US 7,173,025 B1Granted

Aminoheterocyclic derivatives as antithrombotic or anticoagulant agents

AssigneeZeneca Limited

InventorsAndrew Stocker, John Preston, Michael James Smithers

Life of this patent

Estimating the term…

Abstract

Compounds of formula (I), wherein G1 is CH or N; G2 is CH or N; R1 is a variety of optional substituents; L1 is (1-4C)alkylene; T1 is CH or N; R2 and R3 are independently hydrogen or (1-4C)alkyl or are joined to form a ring; X1 and X2 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.

Claims14

Dependent claims

An aminoheterocyclic compound of the formula I

wherein
G1 is CH;
G2 is CH;
m is 1 or 2;
R1 is hydrogen, halogeno, trifluoromethyl, trifluoromethoxy, cyano, amino, hydroxy, nitro, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino or di-(1-4C)alkylamino;
L1 is (1-4C)alkylene or (3-6C)cycloalkane-1,2-diyl,
T1 is CH or N, and
R2 and R3 together form a (1-4C)alkylene or methylenecarbonyl group,
and wherein 1 or 2 methylene groups within L1 or the ring formed when R2 and R3 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 T1 is N, L1 is not optionally substituted methylene and R2 and R3 together do not form an optionally substituted methylene group;
X1 is a group of the formula SO, SO2, C(R4)2, CO, C(R4)2O, C(R4)2S, C(R4)2SO, C(R4)2SO2, COC(R4)2, SOC(R4)2 or SO2C(R4)2 when T1 is CH or N, or, in addition, X1 is a group of the formula O, S, OC(R4)2 or SC(R4)2 when T1 is CH, and wherein each R4 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 Y1 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 Y2 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 —L2—Y1 wherein L2 is (1-4C)alkylene and Y1 has any of the meanings defined immediately hereinbefore,
from a substituent of the formula —L2—Y2 wherein L2 is (1-4C)alkylene and Y2 has any of the meanings defined immediately hereinbefore,
from a substituent of the formula —X3—L2—Y2 wherein X3 is a group of the formula CON(R5), CON(L2—Y2), C(R5)2O, O, N(R5) or N(L2—Y2), L2 is (1-4C)alkylene, Y2 has any of the meanings defined immediately hereinbefore and each R5 is independently hydrogen or (1-4C)alkyl, and
from a substituent of the formula —X3—L3—Y1 wherein X3 is a group of the formula CON(R5), CON(L3—Y1), C(R5)2O, O, N(R5) or N(L3—Y1), L3 is (2-4C)alkylene, Y1 has any of the meanings defined immediately hereinbefore and each R5 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;
X2 is a group of the formula S, SO, SO2, C(R6)2, CO, N(R7)SO2, N(R7)CO, C(R6)2S, C(R6)2SO, C(R6)2SO2, C(R6)2—C(R6)2 or C(R6)2CO, or, in addition, X2 is a group of the formula O, SO2N(R7), CON(R7) or C(R6)2O when Q is other than phenyl-(2-4C)alkenyl or phenyl-(2-4C)alkynyl and wherein each R6 is independently hydrogen or (1-4C)alkyl and R7 is hydrogen, (1-4C)alkyl or a group of the formula —X4—Q wherein X4 is SO2 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 X1 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 X2 is not N(R7)SO2, N(R7)CO, C(R6)2S, C(R6)2SO, C(R6)2SO2, C(R6)2—C(R6)2, C(R6)2CO or C(R6)2O.

22 more elements

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
G1 is CH;
G2 is CH;
m is 1 or 2;
R1 is hydrogen, halogeno, trifluoromethyl, trifluoromethoxy, cyano, amino, hydroxy, nitro, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino or di-(1-4C)alkylamino;
L1 is (1-4C)alkylene, (3-6C)cycloalkane-1,2-diyl or (1-3C)alkylene-carbonyl,
T1 is CH or N, and
R2 and R3 together form a (1-4C)alkylene or methylenecarbonyl group,
and wherein 1 or 2 methylene groups within L1 or the ring formed when R2 and R3 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 T1 is N, L1 is not optionally substituted methylene and R2 and R3 together do not form an optionally substituted methylene group;
X1 is a group of the formula SO, SO2, C(R4)2, CO, C(R4)2O, C(R4)2S, C(R4)2SO, C(R4)2SO2, COC(R4)2, SOC(R4)2 or SO2C(R4)2 when T1 is CH or N, or, in addition, X1 is a group of the formula O, S, OC(R4)2 or SC(R4)2 when T1 is CH, and wherein each R4 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 Y1 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 Y2 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 —L2—Y1 wherein L2 is (1-4C)alkylene and Y1 has any of the meanings defined immediately hereinbefore,
from a substituent of the formula —L2—Y2 wherein L2 is (1-4C)alkylene and Y2 has any of the meanings defined immediately hereinbefore,
from a substituent of the formula —X3—L2—Y2 wherein X3 is a group of the formula CON(R5), CON(L2—Y2), C(R5)2O, O, N(R5) or N(L2—Y2), L2 is (1-4C)alkylene, Y2 has any of the meanings defined immediately hereinbefore and each R5 is independently hydrogen or (1-4C)alkyl, and
from a substituent of the formula —X3—L3—Y1 wherein X3 is a group of the formula CON(R5), CON(L3—Y ), C(R5)2O, O, N(R5) or N(L3—Y1), L3 is (2-4C)alkylene, Y1 has any of the meanings defined immediately hereinbefore and each R5 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;
X2 is a group of the formula S, SO, SO2, C(R6)2, CO, N(R7)SO2, N(R7)CO, C(R6)2S, C(R6)2SO, C(R6)2SO2, C(R6)2—C(R6)2 or C(R6)2CO, or, in addition, X2 is a group of the formula O, SO2N(R7), CON(R7) or C(R6)2O when Q is other than phenyl-(2-4C)alkenyl or phenyl-(2-4C)alkynyl and wherein each R6 is independently hydrogen or (1-4C)alkyl and R7 is hydrogen, (1-4C)alkyl or a group of the formula —X4—Q wherein X4 is SO2 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 X1 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 X2 is not N(R7)SO2, N(R7)CO, C(R6)2S, C(R6)2SO, C(R6)2SO2, C(R6)2—C(R6)2, C(R6)2CO or C(R6)2O.

22 more elements

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.

44 more elements

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
G1 is CH;
G2 is CH;
m is 1 or 2;
R1 is hydrogen, halogeno, trifluoromethyl, trifluoromethoxy, cyano, amino, hydroxy, nitro, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino or di-(1-4C)alkylamino;
L1 is (1-4C)alkylene, (3-6C)cycloalkane-1,2-diyl or (1-3C)alkylene-carbonyl,
T1 is CH or N, and
R2 and R3 together form a (1-4C)alkylene or methylenecarbonyl group, and wherein 1 or 2 methylene groups within L1 or the ring formed when R2 and R3 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 T1 is N, L1 is not optionally substituted methylene and R2 and R3 together do not form an optionally substituted methylene group;
X1 is a group of the formula SO, SO2, C(R4)2, CO, C(R4)2O, C(R4)2S, C(R4)2SO, C(R4)2SO2, COC(R4)2, SOC(R4)2 or SO2C(R4)2 when T1 is CH or N, or, in addition, X1 is a group of the formula O, S, OC(R4)2 or SC(R4)2 when T1 is CH, and wherein each R4 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 Y1 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 Y2 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 —L2—Y1 wherein L2 is (1-4C)alkylene and Y1 has any of the meanings defined immediately hereinbefore,
from a substituent of the formula —L2—Y2 wherein L2 is (1-4C)alkylene and Y2 has any of the meanings defined immediately hereinbefore,
from a substituent of the formula —X3—L2—Y2 wherein X3 is a group of the formula CON(R5), CON(L2—Y2), C(R5)2O, O, N(R5) or N(L2—Y2), L2 is (1-4C)alkylene, Y2 has any of the meanings defined immediately hereinbefore and each R5 is independently hydrogen or (1-4C)alkyl, and
from a substituent of the formula —X3—L3—Y1 wherein X3 is a group of the formula CON(R5), CON(L3—Y1), C(R5)2O, O, N(R5) or N(L3—Y1), L3 is (2-4C)alkylene, Y1 has any of the meanings defined immediately hereinbefore and each R5 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;
X2 is a group of the formula S, SO, SO2, C(R6)2, CO, N(R7)SO2, N(R7)CO, C(R6)2S, C(R6)2SO, C(R6)2SO2, C(R6)2—C(R6)2 or C(R6)2CO, or, in addition, X2 is a group of the formula O, SO2N(R7), CON(R7) or C(R6)2O when Q is other than phenyl-(2-4C)alkenyl or phenyl-(2-4C)alkynyl and wherein each R6 is independently hydrogen or (1-4C)alkyl and R7 is hydrogen, (1-4C)alkyl or a group of the formula —X4—Q wherein X4 is SO2 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 X1 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 X2 is not N(R7)SO2, N(R7)CO, C(R6)2S, C(R6)2SO, C(R6)2SO2, C(R6)2—C(R6)2CO or C(R6)2O.

21 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/117,436Filed 31 Jan 1997
Priority: GB 96021662 Feb 1996
Granted: 6 Feb 2007
Term ends: Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
A61P 7/00
Drugs for disorders of the blood or the extracellular fluid
A61P 7/02
Drugs for disorders of the blood or the extracellular fluid: antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
A61P 9/00
Drugs for disorders of the cardiovascular system

Family

No related US applications are recorded in the indexed filing history.

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Abstract

An aminoheterocyclic compound of the formula I

wherein
G1 is CH;
G2 is CH;
m is 1 or 2;
R1 is hydrogen, halogeno, trifluoromethyl, trifluoromethoxy, cyano, amino, hydroxy, nitro, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino or di-(1-4C)alkylamino;
L1 is (1-4C)alkylene or (3-6C)cycloalkane-1,2-diyl,
T1 is CH or N, and
R2 and R3 together form a (1-4C)alkylene or methylenecarbonyl group,
and wherein 1 or 2 methylene groups within L1 or the ring formed when R2 and R3 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 T1 is N, L1 is not optionally substituted methylene and R2 and R3 together do not form an optionally substituted methylene group;
X1 is a group of the formula SO, SO2, C(R4)2, CO, C(R4)2O, C(R4)2S, C(R4)2SO, C(R4)2SO2, COC(R4)2, SOC(R4)2 or SO2C(R4)2 when T1 is CH or N, or, in addition, X1 is a group of the formula O, S, OC(R4)2 or SC(R4)2 when T1 is CH, and wherein each R4 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 Y1 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 Y2 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 —L2—Y1 wherein L2 is (1-4C)alkylene and Y1 has any of the meanings defined immediately hereinbefore,
from a substituent of the formula —L2—Y2 wherein L2 is (1-4C)alkylene and Y2 has any of the meanings defined immediately hereinbefore,
from a substituent of the formula —X3—L2—Y2 wherein X3 is a group of the formula CON(R5), CON(L2—Y2), C(R5)2O, O, N(R5) or N(L2—Y2), L2 is (1-4C)alkylene, Y2 has any of the meanings defined immediately hereinbefore and each R5 is independently hydrogen or (1-4C)alkyl, and
from a substituent of the formula —X3—L3—Y1 wherein X3 is a group of the formula CON(R5), CON(L3—Y1), C(R5)2O, O, N(R5) or N(L3—Y1), L3 is (2-4C)alkylene, Y1 has any of the meanings defined immediately hereinbefore and each R5 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;
X2 is a group of the formula S, SO, SO2, C(R6)2, CO, N(R7)SO2, N(R7)CO, C(R6)2S, C(R6)2SO, C(R6)2SO2, C(R6)2—C(R6)2 or C(R6)2CO, or, in addition, X2 is a group of the formula O, SO2N(R7), CON(R7) or C(R6)2O when Q is other than phenyl-(2-4C)alkenyl or phenyl-(2-4C)alkynyl and wherein each R6 is independently hydrogen or (1-4C)alkyl and R7 is hydrogen, (1-4C)alkyl or a group of the formula —X4—Q wherein X4 is SO2 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 X1 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 X2 is not N(R7)SO2, N(R7)CO, C(R6)2S, C(R6)2SO, C(R6)2SO2, C(R6)2—C(R6)2, C(R6)2CO or C(R6)2O.

22 more elements

Facts

Application

09/117,436Filed 31 Jan 1997

Priority

GB 96021662 Feb 1996

Granted

6 Feb 2007

Term ends

Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
A61P 7/00
Drugs for disorders of the blood or the extracellular fluid
A61P 7/02
Drugs for disorders of the blood or the extracellular fluid: antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
A61P 9/00
Drugs for disorders of the cardiovascular system