Aminoheterocyclic derivatives as antithrombotic or anticoagulant agents
View Patent ↗Compounds of formula (I), wherein G 1 is CH or N; G 2 is CH or N; R 1 is a variety of optional substituents; L 1 is (1-4C)alkylene; T 1 is CH or N; R 2 and R 3 are independently hydrogen or (1-4C)alkyl or are joined to form a ring; X 1 and X 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. An aminoheterocyclic compound of the formula I
wherein
G 1 is CH;
G 2 is CH;
m is 1 or 2;
R 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 1 is (1-4C)alkylene or (3-6C)cycloalkane-1,2-diyl,
T 1 is CH or N, and
R 2 and R 3 together form a (1-4C)alkylene or methylenecarbonyl group,
and wherein 1 or 2 methylene groups within L 1 or the ring formed when R 2 and R 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, 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 and N , N -di-(1-4C)alkylcarbamoyl-(1-4C)alkyl,
provided that, when T 1 is N, L 1 is not optionally substituted methylene and R 2 and R 3 together do not form an optionally substituted methylene group;
X 1 is a group of the formula SO, SO 2 , C(R 4 ) 2 , CO, C(R 4 ) 2 O, C(R 4 ) 2 S, C(R 4 ) 2 SO, C(R 4 ) 2 SO 2 , COC(R 4 ) 2 , SOC(R 4 ) 2 or SO 2 C(R 4 ) 2 when T 1 is CH or N, or, in addition, X 1 is a group of the formula O, S, OC(R 4 ) 2 or SC(R 4 ) 2 when T 1 is CH, and wherein each R 4 is independently hydrogen or (1-4C)alkyl;
Ar is a 1,3-phenylene or 1,4-phenylene, wherein said phenylene 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 1 which is selected from hydroxy, amino, (1-4C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkynyloxy, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, (2-4C)alkanoylamino, benzamido, (1-4C)alkanesulphonamido and benzenesulphonamido,
from the substituent Y 2 which is selected from carboxy, carbamoyl, (1-4C)alkoxycarbonyl, N -(1-4C)alkylcarbamoyl, N , N -di-(1-4C)alkylcarbamoyl, (1-4C)alkanesulphonamidocarbonyl, benzenesulphonamidocarbonyl and benzylsulphonamidocarbonyl,
from a substituent of the formula —L 2 —Y 1 wherein L 2 is (1-4C)alkylene and Y 1 has any of the meanings defined immediately hereinbefore,
from a substituent of the formula —L 2 —Y 2 wherein L 2 is (1-4C)alkylene and Y 2 has any of the meanings defined immediately hereinbefore,
from a substituent of the formula —X 3 —L 2 —Y 2 wherein X 3 is a group of the formula CON(R 5 ), CON(L 2 —Y 2 ), C(R 5 ) 2 O, O, N(R 5 ) or N(L 2 —Y 2 ), L 2 is (1-4C)alkylene, Y 2 has any of the meanings defined immediately hereinbefore and each R 5 is independently hydrogen or (1-4C)alkyl, and
from a substituent of the formula —X 3 —L 3 —Y 1 wherein X 3 is a group of the formula CON(R 5 ), CON(L 3 —Y 1 ), C(R 5 ) 2 O, O, N(R 5 ) or N(L 3 —Y 1 ), L 3 is (2-4C)alkylene, Y 1 has any of the meanings defined immediately hereinbefore and each R 5 is independently hydrogen or (1-4C)alkyl,
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 2 is a group of the formula S, SO, SO 2 , C(R 6 ) 2 , CO, N(R 7 )SO 2 , N(R 7 )CO, C(R 6 ) 2 S, C(R 6 ) 2 SO, C(R 6 ) 2 SO 2 , C(R 6 ) 2 —C(R 6 ) 2 or C(R 6 ) 2 CO, or, in addition, X 2 is a group of the formula O, SO 2 N(R 7 ), CON(R 7 ) or C(R 6 ) 2 O when Q is other than phenyl-(2-4C)alkenyl or phenyl-(2-4C)alkynyl and wherein each R 6 is independently hydrogen or (1-4C)alkyl and R 7 is hydrogen, (1-4C)alkyl or a group of the formula —X 4 —Q wherein X 4 is SO 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 or phenyl-(2-4C)alkynyl, 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)alkyl, phenyl, phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl, benzyl and benzoyl, and wherein said phenyl, phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl, 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 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 2 is not N(R 7 )SO 2, N(R 7 )CO, C(R 6 ) 2 S, C(R 6 ) 2 SO, C(R 6 ) 2 SO 2 , C(R 6 ) 2 —C(R 6 ) 2 , C(R 6 ) 2 CO or C(R 6 ) 2 O.
2. The compound according to claim 1 wherein:
each of G 1 and G 2 is CH;
m is 1; and
R 1 is hydrogen;
L 1 is (1-4C)alkylene,
T 1 is CH or N, and
R 2 and R 3 together form a (1-4C)alkylene group,
and wherein 1 or 2 methylene groups within L 1 and the ring formed when R 2 and R 3 are linked optionally bears 1 or 2 (1-4C)alkyl substituents,
provided that, when T 1 is N, L 1 is not optionally substituted methylene and R 2 and R 3 together do not form an optionally substituted methylene group;
when T 1 is CH or N, X 1 is a group of the formula SO 2 , CH 2 , CO, CH 2 O, CH 2 S, CH 2 SO 2 , COCH 2 or SO 2 CH 2 , or, when T 1 is CH, X 1 is, in addition, a group of the formula O, S, OCH 2 or SCH 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 and N , N -di-(1-4C)alkylcarbamoyl; or
Ar is 1,3-phenylene or 1,4-phenylene which is optionally substituted with a substituent of the formula —L 2 —Y 1 or of the formula —L 2 —Y 2 wherein L 2 is (1-4C)alkylene, Y 1 is selected from hydroxy, amino, (1-4C)alkoxy, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl and (2-4C)alkanoylamino, and Y 2 is selected from carboxy, carbamoyl, (1-4C)alkoxycarbonyl, N -(1-4C)alkylcarbamoyl and N , N -di-(1-4C)alkylcarbamoyl; or
Ar is 1,3-phenylene or 1,4-phenylene which is optionally substituted with a substituent of the formula —X 3 —L 2 —Y 2 wherein X 3 is a group of the formula CONH, CON(Me), CH 2 O or O, L 2 is methylene, ethylene or trimethylene and Y 2 is selected from carboxy, carbamoyl, (1-4C)alkoxycarbonyl, N -(1-4C)alkylcarbamoyl and N , N -di-(1-4C)alkylcarbamoyl; or
Ar is 1,3-phenylene or 1,4-phenylene which is optionally substituted with a substituent of the formula —X 3 —L 3 —Y 1 wherein X 3 is a group of the formula CONH, CH 2 O, O or NH, L 3 is ethylene or trimethylene and Y 1 is hydroxy, amino, (1-4C)alkoxy, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl and (2-4C)alkanoylamino;
X 2 is a group of the formula SO 2 , CH 2 , CO, NHSO 2 , N(R 7 )SO 2 , NHCO, N(R 7 )CO, CH 2 SO 2 , CH 2 CH 2 or CH 2 CO wherein R 7 is (1-4C)alkyl or a group of the formula —X 4 —Q wherein X 4 is SO 2 and Q has any of the meanings defined hereinafter; or X 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, (1-4C)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 a pharmaceutically-acceptable salt thereof;
provided that when X 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 2 is not N(R 7 )SO 2 , N(R 7 )CO, C(R 6 ) 2 S, C(R 6 ) 2 SO, C(R 6 ) 2 SO 2 , C(R 6 ) 2 —C(R 6 ) 2 , C(R 6 ) 2 CO or C(R 6 ) 2 O.
3. An aminoheterocyclic compound of the formula I
wherein
each of G 1 and G 2 is CH;
m is 1; and
R 1 is hydrogen;
L 1 is ethylene,
T 1 is CH or N, and
R 2 and R 3 together form an ethylene group;
when T 1 is CH or N, X 1 is a group of the formula CH 2 , CO, CH 2 O or SO 2 , or, when T 1 is CH, X 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 , N -dimethylcarbamoyl and 2-(ethylthio)ethylaminocarbonyl;
X 2 is a group of the formula S, SO 2 , CONH, NHSO 2 or N(R 7 )SO 2 wherein R 7 is methyl or a group of the formula —SO 2 Q 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, 4-chlorophenoxy, methyl and methoxy;
or a pharmaceutically-acceptable salt thereof;
provided that when X 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 2 is not NHSO 2 or N(R 7 )SO 2 wherein R 7 is methyl or a group of the formula —SO 2 —Q wherein Q has any of the meanings defined immediately hereinbefore.
4. The compound according to claim 1 or 2 wherein
each of G 1 and G 2 is CH;
m is 1; and
R 1 is hydrogen;
L 1 is ethylene,
T 1 is CH or N, and
R 2 and R 3 together form an ethylene group;
when T 1 is CH or N, X 1 is a group of the formula CH 2 , CO or CH 2 O, or, when T 1 is CH, X 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 and N , N -dimethylcarbamoyl;
X 2 is a group of the formula SO 2 , NHSO 2 or N(R 7 )SO 2 wherein R 7 is methyl or a group of the formula —SO 2 Q 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 1 is CO and Ar is 1,3- or 1,4-phenylene which bears 1 or 2 substituents selected from fluoro, chloro, bromo, trifluoromethyl, methyl and methoxy then X 2 is not NHSO 2 or N(R 7 )SO 2 wherein R 7 is methyl or a group of the formula SO 2 —Q wherein Q has any of the meanings defined immediately hereinbefore.
5. The compound according to claim 1 or 2 wherein
each of G 1 and G 2 is CH;
m is 1; and
R 1 is hydrogen;
L 1 is ethylene,
T 1 is N, and
R 2 and R 3 together form an ethylene group;
X 1 is a group of the formula CO;
Ar is 1,4-phenylene or 2-carboxy-1,4-phenylene;
X 2 is a group of the formula SO 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 claim 1 or 2 wherein
each of G 1 and G 2 is CH;
m is 1; and
R 1 is hydrogen;
L 1 is ethylene,
T 1 is N, and
R 2 and R 3 together form an ethylene group;
X 1 is a group of the formula CO;
Ar is 1,4-phenylene or 2-carboxy-1,4-phenylene;
X 2 is a group of the formula SO 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 method of producing an antithrombotic or anticoagulant effect in a warm-blooded animal in need thereof, which comprises administering to said animal an effective amount of an aminoheterocyclic compound of formula I:
wherein
G 1 is CH;
G 2 is CH;
m is 1 or 2;
R 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 1 is (1-4C)alkylene, (3-6C)cycloalkane-1,2-diyl or (1-3C)alkylene-carbonyl,
T 1 is CH or N, and
R 2 and R 3 together form a (1-4C)alkylene or methylenecarbonyl group,
and wherein 1 or 2 methylene groups within L 1 or the ring formed when R 2 and R 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, 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 and N , N -di-(1-4C)akylcarbamoyl-(1-4C)alkyl,
provided that, when T 1 is N, L 1 is not optionally substituted methylene and R 2 and R 3 together do not form an optionally substituted methylene group;
X 1 is a group of the formula SO, SO 2 , C(R 4 ) 2 , CO, C(R 4 ) 2 O, C(R 4 ) 2 S, C(R 4 ) 2 SO, C(R 4 ) 2 SO 2 , COC(R 4 ) 2 , SOC(R 4 ) 2 or SO 2 C(R 4 ) 2 when T 1 is CH or N, or, in addition, X 1 is a group of the formula O, S, OC(R 4 ) 2 or SC(R 4 ) 2 when T 1 is CH, and wherein each R 4 is independently hydrogen or (1-4C)alkyl;
Ar is a 1,3-phenylene or 1,4-phenylene, wherein said phenylene 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 1 which is selected from hydroxy, amino, (1-4C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkynyloxy, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, (2-4C)alkanoylamino, benzamido, (1-4C)alkanesulphonamido and benzenesulphonamido,
from the substituent Y 2 which is selected from carboxy, carbamoyl, (1-4C)alkoxycarbonyl, N -(1-4C)alkylcarbamoyl, N , N -di-(1-4C)alkylcarbamoyl, (1-4C)alkanesulphonamidocarbonyl, benzenesulphonamidocarbonyl and benzylsulphonamidocarbonyl,
from a substituent of the formula —L 2 —Y 1 wherein L 2 is (1-4C)alkylene and Y 1 has any of the meanings defined immediately hereinbefore,
from a substituent of the formula —L 2 —Y 2 wherein L 2 is (1-4C)alkylene and Y 2 has any of the meanings defined immediately hereinbefore,
from a substituent of the formula —X 3 —L 2 —Y 2 wherein X 3 is a group of the formula CON(R 5 ), CON(L 2 —Y 2 ), C(R 5 ) 2 O, O, N(R 5 ) or N(L 2 —Y 2 ), L 2 is (1-4C)alkylene, Y 2 has any of the meanings defined immediately hereinbefore and each R 5 is independently hydrogen or (1-4C)alkyl, and
from a substituent of the formula —X 3 —L 3 —Y 1 wherein X 3 is a group of the formula CON(R 5 ), CON(L 3 —Y ), C(R 5 ) 2 O, O, N(R 5 ) or N(L 3 —Y 1 ), L 3 is (2-4C)alkylene, Y 1 has any of the meanings defined immediately hereinbefore and each R 5 is independently hydrogen or (1-4C)alkyl,
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 2 is a group of the formula S, SO, SO 2 , C(R 6 ) 2 , CO, N(R 7 )SO 2 , N(R 7 )CO, C(R 6 ) 2 S, C(R 6 ) 2 SO, C(R 6 ) 2 SO 2 , C(R 6 ) 2 —C(R 6 ) 2 or C(R 6 ) 2 CO, or, in addition, X 2 is a group of the formula O, SO 2 N(R 7 ), CON(R 7 ) or C(R 6 ) 2 O when Q is other than phenyl-(2-4C)alkenyl or phenyl-(2-4C)alkynyl and wherein each R 6 is independently hydrogen or (1-4C)alkyl and R 7 is hydrogen, (1-4C)alkyl or a group of the formula —X 4 —Q wherein X 4 is SO 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 or phenyl-(2-4C)alkynyl, 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)alkyl, phenyl, phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl, benzyl and benzoyl, and wherein said phenyl, phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl, 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 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 2 is not N(R 7 )SO 2 , N(R 7 )CO, C(R 6 ) 2 S, C(R 6 ) 2 SO, C(R 6 ) 2 SO 2 , C(R 6 ) 2 —C(R 6 ) 2 , C(R 6 ) 2 CO or C(R 6 ) 2 O.
8. A compound which is:
1-[4-(6-chloronaphth-2-ylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine,
1-[4-(6-bromonaphth-2-ylsulphonyl)benzyl]-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]benzoic acid,
5-(2-naphthylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoic acid,
5-(4′-bromo-4-biphenylylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoic acid,
5-[(E)-4-chlorostyrylsulphonyl]-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoic acid,
4′-bromo- N -{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-4-biphenylylsulphonamide,
4-chloro- N -{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-(E)-styrylsulphonamide,
6-bromo- N -{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-2-naphthalenesulphonamide,
N -{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-4-toluenesulphonamide,
N -{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}- N -(4-tolylsulphonyl)-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-pyridyl)piperidin-4-yloxy]phenyl}-4-biphenylylsulphonamide,
4′-bromo- N -{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl}-4-biphenylylsulphonamide,
6-bromo- N -{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]-phenyl}-2-naphthalenesulphonamide,
4-chloro- N -{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl}-(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-ylmethoxy]phenyl}-2-naphthalenesulphonamide,
6-bromo- N -{3-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-2-naphthalenesulphonamide,
4-[4-chlorophenylsulphonyl)phenoxy]-1-(4-(pyridyl)piperidine,
5-(6-bromonaphth-2-ylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoic acid,
4-(6-bromonaphth-2-ylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoic acid,
1-[4-(4-(4-chlorophenoxy)phenylaminocarbonyl)benzyl]-4-(4-pyridyl)piperazine,
6-bromo- N -{2-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl}-2-naphthalenesulphonamide,
4-chloro- N -{3-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-(E)-styrylsulphonamide,
4-[4-(6-bromonaphth-2-ylsulphonyl)phenoxy]-1-(4-pyridyl)piperidine,
4-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-1-(4-pyridyl)piperidine,
4-[4-(6-bromonaphth-2-ylthio)benzoyl]-1-(4-pyridyl)piperidine,
4-[4-(6-bromonaphth-2-ylsulphonyl)phenylsulphonyl]-1-(4-pyridyl)piperazine,
1-[4-(6-bromonaphth-2-ylthio)benzoyl]-4-(4-pyridyl)piperazine,
1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine,
1-[4-(6-bromonaphth-2-ylsulphonyl-2-trifluoromethylbenzoyl]-4-(4-pyridyl)piperazine,
1-[4-(6-bromonaphth-2-ylthio)-2-trifluoromethylbenzoyl]-4-(4-pyridyl)piperazine,
1-[4-(6-bromonaphth-2-ylthio)-2-carboxybenzoyl]-4-(4-pyridyl)piperazine
1-[5-(6-bromonaphth-2-ylthio)-2-carboxybenzoyl]-4-(4-pyridyl)piperazine,
1-[5-(6-bromonaphth-2-ylsulphonyl)-2-methoxycarbonylbenzoyl]-4-(4-pyridyl)piperazine,
1-[4-(6-bromonaphth-2-ylsulphonyl)-2-methoxycarbonylbenzoyl]-4-(4-pyridyl)piperazine,
1-[4-(6-bromonaphth-2-ylsulphonyl)-2-(2-(ethylthio)-ethylaminocarbonyl)benzoyl]-4-(4-pyridyl)piperazine,
1-[5-(6-bromonaphth-2-ylsulphonyl)-2-(2-ethylthio)ethylaminocarbonyl)benzoyl]-4-(4-pyridyl)piperazine,
1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(2-methylpyrid-4-yl)piperazine,
1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(4-pyridyl)hexahydro-1,4-diazepine,
or a pharmaceutically-acceptable salt thereof.
9. A method of producing an antithrombotic or anticoagulant effect in a warm-blooded animal in need thereof, which comprises administering to said animal an effective amount of a compound as claimed in any one of claims 8 , 1 and 2 .
10. A method of treating coronary artery or cerebro-vascular disease in a warm-blooded animal in need thereof, which comprises administering to said animal an effective amount of an aminoheterocyclic compound of formula I:
wherein
G 1 is CH;
G 2 is CH;
m is 1 or 2;
R 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 1 is (1-4C)alkylene, (3-6C)cycloalkane-1,2-diyl or (1-3C)alkylene-carbonyl,
T 1 is CH or N, and
R 2 and R 3 together form a (1-4C)alkylene or methylenecarbonyl group, and wherein 1 or 2 methylene groups within L 1 or the ring formed when R 2 and R 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, 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 and N , N -di-(1-4C)alkylcarbamoyl-(1-4C)alkyl,
provided that, when T 1 is N, L 1 is not optionally substituted methylene and R 2 and R 3 together do not form an optionally substituted methylene group;
X 1 is a group of the formula SO, SO 2, C(R 4 ) 2 , CO, C(R 4 ) 2 O, C(R 4 ) 2 S, C(R 4 ) 2 SO, C(R 4 ) 2 SO 2 , COC(R 4 ) 2 , SOC(R 4 ) 2 or SO 2 C(R 4 ) 2 when T 1 is CH or N, or, in addition, X 1 is a group of the formula O, S, OC(R 4 ) 2 or SC(R 4 ) 2 when T 1 is CH, and wherein each R 4 is independently hydrogen or (1-4C)alkyl;
Ar is a 1,3-phenylene or 1,4-phenylene, wherein said phenylene 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 1 which is selected from hydroxy, amino, (1-4C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkynyloxy, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, (2-4C)alkanoylamino, benzamido, (1-4C)alkanesulphonamido and benzenesulphonamido,
from the substituent Y 2 which is selected from carboxy, carbamoyl, (1-4C)alkoxycarbonyl, N -(1-4C)alkylcarbamoyl, N , N -di-(1-4C)alkylcarbamoyl, (1-4C)alkanesulphonamidocarbonyl, benzenesulphonamidocarbonyl and benzylsulphonamidocarbonyl,
from a substituent of the formula —L 2 —Y 1 wherein L 2 is (1-4C)alkylene and Y 1 has any of the meanings defined immediately hereinbefore,
from a substituent of the formula —L 2 —Y 2 wherein L 2 is (1-4C)alkylene and Y 2 has any of the meanings defined immediately hereinbefore,
from a substituent of the formula —X 3 —L 2 —Y 2 wherein X 3 is a group of the formula CON(R 5 ), CON(L 2 —Y 2 ), C(R 5 ) 2 O, O, N(R 5 ) or N(L 2 —Y 2 ), L 2 is (1-4C)alkylene, Y 2 has any of the meanings defined immediately hereinbefore and each R 5 is independently hydrogen or (1-4C)alkyl, and
from a substituent of the formula —X 3 —L 3 —Y 1 wherein X 3 is a group of the formula CON(R 5 ), CON(L 3 —Y 1 ), C(R 5 ) 2 O, O, N(R 5 ) or N(L 3 —Y 1 ), L 3 is (2-4C)alkylene, Y 1 has any of the meanings defined immediately hereinbefore and each R 5 is independently hydrogen or (1-4C)alkyl,
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 2 is a group of the formula S, SO, SO 2 , C(R 6 ) 2 , CO, N(R 7 )SO 2 , N(R 7 )CO, C(R 6 ) 2 S, C(R 6 ) 2 SO, C(R 6 ) 2 SO 2 , C(R 6 ) 2 —C(R 6 ) 2 or C(R 6 ) 2 CO, or, in addition, X 2 is a group of the formula O, SO 2 N(R 7 ), CON(R 7 ) or C(R 6 ) 2 O when Q is other than phenyl-(2-4C)alkenyl or phenyl-(2-4C)alkynyl and wherein each R 6 is independently hydrogen or (1-4C)alkyl and R 7 is hydrogen, (1-4C)alkyl or a group of the formula —X 4 —Q wherein X 4 is SO 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 or phenyl-(2-4C)alkynyl, 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)alkyl, phenyl, phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl, benzyl and benzoyl, and wherein said phenyl, heteroaryl, phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl, 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 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 2 is not N(R 7 )SO 2 , N(R 7 )CO, C(R 6 ) 2 S, C(R 6 ) 2 SO, C(R 6 ) 2 SO 2 , C(R 6 ) 2 —C(R 6 ) 2 CO or C(R 6 ) 2 O.
11. A method of treating coronary artery or cerebro-vascular disease in a warm-blooded animal in need thereof, which comprises administering to said animal an effective amount of a compound as claimed in claims 8 , 1 and 2 .
12. A pharmaceutical composition which comprises a compound or a pharmaceutically acceptable salt thereof as claimed in claim 8 , and a pharmaceutically acceptable carrier.
13. A method of producing an antithrombatic or anticoagulant effect comprising administering an aminoheterocyclic derivative of the formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1 or 2 , and a pharmaceutically acceptable carrier.
14. A process for the preparation of an aminoheterocyclic compound 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 1 is N and X 1 is CO, the reaction, conveniently in the presence of a suitable base, of an amine of the formula II
with an acid of the formula III
HO 2 C—Ar—X 2 —Q III
or a reactive derivative thereof;
(aa) for the preparation of those compounds of the formula I wherein T 1 is N and X 1 is a group of the formula COC(R 4 ) 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 2 C—C(R 4 ) 2 —Ar—X 2 —Q
or a reactive derivative thereof;
(b) for the production of those compounds of the formula I wherein T 1 is CH and X 1 is O or C(R 4 ) 2 O, the reaction, conveniently in the presence of a suitable coupling agent, of a compound of the formula IV
wherein n is 0 or 1 and Z is a displaceable group, with a phenolic compound of the formula V
HO—AR—X 2 —Q V
(bb) for the preparation of those compounds of the formula I wherein T 1 is CH and X 1 is a group of the formula S or C(R 4 ) 2 S, 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 2 —Q;
(c) for the production of those compounds of the formula I wherein T 1 is N and X 1 is CH(R 4 ), the reductive amination of a keto compound of the formula VI
R 4 —CO—Ar—X 2 —Q VI
with an amine of the formula VII
(d) for the production of those compounds of the formula I wherein X 2 is a group of the formula N(R 7 )SO 2 , the reaction, conveniently in the presence of a suitable base, of an amine of the formula VIII
with a compound of the formula IX
Z—SO 2 —Q IX
wherein Z is a displaceable group;
(dd) for the production of those compounds of the formula I wherein X 2 is a group of the formula N(R 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 2 is a group of the formula N(R 7 )SO 2 , the reaction, conveniently in the presence of a suitable base, of a sulphonamide of the formula X
with a compound of the formula XI
R 7 —Z XI
wherein Z is a displaceable group;
(ee) for the production of those compounds of the formula I wherein X 2 is a group of the formula N(R 7 )CO, the reaction conveniently in the presence of a suitable base, of a compound of the formula I wherein N(R 7 )CO is NHCO with a compound of the formula XI;
(f) for the production of those compounds of the formula I wherein X 2 is a group of the formula SO 2 N(R 7 ) the reaction, conveniently in the presence of a suitable base of a compound of the formula XII
wherein Z is a displaceable group as defined hereinbefore, with an amine of the formula XIII
(R 7 )NH—Q XIII
(ff) for the preparation of those compounds of the formula I wherein X 2 is a group of the formula CON(R 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 1 is CH and X 1 is a group of the formula OC(R 4 ) 2 , the reaction conveniently in the presence of a suitable coupling agent of an alcohol of the formula XIV
with a compound of the formula XV
Z—C(R 4 ) 2 —Ar—X 2 —Q XV
wherein Z is a displaceable group;
(gg) for the preparation of those compounds of the formula I wherein T 1 is CH and X 1 is a group of the formula SC(R 4 ) 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 2 is a group of the formula C(R 6 ) 2 S, the reaction, conveniently in the presence of a suitable base, of a compound of the formula XVI
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 1 , R 2 , R 3 , Ar or Q bears a carboxy or carboxy-containing group, the hydrolysis of a compound of the formula I wherein L 1 , R 2 , R 3 , Ar or Q bears a (1-4C)alkoxycarbonyl group;
(j) for the production of those compounds of the formula I wherein L 1 , R 2 , R 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 1 , R 2 , R 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 1 is a group of the formula SO, SO 2 , C(R 4 ) 2 SO, C(R 4 ) 2 SO 2 , SOC(R 4 ) 2 or SO 2 C(R 4 ) 2 , wherein Ar bears a (1-4C)alkylsulphinyl or (1-4C)alkylsulphonyl, or a substituent which contains a (1-4C)alkylsulphinyl or (1-4C)alkylsulphonyl, wherein X 2 is a group of the formula SO, SO 2 , C(R 6 ) 2 SO or C(R 6 ) 2 SO 2 , or wherein Q bears a (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, phenylsulphinyl or phenylsulphonyl, 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:
wherein L is a displaceable group as hereinbefore with a compound of the formula XIX:
NH(R 2 )—L 1 —T 1 (R 3 )—X 1 —Ar—Q XIX
and, if necessary, forming a pharmaceutically associated salt.