 71 % yield.
'H NMR (400MHz, DMSO-ds) 8: 7.52 (3H, m), 7.52-7.24 (4H, m), 7.18-7.08 (2H,
m), 7.07-6.98 (2H, m), 6.94 (1 H, m), 5.09 (2H, d), 5.01 (1 H, t), 4.66-4.61
(1 H,
m), 4.54 (2H, d), 3.25 (2H, d), 3.15 (1 H, d), 2.59-2.43 (2H, m), 1.98-1.92
(3H,
m), 1.87 (6H, m), 1.57 (6H, m), 0.96 (6H, dd), 0.79 (9H, d), -0.98 (3H, s), -
0.93
(3H, s) ppm; LRMS ESI m/z 712 [M+H]+
Preparation 151
2-{3-[2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}-N-
(cycloheptylmethyl)acetamide
OTBDMS
H H
N ~ N
/ H3C CH3
HO
HO
The title compound was prepared from 2-(3-{2-[((2R)-2-[4-(benzyloxy)-3-
(hydroxymethyl)phenyl]-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methyl
propyl}phenyl)-N-(cycloheptylmethyl)acetamide (preparation 149), using a
similar method to that of preparation 144, as a yellow oil in 96% yield.
'H NMR (400MHz, CD30D) 8: 7.67 (1 H, m), 7.18-7.04 (5H, m), 6.79 (1 H, d),
4.92-4.84 (1 H, m), 4.67 (2H, m), 3.51 (2H, d), 3.21-3.03 (2H, m), 3.02 (2H,
m),
2.96 (2H, m), 1.86-1.38 (11 H, m), 1.24 (6H, m), 1.21-1.11 (2H, m), 0.82 (9H,
s),
0.06 (3H, s), -0.93 (3H, s) ppm; LRMS ESI m/z 597 [M+H]'
Preparation 152
N-1-Adamantyl-2-{3-[2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-
3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide
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H
N
\CH3
HO
HO
The title compound was prepared from N-1-adamantyl-2-(3-{2-[((2R)-2-[4-
(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert-butyl(dimethyl)silyl] oxy}ethyl)
amino]-2-methylpropyl}phenyl)acetamide (preparation 150), using a similar
method to that of preparation 144, as a white solid in 73% yield.
'H NMR (400MHz, DMSO-ds) b: 7.42 (1 H, m), 7.12 (1 H, d), 7.09-7.05 (1 H, m),
7.03-6.95 (4H, m), 6.64 (1 H, d), 4.95 (1 H, brs), 4.60 (1 H, m), 4.42 (2H,
d), 3.24
(2H, d), 2.75 (1 H, d), 2.57 (2H, d), 1.97 (3H, m), 1.93 (6H, m), 1.57 (6H,
m),
0.92 (6H, dd), 0.78 (9H, d), -0.03 (3H, s), -0.18 (3H, s) ppm; LRMS ESI m/z
621
[M+H]+
Preparation 153
Methyl {3-[2-({(2R)-2-{[tent-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetate
OTBDMS
H
N ~ O~
CH3
3C CH3 / 0
HO
H°
The title compound was prepared from methyl (3-{2-[((2R)-2-[4-(benzyloxy)-3-
(hydroxymethyl)phenyl]-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-2-
methylpropyl}phenyl)acetate (preparation 147), using a similar method to
preparation 21 as a brown oil in 80% yield.
'H NMR (400MHz, CDCI3) 8: 7.30-7.20 (2H, m), 7.19-7.00 (4H, m), 6.80 (1 H, d),
4.75-4.66 (3H, m), 5.10 (2H, s), 3.68 (3H, s), 3.59 (2H, s), 2.85-2.62 (4H,
m),
1.10-1.01 (6H, m), 0.80 (9H, s), -0.02 (3H, s), -0.20 (3H, s) ppm
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Preparation 154
{3-[2-({(2R)-2-{[tent-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetic acid
fs
H
N ~ OH
3C \CH3
O
HO
HO
A mixture of methyl {3-[2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-
hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetate (preparation
153), (5g, 10mmol) and lithium hydroxide (1 M in water, 30mL, 30mmol) in
tetrahydrofuran (50mL) was stirred for 48 hours at room temperature. The
reaction mixture was then acidified with 1 M hydrochloric acid (30mL),
concentrated in vacuo, and the residue was triturated with water and
azeotroped (x3) with methanol to afford the title compound as a white solid in
84% yield, 4.1 g
'H NMR (400MHz, CD30D) b: 7.39-7.31 (2H, m), 7.28 (1H, m), 7.20-7.10 (3H,
m), 6.81 (1 H, d), 4.92-4.83 (1 H, m), 4.65 (2H, m), 3.61 (2H, s), 3.34-3.24
(2H,
m), 3.00 (2H, m), 1.33 (6H, s), 0.82 (9H, s), 0.06 (3H, s), -0.12 (3H, s) ppm
Preparation 155
2-{3-[2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}-N-
(3-pyrrolidin-1-ylpropyl)acetamide
OTBDMS
U
N ~ N ~~/ N
H3 ~ CH3
HO / ~ O
HO
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The title compound was prepared from {3-[2-({(2R)-2-{[tert-
butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyljethyl}amino)-2-
methylpropyl]phenyl)acetic acid (preparation 154) and 1-
pyrrolidinepropanamine, using a similar method to that of preparation 38, in
16% yield.
'H NMR (400MHz, CDC13) s: 7.20 (1 H, m), 7.08-6.96 (3H, m), 6.85 (1 H, m),
6.70 (1 H, m), 6.58 (1 H, m), 4.75 (2H, s), 4.64 (1 H, m), 3.42 (2H, m), 3.24
(2H,
m), 2.80 (1 H, m), 2.62 (3H, m), 2.43 (6H, m), 1.68 (4H, m), 1.60 (2H, m),
1.00
(6H, s), 0.81 (9H, s), -0.05 (3H, s), -0.19 (3H, s) ppm
Preparation 156
N-Benzyl-2-~3-[2-({(2R)-2-{[tent-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}-N-
methylacetamide
OTBDMS CH3
\ N \ N
/ H3C \CH3 I /
HO Y
H
The title compound was prepared from {3-[2-({(2R)-2-{[tert-
butyl(dimethyl)silyljoxy)-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-
methylpropyljphenyl}acetic acid (preparation 154) and N-benzylmethylamine,
using a similar method to that of preparation 38 in 55% yield.
'H NMR (400MHz, CD30D) 8: 7.55-7.01 (11 H, m), 6.73 (1 H, m), 4.63 (5H, m),
2.85 (2H, m), 2.80 (2H, m), 2.72 (1 H, m), 2.68 (3H, m), 1.87 (1 H, m), 1.03
(6H,
m), 0.80 (9H, s), -0.00 (3H, s), -0.19 (3H, s) ppm
Preparation 157
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3-[2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxyl
methyl)phenyl]ethyl}amino)-2-methylpropyl]-N-[2-(3-fluorophenyl)ethyl]
benzamide
OTBDMS O
H
N
_H F
H3C CH3
HO Y
HO
A mixture of 3-f2-[(2R)-2-(tent-butyldimethylsilanyloxy)-2-(4-hydroxy-3-
hydroxy
methyl-phenyl)ethylamino]-2-methylpropyl}benzoic acid (preparation 37)
(473mg, 1 mmol) and O-(1 H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (379mg, 1 mmol) was added to a solution of 3-
fluorophenethylamine (139mg, 1 mmol) in N,N-dimethylacetamide (6mL) and
the mixture was stirred for 18 hours at room temperature. The solvent was
removed in vacuo and the residue was re-dissolved in dichloromethane
(100mL) and washed with saturated sodium hydrogen carbonate solution
(3x20mL) and brine (10mL). The organic solution was then dried over sodium
sulfate, concentrated in vacuo and the residue was purified by column
chromatography on silica gel, eluting with dichloromethane:methano1:0.88
ammonia, 100:0:0 to 90:10:1. The appropriate fractions were then concentrated
in vacuo and the residue was re-dissolved in ethyl acetate, washed with
saturated sodium hydrogen carbonate solution, dried over sodium sulfate and
concentrated in vacuo to afford the title compound in 52% yield, 343mg.
'H NMR (400MHz, CD30D) 8: 7.65-7.62 (2H, m), 7.38-7.23 (4H, m), 7.09-6.99
(3H, m), 6.92 (1 H, d), 6.74 (1 H, d), 4.70 (1 H, m), 4.65 (2H, m), 3.61 (2H,
m),
2.96-2.60 (6H, m), 1.10 (3H, s), 1.07 (3H, s), 0.79 (9H, s), -0.03 (3H, s), -
0.21
(3H, s) ppm; LRMS ESI m/z 595 [M+H]+
Preparation 158
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3-(2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]-N-[2-(5-chloro-2-
methoxyphenyl)ethyl]benzamide
~s o
H
N
-N
C H
O
HO 3 CH3 / H3C~
NU
A mixture of 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-
hydroxy
methyl-phenyl)ethylamino]-2-methylpropyl}benzoic acid (preparation 37)
(400mg, 0.85mmol), O-(1 H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (320mg, 0.85mmol), triethylamine (225,uL, 1.6mmol) and
2-(5-chloro-2-methoxy-phenyl)-ethylamine (preparation 70), (64mg, 0.85mmol)
in N,N-dimethylacetamide (8mL) was stirred for 18 hours at room temperature.
The solvent was removed in vacuo and the residue was partitioned between
dichloromethane (4mL) and saturated sodium hydrogen carbonate solution
(1 mL). The organic solution was then dried over magnesium sulfate,
concentrated in vacuo and the residue was purified using an ISCO
Companion°
silica cartridge, eluting with dichloromethane:methano1:0.88 ammonia, 90:10:1
to 80:20:2, to afford the title compound in 22% yield.
'H NMR (400MHz, CD30D) ~: 7.70-7.60 (2H, m), 7.50-7.38 (3H, m), 7.20-7.10
(3H, m), 6.95 (1 H, d), 6.85 (1 H, d), 4.95 (1 H, s), 4.75-4.60 (2H, m), 3.81
(3H, s),
3.57 (2H, m), 3.10-2.90 (6H, m), 1.25 (6H, s), 0.82 (9H, s), -0.03 (3H, s), -
0.16
(3H, s) ppm
Preparation 159
3-[2-({(2R)-2-{[tent-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]-N-[2-(3-
ethoxyphenyl)ethyl]benzamide
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CH3 CH3
H3C\ I /CH3
H C ~ CH OJ
w
O
\ N \
CHs ~ H
HO
NU
The title compound was prepared from 3-f2-[(2R)-2-(tent-butyldimethyl
silanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}
benzoic acid (preparation 37) and 3-ethoxyphenethylamine, using a similar
method to that of preparation 158, in 67% yield.
LRMS APCI m/z 621 [M+H]+
Preparation 160
3-[2-({(2R)-2-{[tent-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]-N-[2-(3-
methoxyphenyl)ethyl]benzamide
O~CH3
OTBDMS O
H
N \ N \
H
3C CH3 /
HO
11U
The title compound was prepared from 3-{2-[(2R)-2-(tert-
butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxy methyl-phenyl)ethylamino]-2-
methylpropyl}benzoic acid (preparation 37) and 3-methoxyphenethylamine,
using a similar method to that of preparation 158, in 98% yield.
LRMS ESI m/z 607 [M+H]+
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Preparation 161
[3-((2R)-2-~[(1 R)-1-Phenylethyl]amino}propyl)phenyl]acetic acid
H
\ ~ - N \ OH
CH3 CH3 ~ / 101
Lithium hydroxide solution (1 M in water, 90mL, 90mmol) was added to a
solution of methyl [3-((2R)-2-f[(1R)-1-phenyl-ethyl]-amino}-propyl)-phenyl]-
acetate hydrochloride (preparation 26), (13.5g, 43.5mmol) in methanol (200mL)
and the mixture was stirred at room temperature for 18 hours. 1 M Hydrochloric
acid (90mL) was then added to the reaction mixture and the methanol removed
in vacuo. The resulting precipitate was filtered off and washed with water
(20mL) and a mixture of ethanol/diethyl ether, 20:80, to afford the title
compound as a solid in 91 % yield, 11.8g
'H NMR (400MHz, CD30D) b: 7.52-7.45 (5H, m), 7.22-7.18 (2H, m), 7.19 (1H,
s), 6.92 (1 H, d), 4.56-4.48 (1 H, q), 3.46 (2H, s), 3.26-3.13 (2H, m), 2.66-
2.62
(1 H, m), 1.62 (3H, d), 1.16 (3H, d) ppm; LRMS ESI m/z 298 [M+H]+
Preparation 162
N-1-Adamantyl-2-[3-((2R)-2-{[(1 R)-1-
phenylethyl]amino}propyl)phenyl]acetamide
/
\ N \ N
CH3 CH3 ~ / 101
1-Adamantylamine (5.448, 36mmo1) and triethylamine (15mL, 108mmol) were
added to a solution of [3-((2R)-2-{[(1R)-1-phenylethyl]amino}propyl)phenyl]
acetic acid (preparation 161 ), (10.7g, 36mmol) in dichloromethane (200mL). 2-
Chloro-1,3-dimethylimidazolidinum hexafluorophosphate (10g, 36mmol) 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
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magnesium sulfate and concentrated in vacuo. Purification of the residue by
column chromatography on silica gel, eluting with
dichloromethane:methano1:0.88 ammonia, 95:5:0.5, afforded the product as a
foam in quantitative yield, 17.6g.
'H NMR (400MHz, CD30D) 8: 7.38-7.30 (4H, m), 7.27-7.22 (1 H, m), 7.17 (1 H,
t), 7.09 (1 H, d), 6.98 (1 H, s), 6.89 (1 H, d), 3.98 (1 H, q), 3.36 (2H, s),
3.00-2.95
(1 H, dd), 2.74-2.65 (1 H, m), 2.42-2.37 (1 H, dd), 2.04 (3H, m), 1.98 (6H,
m),
1.75-1.65 (6H, m), 1.35 (d, 3H), 0.89 (d, 3H) ppm; LRMS ESI m/z 431 [M+H]+
Preparation 163
N-1-Adamantyl-2-{3-[(2R)-2-aminopropyl]phenyl}acetamide
HZN ~ N
CH3 ~ O
The title compound was prepared from N-1-adamantyl-2-[3-((2R)-2-{[(1R)-1-
phenylethyl]amino)propyl)phenyl]acetamide (preparation 162), using a similar
method to that of preparation 25, as a solid in 92% yield.
'H NMR (400MHz, CD30D) s: 7.28-7.05 (4H, m), 3.40 (2H, s), 3.16-3.10 (1H,
q), 2.70-2.58 (2H, m), 2.03 (3H, m), 2.00 (6H, m), 1.72-1.66 (6H, m), 1.09 (d,
3H) ppm; LRMS ESI m/z 327 [M+H]+
Preparation 164
N-1-Adamantyl-2-{3-[(2R)-2-({(2R)-2-[4-(benzyloxy)-3-
(hydroxymethyl)phenyl]-2-hydroxyethyl}amino)propyl]phenyl}acetamide
is
H H
N ~ N
CH3
-O
HO
A mixture of [2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)
silyl]oxy}ethyl) phenyl]methanol (preparation 23), (900mg, 2mmol) and N-1-
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adamantyl-2-{3-[(2R)-2-aminopropyl)phenyl}acetamide (preparation 163), (1.3g,
4mmol) were heated at 90°C for 24 hours. The reaction mixture was then
cooled to room temperature and the crude product was purified by column
chromatography on silica gel, eluting with dichloromethane:methano1:0.88
ammonia, 95:5:0.5, to afford the title compound as a pale foam in 83% yield,
1.16g.
'H NMR (400MHz, CD30D) 8: 7.48-7.28 (6H, m), 7.17-6.72 (6H, m), 5.14 (2H,
s), 4.78-4.74 (1 H, m), 4.73-4.64 (m, 2H), 3.36 (2H, s), 2.95-2.84 (2H, m),
2.70-
2.63 (2H, m), 2.59-2.50 (1 H, m), 2.03 (3H, m), 2.00 (6H, m), 1.70-1.64 (6H,
m),
1.05 (3H, d), 0.84 (9H, s), 0.00 (3H, s), -0.18 (3H, s) ppm
Abbreviations
TBDMS = tert-butyl(dimethyl)silyl
In vitro activity of the compounds of formula (1 )
The ability of the compounds of the formula (1 ) to act as potent [i2
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-pigs trachea
Male, Dunkin-Hartley guinea pigs (475-525g) are killed by C02 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 ~M Guanethidine (Sigma 68520) and 10 ~.M Atenolol (Sigma
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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
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 effica~
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 EC5o value for beta-2 agonist
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according to the present invention refers to the concentration of compound
required to produce half maximal effect. Data for beta-2 agonists according to
the present invention are then expressed as relative potency to isoprenaline
defined by the ratio (ECSO 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 (i2 antagonist) which results
in
the case of a beta-2 mediated effect in a rightward-shift of the test compound
dose response curve.
According to another alternative, the agonist potency for the (i2 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 (EC5o) for the (i2 receptor.
Compound Preparation
10 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, I-5627) was
used as a standard in every experiment and for control wells on each plate.
Data was expressed as % Isoprenaline response.
Cell Culture
CHO (Chinese Hamster Ovary) cells recombinantly expressing the human a2
adrenergic receptor (from Kobilka et al., PNAS 84: 46-50, 1987 and Bouvier et
al., Mol Pharmacol 33: 133-139 1988 CHOh(i2) 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, 67513),
500 Ng/ml geneticin (Sigma, 67034) and 10 pg/ml puromycin (Sigma, P8833).
Cells were seeded to give about 90 % confluency for testing.
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Assa~r Method
25 NI / 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 NI / 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 NI / well cells for 1 hour. Cells
were then lysed by the addition of 100 NI / well detection buffer (NEN,
SMP004B) containing 0.18 pCi / ml'Z51-cAMP (NEN, NEX-130) and plates were
incubated at room temperature for a further 2 hours. The amount of '251-cAMP
- bound to the Flashplate~ was quantified using a Topcount NXT (Packard),
normal counting efficiency for 1 minute. Dose-response data was expressed as
Isoprenaline activity and fitted using a four parameter sigmoid fit.
It has thus been found that the compounds of formula (1 ) according to the
present invention that have been tested show a (32 cAMP ECSO below lOnM.
The following table illustrate the activity of the compounds of the invention:
Example ECSO (nM)
1 0.143
14 0.0640
16 0.874
23 0.0800
24 0.150
46 0.838
62 0.444
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63 0.0750
66 1.16
88 0.434
102 0.100
114 0.134
