U.S. patent application number 12/354439 was filed with the patent office on 2009-05-07 for chemical compounds.
This patent application is currently assigned to AstraZeneca AB. Invention is credited to Moya Caffrey, Christopher Luckhurst, Tobias Mochel, Matthew Perry, Brian Springthorpe.
Application Number | 20090118513 12/354439 |
Document ID | / |
Family ID | 20290898 |
Filed Date | 2009-05-07 |
United States Patent
Application |
20090118513 |
Kind Code |
A1 |
Caffrey; Moya ; et
al. |
May 7, 2009 |
Chemical Compounds
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) or H1 mediated disease
state.
Inventors: |
Caffrey; Moya;
(Leicestershire, GB) ; Luckhurst; Christopher;
(Leicestershire, GB) ; Mochel; Tobias;
(Leicestershire, GB) ; Perry; Matthew;
(Sodertalje, SE) ; Springthorpe; Brian;
(Sodertalje, SE) |
Correspondence
Address: |
FISH & RICHARDSON P.C.
P.O BOX 1022
MINNEAPOLIS
MN
55440-1022
US
|
Assignee: |
AstraZeneca AB
Sodertalje
SE
|
Family ID: |
20290898 |
Appl. No.: |
12/354439 |
Filed: |
January 15, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10551493 |
Sep 29, 2005 |
7495013 |
|
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PCT/SE04/00489 |
Mar 30, 2004 |
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12354439 |
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Current U.S.
Class: |
546/187 ;
546/190 |
Current CPC
Class: |
A61P 9/10 20180101; A61P
19/00 20180101; A61P 25/28 20180101; A61P 37/02 20180101; A61P
31/18 20180101; A61P 37/06 20180101; A61P 1/02 20180101; A61P 27/02
20180101; A61P 37/08 20180101; A61P 31/08 20180101; A61P 37/00
20180101; A61P 17/06 20180101; A61P 19/08 20180101; A61P 35/00
20180101; A61P 29/00 20180101; A61P 3/10 20180101; A61P 11/02
20180101; A61P 17/00 20180101; A61P 17/04 20180101; A61P 19/02
20180101; A61P 21/04 20180101; A61P 7/00 20180101; C07D 211/46
20130101; A61P 1/00 20180101; A61P 11/00 20180101; A61P 25/00
20180101; A61P 13/12 20180101; A61P 31/04 20180101; A61P 1/04
20180101; A61P 11/06 20180101; A61P 15/00 20180101; A61P 43/00
20180101; A61P 17/14 20180101 |
Class at
Publication: |
546/187 ;
546/190 |
International
Class: |
C07D 401/14 20060101
C07D401/14; C07D 211/06 20060101 C07D211/06 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 1, 2003 |
SE |
0300957-8 |
Claims
1-17. (canceled)
18. A compound of formula (III): ##STR00017## wherein Z is
CHR.sup.d(CH.sub.2).sub.n; or Z, R.sup.2 and R.sup.a, together with
the carbon atom to which Z and R.sup.a are attached, form a ring;
R.sup.2 is aryl or heterocyclyl; or R.sup.2, Z, and R.sup.a,
together with the carbon atom to which Z and R.sup.a are attached,
form a ring; and R.sup.a and R.sup.b are, independently, hydrogen
or C.sub.1-4 alkyl; or R.sup.a, Z, and R.sup.2, together with the
carbon atom to which Z and R.sup.a are attached, form a ring.
19. The compound of claim 18, wherein R.sup.2 is phenyl optionally
substituted by halogen, cyano, hydroxy, or C.sub.1-4 alkyl.
20. The compound of claim 18, wherein R.sup.2 is heterocyclyl, the
heterocyclyl being selected from the group consisting of furyl,
thienyl, pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl,
oxazolyl, isoxazolyl, imidazolyl, piperidinyl, morpholinyl,
pyridinyl, dihydropyridinyl, pyrimidinyl, indolyl,
2,3-dihydroindolyl, benzo[b]furyl, benz[b]thienyl,
2,3-dihydrobenz[b]thienyl, indazolyl, benzimidazolyl,
benztriazolyl, benzoxazolyl, benzthiazolyl,
2,3-dihydrobenzthiazolyl, 1,2,3-benzothiadiazolyl,
imidazopyridinyl, thieno[3,2-b]pyridin-6-yl, 1,2,3-benzoxadiazolyl,
benzo[1,2,3]thiadiazolyl, 2,1,3-benzothiadiazolyl, benzofurazan,
quinoxalinyl, dihydro-1-benzopyryliumyl,
3,4-dihydro-1H-2,1-benzothiazinyl, pyrazolopyridine, purine,
quinolinyl, isoquinolinyl, dihydroisoquinolinyl, naphthyridinyl,
dihydro[1,8]naphthyridinyl, benzothiazinyl, dihydrobenzothiazinyl,
benzo[d]imidazo[2,1-b]thiazol-2-yl, dibenzothiophenyl, an N-oxide
thereof, a S-oxide thereof, and a S-dioxide thereof.
21. The compound of claim 20, wherein the heterocyclyl is selected
from the group consisting of indolyl, imidazolyl, thienyl, and
pyridinyl.
22. A compound of formula (X): ##STR00018## wherein Z is
CHR.sup.d(CH.sub.2).sub.n; L is a leaving group; R.sup.2 is aryl or
heterocyclyl; and R.sup.b is hydrogen or C.sub.1-4 alkyl.
23. The compound of claim 22, wherein L is bromide, triflate, or
methanesulfonate.
24. The compound of claim 22, wherein R.sup.2 is phenyl optionally
substituted by halogen, cyano, hydroxy, or C.sub.1-4 alkyl.
25. The compound of claim 22, wherein R.sup.2 is heterocyclyl, the
heterocyclyl being selected from the group consisting of furyl,
thienyl, pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl,
oxazolyl, isoxazolyl, imidazolyl, piperidinyl, morpholinyl,
pyridinyl, dihydropyridinyl, pyrimidinyl, indolyl,
2,3-dihydroindolyl, benzo[b]furyl, benz[b]thienyl,
2,3-dihydrobenz[b]thienyl, indazolyl, benzimidazolyl,
benztriazolyl, benzoxazolyl, benzthiazolyl,
2,3-dihydrobenzthiazolyl, 1,2,3-benzothiadiazolyl,
imidazopyridinyl, thieno[3,2-b]pyridin-6-yl, 1,2,3-benzoxadiazolyl,
benzo[1,2,3]thiadiazolyl, 2,1,3-benzothiadiazolyl, benzofurazan,
quinoxalinyl, dihydro-1-benzopyryliumyl,
3,4-dihydro-1H-2,1-benzothiazinyl, pyrazolopyridine, purine,
quinolinyl, isoquinolinyl, dihydroisoquinolinyl, naphthyridinyl,
dihydro[1,8]naphthyridinyl, benzothiazinyl, dihydrobenzothiazinyl,
benzo[d]imidazo[2,1-b]thiazol-2-yl, dibenzothiophenyl, an N-oxide
thereof, an S-oxide thereof, and a S-dioxide thereof.
26. The compound of claim 25, wherein the heterocyclyl is selected
from the group consisting of indolyl, imidazolyl, thienyl, and
pyridinyl.
27. A compound of formula (A): ##STR00019## wherein X.sup.1 is
CH.sub.2 or C(O); X is CH.sub.2, C(O), O, S, S(O), S(O).sub.2 or
NR.sup.3; R.sup.1 is hydrogen, C.sub.1-6 alkyl, aryl or
heterocyclyl; and R.sup.c is hydrogen or hydroxy; wherein, unless
stated otherwise, 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, CF.sub.3, C.sub.1-6
alkoxy(C.sub.1-6)alkyl, C.sub.1-6 alkoxy, OCF.sub.3, C.sub.1-6
alkoxy(C.sub.1-6)alkoxy, C.sub.1-6 alkylthio, 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, 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 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 optionally 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.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 optionally 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 optionally 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 optionally 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 optionally 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
optionally 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 optionally 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); 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, independently, form a 4-7
membered heterocyclic ring, azetidine, pyrrolidine, piperidine,
azepine, morpholine or 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 optionally
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 optionally 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 optionally 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 optionally 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
optionally 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 optionally 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 R.sup.3 is
hydrogen, C.sub.1-6 alkyl or benzyl.
28. The compound of claim 27, wherein R.sup.1 is heterocyclyl, the
heterocyclyl being selected from the group consisting of furyl,
thienyl, pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl,
oxazolyl, isoxazolyl, imidazolyl, piperidinyl, morpholinyl,
pyridinyl, dihydropyridinyl, pyrimidinyl, indolyl,
2,3-dihydroindolyl, benzo[b]furyl, benz[b]thienyl,
2,3-dihydrobenz[b]thienyl, indazolyl, benzimidazolyl,
benztriazolyl, benzoxazolyl, benzthiazolyl,
2,3-dihydrobenzthiazolyl, 1,2,3-benzothiadiazolyl,
imidazopyridinyl, thieno[3,2-b]pyridin-6-yl, 1,2,3-benzoxadiazolyl,
benzo[1,2,3]thiadiazolyl, 2,1,3-benzothiadiazolyl, benzofurazan,
quinoxalinyl, dihydro-1-benzopyryliumyl,
3,4-dihydro-1H-2,1-benzothiazinyl, pyrazolopyridine, purine,
quinolinyl, isoquinolinyl, dihydroisoquinolinyl, naphthyridinyl,
dihydro[1,8]naphthyridinyl, benzothiazinyl, dihydrobenzothiazinyl,
benzo[d]imidazo[2,1-b]thiazol-2-yl, dibenzothiophenyl, an N-oxide
thereof, an S-oxide thereof, and a S-dioxide thereof.
29. The compound of claim 28, wherein the heterocyclyl is selected
from the group consisting of indolyl, imidazolyl, thienyl, and
pyridinyl.
30. The compound of claim 27, wherein R.sup.1 is aryl or
heterocyclyl, either of which is optionally substituted with a
heterocyclyl selected from the group consisting of furyl, thienyl,
pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl, oxazolyl,
isoxazolyl, imidazolyl, piperidinyl, morpholinyl, pyridinyl,
dihydropyridinyl, pyrimidinyl, indolyl, 2,3-dihydroindolyl,
benzo[b]furyl, benz[b]thienyl, 2,3-dihydrobenz[b]thienyl,
indazolyl, benzimidazolyl, benztriazolyl, benzoxazolyl,
benzthiazolyl, 2,3-dihydrobenzthiazolyl, 1,2,3-benzothiadiazolyl,
imidazopyridinyl, thieno[3,2-b]pyridin-6-yl, 1,2,3-benzoxadiazolyl,
benzo[1,2,3]thiadiazolyl, 2,1,3-benzothiadiazolyl, benzofurazan,
quinoxalinyl, dihydro-1-benzopyryliumyl,
3,4-dihydro-1H-2,1-benzothiazinyl, pyrazolopyridine, purine,
quinolinyl, isoquinolinyl, dihydroisoquinolinyl, naphthyridinyl,
dihydro[1,8]naphthyridinyl, benzothiazinyl, dihydrobenzothiazinyl,
benzo[d]imidazo[2,1-b]thiazol-2-yl, dibenzothiophenyl, an N-oxide
thereof, an S-oxide thereof, and a S-dioxide thereof.
31. The compound of claim 30, wherein R.sup.1 is aryl or
heterocyclyl, either of which is optionally substituted with a
heterocyclyl selected from the group consisting of indolyl,
imidazolyl, thienyl, and pyridinyl.
32. The compound of claim 27, wherein R.sup.1 is phenyl optionally
substituted with halogen, C.sub.1-4 alkyl or C.sub.1-4 alkoxy.
33. The compound of claim 27, wherein X is O.
34. The compound of claim 27, wherein R.sup.c is hydrogen.
35. The compound of claim 27, wherein the compound is of formula
(IV): ##STR00020##
36. The compound of claim 27, wherein the compound is of formula
(V): ##STR00021##
37. A process of preparing a compound of formula (V) as claimed in
claim 36, the process comprising reacting a compound of formula
(VI): ##STR00022## with osmium tetra-oxide in the presence of
N-methyl-morpholine N-oxide.
38. A process of preparing a compound of formula (IV) as claimed in
claim 35, the process comprising reacting a compound of formula
(V): ##STR00023## with boron trihydride in tetrahydrofuran at
reflux.
39. A compound of formula (II): ##STR00024## wherein X is CH.sub.2,
C(O), O, S, S(O), S(O).sub.2 or NR.sup.3; R.sup.1 is hydrogen,
C.sub.1-6 alkyl, aryl or heterocyclyl; and R.sup.c is hydrogen or
hydroxy; wherein, unless stated otherwise, 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,
CF.sub.3, C.sub.1-6 alkoxy(C.sub.1-6)alkyl, C.sub.1-6 alkoxy,
OCF.sub.3, C.sub.1-6 alkoxy(C.sub.1-6)alkoxy, C.sub.1-6 alkylthio,
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, 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 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 optionally 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.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 optionally 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 optionally 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 optionally 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 optionally 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
optionally 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 optionally 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); 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, independently, form a 4-7
membered heterocyclic ring, azetidine, pyrrolidine, piperidine,
azepine, morpholine or 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 optionally
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 optionally 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 optionally 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 optionally 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
optionally 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 optionally 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 R.sup.3 is
hydrogen, C.sub.1-6 alkyl or benzyl.
40. The compound of claim 39, wherein R.sup.1 is heterocyclyl, the
heterocyclyl being selected from the group consisting of furyl,
thienyl, pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl,
oxazolyl, isoxazolyl, imidazolyl, piperidinyl, morpholinyl,
pyridinyl, dihydropyridinyl, pyrimidinyl, indolyl,
2,3-dihydroindolyl, benzo[b]furyl, benz[b]thienyl,
2,3-dihydrobenz[b]thienyl, indazolyl, benzimidazolyl,
benztriazolyl, benzoxazolyl, benzthiazolyl,
2,3-dihydrobenzthiazolyl, 1,2,3-benzothiadiazolyl,
imidazopyridinyl, thieno[3,2-b]pyridin-6-yl, 1,2,3-benzoxadiazolyl,
benzo[1,2,3]thiadiazolyl, 2,1,3-benzothiadiazolyl, benzofurazan,
quinoxalinyl, dihydro-1-benzopyryliumyl,
3,4-dihydro-1H-2,1-benzothiazinyl, pyrazolopyridine, purine,
quinolinyl, isoquinolinyl, dihydroisoquinolinyl, naphthyridinyl,
dihydro[1,8]naphthyridinyl, benzothiazinyl, dihydrobenzothiazinyl,
benzo[d]imidazo[2,1-b]thiazol-2-yl, dibenzothiophenyl, an N-oxide
thereof, an S-oxide thereof, and a S-dioxide thereof.
41. The compound of claim 40, wherein the heterocyclyl is selected
from the group consisting of indolyl, imidazolyl, thienyl, and
pyridinyl.
42. The compound of claim 39, wherein R.sup.1 is aryl or
heterocyclyl, either of which is optionally substituted with a
heterocyclyl selected from the group consisting of furyl, thienyl,
pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl, oxazolyl,
isoxazolyl, imidazolyl, piperidinyl, morpholinyl, pyridinyl,
dihydropyridinyl, pyrimidinyl, indolyl, 2,3-dihydroindolyl,
benzo[b]furyl, benz[b]thienyl, 2,3-dihydrobenz[b]thienyl,
indazolyl, benzimidazolyl, benztriazolyl, benzoxazolyl,
benzthiazolyl, 2,3-dihydrobenzthiazolyl, 1,2,3-benzothiadiazolyl,
imidazopyridinyl, thieno[3,2-b]pyridin-6-yl, 1,2,3-benzoxadiazolyl,
benzo[1,2,3]thiadiazolyl, 2,1,3-benzothiadiazolyl, benzofurazan,
quinoxalinyl, dihydro-1-benzopyryliumyl,
3,4-dihydro-1H-2,1-benzothiazinyl, pyrazolopyridine, purine,
quinolinyl, isoquinolinyl, dihydroisoquinolinyl, naphthyridinyl,
dihydro[1,8]naphthyridinyl, benzothiazinyl, dihydrobenzothiazinyl,
benzo[d]imidazo[2,1-b]thiazol-2-yl, dibenzothiophenyl, an N-oxide
thereof, an S-oxide thereof, and a S-dioxide thereof.
43. The compound of claim 42, wherein R.sup.1 is aryl or
heterocyclyl, either of which is optionally substituted with a
heterocyclyl selected from the group consisting of indolyl,
imidazolyl, thienyl, and pyridinyl.
44. The compound of claim 39, wherein R.sup.1 is phenyl optionally
substituted with halogen, C.sub.1-4 alkyl or C.sub.1-4 alkoxy.
45. The compound of claim 39, wherein X is O.
46. The compound of claim 39, wherein R.sup.c is hydrogen.
47. A process of preparing a compound of formula (II) as claimed in
claim 39, the process comprising reacting a compound of formula
(IV): ##STR00025## with lead tetra-acetate in the presence of
sodium carbonate in dichloromethane.
Description
[0001] 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.
[0002] Pharmaceutically active piperidine derivatives are disclosed
in WO99/38514, WO99/04794 and WO00/35877.
[0003] 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.
[0004] 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.
[0005] 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).
[0006] 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.).
[0007] 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.
[0008] 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].)
[0009] The present invention provides a compound of formula
(I):
##STR00002##
wherein: R.sup.a and R.sup.b are, independently, hydrogen or
C.sub.1-4 alkyl or R.sup.a forms part of a ring as defined below;
R.sup.c is hydrogen or hydroxy;
X is CH.sub.2, C(O), O, S, S(O), S(O).sub.2 or NR.sup.3;
[0010] Z is CHR.sup.d(CH.sub.2).sub.n; n is 0 or 1; R.sup.d is
hydrogen, C.sub.1-4 alkyl, hydroxy or C.sub.1-4 alkoxy; R.sup.1 is
hydrogen, C.sub.1-6 alkyl, aryl or heterocyclyl; R.sup.2 is aryl or
heterocyclyl; wherein, unless stated otherwise, 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,
CF.sub.3, C.sub.1-6 alkoxy(C.sub.1-6)alkyl, C.sub.1-6 alkoxy,
OCF.sub.3, C.sub.1-6 alkoxy(C.sub.1-6)alkoxy, C.sub.1-6 alkylthio,
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, 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; or Z, R.sup.2 and R.sup.a together with the carbon atom
to which Z and R.sup.a are attached form a ring; p and q are,
independently, 0, 1 or 2; 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,
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) 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); 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, morpholine or 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); R.sup.3 is hydrogen, C.sub.1-6 alkyl or benzyl; or an
N-oxide thereof, or a pharmaceutically acceptable salt thereof; or
a solvate thereof.
[0011] 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.
[0012] Suitable salts include acid addition salts such as a
hydrochloride, dihydrochloride, hydrobromide, phosphate, sulfate,
acetate, diacetate, fumarate, maleate, tartrate, citrate, oxalate,
methanesulfonate or p-toluenesulfonate.
[0013] The compounds of the invention may exist as solvates (such
as hydrates) and the present invention covers all such
solvates.
[0014] Halogen includes fluorine, chlorine, bromine and iodine.
Halogen is, for example, fluorine or chlorine.
[0015] Alkyl groups and moieties are straight or branched chain and
comprise, for example, 1 to 6 (such as 1 to 4) carbon atoms.
Examples of alkyl groups are methyl, ethyl, n-propyl, iso-propyl or
tert-butyl.
[0016] Alkyl optionally substituted by halogen and haloalkyl
comprise an alkyl part and one or more (for example 1 to 6) of the
same or different halogen atoms. Alkyl optionally substituted by
halogen and haloalkyl are, for example, CF.sub.3.
[0017] Alkenyl and alkynyl groups comprise, for example, 2 to 6
(such as 2 to 4) carbon atoms. Examples of alkenyl groups are vinyl
or allyl; and an example of an alkynyl group is propargyl.
[0018] Aryl includes phenyl and naphthyl and in one embodiment of
the invention is, for example, phenyl.
[0019] In one embodiment cycloalkyl groups comprise from 3 to 10
(such as 3 to 8, for example 3 to 6) carbon atoms and are mono-, bi
or tricyclic. Cycloalkyl 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). In a
further embodiment cycloalkyl is monocyclic.
[0020] 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 sulfur; 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, dihydropyridinyl (for example
in a 6-oxo-1,6-dihydro-pyridinyl moiety), 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 a
1-dioxo-2,3-dihydrobenz[b]thienyl moiety), indazolyl,
benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl (for
example in a 1H-benzthiazol-2-one-yl moiety),
2,3-dihydrobenzthiazolyl (for example in a
2,3-dihydrobenzthiazol-2-one-yl moiety), 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 moiety), 3,4-dihydro-1H-2,1-benzothiazinyl (for example
in a 2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl moiety), a
pyrazolopyridine (for example 1H-pyrazolo[3,4-b]pyridinyl), a
purine (for example in a 3,7-dihydro-purin-2,6-dione-8-yl moiety),
quinolinyl, isoquinolinyl, dihydroisoquinolinyl (for example in a
2H-isoquinolin-1-one-yl moiety), a naphthyridinyl (for example
[1,6]naphthyridinyl or [1,8]naphthyridinyl), a
dihydro[1,8]naphthyridinyl (for example in a
1H-[1,8]naphthyridin-4-one-yl moiety), a benzothiazinyl, a
dihydrobenzothiazinyl (for example in a
4H-benzo[1,4]thiazin-3-one-yl moiety),
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.
[0021] An N-oxide of a compound of formula (I) is, for example, a
1-oxy-[1,4']bipiperidinyl-1'-yl compound.
[0022] In one particular aspect the invention provides a compound
of formula (I) wherein R.sup.a and R.sup.b are, independently,
hydrogen or C.sub.1-4 alkyl or R.sup.a forms part of a ring as
defined below; R.sup.c is hydrogen or hydroxy; X is CH.sub.2, C(O),
O, S, S(O), S(O).sub.2 or NR.sup.3; Z is (CH.sub.2).sub.n; n is 1
or 2; R.sup.1 is hydrogen, C.sub.1-6 alkyl, aryl or heterocyclyl;
R.sup.2 is aryl or heterocyclyl; wherein, unless stated otherwise,
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, CF.sub.3, C.sub.1-6
alkoxy(C.sub.1-6)alkyl, C.sub.1-6 alkoxy, OCF.sub.3, C.sub.1-6
alkoxy(C.sub.1-6)alkoxy, C.sub.1-6 alkylthio, 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, 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; or Z, R.sup.2 and R.sup.a together with the carbon atom
to which Z and R.sup.a are attached form a ring; p and q are,
independently, 0, 1 or 2; 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.14R.sup.15R.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, 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) 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, 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); 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, morpholine or 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); R.sup.3 is hydrogen, C.sub.1-6 alkyl or benzyl; or an
N-oxide thereof; or a pharmaceutically acceptable salt thereof; or
a solvate thereof.
[0023] In a further aspect the invention provides a compound of
formula (I) wherein X is O.
[0024] In another aspect of the invention the foregoing aryl (for
example phenyl) and heterocyclyl moieties of R.sup.1 and R.sup.2
are, independently, 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,
CF.sub.3, C.sub.1-6 alkoxy(C.sub.1-6)alkyl, C.sub.1-6 alkoxy or
OCF.sub.3; p is 0, 1 or 2; 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) or 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,
S(O).sub.2NH(C.sub.1-4 alkyl), S(O).sub.2N(C.sub.1-4 alkyl).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, 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.4, R.sup.17 and R.sup.23 are, independently,
C.sub.1-6 alkyl (optionally substituted by halogen) or 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,
S(O).sub.2NH(C.sub.1-4 alkyl), S(O).sub.2N(C.sub.1-4 alkyl).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, 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).
[0025] When Z, R.sup.2 and R.sup.a together with the carbon atom to
which Z and R.sup.a are attached form a ring, the ring is, for
example, a 2,3-dihydro-1H-inden-2-yl ring.
[0026] In yet another aspect R.sup.1 is phenyl optionally
substituted (for example independently mono- or di-substituted)
with halogen (for example chlorine or fluorine), cyano, C.sub.1-4
alkyl (for example methyl) or C.sub.1-4 alkoxy (for example
methoxy).
[0027] In a further aspect R.sup.1 is phenyl optionally substituted
(for example independently mono- or di-substituted) with halogen
(for example chlorine or fluorine), C.sub.1-4 alkyl (for example
methyl) or C.sub.1-4 alkoxy (for example methoxy).
[0028] In a still further aspect R.sup.1 is phenyl optionally
substituted (for example with one, 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).
[0029] In another aspect R.sup.1 is phenyl optionally substituted
(for example with one, two or three of the same or different) with
fluorine, chlorine, C.sub.1-4 alkyl (for example methyl) or
C.sub.1-4 alkoxy (for example methoxy).
[0030] In yet another aspect R.sup.1 is phenyl substituted by one,
two or three (for example two or three) substituents independently
selected from: fluorine, chlorine, cyano and methyl.
[0031] In a further aspect R.sup.1 is phenyl substituted by one,
two or three (for example two or three) substituents independently
selected from: fluorine, chlorine and methyl.
[0032] 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 4-fluorophenyl.
[0033] In a still further aspect of the invention R.sup.a is
hydrogen.
[0034] In another aspect of the invention R.sup.b is hydrogen or
methyl. In yet another aspect R.sup.b is hydrogen.
[0035] In a further aspect of the invention R.sup.c is
hydrogen.
[0036] In a still further aspect of the invention R.sup.d is
hydrogen, hydroxy or C.sub.1-4 alkyl (such as methyl).
[0037] In another aspect Z is CH.sub.2, CH.sub.2CH.sub.2,
CHCH.sub.3 or CHOH. In a further aspect Z is CH.sub.2.
[0038] In another aspect R.sup.2 is phenyl or heterocyclyl
optionally substituted by halogen, cyano, nitro, hydroxy,
NR.sup.7R.sup.8, C.sub.1-6 alkyl (optionally substituted with
halogen), C.sub.1-6 alkoxy (optionally substituted with halogen),
S(O).sub.p(C.sub.1-6 alkyl), S(O).sub.rCF.sub.3 or
S(O).sub.2NR.sup.14R.sup.15; p and r are, independently, 0, 1 or 2;
and R.sup.7, R.sup.8, R.sup.14 and R.sup.15 are, independently,
hydrogen, C.sub.1-6 alkyl (optionally substituted by halogen,
hydroxy or C.sub.3-10 cycloalkyl), CH.sub.2(C.sub.2-5 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,
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.7 and R.sup.8 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.7 and R.sup.8 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, 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.7 and R.sup.8 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.7 and R.sup.8 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 alternatively NR.sup.7R.sup.8 or NR.sup.14R.sup.15
may, independently, form a 4-7 membered heterocyclic ring,
azetidine, pyrrolidine, piperidine, azepine, morpholine or
piperazine, the latter optionally substituted by C.sub.1-4 alkyl on
the distal nitrogen.
[0039] In yet another aspect of the invention R.sup.2 is phenyl or
heterocyclyl optionally substituted by halogen (such as fluoro or
chloro), cyano, hydroxy, C.sub.1-4 alkyl (such as methyl),
C.sub.1-4 haloalkyl (such as CF.sub.3) or C.sub.1-4 alkoxy (such as
methoxy).
[0040] In a further aspect R.sup.2 is phenyl or heterocyclyl
optionally substituted by halogen (such as fluoro or chloro),
C.sub.1-4 alkyl (such as methyl), C.sub.1-4 haloalkyl (such as
CF.sub.3) or C.sub.1-4 alkoxy (such as methoxy).
[0041] In a still further aspect R.sup.2 is phenyl optionally
substituted by halogen (such as fluoro or chloro), cyano, hydroxy,
or C.sub.1-4 alkyl (such as methyl).
[0042] In another aspect heterocyclyl is indolyl, imidazolyl,
thienyl or pyridinyl.
[0043] In yet another aspect the present invention provides a
compound of formula (I) wherein: R.sup.c is hydrogen; X is O; Z is
CH.sub.2; R.sup.1 is phenyl substituted by halogen (for example by
one or two chlorine atoms) or C.sub.1-4 alkyl (for example methyl);
R.sup.2 is phenyl or heterocyclyl optionally substituted by halogen
(such as fluoro or chloro), C.sub.1-4 alkyl (such as methyl),
C.sub.1-4 haloalkyl (such as CF.sub.3) or C.sub.1-4 alkoxy (such as
methoxy); R.sup.b is hydrogen; and heterocyclyl is indolyl,
imidazolyl, thienyl or pyridinyl. R.sup.a is hydrogen.
[0044] In a further aspect the present invention provides a
compound of formula (I) wherein: R.sup.a and R.sup.c are both
hydrogen; R.sup.b is hydrogen or C.sub.1-4 alkyl (such as methyl or
tert-butyl); X is O; Z is CH.sub.2, CH.sub.2CH.sub.2, CHCH.sub.3 or
CHOH; R.sup.1 is phenyl substituted by halogen (for example by one
or two chlorine atoms), cyano or C.sub.1-4 alkyl (for example
methyl); R.sup.2 is phenyl or heterocyclyl optionally substituted
by halogen (such as fluoro or chloro), cyano, hydroxy, C.sub.1-4
alkyl (such as methyl), C.sub.1-4 haloalkyl (such as CF.sub.3) or
C.sub.1-4 alkoxy (such as methoxy); and heterocyclyl is indolyl,
imidazolyl, thienyl or pyridinyl; or a salt thereof (such as a
dihydrochloride).
[0045] The compounds of the present invention can be prepared as
described below.
[0046] A compound of formula (I) can be prepared by reacting a
compound of formula (II):
##STR00003##
with a compound of formula (III):
##STR00004##
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.).
[0047] Alternatively, a compound of formula (I), where R.sup.b is
not hydrogen, can be prepared by reacting a compound of formula
(II) with a compound of formula (III), where R.sup.b is not
hydrogen, in the presence of NaBH(OAc).sub.3 in the presence of a
suitable base (such as triethylamine) in a suitable solvent (such
as tetrahydrofuran) at a suitable temperature (such as in the range
0.degree. C. to 30.degree. C.).
[0048] For a compound of formula (I): [0049] when R.sup.b is
hydrogen said compound may be converted to a compound of the
invention where R.sup.b is not hydrogen by a standard
esterification method well known in the art; and, [0050] when
R.sup.b is not hydrogen said compound may be converted to a
compound of the invention where R.sup.b is hydrogen by a standard
ester hydrolysis method well known in the art. Such methods are
described in undergraduate organic chemistry textbooks (such as
Advanced Organic Chemistry by J March, 5.sup.th edition M B Smith
and J March, Wiley, 2001).
[0051] A compound of formula (II) can be prepared by reacting a
compound of formula (IV):
##STR00005##
with lead tetra-acetate in the presence of sodium carbonate in
dichloromethane.
[0052] A compound of formula (IV) can be prepared by reducing a
compound of formula (V):
##STR00006##
with borane in tetrahydrofuran at reflux.
[0053] A compound of formula (V) can be prepared by oxidising a
compound of formula (VI):
##STR00007##
with osmium tetroxide in the presence of N-methyl morpholine
N-Oxide (NMMO) in aqueous acetone at ambient (for example
10-30.degree. C.) temperature.
[0054] A compound of formula (VI) can be prepared by coupling a
compound of formula (VII):
##STR00008##
and a compound of formula (VIII):
##STR00009##
under conventional conditions (such as EDCI/HOBT/DMAP) in
dichloromethane at ambient (for example 10-30.degree. C.)
temperature.
[0055] Alternatively a compound of formula (I) wherein R.sup.a
represents H may be prepared by reaction of a compound of formula
(IX) with a compound of formula (X) wherein L is a suitable leaving
group (for example bromide, triflate or methanesulfonate) in a
suitable solvent, for example dichloromethane, at a temperature in
the range 0.degree. C. to 30.degree. C., in the presence of a base
(such as a tri(C.sub.1-6 alkyl)amine, for example triethylamine or
Hunig's base).
##STR00010##
[0056] A compound of formula (IX) can be prepared by deprotecting a
compound of formula (XI):
##STR00011##
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 (XI), wherein R.sup.c is hydrogen, can
be prepared by reacting a compound of formula (VII) with a compound
of formula (XII):
##STR00012##
in the presence of NaBH(OAc).sub.3 and acetic acid, in a suitable
solvent (such as tetrahydrofuran or dichloromethane).
[0058] A compound of formula (XI), wherein R.sup.c is hydroxy, can
be prepared by reacting a compound of formula (XI) with a compound
of formula (XIII):
##STR00013##
in a suitable solvent (such as a C.sub.1-6 aliphatic alcohol, for
example ethanol) at room temperature (0.degree. C. to 30.degree.
C., such as 15.degree. C. to 30.degree. C.).
[0059] Alternatively a compound of formula (I) wherein R.sup.a
represents H may be prepared by hydrolysis of a compound of formula
(XIV), wherein Xc represents a chiral auxiliary of a type
well-known in the art (for example
(4R,5S)-1,5-dimethyl-4-phenylimidazolidin-2-one,
(4R)-4-(phenylmethyl)-2-oxazolidinone,
(4S)-4-(phenylmethyl)-2-oxazolidinone or
(3aR,6S,7aS)-hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole
2,2-dioxide), for example with aqueous sodium hydroxide in a
suitable solvent (such as an aliphatic alcohol, for example
methanol), at a temperature between 10.degree. C. and reflux of the
solvent, typically at about 45.degree. C.
##STR00014##
[0060] A compound of formula (XIV) may be prepared by deprotonation
of a compound of formula (XV) for example with lithium hexamethyl
disilazide, at a temperature between -78.degree. C. and 0.degree.
C. followed by reaction with a compound of formula (XVI), at a
temperature between -78.degree. C. and 0.degree. C., typically at
-20.degree. C.
##STR00015##
[0061] A compound of formula (XV) may be prepared by reaction of a
compound of formula (IX) with a compound of formula (XVII) in a
suitable solvent, for example tetrahydrofuran in the presence of a
base, for example aqueous sodium bicarbonate, at ambient
temperature.
##STR00016##
[0062] Further compounds of formula (I) can be prepared by
adaptation of: the routes described above, methods described in the
art or the Examples recited below.
[0063] Compounds of formula (III), VII), (VIII) and (XVII) can be
prepared by using or adapting methods described in the art. The
preparation of various phenoxy piperidines is described in WO
01/77101.
[0064] 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.
[0065] In another aspect the present invention provides processes
for the preparation of compounds of formula (I).
[0066] The compounds of formula (I) 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)).
[0067] Examples of these conditions are: [0068] (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; [0069] (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; [0070] (3) (skin
and eyes) psoriasis, atopic dermatitis, contact dermatitis or other
eczmatous dermitides, seborrhoetic dermatitis, lichen planus,
phemphigus, bullous phemphigus, epidernolysis bullosa, urticaria,
angiodermas, vasculitides erythemas, cutaneous eosinophilias,
uveitis, alopecia greata, corneal ulcer or vernal conjunctivitis;
[0071] (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); [0072] (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 [0073] (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.
[0074] The compounds of formula (I) 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).
[0075] 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 a pharmaceutically acceptable salt thereof or a
solvate thereof.
[0076] 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 a pharmaceutically acceptable salt thereof or a solvate
thereof.
[0077] 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 a pharmaceutically acceptable salt thereof or a solvate
thereof.
[0078] The invention also provides a compound of the formula (I),
or a pharmaceutically acceptable salt thereof or a solvate thereof,
for use in therapy.
[0079] In another aspect the invention provides the use of a
compound of formula (I), 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).
[0080] The invention further provides the use of a compound of
formula (I), or a pharmaceutically acceptable salt thereof, in the
manufacture of a medicament for use in the treatment of: [0081] (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; [0082] (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; [0083] (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;
[0084] (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); [0085] (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 [0086] (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).
[0087] In a further aspect the invention provides a compound of
formula (I), 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}.
[0088] In a still further aspect a compound of formula (I), or a
pharmaceutically acceptable salt thereof, is useful in the
treatment of asthma.
[0089] The present invention also provides a the use of a compound
of formula (I), 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}.
[0090] 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 a
pharmaceutically acceptable salt thereof or a solvate thereof
(active ingredient), and a pharmaceutically acceptable adjuvant,
diluent or carrier.
[0091] 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.
[0092] 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.
[0093] 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.
[0094] The invention further relates to combination therapies
wherein a compound of formula (I) or a pharmaceutically acceptable
salt, solvate or in vivo hydrolysable ester thereof, or a
pharmaceutical composition or formulation comprising a compound of
formula (I) 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.
[0095] 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
such as: --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.
[0096] The present invention still further relates to the
combination of a compound of the invention 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-.alpha.) 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.
[0097] The present invention still further relates to the
combination of a compound of the invention together with modulators
of chemokine receptor function such as antagonists of CCR1, CCR2,
CCR2A, CCR2B, 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.
[0098] The present invention still further relates to the
combination of a compound of the invention together with an
inhibitor of matrix metalloproteases (MMPs), i.e., the
stromelysins, the collagenases, and the gelatinases, as well as
aggrecanase; especially collagenase-1 (MMP-1), collagenase-2
(MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3),
stromelysin-2 (MMP-10), and stromelysin-3 (MMP-1) and MMP-9 and
MMP-12, including agents such as doxycycline.
[0099] The present invention still further relates to the
combination of a compound of the invention together with 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; N-(5-substituted)-thiophene-2-alkylsulfonamides;
2,6-di-tert-butylphenolhydrazones; methoxytetrahydropyrans such as
Zeneca ZD-2138; the compound SB-210661; pyridinyl-substituted
2-cyanonaphthalene compounds such as L-739,010; 2-cyanoquinoline
compounds such as L-746,530; indole and quinoline compounds such as
MK-591, MK-886, and BAY.times.1005.
[0100] The present invention still further relates to the
combination of a compound of the invention together with a receptor
antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4. selected
from the group consisting of the phenothiazin-3-1s 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.times.7195.
[0101] The present invention still further relates to the
combination of a compound of the invention together with a
phosphodiesterase (PDE) inhibitor such as the methylxanthanines
including theophylline and aminophylline; and selective PDE
isoenzyme inhibitors including PDE4 inhibitors and inhibitors of
the isoform PDE4D, and inhibitors of PDE5.
[0102] The present invention still further relates to the
combination of a compound of the invention together with histamine
type 1 receptor antagonists such as cetirizine, loratadine,
desloratadine, fexofenadine, acrivastine, terfenadine, astemizole,
azelastine, levocabastine, chlorpheniramine, promethazine,
cyclizine, and mizolastine applied orally, topically or
parenterally.
[0103] The present invention still further relates to the
combination of a compound of the invention together with a proton
pump inhibitor (such as omeprazole) or gastroprotective histamine
type 2 receptor antagonist.
[0104] The present invention still further relates to the
combination of a compound of the invention with antagonists of the
histamine type 4 receptor.
[0105] The present invention still further relates to the
combination of a compound of the invention together with 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, and ethylnorepinephrine hydrochloride.
[0106] The present invention still further relates to the
combination of a compound of the invention together with
anticholinergic agents including muscarinic receptor (M1, M2, and
M3) antagonists such as atropine, hyoscine, glycopyrrrolate,
ipratropium bromide, tiotropium bromide, oxitropium bromide,
pirenzepine, and telenzepine.
[0107] The present invention still further relates to the
combination of a compound of the invention together with a
beta-adrenoceptor agonist (including beta receptor subtypes 1-4)
such as isoprenaline, salbutamol, formoterol, salmeterol,
terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol,
including chiral enantiomers thereof.
[0108] The present invention still further relates to the
combination of a compound of the invention together with a
chromone, including sodium cromoglycate and nedocromil sodium.
[0109] The present invention still further relates to the
combination of a compound of the invention together with a
glucocorticoid, such as flunisolide, triamcinolone acetonide,
beclomethasone dipropionate, budesonide, fluticasone propionate,
ciclesonide, and mometasone furoate.
[0110] The present invention still further relates to the
combination of a compound of the invention together with an agent
that modulate nuclear hormone receptors such as PPARs.
[0111] The present invention still further relates to the
combination of a compound of the invention together with an
immunoglobulin (Ig) or Ig preparation or an antagonist or antibody
modulating Ig function such as anti-IgE (e.g. omalizumab).
[0112] The present invention still further relates to the
combination of a compound of the invention together with other
systemic or topically-applied anti-inflammatory agents including
thalidomide and derivatives, retinoids, dithranol, and
calcipotriol.
[0113] The present invention still further relates to the
combination of a compound of the invention together with
combinations of aminosalicylates and sulfapyridine such as
sulfasalazine, mesalazine, balsalazide, and olsalazine; and
immunomodulatory agents such as the thiopurines, and
corticosteroids such as budesonide.
[0114] The present invention still further relates to the
combination of a compound of the invention together with an
antibacterial agent including penicillin derivatives,
tetracyclines, macrolides, beta-lactams, fluoroquinolones,
metronidazole, and inhaled aminoglycosides; and antiviral agents
including acyclovir, famciclovir, valaciclovir, ganciclovir,
cidofovir; amantadine, rimantadine; ribavirin; zanamavir and
oseltamavir; protease inhibitors such as indinavir, nelfinavir,
ritonavir, and saquinavir; nucleoside reverse transcriptase
inhibitors such as didanosine, lamivudine, stavudine, zalcitabine,
zidovudine; non-nucleoside reverse transcriptase inhibitors such as
nevirapine, efavirenz.
[0115] The present invention still further relates to the
combination of a compound of the invention together with
cardiovascular agents such as calcium channel blockers,
beta-adrenoceptor blockers, angiotensin-converting enzyme (ACE)
inhibitors, angiotensin-2 receptor antagonists; lipid lowering
agents such as statins, and fibrates; modulators of blood cell
morphology such as pentoxyfylline; thrombolytics, and
anticoagulants including platelet aggregation inhibitors.
[0116] The present invention still further relates to the
combination of a compound of the invention together with CNS agents
such as antidepressants (such as sertraline), anti-Parkinsonian
drugs (such as deprenyl, L-dopa, ropinirole, pramipexole, MAOB
inhibitors such as selegine and rasagiline, comP inhibitors such as
tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA
antagonists, nicotine agonists, dopamine agonists and inhibitors of
neuronal nitric oxide synthase), and anti-Alzheimer's drugs such as
donepezil, rivastigmine, tacrine, COX-2 inhibitors, propentofylline
or metrifonate.
[0117] The present invention still further relates to the
combination of a compound of the invention together with agents for
the treatment of acute and chronic pain, including centrally and
peripherally-acting analgesics such as opioid analogues and
derivatives, carbamazepine, phenyloin, sodium valproate,
amitryptiline and other antidepressant agents, paracetamol, and
non-steroidal anti-inflammatory agents.
[0118] The present invention still further relates to the
combination of a compound of the invention together with
parenterally or topically-applied (including inhaled) local
anaesthetic agents such as lignocaine and analogues.
[0119] The compounds of the present invention may also be used in
combination with anti-osteoporosis agents including hormonal agents
such as raloxifene, and biphosphonates such as alendronate.
[0120] The present invention still further relates to the
combination of a compound of the invention together with (i)
tryptase inhibitors; (ii) platelet activating factor (PAF)
antagonists; (iii) interleukin converting enzyme (ICE) inhibitors;
(iv) IMPDH inhibitors; (v) adhesion molecule inhibitors including
VLA-4 antagonists; (vi) cathepsins; (vii) Kinase inhibitors
including but not limited to inhibitors of tyrosine kinases (such
as Btk, Itk, Jak3 MAP examples of inhibitors might include
Gefitinib, Imatinib mesylate), Serine/threonine kinases (including
but not limited to inhibitors of MAP kinases such as p38, JNK,
protein kinases A, B and C and IKK), and kinases involved in cell
cycle regulation (such as but not limited to the cyclin dependent
kinases); (viii) glucose-6 phosphate dehydrogenase inhibitors; (ix)
kinin-B.sub.1- and B.sub.2-receptor antagonists; (x) anti-gout
agents, e.g., colchicine; (xi) xanthine oxidase inhibitors, e.g.,
allopurinol; (xii) uricosuric agents, e.g., probenecid,
sulfinpyrazone, and benzbromarone; (xiii) growth hormone
secretagogues; (xiv) transforming growth factor (TGF.beta.); (xv)
platelet-derived growth factor (PDGF); (xvi) fibroblast growth
factor, e.g., basic fibroblast growth factor (bFGF); (xvii)
granulocyte macrophage colony stimulating factor (GM-CSF); (xviii)
capsaicin cream; (xix) tachykinin NK.sub.1 and NK.sub.3 receptor
antagonists such as the group consisting of NKP-608C; SB-233412
(talnetant); and D-4418; (xx) elastase inhibitors such as the group
consisting of UT-77 and ZD-0892; (xxi) TNF-alpha converting enzyme
inhibitors (TACE); (xxii) induced nitric oxide synthase (iNOS)
inhibitors or (xxiii) chemoattractant receptor-homologous molecule
expressed on TH2 cells, (such as CRTH2 antagonists) (xxiv)
inhibitors of P38 (xxv) agents modulating the function of Toll-like
receptors (TLR) and (xxvi) agents modulating the activity of
purinergic receptors such as P2.times.7; (xxvii) inhibitors of
transcription factors activation such as NFkB, API, and STATS.
[0121] The compounds of the invention can also be used in
combination with existing therapeutic agents for the treatment of
cancer. Suitable agents to be used in combination include:
(i) antiproliferative/antineoplastic drugs and combinations
thereof, as used in medical oncology, such as alkylating agents
(for example cis-platin, carboplatin, cyclophosphamide, nitrogen
mustard, melphalan, chlorambucil, busulphan and nitrosoureas);
antimetabolites (for example antifolates such as fluoropyrimidines
like 5-fluorouracil and tegafur, raltitrexed, methotrexate,
cytosine arabinoside, hydroxyurea, gemcitabine and paclitaxel;
antitumour antibiotics (for example anthracyclines like adriamycin,
bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin,
mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for
example vinca alkaloids like vincristine, vinblastine, vindesine
and vinorelbine and taxoids like taxol and taxotere); and
topoisomerase inhibitors (for example epipodophyllotoxins like
etoposide and teniposide, amsacrine, topotecan and camptothecins);
(ii) cytostatic agents such as antioestrogens (for example
tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene),
oestrogen receptor down regulators (for example fulvestrant),
antiandrogens (for example bicalutamide, flutamide, nilutamide and
cyproterone acetate), LHRH antagonists or LHRH agonists (for
example goserelin, leuprorelin and buserelin), progestogens (for
example megestrol acetate), aromatase inhibitors (for example as
anastrozole, letrozole, vorazole and exemestane) and inhibitors of
5.alpha.-reductase such as finasteride; (iii) Agents which inhibit
cancer cell invasion (for example metalloproteinase inhibitors like
marimastat and inhibitors of urokinase plasminogen activator
receptor function); (iv) inhibitors of growth factor function, for
example such inhibitors include growth factor antibodies, growth
factor receptor antibodies (for example the anti-erbb2 antibody
trastuzumab and the anti-erbb1 antibody cetuximab [C225]), farnesyl
transferase inhibitors, tyrosine kinase inhibitors and
serine/threonine kinase inhibitors, for example inhibitors of the
epidermal growth factor family (for example EGFR family tyrosine
kinase inhibitors such as
N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-
-amine (gefitinib, AZD 1839),
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine
(erlotinib, OSI-774) and
6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazoli-
n-4-amine (CI 1033)), for example inhibitors of the
platelet-derived growth factor family and for example inhibitors of
the hepatocyte growth factor family; (v) antiangiogenic agents such
as those which inhibit the effects of vascular endothelial growth
factor, (for example the anti-vascular endothelial cell growth
factor antibody bevacizumab, compounds such as those disclosed in
International Patent Applications WO 97/22596, WO 97/30035, WO
97/32856 and WO 98/13354) and compounds that work by other
mechanisms (for example linomide, inhibitors of integrin
.alpha.v.beta.3 function and angiostatin); (vi) vascular damaging
agents such as combretastatin A4 and compounds disclosed in
International Patent Applications WO 99/02166, WO 00/40529, WO
00/41669, WO 01/92224, WO 02/04434 and WO 02/08213; (vii) antisense
therapies, for example those which are directed to the targets
listed above, such as ISIS 2503, an anti-ras antisense; (viii) gene
therapy approaches, including 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; and (ix) immunotherapeutic approaches, including 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.
[0122] 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, version 6.00; (iv) unless stated otherwise, reverse phase HPLC
was conducted using a "Symmetry", "NovaPak" or "Xerra" reverse
phase silica column; (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
[0123] SUPERSLOW 100% to 80% in 2.5 min; and (vi) the following
abbreviations are used:
TABLE-US-00001 HOBT 1-hydroxybenzotriazole DMSO dimethylsulfoxide
HPLC high pressure liquid chromatography EDCI
1-ethyl-3-(3-dimethylaminopropyl)carbodi-imide hydrochloride DMAP
N,N-dimethylaminopyridine TFA trifluoroacetic acid min minutes h
hour
Intermediate 1
4-[[4-(3,4-Dichlorophenoxy)-1-piperidinyl]methyl]-1,2-cyclopentanediol
a)
1-(3-Cyclopenten-1-ylcarbonyl)-4-(3,4-dichlorophenoxy)-piperidine
[0124] 3,4-Dichlorophenoxypiperidine (3.09 g) was dissolved in
dichloromethane (80 mL). HOBT (1.77 g) and DMAP (0.44 g) were added
followed by a solution of 3-cyclopentene-1-carboxylic acid (1.45 g)
in dichloromethane (5 mL). EDCI (2.45 g) was added and the solution
was stirred for 60 h. Water (100 mL) was added and the phases were
separated. The aqueous phase was extracted with dichloromethane
(2.times.40 mL). The organic phases were combined, dried
(MgSO.sub.4), filtered and evaporated to give subtitle compound
(3.40 g) that was used without further purification.
[0125] MS [M+H].sup.+ (ES+) 340/342
[0126] .sup.1H NMR .delta..sub.(CDCl3) 4.47-4.53 (1H, m), 5.67 (2H,
s), 7.33 (1H, d), 6.78 (1H, dd), 7.02 (1H, d), 3.62-3.84 (3H, m),
3.44-3.52 (1H, m), 3.33 (1H, d), 2.68-2.77 (2H, m), 2.54-2.64 (2H,
m), 1.88-1.99 (2H, m), 1.73-1.86 (2H, m).
b)
4-[[4-(3,4-Dichlorophenoxy)-1-piperidinyl]carbonyl]-1,2-cyclopentanedio-
l
[0127]
1-(3-Cyclopenten-1-ylcarbonyl)-4-(3,4-dichlorophenoxy)-piperidine
(1.33 g) was dissolved in acetone (30 mL) and water (20 mL).
N-methylmorpholine N-oxide (1.12 g) was added followed by a
solution of osmium tetroxide (1 mL of 2.5% in 2-methylpropan-2-ol)
and the mixture was stirred for 60 h. Aqueous sodium metabisulfite
solution (40 mL, saturated) was added followed by dichloromethane
(50 mL) and the phases were separated. The organic phase was washed
with ammonium chloride solution, dried, filtered and concentrated.
The residue was purified by chromatography eluting with
dichloromethane:methanol (24:1 then 37:3) to give the subtitle
compound as a mixture of isomers:
Less polar isomer (0.31 g):
[0128] MS [M+H].sup.+ (ES+) 374/376
[0129] .sup.1H NMR .delta..sub.(CDCl3) 1.79-1.98 (6H, m), 2.12-2.22
(2H, m), 3.23 (1H, tt), 3.49-3.56 (1H, m), 3.65-3.79 (3H, m), 3.93
(1H, d), 3.99-4.08 (3H, m), 4.53 (1H, tt), 6.77 (1H, dd), 7.02 (1H,
d), 7.34 (1H, d).
More polar isomer (0.71 g):
[0130] MS [M+H].sup.+ (ES+) 374/376
[0131] .sup.1H NMR .delta..sub.(CDCl3) 1.73-1.86 (2H, m), 1.86-2.00
(4H, m), 2.07-2.16 (2H, m), 2.50-2.60 (2H, m), 3.39 (1H, tt),
3.42-3.48 (1H, m), 3.61-3.78 (3H, m), 4.22-4.27 (2H, m), 4.47-4.53
(1H, m), 6.77 (1H, dd), 7.01 (1H, d), 7.33 (1H, d).
c)
4-[[4-(3,4-Dichlorophenoxy)-1-piperidinyl]methyl]-1,2-cyclopentanediol
[0132] The more polar isomer of
4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]carbonyl]-1,2-cyclopentanediol
(0.71 g) was dissolved in a solution of borane in tetrahydrofuran
(16 mL of 1M solution) and the mixture was heated to reflux for 1.5
h. Methanol (10 mL) was added and the solution was heated under
reflux for 1 h. The volatile components were evaporated and the
residue was loaded onto an HPLC SCX cartridge in methanol and
eluted with methanol, then with 0.7M ammonia in methanol to give
the title compound (0.73 g) as an oil.
[0133] MS [M+H].sup.+ (ES+) 360/362 (standard gradient, retention
time 1.33)
[0134] Similar treatment of the minor isomer of
4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]carbonyl]-1,2-cyclopentanediol
(0.30 g) gave the title compound (0.26 g) as an oil.
[0135] MS [M+H].sup.+ (ES+) 360/362 (standard gradient, retention
time 1.33)
[0136] The following compounds were prepared by analogous routes
starting from the appropriate phenoxypiperidine:
TABLE-US-00002 MS [M + H].sup.+ Intermediate Name (ES+) 2
4-[[4-(2,4-Dichloro-3-methylphenoxy)-1- 374/376
piperidinyl]methyl]-1,2-cyclopentanediol 3
4-[[4-(3,4-Dichloro-2-methylphenoxy)-1- 374/376
piperidinyl]methyl]-1,2-cyclopentanediol
Intermediate 4
4-(3,4-Dichlorophenoxy)-1-(4-piperidinylmethyl)-piperidine
a) 1,1-Dimethylethyl
4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidinecarboxylate
[0137] 4-(3,4-Dichlorophenoxy)piperidine (1.27 g) was dissolved in
tetrahydrofuran (20 mL); acetic acid (0.5 mL) and 1,1-dimethylethyl
4-formyl-1-piperidinecarboxylate (1.43 g) were added to the
solution. The reaction mixture was stirred at room temperature for
30 min then sodium triacetoxyborohydride (1.53 g) was added and the
mixture was stirred at room temperature overnight. The reaction
mixture was poured into 2M sodium hydroxide solution (50 mL) and
product was extracted with ether. The ether was washed with brine,
dried, filtered and evaporated. Crude material was purified by
flash chromatography (eluting with 979:20:1
dichloromethane:methanol:aqueous ammonia) to give the subtitle
compound (2.15 g).
[0138] MS 443/445 [M+H].sup.+ (ES+)
[0139] .sup.1H NMR .delta..sub.(CDCl3) 1.06 (2H, ddd), 1.45 (9H,
s), 1.61-1.82 (5H, m), 1.92-1.98 (2H, m), 2.16-2.27 (4H, m),
2.65-2.73 (4H, m), 4.08 (2H, d), 4.25 (1H, dq), 6.75 (1H, dd), 6.99
(1H, d), 7.30 (1H, d)
b) 4-(3,4-Dichlorophenoxy)-1-(4-piperidinylmethyl)-piperidine
[0140] 1,1-Dimethylethyl
4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidinecarboxylate
(1.0 g) was added to a mixture of 20% TFA in dichloromethane (20
mL) and the mixture was stirred at room temperature for 1 h.
Solvent was removed by evaporation and 2M sodium hydroxide solution
(25 mL) was added to the residue. Product was extracted with ethyl
acetate. The organic phase was washed with brine, dried, filtered
and evaporated to give the title compound (0.5 g).
[0141] MS 343/345 [M+H].sup.+ (ES+)
[0142] .sup.1H NMR .delta..sub.(CDCl3) 1.10 (2H, qd), 1.60 (1H,
qquintet), 1.73-1.83 (4H, m), 1.90-2.01 (2H, m), 2.16-2.26 (4H, m),
2.55-2.70 (4H, m), 3.09 (2H, d), 4.24 (1H, dquintet), 6.75 (1H,
dd), 6.99 (1H, d), 7.27 (1H, d)
[0143] The following intermediates were prepared analogously from
the appropriate aryloxy piperidine or arylmethylpiperidine:
TABLE-US-00003 M + H Retention time Intermediate Name (conditions)
.sup.1H NMR 5 4-[(4-Fluorophenyl)methyl]- 291
.delta..sub.(CD3OD+DMSO) 1.19-1.32 (4H, 1-(4-piperidinylmethyl)-
1.75 m), 1.46-1.54 (1H, m), piperidine (standard) 1.55-1.62 (2H,
m), 1.77-1.84 (1H, m), 1.85-1.93 (4H, m), 2.17 (2H, d), 2.51 (2H,
d), 2.80-2.89 (4H, m), 3.23-3.26 (2H, m), 7.01 (2H, t), 7.16 (2H,
dd) 6 4-(4-Chloro-2- 323/325 .delta..sub.(CDCl3) 1.08-1.21 (2H, m),
methylphenoxy)-1-(4- 1.56-1.68 (1H, m), piperidinylmethyl)-
1.73-1.86 (4H, m), 1.90-1.99 (2H, piperidine m), 2.16-2.31 (7H, m),
2.57-2.69 (4H, m), 3.12 (2H, d), 4.23-4.31 (1H, m), 6.74 (1H, d),
7.06 (1H, dd), 7.11 (1H, d) 7 3-Chloro-4-[[1-(4- 334/336
.delta..sub.(CD3OD) 1.66-1.94 (5H, m), piperidinylmethyl)-4-
2.00-2.11 (2H, m), 2.26 (2H, piperidinyl]oxy]-benzonitrile d),
2.37-2.47 (2H, m), 2.58-2.77 (4H, m), 3.09 (2H, d), 3.30 (2H, s),
4.64-4.73 (1H, m), 7.27 (1H, d), 7.63-7.66 (1H, m), 7.80 (1H, d) 8
2-Chloro-4-[[1-(4- 334/336 .delta..sub.(CD3OD) 1.21-1.32 (2H, m),
piperidinylmethyl)-4- 1.74-1.90 (5H, m),
piperidinyl]oxy]-benzonitrile 1.99-2.10 (2H, m), 2.26 (2H, d),
2.31-2.40 (2H, m), 2.67-2.79 (4H, m), 3.11-3.21 (2H, m), 4.52-4.62
(1H, m), 7.05 (1H, dd), 7.21 (1H, d), 7.70 (1H, d)
Intermediate 9
(4S,5R)-1-[[4-[[4-(3,4-Dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidiny-
l]acetyl]-3,4-dimethyl-5-phenyl-2-imidazolidinone
[0144] 2,6-Lutidine (18.26 mL) was added to a stirred suspension of
(4R,5S)-1,5-dimethyl-4-phenylimidazolidin-2-one (27.33 g) in
anhydrous tetrahydrofuran (300 mL) at 0.degree. C. under nitrogen.
Bromoacetyl bromide (11.95 mL) was added over 5 minutes and the
mixture was stirred for a further 15 minutes. Saturated aqueous
sodium bicarbonate solution (300 mL) was added followed by
4-(3,4-dichlorophenoxy)-1-(4-piperidinylmethyl)piperidine (44.86 g)
and the mixture was stirred for 24 hours at ambient temperature.
Water (300 mL) was added and the mixture was extracted with
tert-butyl methyl ether (300 mL). The organic extracts were dried
over anhydrous magnesium sulfate, filtered and evaporated under
reduced pressure. The residue was suspended in tert-butyl methyl
ether (300 mL) and stirred for 3 days. The resulting solid was
filtered, washed with tert-butyl methyl ether (3.times.50 mL) and
dried in under reduced pressure to give the title compound (45.65
g) as a solid.
[0145] MS (APCI) 573/575 [M+H].sup.+
[0146] .sup.1H NMR .delta..sub.(DMSO) 0.67 (3H, d), 1.02 (2H, qd),
1.37-1.45 (1H, m), 1.55-1.62 (4H, m), 1.85-2.63 (2H, m), 2.02 (1H,
t), 2.10 (2H, d), 2.10-2.19 (3H, m), 2.58-2.63 (2H, m), 2.70 (3H,
s), 2.78 (2H, d), 3.60 (1H, d), 3.78 (1H, d), 3.96 (1H, dt),
4.39-4.46 (1H, m), 5.28 (1H, d), 6.97 (1H, dd), 7.12 (2H, d), 7.23
(1H, d), 7.27 (1H, t), 7.35 (2H, t), 7.48 (1H, d), (contains 1
equivalent of (4R,5S)-1,5-dimethyl-4-phenylimidazolidin-2-one).
EXAMPLE 1
(.alpha.S)-Methyl
4-[[4-(2,4-dichloro-3-methylphenoxy)-1-piperidinyl]methyl]-.alpha.-(pheny-
lmethyl)-1-piperidineacetate
[0147]
4-[[4-(2,4-Dichloro-3-methylphenoxy)-1-piperidinyl]methyl]-1,2-cycl-
opentanediol (0.30 g) was dissolved in dichloromethane (7 mL) and
sodium carbonate (0.282 g) was added. The suspension was cooled to
0.degree. C. Lead tetraacetate (0.389 g) was added over 20 minutes.
The mixture was stirred for 40 min at 0.degree. C.
[0148] The suspension was filtered through a plug of cotton wool
into a solution of L-phenylalanine, methyl ester, hydrochloride
salt (0.173 g), triethylamine (0.13 mL), acetic acid (0.06 mL),
sodium triacetoxyborohydride (0.376 g) and tetrahydrofuran (12 mL).
The reaction mixture was then stirred for 16 h at room temperature,
poured into saturated aqueous sodium bicarbonate solution (50 mL),
extracted into ethyl acetate (3.times.5 mL), washed with brine (50
mL), dried (MgSO.sub.4), filtered, and concentrated. The residue
was purified by column chromatography eluting with ethyl acetate,
and further purified by HPLC (gradient ammonium
acetate/acetonitrile 40:60 to 5:95) to give the title compound
(0.205 g).
[0149] MS [M+H].sup.+ (ES+) 519/521
[0150] Examples 2-31 in TABLE I (below) were prepared by the method
of Example 1 using the appropriate diol and aminoacid ester
precursors.
EXAMPLE 32
(.alpha.S) Methyl
4-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-.alpha.-(phenylmethy-
l)-1-piperidineacetate
[0151] To a stirred, ice-cooled solution of methyl-(R)-3-phenyl
lactate (0.191 g) and powdered 4 .ANG. molecular sieves (0.27 g) in
dichloromethane (2 mL) was added trifluoromethanesulfonic anhydride
(0.195 mL). After 10 min, 2,6-lutidine (0.27 mL) was added dropwise
resulting in a deep red colour. The reaction mixture was stirred
for 40 min at 0.degree. C. A mixture of
4-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methylpiperidine (0.28
g) and 4 .ANG. molecular sieves (0.1 g) in dichloromethane (1.5 mL)
was added. After 2 min, triethylamine (0.323 mL) was added and the
reaction was allowed to warm to room temperature overnight. The
reaction mixture was diluted with ethyl acetate and filtered. The
filtrate was concentrated in vacuo and purified by flash column
chromatography, eluting with ethyl acetate to yield a yellow solid
(0.53 g).
[0152] Retention time: 2.37 min (Standard).
[0153] MS 453 [M+H].sup.+ (ES+).
[0154] .sup.1H NMR .delta..sub.(CD3OD) 1.43-1.58 (2H, m), 1.70-1.89
(6H, m), 2.31 (1H, td), 2.42 (1H, td), 2.61 (2H, d), 2.80-3.03 (9H,
m), 3.03-3.10 (1H, m), 3.43-3.50 (3H, m), 3.55 (3H, s), 7.01 (2H,
ddd), 7.14-7.28 (7H, m).
[0155] Examples 33-35 in TABLE I (below) were prepared by the
method of Example 32 using the appropriate amines.
EXAMPLE 36
(.alpha.S) Methyl
4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-[(2-hydroxyphen-
yl)methyl]-1-piperidineacetate
[0156] (.alpha.S) Methyl
4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-[(2-methoxyphen-
yl)methyl]-1-piperidineacetate (120 mg) in dichloromethane (6 mL)
was cooled to 78 C under nitrogen, and a 1M solution of boron
tribromide in dichloromethane (9 mL) was added dropwise to it. The
mixture was then stirred at -78.degree. C. for 30 minutes, and then
at -5.degree. C. for 30 minutes. The reaction mixture was then
quenched carefully with methanol (20 mL), allowed to warm to room
temperature and the volatiles removed in vacuo. The residue was
purified by reverse-phase HPLC using 75:25 to 5:95 0.1% aqueous
ammonium acetate/acetonitrile over 6 minutes, symmetry column. This
gave 67 mg of the title compound as an oil.
[0157] Lc/ms: RT 1.77 (fast). m/z 521/523 (M+H).
EXAMPLE 37
(.alpha.S)-4-[[4-(2,4-Dichloro-3-methylphenoxy)-1-piperidinyl]methyl]-.alp-
ha.-(phenylmethyl)-1-piperidineacetic acid
[0158] Methyl
4-[[4-(2,4-dichloro-3-methylphenoxy)-1-piperidinyl]methyl]-.alpha.-(pheny-
lmethyl)-(.alpha..sup.1S)-1-piperidineacetate (Example 1, 0.205 g),
6M hydrochloric acid (20 mL), and 2-propanol (5 mL) were heated
together at 80.degree. C. for 24 h, then cooled and concentrated
under reduced pressure. The residue was purified by HPLC (gradient
ammonium acetate/acetonitrile 75:25 to 5:95) to give the title
compound (0.113 g).
[0159] MS [M+H].sup.+ (APCI+) 505/507.
[0160] .sup.1H NMR .delta..sub.(CD3OD) 1.33-1.45 (2H, m), 1.71-1.82
(3H, m), 1.84-1.97 (4H, m), 2.28 (2H, d), 2.35 (3H, s), 2.37-2.47
(2H, m), 2.66-2.76 (2H, m), 2.87 (2H, q), 3.07-3.19 (2H, m), 3.40
(1H, d), 3.50 (1H, d), 3.63 (1H, t), 4.35-4.44 (1H, m), 6.86 (1H,
d), 7.09-7.27 (6H, m).
[0161] Examples 38-70 in TABLE II (below) were prepared using the
method of Example 37 from the appropriate ester (see TABLE I except
for Example 58 which was prepared from (.+-.) methyl
4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-[(R)-[[(1,1-dim-
ethylethyl)dimethylsilyl]oxy]phenylmethyl]-(.alpha..sup.1S)-1-piperidineac-
etate [.sup.1H NMR .delta..sub.(CDCL3) 0.24 (6H, s), 1.07 (9H, s),
1.35-1.47 (2H, m), 1.67-1.74 (1H, m), 1.88-2.06 (4H, m), 2.15-2.24
(2H, m), 2.38-2.49 (4H, m), 2.60 (1H, t), 2.70 (1H, t), 2.86-2.94
(2H, m), 3.12 (1H, d), 3.36 (1H, d), 3.64 (3H, s), 4.36 (1H, q),
4.44-4.51 (1H, m), 5.19 (1H, d), 6.99 (1H, dd), 7.23 (1H, d),
7.43-7.57 (6H, m)] prepared analogously to Example 1 from the
appropriate protected hydroxyaminoacid).
EXAMPLE 71
(.alpha.S)-4-[[4-(2,4-Dichloro-3-methylphenoxy)-1-piperidinyl]methyl]-.alp-
ha.-(phenylmethyl)-1-piperidineacetic acid, dihydrochloride
salt
[0162]
(.alpha.S)-4-[[4-(2,4-Dichloro-3-methylphenoxy)-1-piperidinyl]methy-
l]-.alpha.-(phenylmethyl)-1-piperidineacetic acid (Example 12,
0.062 g) was suspended in acetonitrile (5 mL) and a solution of
hydrogen chloride in 1,4-dioxane (4M, 5 mL) was added. The
suspension was concentrated under reduced pressure, and the process
repeated again, to give the title compound (0.048 g).
[0163] MS [M+H].sup.+ (APCI+) 505/507
[0164] .sup.1H NMR .delta..sub.(DMSO) 1.43-1.65 (2H, m), 1.98-2.11
(4H, m), 2.18-2.30 (3H, m), 2.41 (3H, s), 2.44-2.56 (4H, m),
2.99-3.13 (6H, m), 3.43-3.51 (1H, m), 3.56-3.61 (1H, m), 3.64-3.74
(1H, m), 4.83-4.91 (1H, m), 7.19 (1H, t), 7.27 (3H, d), 7.30-7.36
(2H, m), 7.42 (1H, d).
[0165] Examples 72-78 in Table II were prepared from the
appropriate ester (see Example 1 or TABLE I) following the method
of Example 37 and either the salt crystallised from the hydrolysis
step and was isolated by filtration or the product after
chromatography was converted to the salt following the method of
Example 71.
EXAMPLE 79
(.alpha..sup.1S)-4-[[4-(3,4-Dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-
-[(2-hydroxyphenyl)methyl]-1-piperidineacetic acid
[0166] (.alpha.S) Methyl
4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-[(2-hydroxyphen-
yl)methyl]-1-piperidineacetate (Example 36, 67 mg) in methanol (4
mL) was stirred at room temperature under nitrogen. A solution of
lithium hydroxide (22 mg) in water (1 mL) was added dropwise to
this, keeping the temperature below 30.degree. C. The mixture was
then stirred at room temperature for 20 hours. The volatiles were
removed in vacuo and the residue was purified by HPLC using a
gradient of 95:5 to 5:95 0.1% aqueous ammonium acetate/acetonitrile
to give the title compound as a solid (48 mg).
[0167] MS: 505/507 (M+H)
[0168] .sup.1H NMR .delta..sub.(CD3OD) 1.19-1.37 (2H, m), 1.52-1.62
(1H, m), 1.70-1.83 (4H, m), 1.94-2.03 (2H, m), 2.23 (2H, d), 2.30
(2H, t), 2.42 (1H, t), 2.66-2.74 (2H, m), 2.86 (1H, dd), 2.98-3.09
(2H, m), 3.15 (2H, d), 3.22 (1H, t), 4.32-4.42 (1H, m), 6.42 (1H,
t), 6.61 (1H, dd), 6.82-6.89 (2H, m), 7.04 (1H, dd), 7.07 (1H, d),
7.36 (1H, d).
EXAMPLE 80
(.alpha.S)-4-[[4-(3,4-Dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(2-th-
ienylmethyl)-1-piperidineacetic acid
[0169]
4-[[4-(3,4-Dichlorophenoxy)-1-piperidinyl]methyl]-1,2-cyclopentaned-
iol (0.20 g) was dissolved in dichloromethane (10 mL) and sodium
carbonate (0.212 g) was added. The suspension was cooled to
0.degree. C. Lead tetraacetate (0.248 g) was added over 20 minutes.
The mixture was stirred for 40 min at 0.degree. C.
[0170] MS [M+H].sup.+ (ES+) 358/360.
[0171] The suspension was filtered through a plug of cotton wool
into a solution of
.alpha.-amino-(.alpha..sup.2S)-2-thiophenepropanoic acid (0.94 g)
and acetic acid (0.1 mL) in ethanol (10 mL). Sodium
triacetoxyborohydride (0.198 g) was added and the reaction mixture
was stirred for 16 h at room temperature. The solvent was
evaporated and the residue was redissolved in acetonitrile and
filtered. This was purified by HPLC (gradient ammonium
acetate/acetonitrile 95% to 50%) to give the title compound (0.048
g)
[0172] MS [M+H].sup.+ (ES+) 495/497.
[0173] .sup.1H NMR .delta..sub.(CD3OD) 1.18-1.34 (3H, m), 1.52-1.61
(1H, m), 1.71-1.81 (4H, m), 1.95-2.03 (2H, m), 2.21-2.25 (2H, m),
2.26-2.52 (4H, m), 2.66-2.74 (2H, m), 2.91-3.15 (4H, m), 4.34-4.41
(1H, m), 6.83-6.90 (3H, m), 7.08 (1H, d), 7.12 (1H, dd), 7.37 (1H,
d).
[0174] Example 81 in TABLE II was prepared following the method of
Example 80 using the appropriate amino acid.
EXAMPLE 82
2-[4-[[4-(3,4-Dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidinyl]-2,3-di-
hydro-1H-indene-2-carboxylic acid
[0175]
4-[[4-(3,4-Dichlorophenoxy)-1-piperidinyl]methyl]-1,2-cyclopentaned-
iol (0.20 g) was dissolved in dichloromethane (10 mL) and sodium
carbonate (0.212 g) was added. The suspension was cooled to
0.degree. C. Lead tetraacetate (0.248 g) was added over 20 minutes.
The mixture was stirred for 40 min at 0.degree. C.
[0176] MS [M+H].sup.+ (ES+) 358/360.
[0177] The suspension was filtered through a plug of cotton wool
into a solution of 2-amino-2,3-dihydro-1H-indene-2-carboxylic acid
hydrochloride (0.117 g), hydrochloric acid (0.1 mL), triethylamine
(0.1 mL) and methanol (10 mL). Sodium cyanoborohydride (0.052 g)
was added and the reaction mixture was stirred for 16 h at room
temperature. The reaction mixture was diluted with saturated sodium
bicarbonate solution. The aqueous phase was extracted with
dichloromethane. The organic phases were dried (MgSO.sub.4),
filtered and evaporated and the residue was redissolved in
acetonitrile. This was purified by HPLC (gradient ammonium
acetate/acetonitrile 95% to 50%). The title compound crystallised
from the HPLC fractions and was collected to give pure product (7
mg).
[0178] MS [M+H].sup.+ (ES+) 503/505.
[0179] .sup.1H NMR .delta..sub.(CD3OD) 1.21-1.36 (5H, m), 1.55-1.62
(1H, m), 1.72-1.81 (2H, m), 1.94-2.05 (2H, m), 2.16-2.25 (2H, m),
2.25-2.40 (3H, m), 2.66-2.74 (2H, m), 2.90-3.03 (4H, m), 3.66 (1H,
s), 3.70 (1H, s), 4.34-4.41 (1H, m), 6.88 (1H, dd), 7.01-7.12 (5H,
m), 7.37 (1H, d).
EXAMPLE 83
(.alpha.S)-4-[[4-(3,4-Dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-[(2-m-
ethylphenyl)methyl]-1-piperidineacetic acid
[0180] A solution of lithium hexamethyldisilazide in
tetrahydrofuran (1M, 131 mL) was added dropwise over 30 min to a
stirred suspension
(4S,5R)-1-[[4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidin-
yl]acetyl]-3,4-dimethyl-5-phenyl-2-imidazolidinone (45.65 g) and
2-methylbenzyl bromide (16.3 mL) in anhydrous tetrahydrofuran (130
mL) at -20.degree. C. under nitrogen. After a further 20 hours at
-20.degree. C., water (300 mL) was added, the mixture was warmed to
room temperature and then extracted with tert-butyl methyl ether
(300 mL). The organic extracts were dried over anhydrous magnesium
sulfate, filtered and evaporated under reduced pressure. The
residue was dissolved in tetrahydrofuran (800 mL), then methanol
(103 mL) and a solution of lithium hydroxide monohydrate (3.01 g)
in water (194 mL) was added. The mixture was stirred at 50.degree.
C. for 16 hours then further lithium hydroxide monohydrate (3.01 g)
was added. After a further 4 hours at 50.degree. C., the mixture
was cooled to room temperature. Water (600 mL), tert-butyl methyl
ether (800 mL) and ammonium acetate (200 g) were added. The mixture
was stirred rapidly for 3 days then the precipitate was collected
by filtration of the two-phase mixture. The solid was washed with
water (50 mL) then tert-butyl methyl ether (50 mL) and dried in
vacuo at 50.degree. C. to give the title compound (8.90 g)
[0181] MS (APCI) 503/505 [M-H].sup.-
[0182] .sup.1H NMR .delta..sub.(CD3OD+NaOD) 1.18-1.35 (2H, m),
1.52-1.62 (1H, m), 1.72-1.82 (4H, m), 2.23 (2H, d), 1.95-2.05 (2H,
m), 2.26-2.42 (7H, m), 2.63-2.75 (2H, m), 2.91 (1H, dd), 3.00 (1H,
d), 3.05-3.10 (2H, m), 3.15 (1H, dd), 4.37-4.42 (1H, m), 6.88 (1H,
dd), 6.98-7.10 (4H, m), 7.21-7.23 (1H, m), 7.37 (1H, d).
TABLE-US-00004 TABLE I Example Name (NMR) MS [M + H].sup.+ (ES+) 2
(.alpha.S)Methyl
4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(phenylmethyl)--
1-piperidineacetate 505/507 3 (.alpha.R)Methyl
4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(phenylmethyl)--
1-piperidineacetate 505/507 4 (.alpha.S)Methyl
4-[[4-(3,4-dichloro-2-methylphenoxy)-1-piperdinyl]methyl]-.alpha.-(phenyl-
methyl)-1- 519/521 piperidineacetate 5 (.alpha.S)Methyl
.alpha.-[(4-chlorophenyl)methyl]-4-[[4-(3,4-dichlorophenoxy)-1-piperidiny-
l]methyl]-1- 539/541/543 piperidineacetate 6 (.alpha.S)Methyl
4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-[(2-methylpheny-
l)methyl]-1- 519/521 piperidineacetate 7 (.alpha.S)Methyl
.alpha.-[4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidinyl]-
-3-pyridinepropanoate 506/508 8 (.alpha.S)Methyl
4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-[(2-fluoropheny-
l)methyl]-1- 523/525 piperidineacetate 9 (.alpha.S)Methyl
4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-[[3-(trifluorom-
ethyl)phenyl]methyl]-1- 573/575 piperidineacetate 10
(.alpha.S)Methyl
4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-[(4-methoxyphen-
yl)methyl]-1- 535/537 piperidineacetate 11 (.alpha.S)Methyl
.alpha.-[4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidinyl]-
-1H-indole-3-propanoate 544/546 12 (.alpha.S)1,1-Dimethylethyl
4-[[4-(3,4-dichloro-2-methylphenoxy)-1-piperidinyl]methyl]-.alpha.-[(2-
575/577 methylphenyl)methyl]-1-piperidineacetate 13
(.alpha.R)Methyl
4-[[4-(3,4-Dichloro-2-methylphenoxy)-1-piperidinyl]methyl]-.alpha.-(pheny-
lmethyl)-1- 519/521 piperidineacetate .sup.1H NMR
.delta..sub.(CD3OD) 1.24 (2H, td), 1.51-1.65 (1H, m), 1.75-1.89
(4H, m), 1.97-2.08 (2H, m), 2.23-2.31 (3H, m), 2.32-2.43 (6H, m),
2.66-2.76 (2H, m), 2.94-3.09 (4H, m), 3.42-3.48 (1H, m), 3.57 (3H,
s), 4.41-4.49 (1H, m), 6.93 (1H, d), 7.16-7.32 (6H, m) 14
(.alpha.R)Methyl
4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-[(2-methylpheny-
l)methyl]-1- 519/521 piperidineacetate .sup.1H NMR
.delta..sub.(CD3OD) 1.16-1.31 (2H, m), 1.50-1.62 (1H, m), 1.71-1.83
(4H, m), 1.95-2.03 (2H, m), 2.23 (2H, d), 2.27-2.38 (7H, m),
2.67-2.75 (2H, m), 2.96-3.07 (4H, m), 3.41 (1H, dd), 3.51 (3H, s),
4.35-4.42 (1H, m), 6.88 (1H, dd), 7.04-7.13 (5H, m), 7.37 (1H, d)
15 (.alpha.S)Methyl
4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-[(3-fluoropheny-
l)methyl]-1- 523/525 piperidineacetate 16 (.alpha.S)Methyl
4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-[(4-fluoropheny-
l)methyl]-1- 523/525 piperidineacetate 17 (.alpha.S)Methyl
.alpha.-[4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidinyl]-
-2-pyridinepropanoate 506/508 18 (.alpha.S)Methyl
.alpha.-[(3-cyanophenyl)methyl]-4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl-
]methyl]-1- 530/532 piperidineacetate 19 (.alpha.S)Methyl
.alpha.-[(2-cyanophenyl)methyl]-4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl-
]methyl]-1- 530/532 piperidineacetate 20 (.alpha.S)Methyl
.alpha.-[4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidinyl]-
-4-pyridinepropanoate 506/508 21 (.alpha.S)Methyl
4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-[(2-methoxyphen-
yl)methyl]-1- RT 2.22 (Fast) m/z piperidineacetate 535/537 22
(.alpha.S)Methyl
.alpha.-[(2-cyanophenyl)methyl]-4-[[4-(3,4-dichloro-2-methylphenoxy)-1-pi-
peridinyl]methyl]-1- RT 2.22 (Fast) m/z piperidineacetate 544/546
23 (.alpha.S)Methyl
.alpha.-[(3-cyanophenyl)methyl]-4-[[4-(3,4-dichloro-2-methylphenoxy)-1-pi-
peridinyl]methyl]-1- 530/532 piperidineacetate 24 (.alpha.S)Methyl
4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-[(4-methylpheny-
l)methyl]-1- 519/521 piperidineacetate 25 (.alpha.S)Methyl
4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-[(3-methylpheny-
l)methyl]-1- 519/521 piperidineacetate 26 (.alpha.S)Methyl
.alpha.-[(4-cyanophenyl)methyl]-4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl-
]methyl]-1- 530/532 piperidineacetate 27 (.alpha.S)Methyl
.alpha.-[(2-chlorophenyl)methyl]-4-[[4-(3,4-dichlorophenoxy)-1-piperidiny-
l]methyl]-1- RT (fast) 2.32 m/z piperidineacetate 541/543 28
(.alpha.S)Methyl
4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-[[2-(trifluorom-
ethyl)phenyl]methyl]-1- RT (fast) 2.58 m/z piperidineacetate
573/575 29 (.alpha.S)Methyl
4-[[4-(2,4-dichloro-3-methylphenoxy)-1-piperidinyl]methyl]-.alpha.-[(2-me-
thoxyphenyl)methyl]-1- RT (fast) 2.31 m/z piperidineacetate 549/551
30 (.alpha.S)Methyl
4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-(2-phenylethyl)-
-1-piperidineacetate 519/521 31 (.+-.)(.alpha.S)Methyl
4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-.alpha.-[(1S)-1-phenyle-
thyl]-1- 519/521 piperidineacetate .sup.1H NMR .delta..sub.(CDCl3)
0.66 (1H, dd), 0.87 (1H, dd), 1.17 (3H, d), 1.25-1.36 (1H, m), 1.52
(4H, d), 1.66-1.77 (2H, m), 1.87-1.95 (2H, m), 2.00 (2H, d), 2.13
(1H, t), 2.26 (1H, td), 2.53-2.62 (2H, m), 2.68 (1H, d), 2.87 (1H,
d), 3.17-3.26 (1H, m), 3.32 (1H, d), 3.73 (3H, s), 4.16-4.23 (1H,
m), 6.72 (1H, dd), 6.97 (1H, d), 7.13-7.21 (3H, m), 7.24-7.31 (3H,
m) 33 (.alpha.S)Methyl
4-[[4-(3-chloro-4-cyanophenoxy)-1-piperidinyl]methyl]-.alpha.-(phenylmeth-
yl)-1-piperidineacetate 496/498 .sup.1H NMR .delta..sub.(CD3OD)
1.15-1.31 (2H, m), 1.53-1.66 (1H, m), 1.72-1.89 (4H, m), 2.00-2.10
(2H, m), 2.23-2.49 (6H, m), 2.75-2.85 (2H, m), 2.93-3.07 (4H, m),
3.40-3.45 (1H, m), 3.53 (3H, s), 4.55-4.63 (1H, m), 7.04 (1H, dd),
7.14-7.21 (4H, m), 7.22-7.27 (2H, m), 7.69 (1H, d) 34
(.alpha.S)Methyl
4-[[4-(2-chloro-4-cyanophenoxy)-1-piperidinyl]methyl]-.alpha.-(phenylmeth-
yl)-1-piperidineacetate 496/498 RT 2.53 min .sup.1H NMR
.delta..sub.(CD3OD) 1.75-1.90 (4H, m), 2.07-2.16 (2H, m), 2.18-2.29
(2H, m), 2.35 (1H, tm), 2.46 (1H, td), Standard 2.91-3.12 (8H, m),
3.17-3.35 (3H, m), 3.48 (1H, dd), 3.56 (3H, s), 4.88-4.95 (1H, m),
7.14-7.20 (3H, m), 7.22-7.27 (2H, m), 7.33 (1H, d), 7.67 (1H, dd),
7.82 (1H, d) 35 (.alpha.S)Methyl
4-[[4-(4-chloro-2-methylphenoxy)-1-piperidinyl]methyl]-.alpha.-(phenylmet-
hyl)-1-piperidineacetate 485/487 .sup.1H NMR .delta..sub.(CD3OD)
1.14-1.29 (2H, m), 1.50-1.62 (1H, m), 1.72-1.85 (4H, m), 1.95-2.03
(2H, m), 2.18 (3H, s), 2.23 (2H, d), 2.26-2.38 (4H, m), 2.65-2.73
(2H, m), 2.92-3.06 (4H, m), 3.42 (1H, dd), 3.54 (3H, s), 4.35-4.42
(1H, m), 6.87 (1H, d), 7.06-7.11 (2H, m), 7.15-7.19 (3H, m),
7.22-7.27 (2H, m)
TABLE-US-00005 TABLE II MS [M + H].sup.+ Example Name (ES+) .sup.1H
NMR 38 (.alpha.S)-4-[[4-(3,4-Dichlorophenoxy)-1- 491/493
.delta..sub.(CD3OD/NaOD) 1.02-1.28 (2H, m), 1.38-1.52 (1H, m),
1.59-1.74 (4H, piperidinyl]methyl]-.alpha.-(phenylmethyl)-1- m),
1.81-1.97 (2H, m), 2.10-2.37 (6H, m), 2.54-2.66 (2H, m),
piperidineacetic acid 2.72 (1H, dd), 2.86-3.06 (3H, m), 3.07-3.17
(1H, m), 4.24-4.32 (1H, m), 6.78 (1H, dd), 6.97-7.20 (6H, m), 7.27
(1H, d) 39 (.alpha.R)-4-[[4-(3,4-Dichlorophenoxy)-1- 491/493
.delta..sub.(CD3OD/NaOD) 1.06-1.28 (2H, m), 1.41-1.51 (1H, m),
1.60-1.74 (4H, piperidinyl]methyl]-.alpha.-(phenylmethyl)-1- m),
1.84-1.95 (2H, m), 2.11-2.36 (6H, m), 2.54-2.66 (2H, m),
piperidineacetic acid 2.68-2.76 (1H, m), 2.87-3.04 (3H, m),
3.08-3.16 (1H, m), 4.24-4.33 (1H, m), 6.78 (1H, dd), 6.98-7.19 (6H,
m), 7.27 (1H, d) 40 (.alpha.S)-4-[[4-(3,4-Dichloro-2- 505/507
.delta..sub.(CD3OD/NaOD) 1.18-1.31 (3H, m), 1.46-1.58 (1H, m),
1.70-1.84 (4H, methylphenoxy)-1-piperidinyl]methyl]- m), 1.93-2.03
(2H, m), 2.20 (2H, d), 2.27 (3H, s), 2.29-2.39 (2H,
.alpha.-(phenylmethyl)-1-piperidineacetic acid m), 2.56-2.65 (2H,
m), 2.87 (1H, dd), 2.97-3.15 (5H, m), 4.36-4.44 (1H, m), 6.88 (1H,
d), 7.09 (1H, t), 7.18 (2H, t), 7.21-7.27 (3H, m) 41
(.alpha.S)-4-[[4-(3,4-Dichlorophenoxy)-1- 505/507
.delta..sub.(CD3OD/NaOD) 1.18-1.37 (2H, m) 1.49-1.63 (1H, m),
1.71-1.81 (4H, piperidinyl]methyl]-.alpha.-[(2- m pt 213.degree. C.
m), 1.95-2.04 (2H, m), 2.25-2.27 (2H, d), 2.29-2.40 (4H, m),
methylphenyl)methyl]-1-piperidineacetic 2.33 (3H, s), 2.64-2.74
(2H, m) 2.89-3.04 (2H, m), 3.05-3.22 (3H, m), acid 4.38-4.42 (1H,
m), 6.91 (1H, dd), 7.02-7.10 (4H, m), 7.21-7.24(m, 1H), 7.40 (1H,
d) 42 (.alpha.S)-.alpha.-[4-[[4-(3,4-Dichlorophenoxy)-1- 492/494
.delta..sub.(CD3OD/NaOD) 1.16-1.28 (2H, m), 1.41-1.54 (2H, m),
1.60-1.73 (1H, piperidinyl]methyl]-1-piperidinyl]-3- m), 1.84-1.97
(4H, m), 2.06-2.15 (2H, m), 2.16-2.25 (2H, m), pyridinepropanoic
acid 2.27-2.41 (2H, m), 2.57-2.66 (2H, m), 2.74-2.81 (1H, m),
2.82-2.90 (1H, m), 2.94-3.02 (2H, m), 3.03-3.12 (1H, m), 4.25-4.32
(1H, m), 6.79 (1H, dd), 7.00 (1H, d), 7.19-7.23 (1H, m), 7.27 (1H,
d), 7.64-7.68 (1H, m), 8.20-8.23 (1H, m), 8.34-8.35 (1H, m) 43
(.alpha.S)-4-[[4-(3,4-Dichlorophenoxy)-1- 509/511
.delta..sub.(CD3OD) 1.19-1.35 (2H, m), 1.52-1.61 (1H, m), 1.73-1.82
(4H, m), piperidinyl]methyl]-.alpha.-[(2- 1.98-2.05 (2H, m),
2.21-2.27 (2H, m), 2.29-2.36 (4H, m),
fluorophenyl)methyl]-1-piperidineacetic 2.65-2.74 (2H, m), 2.96
(1H, t), 3.04-3.12 (3H, m), 3.17-3.22 (1H, m), acid 4.36-4.42 (1H,
m), 6.90 (1H, d), 6.99 (1H, t), 7.02-7.07 (2H, m), 7.15-7.21 (1H,
m), 7.34 (1H, t), 7.39 (1H, d) 44
(.alpha.S)-4-[[4-(3,4-Dichlorophenoxy)-1- 559/561
.delta..sub.(CD3OD/NaOD) 1.18-1.39 (2H, m), 1.51-1.65 (1H, m),
1.71-1.85 (4H, piperidinyl]methyl]-.alpha.-[[3- m), 1.95-2.09 (2H,
m), 2.24 (2H, d), 2.28-2.47 (4H, m),
(trifluoromethyl)phenyl]methyl]-1- 2.66-2.77 (2H, m), 2.95 (1H, d),
2.99-3.14 (3H, m), 3.15-3.20 (1H, m), piperidineacetic acid
4.34-4.45 (1H, m), 6.90 (1H, dd), 7.09 (1H, d), 7.39 (1H, d),
7.41-7.45 (2H, m), 7.51-7.59 (2H, m) 45
(.alpha.S)-.alpha.-[4-[[4-(3,4-Dichlorophenoxy)-1- 530/532
.delta..sub.(CD3OD/NaOD) 1.14-1.50 (2H, m), 1.52-1.70 (1H, m),
1.71-1.89 (4H, piperidinyl]methyl]-1-piperidinyl]-1H- m), 1.95-2.09
(2H, m), 2.22-2.56 (6H, m), 2.67-2.81 (2H, m), indole-3-propanoic
acid 2.92-3.30 (5H, m), 4.35-4.46 (1H, m), 6.87-7.15 (5H, m),
7.26-7.31 (1H, m), 7.39 (1H, d), 7.62-7.66 (1H, m) 46
(.alpha.S)-4-[[4-(3,4-Dichloro-2- 517/ .delta..sub.(CD3OD) 1.31
(2H, dd), 1.57-1.66 (1H, m), 1.77-1.90 (4H, m),
methylphenoxy)-1-piperidinyl]methyl]- 519 (M - H) 1.99-2.09 (2H,
m), 2.28 (2H, d), 2.34 (3H, s), 2.35-2.47 (4H, m),
.alpha.-[(2-methylphenyl)methyl]-1- 2.39 (3H, s), 2.66-2.76 (2H,
m), 2.94 (1H, dd), 3.04-3.17 (3H, m), piperidineacetic acid 3.21
(1H, dd), 4.42-4.50 (1H, m), 6.95 (1H, d), 7.03-7.12 (3H, m),
7.25-7.28 (1H, m), 7.31 (1H, dd) 47
(.alpha.R)-4-[[4-(3,4-Dichloro-2- 505/507 .delta..sub.(CD3OD + 1
drop NaOD) 1.16-1.40 (2H, m), 1.52-1.66 (1H, m),
methylphenoxy)-1-piperidinyl]methyl]- 1.73-1.88 (4H, m), 1.96-2.08
(2H, m), 2.25 (2H, d), 2.30-2.45 (8H, m),
.alpha.-(phenylmethyl)-1-piperidineacetic 2.63-2.74 (2H, m), 2.85
(1H, dd), 2.99-3.15 (3H, m), 3.23 (1H, dd), acid 4.38-4.48 (1H, m),
6.93 (1H, d), 7.09-7.31 (6H, m) 48
(.alpha.R)-4-[[4-(3,4-Dichlorophenoxy)-1- 505/507
.delta..sub.(CD3OD) 1.18-1.40 (2H, m), 1.51-1.66 (1H, m), 1.71-1.85
(4H, m), piperidinyl]methyl]-.alpha.-[(2- 1.95-2.07 (2H, m),
2.22-2.48 (9H, m), 2.67-2.78 (2H, m),
methylphenyl)methyl]-1-piperidineacetic 2.91 (1H, dd), 3.02-3.16
(3H, m), 3.22 (1H, dd), 4.34-4.45 (1H, m), acid 6.90 (1H, dd),
6.99-7.12 (4H, m), 7.22-7.28 (1H, m), 7.39 (1H, d) 49
(.alpha.S)-4-[[4-(3,4-Dichlorophenoxy)-1- 509/ .delta..sub.(CD3OD)
1.18-1.35 (2H, m), 1.51-1.61 (1H, m), 1.69-1.82 (4H, m),
piperidinyl]methyl]-.alpha.-[(3- 511 (M + H) 1.95-2.04 (2H, m),
2.23 (2H, d), 2.27-2.35 (2H, m), 2.39 (2H, d),
fluorophenyl)methyl]-1-piperidineacetic 2.65-2.74 (2H, m),
2.81-2.88 (1H, m), 2.97-3.11 (3H, m), acid 3.15-3.20 (1H, m),
4.33-4.42 (1H, m), 6.81-6.90 (2H, m), 7.00 (1H, d), 7.05-7.09 (2H,
m), 7.21 (1H, q), 7.37 (1H, d) 50
(.alpha.S)-4-[[4-(3,4-Dichlorophenoxy)-1- 507/ .delta..sub.(CD3OD)
1.15-1.34 (2H, m), 1.50-1.61 (1H, m), 1.70-1.82 (4H, m),
piperidinyl]methyl]-.alpha.-[(4- 509 (M - H) 1.95-2.04 (2H, m),
2.22 (2H, d), 2.26-2.40 (4H, m), 2.65-2.74 (2H,
fluorophenyl)methyl]-1-piperidineacetic m), 2.83 (1H, dd), 3.04
(3H, t), 3.10-3.15 (1H, m), 4.34-4.42 (1H, acid m), 6.86-6.95 (3H,
m), 7.07 (1H, d), 7.25 (2H, dd), 7.37 (1H, d) 51
(.alpha.S)-.alpha.-[4-[[4-(3,4-Dichlorophenoxy)-1- 490/
.delta..sub.(CD3OD) 1.05-1.32 (2H, m), 1.49-1.60 (1H, m), 1.69-1.80
(4H, m), piperidinyl]methyl]-1-piperidinyl]-2- 492 (M - H)
1.95-2.03 (2H, m), 2.21 (2H, t), 2.26-2.40 (4H, m), 2.55 (1H, t),
pyridinepropanoic acid 2.64-2.73 (2H, m), 2.97-3.11 (3H, m), 3.17
(1H, t), 4.33-4.42 (1H, m), 6.88 (1H, dd), 7.06 (1H, d), 7.18-7.23
(1H, m), 7.37 (2H, d), 7.69 (1H, t), 8.40 (1H, d) 52
(.alpha.S)-.alpha.-[(3-Cyanophenyl)methyl]-4-[[4- 514/
.delta..sub.(CD3OD) 1.17-1.41 (2H, m), 1.53-1.67 (1H, m), 1.73-1.88
(4H, m), (3,4-dichlorophenoxy)-1- 516 (M - H) 1.97-2.09 (2H, m),
2.26 (2H, d), 2.37 (4H, q), 2.67-2.79 (2H, m),
piperidinyl]methyl]-1-piperidineacetic 2.92-3.21 (5H, m), 4.35-4.47
(1H, m), 6.91 (1H, d), 7.11 (1H, s), acid 7.37-7.50 (2H, m), 7.55
(1H, d), 7.59-7.68 (2H, m) 53
(.alpha.S)-.alpha.-[(2-Cyanophenyl)methyl]-4-[[4- 514/
.delta..sub.(CD3OD) 1.40-1.59 (2H, m), 1.81-2.14 (7H, m), 2.55 (2H,
d), (3,4-dichlorophenoxy)-1- 516 (M - H) 2.62-2.75 (2H, m), 2.96
(4H, t), 3.21-3.37 (1H, m), 3.43-3.71 (4H, m),
piperidinyl]methyl]-1-piperidineacetic 4.44-4.56 (1H, m), 6.90-6.96
(1H, m), 7.15 (1H, t), 7.39-7.46 (2H, acid m), 7.52-7.65 (2H, m),
7.71 (1H, d) 54 (.alpha.S)-.alpha.-[4-[[4-(3,4-Dichlorophenoxy)-1-
492/ .delta..sub.(DMSO) 0.93-1.05 (2H, m), 1.38-1.47 (1H, m),
1.50-1.69 (4H, m), piperidinyl]methyl]-1-piperidinyl]-4- 494 (M +
H) 1.83-1.91 (2H, m), 2.07 (2H, d), 2.09-2.26 (4H, m), 2.54-2.66
(2H, pyridinepropanoic acid m), 2.74-2.99 (5H, m), 4.35-4.44 (1H,
m), 6.95 (1H, dd), 7.20-7.25 (3H, m), 7.47 (1H, d), 8.40 (2H, d) 55
(.alpha.S)-4-[[4-(3,4-Dichlorophenoxy)-1- 521/ .delta..sub.(CD3OD)
1.16-1.36 (2H, m), 1.50-1.61 (1H, m), 1.69-1.81 (4H, m),
piperidinyl]methyl]-.alpha.-[(2- 523 (M + H) 1.94-2.03 (2H, m),
2.22 (2H, d), 2.26-2.41 (4H, m), 2.65-2.74 (2H,
methoxyphenyl)methyl]-1- m), 2.87 (1H, dd), 3.01-3.13 (3H, m), 3.26
(1H, dd), 3.80 (3H, s), piperidineacetic acid 4.33-4.41 (1H, m),
6.77 (1H, t), 6.83-6.89 (2H, m), 7.07 (1H, d), 7.11 (1H, td), 7.20
(1H, d), 7.36 (1H, d) 56
(.alpha.S)-.alpha.-[(2-Cyanophenyl)methyl]-4-[[4- 528/
.delta..sub.(CD3OD) 1.18-1.31 (2H, m), 1.49-1.62 (1H, m), 1.70-1.85
(4H, m), (3,4-dichloro-2-methylphenoxy)-1- 530 (M - H) 1.95-2.04
(2H, m), 2.21 (2H, d), 2.29 (3H, s), 2.31-2.44 (4H, m),
piperidinyl]methyl]-1-piperidineacetic 2.60-2.71 (2H, m), 3.01-3.25
(5H, m), 4.36-4.46 (1H, m), acid 6.90 (1H, d), 7.26 (1H, d), 7.33
(1H, t), 7.47-7.56 (2H, m), 7.62 (1H, d) 57
(.alpha.S)-.alpha.-[(3-Cyanophenyl)methyl]-4-[[4- 528/
.delta..sub.(CD3OD) 1.15-1.33 (2H, m), 1.50-1.61 (1H, m), 1.71-1.85
(4H, m), (3,4-dichloro-2-methylphenoxy)-1- 530 (M - H) 1.94-2.04
(2H, m), 2.22 (2H, d), 2.28 (3H, s), 2.31-2.39 (4H, m),
piperidinyl]methyl]-1-piperidineacetic 2.58-2.70 (2H, m), 2.89-3.15
(5H, m), 4.36-4.46 (1H, m), acid 6.90 (1H, d), 7.26 (1H, d), 7.42
(1H, t), 7.51 (1H, d), 7.58 (1H, d), 7.61 (1H, s) 58
(.alpha.S)-4-[[4-(3,4-Dichlorophenoxy)-1- 507/ .delta..sub.(CD3OD)
1.19-1.44 (2H, m), 1.55-1.67 (1H, m), 1.75-1.90 (4H, m),
piperidinyl]methyl]-.alpha.-[(R)- 509 (M + H) 1.99-2.08 (2H, m),
2.25-2.40 (5H, m), 2.75 (3H, t), 2.91 (1H, d),
hydroxyphenylmethyl]-1-piperidineacetic 3.10-3.19 (2H, m),
4.37-4.46 (1H, m), 4.84 (1H, d), 6.92 (1H, dd), acid 7.11 (1H, d),
7.21-7.26 (1H, m), 7.30 (2H, t), 7.41 (1H, d), 7.49 (2H, d) 59
(.alpha.S)-4-[[4-(3,4-Dichlorophenoxy)-1- 503/ .delta..sub.(CD3OD)
0.84-0.96 (1H, m), 1.15-1.44 (6H, m), 1.73-1.93 (5H, m),
piperidinyl]methyl]-.alpha.-[(1S)-1- 505 (M - H) 1.96-2.11 (2H, m),
2.35 (2H, d), 2.43-2.55 (2H, m), 2.75-2.86 (3H,
phenylethyl]-1-piperidineacetic acid m), 2.89-3.12 (1H, m),
3.35-3.58 (1H, m), 3.68 (1H, d), 4.39-4.50 (1H, m), 6.91 (1H, dd),
7.12 (1H, d), 7.22-7.30 (1H, m), 7.32-7.42 (5H, m) 60
(.alpha.S)-4-[[4-(3,4-Dichlorophenoxy)-1- (APCI)
.delta..sub.(CD3OD) 1.14-1.34 (2H, m), 1.49-1.61 (1H, m), 1.69-1.82
(4H, m), piperidinyl]methyl]-.alpha.-[(4- 503/ 1.94-2.03 (2H, m),
2.19-2.34 (4H, m), 2.24 (3H, s), 2.37 (2H, q),
methylphenyl)methyl]-1-piperidineacetic 505 [M - H].sup.+ 2.66-2.73
(2H, m), 2.76 (1H, dd), 2.96-3.09 (3H, m), 3.17 (1H, dd), acid
4.33-4.41 (1H, m), 6.87 (1H, dd), 7.00 (2H, d), 7.08 (1H, d), 7.13
(2H, d), 7.36 (1H, d) 61 (.alpha.S)-4-[[4-(3,4-Dichlorophenoxy)-1-
(APCI) .delta..sub.(CD3OD) 1.17-1.41 (2H, m), 1.51-1.65 (1H, m),
1.72-1.85 (4H, m), piperidinyl]methyl]-.alpha.-[(3- 503/ 1.96-2.07
(2H, m), 2.25 (2H, d), 2.29 (3H, s), 2.31-2.46 (4H, m),
methylphenyl)methyl]-1-piperidineacetic 505 [M - H].sup.+ 2.67-2.77
(2H, m), 2.81 (1H, dd), 3.06 (3H, t), 3.21 (1H, dd), acid 4.34-4.46
(1H, m), 6.88-6.98 (2H, m), 7.04-7.13 (4H, m), 7.39 (1H, d) 62
(.alpha.S)-.alpha.-[(4-Cyanophenyl)methyl]-4-[[4- (APCI)
.delta..sub.(CD3OD) 1.15-1.43 (2H, m), 1.50-1.66 (1H, m), 1.71-1.86
(4H, m), (3,4-dichlorophenoxy)-1- 516/ 1.96-2.08 (2H, m), 2.24 (2H,
d), 2.27-2.48 (4H, m), 2.66-2.80 (2H,
piperidinyl]methyl]-1-piperidineacetic 518 [M + H].sup.+ m),
2.90-3.25 (5H, m), 4.33-4.45 (1H, m), 6.90 (1H, d), 7.10 (1H, acid,
s), 7.39 (1H, d), 7.47 (2H, d), 7.60 (2H, d) 63
(.alpha.S)-.alpha.-[(2-Chlorophenyl)methyl]-4-[[4- (APCI)
.delta..sub.(CD3OD) 1.19-1.35 (2H, m), 1.49-1.61 (1H, m), 1.71-1.82
(4H, m), (3,4-dichlorophenoxy)-1- 525/527/ 1.94-2.05 (2H, m), 2.22
(2H, d), 2.33 (4H, q), 2.65-2.73 (2H, m),
piperidinyl]methyl]-1-piperidineacetic 529 [M - H].sup.+ 2.97-3.27
(5H, m), 4.32-4.42 (1H, m), 6.88 (1H, dd), 7.06 (1H, d), acid
7.10-7.18 (2H, m), 7.27-7.31 (1H, m), 7.37 (2H, d) 64
(.alpha.S)-4-[[4-(3,4-Dichlorophenoxy)-1- (APCI)
.delta..sub.(CD3OD) 1.19-1.45 (2H, m), 1.67-1.81 (3H, m), 1.86-1.98
(4H, m), piperidinyl]methyl]-.alpha.-[[2- 559/ 2.30 (2H, d),
2.34-2.46 (2H, m), 2.68-2.77 (2H, m), 2.84 (2H, q),
(trifluoromethyl)phenyl]methyl]-1- 561 [M + H].sup.+ 3.08-3.16 (1H,
m), 3.31-3.54 (4H, m), 4.30-4.38 (1H, m), piperidineacetic acid
6.80 (1H, dd), 7.01 (1H, d), 7.27-7.34 (2H, m), 7.45 (2H, q), 7.57
(1H, d) 65 (.alpha.S)-4-[[4-(2,4-Dichloro-3- (APCI)
.delta..sub.(CD3OD) 1.17-1.41 (2H, m), 1.50-1.66 (1H, m), 1.72-1.90
(4H, m), methylphenoxy)-1-piperidinyl]methyl]- 533/ 1.93-2.06 (2H,
m), 2.24 (2H, d), 2.31-2.42 (4H, m), 2.44 (3H, s),
.alpha.-[(2-methoxyphenyl)methyl]-1- 535 [M - H].sup.+ 2.64-2.77
(2H, m), 2.88 (1H, t), 3.00-3.15 (4H, m), 3.82 (3H, s),
piperidineacetic acid 4.40-4.51 (1H, m), 6.78 (1H, t), 6.86 (1H,
d), 6.94 (1H, d), 7.12 (1H, t), 7.23 (2H, t) 66
(.alpha.S)-4-[[4-(3,4-Dichlorophenoxy)-1- 503/
.delta..sub.(CD3OD/NaOD) 1.25 (2H, dd), 1.49-1.59 (1H, m),
1.70-1.80 (4H, m), piperidinyl]methyl]-.alpha.-(2-phenylethyl)-1-
505 (M - H) 1.81-1.91 (1H, m), 1.94-2.03 (3H, m), 2.19-2.34 (6H,
m), piperidineacetic acid 2.51-2.61 (1H, m), 2.63-2.73 (3H, m),
2.90 (1H, dd), 2.94-3.04 (2H, m), 4.32-4.42 (1H, m), 6.87 (1H, dd),
7.06 (1H, d), 7.12 (1H, dt), 7.18-7.25 (4H, m), 7.36 (1H, d). 67
(.alpha.S)-4-[[4-[(4-Fluorophenyl)methyl]-1- MS
.delta..sub.(CD3OD)
1.21-1.39 (4H, m), 1.49-1.57 (2H, m), 1.58-1.65 (2H, m),
piperidinyl]methyl]-.alpha.-(phenylmethyl)-1- 439 [M + H]+
1.73-1.81 (2H, m), 1.89 (2H, t), 2.20 (2H, d), 2.28-2.41 (2H, m),
piperidineacetic acid (ES+). 2.54 (2H, d), 2.86-2.93 (3H, m),
3.03-3.12 (3H, m), 3.19 (1H, dd), Retention 7.00 (2H, t), 7.12-7.20
(3H, m), 7.21-7.26 (2H, m), 7.27-7.31 (2H, time: 1.35 m). Standard
68 (.alpha.S)-4-[[4-(2-Chloro-4-cyanophenoxy)- 480/
.delta..sub.(CD3OD) 1.16-1.39 (2H, m), 1.50-1.66 (1H, m), 1.74-1.87
(4H, m), 1-piperidinyl]methyl]-.alpha.-(phenylmethyl)- 482 [M - H]
1.99-2.10 (2H, m), 2.26 (2H, d), 2.30-2.46 (4H, m), 2.68-2.77 (2H,
1-piperidineacetic acid APCI- m), 2.85 (1H, dd), 3.00-3.15 (3H, m),
3.23 (1H, dd), 4.52-4.61 (1H, m), 7.05 (1H, dd), 7.10-7.17 (1H, m),
7.19-7.31 (5H, m), 7.71 (1H, d) 69
(.alpha.S)-4-[[4-(2-Chloro-4-cyanophenoxy)- 482/484
.delta..sub.(DMSO) 0.99-1.13 (2H, m), 1.41-1.52 (1H, m), 1.61-1.73
(3H, m), 1-piperidinyl]methyl]-.alpha.-(phenylmethyl)- [M + H]+
1.87-1.97 (2H, m), 2.11 (2H, d), 2.21-2.30 (3H, m), 2.39-2.47 (2H,
1-piperidineacetic acid (ES+). m), 2.54-2.61 (1H, m), 2.78-2.89
(2H, m), 2.92-3.03 (2H, m), 3.30-3.39 (2H, m), 4.64-4.73 (1H, m),
7.14-7.28 (5H, m), 7.38 (1H, d), 7.77 (1H, dd), 8.01 (1H, d). 70
(.alpha.S)-4-[[4-(4-Chloro-2-methylphenoxy)- 471/473
.delta..sub.(CD3OD) 1.16-1.35 (2H, m), 1.50-1.63 (1H, m), 1.72-1.84
(4H, m), 1-piperidinyl]methyl]-.alpha.-(phenylmethyl)- 1.95-2.03
(2H, m), 2.17 (3H, s), 2.23 (2H, d), 2.30-2.42 (4H, m),
1-piperidineacetic acid 2.63-2.72 (2H, m), 2.83 (1H, dd), 2.98-3.11
(3H, m), 3.20 (1H, dd), 4.34-4.41 (1H, m), 6.87 (1H, d), 7.05-7.13
(3H, m), 7.20 (2H, t), 7.26 (2H, d) 72
(.alpha.S)-4-[[4-(3,4-Dichlorophenoxy)-1- 491/493
.delta..sub.(CD3OD/NaOD) 1.05-1.26 (2H, m), 1.41-1.54 (1H, m),
1.61-1.73 (4H, piperidinyl]methyl]-.alpha.-(phenylmethyl)-1- m),
1.85-1.94 (2H, m), 2.07-2.16 (2H, m), 2.16-2.25 (2H, m),
piperidineacetic acid dihydrochloride 2.26-2.35 (2H, m), 2.57-2.65
(2H, m), 2.72 (1H, dd), 2.87-2.94 (1H, m), 2.95-3.05 (2H, m),
3.10-3.16 (1H, m), 4.24-4.33 (1H, m), 6.76-6.81 (1H, m), 6.98-7.04
(2H, m), 7.10 (2H, t), 7.17 (2H, d), 7.27 (1H, dd) 73
(.alpha.S)-4-[[4-(3,4-Dichloro-2- 505/507 .delta..sub.(CD3OD)
1.56-1.69 (2H, m), 1.92-2.02 (1H, m), 2.05-2.25 (6H, m),
methylphenoxy)-1-piperidinyl]methyl]- 2.31 (3H, s), 3.07-3.15 (4H,
m), 3.14-3.27 (2H, m), 3.39 (1H, dd),
.alpha.-(phenylmethyl)-1-piperidineacetic acid 3.44-3.52 (2H, m),
3.53-3.60 (2H, m), 3.60-3.68 (1H, m), dihydrochloride 3.71-3.81
(1H, m), 4.12-4.21 (1H, m), 6.86-6.96 (1H, m), 7.17-7.29 (6H, m) 74
(.alpha.S)-.alpha.-[(4-Chlorophenyl)methyl]-4-[[4- (APCI)
.delta..sub.(CD3OD) 1.55-1.71 (2H, m), 1.88-2.00 (1H, m), 2.03-2.33
(6H, m), (3,4-dichlorophenoxy)-1- 525/ 3.04-3.15 (4H, m), 3.16-3.30
(3H, m), 3.34-3.48 (3H, m), piperidinyl]methyl]-1-piperidineacetic
531 [M + H].sup.+ 3.52-3.59 (1H, m), 3.60-3.67 (1H, m), 3.70-3.78
(1H, m), acid dihydrochloride 4.11-4.19 (1H, m), 6.83-6.94 (1H, m),
7.09-7.17 (1H, m), 7.24 (4H, q), 7.34 (1H, d) 75
(.alpha.S)-4-[[4-(3,4-Dichlorophenoxy)-1- (APCI)
.delta..sub.(CD3OD) 1.56-1.74 (2H, m), 1.88-1.99 (1H, m), 2.05-2.27
(6H, m), piperidinyl]methyl]-.alpha.-[(2- 505/ 2.30 (3H, s),
3.05-3.15 (4H, m), 3.15-3.33 (3H, m), 3.36-3.49 (3H,
methylphenyl)methyl]-1-piperidineacetic 509 [M + H].sup.+ m),
3.54-3.69 (2H, m), 3.78-3.88 (1H, m), 4.04-4.13 (1H, m), acid,
dihydrochloride 6.84-6.94 (1H, m), 7.00-7.18 (5H, m), 7.34 (1H, d)
76 (.alpha.S)-4-[[4-(3,4-Dichlorophenoxy)-1- (APCI)
.delta..sub.(DMSO) 1.55-1.72 (2H, m), 1.93-2.33 (7H, m), 2.93-3.17
(6H, m), piperidinyl]methyl]-.alpha.-[(4- 521/ 3.31-3.52 (4H, m),
3.54-3.64 (2H, m), 3.73 (3H, s), 4.02-4.16 (1H,
methoxyphenyl)methyl]-1- 525 [M + H].sup.+ m), 4.79-4.86 (1H, m),
6.89 (2H, d), 7.06 (1H, t), 7.18 (2H, d), piperidineacetic acid
dihydrochloride 7.32-7.40 (1H, m), 7.56 (1H, t) 77
(.alpha.R)-4-[[4-(3,4-Dichlorophenoxy)-1- 505/507
.delta..sub.(CD3OD) 1.66-1.88 (2H, m), 1.97-2.43 (10H, m),
3.16-3.27 (6H, piperidinyl]methyl]-.alpha.-[(2- m), 3.37-3.49 (2H,
m), 3.51-3.61 (3H, m), 3.66-3.79 (2H, m),
methylphenyl)methyl]-1-piperidineacetic 4.17-4.26 (1H, m),
6.95-7.06 (1H, m), 7.13-7.30 (5H, m), acid dihydrochloride
7.43-7.50 (1H, m) 78 (.alpha.S)-4-[[4-(3,4-Dichlorophenoxy)-1- 503/
.delta..sub.(CD3OD) 1.63-1.78 (2H, m), 1.97-2.09 (1H, m), 2.11-2.40
(8H, m), piperidinyl]methyl]-.alpha.-(2-phenylethyl)-1- 505 [M - H]
2.69-2.79 (1H, m), 2.83-2.93 (1H, m), 3.13-3.22 (4H, m),
piperidineacetic acid dihydrochloride 3.32-3.38 (1H, m), 3.48-3.57
(3H, m), 3.64-3.77 (2H, m), 3.95-4.03 (1H, m), 4.80 (1H, s), 7.00
(1H, dd), 7.19-7.34 (6H, m), 7.43 (1H, dd) 81
(.alpha.S)-4-[[4-(3,4-Dichlorophenoxy)-1- 495/497 .delta.
(CD.sub.3OD/NaOD) 1.23-1.37 (4H, m), 1.50-1.64 (2H, m),
piperidinyl]methyl]-.alpha.-[(1-methyl-1H- 1.70-1.84 (4H, m),
1.92-2.05 (2H, m), 2.15-2.26 (2H, m),
imidazol-5-yl)methyl]-1-piperidineacetic 2.26-2.50 (3H, m),
2.63-2.82 (2H, m), 2.96-3.10 (2H, m), 3.20-3.27 (1H, m), acid 3.65
(3H, s), 4.34-4.41 (1H, m), 6.79 (1H, s), 6.88 (1H, dd), 7.08 (1H,
d), 7.37 (1H, d), 7.46 (1H, s)
EXAMPLE 84
Pharmacological Analysis: Calcium Flux [Ca.sup.2+].sub.i Assay
Human Eosinophils
[0183] 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-1) and loaded with 5 .mu.M 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.times.g for 5 min 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
min and the cells were washed twice with LKS (200 .mu.l; room
temperature).
[0184] 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 (1.sub.Ex=490 nm
and 1.sub.Em=520 nm) monitored using a FLIPR (Fluorometric Imaging
Plate Reader, Molecular Devices, Sunnyvale, U.S.A.).
[0185] Compounds of the Examples were found to be antagonists if
the increase in fluorescence induced by cotaxin (a selective CCR3
agonist) was inhibited in a concentration dependent manner. The
concentration of antagonist required to inhibit the fluorescence by
50% can be used to determine the IC.sub.50 for the antagonist at
the CCR3 receptor.
EXAMPLE 85
Human Eosinophil Chemotaxis
[0186] 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 sulfate and supplemented with
10% HIFCS, at room temperature.
[0187] Eosinophils (700 .mu.l) were pre-incubated for 15 mins at
37.degree. C. with 7 .mu.l of either vehicle or compound
(100.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 (a
selective CCR3 agonist over this concentration range) 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.
[0188] 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 mins 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.
[0189] Compounds of the Examples were found to be antagonists of
eotaxin mediated human eosinophil chemotaxis if the concentration
response to eotaxin was shifted to the right of the control curve.
Measuring the concentration of eotaxin required to give 50%
chemotaxis in the presence or absence of compounds enables the
apparent affinity of the compounds at CCR3 to be calculated.
EXAMPLE 86
Guinea-Pig Isolated Trachea
[0190] (See for example, Harrison, R. W. S., Carswell, H. &
Young, J. M. (1984) European J. Pharmacol., 106, 405-409.)
[0191] 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 (2.81M) 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
[0192] 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.
[0193] Contraction responses were recorded as a percentage of the
first curve maximum.
Data Analysis
[0194] 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 87
[0195] 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.
[0196] The following compounds of the invention gave inhibition of
[3H]pyrilamine binding:
TABLE-US-00006 Example H1 pKi 37 7.5 38 7.5 39 7.0 40 7.0 41 7.7 45
7.0 42 7.3 43 7.3 44 6.8 50 7.5 53 8.0 56 7.9 57 7.7 58 6.9 59 7.2
66 7.2 71 6.8 72 7.2 73 7.2 74 7.5 78 6.9 80 6.6 81 6.4
* * * * *