U.S. patent application number 10/427991 was filed with the patent office on 2003-11-06 for aminoheterocyclic derivatives as antithrombotic or anticoagulant agents.
This patent application is currently assigned to ZENECA LIMITED. Invention is credited to Preston, John, Smithers, Michael James, Stocker, Andrew.
Application Number | 20030207882 10/427991 |
Document ID | / |
Family ID | 10788043 |
Filed Date | 2003-11-06 |
United States Patent
Application |
20030207882 |
Kind Code |
A1 |
Stocker, Andrew ; et
al. |
November 6, 2003 |
Aminoheterocyclic derivatives as antithrombotic or anticoagulant
agents
Abstract
Compounds of formula (I), wherein G.sup.1 is CH or N; G.sup.2 is
CH or N; R.sup.1 is a variety of optional substituents, L.sup.1 is
(1-4C)alkylene; T.sup.1 is CH or N; R.sup.2 and R.sup.3 are
independently hydrogen or (1-4C)alkyl or are joined to form a ring;
X.sup.1 and X.sup.2 represent various linking groups; Ar is
phenylene or certain heteroaryl rings and Q represents a variety of
aromatic or heterocyclic rings systems, and pharmaceutically
acceptable salts thereof are described as useful antithrombotic and
anticoagulant agents, and are selective Factor Xa inhibitors.
Processes for their preparation and pharmaceutical compositions
containing them are also described. 1
Inventors: |
Stocker, Andrew; (Cheshire,
GB) ; Preston, John; (Cheshire, GB) ;
Smithers, Michael James; (Cheshire, GB) |
Correspondence
Address: |
MORGAN LEWIS & BOCKIUS LLP
1111 PENNSYLVANIA AVENUE NW
WASHINGTON
DC
20004
US
|
Assignee: |
ZENECA LIMITED
|
Family ID: |
10788043 |
Appl. No.: |
10/427991 |
Filed: |
May 2, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10427991 |
May 2, 2003 |
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09117436 |
Jul 30, 1998 |
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09117436 |
Jul 30, 1998 |
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PCT/GB97/00284 |
Jan 31, 1997 |
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Current U.S.
Class: |
514/235.8 ;
514/242; 514/252.02; 514/252.11; 514/252.14; 514/253.01; 514/275;
514/318; 514/340; 544/112; 544/120; 544/124; 544/129; 544/182;
544/238; 544/295; 544/331; 544/360; 544/405; 546/193;
546/279.1 |
Current CPC
Class: |
A61P 7/00 20180101; A61P
25/00 20180101; A61P 7/02 20180101; C07D 237/20 20130101; A61P 9/00
20180101; C07D 401/04 20130101; A61P 9/10 20180101; C07D 401/14
20130101; C07D 401/12 20130101; C07D 239/42 20130101; C07D 213/74
20130101 |
Class at
Publication: |
514/235.8 ;
514/242; 514/252.02; 514/252.11; 514/252.14; 514/275; 514/253.01;
514/318; 514/340; 544/182; 544/112; 544/120; 544/129; 544/124;
544/238; 544/295; 544/405; 544/331; 544/360; 546/193;
546/279.1 |
International
Class: |
A61K 031/5377; A61K
031/53; A61K 031/506; A61K 031/501; A61K 031/497; A61K 031/496;
A61K 031/4545; A61K 031/4439; C07D 43/02; C07D 413/02; C07D
41/02 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 2, 1996 |
GB |
9602166.2 |
Claims
1. An aminoheterocyclic derivative of the formula I 13wherein
G.sup.1 is CH or N; G.sup.2 is CH or N; m is 1 or 2; R.sup.1 is
hydrogen, halogeno, trifluoromethyl, trifluoromethoxy, cyano,
amino, hydroxy, nitro, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino
or di-(1-4C)alkylamino; L.sup.1 is (1-4C)alkylene,
(3-6C)cycloalkane-1,2-diyl or (1-3C)alkylene-carbonyl, T.sup.1 is
CH or N, R.sup.2 is hydrogen or (1-4C)alkyl and R.sup.3 is hydrogen
or (1-4C)alkyl, or R.sup.2 and R.sup.3 together form a
(1-4C)alkylene or methylenecarbonyl group, and wherein 1 or 2
methylene groups within L.sup.1 or the ring formed when R.sup.2 and
R.sup.3 are linked optionally bear 1 or 2 substituents selected
from carboxy, carbanoyl, (1-4C)alkyl, (1-4C)alkoxycarbonyl,
N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkylcarbamoyl,
pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl,
piperazin-1-ylcarbonyl, 4-(1-4C)alkylpiperazin-1-ylcarbonyl,
hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, carboxy-(1-4C)alkyl,
(1-4C)alkoxycarbonyl-(1-4C)alkyl, carbamoyl-(1-4C)alkyl, N-(1
C)alkylcarbamoyl-(1-4C)alkyl,
N,N-di-(1-4C)alkylcarbamoyl-(1-4C)alkyl,
pyrrolidin-1-ylcarbonyl-(1-4C)alkyl, piperidino-(l 14C)alkyl,
morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl and
4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl, and wherein any
heterocyclic group in said substituent optionally bears 1 or 2
(1-4C)alkyl substituents, provided that, when T.sup.1 is N, L.sup.1
is not optionally substituted methylene and R.sup.2 and R.sup.3
together do not form an optionally substituted methylene group;
X.sup.1 is a group of the formula SO, SO.sub.2, C(R.sup.4).sub.2,
CO, C(R.sup.4).sub.2O, C(R.sup.4).sub.2S, C(R.sup.4).sub.2SO,
C(R.sup.4).sub.2SO.sub.2, COC(R.sup.4).sub.2, SOC(R.sup.4).sub.2 or
SO.sub.2C(R.sup.4).sub.2 when T.sup.1 is CH or N, or, in addition,
X.sup.1 is a group of the formula O, S, OC(R.sup.4).sub.2 or
SC(R.sup.4).sub.2 when T.sup.1 is CH, and wherein each R.sup.4 is
independently hydrogen or (1-4C)alkyl; Ar is phenylene, or a 5- or
6-membered monocyclic heteroaryl ring containing up to 3
heteroatoms selected from nitrogen, oxygen and sulphur, and wherein
said phenylene or heteroaryl ring is optionally substituted with 1
or 2 substituents selected from halogeno, trifluoromethyl,
trifluoromethoxy, cyano, nitro, (1-4C)alkyl, (2-4C)alkenyl and
(2-4C)alkynyl, from the substituent Y.sup.1 which is selected from
hydroxy, amino, (1-4C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkynyloxy,
(1-4C)alkylamino, di-(1-4C)alkylamino, pyrrolidin-1-yl, piperidino,
morpholino, thiamorpholino, 1-oxothiamorpholino,
1,1-dioxothiamorpholino, piperazin-1-yl,
4-(1-4C)alkylpiperazin-1-yl, (1-4C)alkylthio, (1-4C)alkylsulphinyl,
(1AC)alkylsulphonyl, (2-4C)alkanoylamino, benzamido,
(1-4C)alkanesulphonamido and benzenesulphonamido, from the
substituent Y.sup.2 which is selected from carboxy, carbamoyl,
(1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl,
N,N-di-(1-4C)alkylcarbamoyl- , pyrrolidin-1-ylcarbonyl,
piperidinocarbonyl, morpholinocarbonyl, thiamorpholinocarbonyl,
1-oxothiamorpholinocarbonyl, 1,1-dioxothiamorpholinocarbonyl,
piperazin-1-ylcarbonyl, 4-(1-4C)alkylpiperazin-1-ylcarbonyl,
(1-4C)alkanesulphonamidocarbonyl, benzenesulphonamidocarbonyl and
benzylsulphonamidocarbonyl, from a substituent of the formula
-L.sup.2-Y.sup.1 wherein L.sup.2 is (1-4C)alkylene and Y.sup.1 has
any of the meanings defined immediately hereinbefore, from a
substituent of the formula -L.sup.2-Y.sup.2 wherein L.sup.2 is
(1-4C)alkylene and Y.sup.2 has any of the meanings defined
immediately hereinbefore, from a substituent of the formula
--X.sup.3-L.sup.2-Y.sup.2 wherein X.sup.3 is a group of the formula
CON(R.sup.5), CON(L.sup.2-Y.sup.2), C(R.sup.5).sub.2O, O,
N(R.sup.5) or N(L.sup.2-Y.sup.2), L.sup.2 is (1-4C)alkylene,
Y.sup.2 has any of the meanings defined immediately hereinbefore
and each R.sup.5 is independently hydrogen or (1-4C)alkyl, and from
a substituent of the formula --X.sup.3-L.sup.3-Y.sup.1 wherein
X.sup.3 is a group of the formula CON(R.sup.5),
CON(L.sup.3-Y.sup.1), C(R.sup.5).sub.2O, O, N(R.sup.5) or
N(L.sup.3-Y.sup.1), L.sup.3 is (2-4C)alkylene, Y.sup.1 has any of
the meanings defined immediately hereinbefore and each R.sup.5 is
independently hydrogen or (1-4C)alkyl, and wherein any heterocyclic
group in said substituent optionally bears 1 or 2 substituents
selected from carboxy, carbamoyl, (1-4C)alkyl,
(1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl and
N,N-di-(1-4C)alkylcarbamoyl, and wherein any phenyl group in said
substituent optionally bears 1 or 2 substituents selected from
halogeno, trifluoromethyl, cyano, (1-4C)alkyl, (2-4C)alkenyl,
(2-4C)alkynyl, (1-4C)alkoxy, (2-4C)alkenyloxy and (2-4C)alkynyloxy;
X.sup.2 is a group of the formula S, SO, SO.sub.2,
C(R.sup.6).sub.2, CO, N(R.sup.7)SO.sub.2, N(R.sup.7)CO,
C(R.sup.6).sub.2S, C(R.sup.6).sub.2SO, C(R.sup.6).sub.2SO.sub.2,
C(R.sup.6).sub.2--C(R.sup.6).sub.2 or C(R.sup.6).sub.2CO, or, in
addition, X.sup.2 is a group of the formula O, SO.sub.2N(R.sup.7),
CON(R.sup.7) or C(R.sup.6).sub.2O when Q is other than
phenyl-(2-4C)alkenyl or phenyl-(2-4C)alkynyl and wherein each
R.sup.6 is independently hydrogen or (1-4C)alkyl and R.sup.7 is
hydrogen, (1-4C)alkyl or a group of the formula --X.sup.4-Q wherein
X.sup.4 is SO.sub.2 or CO and Q has any of the meanings defined
immediately hereinafter; and Q is phenyl, naphthyl,
phenyl-(1-4C)alkyl, phenyl-(2-4C)alkenyl, phenyl-(2-4C)alkynyl or a
heterocyclic moiety containing up to 4 heteroatoms selected from
nitrogen, oxygen and sulphur, and Q optionally bears 1, 2 or 3
substituents selected from halogeno, trifluoromethyl,
trifluoromethoxy, cyano, hydroxy, amino, nitro,
trifluoromethanesulphonyl, carboxy, carbamoyl, (1-4C)alkyl,
(2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (2-4C)alkenyloxy,
(2-4C)alkynyloxy, (1-4C)alkylthio, (1-4C)alkylsulphinyl,
(1-4C)alkylsulphonyl, (1-4C)alkylamino, di-(1-4C)alkylamino,
(1-4C)alkoxycarbonyl, (1-4C)alkylcarbamoyl,
N,N-di-(1-4C)alkylcarbamoyl, (2-4C)alkanoyl, (2-4C)alkanoylamino,
hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, carboxy-(1-4C)alkyl,
(1-4C)alkoxycarbonyl-(1-4C- )alkyl, carbamoyl-(1-4C)alkyl,
N-(1-4C)alkylcarbamoyl-(1-4C)alkyl,
N,N-di-(1-4C)alkylcarbamoyl-(1-4C)alkyl, phenyl, heteroaryl,
phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl, benzyl,
benzoyl, heteroaryloxy, heteroarylthio, heteroarylsulphinyl and
heteroarylsulphonyl, and wherein said heteroaryl substituent or the
heteroaryl group in a heteroaryl-containing substituent comprises a
5- or 6-membered monocyclic heteroaryl ring containing up to 3
heteroatoms selected from nitrogen, oxygen and sulphur, and wherein
said phenyl, heteroaryl, phenoxy, phenylthio, phenylsulphinyl,
phenylsulphonyl, heteroaryloxy, heteroarylthio,
heteroarylsulphinyl, heteroarylsulphonyl, benzyl or benzoyl
substituent optionally bears 1, 2 or 3 substituents selected from
halogeno, trifluoromethyl, cyano, hydroxy, amino, nitro, carboxy,
carbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino,
di-(1-4C)alkylamino, (1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl,
N,N-di-(1-4C)alkylcarbamoyl and (2-4C)alkanoylamino; or a
pharmaceutically-acceptable salt thereof, provided that when
X.sup.1 is CO and Ar is phenylene which optionally bears 1 or 2
substituents selected from halogeno, trifluoromethyl, (1-4C)alkyl
and (1-4C)alkoxy then X.sup.2 is not N(R.sup.7)SO.sub.2,
N(R.sup.7)CO, C(R.sup.6).sub.2S, C(R.sup.6).sub.2SO,
C(R.sup.6).sub.2SO.sub.2, C(R.sup.6).sub.2--C(R.sup.6- ).sub.2,
C(R.sup.6).sub.2CO or C(R.sup.6).sub.2O.
2. A compound according to claim 1 wherein: each of G.sup.1 and
G.sup.2 is CH; or G.sup.1 is CH and G.sup.2 is N, or G.sup.1 is N
and G.sup.2 is CH; m is 1 and R.sup.1 is hydrogen; L.sup.1 is
(1-4C)alkylene, T.sup.1 is CH or N, and R.sup.1 and R.sup.3
together form a (1-4C)alkylene group, and wherein 1 or 2 methylene
groups within L.sup.1 and the ring formed when R.sup.2 and R.sup.3
are linked optionally bears 1 or 2 (1-4C)alkyl substituents,
provided that, when T.sup.1 is N, L.sup.1 is not optionally
substituted methylene and R.sup.2 and R.sup.3 together do not form
an optionally substituted methylene group; when T.sup.1 is CH or N,
X.sup.1 is a group of the formula SO.sub.2, CH.sub.2, CO,
CH.sub.2O, CH.sub.2S, CH.sub.2SO.sub.2, COCH.sub.2 or
SO.sub.2CH.sub.2, or, when T.sup.1 is CH, X.sup.1 is, in addition,
a group of the formula O, S, OCH.sub.2 or SCH.sub.2; Ar is
1,3-phenylene or 1,4-phenylene which is optionally substituted with
1 or 2 substituents selected from halogeno, trifluoromethyl, cyano,
(1-4C)alkyl, hydroxy, amino, (1-4C)alkoxy, (1-4C)alkylamino,
di-(1-4C)alkylamino, (1-4C)alkylthio, (1-4C)alkylsulphinyl,
(1-4C)alkylsulphonyl, (2-4C)alkanoylamino, carboxy, carbamoyl,
(1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl,
N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin-1-ylcarbonyl,
piperidinocarbonyl, morpholinocarbonyl, thiamorpholinocarbonyl,
1-oxothiamorpholinocarbonyl, 1,1-dioxothiamorpholinocarbonyl,
piperazin-1-ylcarbonyl and 4-(1-4C)alkylpiperazin-1-ylcarbonyl; or
Ar is 1,3-phenylene or 1,4-phenylene which is optionally
substituted with a substituent of the formula -L.sup.2-Y.sup.1 or
of the formula, -L.sup.2-Y.sup.2 wherein L.sup.2 is (1-4C)alkylene,
Y.sup.1 is selected from hydroxy, amino, (1-4C)alkoxy,
(1-4C)alkylamino, di-(1-4C)alkylamino, pyrrolidin-1-yl, piperidino,
morpholino, piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl,
(1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl and
(2-4C)alkanoylamino, and Y.sup.2 is selected from carboxy,
carbamoyl, (1-4C)alkoxycarbonyl, L-(1-4C)alkylcarbamoyl,
N,N-di-(1-4C)alkylcarbamoyl- , pyrrolidin-1-ylcarbonyl,
piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl and
4-(1-4C)alkylpiperazin-1-ylcarbonyl; or Ar is 1,3-phenylene or
1,4-phenylene which is optionally substituted with a substituent of
the formula --X.sup.3-L.sup.2-Y.sup.2 wherein X.sup.3 is a group of
the formula CONH, CON(Me), CH.sub.2O or O, L.sup.2 is methylene,
ethylene or trimethylene and Y.sup.2 is selected from carboxy,
carbamoyl, (1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl,
N,N-di-(1-4C)alkylcarbamoyl- , pyrrolidin-1-ylcarbonyl,
piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl and
4-(1-4C)alkylpiperazin-1-yl; or Ar is 1,3-phenylene or
1,4-phenylene which is optionally substituted with a substituent of
the formula --X.sup.3-L.sup.3-Y.sup.1 wherein X.sup.3 is a group of
the formula CONH, CH.sub.2O, O or NH, L.sup.3 is ethylene or
trimethylene and Y.sup.1 is hydroxy, amino, (1-4C)alkoxy,
(1-4C)alkylamino, di-(1-4C)alkylamino, pyrrolidin-1-yl, piperidino,
morpholino, piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl,
(1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl and
(2-4C)alkanoylamino; X.sup.2 is a group of the formula SO.sub.2,
CH.sub.2, CO, NHSO.sub.2, N(R.sup.7)SO.sub.2, NHCO, N(R.sup.7)CO,
CH.sub.2SO.sub.2, CH.sub.2CH.sub.2 or CH.sub.2CO wherein R.sup.7 is
(1-4C)alkyl or a group of the formula --X.sub.4-Q wherein X.sup.4
is SO.sub.2 and Q has any of the meanings defined hereinafter in
this section of particular compounds of the invention; or X.sup.2
is a group of the formula S; Q is phenyl, naphthyl or
phenyl-(1-4C)alkyl which optionally bears 1, 2 or 3 substituents
selected from hydroxy, halogeno, cyano, trifluoromethyl,
(1-4C)alkyl, (1-4C)alkoxy, phenyl, phenoxy, phenylthio,
phenylsulphinyl, phenylsulphonyl, benzyl and benzoyl, and wherein
the phenyl substituent or the phenyl group in a phenyl-containing
substituent optionally bears 1 or 2 substituents selected from
halogeno, (1A-4C)alkyl and (1-4C)alkoxy; or Q is
phenyl-(2-4C)alkenyl or phenyl-(2-4C)alkynyl which optionally bears
1, 2 or 3 substituents selected from halogeno, cyano,
trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy; or Q is phenyl or
phenyl-(1-4C)alkyl which bears 1 substituent selected from
heteroaryl, heteroaryloxy, heteroarylthio, heteroarylsulphinyl and
heteroarylsulphonyl, wherein the heteroaryl substituent or the
heteroaryl group in a heteroaryl-containing substituent comprises a
5- or 6-membered monocyclic heteroaryl ring containing up to 3
heteroatoms selected from nitrogen, oxygen and sulphur, and wherein
said heteroaryl or heteroaryl-containing substituent optionally
bears 1 or 2 substituents selected from halogeno, (1-4C)alkyl and
(1-4C)alkoxy; or Q is a heterocyclic moiety containing up to 2
heteroatoms selected from benzofuranyl, quinolyl,
tetrahydroquinolyl, isoquinolyl, quinoxalinyl, quinazolinyl,
cinnolinyl, indolyl, benzimidazolyl, indazolyl, benzoxazolyl,
benzothiazolyl, dibenzofuranyl and dibenzothienyl, and Q optionally
bears 1 or 2 substituents selected from halogeno, cyano,
trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy; or Q is a
heterocyclic moiety containing up to 4 heteroatoms selected from
furyl, thienyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl,
imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl,
thiadiazolyl and tetrazolyl, and Q optionally bears 1 or 2
substituents selected from halogeno, cyano, carboxy, carbamoyl,
(1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy,
N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl; or Q is a
heterocyclic moiety containing up to 2 heteroatoms selected from
thienyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, oxazolyl and
thiazolyl, and Q optionally bears 1 or 2 substituents selected from
phenyl, heteroaryl, phenoxy, phenylthio, phenylsulphinyl,
phenylsulphonyl, heteroaryloxy, heteroarylthio,
heteroarylsulphinyl, heteroarylsulphonyl, benzyl and benzoyl,
wherein the heteroaryl substituent or the heteroaryl group in a
heteroaryl-containing substituent is selected from thienyl,
pyridyl, pyrimidinyl, pyrazolyl, oxazolyl and thiazolyl, and
wherein said phenyl, phenyl-containing, heteroaryl or
heteroaryl-containing substituent optionally bears 1 or 2
substituents selected from halogeno, (I 4C)alkyl and (1-4C)alkoxy;
or a pharmaceutically-acceptable salt thereof; provided that when
X.sup.1 is CO and Ar is phenylene which optionally bears 1 or 2
substituents selected from halogeno, trifluoromethyl, (1-4C)alkyl
and (1-4C)alkoxy then X.sup.2 is not N(R.sup.7)SO.sub.2,
N(R.sup.7)CO, C(R.sup.6).sub.2S, C(R.sup.6).sub.2SO,
C(R.sup.6).sub.2SO.sub.2, C(R.sup.6).sub.2--C(R.sup.6).sub.2,
C(R.sup.6).sub.2CO or C(R.sup.6).sub.2O.
3. A compound according to claim 1 or 2 wherein each of G.sup.1 and
G.sup.2 is CH, G.sup.1 is CH and G.sup.2 is N, or G.sup.1 is N and
G.sup.2 is CH; m is 1 and R.sup.1 is hydrogen; L.sup.1 is ethylene,
T.sup.1 is CH or N, and R.sup.2 and R.sup.3 are independently
hydrogen or together form an ethylene group; when T.sup.1 is CH or
N. X.sup.1 is a group of the formula CH.sub.2, CO, CH.sub.2O or
SO.sub.2, or, when T, is CH, X.sup.1 is, in addition, a group of
the formula O; Ar is 1,2-phenylene, 1,3-phenylene or 1,4-phenylene
which is optionally substituted with 1 or 2 substituents selected
from fluoro, chloro, bromo, trifluoromethyl, cyano, methyl,
hydroxy, amino, methoxy, methylamino, dimethylamino, methylthio,
methylsulphinyl, methylsulphonyl, acetamido, carboxy, carbamoyl,
methoxycarbonyl, ethoxycarbonyl, N-methylcarbamoyl,
N,N-dimethylcarbamoyl, 2-(ethylthio)ethylaminocarbonyl,
pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl,
piperazin-1-ylcarbonyl and 4-methylpiperazin-1-ylcarbonyl; X.sup.2
is a group of the formula S, SO.sub.2, CONH, NHSO.sub.2 or
N(R.sup.7)SO.sub.2 wherein R.sup.7 is methyl or a group of the
formula --SO.sub.2Q wherein Q has any of the meanings defined
immediately hereinafter; and Q is phenyl, styryl,
1,4-tetrahydroisoquinolinyl, 4-biphenylyl or 2-naphthyl which
optionally bears 1 or 2 substituents selected from fluoro, chloro,
bromo, trifluoromethyl, 4-chlorophenoxy, methyl and methoxy; or a
pharmaceutically-acceptable salt thereof; provided that when
X.sup.1 is CO and Ar is 1,2-, 1,3- or 1,4-phenylene which
optionally bears 1 or 2 substituents selected from fluoro, chloro,
bromo, trifluoromethyl, methyl and methoxy then X.sup.2 is not
NHSO.sub.2 or N(R.sup.7)SO.sub.2 wherein R.sup.7 is methyl or a
group of the formula --SO.sub.2-Q wherein Q has any of the meanings
defined immediately hereinbefore.
4. A compound according to any one of claims 1 to 3 wherein each of
G.sup.1 and G.sup.2 is CH, G.sup.1 is CH and G.sup.2 is N, or
G.sup.1 is N and G.sup.2 is CH; m is 1 and R.sup.1 is hydrogen;
L.sup.1 is ethylene, T.sup.1 is CH or N, and R.sup.2 and R.sup.3
together form an ethylene group; when T.sup.1 is CH or N, X.sup.1
is a group of the formula CH.sub.2, CO or CH.sub.2O, or, when
T.sup.1 is CH, X.sup.1 is, in addition, a group of the formula O;
Ar is 1,3-phenylene or 1,4-phenylene which is optionally
substituted with 1 or 2 substituents selected from fluoro, chloro,
bromo, trifluoromethyl, cyano, methyl, hydroxy, amino, methoxy,
methylamino, dimethylamino, methylthio, methylsulphinyl,
methylsulphonyl, acetamido, carboxy, carbamoyl, methoxycarbonyl,
ethoxycarbonyl, N-methylcarbamoyl, N,-dimethylcarbamoyl,
pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl,
piperazin-1-ylcarbonyl and 4-methylpiperazin-1-ylcarbonyl; X.sup.2
is a group of the formula SO.sub.2, NHSO.sub.2 or
N(R.sup.7)SO.sub.2 wherein R.sup.7 is methyl or a group of the
formula --SO.sub.2Q wherein Q has any of the meanings defined
immediately hereinafter; and Q is phenyl, styryl, 4-biphenylyl or
2-naphthyl which optionally bears 1 or 2 substituents selected from
fluoro, chloro, bromo, trifluoromethyl, methyl and methoxy; or a
pharmaceutically-acceptable salt thereof; provided that when
X.sup.1 is CO and Ar is 1,3- or 1,4-phenylene which optionally
bears 1 or 2 substituents selected from fluoro, chloro, bromo,
trifluoromethyl, methyl and methoxy then X.sup.2 is not NHSO.sub.2
or N(R.sup.7)SO.sub.2 wherein R.sup.7 is methyl or a group of the
formula --SO.sub.2-Q wherein Q has any of the meanings defined
immediately hereinbefore.
5. A compound according to any one of claims 1 to 4 wherein each of
G.sup.1 and G.sup.2 is CH, G.sup.1 is CH; and G.sup.2 is N, or
G.sup.1 is N and G.sup.2 is CH; m is 1 and R.sup.1 is hydrogen;
L.sup.1 is ethylene, T.sup.1 is N, and R.sup.2 and R.sup.3 together
form an ethylene group; X.sup.1 is a group of the formula CO; Ar is
1,4-phenylene, 2-carboxy-1,4-phenylene or
2-piperidinocarbonyl-1,4-phenylene (with the X.sup.1 group in the
1-position and the X.sup.2 group in the 4-position); X.sup.2 is a
group of the formula SO.sub.2; and Q is 2-naphthyl, styryl or
4-biphenylyl which optionally bears 1 or 2 substituents selected
from fluoro, chloro and bromo; or a pharmaceutically-acceptable
salt thereof.
6. A compound according to any one of claims 1 to 5. wherein each
of G.sup.1 and G.sup.2 is CH; m is 1 and R.sup.1 is hydrogen;
L.sup.1 is ethylene. T.sup.1 is N, and R.sup.2 and R.sup.3 together
form an ethylene group; X.sup.1 is a group of the formula CO; Ar is
1,4-phenylene, 2-carboxy-1,4-phenylene or
2-piperidinocarbonyl-1,4-phenylene (with the X.sup.1 group in the
1-position and the X.sup.2 group in the 4-position); X.sup.2 is a
group of the formula SO.sub.2; and Q is 2-naphthyl, styryl or
4-biphenylyl which optionally bears 1 or 2 substituents selected
from fluoro, chloro and bromo; or a pharmaceutically-acceptable
salt thereof.
7. A compound according to any one of claims, 1 to 6 which is:
1-[4-(6-chloronaphth-2-ylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine,
1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine,
1-[4-(2-naphthylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine,
1-{4-[(E)-4-chlorostyrylsulphonyl]benzoyl}-4-(4-pyridyl)piperazine,
1-[4-(4'-bromo-4-biphenylylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine,
1-[4-(4'-chloro-4-biphenylylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine,
1-[4-(4-biphenylylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine,
5-(6-chloronaphth-2-ylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]b-
enzoic acid,
5-(2-naphthylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbony-
l]benzoic acid,
5-(4'-bromo-4-biphenylylsulphonyl)-2-[4-(4-pyridyl)piperaz-
in-1-ylcarbonyl]benzoic acid,
5-[(E)-4-chlorostyrylsulphonyl]-2-[4-(4-pyri-
dyl)piperazin-1-ylcarbonyl]benzoic acid,
1-{5-(6-bromonaphth-2-ylsulphonyl-
)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoyl}-piperidine,
1-{5-(6-chloronaphth-2-ylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbony-
l]benzoyl}-piperidine,
1-{5-(4'-bromo-4-biphenylylsulphonyl)-2-[4-(4-pyrid-
yl)piperazin-1-ylcarbonyl]benzoyl}-piperidine,
1-{5-[(E)-4-chlorostyrylsul-
phonyl]-2-[4-(4-pyridyl)piperazin-ylcarbonyl]benzoyl}piperidine,
4'-bromo-N-{4-[1-(4-pyridyl)piperidin;-4-yloxy]phenyl}4-biphenylylsulphon-
amide,
4-chloro-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-(E)-styrylsul-
phonamide,
6-bromo-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-2-naphthal-
enesulphonamide,
N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-4-toluenesul-
phonamide,
N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-N-(4-tolylsulphony-
l)-4-toluenesulphonamide,
4-chloro-N-methyl-N-{4-[1-(4-pyridyl)piperidin-4-
-yloxy]phenyl}-(E)-styrylsulphonamide,
4'-bromo-N-methyl-N-{4-[1-(4-pyridy-
l)piperidin-4-yloxy]phenyl}-4-biphenylylsulphonamide,
4'-bromo-N-(4-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl)}4-biphenylylsul-
phonamide,
6-bromo-N-{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]-phenyl}-2-nap-
hthalenesulphonamide,
4-chloro-N-{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]ph-
enyl}-(E)-styrylsulphonamide,
4'-bromo-N-(4'-bromo-4-biphenylylsulphonyl)--
N-{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl}4-biphenylylsulphonamide,
6-bromo-N-(6-bromonaphth-2-ylsulphonyl)-N-{4-[1-(4-pyridyl)piperidin-4-yl-
methoxy]phenyl}-2-naphthalenesulphonamide,
6-bromo-N-{3-[1-(4-pyridyl)pipe-
ridin-4-yloxy]phenyl}-2-naphthalenesulphonamide,
4-[4-chlorophenylsulphony- l)phenoxy]-1-(4-(pyridyl)piperidine,
5-(6-bromonaphth-2-ylsulphonyl)-2-[4--
(4-pyridyl)piperazin-1-ylcarbonyl]benzoic acid,
4-(6-bromonaphth-2-ylsulph-
onyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoic acid,
1-[4-(4-(4-chlorophenoxy)phenylaminocarbonyl)benzyl]-4-(4-pyridyl)piperaz-
ine,
6-bromo-N-{2-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl}-2-naphthalen-
esulphonamide,
4-chloro-N-{3-[1-(4-pyridyl)piperidin-4yloxy]phenyl}-(E)-st-
yrylsulphonamide,
4-[4-(6-bromonaphth-2-ylsulphonyl)phenoxy]-1-(4-pyridyl)-
piperidine,
4-[4-(6-bromonaphth-2-ylsulphonyl)bcnzoyl]-1-(4-pyridyl)piperi-
dine,
4-[4-(6-bromonaphth-2-ylthio)benzoyl]-1-(4-pyridyl)piperidine,
1-[4-(6-bromonaphth-2-ylsulphonyl)phenylsulphonyl]-1-(4-pyridyl)piperazin-
e,
6-(bromo-2-(4-(2-pyrimidin-4-yl)aminoethylaminocarbonyl)phenylsulphonyl-
)naphthalene,
1-[4-(6-bromonaphth-2-ylthio)benzoyl]-4-(4-pyridyl)piperazin- e,
1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine,
1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(4-pyrimidinyl)-piperazine,
1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(4-pyridazinyl)piperazine,
1-[4-(6-bromonaphth-2-ylsulphonyl-2-trifluoromethylbenzoyl]-4-(4-pyridyl)-
piperazine,
1-[4-(6-bromonaphth-2-ylthio)-2-trifluoromethylbenzoyl]-4-(4-p-
yridyl)piperazine,
1-[4-(6-bromonaphth-2-ylthio)-2-carboxybenzoyl]-4-(4-py-
ridyl)piperazine
1-[5-(6-bromonaphth-2-ylthio)-2-carboxybenzoyl]-4-(4-pyri-
dyl)piperazine,
1-[5-(6-bromonaphth-2-ylsulphonyl)-2-methoxycarbonylbenzoy-
l]-4-(4-pyridyl)piperazine,
1-[4-(6-bromonaphth-2-ylsulphonyl)-2-methoxyca-
rbonylbenzoyl]44-pyridyl)piperazine,
1-[4-(6-bromonaphth-2-ylsulphonyl)-2--
(2-(ethylthio)-ethylaminocarbonyl)benzoyl]4 (4-pyridyl)piperazine,
1-[5-(6-bromonaphth-2-yisulphonyl)-2-(2-ethylthio)ethylaminocarbonyl)benz-
oyl]-4-(4-pyridyl)piperazine,
1-[4-(6-bromonaphth-2-ylsulphonyl)-2-(piperi-
din-1-ylcarbonyl]-4-(4-pyridyl)piperazine,
1-[5-(6-bromonaphth-2-ylsulphon-
yl)-2-(piperidin-1-ylcarbonyl]-4-(4-pyridyl)piperazine,
1-[4-(4-(3-chlorophenyl)piperazin-1-ylsulphonyl)benzoyl]-4-(4-pyridyl)pip-
erazine,
1-[4-(6-chloro-1,2,3,4-tetrahydroisoquinolin-2-ylsulphonylbenzoyl-
]-4-(4-pyridyl)piperazine,
1-(4-pyridyl)-(5-(6-methoxyindol-2-ylcarbonylam-
ino)pyrid-2-yloxy)pyrrolidine,
1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]--
4-(2-methylpyrid-4-yl)piperazine,
1-[4-(6-bromonaphth-2-ylsulphonyl)benzoy-
l]-4-(4-pyridyl)hexahydro- 1,4-diazepine, or a
pharmaceutically-acceptable salt thereof.
8. A process for the preparation of an aminoheterocyclic derivative
of the formula I or a pharmaceutically acceptable salt thereof as
claimed as claim 1 which comprises: a) for the production of those
compounds of the formula I wherein T.sup.1 is N and X.sup.1 is CO,
the reaction, conveniently in the presence of a suitable base, of
an amine of the formula II 14 with an acid of the formula III
HO.sub.2C--Ar--X.sup.2-Q III or a reactive derivative thereof; (aa)
for the preparation of those compounds of the formula I wherein
T.sup.1 is N and X.sup.1 is a group of the formula
COC(R.sup.4).sub.2, the reaction, conveniently in the presence of a
suitable base, of an amine of the formula II with an acid of the
formula: HO.sub.2C--C(R.sup.4).sub.2--Ar--X.sup.2-Q or a reactive
derivative thereof; (b) for the production of those compounds of
the formula I wherein T.sup.1 is CH and X.sup.1 is O or
C(R.sup.4).sub.2O, the reaction, conveniently in the presence of a
suitable coupling agent, of a compound of the formula IV 15 wherein
n is 0 or 1 and Z is a displaceable group, with a phenolic compound
of the formula V HO--Ar--X.sup.2-Q V (bb) for the preparation of
those compounds of the formula I wherein T.sup.1 is CH and X.sup.1
is a group of the formula S or C(R.sup.4).sub.2S, the reaction,
conveniently in the presence of a suitable coupling agent, of a
compound of the formula IV with a compound of the formula:
HS--Ar--X.sub.2-Q; (c) for the production of those compounds of the
formula I wherein T.sup.1 is N and X.sup.1 is CH(R.sup.4), the
reductive amination of a keto compound of the formula VI
R.sup.4--CO--Ar--X.sup.2-Q VI with an amine of the formula VII
16(d) for the production of those compounds of the formula I
wherein X.sup.2 is a group of the formula N(R.sup.7)SO.sub.2, the
reaction, conveniently in the presence of a suitable base, of an
amine of the formula VIII 17 with a compound of the formula IX
Z-SO.sub.2-Q IX wherein Z is a displaceable group; (dd) for the
production of those compounds of the formula I wherein X.sup.2 is a
group of the formula N(R.sup.7)CO, the reaction, conveniently in
the presence of a suitable base, of an amine of the formula VIII
with a compound of the formula: Z-CO-Q; (e) for the production of
those compounds of the formula I wherein X.sup.2 is a group of the
formula N(R)SO.sub.2, the reaction, conveniently in the presence of
a suitable base, of a sulphonamide of the formula X 18 with a
compound of the formula XI R.sup.5-Z XI wherein Z is a displaceable
group; (ee) for the production of those compounds of the formula I
wherein X.sup.2 is a group of the formula N(R.sup.7)CO, the
reaction conveniently in the presence of a suitable base, of a
compound of the formula I wherein N(R.sup.7)CO is NHCO with a
compound of the formula XI; (f) for the production of those
compounds of the formula I wherein X.sup.2 is a group of the
formula SO.sub.2N(R.sup.7) the reaction, conveniently in the
presence of a suitable base of a compound of the formula XII 19
wherein Z is a displaceable group as defined hereinbefore, with an
amine of the formula XIII (R.sup.7)NH-Q XIII (ff) for the
preparation of those compounds of the formula I wherein X.sup.2 is
a group of the formula CON(R.sup.7), the reaction, conveniently in
the presence of a suitable base, of a compound of the formula XIII
with a carbonyl compound corresponding to the sulphonyl compound of
the formula XII; (g) for the production of those compounds of the
formula I wherein T.sup.1 is CH and X.sup.1 is a group of the
formula OC(R.sup.4).sub.2, the reaction conveniently in the
presence of a suitable coupling agent of an alcohol of the formula
XIV 20 with a compound of the formula XV
Z-C(R.sup.4).sub.2--Ar--X.sup.2-Q XV wherein Z is a displaceable
group; (gg) for the preparation of those compounds of the formula I
wherein T.sup.1 is CH and X.sup.1 is a group of the formula
SC(R.sup.4).sub.2 the reaction conveniently in the presence of a
suitable coupling agent of the thiol equivalent of formula XIV with
a compound of the formula XV; (h) for the production of those
compounds of the formula I wherein X.sup.2 is a group of the
formula C(R.sup.6).sub.2S, the reaction, conveniently in the
presence of a suitable base, of a compound of the formula XVI 21
wherein Z is a displaceable group with a thiol of the formula XVII
HS-Q XVII (i) for the production of those compounds of the formula
I wherein L.sup.1, R.sup.2, R.sup.3, Ar or Q bears a carboxy or
carboxy-containing group, the hydrolysis of a compound of the
formula I wherein L.sup.1, R.sup.2, R.sup.3, Ar or Q bears a
(1-4C)alkoxycarbonyl group; (j) for the production of those
compounds of the formula I wherein L.sup.1, R.sup.2, R.sup.3, Ar or
Q bears a carbamoyl, N-alkylcarbamoyl or N,N-dialkylcarbamoyl
group, the reaction of a compound of the formula I wherein L.sup.1,
R.sup.2, R.sup.3, Ar or Q bears a carboxy group, or a reactive
derivative thereof as defined hereinbefore, with ammonia or an
appropriate alkylamine or dialkylamine; (k) for the production of
those compounds of the formula I wherein X.sup.1 is a group of the
formula SO, SO.sub.2, C(R.sup.4).sub.2SO, C(R.sup.4).sub.2SO.sub.2,
SOC(R.sup.4).sub.2 or SO.sub.2C(R.sup.4).sub.2, wherein Ar bears a
(1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, 1-oxothiamorpholino or
1,1-dioxothiamorpholino group or a substituent which contains a
(1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, 1-oxothiamorpholino or
1,1-dioxothiamorpholino group, wherein X.sup.2 is a group of the
formula SO, SO.sub.2, C(R.sup.6).sub.2SO or
C(R.sup.6).sub.2SO.sub.2, or wherein Q bears a
(1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, phenylsulphinyl,
phenylsulphonyl, heteroarylsulphinyl or heteroarylsulphonyl group,
the oxidation of the corresponding compound of the formula I which
contains a thio group. (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl,
1-oxothiamorpholino or 1,1-dioxothiamorpholino group, wherein
X.sup.2 is a group of the formula SO, SO.sub.2 C(R.sup.6).sub.2SO
or C(R.sup.6).sub.2SO.sub.2, or wherein Q bears a
(1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, phenylsulphinyl,
phenylsulphonyl, heteroarylsulphinyl or heteroarylsulphonyl group,
the oxidation of the corresponding compound of the formula I which
contains a thio group; (l) The reaction of an activated derivative
of a compound of the formula XVIII: 22 wherein L is a displaceable
group as hereinbefore with a compound of the formula XIX:
NH(R.sup.2)-L.sup.1-T.sup.1(R.sup.3)--X.sup.- 1--Ar-Q XIX and, if
necessary, forming a pharmaceutically associated salt.
9. A pharmaceutical composition which comprises an
aminoheterocyclic derivative of the formula I or a pharmaceutically
acceptable salt thereof as claimed in any one of claims 1 to 7 and
a pharmaceutically acceptable carrier.
10. The use of an aminoheterocyclic derivative of the formula I or
a pharmaceutically acceptable salt thereof as claimed in any one of
claims 1 to 7 in the production of a medicament for producing an
antithrombiotic or anticoagulant effect.
11. The use of an aminoheterocyclic derivative of the formula I or
a pharmaceutically acceptable salt thereof as claimed in any one of
claims 1 to 7 in the production of a medicament for treating
coronary artery or cerebro-vascular disease.
Description
[0001] The invention relates to aminoheterocyclic derivatives and
pharmaceutically-acceptable salts thereof, which possess
antithrombotic and anticoagulant properties and are accordingly
useful in methods of treatment of the human or animal body. The
invention also relates to processes for the preparation of said
aminoheterocyclic derivatives, to pharmaceutical compositions
containing them and to their use in the manufacture of medicaments
for use in the production of an antithrombotic or anticoagulant
effect.
[0002] The antithrombotic and anticoagulant effect produced by the
compounds of the invention is believed to be attributable to their
strong inhibitory effect against the activated coagulation protease
known as Factor Xa. Factor Xa is one of a cascade of proteases
involved in the complex process of blood coagulation. The protease
known as thrombin is the final protease in the cascade and Factor
Xa is the preceding protease which cleaves prothrombin to generate
thrombin.
[0003] Certain compounds are known to possess Factor Xa inhibitory
properties and the field has been reviewed by R. B. Wallis, Current
Opinion in Therapeutic Patents, 1993, 1173-1179. Thus it is known
that two proteins, one known as antistasin and the other known as
tick anticoagulant protein (TAP), are specific Factor Xa inhibitors
which possess antithrombotic properties in various animal models of
thrombotic disease.
[0004] It is also known that certain non-peptidic compounds possess
Factor Xa inhibitory properties. Of the low molecular weight
inhibitors mentioned in the review by R. B. Wallis, all possessed a
strongly basic group such as an amidinophenyl or amidinonaphthyl
group.
[0005] It is the object of the present invention to provide a new
class of agent which lacks the amidino group previously believed to
be an essential feature for a Factor Xa inhibitor.
[0006] We have now found that certain amino-substituted
heterocyclic derivatives possess Factor Xa inhibitory activity and
in particular also possess the advantage of being selective Factor
Xa inhibitors, that is the enzyme Factor Xa is inhibited strongly
at concentrations of test compound which do not inhibit or which
inhibit to a lesser extent the enzyme thrombin which is also a
member of the blood coagulation enzymatic cascade.
[0007] The compounds of the present invention possess activity in
the treatment or prevention of a variety of medical disorders where
anticoagulant therapy is indicated, for example in the treatment or
prevention of thrombotic events associated with coronary artery and
cerebro-vascular disease. Further examples of such medical
disorders include various cardiovascular and cerebrovascular
conditions such as myocardial infarction, the formation of
atherosclerotic plaques, venous or arterial thrombosis, coagulation
syndromes, disseminated intravascular coagulation, vascular injury
including reocclusion and restenosis following angioplasty and
coronary artery bypass surgery, thrombus formation after the
application of blood vessel operative techniques or after general
surgery such as hip replacement surgery, the introduction of
artificial heart valves or on the recirculation of blood, cerebral
infarction, cerebral thrombosis, stroke, cerebral embolism,
pulmonary embolism, ischaemia and angina (including unstable
angina).
[0008] The compounds of the invention are also useful as inhibitors
of blood coagulation in an ex-vivo situation such as, for example,
the storage of whole blood or other biological samples suspected to
contain Factor Xa and in which coagulation is detrimental.
[0009] According to one aspect of the invention there is provided
an aminoheterocyclic derivative of the formula I 2
[0010] wherein G.sup.1 is CH or N;
[0011] G.sup.2 is CH or N;
[0012] m is 1 or 2;
[0013] R.sup.1 is hydrogen, halogeno, trifluoromethyl,
trifluoromethoxy, cyano, amino, hydroxy, nitro, (1-4C)alkyl,
(1-4C)alkoxy, (1-4C)alkylamino or di-(1-4C)alkylamino;
[0014] L.sup.1 is (1-4C)alkylene, (3-6C)cycloalkane-1,2-diyl or
(1-3C)alkylene-carbonyl,
[0015] T.sup.1 is CH or N,
[0016] R.sup.1 is hydrogen or (1-4C)alkyl and R.sup.3 is hydrogen
or (1-4C)alkyl, or R.sup.2 and R.sup.3 together form a
(1-4C)alkylene or methylenecarbonyl group,
[0017] and wherein 1 or 2 methylene groups within L.sup.1 or the
ring formed when R.sup.2 and R.sup.3 are linked optionally bear 1
or 2 substituents selected from carboxy, carbamoyl, (1-4C)alkyl,
(1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl,
N,N-di-(1-4C)alkylcarbamoyl- , pyrrolidin-1-ylcarbonyl,
piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl,
4-(1-4C)alkylpiperazin-1-ylcarbonyl, hydroxy-(1-4C)alkyl,
(1-4C)alkoxy-(11C)alkyl, carboxy-(1-4C)alkyl, (1
C)alkoxycarbonyl-(1-4C)alkyl, carbamoyl-(1-4C)alkyl,
N-(1-4C)alkylcarbamoyl-(1-4C)alkyl,
N,N-di-(1-4C)alkylcarbamoyl-(1-4C)alk- yl,
pyrrolidin-1-ylcarbonyl-(1-4C)alkyl, piperidino-(1-4C)alkyl,
morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl and
4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl,
[0018] and wherein any heterocyclic group in said substituent
optionally bears 1 or 2 (1-4C)alkyl substituents, provided that,
when T.sup.1 is N, L.sup.1 is not optionally substituted methylene
and R.sup.2 and R.sup.3 together do not form an optionally
substituted methylene group;
[0019] X.sup.1 is a group of the formula SO, SO.sub.2,
C(R.sup.4).sub.2, CO, C(R.sup.4).sub.2O, C(R.sup.4).sub.2S,
C(R.sup.4).sub.2SO, C(R.sup.4).sub.2SO.sub.2, COC(R.sup.4).sub.2,
SOC(R.sup.4).sub.2 or SO.sub.2C(R.sup.4).sub.2 when T.sup.1 is CH
or N, or, in addition, X.sup.1 is a group of the formula O, S,
OC(R.sup.4).sub.2 or SC(R.sup.4).sub.2 when T.sup.1 is CH, and
wherein each R.sup.4 is independently hydrogen or (1-4C)alkyl;
[0020] Ar is phenylene, or a 5- or 6-membered monocyclic heteroaryl
ring containing up to 3 heteroatoms selected from nitrogen, oxygen
and sulphur,
[0021] and wherein said phenylene or heteroaryl ring is optionally
substituted with 1 or 2 substituents selected from halogeno,
trifluoromethyl, trifluoromethoxy, cyano, nitro, (1-4C)alkyl,
(2-4C)alkenyl and (2-4C)alkynyl,
[0022] from the substituent Y.sup.1 which is selected from hydroxy,
amino, (1-4C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkynyloxy,
(1-4C)alkylamino, di-(1-4C)alkylamino, pyrrolidin-1-yl, piperidino,
morpholino, thiamorpholino, 1-oxothiamorpholino,
1,1-dioxothiamorpholino, piperazin-1-yl,
4-(1-4C)alkylpiperazin-1-yl, (1-4C)alkylthio, (1-4C)alkylsulphinyl,
(1-4C)alkylsulphonyl, (24C)alkanoylamino, benzamido,
(1-4C)alkanesulphonamido and benzenesulphonamido, from the
substituent Y.sup.2which is selected from carboxy, carbamoyl,
(1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl,
N,N-di-(1-4C)alkylcarbamoyl- , pyrrolidin-1-ylcarbonyl,
piperidinocarbonyl, morpholinocarbonyl, thiamorpholinocarbonyl,
1-oxothiamorpholinocarbonyl, 1,1-dioxothiamorpholinocarbonyl,
piperazin-1-ylcarbonyl, 4-(1-4C)alkylpiperazin-1-ylcarbonyl,
(1-4C)alkanesulphonamidocarbonyl, benzenesulphonamidocarbonyl and
benzylsulphonamidocarbonyl,
[0023] from a substituent of the formula -L.sup.2-Y.sup.1 wherein
L.sup.2 is (1-4C)alkylene and Y.sup.1 has any of the meanings
defined immediately hereinbefore, from a substituent of the formula
-L.sup.2-Y.sup.2 wherein L.sup.2 is (1-4C)alkylene and Y.sup.2 has
any of the meanings defined immediately hereinbefore, from a
substituent of the formula --X.sup.3-L.sup.2-Y.sup.2 wherein
X.sup.3 is a group of the formula CON(R.sup.5),
CON(L.sup.2-Y.sup.2), C(R.sup.5).sub.2O, O, N(R.sup.5) or
N(L.sup.2-Y.sup.2), L.sup.2 is (1-4C)alkylene, Y.sup.2 has any of
the meanings defined immediately hereinbefore and each R.sup.5 is
independently hydrogen or (1-4C)alkyl, and
[0024] from a substituent of the formula --X.sup.3-L.sup.3-Y.sup.1
wherein X.sup.3 is a group of the formula CON(R.sup.5),
CON(L.sup.3-Y.sup.1), C(R.sup.5).sub.2O, O, N(R.sup.5) or
N(L.sup.3-Y.sup.1), L.sup.3 is (2-4C)alkylene, Y.sup.1 has any of
the meanings defined immediately hereinbefore and each R.sup.5 is
independently hydrogen or (1-4C)alkyl, and wherein any heterocyclic
group in said substituent optionally bears 1 or 2 substituents
selected from carboxy, carbamoyl, (1-4C)alkyl,
(1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl and
N,N-di-(1-4C)alkylcarbam- oyl, and wherein any phenyl group in said
substituent optionally bears 1 or 2 substituents selected from
halogeno, trifluoromethyl, cyano, (1-4C)alkyl, (2-4C)alkenyl,
(2-4C)alkynyl, (1-4C)alkoxy, (2-4C)alkenyloxy and
(2-4C)alkynyloxy;
[0025] X.sup.2 is a group of the formula S, SO, SO.sub.2,
C(R.sup.6).sub.2, CO, N(R.sup.7)SO.sub.2, N(R.sup.7)CO,
C(R.sup.6).sub.2S, C(R.sup.6).sub.2SO, C(R.sup.6).sub.2SO2,
C(R.sup.6).sub.2--C(R.sup.6).sub.2 or C(R.sup.6).sub.2CO, or, in
addition, X.sup.2 is a group of the formula O, SO.sub.2N(R.sup.7),
CON(R.sup.7) or C(R.sup.7).sub.2O when Q is other than
phenyl-(2-4C)alkenyl or phenyl-(24C)alkynyl and wherein each
R.sup.6 is independently hydrogen or (1-4C)alkyl and R.sup.7 is
hydrogen, (1-4C)alkyl or a group of the formula --X.sup.4-Q wherein
X.sup.4 is SO.sub.2 or CO and Q has any of the meanings defined
immediately hereinafter; and
[0026] Q is phenyl, naphthyl, phenyl-(1-4C)alkyl,
phenyl-(2-4C)alkenyl, phenyl-(2-4C)alkynyl or a heterocyclic moiety
containing up to 4 heteroatoms selected from nitrogen, oxygen and
sulphur, and Q optionally bears 1, 2 or 3 substituents selected
from halogeno, trifluoromethyl, trifluoromethoxy, cyano, hydroxy,
amino, nitro, trifluoromethanesulphonyl- , carboxy, carbamoyl,
(1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy,
(2-4C)alkenyloxy, (2-4C)alkynyloxy, (1-4C)alkylthio,
(1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, (1-4C)alkylamino,
di-(1-4C)alkylamino, (1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl,
N,N-di-(1-4C)alkylcarbamoyl, (2-4C)alkanoyl, (2-4C)alkanoylamino,
hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, carboxy-(1-4C)alkyl,
(1-4C)alkoxycarbonyl-(1-4C)alkyl, carbamoyl-(1-4C)alkyl,
N-(1-4C)alkylcarbamoyl-(1-4C)alkyl,
N,N-di-(1-4C)alkylcarbamoyl-(1-4C)alk- yl, phenyl, heteroaryl,
phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl, benzyl,
benzoyl, heteroaryloxy, heteroarylthio, heteroarylsulphinyl and
heteroarylsulphonyl,
[0027] and wherein said heteroaryl substituent or the heteroaryl
group in a heteroaryl-containing substituent comprises a 5- or
6-membered monocyclic heteroaryl ring containing up to 3
heteroatoms selected from nitrogen, oxygen and sulphur, and wherein
said phenyl, heteroaryl, phenoxy, phenylthio, phenylsulphinyl,
phenylsulphonyl, heteroaryloxy, heteroarylthio,
heteroarylsulphinyl, heteroarylsulphonyl, benzyl or benzoyl
substituent optionally bears 1, 2 or 3 substituents selected from
halogeno, trifluoromethyl, cyano, hydroxy, amino, nitro, carboxy,
carbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino,
di-(1-4C)alkylamino, (1-4C)alkoxycarbdnyl, N-(1-4C)alkylcarbamoyl,
N,N-di-(1-4C)alkylcarbamoyl and (2-4C)alkanoylamino;
[0028] or a pharmaceutically-acceptable salt thereof;
[0029] provided that when X.sup.1 is CO and Ar is phenylene which
optionally bears 1 or 2 substituents selected from halogeno,
trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy then X.sup.2 is not
N(R.sup.7)SO.sub.2, N(R.sup.7)CO, C(R.sup.6).sub.2S,
C(R.sup.6).sub.2SO, C(R.sup.6).sub.2SO.sub.2,
C(R.sup.6).sub.2--C(R.sup.6).sub.2, C(R.sup.6).sub.2CO or
C(R.sup.6).sub.2O.
[0030] In this specification the term "alkyl" includes both
straight and branched chain alkyl groups but references to
individual alkyl groups such as "propyl" are specific for the
straight chain version only. An analogous convention applies to
other generic terms.
[0031] It is to be understood that certain aminoheterocyclic
derivatives of the present invention can exist in solvated as well
as unsolvated forms such as, for example, hydrated forms. It is to
be understood that the invention encompasses all such solvated
forms which possess Factor Xa inhibitory activity.
[0032] It is further to be understood that, insofar as certain of
the compounds of the formula defined above may exist in optically
active or racemic forms by virtue of one or more asymmetric carbon
atoms, the invention encompasses any such optically active or
racemic form which possesses Factor Xa inhibitory activity. The
synthesis of optically active forms may be carried out by standard
techniques of organic chemistry well known in the art, for example
by synthesis from optically active starting materials or by
resolution of a racemic form.
[0033] Suitable values for the generic terms referred to above
include those set out below.
[0034] When m is 2, each R.sup.1 is independently selected from the
list of substituents defined hereinbefore.
[0035] A suitable value for R.sup.1 when it is a halogeno group or
for a halogeno substituent on Ar, on a phenyl group within any
substituent on Ar, on Q or on a phenyl- or heteroaryl-containing
substituent on Q is, for example, fluoro, chloro, bromo or
iodo.
[0036] A suitable value for R.sup.1 when it is a (1-4C)alkyl group
or for a (1-4C)alkyl substituent on Ar, on a heterocyclic or phenyl
group within any substituent on Ar, on Q or on a phenyl- or
heteroaryl-containing substituent on Q is, for example, methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or
tert-butyl.
[0037] A suitable value for R.sup.1 when it is a (1-4C)alkoxy group
or for a (1-4C)alkoxy substituent on Ar, on a phenyl group within
any substituent on Ar, on Q or on a phenyl- or
heteroaryl-containing substituent on Q is, for example, methoxy,
ethoxy, propoxy, isopropoxy or butoxy.
[0038] A suitable value for R.sup.1 when it is a (1-4C)alkylamino
group or for a (1-4C)alkylamino substituent on Ar, on Q or on a
phenyl- or heteroaryl-containing substituent on Q is, for example,
methylamino, ethylamino or propylamino.
[0039] A suitable value for R.sup.1 when it is di-(1-4C)alkylamino
or for a di-(1-4C)alkylamino substituent on Ar, on Q or on a
phenyl- or heteroaryl-containing substituent on Q is, for example,
dimethylamino, N-ethyl-N-methylamino or diethylamino.
[0040] A suitable value for R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6 or R.sup.7 when it is (1-4C)alkyl is, for example, methyl,
ethyl, propyl, isopropyl, butyl or se-butyl.
[0041] A suitable value for a (1-4C)alkylene group formed by
R.sup.2 and R.sup.3 together is, for example, methylene, ethylene,
trimethylene or tetramethylene.
[0042] A suitable value for L.sup.1 when it is (1-4C)alkylene is,
for example, methylene, ethylene, trimethylene or
tetramethylene;
[0043] when it is (3-6C)cycloalkane-1,2-diyl is, for example,
cyclopropane-1,2-diyl, cyclobutane-1,2-diyl, cyclopentane-1,2-diyl
or cyclohexane-1,2-diyl; and when it is (1-3C)alkylene-carbonyl is,
for example, methylenecarbonyl, ethylenecarbonyl or
trimethylenecarbonyl.
[0044] A suitable value for a substituent which may be present on 1
or 2 methylene groups within L.sup.1 or the ring formed when
R.sup.1 and R.sup.3 are linked is, for example, as follows:--
1 for (1-4C)alkyl: methyl, ethyl and propyl; for
(1-4C)alkoxycarbonyl: methoxycarbonyl, ethoxy- carbonyl,
propoxycarbonyl and tert-butoxycarbonyl; for
N-(1-4C)alkylcarbamoyl: N-methylcarbamoyl, N-ethyl- carbamoyl and
N-propyl- carbamoyl; for N,N-di-[(1-4C)alkyl]carbamoyl:
N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl and
N,N-diethylcarbamoyl; for 4-(1-4C)alkylpiperazin-1-ylcarbonyl:
4-methylpiperazin-1- ylcarbonyl and 4-ethyl-
piperazin-1-ylcarbonyl; for hydroxy-(1-4C)alkyl: hydroxymethyl,
1-hydroxy- ethyl, 2-hydroxyethyl and 3-hydroxypropyl; for
(1-4C)alkoxy-(1-4C)alkyl: methoxymethyl, ethoxy- methyl,
1-methoxymethyl, 2-methoxyethyl, 2-ethoxy- ethyl and
3-methoxypropyl; for carboxy-(1-4C)alkyl: carboxymethyl, 1-carboxy-
ethyl, 2-carboxyethyl and 3-carboxypropyl; for
(1-4C)alkoxycarbonyl-(1-4C)alkyl: methoxycarbonylmethyl,
ethoxycarbonylmethyl, tert- butoxycarbonylmethyl, 1-methoxycarbonyl
ethyl, 1-ethoxycarbonylethyl, 2-methoxycarbonylethyl,
2-ethoxycarbonylethyl, 3-methoxycarbonylpropyl and
3-ethoxycarbonylpropyl; for carbamoyl-(1-4C)alkyl: carbamoylmethyl,
1-carbamoylethyl, 2-carbamoylethyl and 3-carbamoylpropyl; for
N-(1-4C)alkylcarbamoyl-(1-4C)alkyl: N-methylcarbamoylmethyl,
N-ethylcarbamoylmethyl, N-propylcarbamoylmethyl,
1-(N-methylcarbamoyl)ethyl, 1-(N-ethylcarbamoyl)ethyl,
2-(N-methylcarbamoyl)ethyl, 2-(N-ethylcarbamoyl)ethyl and
3-(N-methyl- carbamoyl)propyl; for N,N-di-[(1-4C)alkyl]car- bamoyl-
N,N-dimethylcarbamoyl- (1-4C)alkyl: methyl, N-ethyl-N-methyl-
carbamoylmethyl, N,N- diethylcarbamoylmethyl,
1-(N,N-dimethylcarbamoyl) ethyl, 1-(N,N-diethyl- carbamoyl)ethyl,
2-(N,N- dimethylcarbamoyl)ethyl, 2-(N,N-diethylcarbamoyl) ethyl and
3-(N,N-dimethyl- carbamoyl)propyl; for
pyrrolidin-1-ylcarbonyl-(1-4C)alkyl: pyrrolidin-1-ylcarbonyl-
methyl, 1-(pyrrolidin-1- ylcarbonyl)ethyl and 2-
(pyrrolidin-1-ylcarbonyl)ethyl; for piperidinocarbonyl-(1-4C)alkyl-
: piperidinocarbonylmethyl, 1-(piperidinocarbonyl)ethyl and
2-(piperidinocarbonyl) ethyl; for morpholinocarbonyl-(1-4C)alkyl:
morpholinocarbonylmethyl, 1-(morpholinocarbonyl)ethyl and
2-(morpholinocarbonyl) ethyl; for
piperazin-1-ylcarbonyl-(1-4C)alkyl: piperazin-1-ylcarbonylmethyl,
1-(piperazin-1-ylcarbonyl) ethyl and 2-(piperazin-1-
ylcarbonyl)ethyl; for 4-(1-4C)alkylpiperazin-1-ylcarbonyl-
4-methylpiperazin-1- (1-4C)alkyl: ylcarbonylmethyl,
4-ethylpiperazin-1- ylcarbonylmethyl, 2-(4- methylpiperazin-1-
ylcarbonyl)ethyl and 2-(4- ethylpiperazin-1- ylcarbonyl)ethyl.
[0045] For suitable value for a (1-4C)alkyl group which may be
present on a heterocyclic group in a substituent on L.sup.1 or the
ring formed when R.sup.2 and R.sup.3 are linked is, for example,
methyl, ethyl or propyl.
[0046] A suitable value for Ar when it is phenylene is, for
example, 1,2-, 1,3- or 1,4-phenylene.
[0047] A suitable value for Ar when it is a 5- or 6-membered
monocyclic heteroaryl ring containing up to 3 heteroatoms selected
from nitrogen, oxygen and sulphur is, for example, furandiyl,
thiophenediyl, pyridinediyl, pyrazinediyl, pyrimidinediyl,
pyridazinediyl, pyrrolediyl, pyrazolediyl, imidazolediyl,
oxazolediyl, isoxazolediyl, thiazolediyl, isothiazolediyl,
1,2,3-triazolediyl, 1,2,4-triazolediyl, oxadiazolediyl,
furazandiyl, thiadiazolediyl and 1,3,5-triazinediyl which may be
attached through any available position including through any
available nitrogen atom. Convenient values for Ar include 2,4- or
2,5-furandiyl, 2,4- or 2,5-thiophenediyl, 2,4-, 2,5-, 2,6- or
3,5-pyridinediyl, 2,4-, 2,5- or 4,6-pyrimidinediyl, 1,4-, 2,4-,
2,5-, 4,1- or 5,2-imidazolediyl, 2,4- or 2,5-oxazolediyl, 2,4- or
2,5-thiazolediyl, 2,5-oxadiazolediyl, 2,5-thiadiazolediyl and
1,3,5-triazine-2,4-diyl.
[0048] A suitable value for L.sup.2 when it is (1-4C)alkylene is,
for example, methylene, ethylene, trimethylene or tetramethylene;
and for L.sup.3 when it is (2-4C)alkylene is, for example,
ethylene, trimethylene or tetramethylene.
[0049] Suitable values for substituents which may be present on Ar,
on a heterocyclic or phenyl group within a substituent on Ar, on Q
or on a phenyl- or heteroaryl-containing substituent on Q include,
for example:--
2 for (2-4C)alkenyl: vinyl and allyl; for (2-4C)alkynyl: ethynyl
and prop-2-ynyl; for (2-4C)alkenyloxy: vinyloxy and allyloxy; for
(2-4C)alkynyloxy: ethynyloxy and prop-2- ynyloxy; for
4-(1-4C)alkylpiperazin-1-yl: 4-methylpiperazin-1-yl and
4-ethylpiperazin-1-yl; for (1-4C)alkylthio: methylthio, ethylthio
and propylthio; for (1-4C)alkylsulphinyl: methylsulphinyl,
ethylsulphinyl and propylsulphinyl; for (1-4C)alkylsulphonyl:
methylsulphonyl, ethylsulphonyl and propylsulphonyl; for
(2-4C)alkanoylamino: acetamido, propionamido and butyramido; for
(1-4C)alkanesulphonamido: methanesulphonamido and
ethanesulphonamido; for (1-4C)alkoxycarbonyl: methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl; for
N-(1-4C)alkylcarbamoyl: N-methylcarbamoyl, N-ethylcarbamoyl and
N-propylcarbamoyl; for N,N-di-[(1-4C)alkyl]carbamoyl:
N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl and
N,N-diethylcarbamoyl; for 4-(1-4C)alkylpiperazin-1-ylcarbonyl:
4-methylpiperazin-1- ylcarbonyl and 4-ethyl-
piperazin-1-ylcarbonyl; for (1-4C)alkanesulphonamidocarbonyl:
methanesulphonamido- carbonyl and ethane- sulphonamidocarbonyl; for
(2-4C)alkanoyl: acetyl, propionyl and butyryl; for
hydroxy-(1-4C)alkyl: hydroxymethyl, 1-hydroxy- ethyl,
2-hydroxyethyl and 3-hydroxypropyl; for (1-4C)alkoxy-(1-4C)alkyl:
methoxymethyl, ethoxy- methyl, 1-methoxymethyl, 2-methoxyethyl,
2-ethoxy- ethyl and 3-methoxypropyl; for carboxy-(1-4C)alkyl:
carboxymethyl, 1-carboxy- ethyl, 2-carboxyethyl and
3-carboxypropyl; for (1-4C)alkoxycarbonyl-(1-4C)alkyl:
methoxycarbonylmethyl, ethoxycarbonylmethyl,
tert-butoxycarbonylmethyl, 1-methoxycarbonylethyl,
1-ethoxycarbonylethyl, 2-methoxycarbonylethyl,
2-ethoxycarbonylethyl, 3-methoxycarbonylpropyl and
3-ethoxycarbonylpropyl; for carbamoyl-(1-4C)alkyl: carbamoylmethyl,
1-carbamoylethyl, 2-carbamoylethyl and 3-carbamoylpropyl; for
N-(1-4C)alkylcarbarnoyl-(1-4C)alkyl: N-methylcarbamoylmethyl,
N-ethylcarbamoylmethyl, N-propylcarbamoylmethyl,
1-(N-methylcarbamoyl)ethyl, 1-(N-ethylcarbamoyl)ethyl,
2-(N-methylcarbamoyl)ethyl, 2-(N-ethylcarbamoyl)ethyl and
3-(N-methylcarbamoyl) propyl; for N,N-di-[(1-4C)alkyl]carb- amoyl-
N,N-dimethylcarbamoyl- (1-4C)alkyl: methyl, N-ethyl-N-methyl-
carbamoylmethyl, N,N- diethylcarbamoylmethyl,
1-(N,N-dimethylcarbamoyl) ethyl, 1-(N,N-diethyl carbamoyl)ethyl,
2-(N,N- dimethylcarbamoyl)ethyl, 2-(N,N-diethyl- carbamoyl)ethyl
and 3-(N,N-dimethylcarbamoyl) propyl;
[0050] For the avoidance of doubt it is stated that a suitable
heterocyclic group in a substituent which may be present on Ar
includes, for example, pyrrolidin-1-yl, piperidino, morpholino,
piperazin-1-yl and 4-(1-4C)alkylpiperazin-1-yl whether directly
attached or attached by way of a linking group as in, for example,
pyrrolidin-1-ylcarbonyl.
[0051] A suitable value for Q when it is naphthyl is for example,
1-naphthyl or 2-naphthyl; when it is phenyl-(1-4C)alkyl is, for
example, benzyl, phenethyl and 3-phenylpropyl, when it is
phenyl-(2-4C)alkenyl is, for example, styryl, cinnamyl or
3-phenylprop-2-enyl; and when it is phenyl-(2-4C)alkynyl is, for
example, 2-phenylethynyl, 3-phenylprop-2-ynyl and
3-phenylprop-1-ynyl.
[0052] A suitable value for Q when it is a heterocyclic moiety
containing up to 4 heteroatoms selected from nitrogen, oxygen and
sulphur is, for example, a 5- or 6-membered heterocyclic moiety
which is a single ring or is fused to one or two benzo rings such
as furyl, benzofuranyl, tetrahydrofuryl, chromanyl, thienyl,
benzothienyl, pyridyl, piperidinyl, quinolyl,
1,2,3,4-tetrahydroquinolinyl, isoquinolyl,
1,2,3,4-tetrahydroisoquinolinyl, pyrazinyl, piperazinyl,
pyrimidinyl, pyridazinyl, quinoxalinyl, quinazolinyl, cinnolinyl,
pyrrolyl, pyrrolidinyl, indolyl, indolinyl, imidazolyl,
benzimidazolyl, pyrazolyl, indazolyl, oxazolyl, benzoxazolyl,
isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, morpholinyl,
4H-1,4-benzoxazinyl, 4H-1,4-benzothiazinyl, 1,2,3-triazolyl,
1,2,4-triazolyl, oxadiazolyl, furazanyl, thiadiazolyl, tetrazolyl,
dibenzofuranyl and dibenzothienyl, which may be attached through
any available position including, for an appropriate X.sup.2 group
such as, for example, SO.sub.2, C(R.sup.6).sub.2 or CO, through any
available nitrogen atom and which may bear up to three substituents
including a substituent on any available nitrogen atom.
[0053] A suitable value for the heteroaryl substituent on Q or the
heteroaryl group in a heteroaryl-containing substituent on Q which
comprises a 5- or 6-membered monocyclic heteroaryl ring containing
up to 3 heteroatoms selected from oxygen, nitrogen and sulphur is,
for example, furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl,
pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,
thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
oxadiazolyl, furazanyl and thiadiazolyl which may be attached
through any available position including through any available
nitrogen atom.
[0054] For the avoidance of any doubt it is to be understood that,
in the portion of the structure of formula I which has the formula
--N(R.sup.2)-L.sup.1-T.sup.1(R.sup.3)--X.sup.1--, it is the N atom
which is attached to L.sup.1 and it is the T.sup.1 group which is
attached to X.sup.1 i.e. neither of the R.sup.2 and R.sup.3 groups
are attached to L.sup.1. It is further to be understood that,
within the structure of formula I, when R.sup.2 and R.sup.3
together form a methylenecarbonyl group, it is the methylene group
thereof which is attached to the N atom and the carbonyl group
thereof which is attached to T.sup.1. Similarly when L.sup.1 is a
(1-3 C)alkylene-carbonyl group, for example a methylenecarbonyl
group, it is the methylene group thereof which is attached to the N
atom and the carbonyl group thereof which is attached to
T.sup.1.
[0055] It is also to be understood that, within the structure of
formula I, when X.sup.1 is, for example, a group of the formula
C(R.sup.4).sub.2O, it is the C atom which is attached to T.sup.1
and the O atom which is attached to Ar. Likewise, when X.sup.2 is,
for example, a group of the formula N(R.sup.7)SO.sub.2, it is the N
atom which is attached to Ar and the SO.sub.2 group which is
attached to Q. Likewise, when X.sup.3 is, for example, a group of
the formula CON(R.sup.5), it is the CO group which is attached to
Ar and the N atom which is attached to L.sup.2 or L.sup.3 as
appropriate. Likewise when X.sup.3 is, for example a group of the
formula CON(L.sup.2-Y.sup.2), it is the L.sup.2 group which is
attached to the N atom of the CON group.
[0056] A suitable pharmaceutically-acceptable salt of an
aminoheterocyclic derivative of the invention is, for example, an
acid-addition salt of an aminoheterocyclic derivative of the
invention which is sufficiently basic, for example, an
acid-addition salt with, for example, an inorganic or organic acid,
for example hydrochloric, hydrobromic, sulphuric, phosphoric,
trifluoroacetic, citric or maleic acid. In addition a suitable
pharmaceutically-acceptable salt of an aminoheterocyclic derivative
of the invention which is sufficiently acidic is an alkali metal
salt, for example a sodium or potassium salt, an alkaline earth
metal salt, for example a calcium or magnesium salt, an ammonium
salt or a salt with an organic base which affords a
physiologically-acceptable cation, for example a salt with
methylamine, dimethylamine, trimethylamine, piperidine, morpholine
or tris-(2-hydroxyethyl)amine.
[0057] Particular compounds of the invention include, for example,
aminoheterocyclic derivatives of the formula I, or
pharmaceutically-acceptable salts thereof, wherein, unless
otherwise stated, each of G.sup.1, G.sup.2, m, R.sup.1, R.sup.2,
R.sup.3, L.sup.1, T.sup.1, X.sup.1, Ar, X.sup.2 and Q has any of
the meanings defined hereinbefore or in this section concerning
particular compounds of the invention:--
[0058] (a) each of G.sup.1 and G.sup.2 is CH;
[0059] (b) G.sup.1 is CH and G.sup.2 is N, or G.sup.1 is N and
G.sup.2 is CH;
[0060] (c) m is 1 and R.sup.1 is hydrogen;
[0061] (d) L.sup.1 is (1-4C)alkylene, T.sup.1 is CH or N, and
R.sup.2 and R.sup.3 together form a (1-4C)alkylene group, and
wherein 1 or 2 methylene groups within L.sup.1 and the ring formed
when R.sup.1 and R.sup.3 are linked optionally bears 1 or 2
(1-4C)alkyl substituents, provided that, when T.sup.1 is N, L.sup.1
is not optionally substituted methylene and R.sup.2 and R.sup.3
together do not form an optionally substituted methylene group;
[0062] (e) L.sup.1 is ethylene, T.sup.1 is CH, and R.sup.2 and
R.sup.3 together form a methylene or ethylene group;
[0063] (f) L.sup.1 is ethylene, T.sup.1 is N, and R.sup.1 and
R.sup.3 together form an ethylene group;
[0064] (ff) L.sup.1 is ethylene, T.sup.1 is N, and R.sup.2 and
R.sup.3 together form an ethylene or propylene group;
[0065] (g) L.sup.1 is ethylene, T.sup.1 is CH or N, and R.sup.2 and
R.sup.3 together form an ethylene group;
[0066] (h) when T.sup.1 is CH or N, X.sup.1 is a group of the
formula SO.sub.2, CH.sub.2, CO, CH.sub.2O, CH.sub.2S,
CH.sub.2SO.sub.2, COCH.sub.2 or SO.sub.2CH.sub.2, or, when T.sup.1
is CH, X.sup.1 is, in addition, a group of the formula O, S,
OCH.sub.2 or SCH.sub.2;
[0067] (i) when T.sup.1 is CH or N, X.sup.1 is a group of the
formula CH.sub.2, CO or CH.sub.2O, or, when T.sup.1 is CH, X.sup.1
is, in addition, a group of the formula O;
[0068] (j) Ar is 1,3-phenylene or 1,4-phenylene which is optionally
substituted with 1 or 2 substituents selected from halogeno,
trifluoromethyl, cyano, (1-4C)alkyl, hydroxy, amino, (1-4C)alkoxy,
(1-4C)alkylamino, di-(1-4C)alkylamino, (1-4C)alkylthio,
(1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, (2-4C)alkanoylamino,
carboxy, carbamoyl, (1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl,
N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin-1-ylcarbonyl,
piperidinocarbonyl, morpholinocarbonyl, thiamorpholinocarbonyl,
1-oxothiamorpholinocarbonyl, 1,1-dioxothiamorpholinocarbonyl,
piperazin-1-ylcarbonyl and 4-(1-4C)alkylpiperazin-1-ylcarbonyl;
[0069] (k) Ar is 1,3-phenylene or 1,4-phenylene which is optionally
substituted with a substituent of the formula -L.sup.2-Y.sup.1 or
of the formula -L.sup.2-Y.sup.2 wherein L.sup.2 is (1-4C)alkylene,
Y.sup.1 is selected from hydroxy, amino, (1-4C)alkoxy,
(1-4C)alkylamino, di-(1-4C)alkylamino, pyrrolidin-1-yl, piperidino,
morpholino, piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl,
(1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl and
(2-4C)alkanoylamino, and Y.sup.2 is selected from carboxy,
carbamoyl, (1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl,
N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin-1-ylcarbonyl,
piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl and
4-(1-4C)alkylpiperazin-1-ylcarbonyl;
[0070] (l) Ar is 1,3-phenylene or 1,4-phenylene which is optionally
substituted with a substituent of the formula
--X.sup.3-L.sup.2-Y.sup.2 wherein X.sup.3 is a group of the formula
CONH, CON(Me), CH.sub.2O or O, L.sup.2 is methylene, ethylene or
trimethylene and Y.sup.2 is selected from carboxy, carbamoyl,
(1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl,
N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin-1-ylcarbonyl,
piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl and
4-(1-4C)alkylpiperazin-1-y- l;
[0071] (m) Ar is 1,3-phenylene or 1,4-phenylene which is optionally
substituted with a substituent of the formula
--X.sup.3-L.sup.3-Y.sup.1 wherein X.sup.3 is a group of the formula
CONH, CH.sub.2O, O or NH, L.sup.3 is ethylene or trimethylene and
Y.sup.1 is hydroxy, amino, (1-4C)alkoxy, (1-4C)alkylamino,
di-(1-4C)alkylamino, pyrrolidin-1-yl, piperidino, morpholino,
piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl, (1-4C)alkylthio,
(1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl and
(2-4C)alkanoylamino;
[0072] (n) X.sup.2 is a group of the formula SO.sub.2, CH.sub.2,
CO, NHSO.sub.2, N(R.sup.7)SO.sub.2, NHCO, N(R.sup.7)CO,
CH.sub.2SO.sub.2, CH.sub.2CH.sub.2 or CH.sub.2CO wherein R.sup.7 is
(1-4C)alkyl or a group of the formula --X.sup.4-Q wherein X.sup.4
is SO.sub.2 and Q has any of the meanings defined hereinafter in
this section of particular compounds of the invention;
[0073] (nn) X.sup.2 is a group of the formula S;
[0074] (o) X.sup.2 is a group of the formula SO.sub.2 or
NHSO.sub.2;
[0075] (p) X.sup.2 is a group of the formula SO.sub.2;
[0076] (q) X.sup.2 is a group of the formula NHSO.sub.2;
[0077] (r) Q is phenyl, naphthyl or phenyl-(1-4C)alkyl which
optionally bears 1, 2 or 3 substituents selected from hydroxy,
halogeno, cyano, trifluoromethyl. (1-4C)alkyl, (1-4C)alkoxy,
phenyl, phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl,
benzyl and benzoyl, and wherein the phenyl substituent or the
phenyl group in a phenyl-containing substituent optionally bears-1
or 2 substituents selected from halogeno, (1-4C)alkyl and
(1-4C)alkoxy;
[0078] (s) Q is phenyl which bears a phenyl substituent and
optionally bears 1 or 2 substituents selected from hydroxy,
halogeno, cyano, trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy, and
wherein the phenyl substituent optionally bears up to 3
substituents selected from halogeno, trifluoromethyl, cyano,
(1-4C)alkyl and (1-4C)alkoxy;
[0079] (t) Q is phenyl-(1-4C)alkyl, phenyl-(2-4C)alkenyl or
phenyl-(2-4C)alkynyl which optionally bears 1, 2 or 3 substituents
selected from halogeno, cyano, trifluoromethyl, (1-4C)alkyl and
(1-4C)alkoxy;
[0080] (u) Q is phenyl-(2-4C)alkenyl which optionally bears 1, 2 or
3 substituents selected from halogeno, cyano, trifluoromethyl,
(1-4C)alkyl and (1-4C)alkoxy;
[0081] (v) Q is phenyl or phenyl-(1-4C)alkyl which bears 1
substituent selected from heteroaryl, heteroaryloxy,
heteroarylthio, heteroarylsulphinyl and heteroarylsulphonyl,
wherein the heteroaryl substituent or the heteroaryl group in a
heteroaryl-containing substituent comprises a 5- or 6-membered
monocyclic heteroaryl ring containing up to 3 heteroatoms selected
from nitrogen, oxygen and sulphur, and wherein said heteroaryl or
heteroaryl-containing substituent optionally bears 1 or 2
substituents selected from halogeno, (1-4C)alkyl and
(1-4C)alkoxy;
[0082] (w) Q is phenyl which bears 1 substituent selected from
heteroaryl, heteroaryloxy, heteroarylthio and heteroarylsulphonyl,
wherein the heteroaryl substituent or the heteroaryl group in a
heteroaryl-containing substituent is selected from thienyl,
pyridyl, pyrimidinyl, pyrazolyl, oxazolyl, thiazolyl,
1,2,3-triazolyl and 1,2,4-triazolyl, and wherein said heteroaryl or
heteroaryl-containing substituent optionally bears 1 or 2
substituents selected from halogeno and (1-4C)alkyl;
[0083] (x) Q is naphthyl which optionally bears 1 or 2 substituents
selected from hydroxy, halogeno, cyano, trifluoromethyl,
(1-4C)alkyl and (1-4C)alkoxy;
[0084] (y) Q is a heterocyclic moiety containing up to 2
heteroatoms selected from benzofuranyl, quinolyl,
tetrahydroquinolyl, isoquinolyl, quinoxalinyl, quinazolinyl,
cinnolinyl, indolyl, benzimidazolyl, indazolyl, benzoxazolyl and
benzothiazolyl, and Q optionally bears 1 or 2 substituents selected
from halogeno, cyano, trifluoromethyl, (1-4C)alkyl and
(1-4C)alkoxy;
[0085] (z) Q is a heterocyclic moiety containing up to 2
heteroatoms selected from benzofuranyl, quinolyl,
tetrahydroquinolyl, isoquinolyl, quinoxalinyl, quinazolinyl,
cinnolinyl, indolyl, benzimidazolyl, indazolyl, benzoxazolyl,
benzothiazolyl, dibenzofuranyl and dibenzothienyl, and Q optionally
bears 1 or 2 substituents selected from halogeno, cyano,
trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy;
[0086] (aa) Q is a heterocyclic moiety containing up to 4
heteroatoms selected from furyl, thienyl, pyridyl, pyrimidinyl,
pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl, and Q
optionally bears 1 or 2 substituents selected from halogeno, cyano,
carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl,
(1-4C)alkoxy, N-(1-4C)alkylcarbamoyl and
N,N-di-(1-4C)alkylcarbamoyl;
[0087] (bb) Q is a heterocyclic moiety containing up to 2
heteroatoms selected from thienyl, pyridyl, pyrimidinyl,
imidazolyl, pyrazolyl, oxazolyl and thiazolyl, and Q optionally
bears 1 or 2 substituents selected from halogeno, (1-4C)alkyl,
(1-4C)alkoxy, phenyl, heteroaryl, phenoxy, phenylthio,
phenylsulphinyl, phenylsulphonyl, heteroaryloxy, heteroarylthio,
heteroarylsulphinyl, heteroarylsulphonyl, benzyl and benzoyl,
wherein the heteroaryl substituent or the heteroaryl group in a
heteroaryl-containing substituent is selected from thienyl,
pyridyl, pyrimidinyl, pyrazolyl, oxazolyl and thiazolyl, and
wherein said phenyl, phenyl-containing, heteroaryl or
heteroaryl-containing substituent optionally bears 1 or 2
substituents selected from halogeno, (1-4C)alkyl and (1-4C)alkoxy;
or
[0088] (cc) Q is a heterocyclic moiety containing up to 2
heteroatoms selected from thienyl, pyridyl, oxazolyl and thiazolyl,
and Q bears a substituent selected from phenyl, thienyl, pyridyl,
pyrimidinyl, oxazolyl and thiazolyl, which substituent optionally
bears 1 or 2 substituents selected from halogeno, (1-4C)alkyl and
(1-4C)alkoxy, and Q optionally bears a further substituent selected
from halogeno and (1-4C)alkyl;
[0089] or a pharmaceutically-acceptable salt thereof;
[0090] provided that when X.sup.1 is CO and Ar is phenylene which
optionally bears 1 or 2 substituents selected from halogeno,
trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy then X.sup.2 is not
N(R.sup.7)SO.sub.2, N(R.sup.7)CO, C(R.sup.6).sub.2S,
C(R.sup.6).sub.2SO, C(R.sup.6).sub.2SO.sub.2,
C(R.sup.6).sub.2--C(R.sup.6).sub.2, C(R.sup.6).sub.2CO or
C(R.sup.6).sub.2O.
[0091] A particular compound of the invention is an
aminoheterocyclic derivative of the formula I
[0092] wherein each of G.sup.1 and G.sup.2 is CH, G.sup.1 is CH and
G.sup.2 is N, or G.sup.1 is N and G.sup.2 is CH;
[0093] m is 1 and R.sup.1 is hydrogen;
[0094] L.sup.1 is ethylene, T.sup.1 is CH or N, and R.sup.2 and
R.sup.3 are independently hydrogen or together form a methylene,
ethylene or propylene group;
[0095] when T.sup.1 is CH or N, X.sup.1 is a group of the formula
CH.sub.2, CO, CH.sub.2O or SO.sub.2, or, when T.sup.1 is CH,
X.sup.1 is, in addition, a group of the formula O;
[0096] Ar is 1,2-phenylene, 1,3-phenylene, 1,4-phenylene or pyridyl
group which is optionally substituted with 1 or 2 substituents
selected from fluoro, chloro, bromo, trifluoromethyl, cyano,
methyl, hydroxy, amino, methoxy, methylamino, dimethylamino,
methylthio, methylsulphinyl, methylsulphonyl, acetamido, carboxy,
carbamoyl, methoxycarbonyl, ethoxycarbonyl, N-methylcarbamoyl,
N,N-dimethylcarbamoyl, 2-(ethylthio)ethylamino-carbonyl,
pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl,
piperazin-1-ylcarbonyl and 4-methylpiperazin-1-ylcarbonyl;
[0097] X.sup.2 is a group of the formula S, SO.sub.2, CONH,
NHSO.sub.2 or N(R.sup.7)SO.sub.2 wherein R.sup.7 is methyl or a
group of the formula --SO.sub.2Q wherein Q has any of the meanings
defined immediately hereinafter; and
[0098] Q is phenyl, styryl, 1,2,3,4-tetrahydroisoquinolinyl,
indolyl, 4-biphenylyl or 2-naphthyl which optionally bears 1 or 2
substituents selected from fluoro, chloro, bromo, trifluoromethyl,
4-chlorophenoxy, methyl and methoxy;
[0099] or a pharmaceutically-acceptable salt thereof;
[0100] provided that when X.sup.1 is CO and Ar is 1,2-, 1,3- or
1,4-phenylene which optionally bears 1 or. 2 substituents selected
from fluoro, chloro, bromo, trifluoromethyl, methyl and methoxy
then X.sup.2 is not NHSO.sub.2 or N(R.sup.7)SO.sub.2 wherein
R.sup.7 is methyl or a group of the formula --SO.sub.2-Q wherein Q
has any of the meanings defined immediately hereinbefore.
[0101] A preferred compound of the invention is an
aminoheterocyclic derivative of the formula I
[0102] wherein each of G.sup.1 and G.sup.2 is CH, G.sup.1 is CH and
G.sup.2 is N, or G.sup.1 is N and G.sup.2 is CH;
[0103] m is 1 and R.sup.1 is hydrogen;
[0104] L.sup.1 is ethylene, T.sup.1 is CH or N, and R.sup.1 and
R.sup.1 together form an ethylene group;
[0105] when T.sup.1 is CH or N, X.sup.1 is a group of the formula
CH.sub.2, CO or CH.sub.2O, or, when T.sup.1 is CH, X.sup.1 is, in
addition, a group of the formula O;
[0106] Ar is 1,3,phenylene or 1,4-phenylene which is optionally
substituted with 1 or 2 substituents selected from fluoro, chloro,
bromo, trifluoromethyl, cyano, methyl, hydroxy, amino, methoxy,
methylamino, dimethylamino, methylthio, methylsulphinyl,
methylsulphonyl, acetamido, carboxy, carbamoyl, methoxycarbonyl,
ethoxycarbonyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl,
pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl,
piperazin-1-ylcarbonyl and 4-methylpiperazin-1-ylcarb- onyl;
[0107] X.sup.2 is a group of the formula SO.sub.2, NHSO.sub.2 or
N(R.sup.7)SO.sub.2 wherein R.sup.7 is methyl or a group of the
formula --SO.sub.2Q wherein Q has any of the meanings defined
immediately hereinafter; and
[0108] Q is phenyl, styryl, 4-biphenylyl or 2-naphthyl which
optionally bears 1 or 2 substituents selected from fluoro, chloro,
bromo, trifluoromethyl, methyl and methoxy;
[0109] or a pharmaceutically-acceptable salt thereof;
[0110] provided that when X.sup.1 is CO and Ar is 1,3- or
1,4-phenylene which optionally bears 1 or 2 substituents selected
from fluoro, chloro, bromo, trifluoromethyl, methyl and methoxy
then X.sup.2 is not NHSO.sub.2 or N(R.sup.7)SO.sub.2 wherein
R.sup.7 is methyl or a group of the formula --SO.sub.2-Q wherein Q
has any of the meanings defined immediately hereinbefore.
[0111] A further preferred compound of the invention is an
aminoheterocyclic derivative of the formula I
[0112] wherein each of G.sup.1 and G.sup.2 is CH, G.sup.1 is CH and
G.sup.2 is N, or G.sup.1 is N and G.sup.2 is CH;
[0113] m is 1 and R.sup.1 is hydrogen;
[0114] L.sup.1 is ethylene, T.sup.1 is N, and R.sup.2 and R.sup.3
together form an ethylene or propylene group;
[0115] X.sup.1 is a group of the formula CO;
[0116] Ar is 1,4-phenylene, 2-carboxy-1,4-phenylene or
2-piperidinocarbonyl-1,4-phenylene (with the X.sup.1 group in the
1-position and the X.sup.2 group in the 4-position);
[0117] X.sup.2 is a group of the formula SO.sub.2; and Q is
2-naphthyl, styryl or 4-biphenylyl which optionally bears 1 or 2
substituents selected from fluoro, chloro and bromo;
[0118] or a pharmaceutically-acceptable salt thereof.
[0119] A particularly preferred compound of the invention is an
aminoheterocyclic derivative of the formula I
[0120] wherein each of G.sup.1 and G.sup.2 is CH;
[0121] m is 1 and R.sup.1 is hydrogen;
[0122] L.sup.1 is ethylene, T.sup.1 is N, and R.sup.2 and R.sup.3
together form an ethylene group;
[0123] X.sup.1 is a group of the formula CO;
[0124] Ar is 1,4-phenylene, 2-carboxy-1,4-phenylene or
2-piperidinocarbonyl-1,4-phenylene (with the X.sup.1 group in the
1-position and the X.sup.2 group in the 4-position);
[0125] X.sup.2 is a group of the formula SO.sub.2; and Q is
2-naphthyl, styryl or 4-biphenylyl which optionally bears 1 or 2
substituents selected from fluoro, chloro and bromo;
[0126] or a pharmaceutically-acceptable salt thereof.
[0127] Specific compounds of the invention include the following
aminoheterocyclic derivative of the formula I:--
[0128]
1-[4-(6-chloronaphth-2-ylsulphonyl)benzoyl]4-(4-pyridyl)piperazine,
[0129]
1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine,
[0130]
1-[4-(2-naphthylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine,
[0131]
1-{4-[(E)-4-chlorostyrylsulphonyl]benzoyl}-4-(4-pyridyl)piperazine,
[0132]
1-[4-(4'-bromo-4-biphenylylsulphonyl)benzoyl]-4-(4-pyridyl)piperazi-
ne,
[0133]
1-[4'-chloro-4-biphenylylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine-
,
[0134]
1-[4-(4-biphenylylsulphonyl)benzoyl]4-(4-pyridyl)piperazine,
[0135]
5-(6-chloronaphth-2-ylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarb-
onyl]benzoic acid,
[0136]
5-(2-naphthylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benz-
oic acid,
[0137]
5-(4'-bromo-4-biphenylylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylca-
rbonyl]benzoic acid,
[0138]
5-[(E)-4-chlorostyrylsulphonyl]-2-[4-(4-pyridyl)piperazin-1-ylcarbo-
nyl]benzoic acid,
[0139]
1-{5-(6-bromonaphth-2-ylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylca-
rbonyl]benzoyl}-piperidine,
[0140]
1-{5-(6-chloronaphth-2-yisulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylc-
arbonyl]benzoyl}-piperidine,
[0141]
1-{5-(4'-bromo-4-biphenylyisulphonyl)-2-[4-(4-pyridyl)piperazin-1-y-
lcarbonyl]benzoyl}-piperidine,
[0142]
1-{5-[(E)-4-chlorostyrylsulphonyl]-2-[4-(4-pyridyl)piperazin-ylcarb-
onyl]benzoyl}piperidine,
[0143]
4'-bromo-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-4-biphenylyls-
ulphonamide,
[0144]
4-chloro-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-(E)-styryisul-
phonamide,
[0145]
6-bromo-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-2-naphthalenes-
ulphonamide,
[0146]
N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-4-toluenesulphonamide,
[0147]
N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-N-(4-tolylsulphonyl)-4-
-toluenesulphonamide,
[0148]
4-chloro-N-methyl-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-(E)--
styrylsulphonamide,
[0149]
4'-bromo-N-methyl-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-4-bi-
phenylylsulphonamide,
[0150]
4'-bromo-N-{4-[-(4-pyridyl)piperidin-4-ylmethoxy]phenyl}-4-biphenyl-
ylsulphonamide,
[0151]
6-bromo-N-{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]-phenyl}-2-naphtha-
lenesulphonamide,
[0152]
4-chloro-N-{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl}-(E)-styry-
lsulphonamide,
[0153]
4'-bromo-N-(4'-bromo-4-biphenylylsulphonyl)-N-{4-[1-(4-pyridyl)pipe-
ridin-4-ylmethoxy]phenyl}-4-biphenylylsulphonamide,
[0154]
6-bromo-N-(6-bromonaphth-2-ylsulphonyl)-N-{4-[1-(4-pyridyl)piperidi-
n-4-ylmethoxy]phenyl}-2-naphthalenesulphonamide,
[0155]
6-bromo-N-{3-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-2-naphthalenes-
ulphonamide,
[0156]
4-[4-chlorophenylsulphonyl)phenoxy]-1-(4-(pyridyl)piperidine,
[0157]
5-(6-bromonaphth-2-ylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbo-
nyl]benzoic acid,
[0158]
4-(6-bromonaphth-2-ylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbo-
nyl]benzoic acid,
[0159]
1-[4-(4-(4-chlorophenoxy)phenylaminocarbonyl)benzyl]-4-(4-pyridyl)p-
iperazine,
[0160]
6-bromo-N-{2-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl)-2-naphthal-
enesulphonamide,
[0161]
4-chloro-N-{3-[1-(4-pyridyl)piperidin-4yloxy]phenyl}-(E)-styrylsulp-
honamide,
[0162]
4-[4-(6-bromonaphth-2-ylsulphonyl)phenoxy]-1-(4-pyridyl)piperidine,
[0163]
4-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-1-(4-pyridyl)piperidine,
[0164]
4-[4-(6-bromonaphth-2-ylthio)benzoyl]-1-(4-pyridyl)piperidine,
[0165]
1-[4-(6-bromonaphth-2-ylsulphonyl)phenylsulphonyl]-1-(4-pyridyl)pip-
erazine,
[0166]
6-(bromo-2-(4-(2-pyrimidin-4-yl)aminoethylaminocarbonyl)phenylsulph-
onyl)naphthalene,
[0167]
1-[4-(6-bromonaphth-2-ylthio)benzoyl]-4-(4-pyridyl)piperazine,
[0168]
1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine,
[0169]
1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(4-pyrimidinyl)-pipera-
zine,
[0170]
1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(4-pyridazinyl)piperaz-
ine,
[0171]
1-[4-(6-bromonaphth-2-ylsulphonyl-2-trifluoromethylbenzoyl]-4-(4-py-
ridyl)piperazine,
[0172]
1-[4-(6-bromonaphth-2-ylthio)-2-trifluoromethylbenzoyl]-4-(4-pyridy-
l)piperazine,
[0173]
1-[4-(6-bromonaphth-2-ylthio)-2-carboxybenzoyl]-4-(4-pyridyl)pipera-
zine
[0174]
1-[5-(6-bromonaphth-2-ylthio)-2-carboxybenzoyl]-4-(4-pyridyl)pipera-
zine,
[0175]
1-[5-(6-bromonaphth-2-ylsulphonyl)-2-methoxycarbonylbenzoyl]-4-(4-p-
yridyl)piperazine,
[0176]
1-[4-(6-bromonaphth-2-ylsulphonyl)-2-methoxycarbonylbenzoyl]-4-(4-p-
yridyl)piperazine,
[0177]
1-[4-(6-bromonaphth-2-ylsulphonyl)-2-(2-(ethylthio)-ethylaminocarbo-
nyl)benzoyl]-4-(4-pyridyl)piperazine,
[0178]
1-[5-(6-bromonaphth-2-ylsulphonyl)-2-(2-ethylthio)ethylaminocarbony-
l)benzoyl]-4-(4-pyridyl)piperazine,
[0179]
1-[4-(6-bromonaphth-2-ylsulphonyl)-2-(piperidin-1-ylcarbonyl]-4-(4--
pyridyl)piperazine,
[0180]
1-[5-(6-bromonaphth-2-ylsulphonyl)-2-(piperidin-1-ylcarbonyl]-4-(4--
pyridyl)piperazine,
[0181]
1-[4-(4-(3-chlorophenyl)piperazin-1-ylsulphonyl)benzoyl]-4-(4-pyrid-
yl)piperazine,
[0182]
1-[4-(6-chloro-1,2,3,4-tetrahydroisoquinolin-2-ylsulphonylbenzoyl]--
4-(4-pyridyl)piperazine,
[0183]
1-(4-pyridyl)-(5-(6-methoxyindol-2-ylcarbonylamino)pyrid-2-yloxy)py-
rrolidine,
[0184]
1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(2-methylpyrid-4-yl)pi-
perazine,
[0185]
1-[4-(6-bromonlaphth-2-ylsulphonlyl)benzoyl]-4-(4-pyridyl)hexahydro-
-1,4-diazepine,
[0186] or a pharmaceutically-acceptable salt thereof.
[0187] An aminoheterocyclic derivative of the formula I, or
pharmaceutically-acceptable salt thereof, may be prepared by any
process known to be applicable to the preparation of
structurally-related compounds. Such procedures are provided as a
further feature of the invention and are illustrated by the
following representative processes in which, unless otherwise
stated G.sup.1, G.sup.2, m, R.sup.1, R.sup.2, L.sup.1, T.sup.1,
R.sup.3, X.sup.1, Ar, X.sup.2 and Q have any of the meanings
defined hereinbefore, provided that when there is an amino,
alkylamino, hydroxy or carboxy group in R.sup.1, L.sup.1, R.sup.2,
R.sup.3, Ar or Q then any such group is protected by a conventional
protecting group as necessary which may be removed when so desired
by conventional means.
[0188] Necessary starting materials may be obtained by standard
procedures of organic chemistry.
[0189] (a) For the production of those compounds of the formula I
wherein T.sup.1 is N and X.sup.1 is CO, the reaction, conveniently
in the presence of a suitable base, of an amine of the formula II
3
[0190] with an acid of the formula III
HO.sub.2C--Ar--X.sup.2-Q III
[0191] or a reactive derivative thereof.
[0192] A suitable reactive derivative of an acid of the formula III
is, for example, an acyl halide, for example an acyl chloride
formed by the reaction of the acid and an inorganic acid chloride,
for example thionyl chloride; a mixed anhydride, for example an
anhydride formed by the reaction of the acid with a chloroformate
such as isobutyl chloroformate or with an activated ketone such as
1,1'-carbonyldiimidazole; an active ester, for example an ester
formed by the reaction of the acid and a phenol such as
pentafluorophenol, an ester such as pentafluorophenyl
trifluoroacetate or an alcohol such as N-hydroxybenzotriazole or
N-hydroxysuccinimide; an acyl azide, for example an azide formed by
the reaction of the acid and an azide such as diphenylphosphoryl
azide; an acyl cyanide, for example a cyanide formed by the
reaction of an acid and a cyanide such as diethylphosphoryl
cyanide; or the product of the reaction of the acid and a
carbodiimide such as N,N'-dicyclohexylcarbodii- mide or
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide.
[0193] The reaction is conveniently carried out in the presence of
a suitable base such as, for example, an alkali or alkaline earth
metal carbonate, alkoxide, hydroxide or hydride, for example sodium
carbonate, potassium carbonate, sodium ethoxide, potassium
butoxide, sodium hydroxide, potassium hydroxide, sodium hydride or
potassium hydride, or an organometallic base such as an
alkyl-lithium, for example n-butyl-lithium, or a
dialkylamino-lithium, for example lithium di-isopropylamide, or,
for example, an organic amine base such as, for example, pyridine,
2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,
morpholine or diazabicyclo[5.4.0]undec-7-ene. The reaction is also
preferably carried out in a suitable inert solvent or diluent, for
example methylene chloride, chloroform, carbon tetrachloride,
tetrahydrofuran, 1,2-dimethoxyethane, N,N-dimethylformamide,
N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulphoxide
or acetone, and at a temperature in the range, for example,
-78.degree. to 150.degree. C., conveniently at or near ambient
temperature.
[0194] An analogous procedure may be employed for the preparation
of those compounds of the formula I wherein T.sup.1 is N and
X.sup.1 is a group of the formula COC(R.sup.4).sub.2.
[0195] A suitable protecting group for an amino or alkylamino group
is, for example, an acyl group, for example an alkanoyl group such
as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl,
ethoxycarbonyl or tert-butoxycarbonyl group, an arylmethoxycarbonyl
group, for example benzyloxycarbonyl, or an aroyl group, for
example benzoyl. The deprotection conditions for the above
protecting groups necessarily vary with the choice of protecting
group. Thus, for example, an acyl group such as an alkanoyl or
alkoxycarbonyl group or an aroyl group may be removed for example,
by hydrolysis with a suitable base such as an alkali metal
hydroxide, for example lithium or sodium hydroxide. Alternatively
an acyl group such as a tert-butoxycarbonyl group may be removed,
for example, by treatment with a suitable acid such as
hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid
and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group
may be removed, for example, by hydrogenation over a catalyst such
as palladium-on-carbon, or by treatment with a Lewis acid for
example boron tris(trifluoroacetate). A suitable alternative
protecting group for a primary amino group is, for example, a
phthaloyl group which may be removed by treatment with an
alkylamine, for example dimethylaminopropylamine, or with
hydrazine.
[0196] A suitable protecting group for a hydroxy group is, for
example, an acyl group, for example an alkanoyl group such as
acetyl, an aroyl group, for example benzoyl, or an arylmethyl
group, for example benzyl. The deprotection conditions for the
above protecting groups will necessarily vary with the choice of
protecting group. Thus, for example, an acyl group such as an
alkanoyl or an aroyl group may be removed, for example, by
hydrolysis with a suitable base such as an alkali metal hydroxide,
for example lithium or sodium hydroxide. Alternatively an
arylmethyl group such as a benzyl group may be removed, for
example, by hydrogenation over a catalyst such as
palladium-on-carbon.
[0197] A suitable protecting group for a carboxy group is, for
example, an esterifying group, for example a methyl or an ethyl
group which may be removed, for example, by hydrolysis with a base
such as sodium hydroxide, or for example a tert-butyl group which
may be removed, for example, by treatment with an acid, for example
an organic acid such as trifluoroacetic acid, or for example a
benzyl group which may be removed, for example, by hydrogenation
over a catalyst such as palladium-on-carbon.
[0198] (b) For the production of those compounds of the formula I
wherein T.sup.1 is CH and X.sup.1 is O or C(R.sup.4).sub.2O, the
reaction, conveniently in the presence of a suitable coupling
agent, of a compound of the formula IV 4
[0199] wherein n is 0 or 1 and Z is a displaceable group, with a
phenolic compound the formula V
HO--Ar--X.sup.2-Q V
[0200] A suitable value for the displaceable group Z is, for
example, a halogeno or sulphonyloxy group, for example a fluoro,
chloro, bromo, mesyloxy or 4-tolylsulphonyloxy group.
[0201] A suitable reagent for the coupling reaction when Z is a
halogens or sulphonyloxy group is, for example, a suitable base,
for example, an alkali or alkaline earth metal carbonate, hydroxide
or hydride, for example sodium carbonate, hydroxide or hydride, for
example sodium carbonate, potassium carbonate, sodium hydroxide,
potassium hydroxide, sodium hydride or potassium hydride. The
alkylation reaction is preferably performed in a suitable inert
solvent or diluent, for example N,N-dimethylformamide,
N,N-dimethylacetamide, dimethylsulphoxide, acetone,
1,2-dimethoxyethane or tetrahydrofuran, and at a temperature in the
range, for example, -10.degree. to 150.degree. C., conveniently at
or near ambient temperature.
[0202] A suitable reagent for the coupling reaction of the alcohol
of the formula IV wherein Z is a hydroxy group is, for example, the
reagent obtained when said alcohol is reacted with a di-(1-4C)alkyl
azodicarboxylate in the presence of a triarylphosphine or
tri-(1-4C)alkylphosphine, for example with diethyl azodicarboxylate
in the presence of triphenylphosphine or tributylphosphine. The
reaction is preferably performed in a suitable inert solvent or
diluent, for example acetone, 1,2-dimethoxyethane or
tetrahydrofuran, and at a temperature in the range, for example,
10.degree. to 80.degree. C., conveniently at or near ambient
temperature.
[0203] An analogous procedure may be employed for the preparation
of those compounds of the formula I wherein T.sup.1 is CH and
X.sup.1 is a group of the formula S or C(R.sup.4).sub.2S.
[0204] (c) For the production of those compounds of the formula I
wherein T.sup.1 is N and X.sup.1 is CH(R.sup.4), the reductive
amination of a keto compound of the formula VI
R.sup.4--CO--Ar--X.sup.2-Q VI
[0205] with an amine of the formula VII 5
[0206] Any reducing agent known in the art for promoting a
reductive amination reaction may be employed. A suitable reducing
agent is, for example, a hydride reducting agent, for example an
alkali metal aluminium hydride such as lithium aluminium hydride
or, preferably, an alkali metal borohydride such as sodium
borohydride, sodium cyanoborohydride, sodium triethylborohydride,
sodium trimethoxyborohydride and sodium triacetoxyborohydride. The
reaction is conveniently performed in a suitable inert solvent or
diluent, for example tetrahydrofuran and diethyl ether for the more
powerful reducing agents such as lithium aluminium hydride, and,
for example, methylene chloride or a protic solvent such as
methanol and ethanol for the less powerful reducing agents such as
sodium triacetoxyborohydride. The reaction is performed at a
temperature in the range, for example, 10.degree. to 80.degree. C.
conveniently at or near ambient temperature.
[0207] (d) For the production of those compounds of the formula I
wherein X.sup.2 is a group of the formula N(R.sup.7)SO.sub.2, the
reaction, conveniently in the presence of a suitable base as
defined hereinbefore, of an amine of the formula VIII 6
[0208] with a compound of the formula IX
Z-SO.sub.2-Q IX
[0209] wherein Z is a displaceable group as defined
hereinbefore.
[0210] The reaction is conveniently performed in a suitable inert
solvent or diluent as defined hereinbefore and at a temperature in
the range, for example, 0.degree. to 150.degree. C., conveniently
at or near ambient temperature.
[0211] An analogous procedure may be employed for those compounds
of the formula I wherein X.sup.2 is a group of the formula
N(R.sup.7)CO.
[0212] (e) For the production of those compounds of the formula I
wherein X.sup.2 is a group of the formula N(R.sup.7)SO.sub.2, the
reaction, conveniently in the presence of a suitable base as
defined hereinbefore, of a sulphonamide of the formula X 7
[0213] with a compound of the formula XI
R.sup.7-Z XI
[0214] wherein Z is a displaceable group as defined
hereinbefore.
[0215] The reaction is conveniently performed in a suitable inert
solvent or diluent as defined hereinbefore and at a temperature in
the range, for example, 0.degree. to 150.degree. C., conveniently
at or near ambient temperature.
[0216] An analogous procedure may be employed for those compounds
of the formula I wherein X.sup.2 is a group of the formula
N(R.sup.7)CO.
[0217] (f) For the production of those compounds of the formula I
wherein X.sup.2 is a group of the formula SO.sub.2N(R.sup.7) the
reaction, conveniently in the presence of a suitable base as
defined hereinbefore, of a compound of the formula XII 8
[0218] wherein Z is a displaceable group as defined hereinbefore,
with an amine of the formula XIII
(R.sup.7)NH-Q XIII
[0219] The reaction is conveniently performed in a suitable inert
solvent or diluent as defined hereinbefore and at a temperature in
the range, for example, 0.degree. to 150.degree. C., conveniently
at or near ambient temperature.
[0220] An analogous procedure may be employed for the preparation
of those compounds of the formula I wherein X.sup.2 is a group of
the formula CON(R.sup.7).
[0221] (g) For the production of those compounds of the formula I
wherein T.sup.1 is CH and X.sup.1 is a group of the formula
OC(R.sup.4).sub.2, the reaction conveniently in the presence of a
suitable coupling agent as defined hereinbefore, of an alcohol of
the formula XIV 9
[0222] with a compound of the formula XV
Z-C(R.sup.4).sub.2--Ar--X.sup.2-Q XV
[0223] wherein Z is a displaceable group as defined
hereinbefore.
[0224] The reaction is conveniently performed in a suitable inert
solvent or diluent as defined hereinbefore and at a temperature in
the range, for example, 0.degree. to 150.degree. C., conveniently
at or near ambient temperature.
[0225] An analogous procedure may be employed for the preparation
of those compounds of the formula I wherein T.sup.1 is CH and
X.sup.1 is a group of the formula SC(R.sup.4).sub.2.
[0226] (h) For the production of those compounds of the formula I
wherein X.sup.2 is a group of the formula C(R.sup.6).sub.2S, the
reaction, conveniently in the presence of a suitable base as
defined hereinbefore, of a compound of the formula XVI 10
[0227] wherein Z is a displaceable group as defined hereinbefore
with a thiol of the formula XVII
HS-Q XVII
[0228] The reaction is conveniently performed in a suitable inert
solvent or diluent as defined hereinbefore and at a temperature in
the range, for example, 0.degree. to 150.degree. C., conveniently
at or near ambient temperature.
[0229] (i) For the production of those compounds of the formula I
wherein L.sup.1, R.sup.2, R.sup.3, Ar or Q bears a carboxy or
carboxy-containing group, the hydrolysis of a compound of the
formula I wherein L.sup.1, R.sup.2, R.sup.3, Ar or Q bears a
(1-4C)alkoxycarbonyl group.
[0230] The hydrolysis reaction may conveniently be carried out in a
conventional manner using, for example, acidic or basic catalysis.
A suitable acid for the acidic hydrolysis of an ester group is, for
example, an inorganic acid such as hydrochloric or sulphuric acid.
A suitable base for the basic hydrolysis of an ester group is, for
example, an alkali or alkaline earth metal hydroxide such as sodium
hydroxide or potassium hydroxide.
[0231] The reaction is conveniently performed in a suitable solvent
or diluent such as an alcohol, for example methanol or ethanol, and
at a temperature in the range, for example 0.degree. to 120.degree.
C., conveniently in the range of 15.degree. to 60.degree. C.
[0232] (j) For the production of those compounds of the formula I
wherein L.sup.1, R.sup.2, R.sup.3, Ar or Q bears a carbamoyl,
N-alkylcarbamoyl, N,N-dialkylcarbamoyl or other aminocarbonyl group
for example piperidinocarbonyl or
2-(ethylthio)aminoethylaminocarbonyl, the reaction of a compound of
the formula I wherein L.sup.1, R.sup.2, R.sup.3, Ar or Q bears a
carboxy group, or a reactive derivative thereof as defined
hereinbefore, with ammonia, an alkylamine, dialkylamine or an
appropriate amino compound.
[0233] The reaction is conveniently performed in a suitable inert
solvent or diluent as defined hereinbefore and at a temperature in
the range, for example, 0.degree. to 120.degree. C., conveniently
in the range 15.degree. to 600.
[0234] Similarly compounds of the formula I bearing ester groups
may be prepared by esterification of the corresponding carboxy
compound.
[0235] (k) For the production of those compounds of the formula I
wherein X.sup.1 is a group of the formula SO, SO.sub.2,
C(R.sup.4).sub.2SO, C(R.sup.4).sub.2SO.sub.2, SOC(R.sup.4).sub.2 or
SO.sub.2C(R.sup.4).sub.2, wherein Ar bears a (1-4C)alkylsulphinyl,
(1-4C)alkylsulphonyl, 1-oxothiamorpholino or
1,1-dioxothiamorpholino group or a substituent which contains a
(1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, 1-oxothiamorpholino or
1,1-dioxothiamorpholino group, wherein X.sup.2 is a group of the
formula SO, SO.sub.2, C(R.sup.6).sub.2SO or
C(R.sup.6).sub.2SO.sub.2, or wherein Q bears a
(1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, phenylsulphinyl,
phenylsulphonyl, heteroarylsulphinyl or heteroarylsulphonyl group,
the oxidation of the corresponding compound of the formula I which
contains a thio group. A suitable oxidising agent is, for example,
any agent known in the art for the oxidation of thio to sulphinyl
and/or sulphonyl, for example, hydrogen peroxide, a peracid (such
as 3-chloroperoxybenzoic or peroxyacetic acid), an alkali metal
peroxysulphate (such as potassium peroxymonosulphate), chromium
trioxide or gaseous oxygen in the presence of platinum. The
oxidation is generally carried out under as mild conditions as
possible and with the required stoichiometric amount of oxidising
agent in order to reduce the risk of over oxidation and damage to
other functional groups. In general the reaction is carried out in
a suitable solvent or diluent such as methylene chloride,
chloroform, acetone, tetrahydrofuran or tert-butyl methyl ether and
at a temperature, for example, at or near ambient temperature, that
is in the range 15 to 35.degree. C. When a compound carrying a
sulphinyl group is required a milder oxidising agent may also be
used, for example sodium or potassium metaperiodate, conveniently
in a polar solvent such as acetic acid or ethanol. It will be
appreciated that when a compound of the formula I containing a
sulphonyl group is required, it may be obtained by oxidation of the
corresponding sulphinyl compound as well as of the corresponding
thio compound.
[0236] (l) The reaction of an activated derivative of a compound of
the formula XVIII: 11
[0237] wherein L is a displaceable group as hereinbefore defined
with a compound of the formula XIX:
NH(R.sup.2)-L.sup.1-T.sup.1(R.sup.3)--X.sup.1--Ar--X.sup.2-Q
XIX
[0238] Typically L is halo for example fluoro or chloro and the
reaction is performed in a substantially inert solvent, as
hereinbefore defined, at an ambient or elevated temperature, and in
the presence of a suitable base for example an, organic amine such
as triethylamine. The compounds of the formula II-XIX inclusive are
useful intermediates in the processes for making the compounds of
the formula I. In another aspect the present invention provides
novel compounds and classes of compound within the generic formulae
II-XIX inclusive.
[0239] The compounds of the formula II-XIX inclusive may be
prepared by any process known to be applicable to the preparation
of structurally related compounds, for example, where applicable,
by methods related to those described hereinbefore for preparing
compounds of the formula I. Particular reference may be made to the
methods of the Examples described hereinafter.
[0240] Intermediates of particular interest include those of the
formula XX and XXI: 12 HOOC--Ar--X.sup.2-Q XXI
[0241] and active derivatives thereof, wherein G.sup.1, G.sup.2,
R.sup.1, m, R.sup.2, L.sup.1, T.sup.1, R, X.sup.1, Ar, X.sup.2 and
Q are as defined in relation to formula I.
[0242] When a pharmaceutically-acceptable salt of a compound of the
formula I is required, it may be obtained, for example, by reaction
of said compound with a suitable acid or base using a conventional
procedure.
[0243] When an optically active form of a compound of the formula I
is required, it may be obtained, for example, by carrying out one
of the aforesaid procedures using an optically active starting
material or by resolution of a racemic form of said compound using
a conventional procedure.
[0244] As stated previously, the compounds of the formula I are
inhibitors of the enzyme Factor Xa. The effects of this inhibition
may be demonstrated using one or more of the standard procedures
set out hereinafter:--
[0245] a) Measurement of Factor Xa Inhibition
[0246] An in vitro assay system was carried out based on the method
of Kettner et al., J. Biol. Chem., 1990, 265, 18289-18297, whereby
various concentrations of a test compound were dissolved in DMSO
and diluted in a pH 7.5 buffer containing 0.5% of a polyethylene
glycol (PEG 6000) and incubated at 37.degree. C. with human Factor
Xa (0.001 Units/ml, 0.3 ml) for 15 minutes. The chromogenic
substrate S-2765 (KabiVitum AB, 20 .mu.M) was added and the mixture
was incubated at 37.degree. C. for 20 minutes whilst the absorbance
at 405 nm was measured. The maximum reaction velocity (Vmax) was
determined and compared with that of a control sample containing no
test compound. Inhibitor potency was expressed as an IC.sub.50
value.
[0247] b) Measurement of Thrombin Inhibition
[0248] The procedure of method a) was repeated except that human
thrombin (0.005 Units/ml) and the chromogenic substrate S-2238
(KabiVitum AB, 7 .mu.M) were employed.
[0249] c) Measurement of Anticoagulant Activity
[0250] An in vitro assay whereby human, rat or rabbit venous blood
was collected and added directly to a sodium citrate solution (3.2
g/100 ml, 9 parts blood to 1 part citrate solution). Blood plasma
was prepared by centrifugation (1000 g, 15 minutes) and stored at
2-4.degree. C. Conventional prothrombin time (PT) tests were
carried out in the presence of various concentrations of a test
compound and the concentration of test compound required to double
the clotting time, hereinafter referred to as CT2, was determined.
In the PT test, the test compound and blood plasma were incubated
at 37.degree. C. for 10 minutes. Tissue thromboplastin with calcium
(Sigma Limited, Poole, England) was added and fibrin formation and
the time required for a clot to form were determined.
[0251] d) An Ex Vivo Assay of Anticoagulant Activity
[0252] The test compound was administered intravenously or orally
to a group of Alderley Park Wistar rats. At various times
thereafter animals were anaesthetised, blood was collected and PT
coagulation assays analogous to those described hereinbefore were
conducted. In addition the plasma concentration of compounds is
determined by comparison with the anti-Factor Xa activity of a
standard compound.
[0253] e) An In Vivo Measurement of Antithrombotic Activity
[0254] Thrombus formation was induced using an analogous method to
that described by Vogel et al., Thromb. Research, 1989, 54,
399-410. A group of Alderley Park Wistar rats was anaesthetised and
surgery was performed to expose the vena cava. Collateral veins
were ligated and two loose sutures were located, 0.7 cm apart,
round the inferior vena cava. Test compound was administered
intravenously or orally. At an appropriate time thereafter tissue
thromboplastin (30 .mu.l/kg) was administered via the jugular vein
and, after 10 seconds, the two sutures were tightened to induce
stasis within the ligated portion of vena cava. After 10 minutes
the ligated tissue was excised and the thrombus therein was
isolated, blotted and weighed.
[0255] f) An In Vivo Measurement of Antithrombotic Activity
[0256] Using a method similar to that of Smith J R et al Br. J.
Pharmacol. 1982, 77: 29-38, fasted male Alderley Park rats (360-410
g) are pre-dosed at various times by oral (5 ml/kg) or subcutaneous
(1 ml/kg) routes before being anaesthetised with Intraval (120
mg/kg i.p.). The left jugular vein and the right carotid artery are
exposed and cannulated with a polypropylene catheters 12 cm in
length. An arterio-venous shunt is completed by connecting the two
catheters with a 6 cm length of tubing (i.d. 0.3 cm) which contains
a 5 cm length of pre-weighed cotton. All tubes were filled with
saline prior to the establishment of the circuit. Clamps are
removed from the catheters and blood is allowed to flow through the
polypropylene tubing for 20 mins. During this time the effect of
the test compound on template bleeding time is assessed. The shunt
is then closed and the thrombus which has developed on the cotton
thread is removed, blotted dry and weighed. Blood samples are also
taken at this point by cardiac puncture into 3.2% tri-sodium
citrate, plasma is prepared by centrifugation (5 mins 20000 g) and
frozen for subsequent prothrombin time and drug level
determinations.
[0257] The plasma concentration of the compound is extrapolated
from the standard curve and expressed in Anti-Factor Xa units.
Thrombus weight is measured following dosing of vehicle or test
compound. Data is expressed as % inhibition of thrombus formation
in the presence of compound when compared to thrombus weight from a
group of control animals.
[0258] Although the pharmacological potencies of the compounds of
formula I vary with structural changes as expected, in general
compounds of the formula I possess activity at the following
concentrations or doses in at least one of the above tests a) to
c):--
[0259] test a): IC.sub.50 (Factor Xa) in the range, for example,
0.001-25 .mu.M;
[0260] test b): IC.sub.50 (thrombin), for example, greater than 40
.mu.M;
[0261] test c): CT2 (PT) in the range, for example, 0.1-50
.mu.M.
[0262] By way of example, the compound of Example 1 as disclosed
hereinafter has an IC.sub.50 of 0.013 .mu.M against Factor Xa in
test a), an IC.sub.50, of greater than 40 .mu.M against thrombin in
test b) and a CT2 (PT) of 5 .mu.M in test c).
[0263] According to a further feature of the invention there is
provided a pharmaceutical composition which comprises an
aminoheterocyclic derivative of the formula I, or a
pharmaceutically-acceptable salt thereof, in association with a
pharmaceutically-acceptable diluent or carrier.
[0264] The composition may be in a form suitable for oral use, for
example a tablet, capsule, aqueous or oily solution, suspension or
emulsion; for topical use, for example a cream, ointment, gel or
aqueous or oily solution or suspension; for nasal use, for example
a snuff, nasal spray or nasal drops; for vaginal or rectal use, for
example a suppository; for administration by inhalation, for
example as a finely divided powder such as a dry powder, a
microcrystalline form or a liquid aerosol; for sub-lingual or
buccal use, for example a tablet or capsule; or for parenteral use
(including intravenous, subcutaneous, intramuscular, intravascular
or infusion), for example a sterile aqueous or oily solution or
suspension. In general the above compositions may be prepared in a
conventional manner using conventional excipients.
[0265] The amount of active ingredient (that is an
aminoheterocyclic derivative of the formula I, or a
pharmaceutically-acceptable salt thereof) that is combined with one
or more excipients to produce a single dosage form will necessarily
vary depending upon the host treated and the particular route of
administration. For example, a formulation intended for oral
administration to humans will generally contain, for example, from
0.5 mg to 2 g of active agent compounded with an appropriate and
convenient amount of excipients which may vary from about 5 to
about 98 percent by weight of the total composition. Dosage unit
forms will generally contain about 1 mg to about 500 mg of an
active ingredient.
[0266] According to a further feature of the invention there is
provided an aminoheterocyclic derivative of the formula I, or a
pharmaceutically-acceptable salt thereof, for use in a method of
treatment of the human or animal body by therapy.
[0267] The invention also includes the use of such an active
ingredient in the production of a medicament for use in:--
[0268] (i) producing a Factor Xa inhibitory effect;
[0269] (ii) producing an anticoagulant effect;
[0270] (iii) producing an antithrombotic effect;
[0271] (iv) treating a Factor Xa mediated disease or medical
condition;
[0272] (v) treating a thrombosis mediated disease or medical
condition;
[0273] (vi) treating coagulation disorders; and/or
[0274] (vii) treating thrombosis or embolism involving Factor Xa
mediated coagulation.
[0275] The invention also includes a method of producing an effect
as defined hereinbefore or treating a disease or disorder as
defined hereinbefore which comprises administering to a
warm-blooded animal requiring such treatment an effective amount of
an active ingredient as defined hereinbefore.
[0276] The size of the dose for therapeutic or prophylactic
purposes of a compound of the formula I will naturally vary
according to the nature and severity of the medical condition, the
age and sex of the animal or patient being treated and the route of
administration, according to well known principles of medicine. As
mentioned above, compounds of the formula I are useful in the
treatment or prevention of a variety of medical disorders where
anticoagulant therapy is indicated. In using a compound of the
formula I for such a purpose, it will generally be administered so
that a daily dose in the range, for example, 0.5 to 500 mg/kg body
weight is received, given if required in divided doses. In general
lower doses will be administered when a parenteral route is
employed, for example a dose for intravenous administration in the
range, for example, 0.5 to 50 mg/kg body weight will generally be
used. For preferred and especially preferred compounds of the
invention, in general, lower doses will be employed, for example a
daily dose in the range, for example, 0.5 to 10 mg/kg body
weight.
[0277] Although the compounds of the formula I are primarily of
value as therapeutic or prophylactic agents for use in warm-blooded
animals including man, they are also useful whenever it is required
to produce an anticoagulant effect, for example during the ex-vivo
storage of whole blood or in the development of biological tests
for compounds having anticoagulant properties.
[0278] The compounds of the invention may be administered as a sole
therapy or they may be administered in conjunction with other
pharmacologically active agents such as a thrombolytic agent, for
example tissue plasminogen activator or derivatives thereof or
streptokinase. The compounds of the invention may also be
administered with, for example, a known platelet aggregation
inhibitor (for example aspirin, a thromboxane antagonist or a
thromboxane synthase inhibitor), a known hypolipidaemic agent or a
known anti-hypertensive agent.
[0279] The invention will now be illustrated in the following
Examples in which, unless otherwise stated:--
[0280] (i) evaporations were carried out by rotary evaporation in
vacuo and work-up procedures were carried out after removal of
residual solids by filtration;
[0281] (ii) operations were carried out at room temperature, that
is in the range 18-25.degree. C. and under an atmosphere of an
inert gas such as argon;
[0282] (iii) column chromatography (by the flash procedure) and
medium pressure liquid chromatography (MPLC) were generally
performed on Merck Kieselgel silica (Art. 9385) or Merck Lichroprep
RP-18 (Art. 9303) reversed-phase silica obtained from E. Merck,
Darmstadt, Germany; alternatively high pressure liquid
chromatography (HPLC) was performed on a Dynamax C-18 60 .ANG.
preparative reversed-phase column;
[0283] (iv) yields are given for illustration only and are not
necessarily the maximum attainable;
[0284] (v) the end-products of the formula I have satisfactory
microanalyses and their structures were confirmed by nuclear
magnetic resonance (NMR) at 200, 250 or 300 MHz and mass spectral
techniques; unless otherwise stated, CD.sub.3SOCD.sub.3 solutions
of the end-products of the formula I were used for the
determination of NMR spectral data, chemical shift values were
measured on the delta scale; the following abbreviations have been
used: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet;
[0285] (vi) intermediates were not generally fully characterised
and purity was assessed by thin layer chromatographic, infra-red
(IR) or NMR analysis;
[0286] (vii) melting points were determined using a Mettler SP62
automatic melting point apparatus or an oil-bath apparatus; melting
points for the end-products of the formula I were generally
determined after crystallisation from a conventional organic
solvent such as ethanol, methanol, acetone, ether or hexane, alone
or in admixture; and
[0287] (viii) the following abbreviations have been used:--
3 DMF N,N-dimethylformamide; THF tetrahydrofuran; DMSO
dimethylsulphoxide. EDAC 1-(3-dimethylaminopropyl)-3-ethy-
lcarbodiimide hydrochloride BOC tert-butyloxycarbonyl
EXAMPLE 1
[0288] 1,1'-Carbonyldiimidazole (0.15 g) was added to a stirred
solution of 4-(6-chloronaphth-2-ylsulphonyl)benzoic acid (0.29 g)
in DMF (10 ml) which had been cooled to 0.degree. C. and the
mixture was stirred at 0.degree. C. for 30 minutes.
N-(4-Pyridyl)piperazine (0.164 g) was added, the cooling bath was
removed and the mixture was stirred at ambient temperature for 16
hours. The solvent was removed by evaporation and the residue was
partitioned between ethyl acetate and water. The ethyl acetate
extract was washed with water and with brine, dried (MgSO4) and
evaporated. The residue was triturated under diethyl ether to give
1-[4-(6-chloronaphth-2-ylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine
(0.085 g), m.p. 267-269.degree. C.;
[0289] NMR Spectrum 3.25-3.5 (m, 6H), 3.6-3.9 (m, 2H), 6.75 (d,
2H), 7.65 (d, 2H), 7.77 (m, 1H), 8.0 (m, 1H), 8.05-8.25 (m, 6H),
8.3 (d, 1H), 8.6 (s, 1H);
[0290] Mass Spectrum m/z 492 (M+H);
[0291] Elemental Analysis Found C, 63.1; H, 4.7; N, 8.2;
C26H22ClN3O3S 2H2O requires C, 63.5; H, 4.5; N, 8.5%.
[0292] The 4-(6-chloronaphth-2-ylsulphonyl)benzoic acid used as a
starting material was prepared as follows:--
[0293] A solution of sodium nitrite (2.7 g) in water (5 ml) was
added during 2 hours to a stirred mixture of
6-amino-2-naphthalenesulphonic acid (8.8 g), dilute aqueous
hydrochloric acid (2.8% weight/volume, 20 ml) and water (15 ml)
which had been cooled to 0.degree. C. The mixture was stirred at
0.degree. C. for 30 minutes and then poured onto a stirred
suspension of cuprous chloride (3.96 g) in dilute aqueous
hydrochloric acid (2.8%, 20 ml). The mixture was evaporated to give
6-chloro-2-naphthalenesulphonic acid which was used without further
purification.
[0294] The material was suspended in DMF (40 ml) and cooled to
5.degree. C. Thionyl chloride (8.6 ml) was added dropwise and the
mixture was stirred at 5.degree. C. for 3 hours. The mixture was
poured onto ice and extracted with methylene chloride. The organic
solution was dried (MgSO4) and evaporated. The residue was purified
by column chromatography using a 20:1 mixture of hexane and ethyl
acetate as eluent. There was thus obtained
6-chloronaphth-2-ylsulphonyl chloride (2.49 g);
[0295] NMR Spectrum 7.45 (m, 1H), 7.8 (m, 1H), 7.85 (d, 1H), 8.05
(m, 2H), 8.2 (s, 1H).
[0296] 6-Chloronaphth-2-ylsulphonyl chloride (2.61 g) was added in
one portion to a stirred mixture of sodium sulphite heptahydrate
(4.71 g), sodium bicarbonate (1.64 g) and water (25 ml) which had
been heated to 70.degree. C. The resultant mixture was heated to
that temperature for 3 hours and then allowed to cool slowly to
ambient temperature. The crystalline precipitate was isolated
giving sodium 6-chloronaphth-2-ylsulphinate (2.4 g) which was used
without further purification.
[0297] A mixture of a portion (0.5 g) of the material so obtained,
4-fluorobenzaldehyde (0.25 g) and DMSO (10 ml) was stirred and
heated to 110.degree. C. for 5 hours. A second portion (0.5 g) of
the sodium 6-chloronaphth-2-ylsulphinate was added and the mixture
was heated to 110.degree. C. for a further 10 hours. The mixture
was cooled to ambient temperature and partitioned between ethyl
acetate and water. The organic extract was washed with water and
with brine, dried (MgSO4) and evaporated. The residue was purified
by column chromatography using a 1:1 mixture of hexane and ethyl
acetate as eluent. There was thus obtained
4-(6-chloronaphth-2-ylsulphonyl)benzaldehyde (0.25 g);
[0298] NMR Spectrum 7.7 (m, 1H), 8.0 (m, 1H), 8.1-8.3 (m, 7H), 8.8
(s, 1H), 10.0 (s, 1H).
[0299] After repetition of the previous steps, potassium
permanganate (0.4 g) was added in small portions during 1 hour to a
stirred mixture of 4-(6-chloronaphth-2-ylsulphonyl)-benzaldehyde
(0.58 g), cetyltrimethylammonium bromide (0.056 g) and water (25
ml) which had been heated to 60.degree. C. The mixture was heated
to 60.degree. C. for a further 2 hours. The mixture was cooled to
ambient temperature and acidified by the addition of 2M aqueous
hydrochloric acid. Ethyl acetate was added. The mixture was
filtered through a pad of diatomaceous earth. The solid was washed
thoroughly in turn with methylene chloride and with ethyl acetate.
The organic solutions were combined, dried (MgSO4), and evaporated.
The residue was purified by column chromatography using
increasingly polar mixtures of methylene chloride and methanol as
eluent. There was thus obtained
4-(6-chloronaphth-2-ylsulphonyl)benzoic acid (0.376 g);
[0300] NMR Spectrum 7.7 (m, 1H); 7.95 (m, 1H); 8.1-8.2 (m, 6H); 8.6
(s, 1H).
EXAMPLE 2
[0301] Using an analogous procedure to that described in Example 1,
N-(4-pyridyl)piperazine was reacted with
4-(2-naphthylsulphonyl)benzoic acid to give
1-[4-(2-naphthylsulphonyl)-benzoyl]-4-(4-pyridyl)piperazine in 32%
yield;
[0302] NMR Spectrum 3.25-3.5 (m, 6H), 3.6-3.9 (m, 2H), 6.8 (d, 2H),
7.7 (d, 2H), 7.77 (m, 1H), 7.95 (m, 1H), 8.05-8.25 (m, 8H), 8.77
(d, 1H);
[0303] Mass Spectrum m/z 457 (M+H);
[0304] Elemental Analysis Found C, 63.5: H, 5.5: N, 8.6;
C26H23N3O3S 2H2O requires C, 63.5: H, 5.5: N, 8.6%.
[0305] The 4-(2-naphthylsulphonyl)benzoic acid used as a starting
material was prepared from 4-fluorobenzaldehyde and sodium
2-naphthylsulphinate using analogous procedures to those described
in the fourth and fifth paragraphs of the portion of Example 1
which is concerned with the preparation of starting materials.
There was thus obtained 4-(2-naphthylsulphonyl)benzoic acid in 28%
yield;
[0306] NMR Spectrum 7.7 (m, 1H), 7.95 (m, 1H), 8.1-8.2 (m, 8H), 8.7
(d, 1H).
EXAMPLE 3
[0307] Glacial acetic acid (0.178 g) was added to a mixture of
N-(4-pyridyl)piperazine (0.121 g),
4-(6-bromonaphth-2-ylsulphonyl)benzald- ehyde (0.278 g) and
methylene chloride (10 ml) and the mixture was stirred at ambient
temperature for 30 minutes. Sodium triacetoxyborohydride (0.236 g)
was added and the mixture was stirred at ambient temperature for 16
hours. Water (50 ml) was added and the mixture was acidified by the
addition of 2M aqueous hydrochloric acid. The resultant mixture was
washed with diethyl ether. The aqueous phase was basified by the
addition of 2M aqueous sodium hydroxide solution and extracted with
methylene chloride. The resultant organic phase was dried (MgSO4),
and evaporated. The residue was purified by column chromatography
using increasingly polar, mixtures of methylene chloride and
methanol as eluent. There was thus obtained
1-[4-(6-bromonaphth-2-ylsulphonyl)benzyl]4-(4-pyridyl)piper- azine
(0.127 g) as a gum;
[0308] NMR Spectrum 3.2-3.4 (m, 8H), 3.6 (s, 2H), 6.75 (d, 2H), 7.6
(d, 2H), 7.75 (m, 1H), 7.95 (m, 3H), 8.1-8.2 (m, 4H), 8.3 (d, 1H),
8.75 (s, 1H);
[0309] Mass Spectrum m/z 522 (M+H);
[0310] Elemental Analysis Found C, 58.6: H, 4.5: N, 7.8;
C26H24BrN3O2S 0.15CH2Cl2 requires C, 58.7: H, 4.6: N, 7.9%.
[0311] The 4-(6-bromonaphth-2-ylsulphonyl)benzaldehyde used as a
starting material was obtained as follows:--
[0312] 6-Bromonaphth-2-ylsulphonyl chloride was obtained in 22%
yield from 6-amino-2-naphthalenesulphonic acid using an analogous
procedure to that described in the first two paragraphs of the
portion of Example 1 which is concerned with the preparation of
starting materials except that hydrobromic acid and cuprous bromide
were used in place of hydrochloric acid and cuprous chloride
respectively. The material gave the following NMR signals: 7.65 (m,
1H), 7.75-8.0 (m, 3H), 8.15-8.2 (m, 2H).
[0313] 6-Bromonaphth-2-ylsulphonyl chloride (9.4 g) was added in
small portions over 3 hours to a stirred mixture of sodium sulphite
heptahydrate (14.46 g), sodium bicarbonate (5.08 g) and water (100
ml) which had been heated to 70.degree. C. The resultant mixture
was allowed to cool slowly to ambient temperature. The crystalline
precipitate was isolated giving sodium 6-bromonaphth-2-ylsulphinate
(8.07 g) which was used without further purification.
[0314] A mixture of a portion (1.47 g) of the material so obtained,
4-fluorobenzaldehyde (0.72 g) and DMSO (20 ml) was stirred and
heated to 110.degree. C. for 4 hours and at 80.degree. C. for 12
hours. The mixture was cooled to ambient temperature and
partitioned between ethyl acetate and water. The organic extract
was washed with water and with brine, dried (MgSO4) and evaporated.
The residue was purified by column chromatography using
increasingly polar mixtures of hexane and ethyl acetate as eluent.
There was thus obtained 4-(6-bromonaphth-2-ylsulphonyl-
)benzaldehyde (0.28 g);
[0315] NMR Spectrum 7.8 (m, 1H), 8.0 (m, 1H), 8.1-8.2 (m, 6H), 8.4
(d, 1H), 8.8 (s, 1H), 10.1 (s, 1H).
EXAMPLE 4
[0316] A solution of 4'-bromo-4-biphenylylsulphonyl chloride (0.33
g) in methylene chloride (5 ml) was added dropwise to a stirred
solution of 4-[1-(4-pyridyl)piperidin-4-yloxy]aniline (0.269 g) in
methylene chloride (20 ml) and the mixture was stirred at ambient
temperature for 16 hours. The precipitated solid was collected by
filtration and triturated under methanol (5 ml). The resultant
solid was washed with diethyl ether. There was thus obtained
4'-bromo-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-4-
-biphenylylsulphonamide, hydrochloride salt, (0.508 g), m.p.
302-304.degree. C.;
[0317] NMR Spectrum 1.66 (m, 2H), 1.99 (m, 2H), 3.58 (m, 2H), 3.86
(m, 2H), 4.60 (m, 1H), 6.89 (d, 2H), 7.03 (d, 2H), 7.18 (d, 2H)
7.67 (s, 4H), 7.76 (d, 2H), 7.84 (d, 2H), 8.19 (d, 2H), 10.05 (s,
1H);
[0318] Mass Spectrum m/z 564/566 (M+H);
[0319] Elemental Analysis Found C, 54.6; H, 4.7; N, 6.9; S, 5.2;
C.sub.28H.sub.26BrN.sub.3O.sub.3S 1HCl 1H.sub.2O requires C, 54.3;
H, 4.7; N, 6.8; S, 5.2%.
[0320] The 4-[1-(4-pyridyl)piperidin-4-yloxy]aniline used as
starting material was obtained as follows:--
[0321] 1,1'-(Azodicarbonyl)dipiperidine (20.03 g),
tributylphosphine (16.06 g) and 1-(4-pyridyl)piperidin-4-ol
(Chemical Abstracts, vol. 113, abstract 23121 In; European Patent
Application No. 0 359 389; 9.43 g) were added in turn to a stirred
solution of 4-(N-tert-butoxycarbonylamino- )phenol (J. Med. Chem.,
1995, 38, 3983; 11.08 g) in THF (300 ml) which was cooled to
10.degree. C. The mixture was stirred at ambient temperature for 20
hours. The precipitate was removed by filtration and the filtrate
was evaporated. The residue was purified by column chromatography
using initially ethyl acetate and then increasingly polar mixtures
of methylene chloride and methanol as eluent. There was thus
obtained tert-butyl
N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}carbamate (7.38 g),
m.p. 192-195.degree. C., which was used without further
purification.
[0322] A solution of a portion (4.22 g) of the material so obtained
in methylene chloride (400 ml) was treated with a saturated
solution of hydrogen chloride in diethyl ether (50 ml). The mixture
was stirred at ambient temperature for 64 hours. The mixture was
evaporated and the residue was crystallised under a mixture of
diethyl ether and methanol to give the hydrochloride salt of the
required starting material (2.85 g), m.p. 289-291.degree. C. A
portion (1.5 g) of the material was dissolved in water (10 ml) and
a 2M aqueous sodium hydroxide solution was added until
precipitation was complete. There was thus obtained
4-[1-(4-pyridyl)piperidin-4-yloxy]aniline (1.03 g), m.p.
214-215.degree. C.;
[0323] NMR Spectrum 1.57 (m, 2H), 1.86 (m, 2H), 3.24 (m, 2H), 3.67
(m, 2H), 4.31 (m, 1H), 6.47 (d, 2H), 6.66 (d, 2H), 6.87 (d, 2H),
8.13 (d, 2H).
[0324] The 4'-bromo-4-biphenylylsulphonyl chloride used as a
starting material was obtained as follows:--
[0325] Chlorosulphonic acid (8.3 ml) was added dropwise to a
stirred solution of 4-bromobiphenyl (23.3 g) in chloroform (200 ml)
and the mixture was stirred at ambient temperature for 30 minutes.
The precipitate was isolated and washed with chloroform. There was
thus obtained 4'-bromo-4-biphenylylsulphonic acid (30.3 g).
[0326] Thionyl chloride (21.2 ml) was added dropwise to a stirred
solution of 4'-bromo-4-biphenylylsulphonic acid (30.3 g) in DMF
(120 ml) which had been cooled to 5.degree. C. The mixture was
stirred at ambient temperature for 3 hours. The mixture was poured
into a mixture of ice and water (1L) and the resultant precipitate
was isolated, dissolved in diethyl ether, dried (MgSO4) and
re-isolated by evaporation of the solvent. There was thus obtained
4'-bromo-4-biphenylyl-sulphonyl chloride (24.1 g) [after
crystallisation of the residue from a 1:1 mixture of isohexane and
toluene], m.p. 125-127.degree. C.
EXAMPLE 5
[0327] Using an analogous procedure to that described in Example 4,
4-[1-(4-pyridyl)-piperidin-4-yloxy]aniline was reacted with
(E)-4-chlorostyrylsulphonyl chloride. The reaction product was
purified by column chromatography on a C-18 60 .ANG. preparative
reversed-phase HPLC column using 0.1% trifluoroacetic acid in
aqueous acetonitrile and a gradient of 30% to 70% acetonitrile as
eluent. There was thus obtained
4-chloro-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-(E)-styrylsulphonam-
ide, trifluoroacetate salt, as a gum in 10% yield;
[0328] NMR Spectrum 1.64 (m, 2H), 1.99 (m, 2H), 3.62 (m, 2H), 3.91
(m, 2H), 4.64 (m, 1H), 6.82-7.42 (m, 8H), 7.46 (d, 2H), 7.72 (d,
2H), 8.23 (d, 2H), 9.75 (s, 1H);
[0329] Mass Spectrum m/z 470/472 (M+H).
[0330] The (E)-4-chlorostyrylsulphonyl chloride used as a starting
material was obtained as follows:--
[0331] Sulphuryl chloride (1.37 ml) was added dropwise to DMF (1.55
ml) which was stirred and cooled to a temperature in the range 0 to
5.degree. C. The mixture was then stirred at ambient temperature
for 30 minutes. 4-Chlorostyrene (1.2 ml) was added and the mixture
was stirred and heated to 90.degree. C. for 3.5 hours. The mixture
was cooled to ambient temperature and poured onto a mixture (25 ml)
of ice and water. The precipitate was isolated, washed with water
and dried. There was thus obtained (E)-4-chloro-p-styrylsulphonyl
chloride (1.8 g);
[0332] NMR Spectrum 6.95 (s, 2H), 7.4 (d, 2H), 7.55 (d, 2H).
EXAMPLE 6
[0333] 6-Bromonaphth-2-ylsulphonyl chloride (0.1 g) was added to a
mixture of 4-[1-(4-pyridyl)piperidin-4-yloxy]aniline (0.1 g),
triethylamine (0.168 g) and methylene chloride (5 ml) and the
mixture was stirred at ambient temperature for 16 hours. The
mixture was evaporated and the residue was purified on a C-18 60
.ANG. preparative reversed-phase HPLC column using 0.1%
trifluoroacetic acid in aqueous acetonitrile and a gradient of 60%
to 95% acetonitrile as eluent. There were thus obtained in
turn:--6-bromo-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-2-naphthal-
enesulphonamide, trifluoroacetate salt, as a gum (0.026 g);
[0334] NMR Spectrum 1.64 (m, 2H), 1.97 (m, 2H), 3.57 (m, 2H), 3.87
(m, 2H), 4.58 (m, 1H), 6.83 (d, 2H) 6.99 (d, 2H), 7.19 (d, 2H),
7.75 (q, 1H), 7.80 (q, 1H), 8.07 (d, 2H), 8.20 (d, 2H), 8.33 (d,
2H), 10.07 (s, 1H), 13.27 (broad s, 1H);
[0335] Mass Spectrum m/z 538/540 (M+H);
[0336] and
6-bromo-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-N-(6-bromo-
naphth-2-ylsulphonyl)-2-naphthalenesulphonamide, trifluoroacetate
salt, as a waxy solid (0.031 g), m.p. 130-135.degree. C.;
[0337] NMR Spectrum 1.67 (m, 2H), 2.07 (m, 2H), 3.62 (m, 2H), 3.94
(m, 2H), 4.76 (m, 1H), 6.99 (m, 4H), 7.22 (d, 2H), 7.86 (m, 41),
8.06-8.27 (m, 6H), 8.45 (d, 4H);
[0338] Mass Spectrum m/z 808 (M+H).
EXAMPLE 7
[0339] Using an analogous procedure to that described in Example 4,
4-[1-(4-pyridyl)piperidin-4-yloxy]aniline was reacted with
4-toluenesulphonyl chloride to give
N-{4-[1-(4-pyridyl)piperidin-4-yloxy]-
phenyl}-4-toluenesulphonamide, hydrochloride salt, in 54% yield,
m.p. 270-272.degree. C.;
[0340] NMR Spectrum 1.63 (m, 2H), 1.97 (m, 2H), 2.31 (s, 3H), 3.57
(m, 2H), 3.88 (m, 2H), 4.60 (m, 1H), 6.84 (d, 2H), 6.98 (d, 2H),
7.20 (d, 2H), 7.31 (d, 2H), 7.57 (d, 2H), 8.19 (d, 2H), 9.88 (s,
1H);
[0341] Mass Spectrum i/z 424 (M+H);
[0342] Elemental Analysis Found C, 57.7; H, 5.5; N, 8.7;
C.sub.23H.sub.25N.sub.3O.sub.3S 1HCl 1H.sub.2O requires; C, 57.8;
H, 5.9; N, 8.8%.
EXAMPLE 8
[0343] Using an analogous procedure to that described in Example 6,
N-{4-[1*4-pyridyl)-piperidin-4-yloxy]phenyl}4-toluenesulphonamide,
hydrochloride salt, was reacted with 4-toluenesulphonyl chloride.
The crude reaction product was triturated under water. There was
thus obtained
N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-N-(4-tolylsulphonyl-
)-4-toluenesulphonamide in 85% yield, m.p. 196-198.degree. C.;
[0344] NMR Spectrum 1.65 (m, 2H), 2.02 (m, 2H), 2.46 (s, 6H), 3.20
(m, 2H), 3.72 (m, 2H), 4.68 (m, 1H), 6.84 (m, 4H), 7.02 (d, 2H),
7.48 (d, 4H), 7.68 (d, 4H), 8.16 (d, 2H);
[0345] Mass Spectrum n/z 578 (M+H).
EXAMPLE 9
[0346] Sodium hydride (60% dispersion in mineral oil, 0.06 g) was
added to a stirred mixture of
4'-bromo-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl-
}-4-biphenylylsulphonamide, hydrochloride salt (0.309 g), THF (10
ml) and DMF (1 ml), and the mixture was stirred at ambient
temperature for 45 minutes. Methyl iodide (0.142 g) was added and
stirring was continued for 16 hours. The mixture was evaporated.
The residue was triturated under water and the resultant solid was
purified by column chromatography using increasingly polar mixtures
of methylene chloride and methanol as eluent. There was thus
obtained 4'-bromo-N-methyl-N-{4-[1-(4-pyridyl)piperidin-4--
yloxy]phenyl}-4-biphenylylsulphonamide, as a foam (0.045 g);
[0347] NMR Spectrum (CDCl.sub.3) 2.00 (m, 4H), 3.20 (s, 3H), 3.41
(m, 2H), 3.65 (m, 2H), 4.57 (m, 1H), 6.74 (d, 2H), 6.84 (d, 2H),
7.05 (d, 2H), 7.47 (d, 2H), 7.61 (m, 6H), 8.25 (d, 2H);
[0348] Mass Spectrum m/z 578/580 (M+H).
EXAMPLE 10
[0349] Using an analogous procedure to that described in Example 4,
N-methyl-4-[1-(4-pyridyl)piperidin-4-yloxy]aniline was reacted with
(E)-4-chlorostyrylsulphonyl chloride. The yellow reaction liquor
was decanted from a brown gum (which was discarded) and evaporated.
The resultant foam was purified by column chromatography on alumina
(ICN alumina N, grade 3) using methylene chloride as eluent. There
was thus obtained
4-chloro-N-methyl-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-(-
E)-styrylsulphonamide, as a gum in 34% yield;
[0350] NMR Spectrum 1.63 (m, 2H), 1.97 (m, 2H), 2.25 (m, 2H), 3.19
(s, 3H), 3.68 (m, 2H), 4.62 (m, 1H), 6.80 (d, 2H), 6.96 (d, 2H),
7.25 (d, 2H) 7.26 (d, 1H), 7.36 (d, 1H), 7.47 (d, 2H), 7.76 (d,
2H), 8.12 (d, 2H);
[0351] Mass Spectrum m/z 484/486 (M+H).
[0352] The N-methyl-4-[1-(4-pyridyl)piperidin-4-yloxy]aniline used
as a starting material was prepared as follows:--
[0353] Acetic formic anhydride (1.5 g; pre-formed by heating acetic
anhydride and 98% formic acid at 60.degree. C. for 2 hours) was
cooled to 5.degree. C. and
4-[1-(4-pyridyl)piperidin-4-yloxy]aniline (1.0 g) was added. The
mixture was stirred at ambient temperature for 16 hours and then
evaporated. The residue was dissolved in water (50 ml) and the
mixture was basified to pH 110 by the addition of a 2M aqueous
sodium hydroxide solution. The resultant mixture was extracted with
methylene chloride, washed with water and with brine, dried (MgSO4)
and evaporated to give
N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}formamide as a foam
(0.72 g);
[0354] NMR Spectrum 1.63 (m, 2H), 1.96 (m, 2H), 3.22 (m, 2H), 3.67
(m, 2H), 4.56 (m, 1H), 6.82 (d, 2H), 6.94 (d, 2H), 7.48 (d, 2H),
8.12 (d, 2H), 8.20 (d, 1H), 9.96 (broad s, 1H);
[0355] Mass Spectrum m/z 298 (M+H).
[0356] The material so formed was dissolved in THF (5 ml) and added
to a stirred suspension of lithium aluminium hydride (0.18 g) in
THF (5 ml). The mixture was stirred at ambient temperature for 16
hours. The minimum volume of a saturated aqueous ammonium chloride
solution was added to destroy the excess of reducing agent. THF (50
ml) was added, the mixture was filtered and the filtrate was
evaporated to give
N-methyl-4-[1-(4-pyridyl)piperidin-4-yloxy]aniline as a pale yellow
solid (0.62 g), m.p. 161-164.degree. C.;
[0357] NMR Spectrum (CDCl.sub.3) 1.82 (m, 2H), 1.98 (m, 2H), 2.82
(s, 3H), 3.27.(m, 2H), 3.64 (m, 2H), 4.34 (m, 1H), 6.57 (d, 2H),
6.66 (d, 2H), 6.82 (d, 2H), 8.25 (d, 2H);
[0358] Mass Spectrum m/z 284 (M+H).
EXAMPLE 11
[0359] Using an analogous procedure to that described in Example 4,
4-[1-(4-pyridyl)piperidin-4-ylmethoxy]aniline was reacted with
4'-bromo-4-biphenylylsulphonyl chloride. The crude reaction product
was washed with methylene chloride. There was thus obtained
4'-bromo-N-{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl}4-biphenylylsulp-
honamide, hydrochloride salt, as a white solid in 77% yield, m.p.
293-295.degree. C.;
[0360] NMR Spectrum 1.30 (q, 2H), 1.87 (d, 2H), 2.21 (m, 1H). 3.18
(m, 2H), 3.78 (d, 2H), 4.22 (d, 2H), 6.81 (d, 2H), 7.01 (d, 2H),
7.18 (d, 2H) 7.67 (s, 4H), 7.77 (d. 2H), 7.84 (d, 2H), 8.18 (d,
2H), 10.0 (s, 1H), 13.3 (broad s, 1H);
[0361] Mass Spectrum m/z 578/580 (M+H);
[0362] Elemental Analysis Found C, 55.8; H, 4.9; N, 6.6;
C.sub.29H.sub.28BrN.sub.3O.sub.3S 1HCl 1.5H.sub.2O requires C,
55.8; H, 4.9; N, 6.7%.
[0363] The 4-[1-(4-pyridyl)piperidin-4-ylmethoxy]aniline used as
starting material was obtained as follows:--
[0364] Using an analogous procedure to that used in the first
paragraph of the portion of Example 4 which is concerned with the
preparation of starting materials,
1-(4-pyridyl)-piperidin-4-ylmethanol (Chemical Abstracts, vol. 113,
abstract 23121 In; European Patent Application No. 0 359 389) was
reacted with 4-(N-tert-butoxycarbonylamino)phenol. The resultant
product was treated with a saturated solution of hydrogen chloride
in diethyl ether using an analogous procedure to that used in the
second paragraph of the portion of Example 4 which is concerned
with the preparation of starting materials. There was thus obtained
4-[1-(4-pyridyl)piperidin-4-ylmethoxy]aniline in 22% yield, m.p.
210-211.degree. C.
EXAMPLE 12
[0365] Using an analogous procedure to that described in Example 4,
4-[1-(4-pyridyl)piperidin-4-ylmethoxy]aniline was reacted with
6-bromonaphth-2-ylsulphonyl chloride. There was thus obtained
6-bromo-N-{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]-phenyl}-2-naphthalenesu-
lphonamide, hydrochloride salt, as a white solid in 76% yield, m.p.
167-169.degree. C.;
[0366] NMR Spectrum 1.26 (m, 2H), 1.84 (d, 2H), 2.10 (m, 1H), 3.15
(m, 2H), 3.72 (d, 2H), 4.20 (d, 2H), 6.75 (d, 2H), 6.96 (d, 2H),
7.16 (d, 2H), 7.76 (m, 2H), 8.05 (d, 2H), 8.16 (d, 2H), 8.31 (d,
2H), 10.05 (s, 1H);
[0367] Mass Spectrum m/z 552/554 (M+H);
[0368] Elemental Analysis Found C, 53.7; H, 4.9; N, 7.1;
C.sub.27H.sub.26BrN.sub.3O.sub.3S 1HCl 1H.sub.2O requires C, 53.3;
H, 5.0; N, 6.9%.
EXAMPLE 13
[0369] Using an analogous procedure to that described in Example 4,
4-[1-(4-pyridyl)piperidin-4-ylmethoxy]aniline was reacted with
(E)-4-chlorostyrylsulphonyl chloride. There was thus obtained
4-chloro-N-{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl}-(E)-styrylsulph-
onamide, hydrochloride salt, in 34% yield, m.p. 220-223.degree.
C.;
[0370] NMR Spectrum 1.30 (m, 2H), 1.88 (d, 2H), 2.13 (m, 1H), 3.14
(m, 2H), 3.79 (d, 2H), 4.22 (d, 2H), 6.84 (d, 2H), 7.10 (d, 2H),
7.15 (d, 2H), 7.17 (d, 1H), 7.32 (d, 1H), 7.43 (d, 2H), 7.68 (d,
2H), 8.17 (d, 2H), 9.69 (s, 1H);
[0371] Mass Spectrum m/z 484/486 (M+H);
[0372] Elemental Analysis Found C, 54.7; H, 5.2; N, 7.7;
C.sub.25H.sub.26ClN.sub.3O.sub.3S 1HCl 1.5H.sub.2O requires C,
54.9; H, 5.5; N, 7.7%.
EXAMPLE 14
[0373] Using an analogous procedure to that described in Example 6.
4'-bromo-N-{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl}-4-biphenylylsul-
phonamide, hydrochloride salt, was reacted with
4'-bromo-4-biphenylylsulph- onyl chloride. There was thus obtained
4'-bromo-N-(4'-bromo-4-biphenylylsu-
lphonyl)-N-{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl}-4-biphenylylsulp-
honamide in 91% yield, m.p. 136-140.degree. C.;
[0374] NMR Spectrum 1.31 (m, 2H), 1.84 (d, 2H), 2.05 (m, 1H), 2.89
(t, 2H). 3.88 (d, 2H), 3.98 (d, 2H), 6.83 (d, 2H), 6.99 (s, 4H),
7.73 (s, 8H), 7.89 (d, 4H), 7.99 (d, 4H), 8.12 (d, 2H);
[0375] Mass Spectrum m/z 874 (M+H).
EXAMPLE 15
[0376] Using an analogous procedure to that described in Example 6,
6-bromo-N-{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl}-2-naphthalenesul-
phonamide, hydrochloride salt, was reacted with
6-bromonaphth-2-ylsulphony- l chloride. There was thus obtained
6-bromo-N-(6-bromonaphth-2-ylsulphdnyl-
)-N-{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl}-2-naphthalenesulphonami-
de in 99% yield, m.p. 246-252.degree. C.;
[0377] NMR Spectrum 1.47 (m, 2H), 1.93 (d, 2H), 2.07 (m, 0.1H),
2.91 (t, 2H), 3.82 (d, 2H), 3.94 (d, 2H), 6.67 (d, 2H), 6.81 (d,
2H), 6.94 (d, 2H), 7.71 (d, 2H), 7.82 (d, 2H), 7.90 (d, 2H), 7.99
(d, 2H), 8.13 (s, 2H), 8.26 (d, 2H), 8.43 (s, 2H);
[0378] Mass Spectrum m/z 822 (M+H).
EXAMPLE 16
[0379] Using an analogous procedure to that described in Example 4
except that the reaction mixture was stirred at ambient temperature
for 71 hours, 3-[1-(4-pyridyl)piperidin-4-yloxy]aniline was reacted
with 6-bromonaphth-2-ylsulphonyl chloride. The product was washed
with methylene chloride and dried. There was thus obtained
6-bromo-N-{3-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-2-naphthalenesulphon-
amide, hydrochloride salt, in 77% yield, m.p. 298-300.degree.
C.;
[0380] NMR Spectrum 1.63 (m, 2H), 1.92 (m, 2H), 3.57 (m, 2H), 3.81
(m, 2H), 4.57 (m, 1H), 6.70 (m, 3H), 7.18 (m, 3H), 7.77 (m, 2H),
8.08 (m, 2H), 8.21 (d, 2H), 8.30 (s, 1H), 8.47 (s, 1H), 10.41 (s,
1H), 13.47 (broads, 1H);
[0381] Mass Spectrum m/z 538/540 (M+H);
[0382] Elemental Analysis Found C, 53.8; H, 4.5; N, 7.2;
C.sub.26H.sub.24N.sub.3O.sub.3S 1HCl 0.25H.sub.2O requires: C,
53.9; H, 4.4; N, 7.25%.
[0383] The 3-[1-(4-pyridyl)piperidin-4-yloxy]aniline used as a
starting material was prepared as follows:--
[0384] Diethyl azodicarboxylate (3 ml) was added over 15 minutes to
a stirred mixture of 1-(4-pyridyl)piperidin-4-ol (3.39 g),
3-(N-tert-butoxycarbonylamino)phenol (Chemical Abstracts, vol. 119,
abstract 139113; PCT Patent Application WO 9306085; 3.98 g),
triphenylphosphine (4.99 g) and THF (150 ml) which had been cooled
to 4.degree. C. The resultant mixture was stirred for 48 hours at
ambient temperature. The solvent was evaporated and the residue was
purified by column chromatography using a 9:1 mixture of methylene
chloride and methanol as eluent. The resultant foam was
crystallised from diethyl ether to give tert-butyl
N-{3-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}carb- amate (4.65 g),
m.p. 165-166.degree. C.
[0385] A 2.2M solution of hydrogen chloride in methanol (45 ml) was
added over 15 minutes to a stirred solution in methanol (25 ml) of
a portion (2.53 g) of the carbamate so obtained. The mixture was
stirred at ambient temperature for 24 hours. The solvent was
evaporated and the residue was dissolved in water (50 ml). A 1M
aqueous sodium hydroxide solution (25 ml) was added and the mixture
was stirred for 1 hour. The precipitate was collected, washed with
water and with diethyl ether and dried. There was thus obtained
3-[1-(4-pyridyl)piperidin-4-yloxy]aniline (1.71 g), m.p.
184-186.degree. C.;
[0386] NMR Spectrum 1.60 (m, 2H), 1.96 (m, 2H), 3.23 (m, 2H+H2O),
3.65 (m, 2H) 4.48 (m, 1H), 5.00 (s, 2H), 6.16 (m, 3H), 6.82 (d,
2H), 6.88 (t, 1H), 8.15 (d, 2H).
EXAMPLE 17
[0387] Diethyl azodicarboxylate (0.157 ml) was added over 15
minutes to a stirred mixture of 1-(4pyridyl)piperidin-4-ol (0.178
g), 4-(4-chlorophenylsulphonyl)phenol (J. Amer. Chem. Soc., 1956,
78, 3400; 0.269 g), triphenylphosphine (0.265 g) and THF (10 ml)
which had been cooled to 4.degree. C. The resultant mixture was
stirred for 42 hours at ambient temperature. The solvent was
evaporated and the the residue was purified by column
chromatography using a 9:1 mixture of methylene chloride and
methanol as eluent. The residue was triturated under diethyl ether
to give
4-[4-chlorophenylsulphonyl)phenoxy]-1-(4-(pyridyl)piperidin- e
(0.134 g), m.p. 151-152.degree. C.;
[0388] NMR Spectrum 1.68 (m, 2H), 2.02 (m, 2H), 3.24 (m, 2H+H2O),
3.67 (m, 2H), 4.78 (m, 1H), 6.81 (d, 2H), 7.17 (d, 2H), 7.65 (d,
2H), 7.89 (m, 4H), 8.13 (d, 2H);
[0389] Mass Spectrum m/z 429/431 (M+H);
[0390] Elemental Analysis Found C, 60.6; H, 4.8; N, 6.6;
C22H21ClN2O3S 0.5H2O requires C, 60.3; H, 5.1; N, 6.4%.
EXAMPLE 18
[0391] N-(4-Pyridyl)piperazine (0.163 g) was added, in one portion,
to a stirred solution of 5-(6-bromonaphth-2-ylsulphonyl)phthalic
anhydride (0.417 g.) in DMF (10 ml.) and the mixture was stirred at
ambient temperature for 1 hour. Diethyl ether (40 ml.) was added
and the mixture was stirred rapidly. The resultant white, amorphous
precipitate was recovered by filtration. There was thus obtained a
1:1 mixture (0.474 g., 81%) of:--
[0392]
5-(6-bromonaphth-2-ylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbo-
nyl]benzoic acid and
4-(6-bromonaphth-2-ylsulphonyl)-2-[4-(4-pyridyl)piper-
azin-1-ylcarbonyl]benzoic acid; the mixture giving the following
characterising data;
[0393] NMR Spectrum 3.2-3.8 (m, 16H), 6.8 (m, 4H), 7.5 (d, 1H),
7.8-7.9 (m, 3H), 8.0 (m, 2H), 8.05 (s, 2H), 8.1-8.25 (m, 10H), 8.4
(d, 2H), 8.45 (d, 1H), 8.8 (s, 1H);
[0394] Mass Spectrum m/z 579 (M+H);
[0395] Elemental Analysis Found C, 52.9; H, 4.5; N, 6.8;
C27H22BrN3O5S 2H2O requires C, 52.6; H, 4.3; N, 6.8%.
[0396] The 5-(6-bromonaphth-2-ylsulphonyl)phthalic anhydride used
as a starting material was prepared as follows:--
[0397] Triethylamine (3.1 ml) was added dropwise to a stirred
mixture of 5-bromophthalic anhydride
(5-bromo-1,3-dihydro-2-benzofuran-1,3-dione; 4.54 g),
6-bromo-2-naphthalenethiol (European Patent Application No.
0409413, Example 19; 5.25 g) and DMF (50 ml) and the mixture was
stirred at ambient temperature for 10 minutes. The mixture was
heated at 60.degree. C. for 1 hour and then stirred at ambient
temperature for 16 hours. The solvent was evaporated and the
residue was suspended in methanol (60 ml). The mixture was basified
by the addition of 2M aqueous sodium hydroxide solution and the
mixture was heated to reflux for 1 hour. The mixture was cooled
ambient temperature and partitioned between water (300 ml) and
diethyl ether. The aqueous layer was acidified by the addition of
concentrated hydrochloric acid and extracted with ethyl acetate
(2.times.100 ml). The combined extracts were washed with water and
with brine, dried (MgSO4) and evaporated. The residue was
triturated under diethyl ether to give
4-(6-bromonaphth-2-ylthio)phthalic acid (6 g, 74%) as a pale yellow
solid;
[0398] NMR Spectrum (CDCl.sub.3/DMSO) 7.02 (m, 1H), 7.18 (m, 1H),
7.2-7.55 (m, 5H), 7.65 (s, 1H), 7.72 (s, 1H).
[0399] A portion (4.5 g) of the material so obtained was suspended
in glacial acetic acid (50 ml.) and sodium perborate tetrahydrate
(5.13 g) was added in small portions. The reaction mixture was then
stirred at ambient temperature for 16 hours. A further portion
(1.72 g) of sodium perborate tetrahydrate was added and the mixture
was stirred for a further 6 hours. The reaction mixture was poured
into water (500 ml.) and extracted with ethyl acetate. The extracts
were washed with water and with brine, dried (MgSO4) and evaporated
to give 4-(6-bromonaphth-2-ylsul- phonyl)phthalic acid as a white
solid (5.31 g);
[0400] NMR Spectrum 7.85 (m, 2H), 8.0 (m, 1H), 8.1-8.3 (m, 4H),
8.35 (d, 1H), 8.8 (s, 1H).
[0401] A mixture of a portion (0.538 g) of the material so obtained
was suspended in acetic anhydride (5 ml) and the mixture was heated
to 100.degree. C. until a clear solution was obtained. The mixture
was cooled to ambient temperature. The resultant white solid was
recovered by filtration, washed with diethyl ether and dried to
give 5-(6-bromonaphth-2-ylsulphonyl)-phthalic anhydride (0.362
g);
[0402] Mass Spectrum m/z 416 (M+H).
[0403] Elemental Analysis Found C, 52.0; H, 2.1; C18H9BrO5S
requires C, 51.8; H, 2.17%.
EXAMPLE 19
[0404] To a solution of
4-((4-(4-pyridyl)piperazin-1-ylmethyl)benzoic acid chloride (510
mg) in dichloromethane (20 ml) was added triethylamine (1 ml),
followed by a solution of 4-(4-chlorophenoxy)aniline (265 mg). The
resulting mixture was stirred at room temperature for 18 hours. The
mixture was partitioned between water and dichloromethane. The
organic extracts were dried (MgSO.sub.4) and evaporated to give a
gum which was purified by column chromatography on silica eluting
with increasing concentrations of methanol and dichloromethane to
givel-[4-(4-(4-chloroph-
enoxy)phenylaminocarbonyl)benzyl]-4-(4-pyridyl)piperazine as a
glass (32 mg);
[0405] NMR Spectrum 8.15 (d, 2H), 7.95 (d, 2H), 7.8 (d, 2H)7.4-7.5
(m, 4H), 6.95-7.1 (m, 4H), 6.85 (d, 2H), 3.6 (s, 2M), 3.2-3.4 (m,
8H);
[0406] Mass Spectrum m/z 499 (M+H).sup.+;
[0407] Elemental Analysis Found C, 66.3; H, 5.4; N, 10.7;
C.sub.29H.sub.27ClN.sub.4O.sub.2.1.5H.sub.2O requires C, 66.2; H,
5.7; N, 10.65%.
[0408] The acid chloride used as a starting material was prepared
as follows:--
[0409] (a) To a suspension of 4-(4-pyridyl)piperazine (13.1 g) in
ethyl acetate (200 ml) was added triethylamine (56 ml) followed
dropwise, over 5 hours, by a solution of methyl
4-bromomethylbenzoate (18.41 g). The mixture was stirred at room
temperature for 18 hours. The mixture was partitioned between water
and ethyl acetate. The organic extracts were dried (MgSO.sub.4) and
evaporated to give a gum, which was purified by column
chromatograhy on silica eluting with increasing concentrations of
methanol/dichloromethane to give methyl
4-(4-(4-pyridyl)piperazin-1-ylmet- hyl)benzoate (13.1 g) as a
solid;
[0410] NMR Spectrum 8.15 (d, 2H), 7.95 (d, 2H), 7.5 (d, 2H), 6.8
(d, 2H), 3.85 (s, 3H), 3.6 (s, 2H), 3.25-3.35 (m, 4H), 2.45-2.55
(m, 4H);
[0411] Mass Spectrum m/z 311 (M+H).sup.+;
[0412] Elemental Analysis Found C, 69.2; H, 6.6; N, 13.5
C.sub.18H.sub.21N.sub.3O.sub.2 requires C, 69.4; H, 6.8; N,
13.5%.
[0413] (b) To a solution of the product of step (a) (849 mg) in
methanol (15 ml) was added 2N sodium hydroxide (6.8 ml) and the
resulting mixture was stirred for 3 hours. The mixture was
evaporated to dryness. The resulting gum was dissolved in water (7
ml) and acidified with acetic acid. The mixture was filtered to
give 4-(4-(4-pyridyl)piperazin-1-ylmeth- yl)benzoic acid (429
mg);
[0414] NMR Spectrum (CD.sub.3SOCD.sub.3+CD.sub.3COOD) 8.15 (d, 2H),
8.0 (d, 2H), 7.5 (d, 2H), 7.1 (d, 2H), 3.7-3.8 (m, 6H), 2.7-2.8 (m,
4H);
[0415] Mass Spectrum m/z 298 (M+H).sup.+;
[0416] Elemental Analysis Found C, 68.3; H, 6.4; N, 14.0;
C.sub.17H.sub.19N.sub.3O.sub.2 requires: C, 68.7; H, 6.4; N,
14.1%.
[0417] (c) To a suspension of the product from step (b) (5.19 g) in
dichloromethane (100 ml) was added thionyl chloride (7.3 ml). The
resulting mixture was stirred for 3 hours and then evaporated to
give the acid chloride as a solid (7.66 g) which was used without
further purification.
EXAMPLE 20
[0418] To a solution of
2-[1-(4-pyridyl)piperidin-4-ylmethoxy]aniline (131 mg) in pyridine
(5 ml) was added 6-bromonaphthyl-2-sulphonyl chloride (148 mg). The
resulting mixture was heated to 120.degree. C. for 18 hours. The
mixture was concentrated to a gum, which was purified by column
chromatography on silica eluting with increasing concentrations of
methanol and dichloromethane to give
6-bromo-N-{2-[-(4-pyridyl)piperidin--
4-ylmethoxy]phenyl}-2-naphthalenesulphonamide (177 mg), m.p.
197-200.degree. C.;
[0419] NMR Spectrum 8.15 (s, 2H), 8.0-8.1 (m, 4H), 7.8 (dd, 1H),
7.55 (dd, 1H), 7.3 (dd, 1H), 7.05-7.1 (m, 1H), 6.8-6.9 (m, 2H), 6.7
(d, 2H), 3.7 (d, 2H), 3.3-3.4 (m, 2H), 2.4-2.4 (m, 2H), 1.3-1.4 (m,
3H), 0.7-0.9 (m, 2H);
[0420] Mass Spectrum m/z=552/554 (M+H.sup.+);
[0421] Elemental Analysis Found C, 56.5; H, 4.6; N, 7.5;
C.sub.27H.sub.26BrN.sub.3O.sub.3S.H.sub.2O requires C, 56.8; H,
4.9; N, 7.4%.
[0422] The 2-[1-(4-pyridyl)piperidin-4-ylmethoxy]aniline used as a
starting material was prepared as follows:--
[0423] (a) To a solution of 2-aminophenol (2.84 g) in
dichloromethane (120 ml) was added di-tert-butyl dicarbonate (6.55
g). The mixture was stirred at room temperature for 18 hours. The
mixture was partitioned between water and dichloromethane. The
organic extracts were dried (MgSO.sub.4) and evaporated to give a
solid which was purified by column chromatography on silica eluting
with a mixture of ethyl acetate and hexane (20:80) to give
2-tert-butyloxycarbonylaminophenol (1.80 g);
[0424] NMR Spectrum 9.7 (s, 1H), 7.7 (s, 1H), 7.6 (d, 1H), 6.7-6.9
(m, 3H), 1.45 (s, 9H);
[0425] Mass Spectrum m/z=210 (M+H).
[0426] (b) To a solution of 1-(4-pyridyl)piperidin-4-ylmethanol
(357 mg) and 2-tert-butyloxycarbonylaminophenol (328 mg) in
tetrahydrofuran (15 ml) was added triphenylphosphine (447 mg)
followed by diethyl azodicarboxylate (0.27 ml). The mixture was
stirred at room temperature for 18 hours. The reaction mixture was
concentrated to a gum which was purified by column chromatography
on silica eluting with methanol/dichloromethane (10:90) to give the
tert-butyloxycarbonyl protected derivative of
2-[1-(4-pyridyl)piperidin-4-ylmethoxy]aniline (1.05 g);
[0427] NMR Spectrum 8.2 (d. 2H), 7.5-7.7 (m, 2H), 6.95-7.05 (m,
2H), 6.8 (d, 2H), 3.85-4.1 (m. 4H), 2.8-2.95 (m, 2H), 1.8-1.9 (m,
1H), 1.45 (s, 9H), 1.15-1.25 (m, 5H);
[0428] Mass Spectrum m/z=384 (M+H).
[0429] (c) To a solution of the product from step (b) (1.39 g) in
methanol (50 ml) was added methanolic HCl (5 ml) and the resulting
mixture was stirred for 4 days. The reaction mixture was
partitioned between sodium bicarbonate solution and
dichloromethane. The organic extracts were dried (MgSO.sub.4) and
evaporated to give 2-[1-(4-pyridyl)piperidin-4-ylmethoxy- ]aniline
as a solid (971 mg) which was used without further
purification;
[0430] NMR Spectrum 8.1-8.15 (m, 2H), 6.6-6.8 (m, 6H), 3.74.0 (m,
6H), 2.85-3.0 (m, 2H), 1.8-2.2 (m, 5H), 1.2-1.3 (m, 2H).
EXAMPLE 21
[0431] Using an analogous procedure to that described in Example 4
except that the reaction mixture was stirred at ambient temperature
for 26 hours, 3-[1-(4-pyridyl)piperidin-4-yloxy]aniline was reacted
with (E)-4-chlorostyrylsulphonyl chloride. The product was washed
with methylene chloride and dried. There was thus obtained
4-chloro-N-{3-[1-(4-pyridyl)piperidin-4yloxy]phenyl}-(E)-styrylsulphonami-
de, hydrochloride salt, in 73% yield, m.p. 147-150 C;
[0432] NMR Spectrum 1.59 (m, 2H), 2.00 (m, 2H), 3.58 (m, 2H), 3.86
(m, 2H), 4.63 (m, 1H), 6.70 (d, 1H), 6.77 (m, 2H), 7.20 (m, 3H),
7.30 (d, 1H), 7.49 (m, 3H), 7.73 (d, 2H), 8.22 (d, 2H), 10.10 (bs,
1H);
[0433] Mass Spectrum m/z 470/472 (M+H);
[0434] Elemental Analysis Found C, 56.2; H 5.1; N, 8.4;
C.sub.24H.sub.24ClN.sub.3O.sub.3S 1HCl 0.25H.sub.2O requires: C,
56.4; H, 5.0; N, 8.2%.
[0435] The 3-[1-(4-pyridyl)piperidin-4-yloxy]aniline used as
starting material was prepared in Example 16.
EXAMPLE 22
[0436] Using an analogous procedure to that described in Example
17, 1-(4-pyridyl)piperidin-4-ol was reacted with
4-(6-bromonaphth-2-ylsulphon- yl)phenol. There was thus obtained
4-[4-(6-bromonaphth-2-ylsulphonyl)pheno-
xy]-1-(4-pyridyl)piperidine in 62% yield, m.p. 180-183.degree.
C.;
[0437] NMR Spectrum 1.62 (m, 2H), 1.97 (m, 2H), 3.24 (m,
2H+H.sub.2O), 3.65, (m, 2H), 4.77 (m, 1H), 6.80 (d, 2H), 7.19 (d,
2H), 7.80 (d, 1H), 7.91 (d, 3H), 8.05-8.19 (m, 4H), 8.34 (s, 1H),
8.70 (s, 1H);
[0438] Mass Spectrum m/z 523/525 (M+H);
[0439] Elemental Analysis Found C, 59.3; H, 4.4; N, 5.7;
C.sub.26H.sub.23BrN.sub.2O.sub.3S requires: C, 59.7; H, 4.4; N,
5.4%.
[0440] The 4-(6-bromonaphth-2-ylsulphonyl)phenol used as a starting
material was prepared as follows:--
[0441] Aluminium chloride (3.33 g) was added portionwise over 30
minutes to a stirred mixture of 6-30 bromonaphth-2-ylsulphonyl
chloride (6.11 g) and anisole (3.33 g) in dry methylene chloride
(35 ml). The resultant mixture was stirred for 24 hours. Methylene
chloride (75 ml) was added, the mixture cooled to 4.degree. C. and
water (100 ml) added cautiously. The mixture was acidified with 2M
hydrochloric acid, separated and the aqueous phase extracted with
methylene chloride (30 ml). The combined organic phases were washed
with water, dried (MgSO.sub.4) and evaporated. Recrystallisation of
the residue from an ethyl acetate/ethanol mixture gave
4-(6-bromonaphth-2-ylsulphonyl)anisole (1.74 g), m.p.
180-181.degree. C.;
[0442] NMR spectrum 3.80 (s, 3H), 7.12 (d, 2H), 7.80 (d, 1H), 7.92
(m, 3H), 8.08 (d, 1H), 8.16 (d, 1H), 8.32 (s, 1H), 8.69 (s,
1H);
[0443] Mass spectrum m/z 377/379 (M+H).
[0444] A 1M solution of boron tribromide in methylene chloride
(9.65 ml) was slowly added to a stirred, cooled (-78.degree. C.),
methylene chloride (25 ml) solution of a portion (1.21 g) of the
anisole derivative so obtained. The mixture was stirred for 20
hours at ambient temperature, then cooled to -0.degree. C., diethyl
ether (4 ml) slowly added, and stirring continued for 10 minutes.
Water (25 ml) was added and the mixture extracted with ethyl
acetate (2.times.25 ml). The combined organic extracts were washed
with water, dried (MgSO.sub.4) and evaporated. Trituration of the
residue under ether gave 4-(6-bromonaphth-2-ylsulphonyl)phenol
(1.03 g), m.p. 178-180.degree. C.;
[0445] NMR Spectrum 6.92 (d, 2H), 7.77-7.91 (m, 4H), 8.06 (d, 1H),
8.14 (d, 1H), 8.32 (s, 1H), 8.68 (s, 1H), 10.62 (s, 1H);
[0446] Mass Spectrum m/z 361/363 (M-H);
[0447] Elemental Analysis Found C, 52.3; H, 3.2; S, 8.3;
C.sub.16H.sub.11BrO.sub.3S 0.25H.sub.2O requires: C, 52.3; H, 3.15;
S, 8.7%.
EXAMPLE 23
[0448] 6-Bromo-2-naphthylenethiol (2.39 g) was slowly added to a
stirred suspension of sodium hydride (60% w/w suspension in mineral
oil, 404 mg) in DMF (10 ml) at 4.degree. C. After 1 hour, a portion
(569 mg) 4-(4-fluorobenzoyl)-1-(4-pyridyl)piperidine and further
dimethylformamide (8 ml) were added. The mixture was stirred at
50.degree. for 24 hours and then 16 hours at ambient temperature.
The mixture was added to water (50 ml) and extracted with methylene
chloride (3.times.50 ml). The combined organic extracts were washed
with water, dried (Mg SO.sub.4) and evaporated. The residue was
purified by column chromatography using increasingly polar mixtures
of methanol and methylene chloride as eluent. There was thus
obtained 4-[4-(6-bromonaphth-2-ylthio)benzoyl]-1-(4-pyridy-
l)piperidine (613 mg);
[0449] NMR Spectrum (CDCl.sub.3) 1.70-2.02 (m, 4H+H.sub.2O), 3.03
(td, 2H), 3.43 (m, 1H), 3.92, (dm, 2H), 6.68 (d, 2H), 7.25 (s, 2H),
7.51 (d, 1H), 7.60 (d, 1H), 7.67 (d, 1H), 7.77 (d, 1H), 7.84 (d,
2H), 8.01 (d, 2H), 8.25 (bs, 2H);
[0450] Mass Spectrum m/z 503/505 (M+H).
[0451] The 4-(4- fluorobenzoyl)-1-(4-pyridyl)piperidine used as a
starting material was prepared as follows:--
[0452] A stirred mixture of 4-(4-fluorobenzoyl)piperidine,
hydrochloride salt (3.90 g), 4-chloropyridine, hydrochloride salt
(2.85 g) and triethylamine (4.90 ml) in xylene (75 ml) was heated
at 145.degree. C. for 27 hours. The solvent was evaporated and the
residue partitioned between methylene chloride (150 ml) and water
(100 ml), the pH being adjusted to 10 with 0.880 ammonia. The
aqueous phase was extracted with a further methylene chloride (50
ml). The combined organic phases were washed with water, dried (Mg
SO.sub.4) and evaporated. The residue was purified by column
chromatography using a 19:1 mixture of methylene chloride and
methanol as eluent to give 4-(4- fluorobenzoyl)-1-(4-pyridyl-
)piperidine (1.89 g);
[0453] NMR Spectrum (CDCl.sub.3) 1.80-2.06 (m, 4H+H.sub.2O), 3.03
(t, 2H), 3.48 (m, 11H), 3.94, (d, 2H), 6.68 (d, 2H), 7.18 (t, 2H),
8.01 (m, 2H), 8.28 (d, 2H);
[0454] Mass Spectrum m/z 285 (M+H).
EXAMPLE 24
[0455] Sodium perborate tetrahydrate (614 mg) was added to a
stirred solution of
4-[4-(6-bromonaphth-2-ylthio)benzoyl]-1-(4-pyridyl)piperidine (505
mg) in glacial acetic acid (25 ml). After 4 hours further sodium
perborate tetrahydrate (614 mg) was added and stirring continued
for 27 hours. The reaction mixture was poured into an ice/water
mixture (50 ml) and extracted with methylene chloride (4.times.25
ml)., The combined extracts were washed with water and with brine,
dried (Mg SO.sub.4) and evaporated. The residue was purified by
column chromatography using a 19:1 methylene chloride and methanol
mixture as eluent and the resultant foam triturated under
is-hexane. There was thus obtained
4-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-1-(4-pyridyl)piperidine
(21 mg);
[0456] NMR Spectrum (CDCl.sub.3) 1.77-2.05 (m, 4H), 3.15 (td, 2H),
3.52 (m, 1H), 4.00, (m, 2H), 6.71 (d, 2H), 7.72 (dd, 1H), 7.85 (m,
3H), 8.08 (m, 5H), 8.24 (d, 2H), 8.57 (s, 1H);
[0457] Mass Spectrum m/z 535/537 (M+H).
EXAMPLE 25
[0458] A stirred mixture of 4-chloropyridine hydrochloride (78.3
mg), 1-[4-(6-bromonaphth-2-ylsulphonyl)phenylsulphonyl]piperazine
hydrochloride (185 mg), triethylamine (0.145 ml) and xylene (3.0
ml) was heated at 140.degree. C. for 16 hours. The solvent was
evaporated and the residue purified by column chromatography on a
C-18 60 .ANG. preparative reversed-phase HPLC column using 0.1%
trifluoroacetic acid in aqueous acetonitrile and a gradient of 30%
to 70% acetonitrile. There was thus obtained
4-[4-(6-bromonaphth-2-ylsulphonyl)phenylsulphonyl]-1-(4-pyridyl)-
piperazine, trifluoroacetate salt (29.1 mg), m.p. 236-238.degree.
C.:
[0459] NMR Spectrum 3.10 (t, 4H), 3.74 (t, 4H), 7.10 (d, 2H), 7.82
(d, 1H), 7.98 (d, 3H), 8.08-8.29 (m, 6H), 8.36 (s, 1H), 8.78 (s,
1H);
[0460] Mass Spectrum m/z 572/574 (M+H).
[0461] The
1-[4-(6-bromonaphth-2-ylsulphonyl)phenylsulphonyl]piperazine used
as a starting material was prepared as follows:--
[0462] 4-Fluorobenzenesulphonyl chloride (1.95 g) was added to a
stirred solution of N-=-butyloxycarbonylpiperazine (1.86 g) and
triethylamine (6.9 ml) in methylene chloride (100 ml) at 4.degree.
C. and stirring continued at ambient temperature for 16 hours. The
solvent was evaporated and the residue purified by column
chromatography using methylene chloride and 1% methanol in
methylene chloride as eluent. There was thus obtained
4-(4-fluorophenylsulphonyl)-1-(tert-butyloxycarbonyl)piperazine
(3.09 g), m.p. 163-164.degree. C.;
[0463] NMR Spectrum (CDCl.sub.3) 1.42 (s, 9H), 2.98 (t, 4H), 3.51
(t, 4H), 7.23 (m, 2H), 7.77 (m, 2H);
[0464] Mass Spectrum m/z 362 (M+NH.sub.4);
[0465] Elemental Analysis Found C, 52.1; H, 6.1; N, 8.0;
C.sub.15H.sub.21FN.sub.2O.sub.4S requires: C, 52.3; H, 6.15; N,
8.1%.
[0466] Sodium hydride (60% w/w suspension in mineral oil, 88 mg)
was slowly added to a stirred solution of
6-bromo-2-naphthylenethiol (478 mg) in dry DMF (5 ml) at 4.degree.
C. and stirring continued for 30 minutes. A portion of the
piperazine derivative (688 mg) prepared in the previous paragraph
was added and stirring continued for 1 hour at 4.degree. C. and for
64 hours at ambient temperature. The mixture was added to an
ice/water mixture and the precipitated solid collected by
filtration. Purification by column chromatography using initially a
10% then a 15% mixture of ethyl acetate and iso-hexane as eluent
gave
4-[4-(6-bromonaphth-2-ylthio)phenylsulphonyl]-1-(=-butyloxycarbonyl)piper-
azine (630 mg), m.p. 99-101.degree. C.;
[0467] NMR Spectrum (CDCl.sub.3) 1.42 (s, 9H), 2.97 (t, 4H), 3.49
(t, 4H), 7.25 (m, 2H), 7.5-7.8 (m, 6H) 8.06 (d, 2H);
[0468] Mass Spectrum m/z 507/509 (M+H--C.sub.4H.sub.8);
[0469] Elemental Analysis Found C, 53.6; H, 5.1; N, 5.0;
C.sub.25H.sub.27BrN.sub.2O.sub.4S.sub.2 requires: C, 53.3; H, 4.8;
N, 5.0%.
[0470] Sodium perborate tetrahydrate (308 mg) was added to a
stirred solution of a portion (282 mg) of the material prepared
above in glacial acetic acid (2 ml). After stirring for 16 hours,
further acetic acid (2 ml) and sodium perborate tetrahydrate (308
mg) were added, stirring continued for 16 hours when a final
addition of acetic acid (10 ml) and sodium perborate tetrahydrate
(308 mg) was made. After stirring for a further 16 hours the
reaction mixture was poured into an ice/water mixture. The
precipitated solid was isolated giving
4-[4-(6-bromonaphth-2-ylsulphonyl)phenylsulphonyl]-1-(=-butyloxycarbonyl)-
piperazine (295 mg), m.p. 213-215.degree. C., which was used
without further purification.
[0471] A solution of the material so obtained (295 mg) in methylene
chloride (10 ml) was treated with a 2.2M solution of hydrogen
chloride in diethyl ether (1.2 ml). The mixture was stirred at
ambient temperature for 48 hours. The precipitated solid was
collected by filtration and washed with methylene chloride giving
1-[4-(6-bromonaphth-2-ylsulphonyl)p- henyl-sulphonyl]piperazine
hydrochloride salt, (205 mg), m.p. 250-260.degree. C.
(decomposition);
[0472] NMR Spectrum 3.12 (s, 8H), 7.83 (d, 1H), 8.01 (m, 3H), 8.15
(d, 1H), 8.20 (d, 1H), 8.28 (d, 2H), 8.36 (s, 1H), 8.81 (s, 1H),
8.98 (bs, 2H);
[0473] Mass Spectrum m/z 495/497 (M+H).
EXAMPLE 26
[0474] To a solution of
6-(bromo-2-(4-(2-aminoethylaminocarbonyl)phenyl
sulphonyl)naphthalene (400 mg) in ethanol (15 ml) was added
4-chloropyrimidine hydrochloride (131 mg) and triethylamine (294
mg). The mixture was heated to reflux for 3 hours. Further portions
of 4-chloropyrimidine (131 mg) and triethylamine (108 mg) were
added and heating continued for a further 1 hour.
[0475] After cooling, the reaction mixture was diluted with ethyl
acetate (100 ml.), washed with water (2.times.25 ml) and brine (25
ml), dried (MgSO4) and evaporated to give a solid. This was
purified by chromatography on a Mega Bond Elut silica column,
eluting with dichloromethane containing increasing proportions of
methanol (0%-5%) to give
6-(bromo-2-(4-(2-pyrimidin-4-yl)aminoethylaminocarbonyl)phenylsulpho-
nyl)naphthalene (140 mg);
[0476] NMR spectrum 3.3-3.5 (m, 4H); 6.45 (m, 1H); 7.3-7.5 (m, 1H);
7.8 (dd, 1H); 7.9-8.05 (m, 4H); 8.05-8.2 (m, 3H)1; 8.25 (d, 1H);
8.4 (d, 2H); 8.8 (s, 2H);
[0477] Mass spectrum m/z 511 (m+H);
[0478] Elemental Analysis Found C: 50.2;.H: 3.7; N: 10.0;
C23H19BrN4O3S. 0.6 CH2Cl2 requires C: 50.4; H: 3.6; N: 9.9.
[0479] The
6-(bromo-2-(4-(2-aminoethylaminocarbonyl)phenylsulphonyl)naphth-
alene used as starting material may be prepared as follows.
[0480] i) To a suspension of sodium hydride 48% dispersion (960 mg,
20 mmol) in dimethylformamide (50 ml), cooled to 5.degree. C. and
stirred under nitrogen, was added in small portions
6-bromonaphthalene-2-thiol (4.78 g, 20mmol). The mixture was
allowed to warm to ambient temperature over 1 hour.
4-Fluorobenzonitrile (2.66 g, 22 mmol) was then added, the mixture
heated to 90.degree. C. for a further 1 hour and then poured into
water (600 ml). The resulting solid was purified by
recrystallisation from methanol to give
6-(bromo-2-(4-cyanophenylthio)naphthalene (5.7 g);
[0481] NMR Spectrum 7.3 (dd, 2H); 7.55 (dd, 0.1H); 7.7-7.8 (m,
314); 7.9 (d, 1H); 8.0 (d, 1H); 8.2 (s, 1H); 8.3 (s, 11H).
[0482] (ii) A mixture of the product from i) above (5.7 g),
potassium hydroxide (3 g), water (I 5 ml) and ethylene glycol (100
ml.).was heated to 160.degree. C. for 7 hours. After cooling to
ambient temperature the mixture was diluted with water (500 ml.),
acidified with concentrated HCl (pH 2) and extracted with ethyl
acetate (2.times.200 ml). The combined extracts were washed with
water (2.times.100 ml) and brine (100 ml), dried (MgSO4) and
evaporated to give 4-(6-bromonaphth-2-ylthio)benzoic acid (5.3
g);
[0483] NMR Spectrum 7.2 (dd, 2H); 7.5 (dd, 1H); 7.7 (dd, 2H); 7.9
(dd, 2H); 7.95 (d, 1H); 8.0 (d, 1H); 8.1 (s, 1H); 8.2 (s, 1H);
[0484] Mass Spectrum m/z 357 m-H.
[0485] (iii) The acid from ii) above (5.3 g) was suspended in
glacial acetic acid (100 ml). Sodium perborate (9 g) was added and
the mixture stirred at ambient temperature for 24 hours. A further
portion of sodium perborate (9 g) was added and the mixture heated
to 55.degree. C. for 6 hours. After cooling to ambient temperature,
water (200 ml) was added and the resulting white solid precipitate
recovered by filtration to give
4-(6-bromonaphth-2-ylsulphonyl)benzoic acid (4.1 g);
[0486] NMR Spectrum 7.8-7.9 (m, 2H); 7.95 (d, 1H); 8.05-8.15; (m,
4H); 8.2 (d, 1H); 8.3 (s, 1H); 8.8 (s, 1H);
[0487] iv) The acid from iii) above (7.16) was dissolved in
dimethylformamide (100 ml.). N-hydroxysuccinamide (2.88 gm) was
added and the mixture cooled to 5.degree. C. EDAC (4.2 g) was added
in one portion and the mixture stirred 16 hours at ambient
temperature. Ethyl acetate (50 ml) was added and after washing with
water (3.times.100 ml.) and brine (100 ml.) the reaction mixture
was evaporated to give a white solid. This was further purified by
flash column chromatography on silica gel, eluting with
dichloromethane, to give the succinimide ester of the acid product
of iii) (6.3 g), mp 287-290.degree. C.;
[0488] NMR Spectrum (CDCl.sub.3) 2.9 (s, 4H); 7.7 (dd, 1H); 7.8-7.9
(m, 3H); 8.1 (s, 1H); 8.15 (d, 2H); 8.25 (d, 2H); 8.6 (s, 1H);
[0489] Mass Spectrum m/z 389 m-H.
[0490] v) The ester from iv) above (976 mg) was treated with N-BOC
ethylenediamine (320 mg) in dimethylformamide (10 ml) and stirred
at ambient temperature for 18 hours. After diluting with ethyl
acetate (150 ml), washing with 2M sodium hydroxide (2.times.25 ml),
1M citric acid (25 ml), water (25 ml) and brine (25 ml), the
reaction mixture was dried (MgSO4) and evaporated to give the
tert-butoxycarbonyl derivative of the desired starting material as
a white solid. This was dissolved in trifluroacetic acid (5 ml),
stirred at ambient temperature for 2 hours and then evaporated to
give an oil. Ether (50 ml) was added and the mixture stirred
vigorously to give 6-(bromo-2-(4-(2-aminoethylaminocarbon-
yl)phenylsulphonyl)naphthalene as a white solid which was recovered
by filtration (893 mg);
[0491] NMR spectrum 2.95 (t, 2H); 3.4-3.5 (m, 2H); 7.7-7.9 (m, 4H);
7.95 (dd, 1H); 8.1 (d, 2H); 8.15-8.25 (m, 4H); 8.35 (s, 1H);
8.75-8.85 (m, 2H);
[0492] Mass spectrum m/z 433 m+H;
[0493] Elemental Analysis Found C: 45.6; H: 3.1; N: 5.2;
C19H17BrN2O3S. 1.1 TFA requires C: 45.6; H: 3.27; N: 5.01.
EXAMPLE 27
[0494] A mixture of the acid from part (ii) of Example 26 (358 mg),
hydroxybenztriazole (202 mg), N-(4-pyridyl)piperazine (163 mg) and
EDAC (210 mg) was dissolved in dimethylformamide (10 ml) and
stirred at ambient temperature for 1 hour. Water (50 ml) and 2M
sodium hydroxide (10 ml) was added and the mixture extracted with
ethyl acetate (2.times.50 ml.). After washing the combined extracts
with water (2.times.20 ml), drying (MgSO4) and evaporating
1-[4-(6-bromonaphth-2-ylthio)benzoyl]-4-(4- -pyridyl)piperazine was
obtained as a white solid. (345 mg), mp 210-213 C;
[0495] NMR Spectrum CDCl.sub.3 3.2-3.4 (m, 4H); 3.6-4.0 (m, 4H);
6.7 (dd, 2H); 7.3-7.4 (m, 4H); 7.45 (d, 1H), 7.5-7.7 (m, 2H); 7.75
(d, 1H); 7.9 (s, 1H); 8.0 (s, 1H); 8.3 (d, 2H);
[0496] Mass Spectrum m/z 504 m+H;
[0497] Elemental Analysis Found C: 61.8; H: 4.6; N: 8.3;
C26H22BrN30S Requires C: 61.9; H: 4.4; N: 8.3.
EXAMPLE 28
[0498] A mixture of the acid from part (iii) of Example 26 (782
mg), hydroxybenztriazole (297 mg), N-(4-pyridyl)piperazine (326 mg)
and EDAC (382 mg) was dissolved in dimethylformamide (15 ml) and
stirred at ambient temperature for 4 hours. Ethyl acetate (100 ml)
was added and after washing with water (2.times.25 ml) and brine
(25 ml) the reaction mixture was evaporated to give a solid.
Purification by column chromatography on silica gel (Mega Bond
Elut),eluting with dichloromethane containing an increasing
proportion of methanol (0-5%), gave as a solid
1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(4-pyridyl)p-
iperazine (120 mg);
[0499] NMR Spectrum CDCl.sub.3/TFA 3.5-4.0 (b, 8H); 6.9 (d, 2H);
7.6 (d, 2H); 7.7 (dd, 1H); 7.8-7.9 (m, 3H); 8.0-8.1 (m, 3H);
8.15-8.25 (m, 2H); 8.55 (s, 1H);
[0500] Mass Spectrum m/z 536 m+H.
[0501] Elemental Analysis Found C: 57.2; H: 4.5; N: 7.4;
C26H22BrN3O3S.0.5H.sub.2O Requires C: 57.3; H: 4.3; N: 7.7.
EXAMPLE 29
[0502] A mixture of the acid from part (iii) of Example 26 (391
mg), hydroxybenztriazole (202 mg), N-(4-pyrimidyl)piperazine (326
mg) and EDAC (202 mg) was dissolved in dimethylformamide (10 ml)
and stirred at ambient temperature for 3 hours. Ethyl acetate (50
ml) was added and after washing with 2M sodium hydroxide (15 ml),
water (2.times.15 ml) and brine (15 ml) the reaction mixture was
evaporated and the residue triturated with methanol to give a solid
1-[4-(6-bromonaphth-2-ylsulphony-
l)benzoyl]-4-(4-pyrimidinyl)-piperazine (391 mg);
[0503] NMR Spectrum 3.2-3.9 (m, 8H); 6.8 (d, 1H); 7.7 (d, 2H); 7.85
(dd, 1H); 8.0 (dd, 1H); 8.1-8.25 (m, 5H); 8.4 (s, 1H); 8.5 (s, 1H);
8.8 (s, 1H);
[0504] Mass Spectrum m/z 537 m+H;
[0505] Elemental Analysis Found C: 55.5; H: 4.0; N: 10.4;
C25H21BrN4O3S Requires C: 55.9; H: 3.9; N: 10.4.
EXAMPLE 30
[0506] A mixture of N-(4-pyridazinyl)piperazine trifluroacetate
(278 mg), triethylamine (303 mg), N-hydroxysuccinimide ester from
part (iv) of Example 26 (1 mmol) and dimethylformamide (10 ml) was
stirred at ambient temperature for 18 hours. The reaction mixture
was evaporated and the residue dissolved in ethyl acetate, washed
with 2M sodium hydroxide (2.times.25 ml), water (2.times.25 ml) and
brine (25 ml). After drying (MgSO4), evaporation and trituration
with methanol and ether,
1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]4-(4-pyridazinyl)piperazine
was obtained as a white solid 420 mg);
[0507] NMR Spectrum 3.3-3.8 (m, 8H); 6.9 (dd, 1H); 7.7 (d, 2H);
7.85 (dd, 1H); 8.0 (dd, 1H); 8.1 (d, 2H);
[0508] 8.15 (d, 1H); 8.2 (d, 1H); 8.4 (s, 1H); 8.6 (d, 1H); 8.8 (s,
1H); 8.9 (d, 1H);
[0509] Mass Spectrum m/z 537 m+H;
[0510] Elemental Analysis Found C: 55.1; H: 3.8; N: 10.0;
C25H21BrN4O3S.0.5H2O Requires C: 55.0; H: 4.06; N: 10.3.
EXAMPLE 31
[0511] To 4-(6-bromonaphth-2-ylsulphonyl)-2-trifluoromethylbenzoic
acid (1.02 g) was added thionyl chloride (10ml) and
dimethylformamide (1 drop). The mixture was heated on a steam bath
for 30 minutes and then evaporated to give a yellow solid which was
redissolved in dichloromethane (10 ml) and added to an ice cooled
solution of N-(4-pyridyl)piperazine (363 mg) and triethylamine
(1.16 g) in dichloromethane (10 ml). The mixture was allowed to
warn to ambient temperature and stirred for 3 hours. Water (100 ml)
was added and the mixture extracted with ethyl acetate (3.times.50
ml). The combined extracts were washed with water (3.times.25 ml)
and brine (25 ml), dried (MgSO4) and evaporated to give a solid
which was further purified by flash column chromatography on silica
gel, eluting with dichloromethane containing increasing proportions
of methanol (0-5%) to give a solid. Recrystallisation from methanol
gave 1-[4-(6-bromonaphth-2-ylsulphonyl-2--
trifluoromethylbenzoyl]-4-(4-pyridyl)piperazine (649 mg), mp
221-223.degree. C.;
[0512] NMR Spectrum 3.0-3.5 (m, 6H); 3.6-3.8 (m, 2H); 6.75 (d, 2H);
7.8 (dd, 2H); 8.0-8.2 (m, 5H); 8.3-8.4 (m, 3H); 8.85 (s, 1H);
[0513] Mass Spectrum m/z 604 m+H;
[0514] Elemental Analysis Found C: 53.5; H: 3.5; N: 7.0;
C27H21BrF3N3O3S Requires C: 53.7; H: 3.5; N: 6.95.
[0515] 4-(6-Bromonaphth-2-ylsulphonyl-2-trifluoromethylbenzoic acid
used as starting material may be prepared as follows.
[0516] i) A mixture of 6-bromonaphthalene-2-thiol (956 mg) and
4-fluoro-2-trifluoromethyl benzonitrile (756 mg) in
dimethylformamide (15 ml), at ambient temperature, was treated
dropwise with triethylamine (504 mg). After stirring at ambient
temperature for 3 hours the reaction mixture was diluted with ethyl
acetate (100 ml), washed with water (3.times.25 ml) and brine (25
ml), dried (MgSO4) and evaporated to give a yellow oil.
Crystallisation from methanol (20 ml) gave
4-(6-bromonaphth-2-ylthio)-2-trifluoromethylbenzonitrile (1.176 g,
mp 114-116.degree. C.;
[0517] NMR Spectrum 7.4 (d, 1H); 7.6 (d, 1H); 7.75 (m, 2H); 7.9-8.1
(m, 3H); 8.3 (s, 2H);
[0518] Mass Spectrum m/z 407 m.sup.+;
[0519] Elemental Analysis Found C: 53.1; H: 2.2; N: 3.4;
C18H9BrF3NS Requires C: 53.0; H: 2.2; N: 3.4.
[0520] ii) A mixture of nitrile from (i) above (1.0 g), potassium
hydroxide (0.6 g), water (3 ml) and ethylene glycol (20 ml) was
heated at 155.degree. C. for 24 hours. The mixture was cooled to
ambient temperature, diluted with water (100 ml), washed with ether
(2.times.50 ml) and acidified to pH 2 with 2M HCl and extracted
with ethyl acetate (3.times.50 ml). The combined extracts were
washed with water (2.times.50 ml) and brine (50 ml), dried (MgSO4)
and evaporated to give
4-(6-bromonaphth-2-ylthio)-2-trifluoromethylbenzoic acid as a solid
(576 mg);
[0521] Mass Spectrum m.backslash.z 425 m-H.
[0522] The acid from (ii) above (1 g) was suspended in glacial
acetic acid (20 ml). Sodium perborate (1.43 g) was added and the
mixture stirred at ambient temperature for 24 hours. After cooling
to ambient temperature, water (100 ml) was added and the product
extracted with ethyl acetate (2.times.50 ml). The combined extracts
were washed with water (3.times.20 ml) and brine (20 ml), dried
(MgSO4) and evaporated to give
4-(6-bromonaphth-2-ylsulphonyl-2-trifluoromethylbenzoic acid (1.0
g);
[0523] NMR Spectrum 7.8 (dd, 1H); 7.9-8.1 (m, 2H); 8.1-8.2 (m, 2H);
8.3-8.4 (m, 3H); 8.55 (s, 1H);
[0524] Mass Spectrum m/z 457 m-H.
EXAMPLE 32
[0525] To the acid from part (ii) of Example 31 (519 mg) in
dimethylformamide (10 ml) was added carbonyl diimidazole (196 mg).
After stirring at ambient temperature for 30 minutes
N-(4-pyridyl)piperazine (198 mg) was added and stirring continued
for 24 hours. The reaction mixture was diluted with ethyl acetate
(100 ml), washed with water (2.times.50 ml) and brine (25 ml),
dried (MgSO4) and evaporated to give an oil which was further
purified by chromatography on silica gel (Mega Bond Elut column,
eluted with dichloromethane containing increasing proportions of
methanol, 0-4%) to give 1-[4-(6-bromonaphth-2-ylthio)-2-tr-
ifluoromethylbenzoyl]-4-(4-pyridyl)piperazine (128 mg);
[0526] NMR Spectrum 3.2 (m, 4H); 3.4 (m, 4H); 3.7 (m, 2H); 6.8 (md,
2H); 7.4-7.8 (m, 5H); 7.95 (d, 1H); 8.0 (d, 1H); 8.1-8.2 (m, 3H);
8.3 (s, 1H);
[0527] Mass Spectrum m.backslash.z 572 m+H;
[0528] Elemental Analysis Found C: 56.7; H: 3.9; N: 7.2;
C27H21BrF3N30S Requires C: 56.7; H: 3.7; N: 7.3
EXAMPLE 33
[0529] 4-(6-Bromonaphth-2-ylthio)-2-carboxybenzoic acid (200 mg)
was suspended in acetic anhydride (5 ml) and heated to 120.degree.
C. for 1 hour. The precipitate of the anhydride that was obtained
on cooling was recovered by filtration, washed with hexane and
suspended in dimethylformamide (2 ml). N-(4-Pyridyl)piperazine (76
mg) was added and the mixture stirred at ambient temperature for 3
hours. Ether (20 ml) was added with vigourous stirring and the
resulting white solid precipitate was recovered by filtration,
washed with ether and dried in vacuo to give
1-[4-(6-bromonaphth-2-ylthio)-2-carboxybenzoyl]-4-(4-pyridyl)piperazine
and
1-[5-(6-bromonaphth-2-ylthio)-2-carboxybenzoyl]-4-(4-pyridyl)piperazi-
ne (80 mg) as a mixture of two isomers;
[0530] NMR Spectrum 3.1-4.0 (m, 16H); 6.7-6.9 (m, 4H); 7.1 (s, 1H);
7.25 (d, 1H); 7.3 (d, 1H); 7.4-7.6 (m, 3H); 7.7 (d, 2H); 7.75 (s,
1H); 7.8-8.0 (m, 6H); 8.05-8.2 (m, 5H); 8.3 (s, 2H);
[0531] Mass Spectrum m.backslash.z 548 m+H.
EXAMPLE 34
[0532] 5-(6-Bromonaphth-2-ylsulphonyl)-2-methoxycarbonylbenzoic
acid (97 mg) was dissolved in dichloromethane (1 ml.). Oxalyl
chloride (126 mg) was added and the mixture stirred at ambient
temperature for 1 hour. The mixture was evaporated to give a solid
which was redissolved in dichloromethane (1 ml) and added to a
solution-of N-(4-pyridyl)piperazine (34 mg) and triethylamine.(108
mg)-in dichloromethane (2 ml). After stirring for 2 hours at
ambient temperature the mixture was diluted with ethyl acetate (100
ml), washed with water (2.times.25 ml), dried (MgSO.sub.4) and
evaporated to give an oil, which was further purified by
chromatography (Mega Bond Elut column, eluted with dichloromethane
containing an increasing proportion of methanol, 0-5%) to give
1-[5-(6-bromonaphth-2-ylsulphonyl)-2-methoxycarbonylbenzoyl]-4-(4-pyridyl-
)piperazine (55 mg); --
[0533] NMR Spectrum 3.1-3.2 (m, 4H); 3.4-3.5 (m, 2H); 3.7-3.75 (m,
2H); 3.8 (s, 3H); 6.8 (d, 2H); 7.8 (dd, 1H); 8.0 (dd, 1H); 8.05 (s,
1H); 8.1-8.2 (m, 6H); 8.4 (s, 1H); 8.8 (s, 1H);
[0534] Mass Spectrum m.backslash.z 594 m+H;
[0535] Elemental Analysis Found C: 55.7; H: 4.3; N: 6.8;
C228H24BrN3O5S. 0.5H2O Requires C: 55.7; H: 4.18; N: 6.96.
[0536] The benzoic acid used as starting material was prepared as
follows.
[0537] 5-(6-Bromonaphth-2-ylsulphonyl)phthalic anhydride [Example
18] (208 mg) was suspended in methanol (10 ml) and heated to reflux
for 2 hours. The reaction mixture was evaporated and dried under
vacuum to give a mixture of two isomeric esters
4-(6-bromonaphth-2-ylsulphonyl)-2-methoxyc- arbonylbenzoic acid and
5-(6-bromonaphth-2-ylsulphonyl-2-methoxycarbonylbe- nzoic acid (210
mg). Flash column chromatography on silica gel, eluting with a
mixture of ethyl acetate/methanol/acetic acid 94/5/1, gave a sample
of the single isomer used above (97 mg);
[0538] NMR Spectrum 3.8 (s, 3H), 7.8-7.9 (m, 2H); 8.0 (dd, 1H);
8.15 (d, 1H); 8.2 (d, 1H); 8.3 (dd, 1H); 8.35 (s, 1H); 8.4 (s, 1H);
8.8 (s, 1H);
[0539] Mass Spectrum m.backslash.z 449 m+H.
EXAMPLE 35
[0540] A mixture of the two isomeric esters, from the part of
Example 34 relating to the preparation of starting material, (449
mg) was dissolved in dichloromethane (10 ml). Oxalyl chloride (0.4
ml) was added and the mixture stirred at ambient temperature for 1
hour. The mixture was evaporated to give a solid which was
redissolved in dichloromethane (5 ml.) and added dropwise to a
solution of N-(4-pyridyl)piperazine (163 mg) and triethylamine (504
mg) in dichloromethane (10 ml). After stirring for 24 hours at
ambient temperature the mixture was diluted with ethyl acetate (100
ml), washed with water (3.times.25 ml) and brine (25 ml), dried
(MgSO4) and evaporated to give a solid, which was further purified
by chromatography (Mega Bond Elut column, eluted with
dichloromethane containing an increasing proportion of methanol,
0-5%) to give a mixture of
1-[4-(6-bromonaphth-2-ylsulphonyl)-2-methoxycarbonylbenzoyl]-4-(4-pyri-
dyl)piperazine and
1-[5-(6-bromonaphth-2-ylsulphonyl)-2-methoxycarbonylben-
zoyl]-4-(4-pyridyl)piperazine (461 mg);
[0541] NMR Spectrum CDCl.sub.3 300 MHz 3.2-349 (m, 8H); 3.4-3.6 (m,
4H); 3.8-4.0 (m, 1 OH); 6.6-6.7 (m, 2H); 6.6-6.7 (m, 2H); 7.45 (d,
1H); 7.7-7.45 (m, 2H); 7.8-8.0 (m, 7H); 8.05-8.2 (m, 5H); 8.3-8.4
(m, 4H); 8.5-8.6 (m, 2H); 8.7 (s, 1H);
[0542] Mass Spectrum m.backslash.z 594 m+H;
[0543] Elemental Analysis Found C: 52.9; H: 4.1; N: 6.8;
C28H24BrN3O5S. 0.5CH2Cl2 Requires C: 52.7; H: 3.9; N: 6.4.
EXAMPLE 36
[0544] To the isomeric mixture of acids produced in Example 18 (578
mg) was added, dimethylformamide (10 ml), hydroxybenztriazole (162
mg), 2-(ethylthio)ethylamine (210 mg) and EDAC (382 mg). The
mixture was stirred at ambient temperature for 18 hours, diluted
with ethyl acetate (100 ml), washed with water (3.times.25 ml) and
brine (25 ml), dried and evaporated. The residue was purified by
chromatography (Mega Bond Elut column, eluted with dichloromethane
containing an increasing proportion of methanol, 0-5%) to give as a
mixture (420 mg) of isomers,
1-[4-(6-bromonaphth-2-ylsulphonyl)-2-(2-(ethylthio)-ethylaminocarbonyl)be-
nzoyl]-4-(4-pyridyl)piperazine and
1-[5-(6-bromonaphth-2-ylsulphonyl)-2-(2-
-ethylthio)ethylaminocarbonyl)benzoyl]-4-(4-pyridyl)piperazine;
[0545] NMR Spectrum 1.1-1.2 (m, 3H); 2.5-2.6 (m, 4H); 3.1-3.5 (m,
8H); 3.6-3.75 (m, 2H); 6.7-6.8 (m, 2H); 7.6-8.4 (m, 9H); 8.7-9.0
(m, 2H);
[0546] Mass Spectrum m.backslash.z 667 m+H;
[0547] Elemental Analysis Found C: 54.0; H: 4.6; N: 8.1;
C31H31BrN4O4S2. H2O Requires C: 54.3; H: 4.8; N: 8.2.
[0548] A sample of the mixed isomers (100 mg.) was separated by
HPLC, C 18 ODS column eluted with an acetonitrile/water mixture, to
give the 5-naphthylsulphonyl isomer (29 mg).
[0549] NMR Spectrum 500 MHz CH3CN/D2O 1.08 (t, 3H); 2.4-2.5 (m,
2H); 2.6-2.7 (m, 2H); 3.25-3.3 (m, 2H); 3.35-3.4 (m, 2H); 3.45-3.5
(m, 2H); 3.7-3.72 (m, 4H); 6.8-6.9 (m, 2H); 7.72 (dd, 1, H); 7.78
(d, 1H); 7.85 (dd, 1H); 7.91 (s, 1H); 7.95-8.0 (m, 4H); 8.07 (d,
1H); 8.18 (s, 1H); 8.6 (s, 1H);
[0550] Mass Spectrum m.backslash.z 667 m+H.
EXAMPLE 37
[0551] A solution of the isomeric mixture of acids produced in
Example 18 (prepared in situ, 30 from the phthalic anhydride (208
mg) and N-(4-pyridyl)piperazine (81.5 mg)) in dimethylformamide (5
ml.) was treated with carbonyl diimidazole (97.0 mg) and stirred at
ambient temperature for 30 minutes. Piperidine (63 mg) was then
added. The mixture was stirred at ambient temperature for 18 hours,
diluted with ethyl acetate (100 ml), washed with water (3.times.20
ml) and brine (20 ml), dried and evaporated. The residue was
purified by chromatography (Mega Bond Elut column, eluted with
dichloromethane containing an increasing proportion of methanol,
0-5%) to give as a mixture (210 mg) of isomers,
1-[4-(6-bromonaphth-2-ylsulphonyl)-2-(piperidin-1-ylcarbonyl]-4--
(4-pyridyl)piperazine and
1-[5-(6-bromonaphth-2-ylsulphonyl)-2-(piperidin--
1-ylcarbonyl]-4-(4-pyridyl)piperazine (210 mg);
[0552] NMR Spectrum 1.3-1.6 (m, 6H); 3.0-3.6 (m, 12H); 6.7 (d, 2H);
7.6-7.7 (m1H); 7.8 (dd, 1H); 8.0-8.2 (m, 7H); 8.4 (s, 1H); 8.8 (s,
1H);
[0553] Mass Spectrum m.backslash.z 647 m+H
[0554] Elemental Analysis Found C: 58.3; H: 5.0; N: 8.8;
C.sub.32H.sub.31BrN.sub.4O.sub.4S. 0.5H.sub.2O Requires C: 58.5; H:
4.9; N: 8.5.
EXAMPLE 38
[0555] 4-(Chlorosulphonyl)benzoic acid (0.75 g) was added to a
solution of 1-(3-chlorophenyl)piperazine dihydrochloride (0.90 g)
in triethylamine (2.4 ml) and dichloromethane (50 ml). The reaction
mixture was stirred overnight at room temperature then concentrated
in vacuo. The resulting solid was suspended in
N,N-dimethylformamide (50 ml) and carbonyl diimidazole (0.55 g) was
added. The reaction mixture was stirred for one hour at room
temperature then 1-(4-pyridyl)piperazine (0.55 g, 3.4 mmol) was
added. The reaction mixture was stirred for three hours, then
concentrated in vacuo. The resulting solid was separated between
ethyl acetate (100 ml) and water (100 ml). The ethyl acetate layer
was washed with aqueous saturated sodium bicarbonate solution (100
ml) then dried over magnesium sulphate, filtered and concentrated
in vacuo. The resulting yellow oil was subjected to chromatography
(SiO.sub.2: 10%-12% MeOH/EtOAc) to yield
1-[4-(4-(3-chlorophenyl)piperazin-1-ylsulphonyl)benz-
oyl]-4-(4-pyridyl)piperazine as a white solid (300.1 mg);
[0556] NMR Spectrum 3.08 (m, 4H), 3.42 (m, 10H) 3.75 ppm (s, 2H,
6.81 (m, 3H, 6.8 (dd, 1H chlorophenyl 4-H), 6.94 (t, 1H) 7.21 (t,
1H, 7.72 & 7.86 (dd, 4H, phenyl 8.18 (d, 2H);
[0557] Mass Spectrum 528 (M+H).sup.+;
[0558] Elemental Analysis Found Carbon 57.8%, hydrogen 5.5%,
nitrogen 12.3% (Calc. for
C.sub.26H.sub.28ClN.sub.5O.sub.3S.0.2EtOAc.0.8H.sub.2O Carbon
57.7%, hydrogen 5.63%, nitrogen 12.5%).
EXAMPLE 39
[0559] 4-(-Chlorosulphonyl)benzoic acid (733.0 mg) was added to a
solution of 6-chloro-1,2,3,4-tetrohydroisoquinoline (558.1 mg) in
triethylamine (0.46 ml) and tetrahydrofuran (20 ml). The reaction
mixture was stirred for two days at room temperature then
concentrated in vacuo to yield
4-[6-chloro-1,2,3,4-tetrahydroisoquinolin-2-ylsulphonyl]benzoic
acid as an off white solid. This was suspended in dichloromethane
(30 ml) and carbonyl diimidazole (539 mg) was added. The reaction
mixture was stirred for one hour at room temperature then
1-(4-pyridyl)piperazine (541 mg) was added. The reaction mixture
was stirred overnight, then concentrated in vacuo. The resulting
solid was separated between ethyl acetate (50 ml) and water
(2.times.100 ml). The ethyl acetate layer was dried over magnesium
sulphate, filtered and concentrated in vacuo. The resulting solid
was subjected to chromatography (SiO.sub.2: 1-5% Methanol/ethyl
acetate) to yield
1-[4-(6-chloro-1,2,3,4-tetrahydroisoquinolin-2-ylsulpho-
nylbenzoyl]4-(4-pyridyl)piperazine a white solid (984.7 mg);
[0560] NMR Spectrum (CDCl.sub.3, 300 MHz) 2.66 (t, 2H), 3.22 to
3.58 (s, 6H), 3.41 (t, 2H), 3.93 (s, 2H) 4.28 (s, 2H), 6.68 (m. 2H,
6.98 (d, 1H), 7.09 (s, 1H), (dd, 1H, quinoline 6-H), 7.58 and 7.90
(dd, 4H, phenyl Ar H's), 8.33 (d, 2H, pyridyl 2-H & 6-H);
[0561] Mass Spectrum 497 (M+H).sup.+;
[0562] Elemental Analysis Found Carbon 58.1%, hydrogen 4.8%,
nitrogen 10.6% (Calc. for
C.sub.25H.sub.25ClN.sub.4O.sub.3S.0.25CH.sub.2Cl.sub.2 Carbon
58.5%, hydrogen 4.96%, nitrogen 10.8%).
[0563] The 6-Chloro-1,2,3,4-tetrahydroisoquinoline may be prepared
as follows:
[0564] i) 2-(m-Chlorophenyl)ethylamine (21.92 g) was dissolved in
pyridine (250 ml) and cooled to 250.degree. C. Tosyl chloride
(40.28 g) was added portionwise as a solid over one hour keeping
the temperature below 5.degree. C. The reaction mixture was stirred
for two hours at room temperature then concentrated in vacuo. The
resulting oil was dissolved in dichloromethane (500 ml) and washed
twice with 2N aqueous hydrochloric acid (2.times.400 ml). The
dichloromethane layer was dried over magnesium sulphate, filtered
and concentrated in vacuo. The resulting oil was subjected to
chromatography (SiO.sub.2: 100% CH.sub.2Cl.sub.2) to yield the
toluenesulphonyl derivative of the amine as a white solid (7.59
g);
[0565] NMR Spectrum (CDCl.sub.3) 2.42 (s, 3H), 2.73 (t, 2H, 3.21
(q, 2H), 4.38 (t, 1H), 6.98 (t, 1H), 7.01 (s, 1H), 7.20 (d, 2H, 4-H
and 6-H), 7.30 and 7.69 (dd, 4H);
[0566] Mass Spectrum 310 (M+H).sup.+;
[0567] Elemental Analysis Found Carbon 57.4%, hydrogen 5.29%,
nitrogen 4.40% (Calc. for C.sub.15H.sub.16ClNO.sub.20.25H.sub.2O
Carbon 57.3%, hydrogen 5.20%, nitrogen 4.46%).
[0568] ii) To a solution of the tosylated amine from i) above (5.0
g) in chloroform (50 ml) was added formaldehyde 37 wt. % solution
in water (2.62 ml) followed by phosphoryl trichloride (40 ml). The
reaction mixture was stirred under reflux for three hours. The
reaction mixture was cooled to room temperature then poured into a
stirred mixture of dichlorometharie (150 ml) and aqueous saturated
sodium bicarbonate solution (150 ml). Solid sodium bicarbonate was
added portionwise with caution until the aqueous layer became
basic. The dichloromethane layer was separated, washed with water
(200 ml) then dried over magnesium sulphate, filtered and
concentrated in-vacuo. The crude product was subjected to
chromatography (SiO.sub.2: 10-15% Ethyl acetate/iso-hexane) to
yield
4-(6-chloro-1,2,3,4-tetrahydroisoquinolin-2-ylsulphonyl)toluene as
a white crystalline solid which was recrystallised from ethyl
acetate/iso-hexane (2.26 g);
[0569] NMR Spectrum (CDCl.sub.3, 250 MHz) 2.38 (s, 3H), 2.89 (t,
2H), 3.31 (t, 2H), 4.17 (s, 2H), 6.95 (d, 1H), 7.06 (s, 1H), 7.12
(d, 1H), 7.31 and 7.71 (dd, 4H);
[0570] Mass Spectrum 322 (M+H).sup.+;
[0571] Elemental Analysis Found Carbon 60.0%, hydrogen 5.00%,
nitrogen 4.30% (Calc. for C.sub.16H.sub.16ClNO.sub.2S Carbon 59.7%,
hydrogen 5.01%, nitrogen 4.35%).
[0572] iii) Part of the product from ii) above (2.20 g, 6.8 mmol)
was heated at 75.degree. C. with phenol (2.25 g) and 45% w/w
hydrobromic acid in glacial acetic acid (30 ml) for three hours.
The reaction mixture was cooled to room temperature then poured
onto a mixture of ice and dichloromethane. The aqueous layer was
adjusted to pH 14 with 6N sodium hydroxide solution and extracted
with dichloromethane (4.times.100 ml). The dichloromethane layers
were combined then dried over magnesium sulphate, filtered and
concentrated in vacuo. The crude product was subjected to
chromatography (SiO.sub.2: 1-10% methanol/dichloromethane) to yield
6-chloro-1,2,3,4-tetrahydroisoquinoline as a colourless oil (558.1
mg);
[0573] NMR Spectrum 2.66 (t, 2H), 2.88 (q, 2H), 3.78 (s, 2H), 6.98
to 7.13 (m, 3H, Ar H's);
[0574] Mass Spectrum 168 (M+H).sup.+.
EXAMPLE 40
[0575] To a solution of 5-methoxyindole-2-carboxylic acid (168 mg,
0.88 mmol) in DMF (4 ml) was added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimi- de hydrochloride (168
mg, 0.88 mmol), 1-hydroxybenzotriazole (118 mg, 0.88 mmol) and
Et.sub.3N (0.12 ml, 0.88 mmol) followed by
1-(4-pyridyl)-3-(5-amino-2-pyridyloxy)pyrrolidine (150 mg, 0.58
mmol) and the resulting suspension stirred at room temperature for
7 days. The mixture was poured into saturated aqueous NaHCO.sub.3
solution and the solid precipitate collected by filtration and
washed with water then dried (over P.sub.2O.sub.5) to give
1-(4-pyridyl)-(5-(6-methoxyindol-2-yl-
carbonylamino)pyrid-2-yloxy)pyrrolidine as an off white solid (195
mg);
[0576] NMR Spectrum (CDCl.sub.3) 2.20 (m, 2H), 3.50 (m, 4H), 3.80
(s, 3H), 5.70 (m, 1H), 6.60 (m, 2H), 6.90 (m, 2H), 7.15 (s, 11H),
7.30 (m. 2H), 8.10 (m, 3H), 8.60 (s, 11H).
[0577] MS (ESP+): m/e 430 (M+H).sup.+.
[0578] The 1-(4-pyridyl)-3-(5-amino-2-pyridyloxy)pyrrolidine
starting material may be prepared as follows:
[0579] (a) Sodium hydride (60% dispersion in paraffin oil, 146 mg)
1.2 equivalent) was added to an oven-dried round-bottomed flask and
washed under an argon atmosphere with pentane. DMF (5 ml) was then
added, followed by 1-(4-pyridyl)-3-hydroxypyrrolidine (1.0
equivalent, 3.05 mmol) and tetra-n-butylammonium bromide (59 mg,
0.18 mmol). The mixture was added as a slurry to
2-bromo-5-nitropyridine (1.5 equivalent) in a second dry flask
under argon, with stirring. After the reaction was complete the
solvent was evaporated under vacuum. The residue was purified by
chromatography on silica, eluting from
1%MeOH/1%NH.sub.4OH/CH.sub.2Cl.sub.2 to
10%MeOH/1%NH.sub.4OH/CH.sub.2Cl.s- ub.2 (in 1% increments). The
crude product was recrystallised from EtOAc to give
1-(4-pyridyl)-3-(5-nitro-2-pyridyloxy)pyrrolidine as a pale brown
solid (460 mg);
[0580] NMR Spectrum (CDCl.sub.3): 2.4 (m, 2H), 3.58 (m, 3H), 3.8
(dd, 11H), 5.85 (m, 1H), 6.4 (d, 2H), 6.82 (d, 1H), 8.22 (m, 2H),
8.38 (dd, 1H), 9.08 (s. 1H). MS (ESP+): m/e 287 (M+H).sup.+.
[0581] (b) A solution of
1-(4-pyridyl)-3-(5-nitro-2-pyridyloxy)pyrrolidine (15.29 g, 53.46
mmol) in methanol (500 ml) was hydrogenated over 10% Pd/C at 5 bar
for 18 h. The catalyst was removed by filtration and the solvent
evaporated to give the product as a pale yellow solid (12.68
g).
[0582] NMR Spectrum (CDCl.sub.3): 2.30 (m, 2H), 3.40 (m, 5H), 3.70
(dd, 1H), 5.60 (m, 1H), 6.40 (d, 2H), 6.60 (d, 1H), 7.00 (m, 1H),
7.60 (s, 1H), 8.10 (d, 2H). MS (ESP+): m/e 257 (M+H).sup.+.
EXAMPLE 41
[0583] A mixture of 1-(2-methylpyrid-4-yl)piperazine
dihydrochloride (145 mg), triethylamine (0.16 ml),
N-hydroxysuccinimide ester from part (iv) of Example 26 (244 mg)
and DMF (10 ml) was stirred for 16 hours. The solvent was
evaporated and the residue dissolved in methylene chloride and
washed with water. The aqueous washings were extracted with further
methylene chloride and the combined organic extracts dried
(MgSO.sub.4) and evaporated. The residue was further purified by
column chromatography using a 9:1 mixture of methylene chloride and
methanol as eluant and the resulting solid triturated under diethyl
ether. There was thus obtained
1-[4-(6-bromonaphth-2-ylsulphonyl)-benzoyl]-4-(2-methylpyrid-4-yl)piperaz-
ine (115 mg);
[0584] NMR Spectrum (DMSO-d.sup.6+D.sub.2O) 2.28 (s, 3H), 3.20-3.48
(m, 6H), 3.66 (bs, 2H), 6.61 (d, 1H), 6.67 (s, 1H), 7.63 (d, 2H),
7.80 (d, 1H), 7.97 (t, 2H), 8.06-8.17 (m, 4H), 8.32 (s, 1H), 8.72
(s, 1H);
[0585] Mass Spectrum m/z 550/552 (M+H);
[0586] Elemental Analysis Found C, 57.7; H 4.2; N, 7.7, S, 5.8;
C.sub.27H.sub.24BrN.sub.3O.sub.3S 0.5H.sub.2O requires: C, 58.0; H,
4.5; N, 7.5, S, 5.7%.
EXAMPLE 42
[0587] The ester from Example 26 (iv) above (488 mg) was treated
with 1-(4-pyridyl) hexahydro-1,4-diazepine (195 mg) in
dimethylformamide (10 ml) and stirred at ambient temperature for 18
hours. After removal of the solvent in vacuo and addition of ethyl
acetate (30 ml), washing with saturated sodium bicarbonate solution
(30 ml), water (2.times.30 ml) and brine (30 ml), the reaction
mixture was dried (MgSO4) and evaporated to a white solid.
Purification by column chromatography on silica gel, eluting with
dichloromethane containing an increasing proportion of methanol
(2-5%) and a small amount of conc. aqueous ammonia, followed by
recrystallisation from ethyl acatate gave as a solid
1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(4-pyridyl)hexahydro-1,4-dia-
zepine (290 mg).
[0588] NMR Spectrum (CDCl.sub.3) 2.0-2.2 (m, 2H); 3.3 (m, 1H);
3.4-3.5 (m, 1H); 3.6-3.8 (bm, 5H); 4.0 (m, 1H); 6.7 (d, 2H); 7.05
(m, 1H); 7.4 (dd, 1H); 7.7 (m, 1H); 7.9 (m, 3H); 8.0 (m, 2H); 8.1
(m, 1H); 8.15-8.5 (m, 2H); 8.55 (s, 1H).
[0589] Mass Spectrum m/z 550/552 m+H.
[0590] Elemental Analysis Found C: 58.8; H: 4.6; N: 7.1; S: 5.2%.
C.sub.27H.sub.24BrN.sub.3O.sub.3S Requires C: 58.6; H: 4.7; N: 7.1;
S: 5.4%.
[0591] The 1-(4-pyridyl)hexahydro-1,4-diazepine used as starting
material may be prepared as follows:
[0592] A suspension of 4-chloropyridine hydrochloride (7.5 g) in
3-methyl-1-butanol (100 ml) was added dropwise to a refluxing
solution of hexahydro-1,4-diazepine (10.0 g) and triethylamine
(16.8 ml) in 3-methyl-1-butanol (300 ml). After addition the
solution was refluxed for 18 hours. The solvent was removed in
vacuo to give an oil. Purification by sinter-column chromatography
on silica gel, eluting with dichloromethane containing an
increasing proportion of methanol (2-5%) and a small amount of
conc. aqueous ammonia, gave 1-(4-pyridyl)hexahydro-- 1,4-diazepine
as a colourless oil which slowly crystallised on standing.
[0593] NMR Spectrum (CDCl.sub.3) 1.8-2.1 (m, 2H); 2.8 (m, 2H); 3.0
(m, 2H); 3.4-3.7 (m, 5H); 6.5 (d, 2H); 8.2 (d, 2H).
[0594] Mass Spectrum m/z 178 m+H.
EXAMPLE 43
[0595] The following illustrate representative pharmaceutical
dosage forms containing the compound of formula I, or a
pharmaceutically-acceptable salt thereof (hereafter compound X),
for therapeutic or prophylactic use in humans:
4 (a) Tablet I mg/tablet Compound X 100 Lactose Ph. Eur 182.75
Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25
Magnesium stearate 3.0
[0596]
5 (b) Tablet II mg/tablet Compound X 50 Lactose Ph. Eur 223.75
Croscarmellose sodium 6.0 Maize starch 15.0 Polyvinylpyrrolidone
(5% w/v paste) 2.25 Magnesium stearate 3.0
[0597]
6 (c) Tablet III mg/tablet Compound X 1.0 Lactose Ph. Eur 93.25
Croscarmellose sodium 4.0 Maize starch paste (5% w/v paste) 0.75
Magnesium stearate 1.0
[0598]
7 (d) Capsule mg/capsule Compound X 10 Lactose Ph. Eur 488.5
Magnesium stearate 1.5
[0599]
8 (e) Injection I (5.0 mg/ml) Compound X 5.0% w/v 1M Sodium
hydroxide solution 15.0% v/v 0.1M Hydrochloric acid (to adjust pH
to 7.6) Polyethylene glycol 400 4.5% w/v Water for injection to
100%
[0600]
9 (f) Injection II 10 mg/ml) Compound X 1.0% w/v Sodium phosphate
BP 3.6% w/v 0.1M Sodium hydroxide solution 15.0% v/v Water for
injection to 100%
[0601]
10 (g) Injection III (1 mg/ml, buffered to pH6) Compound X 0.1% w/v
Sodium phosphate BP 2.26% w/v Citric acid 0.38% w/v Polyethylene
glycol 400 3.5% w/v Water for injection to 100%
[0602] Note
[0603] The above formulations may be obtained by conventional
procedures well known in the pharmaceutical art. The tablets
(a)-(c) may be enteric coated by conventional means, for example to
provide a coating of cellulose acetate phthalate.
* * * * *