Aminoheterocyclic derivatives as antithrombotic or anticoagulant agents
First Claim
Patent Images
1. An aminoheterocyclic compound of the formula I whereinG1 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.
3 Assignments
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Accused Products
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.
54 Citations
14 Claims
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1. 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, andfrom 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.- View Dependent Claims (2, 4, 5, 6, 9, 11, 13, 14)
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.
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4. The compound according to claim 1 or 2 wherein
each of G1 and G2 is CH; -
m is 1; and
R1 is hydrogen;
L1 is ethylene, T1 is CH or N, and R2 and R3 together form an ethylene group;
when T1 is CH or N, X1 is a group of the formula CH2, CO or CH2O, or, when T1 is CH, X1 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;
X2 is a group of the formula SO2, NHSO2 or N(R7)SO2 wherein R7 is methyl or a group of the formula —
SO2Q 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 X1 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 X2 is not NHSO2 or N(R7)SO2 wherein R7 is methyl or a group of the formula SO2—
Q wherein Q has any of the meanings defined immediately hereinbefore.
-
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5. The compound according to claim 1 or 2 wherein
each of G1 and G2 is CH; -
m is 1; and
R1 is hydrogen;
L1 is ethylene, T1 is N, and R2 and R3 together form an ethylene group;
X1 is a group of the formula CO;
Ar is 1,4-phenylene or 2-carboxy-1,4-phenylene;
X2 is a group of the formula SO2; 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.
-
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6. A compound according to claim 1 or 2 wherein
each of G1 and G2 is CH; -
m is 1; and
R1 is hydrogen;
L1 is ethylene, T1 is N, and R2 and R3 together form an ethylene group;
X1 is a group of the formula CO;
Ar is 1,4-phenylene or 2-carboxy-1,4-phenylene;
X2 is a group of the formula SO2; 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.
-
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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.
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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.
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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.
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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:
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a) for the production of those compounds of the formula I wherein T1 is N and X1 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
HO2C—
Ar—
X2—
Q
III
or a reactive derivative thereof;
(aa) for the preparation of those compounds of the formula I wherein T1 is N and X1 is a group of the formula COC(R4)2, the reaction, conveniently in the presence of a suitable base, of an amine of the formula II with an acid of the formula;
HO2C—
C(R4)2—
Ar—
X2—
Q
or a reactive derivative thereof;
(b) for the production of those compounds of the formula I wherein T1 is CH and X1 is O or C(R4)2O, 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—
X2—
Q
V(bb) for the preparation of those compounds of the formula I wherein T1 is CH and X1 is a group of the formula S or C(R4)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—
X2—
Q;
(c) for the production of those compounds of the formula I wherein T1 is N and X1 is CH(R4), the reductive amination of a keto compound of the formula VI
R4—
CO—
Ar—
X2—
Q
VI
with an amine of the formula VII(d) for the production of those compounds of the formula I wherein X2 is a group of the formula N(R7)SO2, 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—
SO2—
Q
IX
wherein Z is a displaceable group;
(dd) for the production of those compounds of the formula I wherein X2 is a group of the formula N(R7)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 X2 is a group of the formula N(R7)SO2, the reaction, conveniently in the presence of a suitable base, of a sulphonamide of the formula X
with a compound of the formula XI
R7—
Z
XI
wherein Z is a displaceable group;
(ee) for the production of those compounds of the formula I wherein X2 is a group of the formula N(R7)CO, the reaction conveniently in the presence of a suitable base, of a compound of the formula I wherein N(R7)CO is NHCO with a compound of the formula XI;
(f) for the production of those compounds of the formula I wherein X2 is a group of the formula SO2N(R7) 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
(R7)NH—
Q
XIII(ff) for the preparation of those compounds of the formula I wherein X2 is a group of the formula CON(R7), 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 T1 is CH and X1 is a group of the formula OC(R4)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(R4)2—
Ar—
X2—
Q
XV
wherein Z is a displaceable group;
(gg) for the preparation of those compounds of the formula I wherein T1 is CH and X1 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 X2 is a group of the formula C(R6)2S, 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 L1, R2, R3, Ar or Q bears a carboxy or carboxy-containing group, the hydrolysis of a compound of the formula I wherein L1, R2, R3, Ar or Q bears a (1-4C)alkoxycarbonyl group;
(j) for the production of those compounds of the formula I wherein L1, R2, R3, Ar or Q bears a carbamoyl, N-alkylcarbamoyl or N,N-dialkylcarbamoyl group, the reaction of a compound of the formula I wherein L1, R2, R3, 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 X1 is a group of the formula SO, SO2, C(R4)2SO, C(R4)2SO2, SOC(R4)2 or SO2C(R4)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 X2 is a group of the formula SO, SO2, C(R6)2SO or C(R6)2SO2, 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(R2)—
L1—
T1(R3)—
X1—
Ar—
Q
XIX
and, if necessary, forming a pharmaceutically associated salt.
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3. An aminoheterocyclic compound of the formula I
wherein each of G1 and G2 is CH; -
m is 1; and
R1 is hydrogen;
L1 is ethylene, T1 is CH or N, and R2 and R3 together form an ethylene group;
when T1 is CH or N, X1 is a group of the formula CH2, CO, CH2O or SO2, or, when T1 is CH, X1 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;
X2 is a group of the formula S, SO2, CONH, NHSO2 or N(R7)SO2 wherein R7 is methyl or a group of the formula —
SO2Q 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 X1 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 X2 is not NHSO2 or N(R7)SO2 wherein R7 is methyl or a group of the formula —
SO2—
Q wherein Q has any of the meanings defined immediately hereinbefore.
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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 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, andfrom 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.
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8. A compound which is:
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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. - View Dependent Claims (12)
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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:
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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, andfrom 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.
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Specification