U.S. patent application number 13/560339 was filed with the patent office on 2013-01-24 for novel piperidine derivatives.
This patent application is currently assigned to ASTRAZENECA AB. The applicant listed for this patent is Talbir Austin, David O'Sullivan, Matthew Perry, Brian Springthorpe. Invention is credited to Talbir Austin, David O'Sullivan, Matthew Perry, Brian Springthorpe.
Application Number | 20130023562 13/560339 |
Document ID | / |
Family ID | 37669086 |
Filed Date | 2013-01-24 |
United States Patent
Application |
20130023562 |
Kind Code |
A1 |
Austin; Talbir ; et
al. |
January 24, 2013 |
NOVEL PIPERIDINE DERIVATIVES
Abstract
The present invention provides a compound of a formula (I):
##STR00001## wherein the variables are defined herein; to a process
for preparing such a compound; and to the use of such a compound in
the treatment of a chemokine (such as CCR3) mediated disease
state.
Inventors: |
Austin; Talbir;
(Macclesfield, GB) ; O'Sullivan; David;
(Macclesfield, GB) ; Perry; Matthew;
(Macclesfield, GB) ; Springthorpe; Brian;
(Macclesfield, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Austin; Talbir
O'Sullivan; David
Perry; Matthew
Springthorpe; Brian |
Macclesfield
Macclesfield
Macclesfield
Macclesfield |
|
GB
GB
GB
GB |
|
|
Assignee: |
ASTRAZENECA AB
Sodertalje
SE
|
Family ID: |
37669086 |
Appl. No.: |
13/560339 |
Filed: |
July 27, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11996133 |
Jan 18, 2008 |
8314127 |
|
|
PCT/SE2006/000893 |
Jul 19, 2006 |
|
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13560339 |
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Current U.S.
Class: |
514/316 ;
546/188 |
Current CPC
Class: |
A61P 27/16 20180101;
A61P 9/00 20180101; A61P 9/10 20180101; A61P 11/00 20180101; A61P
11/08 20180101; A61P 17/10 20180101; A61P 37/06 20180101; A61P
37/08 20180101; A61P 19/02 20180101; A61P 25/28 20180101; C07D
211/46 20130101; A61P 17/14 20180101; A61P 35/00 20180101; A61P
19/06 20180101; A61P 31/00 20180101; A61P 19/00 20180101; A61P
13/02 20180101; A61P 1/00 20180101; A61P 37/00 20180101; A61P 31/12
20180101; A61P 13/12 20180101; A61P 17/00 20180101; A61P 15/10
20180101; A61P 17/06 20180101; A61P 7/02 20180101; A61P 1/16
20180101; A61P 19/08 20180101; A61P 13/10 20180101; A61P 27/02
20180101; A61P 1/04 20180101; A61P 11/06 20180101; C07C 309/73
20130101; A61P 15/00 20180101; A61P 31/18 20180101; A61P 31/04
20180101; A61P 29/00 20180101; A61P 19/10 20180101 |
Class at
Publication: |
514/316 ;
546/188 |
International
Class: |
C07D 211/46 20060101
C07D211/46; A61P 11/00 20060101 A61P011/00; A61P 11/06 20060101
A61P011/06; A61P 19/02 20060101 A61P019/02; A61P 25/28 20060101
A61P025/28; A61P 17/06 20060101 A61P017/06; A61P 17/00 20060101
A61P017/00; A61P 27/02 20060101 A61P027/02; A61P 1/04 20060101
A61P001/04; A61K 31/4545 20060101 A61K031/4545; A61P 19/10 20060101
A61P019/10 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 21, 2005 |
SE |
0501719-9 |
Apr 13, 2006 |
SE |
0600838-7 |
Claims
1. The compound
(S)-{4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperidin-
-1-yl}-3-(4-fluoro-phenyl)-propionic acid, or a pharmaceutically
acceptable salt thereof.
2. A pharmaceutically acceptable salt of
(S)-{4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperidin-
-1-yl}-3-(4-fluoro-phenyl)-propionic acid which is a sodium,
potassium or (CH.sub.2CH.sub.2OH).sub.3NH.sup.+ salt, or a
hydrochloride, dihydrochloride, hydrobromide, phosphate, sulfate,
acetate, fumarate, maleate, malonate, succinate, tartrate, citrate,
oxalate, methanesulfonate, benzenesulfonate or p-toluenesulfonic
acid salt.
3. The compound
(S)-{4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperidin-
-1-yl}-3-(4-fluoro-phenyl)-propionic acid.
4. A polymorph of
(S)-{4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperidin-
-1-yl}-3-(4-fluoro-phenyl)-propionic acid (Form I) having an X-ray
powder diffraction pattern containing specific peaks at: 2.2
(.+-.0.1.degree.), 2.7 (.+-.0.1.degree.), 7.1 (.+-.0.1.degree.),
10.7 (.+-.0.1.degree.), 13.3 (.+-.0.1.degree.) and 18.8
(.+-.0.1.degree.) 2.theta..
5. A polymorph of
(S)-{4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperidin-
-1-yl}-3-(4-fluoro-phenyl)-propionic acid (Form II) having an X-ray
powder diffraction pattern containing specific peaks at: 2.2
(.+-.0.1.degree.), 2.67 (.+-.0.1.degree.), 7.2 (.+-.0.1.degree.),
13.2 (.+-.0.1.degree.), 17.0 (.+-.0.1.degree.), 17.4
(.+-.0.1.degree.), 19.1 (.+-.0.1.degree.), 19.4 (.+-.0.1.degree.),
21.1 (.+-.0.1.degree.), 24.4 (.+-.0.1.degree.) and 25.2
(.+-.0.1.degree.) 2.theta..
6. A pharmaceutical composition which comprises a compound of
formula (I), or a pharmaceutically acceptable salt thereof, as
claimed in claim 1, or a salt as claimed in claim 2, and a
pharmaceutically acceptable adjuvant, diluent or carrier.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 11/996,133, which is a national phase application under 35
U.S.C. .sctn.371 of PCT International Application No.
PCT/SE2006/000893, filed Jul. 19, 2006, which claims the benefit of
Swedish Application Serial No. 0501719-9, filed Jul. 21, 2005, and
Swedish Application Serial No. 0600838-7, filed Apr. 13, 2006. Each
of these prior applications is incorporated herein by reference in
their entirety.
[0002] The present invention concerns piperidine derivatives having
pharmaceutical activity, to processes for preparing such
derivatives, to pharmaceutical compositions comprising such
derivatives and to the use of such derivatives as active
therapeutic agents.
[0003] Pharmaceutically active piperidine derivatives are disclosed
in WO 2004/087659.
(2S)-2-[4-[[4-(3,4-Dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piper-
idyl]-3-phenylpropanoic acid and its dihydrochloride salt are
disclosed in WO 2004/087659 (see examples 40 and 73). Compounds of
present invention have higher potency at CCR3 than comparable
compounds in WO 2004/087659 [which translates to a lower dose
meaning less serious side-effects, for example at the IKr channel
(for example using the assay described in WO 2005/037052, or the
electrophysiology method described in the paper: `Optimisation and
validation of a medium-throughput electrophysiology-based hERG
assay using IonWorks.TM. HT` by M. H. Bridgland-Taylor, C. E.
Pollard et al in Journal of Pharmacological and Toxicological
Methods (2006; available on the internet Elsevier publications
www.sciencedirect.com, and in press))]. The higher potency of the
compounds of the invention also translates to increased selectivity
over the histamine type 1 (H1) receptor.
[0004] Histamine is a basic amine, 2-(4-imidazolyl)-ethylamine, and
is formed from histidine by histidine decarboxylase. It is found in
most tissues of the body, but is present in high concentrations in
the lung, skin and in the gastrointestinal tract. At the cellular
level inflammatory cells such as mast cells and basophils store
large amounts of histamine. It is recognised that the degranulation
of mast cells and basophils and the subsequent release of histamine
is a fundamental mechanism responsible for the clinical
manifestation of an allergic process. Histamine produces its
actions by an effect on specific histamine G-protein coupled
receptors, which are of three main types, H1, H2 and H3. Histamine
H1 antagonists comprise the largest class of medications used in
the treatment of patients with allergic disorders, for example
rhinitis or urticaria. H1 antagonists are useful in controlling the
allergic response by for example blocking the action of histamine
on post-capillary venule smooth muscle, resulting in decreased
vascular permeability, exudation and oedema. The antagonists also
produce blockade of the actions of histamine on the H1 receptors on
c-type nociceptive nerve fibres, resulting in decreased itching and
sneezing.
[0005] Chemokines are chemotactic cytokines that are released by a
wide variety of cells to attract macrophages, T cells, eosinophils,
basophils and neutrophils to sites of inflammation and also play a
role in the maturation of cells of the immune system. Chemokines
play an important role in immune and inflammatory responses in
various diseases and disorders, including asthma and allergic
diseases, as well as autoimmune pathologies such as rheumatoid
arthritis and atherosclerosis. These small secreted molecules are a
growing superfamily of 8-14 kDa proteins characterised by a
conserved four cysteine motif. The chemokine superfamily can be
divided into two main groups exhibiting characteristic structural
motifs, the Cys-X-Cys (C-X-C, or .alpha.) and Cys-Cys (C-C, or
.beta.) families. These are distinguished on the basis of a single
amino acid insertion between the NH-proximal pair of cysteine
residues and sequence similarity.
[0006] The C-X-C chemokines include several potent chemoattractants
and activators of neutrophils such as interleukin-8 (IL-8) and
neutrophil-activating peptide 2 (NAP-2).
[0007] The C-C chemokines include potent chemoattractants of
monocytes and lymphocytes but not neutrophils such as human
monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES
(Regulated on Activation, Normal T Expressed and Secreted),
eotaxin, eotaxin-2, eotaxin-3 and the macrophage inflammatory
proteins 1.alpha. and 1.beta. (MIP-1.alpha. and MIP-1.beta..
[0008] Studies have demonstrated that the actions of the chemokines
are mediated by subfamilies of G protein-coupled receptors, among
which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3,
CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and
CXCR4. These receptors represent good targets for drug development
since agents which modulate these receptors would be useful in the
treatment of disorders and diseases such as those mentioned
above.
[0009] Viral infections are known to cause lung inflammation. It
has been shown experimentally that the common cold increases
mucosal output of eotaxin in the airways. Instillation of eotaxin
into the nose can mimic some of the signs and symptoms of a common
cold. (See, Greiff L et at Allergy (1999) 54(11) 1204-8
[Experimental common cold increase mucosal output of eotaxin in
atopic individuals] and Kawaguchi M et at Int. Arch. Allergy
Immunol. (2000) 122 S1 44 [Expression of eotaxin by normal airway
epithelial cells after virus A infection].)
[0010] The present invention provides a compound of formula
(I):
##STR00002##
to wherein: R.sup.1 is phenyl optionally substituted by halogen,
cyano, C.sub.1-4 alkyl or C.sub.1-4 alkoxy; R.sup.2 is methyl or
ethyl; R is hydrogen, or CO.sub.2R is
(CO.sub.2.sup.-).sub.pR.sup.p+ wherein R.sup.p+ is a univalent
cation (for example an alkali metal cation) or two carboxylates may
coordinate a divalent cation (for example an alkaline earth metal
cation); p is 1 or 2; R.sup.3 is phenyl optionally substituted with
halogen, cyano, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CF.sub.3 or
OCF.sub.3; when R.sup.1 is 2-methyl-3,4-dichlorophenyl and R.sup.3
is 4-fluorophenyl, 4-cyanophenyl or 2-methoxyphenyl, then R.sup.2
can also be hydrogen; or an N-oxide thereof; or a pharmaceutically
acceptable salt thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1 shows the XRPD of Form I (as described in Example
28).
[0012] FIG. 2 shows the XRPD of Form II (as described in Example
29).
[0013] FIG. 3 shows the XRPD of Form A (as described in Example
32).
[0014] FIG. 4 shows the XRPD for
(2S)-2-(4-{[4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]methyl}piperidin-1-
-yl)-3-(4-fluorophenyl)-2-methylpropanoic acid ethanol solvate Form
B (as described in Example 34).
[0015] Compounds of formula (I) wherein R.sup.2 is methyl are
surprisingly more soluble (sometimes up to 10 times more soluble)
in certain solvents (for example phosphate buffer at pH 7.4) than
compounds of formula (I) wherein R.sup.2 is hydrogen. The increased
solubility is advantageous for a oral pharmaceutical as the active
ingredient will be more readily available for absorption from the
gastrointestinal tract.
[0016] Certain compounds of the present invention can exist in
different isomeric forms (such as enantiomers, diastereomers,
geometric isomers or tautomers). The present invention covers all
such isomers and mixtures thereof in all proportions.
[0017] The compounds of the invention can be zwitterionic and all
such zwitterions are within the invention.
[0018] Suitable pharmaceutically acceptable salts include acid
addition salts such as a hydrochloride, dihydrochloride,
hydrobromide, phosphate, sulfate, acetate, fumarate, maleate,
malonate, succinate, tartrate, citrate, oxalate, methanesulfonate,
benzenesulfonate or p-toluenesulfonic acid.
(CO.sub.2.sup.-).sub.pR.sup.p+ are salts of the invention.
[0019] An alkali metal cation is, for example sodium or potassium,
and an alkaline earth metal cation is, for example, magnesium or
calcium.
[0020] The univalent cation R.sup.p+, wherein p is 1, can also be,
for example, a protonated tertiary amine such as
(CH.sub.2CH.sub.2OH).sub.3NH'.
[0021] The compounds of the invention may exist as solvates (such
as hydrates) and the present invention covers all such solvates.
Examples of alternative solvates include compounds of the invention
having ethanol or ethyl acetate included in the solid phase.
Solvates can exist as, for example, a compound of the invention
having solvate molecules within the crystal lattice, or, where
solvent is within one or more channels within the crystal lattice
(such as a channel hydrate), or a mixture of these two.
[0022] Halogen includes fluorine, chlorine, bromine and iodine.
Halogen is, for example, fluorine or chlorine.
[0023] Alkyl is straight or branched chain and is, for example,
methyl, ethyl, n-propyl, iso-propyl or tert-butyl.
[0024] In one particular aspect the present invention provides a
compound of formula (I) wherein: R.sup.1 is phenyl optionally
substituted by halogen, cyano, C.sub.1-4 alkyl or C.sub.1-4 alkoxy;
R.sup.2 is methyl; R is hydrogen, or CO.sub.2R is
(CO.sub.2.sup.-).sub.pR.sup.p+ wherein R.sup.p+ is a univalent
cation (for example an alkali metal cation) or two carboxylates may
coordinate a divalent cation (for example an alkaline earth metal
cation); p is 1 or 2; R.sup.3 is phenyl optionally substituted with
halogen, cyano, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CF.sub.3 or
OCF.sub.3; when R.sup.1 is 2-methyl-3,4-dichlorophenyl and R.sup.3
is 4-fluorophenyl, 4-cyanophenyl or 2-methoxyphenyl, then R.sup.2
can also be hydrogen; or an N-oxide thereof; or a pharmaceutically
acceptable salt thereof.
[0025] In a further aspect the present invention provides a
compound of formula (I) wherein: R.sup.1 is phenyl optionally
substituted by halogen, cyano, C.sub.1-4 alkyl or C.sub.1-4 alkoxy;
R.sup.2 is methyl; R is hydrogen, or CO.sub.2R is
(CO.sub.2.sup.-).sub.pR.sup.p+ wherein R.sup.p+ is a univalent
cation (for example an alkali metal cation) or two carboxylates may
coordinate a divalent cation (for example an alkaline earth metal
cation); p is 1 or 2; R.sup.3 is phenyl optionally substituted with
halogen, cyano, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CF.sub.3 or
OCF.sub.3; when R.sup.1 is 2-methyl-3,4-dichlorophenyl and R.sup.3
is 4-fluorophenyl, 4-cyanophenyl or 2-methoxyphenyl, then R.sup.2
can also be hydrogen; or a pharmaceutically acceptable salt
thereof.
[0026] In another aspect the present invention provides a compound
of formula (I) wherein, R.sup.1 is phenyl optionally substituted by
halogen, cyano, C.sub.1-4 alkyl or C.sub.1-4 alkoxy; R.sup.2 is
methyl; R is hydrogen, or CO.sub.2R is
(CO.sub.2.sup.-).sub.pR.sup.p+ wherein R.sup.p+ is a univalent
cation (for example an alkali metal cation) or two carboxylates may
coordinate a divalent cation (for example an alkaline earth metal
cation); p is 1 or 2; R.sup.3 is phenyl optionally substituted with
halogen, cyano, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CF.sub.3 or
OCF.sub.3; or a pharmaceutically acceptable salt thereof.
[0027] In a further aspect the present invention provides a
compound wherein R.sup.1 is phenyl optionally substituted (for
example with two or three of the same or different) with fluorine,
chlorine, cyano, C.sub.1-4 alkyl (for example methyl) or C.sub.1-4
alkoxy (for example methoxy).
[0028] In another aspect the present invention provides a compound
wherein R.sup.1 is phenyl optionally substituted (for example with
two or three of the same or different) with fluorine, chlorine,
cyano or C.sub.1-4 alkyl (for example methyl).
[0029] In yet another aspect the present invention provides a
compound wherein R.sup.1 is phenyl substituted by two or three
substituents independently selected from: fluorine, chlorine, cyano
and methyl.
[0030] In a further aspect the present invention provides a
compound wherein R.sup.1 is phenyl substituted by two or three
substituents independently selected from: chlorine and methyl.
[0031] For example R.sup.1 is 3,4-dichlorophenyl,
4-chloro-2-methylphenyl, 2,4-dichloro-3-methylphenyl or
3,4-dichloro-2-methylphenyl. R.sup.1 can also be
4-fluoro-2-methylphenyl or 4-chloro-3-methylphenyl. For example
R.sup.1 is 3,4-dichloro-2-methylphenyl. For example R.sup.1 is
4-chloro-2-methylphenyl.
[0032] In a still further aspect the present invention provides a
compound of formula (I) wherein R is hydrogen.
[0033] In another aspect the present invention provides a compound
of formula (I) wherein CO.sub.2R is CO.sub.2.sup.-R.sup.+, wherein
R.sup.+ is sodium or potassium.
[0034] In yet another aspect R.sup.2 is methyl.
[0035] In a still further aspect the present invention provides a
compound of formula (I) wherein R.sup.2 is hydrogen and R.sup.3 is
4-fluorophenyl, 4-cyanophenyl or 2-methoxyphenyl (for example
R.sup.3 is 4-fluorophenyl).
[0036] The invention further provides
(2S)-2-(4-{[4-(4-chloro-2-methylphenoxy)piperidin-1-yl]methyl}piperidin-1-
-yl)-3-(4-fluorophenyl)-2-methylpropanoic acid or a
pharmaceutically acceptable salt thereof (for example a sodium,
potassium or (CH.sub.2CH.sub.2OH).sub.3NH.sup.+ salt, or an acid
addition salt, such as a hydrochloride, dihydrochloride,
hydrobromide, phosphate, sulfate, acetate, fumarate, maleate,
malonate, succinate, tartrate, citrate, oxalate, methanesulfonate,
benzenesulfonate or p-toluenesulfonic acid).
[0037] In a still further aspect the present invention provides
(2S)-2-(4-{[4-(4-chloro-2-methylphenoxy)piperidin-1-yl]methyl}piperidin-1-
-yl)-3-(4-fluorophenyl)-2-methylpropanoic acid.
[0038] In another aspect the present invention provides a polymorph
of
(2S)-2-(4-{[4-(4-chloro-2-methylphenoxy)piperidin-1-yl]methyl}piperidin-1-
-yl)-3-(4-fluorophenyl)-2-methylpropanoic acid hydrate (Form A)
{water of varying stoichiometry, for example 1.5-2.5 equivalents}
having an X-ray powder diffraction pattern containing specific
peaks at: 5.3 (.+-.0.1.degree.), 10.6 (.+-.0.1.degree.), 12.3
(.+-.0.1.degree.), 12.9 (.+-.0.1.degree.), 13.9 (.+-.0.1.degree.),
15.5 (.+-.0.1.degree.), 15.9 (.+-.0.1.degree.), 16.9
(.+-.0.1.degree.), 19.6 (.+-.0.1.degree.), 20.0 (.+-.0.1.degree.),
20.4 (.+-.0.1.degree.), 21.1 (.+-.0.1.degree.), 21.5
(.+-.0.1.degree.), 24.0 (.+-.0.1.degree.), 24.8 (.+-.0.1.degree.),
25.1 (.+-.0.1.degree.), 25.8 (.+-.0.1.degree.), 29.4
(.+-.0.1.degree.) and 29.6 (.+-.0.1.degree.) 2.theta..
[0039] In yet another aspect the present invention provides a
polymorph of
(2S)-2-(4-{[4-(4-chloro-2-methylphenoxy)piperidin-1-yl]methyl}piperidin-1-
-yl)-3-(4-fluorophenyl)-2-methylpropanoic acid ethanol solvate
(Form B) having an X-ray powder diffraction pattern containing
specific peaks at: 7.7 (.+-.0.1.degree.), 13.3 (.+-.0.1.degree.),
15.2 (.+-.0.1.degree.), 15.4 (.+-.0.1.degree.), 17.4)
(.+-.0.1.degree.), 18.4 (.+-.0.1.degree.), 19.7 (.+-.0.1.degree.),
20.6 (.+-.0.1.degree.), 21.7 (.+-.0.1.degree.) and 22.7
(.+-.0.1.degree.) 2.theta..
[0040] In another aspect the present invention provides a compound
wherein R.sup.3 is phenyl optionally substituted with halogen (such
as fluoro), cyano or C.sub.1-4 alkoxy (such as methoxy).
[0041] In yet another aspect the present invention provides a
compound of formula (I) wherein R.sup.2 is methyl and R.sup.3 is
fluorophenyl (for example 4-fluorophenyl).
[0042] In another aspect the present invention provides
(S)-{4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperidin-
-1-yl}-3-(4-fluoro-phenyl)-propionic acid or a pharmaceutically
acceptable salt thereof (for example a sodium, potassium or
(CH.sub.2CH.sub.2OH).sub.3NH.sup.+ salt, or an acid addition salt,
such as a hydrochloride, dihydrochloride, hydrobromide, phosphate,
sulfate, acetate, fumarate, maleate, malonate, succinate, tartrate,
citrate, oxalate, methanesulfonate, benzenesulfonate or
p-toluenesulfonic acid).
[0043] In yet another aspect the present invention provides
(S)-{4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperidin-
-1-yl}-3-(4-fluoro-phenyl)-propionic acid.
[0044] In a further aspect the present invention provides a
polymorph of
(S)-{4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperidin-
-1-yl}-3-(4-fluoro-phenyl)-propionic acid (Form I) having an X-ray
powder diffraction pattern containing specific peaks at: 2.2
(.+-.0.1.degree.), 2.7 (.+-.0.1.degree.), 7.1 (.+-.0.1.degree.),
10.7 (.+-.0.1.degree.), 13.3 (.+-.0.1.degree.) and 18.8
(.+-.0.1.degree.) 2.theta..
[0045] In a still further aspect the present invention provides a
polymorph of
(S)-{4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperidin-
-1-yl}-3-(4-fluoro-phenyl)-propionic acid (Form II) having an X-ray
powder diffraction pattern containing specific peaks at: 2.2
(.+-.0.1.degree.), 2.67 (.+-.0.1.degree.), 7.2 (.+-.0.1.degree.),
13.2 (.+-.0.1.degree.), 17.0 (.+-.0.1.degree.), 17.4
(.+-.0.1.degree.), 19.1 (.+-.0.1.degree.), 19.4 (.+-.0.1.degree.),
21.1 (.+-.0.1.degree.), 24.4 (.+-.0.1.degree.) and 25.2
(.+-.0.1.degree.) 2.theta..
[0046] In a further aspect the present invention provides a
pharmaceutically acceptable salt of a compound of formula (I),
having the (2S) absolute configuration, wherein R.sup.1 is
2-methyl-3,4-dichlorophenyl, R.sup.2 is hydrogen and R.sup.3 is
phenyl, provided it is not the dihydrochloride salt; such as a
methanesulfonate or benzenesulfonate salt.
[0047] In another aspect the present invention provides a salt of
(2S)-2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piper-
idyl]-3-phenylpropanoic acid, but not the dihydrochloride salt,
[for example an alkali metal salt (such as a sodium or potassium
salt) or an acid addition salt (such as one of those listed above,
for example a methanesulfonic acid or benzenesulfonic acid salt)].
In yet another aspect the present invention provides a sodium or
potassium (for example a sodium salt) of
(2S)-2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piper-
idyl]-3-phenylpropanoic acid.
[0048] In a further aspect the present invention provides one of
the following individualised compounds of the invention: [0049]
(2S)-2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piper-
idyl]-3-(4-fluorophenyl)-propanoic acid; [0050]
(2S)-2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piper-
idyl]-342-methoxyphenyl)-propanoic acid; [0051]
(2S)-3(4-cyanophenyl)-2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidy-
l]methyl]-1-piperidyl]-propanoic acid; [0052]
(2S)-2-[4-[[4-(3,4-dichloro-2-ethyl-phenoxy)-1-piperidyl]methyl]-1-piperi-
dyl]-3-phenylpropanoic acid; [0053]
(2S)-2-[4-[[4-(3,4-dichloro-2-ethyl-phenoxy)-1-piperidyl]methyl]-1-piperi-
dyl]-3-(4-fluorophenyl)-propanoic acid;
[0054]
(2S)-2-(4-{[4-(3-chloro-4-cyano-2-methylphenoxy)piperidin-1-yl]meth-
yl}piperidin-1-yl)-3-phenylpropanoic acid;
[0055]
(2S)-2-(4-{[4-(3-chloro-4-cyano-2-methylphenoxy)piperidin-1-yl]meth-
yl}piperidin-1-yl)-3-(4-fluorophenyl)propanoic acid; [0056]
(2S)-2-[4-[[4-(2,4-dichloro-3-methyl-phenoxy)-1-piperidyl]methyl]-1-piper-
idyl]-3-(4-fluorophenyl)-propanoic acid; [0057]
(2S)-2-[4-[[4-(4-chloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piperidyl-
]-3-(4-fluorophenyl)-propanoic acid; [0058]
(2S)-2-[4-[[4-(2,4-dichloro-phenoxy)-1-piperidyl]methyl]-1-piperidyl]-3-(-
4-fluorophenyl)-propanoic acid; [0059]
(S)-2-(4-{[4-(3,4-dichlorophenoxy)piperidin-1-yl]methyl}piperidin-1-yl)-3-
-(4-fluorophenyl)-2-methylpropanoic acid; [0060]
(S)-2-[4-[[4-(4-chloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piperidyl]-
-3-(4-fluorophenyl)-2-methyl-propanoic acid; [0061]
(S)-2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piperi-
dyl]-3-(4-fluorophenyl)-2-methyl-propanoic acid; [0062] Isomer 1 of
2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piperidyl]-
-2-methyl-3-phenyl-propanoic acid; [0063] Isomer 2 of
2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piperidyl]-
-2-methyl-3-phenyl-propanoic acid; [0064]
2-(4-{[4-(3,4-dichloro-2-methylphenoxy)piperidin-1-yl]methyl}piperidin-1--
yl)-2-methyl-3-phenylpropanoic acid; [0065] Isomer 1 of
2-[4-[[4-(3,4-dichlorophenoxy)-1-piperidyl]methyl]-1-piperidyl]-2-methyl--
3-phenyl-propanoic acid; [0066] Isomer 2 of
2-[4-[[4-(3,4-dichlorophenoxy)-1-piperidyl]methyl]-1-piperidyl]-2-methyl--
3-phenyl-propanoic acid; [0067]
(.+-.)-2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-pip-
eridyl]-2-methyl-3-phenyl-propanoic acid; [0068]
(2S)-2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piper-
idyl]-3-phenylpropanoic acid sodium salt; [0069]
(2S)-2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piper-
idyl]-3-(4-fluorophenyl)-propanoic acid sodium salt; [0070]
(2S)-2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piper-
idyl]-3-(4-fluorophenyl)-propanoic acid potassium salt; [0071]
(2S)-2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piper-
idyl]-3-phenylpropanoic acid methanesulfonic acid salt; [0072]
(2S)-2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piper-
idyl]-3-phenylpropanoic acid benzenesulfonic acid salt; [0073]
(2S)-2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piper-
idyl]-3-(4-fluorophenyl)-propanoic acid benzenesulfonic acid salt;
[0074]
(2S)-2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piper-
idyl]-3-(4-fluorophenyl)-propanoic acid hydrochloride; [0075]
2-Benzyl-2-(4-{[4-(3,4-dichlorophenoxy)piperidin-1-yl]methyl}piperidin-1--
yl)butanoic acid; [0076]
(S)-2-{4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperid-
in-1-yl}-3-phenyl-propionic acid; [0077]
(S)-{4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperidin-
-1-yl}-3-(4-fluoro-phenyl)-propionic acid (Form I); [0078]
(S)-{4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperidin-
-1-yl}-3-(4-fluoro-phenyl)-propionic acid (form II); [0079]
(2S)-2-(4-{[4-(3,4-dichloro-2-methylphenoxy)piperidin-1-yl]methyl}piperid-
in-1-yl)-3-(4-fluorophenyl)propanoic acid; or, [0080] s
(2S)-2-(4-{[4-(3,4-dichloro-2-methylphenoxy)piperidin-1-yl]methyl}piperid-
in-1-yl)-3-phenylpropanoic acid; or a pharmaceutically acceptable
salt thereof.
[0081] The compounds of the present invention can be prepared as
described below or by methods analogous to those described in WO
2004/087659 or WO 2004/029041.
[0082] A compound of formula (I) can be prepared by reacting a
compound of formula (II):
##STR00003##
with a compound of formula (III):
##STR00004##
wherein R is alkyl (for example C.sub.1-6 alkyl) in the presence of
NaBH(OAc).sub.3 or NaBH.sub.3(CN) in a suitable solvent (for
example an aliphatic alcohol such as methanol or ethanol) at a
suitable temperature (such as in the range 0.degree. C. to
30.degree. C.), and subsequent ester hydrolysis by using or
adapting the methods given in the Examples below.
[0083] A compound of formula (II) can be prepared by reacting a
compound of formula (IV):
##STR00005##
with lead tetra-acetate in dichloromethane or sodium periodate in
water.
[0084] Alternatively a compound of formula (I) wherein R.sup.2
represents H may be prepared by reaction of a compound of formula
(V) with a compound of formula (VI)
##STR00006##
wherein R is alkyl (for example C.sub.1-6 alkyl) and L is a
suitable leaving group (for example a sulfonate ester, typically
triflate or para-nitrobenzenesulfonate), in a suitable solvent, for
example dichloromethane or acetonitrile, at a temperature in the
range 0-30.degree. C. in the presence of a base, for example a
tertiary amine, such as triethylamine, or an inorganic base, such
as potassium carbonate; and subsequent ester hydrolysis by using or
adapting the methods given in the Examples below.
[0085] The preparations of various phenoxy piperidines and other
intermediates are described in the literature and in WO 01/77101,
WO 2004/087659 or WO 2004/029041.
[0086] A compound of the present invention wherein R is hydrogen
can be prepared by hydrolysis of the corresponding ester (prepared
by a method known in the art) under standard hydrolysis conditions
(for example using lithium hydroxide, sodium hydroxide, potassium
hydroxide or barium hydroxide).
[0087] In the above processes it may be desirable or necessary to
protect an acid group or a hydroxy or other potentially reactive
group. Suitable protecting groups and details of processes for
adding and removing such groups may be found in "Protective Groups
in Organic Synthesis", 3rd Edition (1999) by Greene and Wuts.
[0088] In another aspect the present invention provides processes
for the preparation of compounds of formula (I).
[0089] In a further aspect the invention provides the
intermediates:
##STR00007##
[0090] Salts of
(2S)-2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piper-
idyl]-3-phenylpropanoic acid can be prepared by using or adapting
the methods of the Examples or by using or adapting methods known
in the art.
[0091] The compounds of the invention and their pharmaceutically
acceptable salts have activity as pharmaceuticals, in particular as
modulators of chemokine receptor (for example CCR3) activity, and
may be used in the treatment of autoimmune, inflammatory,
proliferative or hyperproliferative diseases, or
immunologically-mediated diseases (including rejection of
transplanted organs or tissues and Acquired Immunodeficiency
Syndrome (AIDS)).
[0092] Examples of these conditions are:
1. respiratory tract: obstructive diseases of the airways
including: asthma, including bronchial, allergic, intrinsic,
extrinsic, exercise-induced, drug-induced (including aspirin and
NSAID-induced) and dust-induced asthma, both intermittent and
persistent and of all severities, and other causes of airway
hyper-responsiveness; chronic obstructive pulmonary disease (COPD);
bronchitis, including infectious and eosinophilic bronchitis;
emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's
lung and related diseases; hypersensitivity pneumonitis; lung
fibrosis, including cryptogenic fibrosing alveolitis, idiopathic
interstitial pneumonias, fibrosis complicating anti-neoplastic
therapy and chronic infection, including tuberculosis and
aspergillosis and other fungal infections; complications of lung
transplantation; vasculitic and thrombotic disorders of the lung
vasculature, and pulmonary hypertension; antitussive activity
including treatment of chronic cough associated with inflammatory
and secretory conditions of the airways, and iatrogenic cough;
acute and chronic rhinitis including rhinitis medicamentosa, and
vasomotor rhinitis; perennial and seasonal allergic rhinitis
including rhinitis nervosa (hay fever); nasal polyposis; acute
viral infection including the common cold, and infection due to
respiratory syncytial virus (RSV), influenza, coronavirus
(including SARS) or adenovirus; or eosinophilic esophagitis; 2.
bone and joints: arthritides associated with or including
osteoarthritis/osteoarthrosis, both primary and secondary to, for
example, congenital hip dysplasia; cervical and lumbar spondylitis,
and low back and neck pain; osteoporosis; rheumatoid arthritis and
Still's disease; seronegative spondyloarthropathies including
ankylosing spondylitis, psoriatic arthritis, reactive arthritis and
undifferentiated spondarthropathy; septic arthritis and other
infection-related arthopathies and bone disorders such as
tuberculosis, including Potts' disease and Poncet's syndrome; acute
and chronic crystal-induced synovitis including urate gout, calcium
pyrophosphate deposition disease, and calcium apatite related
tendon, bursal and synovial inflammation; Behcet's disease; primary
and secondary Sjogren's syndrome; systemic sclerosis and limited
scleroderma; systemic lupus erythematosus, mixed connective tissue
disease, and undifferentiated connective tissue disease;
inflammatory myopathies including dermatomyositits and
polymyositis; polymalgia rheumatica; juvenile arthritis including
idiopathic inflammatory arthritides of whatever joint distribution
and associated syndromes, and rheumatic fever and its systemic
complications; vasculitides including giant cell arteritis,
Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa,
microscopic polyarteritis, and vasculitides associated with viral
infection, hypersensitivity reactions, cryoglobulins, and
paraproteins; low back pain; Familial Mediterranean fever,
Muckle-Wells syndrome, and Familial Hibernian Fever, Kikuchi
disease; drug-induced arthalgias, tendonititides, and myopathies;
3. pain and connective tissue remodelling of musculoskeletal
disorders due to injury [for example sports injury] or disease:
arthritides (for example rheumatoid arthritis, osteoarthritis, gout
or crystal arthropathy), other joint disease (such as
intervertebral disc degeneration or temporomandibular joint
degeneration), bone remodelling disease (such as osteoporosis,
Paget's disease or osteonecrosis), polychondritits, scleroderma,
mixed connective tissue disorder, spondyloarthropathies or
periodontal disease (such as periodontitis); 4. skin: psoriasis,
atopic dermatitis, contact dermatitis or other eczematous
dermatoses, and delayed-type hypersensitivity reactions; phyto- and
photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis,
lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum,
skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid,
epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic
erythemas, cutaneous eosinophilias, alopecia greata, male-pattern
baldness, Sweet's syndrome, Weber-Christian syndrome, erythema
multiforme; cellulitis, both infective and non-infective;
panniculitis; cutaneous lymphomas, non-melanoma skin cancer and
other dysplastic lesions; drug-induced disorders including fixed
drug eruptions; 5. eyes: blepharitis; conjunctivitis, including
perennial and vernal allergic conjunctivitis; iritis; anterior and
posterior uveitis; choroiditis; autoimmune; degenerative or
inflammatory disorders affecting the retina; ophthalmitis including
sympathetic ophthalmitis; sarcoidosis; infections including viral,
fungal, and bacterial; 6. gastrointestinal tract: glossitis,
gingivitis, periodontitis; oesophagitis, including reflux;
eosinophilic gastro-enteritis, mastocytosis, Crohn's disease,
colitis (including ulcerative colitis, microscopic colitis and
indeterminant colitis), proctitis, pruritis ani; coeliac disease,
irritable bowel syndrome, irritable bowel disorder,
non-inflammatory diarrhea, and food-related allergies which may
have effects remote from the gut (for example migraine, rhinitis or
eczema); 7. abdominal: hepatitis, including autoimmune, alcoholic
and viral; fibrosis and cirrhosis of the liver; cholecystitis;
pancreatitis, both acute and chronic; 8. genitourinary: nephritis
including interstitial and glomerulonephritis; nephrotic syndrome;
cystitis including acute and chronic (interstitial) cystitis and
Hunner's ulcer; acute and chronic urethritis, prostatitis,
epididymitis, oophoritis and salpingitis; vulvo-vaginitis;
Peyronie's disease; erectile dysfunction (both male and female); 9.
allograft rejection: acute and chronic following, for example,
transplantation of kidney, heart, liver, lung, bone marrow, skin or
cornea or following blood transfusion; or chronic graft versus host
disease; 10. CNS: Alzheimer's disease and other dementing disorders
including CJD and nvCJD; amyloidosis; multiple sclerosis and other
demyelinating syndromes; cerebral atherosclerosis and vasculitis;
temporal arteritis; myasthenia gravis; acute and chronic pain
(acute, intermittent or persistent, whether of central or
peripheral origin) including visceral pain, headache, migraine,
trigeminal neuralgia, atypical facial pain, joint and bone pain,
pain arising from cancer and tumour invasion, neuropathic pain
syndromes including diabetic, post-herpetic, and HIV-associated
neuropathies; neurosarcoidosis; central and peripheral nervous
system complications of malignant, infectious or autoimmune
processes; 11. other auto-immune and allergic disorders including
Hashimoto's thyroiditis, Graves' disease, Addison's disease,
diabetes mellitus, idiopathic thrombocytopaenic purpura,
eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid
syndrome; 12. other disorders with an inflammatory or immunological
component; including acquired immune deficiency syndrome (AIDS),
leprosy, Sezary syndrome, and paraneoplastic syndromes; 13.
cardiovascular: atherosclerosis, affecting the coronary and
peripheral circulation; pericarditis; myocarditis, inflammatory and
auto-immune cardiomyopathies including myocardial sarcoid;
ischaemic reperfusion injuries; endocarditis, valvulitis, and
aortitis including infective (for example syphilitic);
vasculitides; disorders of the proximal and peripheral veins
including phlebitis and thrombosis, including deep vein thrombosis
and complications of varicose veins; or, 14. oncology: treatment of
common cancers including prostate, breast, lung, ovarian,
pancreatic, bowel and colon, stomach, skin and brain tumours and
malignancies affecting the bone marrow (including the leukaemias)
and lymphoproliferative systems, such as Hodgkin's and
non-Hodgkin's lymphoma; including the prevention and treatment of
metastatic disease and tumour recurrences, and paraneoplastic
syndromes.
[0093] According to a further feature of the present invention
there is provided a method for treating a chemokine mediated
disease state (for example a CCR3 mediated disease state) in a
mammal, such as man, suffering from, or at risk of, said disease
state, which comprises administering to a mammal in need of such
treatment a therapeutically effective amount of a compound of the
invention or a pharmaceutically acceptable salt thereof.
[0094] According to yet another feature of the present invention
there is provided a method for treating a sign and/or symptom of
what is commonly referred to as a cold in a mammal, such as man,
suffering from, or at risk of, said disease state, which comprises
administering to a mammal in need of such treatment a
therapeutically effective amount of a compound of the invention or
a pharmaceutically acceptable salt thereof.
[0095] The invention also provides a compound of the invention, or
a pharmaceutically acceptable salt thereof, for use in therapy.
[0096] In another aspect the invention provides the use of a
compound of the invention, or a pharmaceutically acceptable salt
thereof, in the manufacture of a medicament for use in therapy (for
example modulating chemokine receptor activity (for example CCR3
receptor activity) or treating a sign and/or symptom of what is
commonly referred to as a cold).
[0097] The invention further provides the use of a compound of the
invention, or a pharmaceutically acceptable salt thereof, in the
manufacture of a medicament for use in the treatment of:
1. respiratory tract: obstructive diseases of the airways
including: asthma, including bronchial, allergic, intrinsic,
extrinsic, exercise-induced, drug-induced (including aspirin and
NSAID-induced) and dust-induced asthma, both intermittent and
persistent and of all severities, and other causes of airway
hyper-responsiveness; chronic obstructive pulmonary disease (COPD);
bronchitis, including infectious and eosinophilic bronchitis;
emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's
lung and related diseases; hypersensitivity pneumonitis; lung
fibrosis, including cryptogenic fibrosing alveolitis, idiopathic
interstitial pneumonias, fibrosis complicating anti-neoplastic
therapy and chronic infection, including tuberculosis and
aspergillosis and other fungal infections; complications of lung
transplantation; vasculitic and thrombotic disorders of the lung
vasculature, and pulmonary hypertension; antitussive activity
including treatment of chronic cough associated with inflammatory
and secretory conditions of the airways, and iatrogenic cough;
acute and chronic rhinitis including rhinitis medicamentosa, and
vasomotor rhinitis; perennial and seasonal allergic rhinitis
including rhinitis nervosa (hay fever); nasal polyposis; acute
viral infection including the common cold, and infection due to
respiratory syncytial virus, influenza, coronavirus (including
SARS) or adenovirus; or eosinophilic esophagitis; 2. bone and
joints: arthritides associated with or including
osteoarthritis/osteoarthrosis, both primary and secondary to, for
example, congenital hip dysplasia; cervical and lumbar spondylitis,
and low back and neck pain; osteoporosis, rheumatoid arthritis and
Still's disease; seronegative spondyloarthropathies including
ankylosing spondylitis, psoriatic arthritis, reactive arthritis and
undifferentiated spondarthropathy; septic arthritis and other
infection-related arthopathies and bone disorders such as
tuberculosis, including Potts' disease and Poncet's syndrome; acute
and chronic crystal-induced synovitis including urate gout, calcium
pyrophosphate deposition disease, and calcium apatite related
tendon, bursal and synovial inflammation; Behcet's disease; primary
and secondary Sjogren's syndrome; systemic sclerosis and limited
scleroderma; systemic lupus erythematosus, mixed connective tissue
disease, and undifferentiated connective tissue disease;
inflammatory myopathies including dermatomyositits and
polymyositis; polymalgia rheumatica; juvenile arthritis including
idiopathic inflammatory arthritides of whatever joint distribution
and associated syndromes, and rheumatic fever and its systemic
complications; vasculitides including giant cell arteritis,
Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa,
microscopic polyarteritis, and vasculitides associated with viral
infection, hypersensitivity reactions, cryoglobulins, and
paraproteins; low back pain; Familial Mediterranean fever,
Muckle-Wells syndrome, and Familial Hibernian Fever, Kikuchi
disease; drug-induced arthalgias, tendonititides, and myopathies;
3. pain and connective tissue remodelling of musculoskeletal
disorders due to injury [for example sports injury] or disease:
arthritides (for example rheumatoid arthritis, osteoarthritis, gout
or crystal arthropathy), other joint disease (such as
intervertebral disc degeneration or temporomandibular joint
degeneration), bone remodelling disease (such as osteoporosis,
Paget's disease or osteonecrosis), polychondritits, scleroderma,
mixed connective tissue disorder, spondyloarthropathies or
periodontal disease (such as periodontitis); 4. skin: psoriasis,
atopic dermatitis, contact dermatitis or other eczematous
dermatoses, and delayed-type hypersensitivity reactions; phyto- and
photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis,
lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum,
skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid,
epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic
erythemas, cutaneous eosinophilias, alopecia greata, male-pattern
baldness, Sweet's syndrome, Weber-Christian syndrome, erythema
multiforme; cellulitis, both infective and non-infective;
panniculitis; cutaneous lymphomas, non-melanoma skin cancer and
other dysplastic lesions; drug-induced disorders including fixed
drug eruptions; 5. eyes: blepharitis; conjunctivitis, including
perennial and vernal allergic conjunctivitis; iritis; anterior and
posterior uveitis; choroiditis; autoimmune; degenerative or
inflammatory disorders affecting the retina; ophthalmitis including
sympathetic ophthalmitis; sarcoidosis; infections including viral,
fungal, and bacterial; 6. gastrointestinal tract: glossitis,
gingivitis, periodontitis; oesophagitis, including reflux;
eosinophilic gastro-enteritis, mastocytosis, Crohn's disease,
colitis (including ulcerative colitis, microscopic colitis and
indeterminant colitis), proctitis, pruritis ani; coeliac disease,
irritable bowel syndrome, irritable bowel disorder,
non-inflammatory diarrhoea, and food-related allergies which may
have effects remote from the gut (for example migraine, rhinitis or
eczema); 7. abdominal: hepatitis, including autoimmune, alcoholic
and viral; fibrosis and cirrhosis of the liver; cholecystitis;
pancreatitis, both acute and chronic; 8. genitourinary: nephritis
including interstitial and glomerulonephritis; nephrotic syndrome;
cystitis including acute and chronic (interstitial) cystitis and
Hunner's ulcer; acute and chronic urethritis, prostatitis,
epididymitis, oophoritis and salpingitis; vulvo-vaginitis;
Peyronie's disease; erectile dysfunction (both male and female); 9.
allograft rejection: acute and chronic following, for example,
transplantation of kidney, heart, liver, lung, bone marrow, skin or
cornea or following blood transfusion; or chronic graft versus host
disease; 10. CNS: Alzheimer's disease and other dementing disorders
including CJD and nvCJD; amyloidosis; multiple sclerosis and other
demyelinating syndromes; cerebral atherosclerosis and vasculitis;
temporal arteritis; myasthenia gravis; acute and chronic pain
(acute, intermittent or persistent, whether of central or
peripheral origin) including visceral pain, headache, migraine,
trigeminal neuralgia, atypical facial pain, joint and bone pain,
pain arising from cancer and tumour invasion, neuropathic pain
syndromes including diabetic, post-herpetic, and HIV-associated
neuropathies; neurosarcoidosis; central and peripheral nervous
system complications of malignant, infectious or autoimmune
processes; 11. other auto-immune and allergic disorders including
Hashimoto's thyroiditis, Graves' disease, Addison's disease,
diabetes mellitus, idiopathic thrombocytopaenic purpura,
eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid
syndrome; 12. other disorders with an inflammatory or immunological
component; including acquired immune deficiency syndrome (AIDS),
leprosy, Sezary syndrome, and paraneoplastic syndromes; 13.
cardiovascular: atherosclerosis, affecting the coronary and
peripheral circulation; pericarditis; myocarditis, inflammatory and
auto-immune cardiomyopathies including myocardial sarcoid;
ischaemic reperfusion injuries; endocarditis, valvulitis, and
aortitis including infective (for example syphilitic);
vasculitides; disorders of the proximal and peripheral veins
including phlebitis and thrombosis, including deep vein thrombosis
and complications of varicose veins; or, 14. oncology: treatment of
common cancers including prostate, breast, lung, ovarian,
pancreatic, bowel and colon, stomach, skin and brain tumours and
malignancies affecting the bone marrow (including the leukaemias)
and lymphoproliferative systems, such as Hodgkin's and
non-Hodgkin's lymphoma; including the prevention and treatment of
metastatic disease and tumour recurrences, and paraneoplastic
syndromes; in a mammal (for example man).
[0098] In a further aspect the invention provides a compound of the
invention, or a pharmaceutically acceptable salt thereof, for use
in the treatment of asthma {such as bronchial, allergic, intrinsic,
extrinsic or dust asthma, particularly chronic or inveterate asthma
(for example late asthma or airways hyper-responsiveness)}; or
rhinitis {including acute, allergic, atrophic or chronic rhinitis,
such as rhinitis caseosa, hypertrophic rhinitis, rhinitis
purulenta, rhinitis sicca or rhinitis medicamentosa; membranous
rhinitis including croupous, fibrinous or pseudomembranous rhinitis
or scrofulous rhinitis; seasonal rhinitis including rhinitis
nervosa (hay fever) or vasomotor rhinitis}.
[0099] In a still further aspect a compound of the invention, or a
pharmaceutically acceptable salt thereof, is useful in the
treatment of asthma.
[0100] In another aspect a compound of the invention, or a
pharmaceutically acceptable salt thereof, is useful in the
treatment of respiratory syncytial virus (RSV).
[0101] The present invention also provides a the use of a compound
of the invention, or a pharmaceutically acceptable salt thereof, in
the manufacture of a medicament for use in the treatment of asthma
{such as bronchial, allergic, intrinsic, extrinsic or dust asthma,
particularly chronic or inveterate asthma (for example late asthma
or airways hyper-responsiveness)}; or rhinitis {including acute,
allergic, atrophic or chronic rhinitis, such as rhinitis caseosa,
hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or
rhinitis medicamentosa; membranous rhinitis including croupous,
fibrinous or pseudomembranous rhinitis or scrofulous rhinitis;
seasonal rhinitis including rhinitis nervosa (hay fever) or
vasomotor rhinitis}.
[0102] In order to use a compound of formula (I), or a
pharmaceutically acceptable salt thereof, for the therapeutic
treatment of a mammal, such as man, said ingredient is normally
formulated in accordance with standard pharmaceutical practice as a
pharmaceutical composition. Therefore in another aspect the present
invention provides a pharmaceutical composition which comprises a
compound of formula (I), or a pharmaceutically acceptable salt
thereof (active ingredient), and a pharmaceutically acceptable
adjuvant, diluent or carrier.
[0103] In a further aspect the present invention provides a process
for the preparation of said composition which comprises mixing
active ingredient with a pharmaceutically acceptable adjuvant,
diluent or carrier. Depending on the mode of administration, the
pharmaceutical composition will, for example, comprise from 0.05 to
99% w (percent by weight), such as from 0.05 to 80% w, for example
from 0.10 to 70% w, such as from 0.10 to 50% w, of active
ingredient, all percentages by weight being based on total
composition.
[0104] The pharmaceutical compositions comprising a compound of
formula (I), or a pharmaceutically acceptable salt thereof, may be
administered in standard manner for the disease condition that it
is desired to treat, for example by topical (such as to the lung
and/or airways or to the skin), oral, rectal or parenteral (such as
intravenous, sub-cutaneous, intramuscular or intra-articular)
administration. For these purposes the compounds of this invention
may be formulated by means known in the art. A suitable
pharmaceutical composition of this invention is one suitable for
oral administration in unit dosage form, for example a tablet or
capsule which contains between 0.1 mg and 1 g of active
ingredient.
[0105] Each patient may receive, for example, a dose of 0.01
mgkg.sup.-1 to 100 mgkg.sup.-1, for example in the range of 0.1
mgkg.sup.-1 to 20 mgkg.sup.-1, of the active ingredient
administered, for example, 1 to 4 times per day.
[0106] The invention further relates to a combination therapy
wherein a compound of formula (I), or a pharmaceutically acceptable
salt thereof, or a pharmaceutical composition or formulation
comprising a compound of the invention, is administered
concurrently or sequentially or as a combined preparation with
another therapeutic agent or agents, for the treatment of one or
more of the conditions listed.
[0107] In particular, for the treatment of the inflammatory
diseases such as (but not restricted to) rheumatoid arthritis,
osteoarthritis, asthma, allergic rhinitis, chronic obstructive
pulmonary disease (COPD), psoriasis, and inflammatory bowel
disease, the compounds of the invention may be combined with agents
listed below.
[0108] Non-steroidal anti-inflammatory agents (hereinafter NSAIDs)
including non-selective cyclo-oxygenase COX-1/COX-2 inhibitors
whether applied topically or systemically (such as piroxicam,
diclofenac, propionic acids such as naproxen, flurbiprofen,
fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic
acid, indomethacin, sulindac, azapropazone, pyrazolones such as
phenylbutazone, salicylates such as aspirin); selective COX-2
inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib,
lumarocoxib, parecoxib and etoricoxib); cyclo-oxygenase inhibiting
nitric oxide donors (CINODs); glucocorticosteroids (whether
administered by topical, oral, intramuscular, intravenous, or
intra-articular routes); methotrexate; leflunomide;
hydroxychloroquine; d-penicillamine; auranofin or other parenteral
or oral gold preparations; analgesics; diacerein; intra-articular
therapies such as hyaluronic acid derivatives; and nutritional
supplements such as glucosamine.
[0109] The present invention still further relates to the
combination of a compound of the invention, or a pharmaceutically
acceptable salt thereof, together with a cytokine or agonist or
antagonist of cytokine function, (including agents which act on
cytokine signalling pathways such as modulators of the SOCS system)
including alpha-, beta-, and gamma-interferons; insulin-like growth
factor type I (IGF-1); interleukins (IL) including IL1 to 17, and
interleukin antagonists or inhibitors such as anakinra; tumour
necrosis factor alpha (TNF-a) inhibitors such as anti-TNF
monoclonal antibodies (for example infliximab; adalimumab, and
CDP-870) and TNF receptor antagonists including immunoglobulin
molecules (such as etanercept) and low-molecular-weight agents such
as pentoxyfylline.
[0110] In addition the invention relates to a combination of a
compound of the invention, or a pharmaceutically acceptable salt
thereof, with a monoclonal antibody targeting B-Lymphocytes (such
as CD20 (rituximab), MRA-aIL16R) or T-Lymphocytes (such as
CTLA4-Ig, HuMax I1-15).
[0111] The present invention still further relates to the
combination of a compound of the invention, or a pharmaceutically
acceptable salt thereof, with a modulator of chemokine receptor
function such as an antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3,
CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C
family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C
family) and CX.sub.3CR1 for the C-X.sub.3-C family.
[0112] The present invention further relates to the combination of
a compound of the invention, or a pharmaceutically acceptable salt
thereof, with an inhibitor of matrix metalloprotease (MMPs), i.e.,
the stromelysins, the collagenases, and the gelatinases, as well as
aggrecanase; for example collagenase-1 (MMP-1), collagenase-2
(MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3),
stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) and MMP-9 and
MMP-12, including agents such as doxycycline.
[0113] The present invention still further relates to the
combination of a compound of the invention, or a pharmaceutically
acceptable salt thereof, and a leukotriene biosynthesis inhibitor,
5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating
protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton;
tepoxalin; Abbott-79175; Abbott-85761; a
N-(5-substituted)-thiophene-2-alkylsulfonamide;
2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyran such as
Zeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted
2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinoline
compound such as L-746,530; or an indole or quinoline compound such
as MK-591, MK-886, and BAY x 1005.
[0114] The present invention further relates to the combination of
a compound of the invention, or a pharmaceutically acceptable salt
thereof, and a receptor antagonist for leukotrienes (LT) B4, LTC4,
LTD4, and LTE4. selected from the group consisting of the
phenothiazin-3-yls such as L-651,392; amidino compounds such as
CGS-25019c; benzoxalamines such as ontazolast;
benzenecarboximidamides such as BIIL 284/260; and compounds such as
zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679),
RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.
[0115] The present invention still further relates to the
combination of a compound of the invention, or a pharmaceutically
acceptable salt thereof, and a phosphodiesterase (PDE) inhibitor
such as a methylxanthanine including theophylline and
aminophylline; a selective PDE isoenzyme inhibitor including a PDE4
inhibitor, an inhibitor of the isoform PDE4D, or an inhibitor of
PDE5.
[0116] The present invention further relates to the combination of
a compound of the invention, or a pharmaceutically acceptable salt
thereof, and a histamine type 1 receptor antagonist such as
cetirizine, levocetirizine, loratadine, desloratadine,
fexofenadine, acrivastine, terfenadine, astemizole, azelastine,
levocabastine, chlorpheniramine, promethazine, cyclizine, or
mizolastine; applied orally, topically or parenterally.
[0117] The present invention still further relates to the
combination of a compound of the invention, or a pharmaceutically
acceptable salt thereof, and a proton pump inhibitor (such as
omeprazole) or a gastroprotective histamine type 2 receptor
antagonist.
[0118] The present invention further relates to the combination of
a compound of the invention, or a pharmaceutically acceptable salt
thereof, and an antagonist of the histamine type 4 receptor.
[0119] The present invention still further relates to the
combination of a compound of the invention, or a pharmaceutically
acceptable salt thereof, and an alpha-1/alpha-2 adrenoceptor
agonist vasoconstrictor sympathomimetic agent, such as
propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine,
pseudoephedrine, naphazoline hydrochloride, oxymetazoline
hydrochloride, tetrahydrozoline hydrochloride, xylometazoline
hydrochloride, tramazoline hydrochloride or ethylnorepinephrine
hydrochloride.
[0120] The present invention further relates to the combination of
a compound of the invention, or a pharmaceutically acceptable salt
thereof, and an anticholinergic agent including muscarinic receptor
(M1, M2, and M3) antagonist such as atropine, hyoscine,
glycopyrrrolate, ipratropium bromide, tiotropium bromide,
oxitropium bromide, pirenzepine or telenzepine.
[0121] The present invention still further relates to the
combination of a compound of the invention, or a pharmaceutically
acceptable salt thereof, and a beta-adrenoceptor agonist (including
beta receptor subtypes 1-4) such as isoprenaline, salbutamol,
formoterol, salmeterol, terbutaline, orciprenaline, bitolterol
mesylate, or pirbuterol, or a chiral enantiomer thereof.
[0122] The present invention further relates to the combination of
a compound of the invention, or a pharmaceutically acceptable salt
thereof, and a chromone, such as sodium cromoglycate or nedocromil
sodium.
[0123] The present invention still further relates to the
combination of a compound of the invention, or a pharmaceutically
acceptable salt thereof, with a glucocorticoid, such as
flunisolide, triamcinolone acetonide, beclomethasone dipropionate,
budesonide, fluticasone propionate, ciclesonide or mometasone
furoate.
[0124] The present invention further relates to the combination of
a compound of the invention, or a pharmaceutically acceptable salt
thereof, with an agent that modulates a nuclear hormone receptor
such as PPARs.
[0125] The present invention still further relates to the
combination of a compound of the invention, or a pharmaceutically
acceptable salt thereof, together with an immunoglobulin (Ig) or Ig
preparation or an antagonist or antibody modulating Ig function
such as anti-IgE (for example omalizumab).
[0126] The present invention further relates to the combination of
a compound of the invention, or a pharmaceutically acceptable salt
thereof, and another systemic or topically-applied
anti-inflammatory agent, such as thalidomide or a derivative
thereof, a retinoid, dithranol or calcipotriol.
[0127] The present invention still further relates to the
combination of a compound of the invention, or a pharmaceutically
acceptable salt thereof, and combinations of aminosalicylates and
sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and
olsalazine; and immunomodulatory agents such as the thiopurines,
and corticosteroids such as budesonide.
[0128] The present invention further relates to the combination of
a compound of the invention, or a pharmaceutically acceptable salt
thereof, together with an antibacterial agent such as a penicillin
derivative, a tetracycline, a macrolide, a beta-lactam, a
fluoroquinolone, metronidazole, an inhaled aminoglycoside; an
antiviral agent including acyclovir, famciclovir, valaciclovir,
ganciclovir, cidofovir, amantadine, rimantadine, ribavirin,
zanamavir and oseltamavir; a protease inhibitor such as indinavir,
nelfinavir, ritonavir, and saquinavir; a nucleoside reverse
transcriptase inhibitor such as didanosine, lamivudine, stavudine,
zalcitabine or zidovudine; or a non-nucleoside reverse
transcriptase inhibitor such as nevirapine or efavirenz.
[0129] The present invention still further relates to the
combination of a compound of the invention, or a pharmaceutically
acceptable salt thereof, and a cardiovascular agent such as a
calcium channel blocker, a beta-adrenoceptor blocker, an
angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2
receptor antagonist; a lipid lowering agent such as a statin or a
fibrate; a modulator of blood cell morphology such as
pentoxyfylline; thrombolytic, or an anticoagulant such as a
platelet aggregation inhibitor.
[0130] The present invention further relates to the combination of
a compound of the invention, or a pharmaceutically acceptable salt
thereof, and a CNS agent such as an antidepressant (such as
sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa,
ropinirole, pramipexole, a MAOB inhibitor such as selegine and
rasagiline, a comP inhibitor such as tasmar, an A-2 inhibitor, a
dopamine reuptake inhibitor, an NMDA antagonist, a nicotine
agonist, a dopamine agonist or an inhibitor of neuronal nitric
oxide synthase), or an anti-Alzheimer's drug such as donepezil,
rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or
metrifonate.
[0131] The present invention still further relates to the
combination of a compound of the invention, or a pharmaceutically
acceptable salt thereof, and an agent for the treatment of acute or
chronic pain, such as a centrally or peripherally-acting analgesic
(for example an opioid or derivative thereof), carbamazepine,
phenyloin, sodium valproate, amitryptiline or other anti-depressant
agents, paracetamol, or a non-steroidal anti-inflammatory
agent.
[0132] The present invention further relates to the combination of
a compound of the invention, or a pharmaceutically acceptable salt
thereof, together with a parenterally or topically-applied
(including inhaled) local anaesthetic agent such as lignocaine or a
derivative thereof.
[0133] A compound of the present invention, or a pharmaceutically
acceptable salt thereof, can also be used in combination with an
anti-osteoporosis agent including a hormonal agent such as
raloxifene, or a biphosphonate such as alendronate.
[0134] The present invention still further relates to the
combination of a compound of the invention, or a pharmaceutically
acceptable salt thereof, together with a: (i) tryptase inhibitor;
(ii) platelet activating factor (PAF) antagonist; (iii) interleukin
converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v)
adhesion molecule inhibitors including VLA-4 antagonist; (vi) a
cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine
kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or
Imatinib mesylate), a serine/threonine kinase (such as an inhibitor
of a MAP kinase such as p38, JNK, protein kinase A, B or C, or
IKK), or a kinase involved in cell cycle regulation (such as a
cylin dependent kinase); (viii) glucose-6 phosphate dehydrogenase
inhibitor; (ix) kinin-B.sub1.- or B.sub2.-receptor antagonist; (x)
anti-gout agent, for example colchicine; (xi) xanthine oxidase
inhibitor, for example allopurinol; (xii) uricosuric agent, for
example probenecid, sulfinpyrazone or benzbromarone; (xiii) growth
hormone secretagogue; (xiv) transforming growth factor (TGF.beta.);
(xv) platelet-derived growth factor (PDGF); (xvi) fibroblast growth
factor for example basic fibroblast growth factor (bFGF); (xvii)
granulocyte macrophage colony stimulating factor (GM-C SF); (xviii)
capsaicin cream; (xix) tachykinin NK.sub1. or NK.sub3. receptor
antagonist such as NKP-608C, SB-233412 (talnetant) or D-4418; (xx)
elastase inhibitor such as UT-77 or ZD-0892; (xxi) TNF-alpha
converting enzyme inhibitor (TACE); (xxii) induced nitric oxide
synthase (iNOS) inhibitor; (xxiii) chemoattractant
receptor-homologous molecule expressed on TH2 cells, (such as a
CRTH2 antagonist); (xxiv) inhibitor of p38; (xxv) agent modulating
the function of Toll-like receptors (TLR), (xxvi) agent modulating
the activity of purinergic receptors such as P2.times.7; (xxvii)
inhibitor of transcription factor activation such as NFkB, API, or
STATS; or (xxviii) a non-steroidal glucocorticoid receptor
agonist.
[0135] In particular a compound of formula (I), or a
pharmaceutically acceptable salt thereof, can be combined with a
histamine type 1 receptor antagonist such as cetirizine,
levocitirizine, loratadine, desloratadine, fexofenadine,
acrivistine, azelastine, levocabastine, chlorpheniramine,
promethazine, cyclizine or mizolastine; applied orally, topically
or parenterally (for example orally).
[0136] A compound of the invention, or a pharmaceutically
acceptable salt thereof, can also be used in combination with an
existing therapeutic agent for the treatment of cancer, for example
suitable agents include:
(i) an antiproliferative/antineoplastic drug or a combination
thereof, as used in medical oncology, such as an alkylating agent
(for example cis-platin, carboplatin, cyclophosphamide, nitrogen
mustard, melphalan, chlorambucil, busulphan or a nitrosourea); an
antimetabolite (for example an antifolate such as a
fluoropyrimidine like 5-fluorouracil or tegafur, raltitrexed,
methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or
paclitaxel); an antitumour antibiotic (for example an anthracycline
such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin,
idarubicin, mitomycin-C, dactinomycin or mithramycin); an
antimitotic agent (for example a vinca alkaloid such as
vincristine, vinblastine, vindesine or vinorelbine, or a taxoid
such as taxol or taxotere); or a topoisomerase inhibitor (for
example an epipodophyllotoxin such as etoposide, teniposide,
amsacrine, topotecan or a camptothecin); (ii) a cytostatic agent
such as an antioestrogen (for example tamoxifen, toremifene,
raloxifene, droloxifene or iodoxyfene), an oestrogen receptor down
regulator (for example fulvestrant), an antiandrogen (for example
bicalutamide, flutamide, nilutamide or cyproterone acetate), a LHRH
antagonist or LHRH agonist (for example goserelin, leuprorelin or
buserelin), a progestogen (for example megestrol acetate), an
aromatase inhibitor (for example as anastrozole, letrozole,
vorazole or exemestane) or an inhibitor of 5.alpha.-reductase such
as finasteride; (iii) an agent which inhibits cancer cell invasion
(for example a metalloproteinase inhibitor like marimastat or an
inhibitor of urokinase plasminogen activator receptor function);
(iv) an inhibitor of growth factor function, for example: a growth
factor antibody (for example the anti-erb b2 antibody trastuzumab,
or the anti-erb b1 antibody cetuximab [C225]), a farnesyl
transferase inhibitor, a tyrosine kinase inhibitor or a
serine/threonine kinase inhibitor, an inhibitor of the epidermal
growth factor family (for example an EGFR family tyrosine kinase
inhibitor such as
N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoli-
n-4-amine (gefitinib, AZD1839),
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine
(erlotinib, OSI-774) or
6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazoli-
n-4-amine (CI 1033)), an inhibitor of the platelet-derived growth
factor family, or an inhibitor of the hepatocyte growth factor
family; (v) an antiangiogenic agent such as one which inhibits the
effects of vascular endothelial growth factor (for example the
anti-vascular endothelial cell growth factor antibody bevacizumab,
a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO
98/13354), or a compound that works by another mechanism (for
example linomide, an inhibitor of integrin .alpha.v.beta.3 function
or an angiostatin); (vi) a vascular damaging agent such as
combretastatin A4, or a compound disclosed in WO 99/02166, WO
00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213;
(vii) an agent used in antisense therapy, for example one directed
to one of the targets listed above, such as ISIS 2503, an anti-ras
antisense; (viii) an agent used in a gene therapy approach, for
example approaches to replace aberrant genes such as aberrant p53
or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug
therapy) approaches such as those using cytosine deaminase,
thymidine kinase or a bacterial nitroreductase enzyme and
approaches to increase patient tolerance to chemotherapy or
radiotherapy such as multi-drug resistance gene therapy; or, (ix)
an agent used in an immunotherapeutic approach, for example ex-vivo
and in-vivo approaches to increase the immunogenicity of patient
tumour cells, such as transfection with cytokines such as
interleukin 2, interleukin 4 or granulocyte-macrophage colony
stimulating factor, approaches to decrease T-cell anergy,
approaches using transfected immune cells such as
cytokine-transfected dendritic cells, approaches using
cytokine-transfected tumour cell lines and approaches using
anti-idiotypic antibodies.
[0137] The invention will now be illustrated by the following
non-limiting examples in which, unless stated otherwise:
(i) when given, .sup.1H NMR data is quoted and is in the form of
delta values for major diagnostic protons, given in parts per
million (ppm) relative to tetramethylsilane (TMS) as an internal
standard, determined at 300 MHz or 400 MHz using perdeuterio
DMSO-D6 (CD.sub.3SOCD.sub.3) or CDCl.sub.3 as the solvent unless
otherwise stated; (ii) mass spectra (MS) were run with an electron
energy of 70 electron volts in the chemical ionisation (CI) mode
using a direct exposure probe; where indicated ionisation was
effected by electron impact (EI) or fast atom bombardment (FAB);
where values for m/z are given, generally only ions which indicate
the parent mass are reported, and unless otherwise stated the mass
ion quoted is the positive mass ion--(M+H)'; (iii) the title and
sub-title compounds of the examples and methods were named using
either the name program from Advanced Chemistry Development Inc,
version 6.00; or the index name program from Ogham with the
stereochemical descriptors being added by hand (see
www.eyesopen.com/products/applications/ogham.html); (iv) unless
stated otherwise, reverse phase HPLC was conducted using a
"Symmetry", "NovaPak" or "Xterra" reverse phase silica column, all
available from Waters Corp.; (v) for analytical HPLC the following
conditions were used: Reverse phase analytical HPLC (Hewlett
Packard Series 1100) using Waters "Symmetry" C8 column 3.5 .mu.m;
4.6.times.50 mm column using 0.1% ammonium acetate/acetonitrile
gradients at 2 mL/min given as % aqueous STANDARD 75% to 5% over 3
min FAST 45% to 5% over 2.5 min
MEDIUM FAST 65% to 5% in 2.5 min
SLOW 95% to 50% in 2.5 min
[0138] SUPERSLOW 100% to 80% in 2.5 min;
(vi) Method for X-Ray Powder Diffractometry (XRPD)
[0139] Analyses were performed on a Siemens model D5000 fitted with
a position sensitive detector (PSD), a Philips X' pert Pro fitted
with an X' celerator detector or a Rigaku MiniFlex X-ray powder
diffractometer fitted with a scintillation detector. Samples (1-2
mg) were sprinkled on a silicon wafer zero-background holder and
irradiated with copper K.sub..alpha. radiation (.lamda.=1.54056
.ANG.). Reflections were collected between 2.017-39.967.degree.
2.theta., typically at a step size of 0.033.degree. 2.theta.. Other
parameters for these analyses were: [0140] Generator=45 kV 40 mA
[0141] Scan time .about.30 min [0142] Measured time/step=200.025
sec [0143] Divergence slit fixed=1.0 [0144] Scan axis=Gonio [0145]
PSD length=2.122 [0146] PSD mode=scanning [0147] Incident beam
monochromator [0148] Sample=spinning and (v) the following
abbreviations are used:
TABLE-US-00001 [0148] RPHPLC Reverse phase high pressure liquid
chromatography min minutes DMEM tissue culture medium Dulbecco's
Modified Eagles Medium PSG a combination of penicillin,
streptomycin and L-glutamine FCS foetal calf serum NEAA
Non-essential amino acids h hour THF Tetrahydrofuran LC/MS HPLC
coupled with mass spectrometry SCX Strong cation exchange resin
(Isolute SCX-2)
PREPARATION 1
2-Chloro-4-({1-[(3,4-dihydroxycyclopentyl)methyl]piperidin-4-yl}oxy)-3-met-
hylbenzonitrile
A
2-Chloro-4-{[1-(cyclopent-3-en-1-ylmethyl)piperidin-4-yl]oxy}-3-methylbe-
nzonitrile
[0149] 2-Chloro-3-methyl-4-(piperidin-4-yloxy)benzonitrile (1.3 g)
and acetic acid (0.32 ml) were combined in THF (20 ml). Sodium
triacetoxyborohydride was added (1.4 g) followed by
cyclopent-3-ene-1-carbaldehyde (0.62 g). The reaction was stirred
for 1 h and then concentrated. The residue was partitioned between
aqueous sodium bicarbonate solution and dichloromethane. The
organic phase was washed with brine, dried, filtered and
evaporated. The residue was purified by chromatography eluting with
ethyl acetate to give the subtitle compound (1.5 g).
[0150] .sup.1H NMR .delta..sub.(CDCl3): 1.78-1.90 (2H, m),
1.93-2.14 (4H, m), 2.28-2.39 (7H, m), 2.41-2.53 (3H, m), 2.63-2.72
(2H, m), 4.38-4.48 (1H, m), 5.64 (2H, s), 6.79 (1H, d), 7.46 (1H,
d).
[0151] MS (ES+ve) 331/333 (M+H)+
[0152] Retention time (standard) 2.66
B
2-Chloro-4-({1-[(3,4-dihydroxycyclopentyl)methyl]piperidin-4-yl}oxy)-3-m-
ethylbenzonitrile
[0153]
2-Chloro-4-(1-cyclopent-3-enylmethyl-piperidin-4-yloxy)-3-methyl-be-
nzonitrile (1.5 g), potassium osmate (vi) dihydrate (0.042 g) and
4-methylmorpholine 4-oxide monohydrate (3.2 ml of a 50% soln in
water) were added to acetone (40 ml) and water (5 ml). The reaction
mixture was heated under reflux for 1 h. LC/MS showed complete
conversion to the desired diol. The reaction was allowed to cool to
room temperature and then sodium metabisulfite solution was added.
The reaction mixture was extracted with dichloromethane, then
sodium bicarbonate solution was added and the aqueous mixture was
extracted again with dichloromethane. The organic extracts were
combined and evaporated. The residue was loaded onto an SCX
cartridge and eluted with dichloromethane/methanol and then with
0.7M ammonia in methanol to give the title compound (1.3 g).
[0154] .sup.1H NMR .delta..sub.(CDCl3): 1.42-1.64 (2H, m),
1.78-2.14 (4H, m), 2.23-2.47 (9H, m), 2.51-2.86 (4H, m), 3.72 (1H,
t), 3.92-4.18 (2H, m), 4.38-4.50 (1H, m), 6.78 (1H, d), 7.46 (1H,
d).
[0155] MS (ES+ve) 365/367 (M+H)+
[0156] Retention time (standard) 1.53
INTERMEDIATE 1
[0157] This illustrates the preparation of methyl
2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piperidyl]-
-3-(4-fluorophenyl)-propanoate
[0158]
4-[4-(3,4-Dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-cyclopen-
tane-1,2-diol (0.50 g) was stirred with acetic acid (0.077 ml) in
water until it dissolved. Sodium periodate (0.286 g) was added and
the reaction mixture was stirred, under nitrogen, for 15 min. The
reaction mixture was neutralised by addition of potassium carbonate
(240 mg) and product was extracted with dichloromethane. The
dichloromethane was washed with brine, dried (MgSO.sub.4), and
filtered into a reaction flask containing
2-amino-3-(4-fluoro-phenyl)-propionic acid methyl ester (0.312 g),
sodium triacetoxy borohydride (0.651 g) and acetic acid (0.077 ml)
in dichloromethane (10 ml). The mixture was stirred at room
temperature for 1 h. A saturated solution of sodium bicarbonate was
added and product was extracted with dichloromethane. The
dichloromethane was washed with brine, dried (MgSO.sub.4), filtered
and concentrated. Crude product was purified by flash
chromatography eluting with ethyl acetate to give the title
compound (0.52 g).
[0159] .sup.1H NMR .delta..sub.(CDCL3): 1.08-1.29 (m, 2H),
1.41-1.63 (m, 1H), 1.69-1.86 (m, 4H), 1.90-2.00 (m, 2H), 2.14-2.39
(m, 9H), 2.57-2.68 (m, 2H), 2.82-2.95 (m, 2H), 2.97-3.09 (m, 2H),
3.39 (dd, 1H), 3.59 (s, 3H), 4.22-4.33 (m, 1H), 6.71 (d, 1H),
6.90-7.03 (m, 2H), 7.11-7.23 (m, 3H).
[0160] The following Intermediates were prepared analogously from
the appropriate amino esters and diols (diols not previously
described were prepared analogously to WO2004087659):
TABLE-US-00002 MS Retention Inter- [M + H].sup.+ time (fast mediate
Name (ES+) gradient) .sup.1H NMR .delta..sub.(CD3OD) 2 Methyl
(2S)-2-[4-[[4- 2.41 (3,4-dichloro-2-methyl- phenoxy)-1-
piperidyl]methyl]-1- piperidyl]-3-(2- methoxyphenyl)- propanoate 3
Methyl (2S)-3-(4- 0.97-1.14 (m, 2H), 1.37- cyanophenyl)-2-[4-[[4-
1.52 (m, 1H), 1.58-1.76 (3,4-dichloro-2-methyl- (m, 4H), 1.84-1.95
(m, phenoxy)-1- 2H), 2.10-2.15 (m, 2H), piperidyl]methyl]-1-
2.16-2.39 (m, 7H), 2.53- piperidyl]-propanoate 2.63 (m, 2H),
2.73-2.81 (m, 1H), 2.89-2.99 (m, 3H), 3.35-3.42 (m, 1H), 3.50 (s,
3H), 4.27-4.37 (m, 1H), 6.81 (d, 1H), 7.17 (d, 1H), 7.30 (d, 2H),
7.53 (d, 2H) 4 Methyl (2S)-2-(4-{[4- 537/539 2.23
(3,4-dichlorophenoxy)- piperidin-1- yl]methyl}piperidin-1-
yl)-3-(4-fluorophenyl)- 2-methylpropanoate 5 Methyl
(2S)-2-[4-[[4-(4- 517/519 2.20 chloro-2-methyl- phenoxy)-1-
piperidyl]methyl]-1- piperidyl]-3-(4- fluorophenyl)-2-methyl-
propanoate 6 Methyl (2S)-2-[4-[[4- 551/553 2.54
(3,4-dichloro-2-methyl- phenoxy)-1- piperidyl]methyl]-1-
piperidyl]-3-(4- fluorophenyl)-2-methyl- propanoate 7 (.+-.)-Methyl
2-[4-[[4- 519/521 2.24 (3,4-dichlorophenoxy)-
1-piperidyl]methyl]-1- piperidyl]-2-methyl-3- phenyl-propanoate 10
(.+-.)-Methyl 2-[4-[[4- 533/535 2.69 (3,4-dichloro-2-methyl-
phenoxy)-1- piperidyl]methyl]-1- piperidyl]-2-methyl-3-
phenyl-propanoate 13 Methyl (2S)-2-[4-[[4- 533/535 2.66
(3,4-dichloro-2-ethyl- phenoxy)-1- piperidyl]methyl]-1-
piperidyl]-3- phenylpropanoate 14 Methyl (2S)-2-[4-[[4- 551/553
2.71 (3,4-dichloro-2-ethyl- phenoxy)-1- piperidyl]methyl]-1-
piperidyl]-3-(4- fluorophenyl)- propanoate 15 Methyl
(2S)-2-(4-{[4-(3- 1.14-1.33 (2H, m), 1.50- chloro-4-cyano-2- 1.65
(1H, m), 1.74-1.92 methylphenoxy)- (4H, m), 2.00-2.11 (2H,
piperidin-1- m), 2.24-2.30 (3H, m), yl]methyl}piperidin-1- 2.33
(3H, s), 2.36-2.46 yl)-3-phenylpropanoate (3H, m), 2.64-2.74 (2H,
m), 2.94-3.10 (4H, m), 3.45 (1H, dd), 3.57 (3H, s), 4.58-4.66 (1H,
m), 7.09 (1H, d), 7.16-7.30 (5H, m), 7.61 (1H, d) 16 Methyl
(2S)-2-(4-{[4-(3- 2.82 1.08-1.29 (m, 2H), 1.41- chloro-4-cyano-2-
(standard 1.63 (m, 1H), 1.69-1.86 methylphenoxy)- gradient) (m,
4H), 1.90-2.00 (m, piperidin-1- 2H), 2.14-2.39 (m, 9H),
yl]methyl}piperidin-1- 2.57-2.68 (m, 2H), 2.82- yl)-3-(4- 2.95 (m,
2H), 2.97-3.09 fluorophenyl)propanoate (m, 2H), 3.39 (dd, 1H), 3.59
(s, 3H), 4.22-4.33 (m, 1H), 6.71 (d, 1H), 6.90- 7.03 (m, 2H),
7.11-7.23 (m, 3H) 17 Methyl (2S)-2-[4-[[4- 537/539 1.12-1.32 (2H,
m), 1.49- (2,4-dichloro-3-methyl- 1.64 (1H, m), 1.73-1.92
phenoxy)-1- (4H, m), 1.95-2.06 (2H, piperidyl]methyl]-1- m), 2.25
(2H, d), 2.30- piperidyl]-3-(4- 2.43 (3H, m), 2.47 (3H, s),
fluorophenyl)- 2.66-2.77 (2H, m), 2.89- propanoate 3.06 (4H, m),
3.42 (1H, dd), 3.58 (3H, s), 3.67- 3.73 (1H, m), 4.43-4.52 (1H, m),
6.94-7.07 (3H, m), 7.18-7.29 (3H, m) 18 Methyl (2S)-2-[4-[[4-(4-
1.11-1.33 (2H, m), 1.49- chloro-2-methyl- 1.66 (1H, m), 1.73-1.88
phenoxy)-1- (4H, m), 1.97-2.07 (2H, piperidyl]methyl]-1- m), 2.20
(3H, s), 2.23- piperidyl]-3-(4- 2.28 (3H, m), 2.30-2.44
fluorophenyl)- (3H, m), 2.66-2.76 (2H, propanoate m), 2.91-3.08
(4H, m), 3.39-3.46 (1H, m), 3.58 (3H, s), 4.36-4.44 (1H, m), 6.89
(1H, d), 6.96- 7.04 (2H, m), 7.07-7.14 (2H, m), 7.18-7.25 (2H, m)
19 Methyl (2S)-2-[4-[[4- 1.12-1.32 (2H, m), 1.49-
(2,4-dichloro-phenoxy)- 1.64 (1H, m), 1.73-1.91
1-piperidyl]methyl]-1- (4H, m), 1.95-2.05 (2H, piperidyl]-3-(4- m),
2.22-2.28 (2H, m), fluorophenyl)- 2.30-2.43 (3H, m), 2.67-
propanoate 2.77 (2H, m), 2.90-3.07 (4H, m), 3.42 (1H, dd), 3.58
(3H, s), 3.69-3.73 (1H, m), 4.43-4.53 (1H, m), 6.96-7.11 (3H, m),
7.18-7.27 (3H, m), 7.41 (1H, d)
INTERMEDIATES 8 & 9
[0161] This illustrates the preparation of the 2 enantiomers of
methyl
2-[4-[[4-(3,4-dichlorophenoxy)-1-piperidyl]methyl]-1-piperidyl]-2-methyl--
3-phenyl-propanoate
[0162] (.+-.)-Methyl
2-[4-[[4-(3,4-dichlorophenoxy)-1-piperidyl]methyl]-1-piperidyl]-2-methyl--
3-phenyl-propanoate (185 mg) was eluted through a Chiralpak AD HPLC
column in ethanol containing 0.1% diethylamine to give two
enantiomers.
[0163] Isomer 1 (76 mg) retention time (Chiralpak AD 4.6.times.250
mm; 0.5 ml/min ethanol) 7.68 min.
[0164] Isomer 2 (73 mg) retention time (Chiralpak AD 4.6.times.250
mm; 0.5 ml/min ethanol) 9.57 min.
INTERMEDIATES 11 & 12
[0165] This illustrates the preparation of the 2 enantiomers of
methyl
2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piperidyl]-
-2-methyl-3-phenyl-propanoate
[0166] These were prepared following the method of Intermediates 8
& 9 using (.+-.)-methyl
2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piperidyl]-
-2-methyl-3-phenyl-propanoate to give two enantiomers.
[0167] Isomer 3 retention time (Chiralpak AD 4.6.times.250 mm; 0.5
ml/min ethanol containing 0.1% diethylamine) 12.58 min.
[0168] Isomer 4 retention time (Chiralpak AD 4.6.times.250 mm; 0.5
ml/min ethanol containing 0.1% diethylamine) 15.76 min.
INTERMEDIATE 20
[0169] This illustrates the preparation of methyl
2-benzyl-2-(4-{[4-(3,4-dichlorophenoxy)piperidin-1-yl]methyl}piperidin-1--
yl)butanoate
[0170] This compound was prepared following the method of Example 1
using 2-amino-2-benzyl-butyric acid methyl ester and
4-[4-(3,4-dichloro-phenoxy)-piperidin-1-ylmethyl]-cyclopentane-1,2-diol.
[0171] MS (ESI.sup.+) 533/535 (M+H.sup.+)
[0172] RT (fast gradient) 2.94 min.
INTERMEDIATE 21
[0173] This illustrates the preparation of
4-(3,4-dichloro-2-methyl-phenoxy)-piperidine hydrochloride
[0174] 4-Hydroxypiperidine (32.5 g) and potassium tert-butoxide
(62.7 g) were added to a 1 L jacketed vessel. Tetrahydrofuran (275
mL) was added followed by N-methylpyrrolidone (25 mL).
1,2-Dichloro-4-fluoro-3-methylbenzene (50 g) in tetrahydrofuran
(100 mL) was then added, followed by tetrahydrofuran (100 mL). The
mixture was heated to 67.degree. C. overnight then cooled to
50.degree. C. Water (250 mL) was added and the mixture was stirred
for 10 min at 50.degree. C. The layers were separated and the
heating was removed. The organic layer was washed with twice with
10% w/w brine (250 mL). The organic layer was heated to remove
solvent by distillation firstly at atmospheric pressure and then
under vacuum (400 mbar) whilst isopropanol (950 mL) was added until
the tetrahydrofuran was replaced by isopropanol. The solution was
then heated to 50.degree. C. Hydrogen chloride in isopropanol
(5.5M, 125 mL) was added, an exotherm to 60.degree. C. was observed
and the solution was cooled to 50.degree. C. The mixture was cooled
from 50.degree. C. to 10.degree. C. over 1 h and then stirred
overnight at 10.degree. C. The product was collected by filtration,
washed with isopropanol (50 mL) and dried under vacuum at
40.degree. C. to give 4-(3,4-dichloro-2-methyl-phenoxy)-piperidine
hydrochloride as an off-white solid (62.3 g).
[0175] .sup.1H NMR .delta..sub.(CDCL3) 2.17 (2H, dd), 2.29-2.39
(2H, m), 2.34 (3H, s), 3.33 (4H, dd), 4.61-4.66 (1H, m), 6.68 (1H,
d), 7.25 (1H, d), 9.64-9.83 (1H, m).
INTERMEDIATE 22
[0176] This illustrates the preparation of
4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperidine-1-c-
arboxylic acid tert-butyl ester
[0177] Acetonitrile (144 mL) and water (336 mL) were added to a
mixture of 4-(3,4-dichloro-2-methyl-phenoxy)-piperidine
hydrochloride (60 g),
4-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acid
tert-butyl ester (74.7 g) and potassium carbonate (57.3 g) and the
mixture was heated to reflux for 7 h, then cooled over 30 min to
75.degree. C. and held at 75.degree. C. for 14 h, then heated over
30 min to reflux. Acetonitrile (192 mL) was added and then the
mixture was cooled to 20.degree. C. over 2 h to give a suspension.
The suspension was filtered under vacuum, the filter cake was
washed with water (180 mL) and then with acetonitrile (180 mL) and
dried under vacuum at 40.degree. C. to give
4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperidin-
e-1-carboxylic acid tert-butyl ester as a white solid (73.9 g).
[0178] .sup.1H NMR .delta..sub.(CD3OD) 0.99-1.12 (2H, m), 1.45 (9H,
s), 1.69-1.85 (5H, m), 1.95-2.04 (2H, m), 2.23 (2H, d), 2.31 (3H,
s), 2.32-2.40 (2H, m), 2.64-2.82 (4H, m), 4.05 (2H, d), 4.38-4.46
(1H, m), 6.91 (1H, d), 7.27 (1H, d)
INTERMEDIATE 23
[0179] This illustrates the preparation of
4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperidine
di-benzenesulfonate salt
[0180] A suspension of
4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperidine-1-c-
arboxylic acid tert-butyl ester (120 g) and ethanol (600 mL) were
heated to 75.degree. C. to give a solution. Benzenesulfonic acid
(70% in water, 144.2 g) in ethanol (120 mL) was added dropwise over
45 min followed by a rinse with ethanol (60 mL). The solution was
heated at 75.degree. C. for 1 h and was then cooled to 20.degree.
C. over 1 h 45 min. The resultant solid was collected, the filter
cake was washed with ethanol (480 mL) then dried under vacuum
overnight at 40.degree. C. to give
4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperidine
di-benzenesulfonate salt as a white solid (161.9 g).
[0181] .sup.1H NMR .delta..sub.(DMSO) 1.3-1.41 (2H, m), 1.89-1.93
(3H, m), 2.02-2.15, (4H, m), 2.25, s and 2.34 (3H, s), 2.83-2.94
(2H, m), 3.06-3.12, (4H, m), 3.28-3.36, (2H, m), 3.45-3.49, (1H,
m), 3.58-3.62 (1H, m) 4.5-4.65 and 4.78-4.84 (2.times.m, 1H) 7.09
and 7.14 (2.times.d, 1H), 7.3-7.37, (6H, m), 7.45 (1H, d);
7.59-7.63 (4H, m), 8.23 (1H, br s), 8.49 (1H, br s), 8.98 (1H, br
s).
INTERMEDIATE 24
[0182] This illustrates the preparation of
(R)-2-(4-nitro-benzenesulfonyloxy)-3-phenyl-propionic acid methyl
ester
[0183] Toluene (160 mL) was added to (R)-3-phenyllactic acid,
methyl ester (20 g) and p-nitrobenzenesulfonyl chloride (25.8 g) to
give a clear yellow solution which was cooled to 0.degree. C.
Triethylamine (16.4 mL) was added over 15 min, the mixture was
stirred at 3.degree. C. for 2 h and then overnight at room
temperature. Water (120 mL) was added and the reaction mixture
stirred at RT for 1 h. The layers were separated and the organic
layer was washed with water (120 mL). Toluene (20 mL) was added to
the resulting organic layer and the solution was heated to remove
solvent by distillation under vacuum (60 mbar) to leave 140 mL
solvent in the vessel. Isohexane (120 mL) was added at 40.degree.
C. and the mixture was stirred at this temperature overnight. The
mixture was then cooled to 25.degree. C. over 115 min and was then
filtered. The filter cake was washed with toluene (20 mL) and
isohexane (20 mL), then dried under vacuum at 40.degree. C. to give
(R)-2-(4-nitro-benzenesulfonyloxy)-3-phenyl-propionic acid methyl
ester as a cream solid (31.6 g).
[0184] .sup.1H NMR .delta..sub.(CDCl3) 3.0-3.08 (1H, dd), 3.2-3.26
(1H, dd), 3.78 (3H, s), 5.0-5.04 (1H, dd), 7.02-7.06 (2H, m),
7.12-7.2 (3H, m), 7.73-7.78 (2H, d), 8.13-8.18 (2H, d).
INTERMEDIATE 25
[0185] This illustrates the preparation of
(R)-3-(4-fluoro-phenyl)-2-(4-nitro-benzenesulfonyloxy)-propionic
acid methyl ester
[0186] (R)-3-(4-Fluorophenyl)-2-hydroxypropionic acid methyl ester
(20 g) and 4-nitrobenzenesulfonyl chloride (22.8 g) were dissolved
in methylisobutyl ketone (240 mL). The solution was cooled to
0-5.degree. C. and triethylamine (10.74 g) was added dropwise over
15 min. The reaction mixture was stirred at 0-5.degree. C. for 2
hours. Water (80 mL) was added and the mixture heated to
35-40.degree. C. to obtain a clear biphasic solution. The aqueous
layer was removed and the organic phase washed successively with
dilute hydrochloric acid (1M, 80 mL) and then water at
35-40.degree. C. The organic phase was concentrated by distillation
under reduced pressure at 35-40.degree. C. to a final volume of
about 120 mL. To the resulting slurry of the product was added
isohexane (120 mL) and the mixture cooled to 0-5.degree. C. for 2
h. The solid was filtered, washed with isohexane (60 mL) and then
dried in a vacuum oven at 40.degree. C. under reduced pressure to
yield the title compound as a yellow solid (32.64 g).
[0187] .sup.1H NMR .delta..sub.(CDCl3) 3.02-3.10 (1H, dd),
3.18-3.24 (1H, dd), 3.73 (3H, s), 6.85-6.91 (2H, m), 7.03-7.07 (2H,
m), 7.86 (2H, d), 8.25 (2H, d).
INTERMEDIATE 26
[0188] This illustrates the preparation of
(S)-2-{4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperid-
in-1-yl}-3-phenyl-propionic acid methyl ester
[0189] Water (90 mL) was added to
4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperidine
di-benzenesulfonate salt (30 g) to give a suspension. The
suspension was stirred at room temperature for 2 min to give a
clear solution. Tert-butyl methyl ether (150 mL) was then charged
in one portion and the vessel contents were warmed to 30.degree. C.
A solution of 10M Sodium Hydroxide (13.9 g) in water (90 mL) was
added over 2 min and the solution was stirred at 30.degree. C. for
10 min then the layers were separated. The organic layer was
evaporated to dryness, acetonitrile (100 mL) was added and the
evaporation was continued until the volume equalled 80 mL.
Acetonitrile (70 mL) was then added and to this solution was added
potassium carbonate (7.8 g) followed by a solution of
(R)-2-(4-nitro-benzenesulfonyloxy)-3-phenyl-propionic acid methyl
ester (16.3 g) in acetonitrile (30 mL). The resulting suspension
was heated to 60.degree. C. and held at this temperature overnight.
The mixture was cooled to 20.degree. C. then tert-butyl methyl
ether (150 mL) was added. The suspension was filtered and the
vessel and cake were washed with tert-butyl methyl ether (30 mL).
The filtrate was washed with 5% brine (90 mL). The layers were
separated and the organic layer was washed with ammonium
acetate/acetic acid solution (72 mL; 15 g Ammonium acetate in 1 L
0.5 M aqueous acetic acid) at 25.degree. C. and then warmed to
40.degree. C. whereupon hydrochloric acid (1M, 90 mL) was added.
The layers were separated, the organic layer was re-extracted with
hydrochloric acid (1M, 30 mL) and then the aqueous phases were
combined. Tert-butyl methyl ether (150 mL) and 2M Sodium Hydroxide
(90 mL) were added and the mixture stirred at 40.degree. C. for 10
min before the phases were separated. The organic phase was reduced
in vacuo to a low volume then ethanol (120 mL) was added and
distillation was continued for a short time till some of the
ethanol had been removed. Ethanol (5 mL) was added to the residue
(volume 90 mL) and the solution seeded with
(S)-2-{4-[4-(3,4-Dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperid-
in-1-yl}-3-phenyl-propionic acid methyl ester (50 mg) and the
mixture was cooled to 5.degree. C. over 3 h. A colourless solid was
collected by filtration, the cake was washed with ethanol (15 mL)
and the solid dried under vacuum at 35.degree. C. overnight to give
the title compound (16.3 g).
INTERMEDIATE 27
[0190] This illustrates the preparation of
(S)-{4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperidin-
-1-yl}-3-(4-fluoro-phenyl)-propionic acid methyl ester
[0191]
4-[4-(3,4-Dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperidi-
ne di-benzenesulfonate salt (40 g) was dissolved in water (120 mL).
To the stirred solution was added methyl t-butylether (320 mL),
followed by a solution of sodium hydroxide (10M, 22.25 mL) in water
(120 mL). The solution was heated at 25-30.degree. C. for 20
minutes. The organic layer was separated from the aqueous and about
200 mL of the solvent was removed by distillation at atmospheric
pressure. To the residue was added acetonitrile (200 mL) and
further solvent removed by distillation to a final volume of about
240 mL. Karl-Fisher analysis of this solution indicated 0.35% w/w
water was present. To this solution of the free base in
acetonitrile was added potassium carbonate (10.40 g) and a solution
of 3-(4-fluorophenyl)-2-(4-nitrobenzenesulfonyloxy)-propionic acid
methyl ester (22.80 g) in acetonitrile (24 mL--prepared by heating
the acetonitrile to 35.degree. C.). A small amount of solid residue
was washed in with acetonitrile (16 mL). The reaction mixture was
heated at 60-65.degree. C. for 16 h, then cooled to room
temperature and methyl t-butylether (200 mL) added. After stirring
at room temperature for 20 minutes, the precipitated salts were
filtered and washed with methyl t-butylether (40 mL). The filtrate
was stirred successively with sodium chloride solution (5% w/v in
water, 120 mL), ammonium acetate solution (96 mL, 0.2M ammonium
acetate in 0.5M aqueous acetic acid solution) and sodium chloride
solution (5% w/v, 120 mL), each for 10 minutes. The organic layer
was separated and solvent distilled off to a final volume of about
120 mL. To the residue was added acetonitrile (120 mL) and the
volume reduced to about 120 mL (the final distillate temperature
was 78-80.degree. C.). The residue was diluted with acetonitrile
(120 mL). A sample was withdrawn and evaporated and weighed to
indicate that this solution contained about 33 g of the title
compound in 240 mL of acetonitrile.
[0192] .sup.1H NMR .delta..sub.(CDCl3) 1.18-2.30 (2H, m), 1.4-1.56
(1H, m), 1.74-1.90 (4H, m), 1.90-1.93 (2H, m), 2.13-2.25 (5H, m),
2.3-2.4 (4H, m), 2.6-2.7 (2H, m), 2.8-2.98 (2H, m), 2.98-3.10 (2H,
m), 3.35-3.41 (1H, m), 3.6 (3H, s), 4.25-4.35 (1H, s), 6.9-6.70
(1H, d), 6.91-6.97 (2H, m), 7.12-7.26 (3H, m).
MS (ES+ve) 537 (M+H)+
INTERMEDIATE 28
[0193] This illustrates the preparation of
4-{[4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]methyl}cyclopentane-1,2-di-
ol
a)
4-(4-Chloro-2-methylphenoxy)-1-(cyclopent-3-en-1-ylcarbonyl)piperidine
[0194] 4-(4-Chloro-2-methylphenoxy)piperidine hydrochloride (28.6
g) and triethylamine (45.5 mL) were stirred in dichloromethane (100
mL) and cyclopent-3-ene-1-carbonyl chloride (14.26 g) in
dichloromethane (100 mL) was added dropwise. When addition was
complete, the reaction mixture was stirred at room temperature for
2 h. Water (250 mL) was added to the reaction mixture and product
was extracted with dichloromethane. The dichloromethane was washed
with brine, dried (MgSO.sub.4), filtered and concentrated in vacuo.
The crude product was filtered through a plug of silica eluting
with diethyl ether to give the subtitle compound (29.5 g).
[0195] Retention Time (standard): 2.63
[0196] MS (ES+): 320/322 [M+H].sup.+
[0197] .sup.1H NMR .delta..sub.(CDCL3) 1.76-1.98 (4H, m), 2.21 (3H,
s), 2.53-2.64 (2H, m), 2.69-2.77 (2H, m), 3.29-3.38 (1H, m),
3.46-3.54 (1H, m), 3.68-3.77 (3H, m), 4.49-4.56 (1H, m), 5.68 (2H,
d), 6.75 (1H, d), 7.06-7.15 (2H, m)
b)
4-{[4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]carbonyl}cyclopentane-1,-
2-diol
[0198]
4-(4-Chloro-2-methylphenoxy)-1-(cyclopent-3-en-1-ylcarbonyl)piperid-
ine (29.5 g), N-methylmorpholine-N-oxide (37 g) and potassium
osmate dihydrate (0.85 g) were stirred in a mixture of acetone (200
mL) and water (50 mL) overnight. A saturated solution of sodium
metabisulphite (200 mL) was added and the mixture was stirred for
15 min. Product was extracted with dichloromethane. The
dichloromethane was washed with ammonium chloride solution then
with brine, dried (MgSO.sub.4), filtered and concentrated in vacuo
to give the subtitle compound (32.0 g) as a mixture of 2
stereoisomers.
[0199] Retention Time (standard) 1.74 and 1.85 min
[0200] MS (ES+) 354/356 [M+H].sup.+; base peak: 226
c)
4-{[4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]methyl}cyclopentane-1,2--
diol
[0201]
4-{[4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]carbonyl}cyclopentan-
e-1,2-diol (32.0 g) was dissolved in tetrahydrofuran (100 mL) and
stirred, at room temperature, under nitrogen. Borane (1 M solution
in THF; 300 mL) was added dropwise and then the reaction mixture
was heated under reflux for 2 h. The reaction mixture was allowed
to cool slightly and methanol (60 mL) was added carefully. Heating
was resumed and continued overnight. The reaction mixture was
concentrated in vacuo and the residue was purified using SCX resin:
Non-basic impurities were eluted with methanol then product was
eluted with 0.7 M ammonia in methanol. Solvent was removed in vacuo
to give the title compound (30 g) as a mixture of 2
stereoisomers.
[0202] Retention Time (standard) 1.51
[0203] MS (ES+) 340/342 [M+H].sup.+
INTERMEDIATE 29
[0204] This illustrates the preparation of methyl
(2S)-2-(4-{[4-(4-chloro-2-methylphenoxy)piperidin-1-yl]methyl}piperidin-1-
-yl)-3-(4-fluorophenyl)-2-methylpropanoate
[0205]
4-{[4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]methyl}cyclopentane--
1,2-diol (13.18 g) was dissolved in water (85 ml). Acetic acid
(2.22 ml) and sodium periodate (8.38 g) were added. The mixture was
then stirred under nitrogen for 30 min. Potassium carbonate (6.97
g) was added and the solution was diluted with water and extracted
into chloroform (210 ml) and then dichloromethane (2.times.120 ml).
The combined extracts were washed with brine, dried over magnesium
sulfate and then poured directly into a solution of methyl
4-fluoro-.alpha.-methyl-L-phenylalaninate (8.196 g), sodium
triacetoxyborohydride (18.91 g) and acetic acid (2.22 ml) in
dichloromethane (35 ml). The resultant mixture was stirred under
nitrogen for 1 h. The solution was poured into saturated sodium
bicarbonate solution (1 l). The mixture was extracted with
dichloromethane (3.times.500 ml). The extracts were dried over
magnesium sulfate and evaporated in vacuo. The crude material was
purified by chromatography on neutral alumina (wetted with 5%
water, 1 kg) eluting with 1:1 isohexane:ethyl acetate to give the
subtitle compound (15.5 g) as an oil.
[0206] MS ESI (+ve) 517/519 (M+H).sup.+
[0207] Retention Time (fast gradient) 2.03 min.
INTERMEDIATE 30
[0208] This illustrates the preparation of methyl
(2R)-2-(4-{[4-(4-chloro-2-methylphenoxy)piperidin-1-yl]methyl}piperidin-1-
-yl)-3-(4-fluorophenyl)-2-methylpropanoate
[0209] Prepared following the method of Intermediate 29 using
methyl 4-fluoro-a-methyl-R-phenylalaninate.
[0210] MS ESI (+ve) 517/519 (M+H).sup.+
[0211] Retention Time (fast gradient) 2.24 min.
EXAMPLE 1
[0212] This Example illustrates the preparation of
(2S)-2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piper-
idyl]-3-(4-fluorophenyl)-propanoic acid
[0213] A solution of lithium hydroxide monohydrate (0.162 g) in
water was added to a stirred solution of
2-{4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperidin-1-
-yl}-3-(4-fluoro-phenyl)-propionic acid methyl ester (0.52 g) in
tetrahydrofuran (6 ml) and methanol (2 ml). The mixture was stirred
at room temperature overnight. Ammonium acetate (3 g) in water (5
mL) was added followed by ether (10 mL). The mixture was stirred
for 1 h then a white solid was collected by filtration. 100 mg was
further purified by RP HPLC (gradient ammonium acetate:acetonitrile
95:5-5:95) to give the title compound (80 mg).
[0214] MS [M-H].sup.- (APCI-) 521/523
[0215] Retention time (standard) 1.89
[0216] .sup.1H NMR .delta..sub.(CD3D): 1.15-1.39 (2H, m), 1.51-1.66
(1H, m), 1.74-1.88 (4H, m), 1.95-2.08 (2H, m), 2.25 (2H, d),
2.31-2.45 (7H, m), 2.64-2.74 (2H, m), 2.84 (1H, dd), 2.98-3.12 (3H,
m), 3.17 (1H, dd), 4.39-4.49 (1H, m), 6.90-6.98 (3H, m), 7.23-7.32
(3H, m).
[0217] The following compounds were prepared from the corresponding
ester using the method of Example 1:
TABLE-US-00003 MS [M + H].sup.+ Example Name (APCI+) .sup.1H NMR
.delta..sub.(CD3OD) 2 (2S)-2-[4-[[4-(3,4- 535/537 1.15-1.41 (2H,
m), 1.50-1.66 (1H, dichloro-2-methyl- m), 1.72-1.88 (4H, m),
1.95-2.06 phenoxy)-1- (2H, m), 2.25 (2H, d), 2.30-2.45 (7H,
piperidyl]methyl]-1- m), 2.63-2.75 (2H, m), 2.90 (1H, t),
piperidyl]-3-(2- 3.02-3.14 (3H, m), 3.25-3.37 (1H, methoxyphenyl)-
m), 3.83 (3H, s), 4.38-4.48 (1H, m), propanoic acid 6.80 (1H, t),
6.90 (2H, dd), 7.13 (1H, t), 7.22-7.31 (2H, m). 3 (2S)-3-(4-
530/532 1.15-1.36 (2H, m), 1.51-1.66 (1H, cyanophenyl)-2-[4- m),
1.74-1.88 (4H, m), 1.96-2.07 [[4-(3,4-dichloro-2- (2H, m), 2.25
(2H, d), 2.31-2.46 (7H, methyl-phenoxy)-1- m), 2.64-2.74 (2H, m),
2.93-3.22 piperidyl]methyl]-1- (5H, m), 4.39-4.49 (1H, m), 6.93
(1H, piperidyl]-propanoic d), 7.29 (1H, dd), 7.47 (2H, d), 7.60
acid (2H, dd) 13 (2S)-2-[4-[[4-(3,4- 519/521 1.12 (3H, t),
1.16-1.37 (2H, m), 1.48- dichloro-2-ethyl- 1.63 (1H, m), 1.71-1.86
(4H, m), 1.96- phenoxy)-1- 2.05 (2H, m), 2.23 (2H, d), 2.31-2.44
piperidyl]methyl]-1- (4H, m), 2.63-2.72 (2H, m), 2.76-
piperidyl]-3- 2.90 (3H, m), 2.94-3.03 (1H, m), 3.04-
phenylpropanoic acid 3.14 (2H, m), 3.18-3.25 (1H, m), 4.39-4.48
(1H, m), 6.90 (1H, d), 7.07- 7.13 (1H, m), 7.19 (2H, t), 7.23-7.29
(3H, m) 14 (2S)-2-[4-[[4-(3,4- 537/539 1.11 (3H, t), 1.16-1.35 (2H,
m), 1.50- dichloro-2-ethyl- 1.62 (1H, m), 1.71-1.86 (4H, m), 1.96-
phenoxy)-1- 2.05 (2H, m), 2.23 (2H, d), 2.30-2.43
piperidyl]methyl]-1- (4H, m), 2.62-2.71 (2H, m), 2.75-
piperidyl]-3-(4- 2.90 (3H, m), 2.95-3.09 (3H, m), 3.11-
fluorophenyl)- 3.19 (1H, m), 4.39-4.47 (1H, m), propanoic acid
6.87-6.95 (3H, m), 7.22-7.28 (3H, m) 15 (22S)-2-(4-{[4-(3- 494/496
1.16-1.39 (2H, m), 1.51-1.67 (1H, chloro-4-cyano-2- (M - H, m),
1.74-1.93 (4H, m), 2.00-2.11 methylphenoxy)- ES-) (2H, m), 2.26
(2H, d), 2.33 (3H, s), 2.35- piperidin-1- 2.47 (4H, m), 2.64-2.73
(2H, m), yl]methyl}piperidin-1- 2.85 (1H, dd), 2.99-3.16 (3H, m),
3.23 yl)-3-phenylpropanoic (1H, dd), 4.57-4.67 (1H, m), 7.07- acid
7.17 (2H, m), 7.19-7.31 (4H, m), 7.62 (1H, d) 16 (2S)-2-(4-{[4-(3-
514/516 1.13-1.32 (2H, m), 1.49-1.63 (1H, chloro-4-cyano-2- m),
1.74-1.91 (4H, m), 2.00-2.11 methylphenoxy)- (2H, m), 2.25 (3H, d),
2.33 (3H, s), 2.37- piperidin-1- 2.45 (3H, m), 2.63-2.74 (2H, m),
yl]methyl}piperidin-1- 2.91-3.08 (4H, m), 3.43 (1H, dd), 3.58
yl)-3-(4-fluorophenyl)- (3H, s), 4.56-4.66 (1H, m), 6.96-7.04
propanoic acid (2H, m), 7.09 (1H, d), 7.19-7.24 (2H, m), 7.61 (1H,
d) 17 (2S)-2-[4-[[4-(2,4- 523/525 1.16-1.39 (2H, m), 1.51-1.67 (1H,
dichloro-3-methyl- m), 1.74-1.91 (4H, m), 1.95-2.06 phenoxy)-1-
(2H, m), 2.25 (2H, d), 2.31-2.43 (4H, piperidyl]methyl]-1- m), 2.45
(3H, s), 2.66-2.76 (2H, m), piperidyl]-3-(4- 2.81-2.89 (1H, m),
3.00-3.18 (4H, fluorophenyl)- m), 4.42-4.51 (1H, m), 6.94 (3H, t),
propanoic acid 7.24-7.30 (3H, m) 18 (2S)-2-[4-[[4-(4- 489/491
1.16-1.39 (2H, m), 1.50-1.64 (1H, chloro-2-methyl- m), 1.75-1.87
(4H, m), 1.96-2.07 phenoxy)-1- (2H, m), 2.19 (3H, s), 2.25 (2H, d),
2.30- piperidyl]methyl]-1- 2.42 (4H, m), 2.64-2.74 (2H, m),
piperidyl]-3-(4- 2.86 (1H, dd), 3.00-3.17 (4H, m), 4.35-
fluorophenyl)- 4.44 (1H, m), 6.86-6.97 (3H, m), propanoic acid
7.07-7.12 (2H, m), 7.24-7.30 (2H, m) 19 (2S)-2-[4-[[4-(2,4- 509/511
1.16-1.39 (2H, m), 1.51-1.67 (1H, dichloro-phenoxy)-1- m),
1.74-1.91 (4H, m), 1.96-2.07 piperidyl]methyl]-1- (2H, m), 2.26
(2H, d), 2.33-2.44 (4H, piperidyl]-3-(4- m), 2.66-2.76 (2H, m),
2.87 (1H, d), fluorophenyl)- 3.06 (3H, t), 3.15 (1H, d), 4.44-4.54
propanoic acid (1H, m), 6.94 (2H, t), 7.10 (1H, d), 7.23- 7.31 (3H,
m), 7.40 (1H, dd)
EXAMPLE 4
[0218] This Example illustrates the preparation of
(S)-2-(4-{[4-(3,4-dichlorophenoxy)piperidin-1-yl]methyl}piperidin-1-yl)-3-
-(4-fluorophenyl)-2-methylpropanoic acid
[0219] A mixture of methyl
(S)-2-(4-{[4-(3,4-dichlorophenoxy)piperidin-1-yl]methyl}piperidin-1-yl)-3-
-(4-fluorophenyl)-2-methylpropanoate (123 mg), barium hydroxide
(130 mg), tetrahydrofuran (2 ml), water (1 ml) and methanol (1 ml)
were heated together in the microwave at 190.degree. C. for 2.5 h.
The mixture was then acidified with acetic acid (1 ml),
concentrated, and purified by reverse-phase hplc (95:5 0.1% aqueous
ammonium acetate/acetonitrile to 5:95 0.1% aqueous ammonium
acetate/acetonitrile over 10 minutes, symmetry column to give the
title compound (109 mg).
[0220] .sup.1H NMR .delta..sub.(CD3OD) 1.00 (3H, s), 1.18-1.35 (2H,
m), 1.48-1.62 (1H, m), 1.70-1.81 (4H, m), 1.94-2.04 (2H, m),
2.16-2.45 (6H, m), 2.71 (3H, d), 3.03-3.16 (2H, m), 3.23 (1H, d),
4.32-4.43 (1H, m), 6.89 (3H, t), 7.08 (1H, d), 7.25 (2H, t), 7.37
(1H, d).
[0221] MS (ES+ve) 523/525 (M+H).sup.+
[0222] The following compounds were prepared from the corresponding
ester using the method of Example 4:
TABLE-US-00004 MS [M + H].sup.+ Example Name (APCI+) .sup.1H NMR
.delta..sub.(CD3OD) 5 (S)-2-[4-[[4-(4-chloro-2- 503/505 1.00 (3H,
s), 1.20-1.36 (2H, m), 1.50- methyl-phenoxy)-1- 1.63 (1H, m),
1.71-1.85 (4H, m), 1.94- piperidyl]methyl]-1- 2.04 (2H, m), 2.17
(3H, s), 2.19-2.25 piperidyl]-3-(4- (3H, m), 2.29-2.44 (3H, m),
2.63-2.74 fluorophenyl)-2-methyl- (3H, m), 3.03-3.16 (2H, m), 3.22
(1H, propanoic acid d), 4.33-4.42 (1H, m), 6.85-6.92 (3H, m),
7.05-7.10 (2H, m), 7.25 (2H, dd) 6 (S)-2-[4-[[4-(3,4- 537/539 1.00
(3H, s), 1.21-1.36 (2H, m), 1.49- dichloro-2-methyl- 1.63 (1H, m),
1.71-1.86 (4H, m), 1.95- phenoxy)-1- 2.06 (2H, m), 2.16-2.26 (3H,
m), 2.28- piperidyl]methyl]-1- 2.44 (3H, m), 2.31 (3H, s),
2.62-2.75 piperidyl]-3-(4- (3H, m), 3.02-3.17 (2H, m), 3.22 (1H,
fluorophenyl)-2-methyl- d), 4.37-4.46 (1H, m), 6.85-6.93 (3H,
propanoic acid m), 7.21-7.29 (3H, m) 12 Isomer 4 of 2-[4-[[4-(3,4-
519/521 0.96 (3H, d), 1.15-1.33 (2H, m), 1.44- dichloro-2-methyl-
1.59 (1H, m), 1.66-1.82 (4H, m), 1.89- phenoxy)-1- 2.02 (2H, m),
2.08-2.43 (9H, m), 2.56- piperidyl]methyl]-1- 2.72 (4H, m), 3.05
(2H, d), 4.32-4.43 piperidyl]-2-methyl-3- (1H, m), 6.83-6.91 (1H,
m), 7.02-7.16 phenyl-propanoic acid (3H, m), 7.17-7.27 (3H, m)
EXAMPLE 11
[0223] This Example illustrates the preparation of Isomer 3 of
2-(4-{[4-(3,4-dichloro-2-methylphenoxy)piperidin-1-yl]methyl}piperidin-1--
yl)-2-methyl-3-phenylpropanoic acid.
[0224] Methyl
2-(4-{[4-(3,4-dichloro-2-methylphenoxy)piperidin-1-yl]methyl}piperidin-1--
yl)-2-methyl-3-phenylpropanoate (Isomer 3; 177 mg), 6M hydrochloric
acid (20 ml) and isopropyl alcohol (10 ml) were heated together at
98.degree. C. for 22 days. The mixture was then cooled,
concentrated and purified by reverse-phase hplc using 95:5 0.1%
aqueous ammonium acetate/acetonitrile to 5:95 0.1% aqueous ammonium
acetate/acetonitrile over 10 minutes, symmetry column, to give the
title compound (38 mg).
[0225] MS [M-H].sup.- 519/521 (APCI-)
[0226] .sup.1H NMR .delta..sub.(CD3OD): 1.01 (3H, s), 1.24-1.35
(2H, m), 1.50-1.62 (1H, m), 1.71-1.87 (4H, m), 1.96-2.05 (2H, m),
2.15-2.26 (4H, m), 2.30 (3H, s), 2.32-2.43 (2H, m), 2.61-2.75 (3H,
m), 3.01-3.18 (2H, m), 3.25 (1H, d), 4.38-4.46 (1H, m), 6.91 (1H,
d), 7.08-7.29 (6H, m).
[0227] The following compounds were prepared from the corresponding
ester using the method of Example 11:
TABLE-US-00005 MS [M + H].sup.+ Example Name (APCI+) .sup.1H NMR
.delta..sub.(CD3OD) 8 Isomer 1 of 2-[4-[[4-(3,4- 505/507 1.01 (3H,
s), 1.17-1.37 (2H, m), 1.50- dichlorophenoxy)-1- 1.62 (1H, m),
1.70-1.82 (4H, m), 1.94- piperidyl]methyl]-1- 2.06 (2H, m),
2.15-2.47 (6H, m), 2.66- piperidyl]-2-methyl-3- 2.76 (4H, m),
3.05-3.18 (2H, m), 4.34- phenyl-propanoic acid 4.42 (1H, m), 6.88
(1H, dd), 7.07-7.13 (2H, m), 7.17 (2H, t), 7.25 (2H, d), 7.37 (1H,
d) 9 Isomer 2 of 2-[4-[[4-(3,4- 505/507 1.01 (3H, s), 1.19-1.36
(2H, m), 1.50- dichlorophenoxy)-1- 1.63 (1H, m), 1.76 (4H, d),
1.95-2.04 piperidyl]methyl]-1- (2H, m), 2.16-2.26 (4H, m), 2.31
(2H, t), piperidyl]-2-methyl-3- 2.43 (1H, t), 2.65-2.76 (3H, m),
3.13 phenyl-propanoic acid (2H, t), 4.34-4.43 (1H, m), 6.87-6.90
(1H, m), 7.08-7.13 (2H, m), 7.17 (2H, t), 7.25 (2H, d), 7.37 (1H,
d) 10 (.+-.)-2-[4-[[4-(3,4- 519/521 1.01 (3H, s), 1.24-1.35 (2H,
m), 1.50- dichloro-2-methyl- 1.62 (1H, m), 1.71-1.87 (4H, m), 1.96-
phenoxy)-1- 2.05 (2H, m), 2.15-2.26 (4H, m), 2.30
piperidyl]methyl]-1- (3H, s), 2.32-2.43 (2H, m), 2.61-2.75
piperidyl]-2-methyl-3- (3H, m), 3.01-3.18 (2H, m), 3.25 (1H,
phenyl-propanoic acid d), 4.38-4.46 (1H, m), 6.91 (1H, d), 7.08-
7.29 (6H, m)
EXAMPLE 20
[0228] This Example illustrates the preparation of
(2S)-2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piper-
idyl]-3-phenylpropanoic acid sodium salt
[0229]
(2S)-2-[4-[[4-(3,4-Dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-
-piperidyl]-3-phenylpropanoic acid (1.0 g) was suspended in
methanol. Sodium hydroxide (79 mg) in water (1 ml) was added and
the resulting solution was stirred for 1 h and then the solvent was
evaporated. The residue was dissolved in ethanol (50 ml) at reflux
and then allowed to cool. The volume was reduced to 30 ml by
evaporation and the resulting solution was left to crystallise
overnight. Collection of the resultant crystals gave the title
compound (0.6 g).
[0230] Melting point: 227-229.degree. C.
[0231] 2.48% water by Karl Fisher analysis
[0232] .sup.1H NMR .delta..sub.(CD3OD): 1.10-1.26 (2H, m),
1.43-1.53 (1H, m), 1.62-1.75 (4H, m), 1.85-1.95 (2H, m), 2.13 (2H,
d), 2.21 (3H, s), 2.18-2.27 (2H, m), 2.33 (2H, t), 2.53-2.62 ((2H,
m), 2.67-2.75 (1H, m), 2.86-2.95 (1H, m), 2.96-3.07 (2H, m),
3.11-3.17 (1H, m), 4.26-4.36 (1H, m), 6.81 (1H, d), 7.01 (1H, t),
7.10 (2H, t), 7.13-7.20 (3H, m).
EXAMPLE 21
[0233] This Example illustrates the preparation of
(2S)-2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piper-
idyl]-3-(4-fluorophenyl)-propanoic acid sodium salt
[0234] This compound was prepared following the method of Example
20 using
(2S)-2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piper-
idyl]-3-(4-fluorophenyl)-propanoic acid and recrystallising by
stirring with isopropanol.
[0235] Melting point: 230-232.degree. C.
[0236] .sup.1H NMR .delta..sub.(CD3OD) 1.13-1.40 (2H, m), 1.53-1.68
(1H, m), 1.75-1.89 (4H, m), 1.96-2.08 (2H, m), 2.25 (2H, d),
2.31-2.50 (7H, m), 2.66-2.75 (2H, m), 2.82 (1H, dd), 2.98-3.15 (3H,
m), 3.22 (1H, dd), 4.38-4.49 (1H, m), 6.91-7.00 (3H, m), 7.25-7.32
(3H, m).
EXAMPLE 22
[0237] This Example illustrates the preparation of
(2S)-2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piper-
idyl]-3-(4-fluorophenyl)-propanoic acid potassium salt
[0238] This compound was prepared following the method of Example
20 using
(2S)-2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piper-
idyl]-3-(4-fluorophenyl)-propanoic acid and potassium hydroxide.
The initial product from evaporation of the solvent was resuspended
in methanol and evaporated and then suspended in diethyl ether and
evaporated to give the title compound.
[0239] Melting point: 210-214.degree. C.
EXAMPLE 23
[0240] This Example illustrates the preparation of
(2S)-2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piper-
idyl]-3-phenylpropanoic acid methanesulfonic acid salt
[0241]
(2S)-2-[4-[[4-(3,4-Dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-
-piperidyl]-3-phenylpropanoic acid (1.0 g) was suspended in
methanol-water (3:1, 30 mL). Methanesulfonic acid (190 mg) was
added and the mixture was heated under reflux until solution was
obtained. The solution was cooled and the solvent was evaporated.
Recrystallisation from ethanol gave the title compound (0.9 g)
[0242] Melting point: 225-228.degree. C.
[0243] 3.09% water by Karl Fisher analysis
[0244] .sup.1H NMR .delta..sub.(CD3OD) 1.54-1.71 ((2H, m),
2.00-2.29 (7H, m), 2.35 (3H, s), 2.70 (3H, s), 2.98-3.07 (2H, m),
3.10 (2H, d), 3.23 (2H, d), 3.27-3.43 (4H, m), 3.53 (1H, d), 3.65
(1H, d), 3.75-3.84 (1H, m), 4.63-4.73 (1H, m), 6.96 (1H, d),
7.20-7.26 (1H, m), 7.26-7.39 (5H, m).
EXAMPLE 24
[0245] This Example illustrates the preparation of
(2S)-2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piper-
idyl]-3-phenylpropanoic acid benzenesulfonic acid salt
[0246] This compound was prepared following the method of Example
23 using benzenesulfonic acid. The salt crystallised directly on
cooling the initial solution.
[0247] Melting point: 160-162.degree. C.
[0248] 2.4% water by Karl Fisher analysis.
[0249] .sup.1H NMR .delta..sub.(CD3OD) 1.55-1.71 (2H, m), 2.00-2.27
(7H, m), 2.34 (3H, s), 2.98-3.13 (4H, m), 3.23 (2H, d), 3.26-3.43
(4H, m), 3.52 (1H, d), 3.64 (1H, d), 3.79 (1H, t), 4.61-4.71 (1H,
m), 6.96 (1H, d), 7.19-7.26 (1H, m), 7.27-7.35 (5H, m), 7.39-7.46
(3H, m), 7.81-7.86 (2H, m).
EXAMPLE 25
[0250] This Example illustrates the preparation of
(2S)-2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piper-
idyl]-3-(4-fluorophenyl)-propanoic acid benzenesulfonic acid
salt
[0251] This compound was prepared following the method of Example
24.
[0252] Melting point: 259-260.degree. C.
EXAMPLE 26
[0253] This Example illustrates the preparation of
(2S)-2-[4-[[4-(3,4-dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-piper-
idyl]-3-(4-fluorophenyl)-propanoic acid hydrochloride
[0254]
(2S)-2-[4-[[4-(3,4-Dichloro-2-methyl-phenoxy)-1-piperidyl]methyl]-1-
-piperidyl]-3-(4-fluorophenyl)-propanoic acid (0.75 g) was
suspended in ether and a solution of HCl in dioxane (4M, 0.37 mL)
was added. The mixture was stirred overnight and then evaporated.
The residue was treated with ether and then evaporated and this
procedure was repeated several times until a free-flowing solid was
obtained. This solid was dried under vacuum at 50.degree. C.
overnight. The resultant solid was suspended in methanol with
warming and then collected and dried to give the title compound
(0.55 g)
[0255] Melting point: 281-283.degree. C.
EXAMPLE 26
[0256] This illustrates the preparation of
2-Benzyl-2-(4-{[4-(3,4-dichlorophenoxy)piperidin-1-yl]methyl}piperidin-1--
yl)butanoic acid
[0257] This compound was prepared from methyl
2-benzyl-2-(4-{[4-(3,4-dichlorophenoxy)piperidin-1-yl]methyl}piperidin-1--
yl)butanoate following the method of Example 4 to give the title
compound
[0258] MS (APCI.sup.+) 519/521 (M+H.sup.+)
EXAMPLE 27
[0259] This illustrates the preparation of
(S)-2-{4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperid-
in-1-yl}-3-phenyl-propionic acid
[0260] Tetra-n-butylammonium hydroxide (3.12 g) was dissolved in
acetonitrile (5 mL) and added to a suspension of
(S)-2-{4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperid-
in-1-yl}-3-phenyl-propionic acid methyl ester (1.0 g) in
acetonitrile (9 mL) at room temperature. The mixture was stirred at
this temperature for 3 h then methyl tert-butyl ether (10 mL) was
added, followed by water (4 mL). A solution of ammonium acetate
(0.89 g) in water (5 mL) was added causing the product to
precipitate from solution. The mixture was stirred for 3 h at room
temperature and then filtered. The filter cake was washed with
water (50 mL) and methyl tert-butyl ether (20 mL). The product was
dried under vacuum at 40.degree. C. to give the title compound
(0.88 g).
EXAMPLE 28
[0261] This illustrates the preparation of
(S)-{4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperidin-
-1-yl}-3-(4-fluoro-phenyl)-propionic acid (Form I)
[0262] To
(S)-{4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]--
piperidin-1-yl}-3-(4-fluoro-phenyl)-propionic acid methyl ester (1
g) in acetonitrile (9 mL) solution (Intermediate 28) was added a
solution of tetra-n-butylammonium hydroxide (3.31 g, 48% w/w in
water) in acetonitrile (5 mL) over 10 minutes at 20.degree. C.
[0263] The reaction mixture was stirred at 20-22.degree. C. for 2
hours. Methyl-tert-butyl ether (10 mL) was added to the reaction
mixture followed by a solution of ammonium acetate (0.87 g) in
water (5 mL). After 1 h of stirring at room temperature water (5
mL) was added. The precipitate formed was stirred overnight at room
temperature.
[0264] The solid was filtered and washed (slurry wash) with water
(2.times.4 mL) and methyl tert-butylmethyl ether (6 mL). The solid
was dried at 40.degree. C. under reduced pressure overnight to
yield the title compound as a colourless solid (0.44 g; melting
point 230-237.degree. C., starts degrading at 220.degree. C.).
[0265] .sup.1H NMR .delta..sub.(CD3OD) 1.25-1.40 (2H, m), 1.5-1.65
(1H, m), 1.70-1.90 (4H, m), 1.92-2.10 (2H, m), 2.20-2.25 (2H, m),
2.35 (3H, s), 2.35-2.42 (4H, m) 2.6-2.75 (2H, m), 2.78-2.90 (1H,
m), 2.97-3.20 (4H, m), 4.38-4.50 (1H, m), 6.85-7.00 (3H, m),
7.20-7.30 (3H, m) MS (ES+ve) 523 (M+H).sup.+.
[0266] XRPD of Form I is shown in FIG. 1.
TABLE-US-00006 Pos. [.degree.2Th.] d-spacing [.ANG.] Rel. Int. [%]
2.2272 39.63447 50.62 2.6914 32.79941 35.64 5.3443 16.52252 1.17
7.1482 12.35663 100 8.75 10.09782 3.57 10.7172 8.24831 6.89 12.6424
6.9962 2.39 13.2608 6.67132 10.35 14.0758 6.28685 2.26 14.2953
6.19079 2.23 15.1222 5.85406 1.09 15.9917 5.53767 5.72 17.8742
4.95848 2.63 18.2983 4.8445 7.36 18.7722 4.72326 21.26 19.2498
4.60712 7.52 19.7833 4.48407 4.5 20.1738 4.39815 3.34 21.237 4.1803
2.3 22.2454 3.99304 1.4 23.3765 3.80232 2.41 24.3555 3.65165 5.04
24.6251 3.61229 5.33 25.4107 3.50236 2.98 25.9888 3.42575 1.53
26.3646 3.37776 1.87 26.8953 3.31231 1.55 31.2745 2.85777 0.79
33.0542 2.70785 1.22 34.2844 2.61345 1.18
EXAMPLE 29
[0267] This illustrates the preparation of
(S)-{4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperidin-
-1-yl}-3-(4-fluoro-phenyl)-propionic acid (Form II)
[0268] To
(S)-{4-[4-(3,4-Dichloro-2-methylphenoxy)-piperidin-1-ylmethyl]-p-
iperidin-1-yl}-3-(4-fluorophenyl)-propionic acid methyl ester (5 g)
in acetonitrile (40 mL) was added a solution of
tetra-n-butylammonium hydroxide (15.10 g, 48% w/w in water) in
acetonitrile (25 mL) over 10 minutes between 10-20.degree. C. The
reaction mixture was stirred at 20-22.degree. C. for 2 h. To the
reaction mixture was added a solution of ammonium acetate (4.35 g)
in water (50 mL) forming a precipitate. A small amount of the solid
was withdrawn, isolated by filtration and washed with water three
times. The XRPD analysis of this solid indicated that it was form
II. The slurry was then stirred overnight at room temperature. A
sample of the slurry was again checked by XRPD which showed that it
was now form I. The solid was filtered and washed (slurry wash)
with water (3.times.20 mL). The solid was dried in the oven at
40.degree. C. under reduced pressure overnight to yield the title
compound as a colourless solid (3.60 g).
[0269] XRPD for Form II is shown in FIG. 2
TABLE-US-00007 Pos. [.degree.2Th.] d-spacing [.ANG.] Rel. Int. [%]
2.2315 39.55948 99.14 2.6749 33.00216 76.85 5.3589 16.47747 3.63
7.186 12.29168 100 8.6551 10.20831 1.83 10.0439 8.79962 3.1 11.0966
7.96713 1.2 12.1727 7.26509 4.68 13.1501 6.72725 14.53 14.3825
6.15345 3.85 15.1743 5.83409 2.28 17.0236 5.20427 40.99 17.3697
5.10133 64.11 18.5373 4.78257 8.87 19.1233 4.63731 67.78 19.3663
4.57968 30.28 20.0799 4.41851 6.99 21.069 4.21325 10.79 22.247
3.99275 7.08 22.8768 3.88424 3.31 24.417 3.64259 28.48 25.1834
3.53346 18.08 27.5786 3.23177 3.67 33.7683 2.6522 1.92 34.6377
2.58759 6.2 38.741 2.32245 1.74
EXAMPLE 30
[0270] This illustrates the preparation of
(2S)-2-(4-{[4-(3,4-dichloro-2-methylphenoxy)piperidin-1-yl]methyl}piperid-
in-1-yl)-3-(4-fluorophenyl)propanoic acid
A Methyl
(2S)-2-(4-{[4-(3,4-dichloro-2-methylphenoxy)piperidin-1-yl]methyl-
}piperidin-1-yl)-3-(4-fluorophenyl)propanoate
[0271] Powdered sieves (20 g, 4 .ANG.) were added to a solution of
methyl (2R)-3-(4-fluorophenyl)-2-hydroxypropanoate (32 g) in
dichloromethane (200 mL). The mixture was stirred, under nitrogen,
at room temperature, for 15 min then cooled to 0.degree. C. Triflic
anhydride (29.9 mL) was added, followed, after 10 min, by
2,6-lutidine (41.4 mL), which was added over approximately 1 h.
Stirring was continued for 1 h at 0.degree. C. A solution of
4-(3,4-dichloro-2-methylphenoxy)-1-(piperidin-4-ylmethyl)piperidine
(57.6 g) in dichloromethane (600 mL) was added at such a rate that
the internal temperature did not exceed 5.degree. C. Triethylamine
(49.5 mL) was added dropwise and the mixture was stirred at
0.degree. C. for 1 h. The reaction mixture was filtered through a
plug of silica; washing through with dichloromethane. The filtrate
was reduced in volume by evaporation under reduced pressure and
then washed (.times.2) with water. The organic fraction was dried
(MgSO.sub.4), filtered and concentrated in vacuo to give the title
compound as a brown oil.
B
(2S)-2-(4-{[4-(3,4-dichloro-2-methylphenoxy)piperidin-1-yl]methyl}piperi-
din-1-yl)-3-(4-fluorophenyl)propanoic acid
[0272] A solution of lithium hydroxide monohydrate (27.0 g) in
water (180 mL) was added dropwise to an ice cooled solution of
methyl
(2S)-2-(4-{[4-(3,4-dichloro-2-methylphenoxy)piperidin-1-yl]methyl}piperid-
in-1-yl)-3-(4-fluorophenyl)propanoate (from step A) in methanol
(115 mL) and THF (450 mL). The mixture was stirred at room
temperature overnight. A solution of ammonium acetate (165 g) in
water (300 mL) was added to the reaction mixture, followed by
diethyl ether (550 mL). The two phase mixture was stirred rapidly
for 5.5 h then solid was collected. The solid was washed with water
(2.times.300 mL) and diethyl ether (3.times.300 mL) and then dried
in a vacuum oven at 40.degree. C. overnight (batch one).
[0273] A second batch of solid was collected from the filtrate
after standing for 24 h. This was similarly washed with water and
diethyl ether then dried (batch two).
[0274] Lithium hydroxide monohydrate (1 eq in water) was added to a
mixture of batch one in methanol and THF. The free acid was
precipitated by addition of ammonium acetate in water. Once again,
two crops of crystals were obtained at different time points
(batches three and four). Batch three was treated with lithium
hydroxide and then ammonium acetate as before to produce two
further crops (batches five and six).
[0275] The lithium salt of batch two was prepared by addition of
lithium hydroxide monohydrate (1 eq in water). This solution was
extracted with dichloromethane. A solution of ammonium acetate in
water was added to the dichloromethane layer and a solid
precipitated which was collected by filtration (batch seven).
[0276] Batches four, six and seven were combined and dried to give
the title compound (31.19 g).
[0277] .sup.1H NMR .delta..sub.(CD3OD+1 drop NaOD) 1.25 (2H, ddd),
1.50-1.61 (1H, m), 1.72-1.84 (4H, m), 1.94-2.02 (2H, m), 2.22 (2H,
d), 2.27-2.40 (7H, m), 2.61-2.68 (2H, m), 2.82 (1H, dd), 2.99-3.08
(3H, m), 3.13 (1H, dd), 4.36-4.43 (1H, m), 6.87-6.95 (3H, m),
7.22-7.27 (3H, m).
[0278] MS 521/523 [M-H].sup.- (APCI-)
EXAMPLE 31
[0279] This illustrates the preparation of
(2S)-2-(4-{[4-(3,4-dichloro-2-methylphenoxy)piperidin-1-yl]methyl}piperid-
in-1-yl)-3-phenylpropanoic acid
[0280] A Methyl
(2S)-2-(4-{[4-(3,4-dichloro-2-methylphenoxy)piperidin-1-yl]methyl}piperid-
in-1-yl)-3-phenylpropanoate
[0281] Powdered sieves (20 g, 4 .ANG.) were added to a solution of
methyl (2R)-2-hydroxy-3-phenylpropanoate (32.8 g) in
dichloromethane (200 mL). The mixture was stirred, under nitrogen,
at room temperature, for 15 min then cooled to 0.degree. C. Triflic
anhydride (33.7 mL) was added, followed, after 10 min, by
2,6-lutidine (46.7 mL), which was added over approximately 1 h.
Stirring was continued for 1 h at 0.degree. C. A solution of
4-(3,4-dichloro-2-methylphenoxy)-1-(piperidin-4-ylmethyl)piperidine
(65.0 g) in dichloromethane (600 mL) was added at such a rate that
the internal temperature did not exceed 5.degree. C. Triethylamine
(55.8 mL) was added dropwise and the mixture was stirred at
0.degree. C. for 1 h. The reaction mixture was filtered through a
plug of silica; washing through with dichloromethane. The filtrate
was reduced in volume by evaporation under reduced pressure and
then washed (.times.2) with water. The organic fraction was dried
(MgSO.sub.4), filtered and concentrated in vacuo to give the title
compound as a brown oil.
B
(2S)-2-(4-{[4-(3,4-Dichloro-2-methylphenoxy)piperidin-1-yl]methyl}piperi-
din-1-yl)-3-phenylpropanoic acid
[0282] A solution of lithium hydroxide monohydrate (30.5 g) in
water (180 mL) was added dropwise to an ice cooled solution of
methyl
(2S)-2-(4-{[4-(3,4-dichloro-2-methylphenoxy)piperidin-1-yl]methyl}piperid-
in-1-yl)-3-phenylpropanoate (from step A) in methanol (115 mL) and
THF (450 mL). The mixture was stirred at room temperature
overnight. A solution of ammonium acetate (165 g) in water (300 mL)
was added to the reaction mixture, followed by tert-butylmethyl
ether (300 mL). The two phase mixture was stirred rapidly for 2 h.
The solid was collected, washed with water (3.times.300 mL) and
diethyl ether (3.times.200 mL). The solid was added to diethyl
ether and stirred for 1 h then filtered. Fresh diethyl ether was
added and the stirring, filtering procedure was repeated. The solid
obtained was dried under vacuum at 50.degree. C. overnight to give
the title compound (33 g).
[0283] .sup.1H NMR .delta..sub.(CD3OD+1 drop NaOD) 1.16-1.35 (2H,
m), 1.50-1.62 (1H, m), 1.72-1.84 (4H, m), 1.94-2.03 (2H, m), 2.22
(2H, d), 2.27-2.39 (7H, m), 2.59-2.69 (2H, m), 2.85 (1H, dd),
3.01-3.09 (3H, m), 3.16 (1H, dd), 4.36-4.44 (1H, m), 6.89 (1H, d),
7.11 (1H, dt), 7.17-7.27 (5H, m).
MS 503/505 [M-H]- (APCI-)
EXAMPLE 32
[0284] This illustrates the preparation of
(2S)-2-(4-{[4-(4-chloro-2-methylphenoxy)piperidin-1-yl]methyl}piperidin-1-
-yl)-3-(4-fluorophenyl)-2-methylpropanoic acid hydrate (Form A)
[0285] Methyl
(2S)-2-(4-{[4-(4-chloro-2-methylphenoxy)piperidin-1-yl]methyl}piperidin-1-
-yl)-3-(4-fluorophenyl)-2-methylpropanoate (34.5 g) and 50% aqueous
hydrobromic acid (1.5 l) were heated together at 160.degree. C. for
72 h. The hydrobromic acid was then removed in vacuo. The resulting
solid was dissolved in a 3:1 mixture of acetonitrile:water (350 ml)
and a solution of lithium hydroxide monohydrate (7 g) in water (50
ml) was added. A solution of ammonium acetate (15.42 g) in water
(30 ml) was then added, followed by isohexane (150 ml). The mixture
was then stirred vigorously for 1 h. and allowed to stand for 1 h.
The solid precipitate was collected, washed well with diethyl ether
and dried overnight in vacuo. The solid was recrystallised from 3:1
acetonitrile:water (400 ml) to give the title compound (21 g) as a
channel hydrate (Form A).
[0286] 3.85% water (Karl-Fischer analysis)
[0287] MS ES+ (+ve) 503/505 (M+H).sup.+
[0288] .sup.1H NMR .delta..sub.(CD3OD) 1.32 (3H, s), 1.41-1.68 (2H,
m), 1.72-1.84 (3H, m), 1.85-2.13 (4H, m), 2.15 (3H, s), 2.24-2.29
(2H, m), 2.31-2.41 (2H, m), 2.61-2.76 (2H, m), 2.96-3.09 (3H, m),
3.18 (1H, d), 3.32-3.40 (1H, m), 3.59-3.72 (1H, m), 4.30-4.42 (1H,
m), 6.85 (1H, d), 6.96 (2H, t), 7.03-7.11 (2H, m), 7.23-7.31 (2H,
m)
[0289] XRPD for Form A is shown in FIG. 3
TABLE-US-00008 Pos. [.degree.2Th.] d-spacing [.ANG.] Rel. Int. [%]
5.3042 16.64746 38.18 10.6081 8.33289 15.1 12.2996 7.19041 21.34
12.9368 6.83768 17.84 13.8637 6.38254 100 15.4899 5.71594 21.07
15.9475 5.55295 43.36 16.9292 5.23307 45.21 19.6122 4.52282 46.88
20.0506 4.4249 39.58 20.4452 4.34037 43.68 21.1148 4.20421 37.21
21.4664 4.13615 17.97 22.5577 3.93845 5.89 23.5073 3.78147 5.72
24.0362 3.69943 31.3 24.7697 3.59152 30.35 25.1369 3.53988 10.04
25.8045 3.4498 15.74 26.74 3.33119 9.4 27.8356 3.20251 4.01 29.399
3.03566 11.28 29.642 3.01133 11.65 31.3761 2.84874 7.22 32.3322
2.76665 7.42 33.6764 2.65923 5.23 34.41 2.6042 4.99 35.8167 2.50508
4.12
EXAMPLE 33
[0290] This illustrates the preparation of
(2R)-2-(4-{[4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]methyl}piperidin-1-
-yl)-3-(4-fluorophenyl)-2-methylpropanoic acid
[0291] This was prepared following the method of Example 32 using
methyl
(2R)-2-(4-{[4-(4-chloro-2-methylphenoxy)piperidin-1-yl]methyl}piperidin-1-
-yl)-3-(4-fluorophenyl)-2-methylpropanoate.
[0292] .sup.1H NMR .delta..sub.(CD3OD) 1.31 (3H, s), 1.50 (1H, q),
1.62 (1H, q), 1.73-1.84 (2H, m), 1.85-2.12 (5H, m), 2.16 (3H, s),
2.31 (2H, d), 2.35-2.46 (2H, m), 2.66-2.78 (2H, m), 2.95-3.11 (3H,
m), 3.18 (1H, d), 3.36 (1H, d), 3.60-3.71 (1H, m), 4.33-4.43 (1H,
m), 6.86 (1H, d), 6.96 (2H, t), 7.03-7.11 (2H, m), 7.26 (2H, t)
[0293] MS (ES-ve) 501/503 (M-H).sup.+
EXAMPLES 34
(2S)-2-(4-{[4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]methyl}piperidin-1--
yl)-3-(4-fluorophenyl)-2-methylpropanoic acid Form B
[0294]
(2S)-2-(4-{[4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]methyl}piper-
idin-1-yl)-3-(4-fluorophenyl)-2-methylpropanoic acid (for example
amorphous or crystalline) can initially be partly dissolved in an
organic solvent and stirred until Form B is obtained. The process
involves a solution mediated transformation in the slurry without
complete dissolution of the starting material. This transformation
is thermodynamically driven to yield a more stable form with a
lower solubility under the conditions evaluated.
[0295] Form B is typically formed when a slurry of Form A of
(2S)-2-(4-{[4-(4-chloro-2-methylphenoxy)piperidin-1-yl]methyl}piperidin-1-
-yl)-3-(4-fluorophenyl)-2-methylpropanoic acid is stirred in
ethanol at 25.degree. C. or 60.degree. C. for greater than 1
day.
[0296] XRPD for
(2S)-2-(4-{[4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]methyl}piperidin-1-
-yl)-3-(4-fluorophenyl)-2-methylpropanoic acid ethanol solvate Form
B is shown in FIG. 4
TABLE-US-00009 Pos. [.degree.2Th.] d-spacing [.ANG.] Rel. Int. [%]
7.6772 11.50625 32.02 8.9078 9.91929 3.67 13.307 6.64824 100
13.7582 6.43123 6.47 15.2087 5.82096 32.61 15.4305 5.73779 15.65
16.3607 5.41362 6.19 17.3791 5.09859 18.01 18.3842 4.82206 71.89
19.6742 4.5087 87.16 20.0571 4.42348 6.95 20.6439 4.29904 13.54
21.6962 4.09284 43.29 22.7189 3.91087 19.79 23.0611 3.85361 8.87
24.3742 3.6489 5.79 26.3108 3.38455 2.6 26.7429 3.33083 4.82 29.037
3.07268 1.93 29.8487 2.99095 1.32 32.0179 2.79309 2.41
EXAMPLE 35
[0297] Histamine H1 receptor binding activity of compounds of the
invention was assessed by competition displacement of 1 nM
[3H]-pyrilamine (Amersham, Bucks, Product code TRK 608, specific
activity 30 Ci/mmol) to 2 .mu.g membranes prepared from recombinant
CHO-K1 cells expressing the human H1 receptor (Euroscreen SA,
Brussels, Belgium, product code ES-390-M) in assay buffer (50 mM
Tris pH 7.4 containing 2 mM MgCl.sub.2, 250 mM sucrose and 100 mM
NaCl) for 1 hour at room temperature.
[0298] The following compounds of the invention gave inhibition of
[3H]pyrilimine binding:
TABLE-US-00010 Example H1 pKi 3 7.5 4 7.1 6 7.5 13 7.0
EXAMPLE 36
Eotaxin-2-Induced Shape Change in Eosinophils in Human Blood In
Vitro
[0299] See for example, Differential regulation of eosinophil
chemokine signaling via CCR3 and non-CCR3 pathways. Sabroe I,
Hartnell A, Jopling L A, Bel S, Ponath P D, Pease J E, Collins P D,
Williams T J. J. Immunol. 1999 Mar. 1; 162(5):2946-55.
[0300] Human blood, collected by venous puncture into 9 mL
lithium-heparin tubes, was incubated with the CCR3 agonist
eotaxin-2 in the presence of vehicle (0.1% (v/v) DMSO) or test
compound for 4 min at 37.degree. C. in a deep, 96-square-well
plate. The blood was fixed with Optilyse B (100 .mu.L) at room
temperature for 10 min and then the red blood cells were lysed with
distilled water (1 mL) for 60 min at room temperature.
[0301] The plate was centrifuged at room temperature for 5 min at
300 g. The pellet was re-suspended in assay buffer (PBS without
CaCl.sub.2 and MgCl.sub.2, containing HEPES (10 mM), Glucose (10
mM) and 0.1% (w/v) BSA, pH 7.4)) and the samples were analysed
using flow cytometry (FC500, Beckman Coulter). The high
autofluorescence of eosinophils allowed them to be identified as a
discrete population from the other blood cell types. Eosinophil
shape was monitored as the refractive index of the eosinophil
population as determined using the forward scatter signal in flow
cytometry.
[0302] Eotaxin-2 induced a concentration-dependent change in the
forward scatter of eosinophils and these data were used to
construct a concentration effect curve (E/[A] curve). The rightward
displacement of the eotaxin-2 E/[A] curve in the presence of a CCR3
antagonist was used to estimate a pA.sub.2 value in blood using the
following equation:
Single pA.sub.2=-log.sub.10 ([B]/(r-1))
where r is the ratio of the concentrations required for half
maximal effects of eotaxin-2 in the absence and presence of
antagonist ([A].sub.50 for eotaxin-2 in the presence of antagonist
divided by [A].sub.50 for control eotaxin-2 curve) and [B] is the
molar concentration of antagonist.
[0303] The following compounds of the invention gave inhibition of
shape-change:
TABLE-US-00011 Example CCR3 pA.sub.2 1 7.3 2 7.7 3 7.7 4 7.6 5 7.9
6 8.2 12 8.0 13 6.7 14 6.7 16 7.1 20 7.2 21 7.3 22 7.3 23 7.2 24
7.2 25 7.3 26 7.3
EXAMPLE 37
Determination of Compound Affinity at Human Recombinant CCR3
Receptors Assessed by Competition of
[.sup.3H]-4-(2,4-dichloro-3-methylphenoxy)-1'-[4-(methylsulfonyl)benzoyl]-
-1,4'-bipiperidine for CHO-K1 Cell Membranes In Vitro
[0304] Membranes, prepared from CHO-K1 cells stably expressing
recombinant human CCR3, suspended in assay buffer (50 mM Tris-Base,
pH 7.4; containing sodium chloride (100 mM) and magnesium chloride
(2 mM)) were incubated in the presence of 2 nM
[.sup.3H]-4-(2,4-dichloro-3-methylphenoxy)-1'-[4-(methylsulfonyl)benzoyl]-
-1,4'-bipiperidine, along with vehicle (1% (v/v) DMSO),
4-(4-chloro-3-methylphenoxy)-1'-[2-(methylsulfonyl)benzoyl]-1,4'-bipiperi-
dine (to define non-specific binding) or test compound for 2 h at
37.degree. C. in round bottomed 96-well plates. The plates were
then filtered onto GF/B filter plates, pre-soaked for 1 hour in
plate-coating solution (0.3% (w/v) polyethylenimine, 0.2% (w/v) BSA
in de-ionised water), using a 96-well plate Tomtec cell harvester.
Four washes (250 .mu.L) with wash buffer (50 mM Tris-Base, pH 7.4
containing sodium chloride (500 mM) and magnesium chloride (2 mM))
were performed at 4.degree. C. to remove unbound radioactivity.
Plates were dried and MicroScint-O (50 .mu.L) was added to each
well. The plates were sealed (TopSeal A) and filter-bound
radioactivity was measured with a scintillation counter (TopCount,
Packard BioScience) using a 1 minute counting protocol.
[0305] Specific binding was determined from values of the control
wells minus the values for the NSB wells for each assay plate.
pIC.sub.50 values were calculated using a four parameter logistic
fit (where pIC.sub.50 is defined as the negative logarithm of the
concentration of compound required for 50% reduction in specific
[.sup.3H]-4-(2,4-dichloro-3-methylphenoxy)-1'-[4-(methylsulfonyl)benzoyl]-
-1,4'-bipiperidine binding). Data were presented as mean pKi values
(calculated by applying a Cheng-Prussof correction to pIC.sub.50
values) from a minimum of 2 separate experiments.
[0306] The following compounds of the invention gave inhibition of
binding:
TABLE-US-00012 Example CCR3 pKi 1 9.3 2 9.2 3 9.3 4 9.1 5 9.2 6 9.7
8 7.6 9 8.6 10 8.3 11 8.8 12 9.7 13 8.9 14 9.3 15 8.2 16 8.9 17 9.3
18 8.4 19 8.3 20 8.7 21 9.3 22 9.3 23 8.7 24 8.7 25 9.3 26 9.3
* * * * *
References