U.S. patent application number 12/267983 was filed with the patent office on 2009-03-12 for piperidine derivatives useful as modulators of chemokine receptor activity.
This patent application is currently assigned to AstraZeneca AB. Invention is credited to Christopher Luckhurst, Matthew Perry, Hitesh Sanganee, Brian Springthorpe.
Application Number | 20090069325 12/267983 |
Document ID | / |
Family ID | 20287326 |
Filed Date | 2009-03-12 |
United States Patent
Application |
20090069325 |
Kind Code |
A1 |
Luckhurst; Christopher ; et
al. |
March 12, 2009 |
Piperidine Derivatives Useful as Modulators of Chemokine Receptor
Activity
Abstract
The present invention relates to the compounds of formula (I):
##STR00001## in which: ##STR00002## and the remaining variables are
defined herein. The present invention also relates to a process for
preparing such compounds and use of such compounds in the treatment
of a chemokine (such as CCR3) or H1 mediated disease state.
Inventors: |
Luckhurst; Christopher;
(Leicestershire, GB) ; Perry; Matthew;
(Leicestershire, GB) ; Sanganee; Hitesh;
(Leicestershire, GB) ; Springthorpe; Brian;
(Leicestershire, GB) |
Correspondence
Address: |
FISH & RICHARDSON P.C.
P.O BOX 1022
MINNEAPOLIS
MN
55440-1022
US
|
Assignee: |
AstraZeneca AB
Sodertalje
SE
|
Family ID: |
20287326 |
Appl. No.: |
12/267983 |
Filed: |
November 10, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10508331 |
Sep 17, 2004 |
|
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PCT/SE03/00443 |
Mar 17, 2003 |
|
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12267983 |
|
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Current U.S.
Class: |
514/235.5 ;
544/129 |
Current CPC
Class: |
A61P 29/00 20180101;
A61P 9/10 20180101; A61P 25/28 20180101; C07D 413/14 20130101; A61P
17/06 20180101; A61P 31/18 20180101; A61P 43/00 20180101; C07D
211/44 20130101; A61P 27/02 20180101; A61P 35/00 20180101; A61P
3/04 20180101; A61P 11/02 20180101; A61P 17/00 20180101; A61P 31/00
20180101; A61P 11/00 20180101; A61P 37/04 20180101; A61P 37/02
20180101; A61P 1/00 20180101; A61P 21/04 20180101; A61P 1/04
20180101; A61P 37/00 20180101; A61P 19/02 20180101; A61P 1/02
20180101; A61P 37/06 20180101; A61P 3/10 20180101; A61P 37/08
20180101; A61P 11/06 20180101; A61P 15/00 20180101; A61P 25/06
20180101; A61P 25/00 20180101; C07D 413/06 20130101; C07D 409/14
20130101 |
Class at
Publication: |
514/235.5 ;
544/129 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; C07D 413/02 20060101 C07D413/02; A61P 37/00 20060101
A61P037/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 19, 2002 |
SE |
0200844-9 |
Claims
1. A compound of formula (I): ##STR00023## wherein: ##STR00024## n
is 0 or 1; X is CH.sub.2, C(O), O, S, S(O), S(O).sub.2 or NR.sup.3;
Y is O; R.sup.1 is hydrogen, C.sub.1-6 alkyl, aryl or heterocyclyl;
R.sup.2 is C.sub.3-7 cycloalkyl {optionally substituted by
C.sub.1-4 alkyl, aryl or oxo}, C.sub.3-7 cycloalkenyl {optionally
substituted by oxo, C.sub.1-6 alkyl or aryl}, aryl or heterocyclyl;
wherein the foregoing aryl and heterocyclyl moieties are optionally
substituted by: halogen, cyano, nitro, hydroxy, oxo,
S(O).sub.pR.sup.4, OC(O)NR.sup.5R.sup.6, NR.sup.7R.sup.8,
NR.sup.9C(O)R.sup.10, NR.sup.11C(O)NR.sup.12R.sup.13,
S(O).sub.2NR.sup.14R.sup.15, NR.sup.16S(O).sub.2R.sup.17,
C(O)NR.sup.18R.sup.19, C(O)R.sup.20, CO.sub.2R.sup.21,
NR.sup.22CO.sub.2R.sup.23, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.1-6 alkoxy(C.sub.1-6)alkyl, C.sub.1-6 alkoxy, C.sub.1-6
haloalkoxy, C.sub.1-6 alkoxy(C.sub.1-6)alkoxy, C.sub.1-6 alkylthio,
C.sub.1-6 haloalkylthio, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl (optionally substituted by C.sub.1-4 alkyl or
oxo), methylenedioxy, difluoromethylenedioxy, phenyl,
phenyl(C.sub.1-4)alkyl, phenoxy, phenylthio,
phenyl(C.sub.1-4)alkoxy, heterocyclyl,
heterocyclyl(C.sub.1-4)alkyl, heterocyclyloxy or
heterocyclyl(C.sub.1-4)alkoxy; wherein any of the immediately
foregoing phenyl and heterocyclyl moieties are optionally
substituted with halogen, hydroxy, nitro, S(O).sub.q(C.sub.1-4
alkyl), S(O).sub.2NH.sub.2, cyano, C.sub.1-4 alkyl, C.sub.1-4
alkoxy, C(O)NH.sub.2, C(O)NH(C.sub.1-4 alkyl), C(O)N(C.sub.1-4
alkyl).sub.2 (and these alkyl groups optionally being joined to
form a ring as described for R.sup.5 and R.sup.6 below), CO.sub.2H,
CO.sub.2(C.sub.1-4 alkyl), NHC(O)(C.sub.1-4 alkyl),
NHS(O).sub.2(C.sub.1-4 alkyl), C(O)(C.sub.1-4 alkyl), CF.sub.3 or
OCF.sub.3; M and T are, independently, hydrogen, halogen, cyano,
nitro, hydroxy, oxo, S(O).sub.pR.sup.4, OC(O)NR.sup.5R.sup.6,
NR.sup.7R.sup.8, NR.sup.9C(O)R.sup.10,
NR.sup.11C(O)NR.sup.12R.sup.13, S(O).sub.2NR.sup.14R.sup.15,
NR.sup.16S(O).sub.2R.sup.17, C(O)NR.sup.18R.sup.19, C(O)R.sup.20,
CO.sub.2R.sup.21, NR.sup.22CO.sub.2R.sup.23, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy(C.sub.1-6)alkyl, C.sub.1-6
alkoxy, C.sub.1-6 haloalkoxy, C.sub.1-6 alkoxy(C.sub.1-6)alkoxy,
C.sub.1-6 alkylthio, C.sub.1-6 haloalkylthio, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl (optionally substituted by
C.sub.1-4 alkyl or oxo), methylenedioxy, difluoromethylenedioxy,
phenyl, phenyl(C.sub.1-4)alkyl, phenoxy, phenylthio,
phenyl(C.sub.1-4)alkoxy, heterocyclyl,
heterocyclyl(C.sub.1-4)alkyl, heterocyclyloxy or
heterocyclyl(C.sub.1-4)alkoxy; wherein any of the immediately
foregoing phenyl and heterocyclyl moieties are optionally
substituted with halogen, hydroxy, nitro, S(O).sub.q(C.sub.1-4
alkyl), S(O).sub.2NH.sub.2, cyano, C.sub.1-4 alkyl, C.sub.1-4
alkoxy, C(O)NH.sub.2, C(O)NH(C.sub.1-4 alkyl), C(O)N(C.sub.1-4
alkyl).sub.2 (and these alkyl groups optionally being joined to
form a ring as described for R.sup.5 and R.sup.6 below), CO.sub.2H,
CO.sub.2(C.sub.1-4 alkyl), NHC(O)(C.sub.1-4 alkyl),
NHS(O).sub.2(C.sub.1-4 alkyl), C(O)(C.sub.1-4 alkyl), CF.sub.3 or
OCF.sub.3; p and q are, independently, 0, 1 or 2; R.sup.3, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.18, R.sup.19,
R.sup.20, R.sup.21 and R.sup.22 are, independently, hydrogen,
C.sub.1-6 alkyl (optionally substituted by halogen, hydroxy or
C.sub.3-10 cycloalkyl), CH.sub.2(C.sub.2-6 alkenyl), phenyl
(optionally substituted by halogen, hydroxy, nitro, NH.sub.2,
NH(C.sub.1-4 alkyl), N(C.sub.1-4 alkyl).sub.2 (and these alkyl
groups optionally being joined to form a ring as described for
R.sup.5 and R.sup.6 below), S(O).sub.2(C.sub.1-4 alkyl),
S(O).sub.2NH.sub.2, cyano, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
C(O)NH.sub.2, C(O)NH(C.sub.1-4 alkyl), C(O)N(C.sub.1-4 alkyl).sub.2
(and these alkyl groups optionally being joined to form a ring as
described for R.sup.5 and R.sup.6 below), CO.sub.2H,
CO.sub.2(C.sub.1-4 alkyl), NHC(O)(C.sub.1-4 alkyl),
NHS(O).sub.2(C.sub.1-4 alkyl), C(O)(C.sub.1-4 alkyl), CF.sub.3 or
OCF.sub.3) or heterocyclyl (optionally substituted by halogen,
hydroxy, nitro, NH.sub.2, NH(C.sub.1-4 alkyl), N(C.sub.1-4
alkyl).sub.2 (and these alkyl groups optionally being joined to
form a ring as described for R.sup.5 and R.sup.6 below),
S(O).sub.2(C.sub.1-4 alkyl), S(O).sub.2NH.sub.2,
S(O).sub.2NH(C.sub.1-4 alkyl), S(O).sub.2N(C.sub.1-4 alkyl).sub.2
(and these alkyl groups optionally being joined to form a ring as
described for R.sup.5 and R.sup.6 below), cyano, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C(O)NH.sub.2, C(O)NH(C.sub.1-4 alkyl),
C(O)N(C.sub.1-4 alkyl).sub.2 (and these alkyl groups optionally
being joined to form a ring as described for R.sup.5 and R.sup.6
below), CO.sub.2H, CO.sub.2(C.sub.1-4 alkyl), NHC(O)(C.sub.1-4
alkyl), NHS(O).sub.2(C.sub.1-4 alkyl), C(O)(C.sub.1-4 alkyl),
CF.sub.3 or OCF.sub.3); alternatively NR.sup.5R.sup.6,
NR.sup.7R.sup.8, NR.sup.12R.sup.13 or NR.sup.14R.sup.15, or
NR.sup.18R.sup.19, independently, form a 4-7 membered heterocyclic
ring, azetidine, pyrrolidine, piperidine, azepine, 1,4-morpholine
or 1,4-piperazine, the latter optionally substituted by C.sub.1-4
alkyl on the distal nitrogen; R.sup.4, R.sup.17 and R.sup.23 are,
independently, C.sub.1-6 alkyl (optionally substituted by halogen,
hydroxy or C.sub.3-10 cycloalkyl), CH.sub.2(C.sub.2-6 alkenyl),
phenyl (optionally substituted by halogen, hydroxy, nitro,
NH.sub.2, NH(C.sub.1-4 alkyl), N(C.sub.1-4 alkyl).sub.2 (and these
alkyl groups optionally being joined to form a ring as described
for R.sup.5 and R.sup.6 above), S(O).sub.2(C.sub.1-4 alkyl),
S(O).sub.2NH.sub.2, S(O).sub.2NH(C.sub.1-4 alkyl),
S(O).sub.2N(C.sub.1-4 alkyl).sub.2 (and these alkyl groups
optionally being joined to form a ring as described for R.sup.5 and
R.sup.6 above), cyano, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
C(O)NH.sub.2, C(O)NH(C.sub.1-4 alkyl), C(O)N(C.sub.1-4 alkyl).sub.2
(and these alkyl groups optionally being joined to form a ring as
described for R.sup.5 and R.sup.6 above), CO.sub.2H,
CO.sub.2(C.sub.1-4 alkyl), NHC(O)(C.sub.1-4 alkyl),
NHS(O).sub.2(C.sub.1-4 alkyl), C(O)(C.sub.1-4 alkyl), CF.sub.3 or
OCF.sub.3) or heterocyclyl (optionally substituted by halogen,
hydroxy, nitro, NH.sub.2, NH(C.sub.1-4 alkyl), N(C.sub.1-4
alkyl).sub.2 (and these alkyl groups optionally being joined to
form a ring as described for R.sup.5 and R.sup.6 above),
S(O).sub.2(C.sub.14 alkyl), S(O).sub.2NH.sub.2,
S(O).sub.2NH(C.sub.1-4 alkyl), S(O).sub.2N(C.sub.1-4 alkyl).sub.2
(and these alkyl groups optionally being joined to form a ring as
described for R.sup.5 and R.sup.6 above), cyano, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C(O)NH.sub.2, C(O)NH(C.sub.1-4 alkyl),
C(O)N(C.sub.1-4 alkyl).sub.2 (and these alkyl groups optionally
being joined to form a ring as described for R.sup.5 and R.sup.6
above), CO.sub.2H, CO.sub.2(C.sub.1-4 alkyl), NHC(O)(C.sub.1-4
alkyl), NHS(O).sub.2(C.sub.1-4 alkyl), C(O)(C.sub.1-4 alkyl),
CF.sub.3 or OCF.sub.3); and R.sup.24 is hydrogen, C.sub.1-6 alkyl
or benzyl; or an N-oxide thereof; or a pharmaceutically acceptable
salt thereof.
2. A compound of formula (I) as claimed in claim 1 wherein X is
O.
3. A compound of formula (I) as claimed in claim 1 wherein R.sup.24
is hydrogen.
4. A compound of formula (I) as claimed in claim 1 wherein R.sup.1
is phenyl optionally substituted with fluorine, chlorine or
C.sub.1-4 alkyl.
5. A compound of formula (I) as claimed in claim 1 wherein R.sup.2
is phenyl or heterocyclyl, either of which is optionally
substituted by: halo, hydroxy, nitro, cyano, amino, C.sub.1-4 alkyl
(optionally substituted by S(O).sub.2(C.sub.1-4 alkyl) or
S(O).sub.2phenyl), C.sub.1-4 alkoxy, S(O).sub.pR.sup.4 (wherein p
is 0, 1 or 2), C(O)NH.sub.2, NHS(O).sub.2(C.sub.1-4 alkyl),
S(O).sub.2NH.sub.2, S(O).sub.2NH(C.sub.1-4 alkyl) or
S(O).sub.2N(C.sub.1-4 alkyl).sub.2; and R.sup.4 is C.sub.1-4 alkyl,
C.sub.1-4 hydroxyalkyl, C.sub.3-7 cycloalkyl or C.sub.3-7
cycloalkyl(C.sub.1-4 alkyl).
6. A process for preparing a compound of formula (I) as claimed in
claim 1, the process comprising: A. when Z is
CHR.sup.2CO.sub.2R.sup.24: i. coupling a compound of formula (II):
##STR00025## with a compound of formula (III): ##STR00026## wherein
L is a suitable leaving group, in a suitable solvent; or, ii.
reductive amination of a compound (II) with an ester compound of
formula (IIIa): ##STR00027## in the presence of NaBH(OAc).sub.3 and
acetic acid, followed optionally by removal of the ester group; or
iii. a three component coupling of a compound of formula (II) with
compounds of formula (IIIb) and (IIlc): ##STR00028## B. when
##STR00029## a. when n is 1, reacting a compound of formula (II)
with a compound of formula (XIV): ##STR00030## wherein L is a
leaving group; b. when n is 1, reacting a compound of formula (II)
with a compound of formula (XVI): ##STR00031## under reductive
amination conditions; and, c. when n is 0, reacting a compound of
formula (II) with a compound of formula (XV): ##STR00032## in the
presence of potassium carbonate, in a suitable solvent at a
suitable temperature.
7. A pharmaceutical composition which comprises a compound of the
formula (I), or a pharmaceutically acceptable salt thereof, as
claimed in claim 1, and a pharmaceutically acceptable adjuvant,
diluent or carrier.
8. A method comprising: treating a chemokine mediated disease state
in a mammal suffering from, or at risk of, said disease, which
comprises administering to a mammal in need of such treatment a
therapeutically effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt thereof as claimed in claim 1.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 10/508,331, filed on Sep. 17, 2004, which is the national phase
application under 35 U.S.C. .sctn.371 of International Application
No. PCT/SE03/00443, filed Mar. 17, 2003, which claims priority to
Swedish Application Serial No. 0200844-9, filed Mar. 19, 2002. The
contents of all parent applications are hereby incorporated by
reference in their entirety.
BACKGROUND
[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 WO99/38514, WO99/04794 and WO00/35877.
[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 and 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 rolein 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
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 al Allergy (1999) 54(11) 1204-8
[Experimental common cold increase mucosal output of eotaxin in
atopic individuals] and Kawaguchi M et al Int. Arch. Allergy
Immunol. (2000) 122 S1 44 [Expression of eotaxin by normal airway
epithelial cells after virus A infection].)
DETAILED DESCRIPTION
[0010] The present invention provides a compound of formula
(I):
##STR00003##
in which:
##STR00004##
[0011] n is 0 or 1;
[0012] X is CH.sub.2, C(O), O, S, S(O), S(O).sub.2 or NR.sup.3;
[0013] Y is O or CH.sub.2;
[0014] R.sup.1 is hydrogen, C.sub.1-6 alkyl, aryl or
heterocyclyl;
[0015] R.sup.2 is C.sub.3-7 cycloalkyl {optionally substituted by
C.sub.1-4 alkyl, aryl or oxo}, C.sub.3-7 cycloalkenyl {optionally
substituted by oxo, C.sub.1-6 alkyl or aryl}, aryl or heterocyclyl;
wherein the foregoing aryl and heterocyclyl moieties are optionally
substituted by: halogen, cyano, nitro, hydroxy, oxo,
S(O).sub.pR.sup.4, OC(O)NR.sup.5R.sup.6, NR.sup.7R.sup.8,
NR.sup.9C(O)R.sup.10, NR.sup.11C(O)NR.sup.12R.sup.13,
S(O).sub.2NR.sup.14R.sup.15, NR.sup.16S((O).sub.2R.sup.17,
C(O)NR.sup.18R.sup.19, C(O)R.sup.20, CO.sub.2R.sup.21,
NR.sup.22CO.sub.2R.sup.23, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.1-6 alkoxy(C.sub.1-6)alkyl, C.sub.1-6 alkoxy, C.sub.1-6
haloalkoxy, C.sub.1-6 alkoxy(C.sub.1-6)alkoxy, C.sub.1-6 alkylthio,
C.sub.1-6 haloalkylthio, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl (itself optionally substituted by C.sub.1-4
alkyl or oxo), methylenedioxy, difluoromethylenedioxy, phenyl,
phenyl(C.sub.1-4)alkyl, phenoxy, phenylthio,
phenyl(C.sub.1-4)alkoxy, heterocyclyl,
heterocyclyl(C.sub.1-4)alkyl, heterocyclyloxy or
heterocyclyl(C.sub.1-4)alkoxy; wherein any of the immediately
foregoing phenyl and heterocyclyl moieties are optionally
substituted with halogen, hydroxy, nitro, S(O).sub.q(C.sub.1-4
alkyl), S(O).sub.2NH.sub.2, cyano, C.sub.1-4 alkyl, C.sub.1-4
alkoxy, C(O)NH.sub.2, C(O)NH(C.sub.1-4 alkyl), C(O)N(C.sub.1-4
alkyl).sub.2 (and these alkyl groups may join to form a ring as
described for R.sup.5 and R.sup.6 below), CO.sub.2H,
CO.sub.2(C.sub.1-4 alkyl), NHC(O)(C.sub.1-4 alkyl),
NHS(O).sub.2(C.sub.1-4 alkyl), C(O)(C.sub.1-4 alkyl), CF.sub.3 or
OCF.sub.3;
[0016] M and T are, independently, hydrogen, halogen, cyano, nitro,
hydroxy, oxo, S(O).sub.pR.sup.4, OC(O)NR.sup.5R.sup.6,
NR.sup.7R.sup.8, NR.sup.9C(O)R.sup.10,
NR.sup.11C(O)NR.sup.12R.sup.13, S(O).sub.2NR.sup.14R.sup.15,
NR.sup.16S(O).sub.2R.sup.17, C(O)N.sup.18R.sup.19, C(O)R.sup.20,
CO.sub.2R.sup.21, NR.sup.22CO.sub.2R.sup.23, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy(C.sub.1-6)alkyl, C.sub.1-6
alkoxy, C.sub.1-6 haloalkoxy, C.sub.1-6 alkoxy(C.sub.1-6)alkoxy,
C.sub.1-6 alkylthio, C.sub.1-6 haloalkylthio, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl (itself optionally
substituted by C.sub.1-4 alkyl or oxo), methylenedioxy,
difluoromethylenedioxy, phenyl, phenyl(C.sub.1-4)alkyl, phenoxy,
phenylthio, phenyl(C.sub.1-4)alkoxy, heterocyclyl,
heterocyclyl(C.sub.1-4)alkyl, heterocyclyloxy or
heterocyclyl(C.sub.1-4)alkoxy; wherein any of the immediately
foregoing phenyl and heterocyclyl moieties are optionally
substituted with halogen, hydroxy, nitro, S(O).sub.q(C.sub.1-4
alkyl), S(O).sub.2NH.sub.2, cyano, C.sub.1-4 alkyl, C.sub.1-4
alkoxy, C(O)NH.sub.2, C(O)NH(C.sub.1-4 alkyl), C(O)N(C.sub.1-4
alkyl).sub.2 (and these alkyl groups may join to form a ring as
described for R.sup.5 and R.sup.6 below), CO.sub.2H,
CO.sub.2(C.sub.1-4 alkyl), NHC(O)(C.sub.1-4 alkyl),
NHS(O).sub.2(C.sub.1-4 alkyl), C(O)(C.sub.1-4 alkyl), CF.sub.3 or
OCF.sub.3;
[0017] p and q are, independently, 0, 1 or 2;
[0018] R.sup.3, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9,
R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15,
R.sup.16, R.sup.18, R.sup.19, R.sup.20, R.sup.21 and R.sup.22 are,
independently, hydrogen, C.sub.1-6 alkyl (optionally substituted by
halogen, hydroxy or C.sub.3-10 cycloalkyl), CH.sub.2(C.sub.2-6
alkenyl), phenyl (itself optionally substituted by halogen,
hydroxy, nitro, NH.sub.2, NH(C.sub.1-4 alkyl), N(C.sub.1-4
alkyl).sub.2 (and these alkyl groups may join to form a ring as
described for R.sup.5 and R.sup.6 below), S(O).sub.2(C.sub.1-4
alkyl), S(O).sub.2NH.sub.2, cyano, C.sub.1-4 alkyl, C.sub.1-4
alkoxy, C(O)NH.sub.2, C(O)NH(C.sub.1-4 alkyl), C(O)N(C.sub.1-4
alkyl).sub.2 (and these alkyl groups may join to form a ring as
described for R.sup.5 and R.sup.6 below), CO.sub.2H,
CO.sub.2(C.sub.1-4 alkyl), NHC(O)(C.sub.1-4 alkyl),
NHS(O).sub.2(C.sub.1-4 alkyl), C(O)(C.sub.1-4 alkyl), CF.sub.3 or
OCF.sub.3) or heterocyclyl (itself optionally substituted by
halogen, hydroxy, nitro, NH.sub.2, NH(C.sub.1-4 alkyl), N(C.sub.1-4
alkyl).sub.2 (and these alkyl groups may join to form a ring as
described for R.sup.5 and R.sup.6 below), S(O).sub.2(C.sub.1-4
alkyl), S(O).sub.2NH.sub.2, S(O).sub.2NH(C.sub.1-4 alkyl),
S(O).sub.2N(C.sub.1-4 alkyl).sub.2 (and these alkyl groups may join
to form a ring as described for R.sup.5 and R.sup.6 below), cyano,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C(O)NH.sub.2, C(O)NH(C.sub.1-4
alkyl), C(O)N(C.sub.1-4 alkyl).sub.2 (and these alkyl groups may
join to form a ring as described for R.sup.5 and R.sup.6 below),
CO.sub.2H, CO.sub.2(C.sub.1-4 alkyl), NHC(O)(C.sub.1-4 alkyl),
NHS(O).sub.2(C.sub.1-4 alkyl), C(O)(C.sub.1-4 alkyl), CF.sub.3 or
OCF.sub.3);
[0019] alternatively NR.sup.5R.sup.6, NR.sup.7R.sup.8,
NR.sup.12R.sup.13, NR.sup.14R.sup.15, NR.sup.18R.sup.19, may,
independently, form a 4-7 membered heterocyclic ring, azetidine,
pyrrolidine, piperidine, azepine, 1,4-morpholine or 1,4-piperazine,
the latter optionally substituted by C.sub.1-4 alkyl on the distal
nitrogen;
[0020] R.sup.4, R.sup.17 and R.sup.23 are, independently, C.sub.1-6
alkyl (optionally substituted by halogen, hydroxy or C.sub.3-10
cycloalkyl), CH.sub.2(C.sub.2 (alkenyl), phenyl (itself optionally
substituted by halogen, hydroxy, nitro, NH.sub.2, NH(C.sub.1-4
alkyl), N(C.sub.1-4 alkyl).sub.2 (and these alkyl groups may join
to form a ring as described for R.sup.5 and R.sup.6 above),
S(O).sub.2(C.sub.1-4 alkyl), S(O).sub.2NH.sub.2,
S(O).sub.2NH(C.sub.1-4 alkyl), S(O).sub.2N(C.sub.1-4 alkyl).sub.2
(and these alkyl groups may join to form a ring as described for
R.sup.5 and R.sup.6 above), cyano, C.sub.1-4 alkyl, C.sub.1-4
alkoxy, C(O)NH.sub.2, C(O)NH(C.sub.1-4 alkyl), C(O)N(C.sub.1-4
alkyl).sub.2 (and these alkyl groups may join to form a ring as
described for R.sup.5 and R.sup.6 above), CO.sub.2H,
CO.sub.2(C.sub.1-4 alkyl), NHC(O)(C.sub.1-4 alkyl),
NHS(O).sub.2(C.sub.1-4 alkyl), C(O)(C.sub.1-4 alkyl), CF.sub.3 or
OCF.sub.3) or heterocyclyl (itself optionally substituted by
halogen, hydroxy, nitro, NH.sub.2, NH(C.sub.1-4 alkyl), N(C.sub.1-4
alkyl).sub.2 (and these alkyl groups may join to form a ring as
described for R.sup.5 and R.sup.6 above), S(O).sub.2(C.sub.1-4
alkyl), S(O).sub.2NH.sub.2, S(O).sub.2NH(C.sub.1-4 alkyl),
S(O).sub.2N(C.sub.1-4 alkyl).sub.2 (and these alkyl groups may join
to form a ring as described for R.sup.5 and R.sup.6 above), cyano,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C(O)NH.sub.2, C(O)NH(C.sub.1-4
alkyl), C(O)N(C.sub.1-4 alkyl).sub.2 (and these alkyl groups may
join to form a ring as described for R.sup.5 and R.sup.6 above),
CO.sub.2H, CO.sub.2(C.sub.1-4 alkyl), NHC(O)(C.sub.1-4 alkyl),
NHS(O).sub.2(C.sub.1-4 alkyl), C(O)(C.sub.1-4 alkyl), CF.sub.3 or
OCF.sub.3); and
[0021] R.sup.24 is hydrogen, C.sub.1-6 alkyl or benzyl;
[0022] or an N-oxide thereof; or a pharmaceutically acceptable salt
thereof; or a solvate thereof.
[0023] 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.
[0024] Suitable salts include acid addition salts such as a
hydrochloride, dihydrochloride, hydrobromide, phosphate, acetate,
diacetate, fumarate, maleate, tartrate, citrate, oxalate,
methanesulphonate or p-toluenesulphonate. Another example of an
addition salt is sulphate. Salts also include metal salts, such as
a sodium, potassium, magnesium or calcium salt.
[0025] The compounds of the invention may exist as solvates (such
as hydrates) and the present invention covers all such
solvates.
[0026] Halogen includes fluorine, chlorine, bromine and iodine.
Halogen is, for example, fluorine or chlorine.
[0027] Alkyl groups and moieties are straight or branched chain and
are, for example, methyl, ethyl, n-propyl, iso-propyl or
tert-butyl.
[0028] Alkenyl group are, for example, vinyl or allyl.
[0029] Cycloalkyl is mono-, bi or tricyclic and is, for example,
cyclopropyl, cyclopentyl, cyclohexyl, norbornyl or camphoryl. The
cycloalkyl ring is optionally fused to a benzene ring (for example
forming a bicyclo[4.2.0]octa-1,3,5-trienyl or indanyl ring
system).
[0030] Cycloalkenyl is, for example, monocyclic and is, for
example, cyclopentenyl or cyclohexenyl.
[0031] Aryl is, for example, phenyl or naphthyl.
[0032] Heterocyclyl is an aromatic or non-aromatic 5 or 6 membered
ring, optionally fused to one or more other rings, comprising at
least one heteroatom selected from the group comprising nitrogen,
oxygen and sulphur; or an N-oxide thereof, or an S-oxide or
S-dioxide thereof. Heterocyclyl is, for example, furyl, thienyl
(also known as thiophenyl), pyrrolyl, 2,5-dihydropyrrolyl,
thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl,
piperidinyl, morpholinyl, pyridinyl (for example in
6-oxo-1,6-dihydro-pyridinyl), pyrimidinyl, indolyl,
2,3-dihydroindolyl, benzo[b]furyl (also known as benzfuryl),
benz[b]thienyl (also known as benzthienyl or benzthiophenyl),
2,3-dihydrobenz[b]thienyl (for example in
1-dioxo-2,3-dihydrobenz[b]thienyl), indazolyl, benzimidazolyl,
benztriazolyl, benzoxazolyl, benzthiazolyl (for example in
1H-benzthiazol-2-one-yl), 2,3-dihydrobenzthiazolyl (for example in
2,3-dihydrobenzthiazol-2-one-yl), 1,2,3-benzothiadiazolyl, an
imidazopyridinyl (such as imidazo[1,2a]pyridinyl),
thieno[3,2-b]pyridin-6-yl 1,2,3-benzoxadiazolyl,
benzo[1,2,3]thiadiazolyl, 2,1,3-benzothiadiazolyl, benzofurazan
(also known as 2,1,3-benzoxadiazolyl), quinoxalinyl,
dihydro-1-benzopyryliumyl (for example in a coumarinyl or a
chromonyl), 3,4-dihydro-1H-2,1-benzothiazinyl (for example in
2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl), a pyrazolopyridine (for
example 1H-pyrazolo[3,4-b]pyridinyl), a purine (for example in
3,7-dihydro-purin-2,6-dione-8-yl), quinolinyl, isoquinolinyl (for
example in 2H-isoquinolin-1-one-yl), a naphthyridinyl (for example
[1,6]naphthyridinyl or [1,8]naphthyridinyl or in
1H-[1,8]naphthyridin-4-one-yl), a benzothiazinyl (for example in
4H-benzo[1,4]thiazin-3-one-yl), benzo[d]imidazo[2,1-b]thiazol-2-yl
or dibenzothiophenyl (also known as dibenzothienyl); or an N-oxide
thereof, or an S-oxide or S-dioxide thereof. Heterocyclyl also
includes isothiazolyl.
[0033] In one aspect the present invention provides a compound of
formula (Ia):
##STR00005##
in which X is CH.sub.2, C(O), O, S, S(O), S(O).sub.2 or NR.sup.3; Y
is O or CH.sub.2; R.sup.1 is hydrogen, C.sub.1-6 alkyl, aryl or
heterocyclyl; R.sup.2 is C.sub.3-7 cycloalkyl {optionally
substituted by C.sub.1-4 alkyl, aryl or oxo}, C.sub.3-7
cycloalkenyl {optionally substituted by oxo, C.sub.1-6 alkyl or
aryl}, aryl or heterocyclyl; wherein the foregoing aryl and
heterocyclyl moieties are optionally substituted by: halogen,
cyano, nitro, hydroxy, oxo, S(O).sub.pR.sup.4,
OC(O)NR.sup.5R.sup.6, NR.sup.7R.sup.8, NR.sup.9C(O)R.sup.10,
NR.sup.11C(O)NR.sup.12R.sup.13, S(O).sub.2NR.sup.14R.sup.15,
NR.sup.16S(O).sub.2R.sup.17, C(O)NR.sup.18R.sup.19, C(O)R.sup.20,
CO.sub.2R.sup.21, NR.sup.22CO.sub.2R.sup.23, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy(C.sub.1-6)alkyl, C.sub.1-6
alkoxy, C.sub.1-6 haloalkoxy, C.sub.1-6 alkoxy(C.sub.1-6)alkoxy,
C.sub.1-6 alkylthio, C.sub.1-6 haloalkylthio, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl (itself optionally
substituted by C.sub.1-4 alkyl or oxo), methylenedioxy,
difluoromethylenedioxy, phenyl, phenyl(C.sub.1-4)alkyl, phenoxy,
phenylthio, phenyl(C.sub.1-4)alkoxy, heteroaryl,
heteroaryl(C.sub.1-4)alkyl, heteroaryloxy or
heteroaryl(C.sub.1-4)alkoxy; wherein any of the immediately
foregoing phenyl and heteroaryl moieties are optionally substituted
with halogen, hydroxy, nitro, S(O).sub.q(C.sub.1-4 alkyl),
S(O).sub.2NH.sub.2, cyano, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
C(O)NH.sub.2, C(O)NH(C.sub.1-4 alkyl), C(O)N(C.sub.1-4 alkyl).sub.2
(and these alkyl groups may join to form a ring as described for
R.sup.5 and R.sup.6 below), CO.sub.2H, CO.sub.2(C.sub.1-4 alkyl),
NHC(O)(C.sub.1-4 alkyl), NHS(O).sub.2(C.sub.1-4 alkyl),
C(O)(C.sub.1-4 alkyl), CF.sub.3 or OCF.sub.3; p and q are,
independently, 0, 1 or 2; R.sup.3, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16, R.sup.18 R.sup.19, R.sup.20, R.sup.21 and
R.sup.22 are, independently, hydrogen, C.sub.1-6 alkyl (optionally
substituted by halogen, hydroxy or C.sub.3-10 cycloalkyl),
CH.sub.2(C.sub.2-6 alkenyl), phenyl (itself optionally substituted
by halogen, hydroxy, nitro, NH.sub.2, NH(C.sub.1-4 alkyl),
N(C.sub.1-4 alkyl).sub.2, S(O).sub.2(C.sub.1-4 alkyl),
S(O).sub.2NH.sub.2, cyano, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
C(O)NH.sub.2, C(O)NH(C.sub.1-4 alkyl), C(O)N(C.sub.1-4 alkyl).sub.2
(and these alkyl groups may join to form a ring as described for
R.sup.5 and R.sup.6 below), CO.sub.2H, CO.sub.2(C.sub.1-4 alkyl),
NHC(O)(C.sub.1-4 alkyl), NHS(O).sub.2(C.sub.1-4 alkyl),
C(O)(C.sub.1-4 alkyl), CF.sub.3 or OCF.sub.3) or heterocyclyl
(itself optionally substituted by halogen, hydroxy, nitro,
NH.sub.2, NH(C.sub.1-4 alkyl), N(C.sub.1-4 alkyl).sub.2 (and these
alkyl groups may join to form a ring as described for R.sup.5 and
R.sup.6 below), S(O).sub.2(C.sub.1-4 alkyl), S(O).sub.2NH.sub.2,
S(O).sub.2NH(C.sub.1-4 alkyl), S(O).sub.2N(C.sub.1-4 alkyl).sub.2
(and these alkyl groups may join to form a ring as described for
R.sup.5 and R.sup.6 below), cyano, C.sub.1-4 alkyl, C.sub.1-4
alkoxy, C(O)NH.sub.2, C(O)NH(C.sub.1-4 alkyl), C(O)N(C.sub.1-4
alkyl).sub.2 (and these alkyl groups may join to form a ring as
described for R.sup.5 and R.sup.6 below), CO.sub.2H,
CO.sub.2(C.sub.1-4 alkyl), NEC(O)(C.sub.1-4 alkyl),
NHS(O).sub.2(C.sub.1-4 alkyl), C(O)(C.sub.1-4 alkyl), CF.sub.3 or
OCF.sub.3); alternatively NR.sup.5R.sup.6, NR.sup.7R.sup.8,
NR.sup.12R.sup.13, NR.sup.14R.sup.15, NR.sup.18R.sup.19, may,
independently, form a 4-7 membered heterocyclic ring, azetidine,
pyrrolidine, piperidine, azepine, 1,4-morpholine or 1,4-piperazine,
the latter optionally substituted by C.sub.1-4 alkyl on the distal
nitrogen; R.sup.4, R.sup.17 and R.sup.23 are, independently,
C.sub.1-6 alkyl (optionally substituted by halogen, hydroxy or
C.sub.3-10 cycloalkyl), CH.sub.2(C.sub.2-6 alkenyl), phenyl (itself
optionally substituted by halogen, hydroxy, nitro, NH.sub.2,
NH(C.sub.1-4 alkyl), N(C.sub.1-4 alkyl).sub.2 (and these alkyl
groups may join to form a ring as described for R.sup.5 and R.sup.6
above), S(O).sub.2(C.sub.1-4 alkyl), S(O).sub.2NH.sub.2,
S(O).sub.2NH(C.sub.1-4 alkyl), S(O).sub.2N(C.sub.1-4 alkyl).sub.2
(and these alkyl groups may join to form a ring as described for
R.sup.5 and R.sup.6 above), cyano, C.sub.1-4 alkyl, C.sub.1-4
alkoxy, C(O)NH.sub.2, C(O)NH(C.sub.1-4 alkyl), C(O)N(C.sub.1-4
alkyl).sub.2 (and these alkyl groups may join to form a ring as
described for R.sup.5 and R.sup.6 above), CO.sub.2H,
CO.sub.2(C.sub.1-4 alkyl), NHC(O)(C.sub.1-4 alkyl),
NHS(O).sub.2(C.sub.1-4 alkyl), C(O)(C.sub.1-4 alkyl), CF.sub.3 or
OCF.sub.3) or heterocyclyl (itself optionally substituted by
halogen, hydroxy, nitro, NH.sub.2, NH(C.sub.1-4 alkyl), N(C.sub.1-4
alkyl).sub.2 (and these alkyl groups may join to form a ring as
described for R.sup.5 and R.sup.6 above), S(O).sub.2(C.sub.1-4
alkyl), S(O).sub.2NH.sub.2, S(O).sub.2NH(C.sub.1-4 alkyl),
S(O).sub.2N(C.sub.1-4 alkyl).sub.2 (and these alkyl groups may join
to form a ring as described for R.sup.5 and R.sup.6 above), cyano,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C(O)NH.sub.2, C(O)NH(C.sub.1-4
alkyl), C(O)N(C.sub.1-4 alkyl).sub.2 (and these alkyl groups may
join to form a ring as described for R.sup.5 and R.sup.6 above),
CO.sub.2H, CO.sub.2(C.sub.1-4 alkyl), NHC(O)(C.sub.1-4 alkyl),
NHS(O).sub.2(C.sub.1-4 alkyl), C(O)(C.sub.1-4 alkyl), CF.sub.3 or
OCF.sub.3); or an N-oxide thereof; or a pharmaceutically acceptable
salt thereof, or a solvate thereof.
[0034] In one particular aspect, the invention provides a compound
of the invention wherein X is O.
[0035] In a further aspect, the invention provides a compound of
the invention wherein Y is O.
[0036] In a still further aspect, the invention provides a compound
of the invention wherein Y is CH.sub.2.
[0037] In another aspect, R.sup.24 is hydrogen.
[0038] In yet another aspect, Z is CHR.sup.2CO.sub.2R.sup.24.
[0039] In another aspect, R.sup.1 is phenyl optionally substituted
with fluorine, chlorine, C.sub.1-4 alkyl (for example methyl) or
C.sub.1-4 alkoxy (for example methoxy). In another aspect R.sup.1
is phenyl optionally substituted with fluorine, chlorine or
C.sub.1-4 alkyl (for example methyl).
[0040] In a further aspect, R.sup.1 is phenyl optionally
substituted (for example with one, two or three) with fluorine,
chlorine, C.sub.1-4 alkyl (for example methyl) or C.sub.1-4 alkoxy
(for example methoxy). In a still further aspect R.sup.1 is phenyl
substituted by one, two or three of fluorine, chlorine, methyl or
methoxy. For example R.sup.1 is 3,4-dichlorophenyl,
2,4-dichloro-3-methylphenyl, 3,4-dichloro-2-methylphenyl,
2,4-dichlorophenyl, 4-chloro-2-methylphenyl or
2-chloro-4-fluorophenyl.
[0041] In a further aspect, R.sup.2 is unsubstituted phenyl, mono-,
di- or tri-substituted phenyl, unsubstituted or mono-substituted
naphthyl or mono-substituted heterocyclyl, the substituents being
chosen from those described above.
[0042] In a still further aspect, R.sup.2 is oxo substituted
heterocyclyl, said heterocyclyl optionally further substituted with
one or more substituents chosen from those described above.
[0043] In another aspect, R.sup.2 is phenyl or heterocyclyl, either
of which is optionally substituted by: halo, hydroxy, nitro, cyano,
amino, C.sub.1-4 alkyl (itself optionally substituted by
S(O).sub.2(C.sub.1-4 alkyl) or S(O).sub.2phenyl), C.sub.1-4 alkoxy,
S(O).sub.pR.sup.4 (wherein p is 0, 1 or 2 (such as 2)),
C(O)NH.sub.2, NHS(O).sub.2(C.sub.1-4 alkyl), S(O).sub.2NH.sub.2,
S(O).sub.2NH(C.sub.1-4 alkyl) or S(O).sub.2N(C.sub.1-4
alkyl).sub.2; and R.sup.4 is C.sub.1-4 alkyl, C.sub.1-4
hydroxyalkyl, C.sub.3-7 cycloalkyl or C.sub.3-7
cycloalkyl(C.sub.1-4 alkyl) (such as cyclopropylmethyl).
[0044] In a further aspect, R.sup.2 is phenyl optionally
mono-substituted by: halo, hydroxy, nitro, cyano, amino, C.sub.1-4
alkyl (itself optionally substituted by S(O).sub.2(C.sub.1-4 alkyl)
or S(O).sub.2phenyl), C.sub.1-4 alkoxy, S(O).sub.pR.sup.4 (wherein
p is 0, 1 or 2 (such as 2)), C(O)NH.sub.2, NHS(O).sub.2(C.sub.1-4
alkyl), S(O).sub.2NH.sub.2, S(O).sub.2NH(C.sub.1-4 alkyl) or
S(O).sub.2N(C.sub.1-4 alkyl).sub.2; and R.sup.4 is C.sub.1-4 alkyl,
C.sub.4 hydroxyalkyl, C.sub.3-7 cycloalkyl or C.sub.3-7
cycloalkyl(C.sub.1-4 alkyl) (such as cyclopropylmethyl).
[0045] Heterocyclyl includes thienyl, furanyl or benzofuranyl; for
example furanyl monosubstituted by C.sub.1-4 alkyl.
[0046] In yet another aspect, R.sup.2 is phenyl (optionally
substituted by halogen, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
benzyloxy or 9H-carbazylmethyl), naphthylenyl (optionally
substituted by C.sub.1-4 alkoxy) or heterocyclyl (optionally
substituted by C.sub.1-4 alkyl).
[0047] In a further aspect the present invention provides a
compound of formula (I) in which X is O; Y is O or CH.sub.2;
R.sup.1 is phenyl optionally substituted by halogen (for example
chlorine) or C.sub.1-4 alkyl (for example methyl); and R.sup.2 is
as defined above.
[0048] A compound of the invention, wherein Z is
CHR.sup.2CO.sub.2R.sup.24, can be prepared by coupling a compound
of formula (II):
##STR00006##
with a compound of formula (III):
##STR00007##
in which L is a suitable leaving group (for example halogen or
C.sub.1-6 alkylsulfonyl) and the coupling can be carried out in a
suitable solvent (such as water).
[0049] Alternatively, a compound of the invention, wherein Z is
CHR.sup.2CO.sub.2R.sup.24, can be prepared by reductive amination
of a compound (II) with an ester (such as a C.sub.1-6 alkyl ester
or a benzyl ester) compound of formula (IIIa):
##STR00008##
in the presence of NaBH(OAc).sub.3 and acetic acid, followed
optionally by removal of the ester group.
[0050] Alternatively, a compound of the invention, in which Z is
CHR.sup.2CO.sub.2R.sup.24, can be prepared by a three component
coupling of a compound of formula (II) with compounds of formula
(IIIb) and (IIIc):
##STR00009##
[0051] A compound of formula (II), where X is CH.sub.2, may be
prepared following methods in WO 00/35877. A compound of formula
(II) can be prepared by deprotecting a compound of formula
(IV):
##STR00010##
for example using trifluoroacetic acid in a suitable solvent (such
as dichloromethane) or using a source of hydrogen chloride in a
suitable solvent (such as dioxane).
[0052] A compound of formula (IV), in which X is O, can be prepared
by reacting a compound of formula (V):
##STR00011##
with a compound of formula (VI):
##STR00012##
in the presence of NaBH(OAc).sub.3 and acetic acid.
[0053] Alternatively, a compound of formula (IV), in which X is O,
can be prepared by reacting a compound of formula (V) with a
compound of formula (VIa):
##STR00013##
where L represents a suitable leaving group, for example mesylate,
in the presence of a suitable base, for example, potassium
carbonate, in a suitable solvent, such as acetone.
[0054] A compound of formula (IV), wherein X is CO or CH.sub.2, can
be prepared by oxidising or reducing a compound of formula
(VII):
##STR00014##
[0055] A compound of formula (VII) can be prepared by reacting a
compound of formula (VIII):
##STR00015##
with a compound of formula (VI) in the presence of NaBH(OAc).sub.3
and acetic acid. A compound of formula (VIII) can be prepared by
reduction of a compound of formula (IX):
##STR00016##
[0056] A compound of formula (IV) wherein X is NR.sup.3 can be
prepared by reacting a compound of formula (X):
##STR00017##
with a compound of formula (VI) in the presence of NaBH(OAc).sub.3
and acetic acid. A compound of formula (X) can be prepared by
reacting NHR.sup.1R.sup.3 with a compound of formula (XI):
##STR00018##
in the presence of NaBH(OAc).sub.3 and acetic acid and then
deprotecting the piperidine nitrogen {for example using
trifluoroacetic acid in a suitable solvent (such as
dichloromethane) or using a source of hydrogen chloride in a
suitable solvent (such as dioxane)}.
[0057] A compound of formula (I) in which:
##STR00019##
can be prepared by reacting a compound of formula (II) with: (1)
when n is 1, a compound of formula (XIV):
##STR00020##
in which L is a leaving group (such as chlorine, bromine or
OS(O).sub.2CH.sub.3); (2) when n is 1, a compound of formula
(XVI):
##STR00021##
under reductive amination conditions (for example using
NaBH(OAc).sub.3 and acetic acid in tetrahydrofuran); and (3) when n
is 0, a compound of formula (XV):
##STR00022##
in the presence of potassium carbonate, in a suitable solvent (such
as N,N-dimethylformamide) at a suitable temperature (such as in the
range 80-110.degree. C.).
[0058] Compounds of the invention where R.sup.24 is hydrogen may be
converted to compounds of the invention where R.sup.24 is not
hydrogen by standard esterification methods well known in the
art.
[0059] Compounds of the invention where R.sup.24 is not hydrogen
may be converted to compounds of the invention where R.sup.24 is
hydrogen by standard ester hydrolysis methods well known in the
art.
[0060] A compound of formula (VI) or formula (VIa) may be prepared
by following methods descibed in WO 00/35877. Alternatively a
compound of formula (VI) or (VIa) can be prepared by routes
described in the literature from the corresponding alcohol (for
example: when Y is CH.sub.2 see Tet. Asym., 1992, 3,1049; Bioorg.
Med. Chem. Lett., 1997, 7, 1525 and 1998, 8, 1595; and when Y is O
see Farmaco. Ed. Sci., 1994, 49, 77; Heterocycles, 1994, 38, 1033
and 1993, 35, 105).
[0061] Further compounds of the invention can be prepared by
adaptation of the routes described above, methods described in the
art, or the Examples recited below.
[0062] Compounds of formula (V), (VI), (IX) and (XI) can be
prepared by using or adapting methods described in the art.
[0063] In another aspect, the present invention provides processes
for the preparation of compounds of the invention.
[0064] The compounds of the invention 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)).
[0065] Examples of these conditions are: [0066] (1) (the
respiratory tract) obstructive diseases of airways including:
chronic obstructive pulmonary disease (COPD) (such as irreversible
COPD); asthma {such as bronchial, allergic, intrinsic, extrinsic or
dust asthma, particularly chronic or inveterate asthma (for example
late asthma or airways hyper-responsiveness)}; bronchitis {such as
eosinophilic bronchitis}; acute, allergic, atrophic rhinitis or
chronic rhinitis including 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;
sarcoidosis; farmer's lung and related diseases; nasal polyposis;
fibroid lung, idiopathic interstitial pneumonia, antitussive
activity, treatment of chronic cough associated with inflammatory
conditions of the airways or iatrogenic induced cough; [0067] (2)
(bone and joints) arthrides including rheumatic, infectious,
autoimmune, seronegative spondyloarthropathies (such as ankylosing
spondylitis, psoriatic arthritis or Reiter's disease), Behcet's
disease, Sjogren's syndrome or systemic sclerosis; [0068] (3) (skin
and eyes) psoriasis, atopic dertnatitis, contact dermatitis or
other eczmatous dermitides, seborrhoetic dermatitis, lichen planus,
phemphigus, bullous phemphigus, epidermolysis bullosa, urticaria,
angiodermas, vasculitides erythemas, cutaneous eosinophilias,
uveitis, alopecia greata, corneal ulcer or vernal conjunctivitis;
[0069] (4) (gastrointestinal tract) Coeliac disease, proctitis,
eosinophilic gastro-enteritis, mastocytosis, Crohn's disease,
ulcerative colitis, irritable bowel disease or food-related
allergies which have effects remote from the gut (for example
migraine, rhinitis or eczema); [0070] (5) (Allograft rejection)
acute and chronic following, for example, transplantation of
kidney, heart, liver, lung, bone marrow, skin or cornea; or chronic
graft versus host disease; and/or [0071] (6) (other tissues or
diseases) Alzheimer's disease, multiple sclerosis, atherosclerosis,
Acquired Immunodeficiency Syndrome (AIDS), lupus disorders (such as
lupus erythematosus or systemic lupus), erythematosus, Hashimoto's
thyroiditis, myasthenia gravis, type I diabetes, nephrotic
syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such
as lepromatous leprosy), peridontal disease, Sezary syndrome,
idiopathic thrombocytopenia pupura or disorders of the menstrual
cycle.
[0072] The compounds of the invention or a pharmaceutically
acceptable salt thereof or a solvate thereof, are also H1
antagonists (and can, therefore, be used in the treatment of
allergic disorders); and may also be used to control a sign and/or
symptom of what is commonly referred to as a cold (for example a
sign and/or symptom of a common cold or influenza or other
associated respiratory virus infection).
[0073] 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
formula (I) or (Ia) or a pharmaceutically acceptable salt thereof
or a solvate thereof.
[0074] According to another feature of the present invention there
is provided a method for antagonising H1 in a mammal, such as man,
suffering from, or at risk of, an H1 mediated disease state, which
comprises administering to a mammal in need of such treatment a
therapeutically effective amount of a compound of the formula (I)
or (Ia) or a pharmaceutically acceptable salt thereof or a solvate
thereof.
[0075] 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 formula (I)
or (Ia) or a pharmaceutically acceptable salt thereof or a solvate
thereof.
[0076] The invention also provides a compound of the formula (I) or
(Ia), or a pharmaceutically acceptable salt thereof or a solvate
thereof, for use in therapy.
[0077] In another aspect, the invention provides the use of a
compound of formula (I) or (Ia), or a pharmaceutically acceptable
salt thereof or a solvate thereof, in the manufacture of a
medicament for use in therapy (for example modulating chemokine
receptor activity (for example CCR3 receptor activity),
antagonising H1 or treating a sign and/or symptom of what is
commonly referred to as a cold).
[0078] The invention further provides the use of a compound of
formula (I) or (Ia), or a pharmaceutically acceptable salt thereof,
in the manufacture of a medicament for use in the treatment of:
[0079] (1) (the respiratory tract) obstructive diseases of airways
including: chronic obstructive pulmonary disease (COPD) (such as
irreversible COPD); asthma {such as bronchial, allergic, intrinsic,
extrinsic or dust asthma, particularly chronic or inveterate asthma
(for example late asthma or airways hyper-responsiveness)};
bronchitis {such as eosinophilic bronchitis}; acute, allergic,
atrophic rhinitis or chronic rhinitis including 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; sarcoidosis; farmer's lung and related
diseases; nasal polyposis; fibroid lung, idiopathic interstitial
pneumonia, antitussive activity, treatment of chronic cough
associated with inflammatory conditions of the airways or
iatrogenic induced cough; [0080] (2) (bone and joints) arthrides
including rheumatic, infectious, autoimmune, seronegative
spondyloarthropathies (such as ankylosing spondylitis, psoriatic
arthritis or Reiter's disease), Behcet's disease, Sjogren's
syndrome or systemic sclerosis; [0081] (3) (skin and eyes)
psoriasis, atopic dermatitis, contact dermatitis or other eczmatous
dermitides, seborrhoetic dermatitis, lichen planus, phemphigus,
bullous phemphigus, epidermolysis bullosa, urticaria, angiodermas,
vasculitides erythemas, cutaneous eosinophilias, uveitis, alopecia
greata, corneal ulcer or vernal conjunctivitis; [0082] (4)
(gastrointestinal tract) Coeliac disease, proctitis, eosinophilic
gastro-enteritis, mastocytosis, Crohn's disease, ulcerative
colitis, irritable bowel disease or food-related allergies which
have effects remote from the gut (for example migraine, rhinitis or
eczema); [0083] (5) (Allograft rejection) acute and chronic
following, for example, transplantation of kidney, heart, liver,
lung, bone marrow, skin or cornea; or chronic graft versus host
disease; and/or [0084] (6) (other tissues or diseases) Alzheimer's
disease, multiple sclerosis, atherosclerosis, Acquired
Immunodeficiency Syndrome (AIDS), lupus disorders (such as lupus
erythematosus or systemic lupus), erythematosus, Hashimoto's
thyroiditis, myasthenia gravis, type I diabetes, nephrotic
syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such
as lepromatous leprosy), Peridontal disease, sezary syndrome,
idiopathic thrombocytopenia pupura or disorders of the menstrual
cycle; in a mammal (for example man).
[0085] In a further aspect, the invention provides a compound of
formula (I) or (Ia), 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}.
[0086] In a still further aspect, a compound of formula (I) or
(Ia), or a pharmaceutically acceptable salt thereof, is useful in
the treatment of asthma.
[0087] The present invention also provides the use of a compound of
formula (I) or (Ia), or a pharmaceutically acceptable salt thereof,
in the manufacture of a medicament for use in the treatment of
asthma I 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}.
[0088] In order to use a compound of the invention, or a
pharmaceutically acceptable salt thereof or solvate 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 the formula (I) or (Ia), or a
pharmaceutically acceptable salt thereof or a solvate thereof
(active ingredient), and a pharmaceutically acceptable adjuvant,
diluent or carrier.
[0089] In a further aspect, the present invention provides a
process for the preparation of said composition which includes
mixing active ingredient with a pharmaceutically acceptable
adjuvant, diluent or carrier. Depending on the mode of
administration, the pharmaceutical composition will, for example,
include 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, and such as from 0.10 to
50% w, of active ingredient, all percentages by weight being based
on total composition.
[0090] The pharmaceutical compositions of this invention 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
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.
[0091] Each patient may receive, for example, a dose of 0.01
mgkg.sup.-1 to 100 mgkg.sup.-1, such as 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.
[0092] 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).sup.+; (iii) the title
and sub-title compounds of the examples and methods were named
using the Index name program from Advanced Chemistry Development
Inc.; (iv) unless stated otherwise, reverse phase HPLC was
conducted using a Symmetry.TM., NovaPak.TM. or Xerra.TM. reverse
phase silica column; and (v) the following abbreviations are
used:
TABLE-US-00001 RT room temperature DMSO dimethylsulfoxide Boc or
BOC tert-butoxycarbonyl aq aqueous HPLC high pressure liquid
chromatography
Preparation 1
(2S) 2-[[4-(3,4-Dichlorophenoxy)-1-piperidinyl]methyl]-morpholine
(Intermediate 1)
Step a: (2S) 1,1-Dimethylethyl
2-[[(methylsulfonyl)oxy]methyl]-2-(hydroxymethyl)-4-morpholinecarboxylate
[0093] To a solution of (25) 1,1-dimethylethyl
2-(hydroxymethyl)-4-morpholinecarboxylate (5.63 g) (Heterocycles,
1993, 35, 105) and N-ethyl-N,N-diisopropylamine (9 ml) in
dichloromethane (200 ml) at room temperature was added
methanesulfonic anhydride (5.42 g). The reaction was stirred for 16
hours. The reaction mixture was poured onto saturated aqueous
NaHCO.sub.3 solution and the organics were extracted with
dichloromethane. The combined organic extracts were dried with
MgSO.sub.4 and concentrated to give an oil (8.33 g). This was used
without further purification.
Step b: (2R) 1,1-Dimethylethyl
2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-4-morpholinecarboxylate
[0094] To a solution of 4-(3,4-dichlorophenoxy)piperidine (WO
01/77101; 9.22 g) dissolved in acetonitrile (60 ml) was added the
product of Step (a) (5.53 g). The mixture was refluxed for 12 hours
and the solvents were evaporated. Purification by flash
chromatography eluting with dichloromethane: methanol: NH.sub.3
(aq) (2:97.9:0.1) gave the sub-title compound as an oil (5.76
g).
[0095] .sup.1H NMR (CDCl.sub.3) .delta. 1.47 (9H, s), 1.87-1.77
(2H, m), 2.02-1.94 (2H, m), 2.39-2.30 (2H, m), 2.60-2.51 (2H, m),
2.77-2.70 (2H, m), 2.95-2.89 (1H, m), 3.58-3.50 (2H, m), 3.73-3.67
(1H, m), 3.96-3.81 (2H, m), 4.30-4.22 (2H, m), 6.75 (1H, dd), 6.99
(1H, d), 7.30 (1H, d).
Step c: (2S)
2-[[4-(3,4-Dichlorophenoxy)-1-piperidinyl]methyl]morpholine
[0096] The product from Step (b) (5.76 g) was dissolved in
dichloromethane (100 ml) and trifluoroacetic acid (40 ml) was
added. After 16 hours at room temperature the solution was
evaporated. The free base was liberated by addition of aqueous NaOH
(2 M) and extraction with dichloromethane. The combined organic
extracts were dried with MgSO.sub.4 and concentrated. Purification
by flash chromatography eluting with dichloromethane: methanol:
NH.sub.3 (aq) (8:91.9:0.1) gave the title compound as an oil (3.84
g).
[0097] .sup.1H NMR (CDCl.sub.3) .delta. 1.75-1.88 (2H, m),
1.92-2.04 (2H, m), 2.23-2.39 (3H, m), 2.47-2.58 (2H, m), 2.72-2.93
(5H, m), 3.55-3.65 (2H, m), 3.86-3.90 (1H, m), 4.22-4.31 (1H, m),
6.75 (1H, dd), 6.99 (1H, d), 7.30 (1H, d).
Preparation 2
(2R) 2-[[4-(3,4-Dichlorophenoxy)-1-piperidinyl]methyl]-morpholine
(Intermediate 2)
[0098] Prepared analogously to the S isomer in Preparation 1
starting with the antipodal morpholine in Step a of Preparation
1.
Preparation 3
(2S)
2-[[4-(2,4-Dichloro-3-methylphenoxy)-1-piperidinyl]methyl]-morpholine
(Intermediate 3)
[0099] Prepared analogously to Preparation 1 starting with the
appropriate phenoxypiperidine (WO 01/77101) in Step a of
Preparation 1.
[0100] .sup.1H NMR 6(CDCl.sub.3) 1.83-2.04 (4H, m), 2.25-2.60 (8H,
m), 2.69-2.95 (5H, m), 3.55-3.70 (2H, m), 3.86 (1H, d), 4.35 (1H,
s), 6.74 (1H, d), 7.18 (1H, d)
Preparation 4
(2R)
2-[[4-(2,4-Dichloro-3-methylphenoxy)-1-piperidinyl]methyl]-morpholine
(Intermediate 4)
[0101] Prepared analogously to the S isomer in Preparation 3
starting with the antipodal morpholine in Step a of Preparation
1.
Preparation 5
(2S)
2-[[4-(4-Chloro-2-methylphenoxy)-1-piperidinyl]methyl]-morpholine
(Intermediate 5)
[0102] Prepared analogously to the S isomer in Preparation 1
starting with the appropriate phenoxypiperidine (WO 01/77101) in
Step a of Preparation 1.
[0103] .sup.1H NMR 8(CDCl.sub.3) 1.70 (4H, s), 1.86 (2H, dd), 1.96
(2H, dd), 2.19 (3H, s), 2.35-2.45 (2H, m), 2.67-2.77 (2H, m),
2.80-2.96 (2H, m), 3.58-3.69 (2H, m), 3.85-3.92 (1H, m), 4.26-4.34
(1H, m), 6.73 (1H, d), 7.08 (2H, td).
Preparation 6
(2R)
2-[[4-(4-Chloro-2-methylphenoxy)-1-piperidinyl]methyl]-morpholine
(Intermediate 6)
[0104] Prepared analogously to the S isomer in Preparation 5
starting with the antipodal morpholine in Step a of Preparation
1.
Preparation 7
4-(3,4-Dichlorophenoxy)-1-(3-piperidinylmethyl)-piperidine
(Intermediate 7)
Step a: 1,1-Dimethylethyl
3-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidinecarboxylate
[0105] 4-(3,4-Dichlorophenoxy)piperidine (1 g) and
1,1-dimethylethyl 3-formyl-1-piperidinecarboxylate (Bioorg. Med.
Chem. Lett., 1998, 8, 1595) were combined in tetrahydrofuran (4 ml)
at 0.degree. C., acetic acid (0.25 ml) was added and the mixture
was stirred for 10 minutes, then at RT for 5 minutes. Sodium
triacetoxyborohydride (1.25 g) was added in two portions and the
resulting mixture was stirred for 16 hours. Sodium hydroxide
solution (2 M) was added to neutralise the acid. The mixture was
extracted with diethyl ether, the extracts were dried, filtered and
evaporated to give an oil which was chromatographed eluting with
dichloromethane: methanol: aqueous ammonia (97:2:1) to give the
subtitle compound (1.63 g).
[0106] MS [M+H].sup.+ (ES.sup.+) 443.
[0107] .sup.1H NMR .delta.(CDCl.sub.3) 1.05-1.14 (1H, m), 1.46
(11H, s), 1.61-1.66 (2H, m), 1.76-1.81 (3H, m), 1.92-1.98 (2H, m),
2.11-2.29 (4H, m), 2.62-2.81 (3H, m), 3.90-4.04 (2H, m), 4.21-4.27
(1H, m), 6.75 (1H, dd), 6.99 (1H, d), 7.30 (1H, d).
Step b:
4-(3,4-Dichlorophenoxy)-1-(piperidin-3-ylmethyl)piperidine
[0108] 1,1-Dimethylethyl
3-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidinecarboxylate
(1.63 g) was dissolved in dichloromethane (30 ml) and
trifluoroacetic acid (10 ml) was added. The mixture was stirred for
3 hours, then concentrated. The residue was neutralised with sodium
hydroxide solution (2 M) and extracted with ethyl acetate thrice.
The extracts were dried, filtered and evaporated to give the title
compound (1.06 g).
[0109] .sup.1H NMR .delta.(CDCl.sub.3) 0.99-1.08 (1H, m), 1.45-1.56
(1H, m), 1.67-1.84 (5H, m), 1.94 (2H, s), 2.10-2.35 (6H, m),
2.54-2.71 (3H, m), 3.05 (1H, d), 3.19 (1H, d), 4.22-4.26 (1H, m),
6.73-6.77 (1H, m), 6.98-7.00 (1H, m), 7.27-7.32 (1H, m).
EXAMPLES 1 & 2
[0110] This Example illustrates the preparation of
(.alpha..sup.4S,2R)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.al-
pha.-phenyl-4-morpholineacetic acid and
(.alpha..sup.4R,2R)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.al-
pha.-phenyl-4-morpholineacetic acid.
[0111] To a solution of (2S)
2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-morpholine (0.300
g) in acetonitrile (3 ml) was added phenylboronic acid (0.106 g)
and oxoacetic acid (0.08 ml). The mixture was heated for 4 minutes
at 120.degree. C. using microwaves at 50 Watts. The solvent was
removed by evaporation and the product as two diasteroisomers was
purified using reverse phase HPLC (25% MeCN/75% NH.sub.3 aq (0.1%))
to give the title compounds as white solids (0.048 g and 0.044
g).
Faster Eluting Isomer
[0112] MS: ES(+ve): 479 (M+H).
[0113] .sup.1H NMR (CDCl.sub.3) .delta. 1.67-1.74 (3H, m),
1.83-1.97 (2H, m), 2.08-2.18 (1H, m), 2.44-2.51 (1H, m), 2.73-2.88
(4H, m), 2.91-3.03 (2H, m), 3.30-3.37 (1H, m), 3.64-3.74 (2H, m),
3.76-3.80 (1H, m), 4.08-4.20 (2H, m), 6.62-6.67 (1H, m), 6.87-6.91
(1H, m), 7.21-7.34 (4H, m), 7.49-7.56 (2H, m).
Slower Eluting Isomer
[0114] MS: ES(+ve): 479 (M+H).
[0115] .sup.1H NMR (CDCl.sub.3) .delta. 1.72-1.85 (3H, m),
1.87-1.98 (3H, m), 2.37-2.48 (2H, m), 2.57-2.65 (3H, m), 2.68-2.85
(4H, m), 3.70-3.80 (1H, m), 3.95-4.04 (2H, m), 4.20-4.29 (1H, m),
6.65-6.72 (1H, m), 6.90-6.95 (1H, m), 7.23-7.33 (4H, m), 7.39-7.44
(2H, m).
EXAMPLES 3 & 4
[0116] This Example illustrates the preparation of
(.alpha..sup.4S,2S)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.al-
pha.-phenyl-4-morpholineacetic acid and
(2S)-((2S)-2-{[4-(3,4-dichlorophenoxy)piperidin-1-yl]methyl}morpholin-4-y-
l)(phenyl)acetic
acid(.alpha..sup.4R,2S)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-
-.alpha.-phenyl-4-morpholineacetic acid.
[0117] To a solution of (2R)
2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-morpholine (0.345
g) in acetonitrile (3 ml) was added phenylboronic acid (0.122 g)
and oxoacetic acid (0.3 ml). The mixture was heated for 5 minutes
at 100.degree. C. using microwaves at 50 Watts. The solvent was
removed by evaporation and the product as two diastereoisomers was
purified using reverse phase HPLC (25% MeCN/75% NH.sub.3 aq (0.1%))
to give the title compounds as white solids (0.048 g and 0.044
g).
Faster Eluting Isomer
[0118] MS: ES(+ve): 479 (M+H).
[0119] .sup.1H NMR 6(CD.sub.3OD) 1.25-1.35 (1H, m), 1.70-1.81 (2H,
m), 1.95-2.03 (2H, m), 2.32 (2H, dd), 2.36-2.44 (3H, m), 2.52 (1H,
d), 2.72-2.86 (2H, m), 3.09-3.18 (1H, m), 3.58-3.62 (1H, m),
3.61-3.68 (1H, m), 3.68-3.75 (1H, m), 3.87-3.97 (1H, m), 4.32-4.43
(1H, m), 6.88 (1H, dd), 7.09 (1H, d), 7.21-7.30 (3H, m), 7.37 (1H,
d), 7.52 (2H, d).
Slower Eluting Isomer
[0120] MS: ES(+ve): 479 (M+H).
[0121] .sup.1H NMR 6(CD.sub.3OD) 1.29-1.38 (1H, m), 1.64 (1H, t),
1.69-1.79 (2H, m), 1.92-2.00 (2H, m), 2.17 (1H, dd), 2.22 (1H, dd),
2.32-2.39 (1H, m), 2.43 (1H, dd), 2.52 (1H, d), 2.68-2.78 (2H, m),
3.13 (1H, d), 3.65 (1H, s), 3.74-3.81 (1H, m), 3.82-3.89 (2H, m),
4.32-4.42 (1H, m), 6.89 (1H, dd), 7.09 (1H, d), 7.25-7.35 (3H, m),
7.39 (1H, d), 7.56 (2H, d).
EXAMPLES 5 AND 6
[0122] This Example illustrates the preparation of
3-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-alpha-phenyl-1-piperidi-
neacetic acid.
[0123] To a solution of
4-(3,4-dichlorophenoxy)-1-(piperidin-3-ylmethyl)piperidine (1.0 g)
in ethanol (5 ml) was added phenylboronic acid (0.3 6 g) and
oxoacetic acid (0.45 ml 50% solution in water). The mixture was
heated to 100.degree. C. for 6 minutes using microwaves at 50
Watts. The crude reaction mixture was diluted with methanol and
purified by reverse phase HPLC eluting with an acetonitrile
ammonium acetate mixture. Gradient from 75% aqueous/25%
acetonitrile to 5% aqueous/95% acetonitrile. This gave a mixture of
diastereoisomers which were separated by reverse phase HPLC eluting
with an acetonitrile ammonium acetate mixture. Gradient from 95%
aqueous/5% acetonitrile to 50% aqueous/50% acetonitrile.
First Eluting Diastereoisomer
[0124] MS: APCl(+ve): 477 (M+H).
[0125] .sup.1H NMR 6 (CD.sub.3OD plus 1 drop NaOD) 1.53-1.63 (2H,
m), 1.69-1.85 (5H, m), 1.90-2.08 (4H, m), 2.18-2.38 (4H, m),
2.58-2.80 (3H, m), 3.18-3.27 (1H, m), 3.64 (1H, s), 4.33-4.46 (1H,
m), 6.89 (1H, dd), 7.09 (1H, d), 7.20-7.30 (3H, m), 7.38 (1H, d),
7.54 (2H, d).
Second Eluting Diastereoisomer
[0126] MS: APCI(+ve): 477 (M+H).
[0127] .sup.1H NMR .delta. (CD.sub.3OD plus 1 drop NaOD) 1.31-1.42
(1H, m), 1.56-2.25 (14H, m), 2.52-2.67 (2H, m), 2.76-2.83 (1H, m),
3.19-3.25 (1H, m), 3.64 (1H, s), 4.26-4.37 (1H, m), 6.83-6.88 (1H,
m), 7.05 (1H, d), 7.22-7.32 (3H, m), 7.37 (1H, d), 7.53 (2H,
d).
EXAMPLES 7-12
[0128] Examples 7-12 were prepared by similar methods to Examples
1-6 using the appropriate intermediate (preparations 2-6).
TABLE-US-00002 Example Name .sup.1H NMR M + H 7 2-[[4-(4-chloro-2-
.delta.(CDCl.sub.3) 1.80-2.01 (4H, m), 459/461 methylphenoxy)-1-
2.08-2.18 (2H, m), 2.15 (3H, s), 2.42-2.51 (1H, m),
piperidinyl]methyl]- 2.62-2.71 (1H, m), 2.74-3.07 (4H, m),
alpha-phenyl-, (2R)-4- 3.08-3.31 (2H, m), 3.64-3.81 (3H, m),
morpholineacetic acid 4.04-4.10 (1H, m), 4.15-4.24 (1H, m),
4.26-4.34 (1H, m), 6.62 (1H, dd), 7.06 (1H, dd), 7.10 (1H, d),
7.22-7.33 (3H, m), 7.41 (1H, d), 7.50-7.53 (1H, m) 8
2-[[4-(4-chloro-2- .delta.(CDCl.sub.3) 1.80-2.00 (4H, m), 459/461
methylphenoxy)-1- 2.07-2.19 (2H, m), 2.15 (3H, s), 2.41-2.54 (1H,
m), piperidinyl]methyl]- 2.60-3.31 (6H, m), 3.65-3.79 (3H, m),
alpha-phenyl-, (2S)-4- 4.02-4.11 (1H, m), 4.15-4.24 (1H, m),
morpholineacetic acid 4.26-4.34 (1H, m), 6.62 (1H, t), 7.06 (1H,
dd), 7.10 (1H, d), 7.22-7.34 (3H, m), 7.39-7.44 (1H, m), 7.49-7.55
(1H, m) 9 2-[[4-(2,4-dichloro-3- .delta.(CDCl.sub.3) 1.59-2.01 (5H,
m), 2.19 (1H, t), 493/495 methylphenoxy)-1- 2.41-2.51 (4H, m),
2.89-3.03 (4H, m), piperidinyl]methyl]- 3.17-3.30 (2H, m),
3.34-3.42 (2H, m), alpha-phenyl-, (2R)-4- 3.68-3.80 (2H, m),
4.17-4.32 (2H, m), morpholineacetic acid 6.60 (1H, d), 7.17 (1H,
d), 7.21-7.33 (3H, m), 7.50-7.56 (2H, m) 10 2-[[4-(2,4-dichloro-3-
.delta.(CDCl.sub.3) 1.78-2.07 (5H, m), 493/495 methylphenoxy)-1-
2.30-2.41 (1H, m), 2.45 (3H, s), 2.56-2.89 (4H, m),
piperidinyl]methyl]- 3.03-3.42 (4H, m), 3.66-3.79 (2H, m),
alpha-phenyl-, (2R)-4- 3.92-4.05 (2H, m), 4.34 (1H, s), 6.67 (1H,
morpholineacetic acid d), 7.18 (1H, d), 7.21-7.27 (3H, m),
7.36-7.43 (2H, m) 11 2-[[4-(2,4-dichloro-3- .delta.(CDCl.sub.3)
1.70-1.83 (2H, m), 493/495 methylphenoxy)-1- 1.88-1.99 (2H, m),
2.19 (1H, t), 2.42-2.52 (4H, m), piperidinyl]methyl]- 2.90-3.00
(4H, m), 3.13-3.47 (5H, m), alpha-phenyl-, (2S)-4- 3.69-3.78 (3H,
m), 4.19-4.31 (2H, m), morpholineacetic acid 6.59 (1H, d), 7.17
(1H, d), 7.23-7.33 (3H, m), 7.55 (2H, d) 12 2-[[4-(2,4-dichloro-3-
.delta.(CDCl.sub.3) 1.80-2.07 (4H, m), 493/495 methylphenoxy)-1-
2.14-2.14 (1H, m), 2.41-2.52 (3H, m), piperidinyl]methyl]-
2.66-3.54 (10H, m), 3.67-3.79 (2H, m), alpha-phenyl-, (2S)-4-
4.04-4.14 (2H, m), 4.34-4.43 (1H, m), 6.66 (1H, d),
morpholineacetic acid 7.19 (1H, d), 7.24-7.31 (4H, m), 7.39-7.45
(1H, m)
EXAMPLE 13
[0129] This Example illustrates the preparation of
2-[[(2R)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-4-morpholinyl]-
methyl]-benzoic acid.
[0130]
2-[[4-(3,4-Dichlorophenoxy)-1-piperidinyl]methyl]-(2S)-morpholine
(0.58 g), 2-carboxybenzaldehyde (0.30 g) and acetic acid (0.5 ml)
were added to tetrahydrofuran (3 ml) and stirred at room
temperature for 5 minutes. The reaction mixture was then treated
with sodium triacetoxyborohydride (0.53 g) and stirring continued
overnight. The crude reaction mixture was filtered, diluted with
methanol (1 ml) and purified by reverse phase HPLC (eluents 0.1%
aqueous ammonium acetate and acetonitrile, gradient, 95%
aqueous--50% aqueous) to give the title compound as a white solid
(0.15 g).
[0131] MS [M-H].sup.- (ES-) 477/479.
[0132] .sup.1H NMR 8(CD.sub.3OD) 1.59-1.73 (2H, m), 1.74-1.93 (3H,
m), 2.08 (1H, d), 2.18-2.42 (4H, m), 2.57-2.71 (4H, m), 3.54 (1H,
d), 3.62-3.74 (4H, m), 4.23-4.32 (1H, m), 6.78 (1H, dd), 6.98 (1H,
d), 7.08-7.19 (2H, m), 7.26-7.36 (3H, m).
EXAMPLE 14
[0133] This Example illustrates the preparation of methyl
2-[(2R)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-4-morpholinyl]--
benzoate.
[0134]
2-[[4-(3,4-Dichlorophenoxy)-1-piperidinyl]methyl]-(2S)-morpholine
(0.2 g), methyl 2-fluorobenzoate (0.09 g) and potassium carbonate
(0.12 g) were added to dimethylformamide (1 ml) and the mixture was
heated at 100.degree. C. overnight. The reaction mixture was poured
into water and product was extracted with ethyl acetate. The ethyl
acetate was washed with brine, dried (MgSO.sub.4), filtered and
concentrated by evaporation under reduced pressure to give crude
product. This was purified by flash chromatography, eluting with 2%
methanol, 0.1% triethylamine in dichloromethane to give the title
compound (0.06 g).
[0135] MS [M+H].sup.+ (ES.sup.+) 477/479.
EXAMPLE 15
[0136] This Example illustrates the preparation of
2-[(2R)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-4-morpholinyl]--
benzoic acid.
[0137]
2-[(2R)-2-[[4-(3,4-Dichlorophenoxy)-1-piperidinyl]methyl]-4-morphol-
inyl]-methyl benzoate (0.06 g) was dissolved in tetrahydrofuran (1
ml) and treated with potassium trimethylsilanolate (0.02 g). The
reaction mixture was stirred at room temperature overnight. The
crude reaction mixture was diluted with methanol (1 ml), acidified
to pH 5 by addition of acetic acid and purified by reverse phase
HPLC (eluents 0.1% aqueous ammonium acetate and acetonitrile,
gradient, 95% aqueous--5% aqueous) to give the title compound as a
white solid (0.02 g).
[0138] MS [M-H].sup.- (ES-) 463/465.
[0139] .sup.1H NMR 6(CD.sub.3OD) 1.73-1.85 (2H, m), 1.91-2.04 (2H,
m), 2.56-2.76 (5H, m), 2.86-2.96 (3H, m), 3.04-3.18 (2H, m), 3.76
(1H, td), 3.87-3.96 (2H, m), 4.35-4.44 (1H, m), 6.81 (1H, dd),
7.01-7.07 (2H, m), 7.13 (1H, d), 7.27-7.34 (2H, m), 7.58 (1H,
dd).
EXAMPLES 16-55
[0140] Examples 16-55 are examples of compounds of formula (I) and
were prepared by the following general method:
[0141] To a solution of
(2R)-2-{[4-(3,4-dichlorophenoxy)piperidin-1-yl]methyl}morpholine or
(2S)-2-{[4-(3,4-dichlorophenoxy)piperidin-1-yl]methyl}morpholine as
appropriate (2.8 mg) in dimethylacetamide (0.05 ml) was added the
appropriate boronic acid (1 molar equivalent in 0.07 ml
dimethylacetamide) and oxoacetic acid (1 molar equivalent of a 50%
aqueous solution in 0.01 ml dimethyl-acetamide). The mixture was
heated to 100.degree. C. for 6 minutes using microwaves at 300
Watts. Purification using reverse phase HPLC (with a gradient 0.1%
aqueous formic acid:acetonitrile 90:10 to 35:65) gave the compounds
of Examples 16-55.
TABLE-US-00003 Example Name (M + H).sup.+ 16
(2S)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methy1]-.alpha.-(6-
559 methoxy-2-naphthalenyl)-4-morpholineacetic acid 17
(2S)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(4-
509 methoxyphenyl)-4-morpholineacetic acid 18
(2S)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(4-
493 methylphenyl)-4-morpholineacetic acid 19
(2S)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(2-
485 thienyl)-4-morpholineacetic acid 20
(2S)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(3-
485 thienyl)-4-morpholineacetic acid 21
(2S)-.alpha.-(2-benzofuranyl)-2-[[4-(3,4-dichlorophenoxy)-1- 519
piperidinyl]methyl]-4-morpholineacetic acid 22
(2S)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(2-
509 methoxyphenyl)-4-morpholineacetic acid 23
(2S)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(3-fluor-
o- 555 4-propoxyphenyl)-4-morpholineacetic acid 24
(2S)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-[4-(1,1-
551 dimethylethoxy)phenyl]-4-morpholineacetic acid 25
(2S)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-[4-
585 (phenylmethoxy)phenyl]-4-morpholineacetic acid 26
(2S)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(5-methy-
l- 483 2-furanyl)-4-morpholineacetic acid 27
(2S)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(2,3,4-
569 trimethoxyphenyl)-4-morpholineacetic acid 28
(2S)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(2,6-
539 dimethoxyphenyl)-4-morpholineacetic acid 29
(2S)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(3,4-
539 dimethoxyphenyl)-4-morpholineacetic acid 30
(2S)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(2-
469 furanyl)-4-morpholineacetic acid 31
(2S)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(2,4-
539 dimethoxyphenyl)-4-morpholineacetic acid 32
(2S)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(4-
507 ethylphenyl)-4-morpholineacetic acid 33
(2S)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(4-
495 hydroxyphenyl)-4-morpholineacetic acid 34
(2S)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-[4-(1,1-
535 dimethylethyl)phenyl]-4-morpholineacetic acid 35
(2S)-.alpha.-[4-(9H-carbazol-9-ylmethyl)phenyl]-2-[[4-(3,4- 658
dichlorophenoxy)-1-piperidinyl]methyl]-4-morpholineacetic acid 36
(2R)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(6-
559 methoxy-2-naphthalenyl)-4-morpholineacetic acid 37
(2R)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(4-
509 methoxyphenyl)-4-morpholineacetic acid 38
(2R)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(4-
493 methylphenyl)-4-morpholineacetic acid 39
(2R)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(2-
485 thienyl)-4-morpholineacetic acid 40
(2R)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(3-
485 thienyl)-4-morpholineacetic acid 41
(2R)-.alpha.-(2-benzofuranyl)-2-[[4-(3,4-dichlorophenoxy)-1- 519
piperidinyl]methyl]-4-morpholineacetic acid 42
(2R)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(2-
509 methoxyphenyl)-4-morpholineacetic acid 43
(2R)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.a-(3-
555 fluoro-4-propoxyphenyl)-4-morpholineacetic acid 44
(2R)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-[4-(1,1-
551 dimethylethoxy)phenyl]-4-morpholineacetic acid 45
(2R)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-[4-
585 (phenylmethoxy)phenyl]-4-morpholineacetic acid 46
(2R)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(5-methy-
l- 483 2-furanyl)-4-morpholineacetic acid 47
(2R)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(2,3,4-
569 trimethoxyphenyl)-4-morpholineacetic acid 48
(2R)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(2,6-
539 dimethoxyphenyl)-4-morpholineacetic acid 49
(2R)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(3,4-
539 dimethoxyphenyl)-4-morpholineacetic acid 50
(2R)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(2-
469 furanyl)-4-morpholineacetic acid 51
(2R)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(2,4-
539 dimethoxyphenyl)-4-morpholineacetic acid 52
(2R)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(4-
507 ethylphenyl)-4-morpholineacetic acid 53
(2R)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(4-
495 hydroxyphenyl)-4-morpholineacetic acid 54
(2R)-2-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-[4-(1,1-
535 dimethylethyl)phenyl]-4-morpholineacetic acid 55
(2R)-.alpha.-[4-(9H-carbazol-9-ylmethyl)phenyl]-2-[[4-(3,4- 658
dichlorophenoxy)-1-piperidinyl]methyl]-4-morpholineacetic acid
EXAMPLE 56
Pharmacological Analysis: Calcium flux [Ca.sup.2+].sub.i assay
Human Eosinophils
[0142] Human eosinophils were isolated from EDTA anticoagulated
peripheral blood as previously described (Hansel et al., J.
Immunol. Methods, 1991, 145, 105-110). The cells were resuspended
(5.times.10.sup.6 ml.sup.-1) and loaded with 51M FLUO-3/AM+Pluronic
F127 2.2 .mu.l/ml (Molecular Probes) in low potassium solution
(LKS; NaCl 118 mM, MgSO.sub.4 0.8 mM, glucose 5.5 mM,
Na.sub.2CO.sub.3 8.5 mM, KCl 5 mM, HEPES 20 mM, CaCl.sub.2 1.8 mM,
BSA 0.1%, pH 7.4) for one hour at room temperature. After loading,
cells were centrifuged at 200 g for 5 minutes and resuspended in
LKS at 2.5.times.10.sup.6 ml.sup.-1. The cells were then
transferred to 96 well FLIPr plates (Poly-D-Lysine plates from
Becton Dickinson pre-incubated with 5 .mu.M fibronectin for two
hours) at 25 .mu.l/well. The plate was centrifuged at 200 g for 5
minutes and the cells were washed twice with LKS (200 .mu.l; room
temperature).
[0143] A compound of the Examples was pre-dissolved in DMSO and
added to a final concentration of 0.1% (v/v) DMSO. Assays were
initiated by the addition of an A.sub.50 concentration of eotaxin
and the transient increase in fluo-3 fluorescence (l.sub.Ex=490 nm
and l.sub.Em=520 nm) monitored using a FLIPR (Fluorometric Imaging
Plate Reader, Molecular Devices, Sunnyvale, U.S.A.).
EXAMPLE 57
Human Eosinophil Chemotaxis
[0144] Human eosinophils were isolated from EDTA anticoagulated
peripheral blood as previously described (Hansel et al., J.
Immunol. Methods, 1991, 145, 105-110). The cells were resuspended
at 10.times.10.sup.6 ml.sup.-1 in RPMI containing 200 IU/ml
penicillin, 200 .mu.g/ml streptomycin sulphate and supplemented
with 10% HIFCS, at room temperature.
[0145] Eosinophils (700 .mu.l) were pre-incubated for 15 mins at
37.degree. C. with 7 .mu.l of either vehicle or compound (10.times.
required final concentration in 10% DMSO). The chemotaxis plate
(ChemoTx, 3 .mu.m pore, Neuroprobe) was loaded by adding 28 .mu.l
of a concentration of eotaxin (0.1 to 100 nM) containing a
concentration of a compound according to the Examples or solvent to
the lower wells of the chemotaxis plate. The filter was then placed
over the wells and 25 .mu.l of eosinophil suspension were added to
the top of the filter. The plate was incubated for 1 hr at
37.degree. C. in a humidified incubator with a 95% air/5% CO.sub.2
atmosphere to allow chemotaxis.
[0146] The medium, containing cells that had not migrated, was
carefully aspirated from above the filter and discarded. The filter
was washed once with phosphate buffered saline (PBS) containing 5
mM EDTA to remove any adherent cells. Cells that had migrated
through the filter were pelleted by centrifugation (300.times.g for
5 minutes at room temperature) and the filter removed and the
supernatant transferred to each well of a 96-well plate (Costar).
The pelleted cells were lysed by the addition of 28 .mu.l of PBS
containing 0.5% Triton.times.100 followed by two cycles of
freeze/thawing. The cell lysate was then added to the supernatant.
The number of eosinophils migrating was quantified according to the
method of Strath et al., J. Immunol. Methods, 1985, 83, 209 by
measuring eosinophil peroxidase activity in the supernatant.
[0147] Compounds of the Examples were found to be antagonists of
the eotaxin mediated human eosinophil chemotaxis.
TABLE-US-00004 Example % Inhibition (3 nM Human Eotaxin) 2 96.4 5
96.9
EXAMPLE 58
Guinea-Pig Isolated Trachea
[0148] (See for example, Harrison, R. W. S., Carswell, H. &
Young, J. M. (1984) European J. Pharmacol., 106, 405-409.)
[0149] Male albino Dunkin-Hartley guinea-pigs (250 g) were killed
by cervical dislocation and the whole trachea removed. After
clearing the adherent connective tissue, the trachea was cut into
six ring segments each three cartilage bands wide and then
suspended in 20 ml organ baths containing Krebs-Henseleit solution
of the following composition (mM): NaCl 117.6, NaH.sub.2PO.sub.4
0.9, NaHCO.sub.3 25.0, MgSO.sub.4 1.2, KCl 5.4, CaCl.sub.2 2.6 and
glucose 11.1. The buffer was maintained at 37.degree. C. and gassed
with 5% CO.sub.2 in oxygen. Indomethacin (2.8 .mu.M) was added to
the Krebs solution to prevent development of smooth muscle tone due
to the synthesis of cyclo-oxygenase products. The tracheal rings
were suspended between two parallel tungsten wire hooks, one
attached to an Ormed beam isometric force transducer and the other
to a stationary support in the organ bath. Changes in isometric
force were recorded on 2-channel Sekonic flat bed chart
recorders.
Experimental Protocols
[0150] At the beginning of each experiment a force of 1 g was
applied to the tissues and this was reinstated over a 60 minute
equilibration period until a steady resting tone was achieved.
Subsequently, a cumulative histamine concentration effect (E/[A])
curve was constructed at 0.5 log.sub.10 unit increments, in each
tissue. The tissues were then washed and approximately 30 minutes
later, test compound or vehicle (20% DMSO) was added. Following an
incubation period of 60 minutes a second E/[A] curve was performed
to histamine.
[0151] Contraction responses were recorded as a percentage of the
first curve maximum.
Data Analysis
[0152] Experimental E/[A] curve data were analysed for the purposes
of estimating the potencies (p[A.sub.50] values) of histamine in
the absence and presence of the test compound. Affinity (pA.sub.2)
values of test compounds were subsequently calculated using the
following equation:
log(r-1)=log[B]+pA.sub.2
where r=[A].sub.50 in presence of test compound/[A].sub.50 in
absence of antagonist and [B] is the concentration of test
compound. Compounds of the Examples were found to be H1
antagonists.
EXAMPLE 59
[0153] 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 30Ci/mmol) to 2 .mu.g membranes prepared from recombinant
CHO-K1 cells expressing the human H1 receptor (Euroscreen S A,
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.
[0154] The following compounds of the invention gave inhibition of
[3H]pyrilimine binding:
TABLE-US-00005 Example H1 antagonism pKi 1 7.1 2 6.9 5 7.2 6 7.3 7
6.2 8 6.9 9 6.5 10 6.1 11 6.6 12 7.5 13 7.5 15 7.6
* * * * *