Aminoheterocyclic derivatives as antithrombotic or anticoagulant agents

• US 7,173,025 B1
• Filed: 01/31/1997
• Issued: 02/06/2007
• Est. Priority Date: 02/02/1996
• Status: Expired due to Fees

• Current Assignee: Astrazeneca UK Limited (Astrazeneca PLC)
• Original Assignee: Zeneca Incorporated (Astrazeneca PLC)
• Inventors: Stocker, Andrew, Smithers, Michael James, Preston, John
• Primary Examiner(s): Rotman; Alan L.
• Assistant Examiner(s): ROBINSON, BINTA M
• Application Number:
  US09/117,436
• Time in Patent Office: 3,658 Days
• Field of Search: 546/278.7, 546/278.4, 514/255, 514/422, 514/252.18, 514/218, 544/360, 540/484
• US Class Current: 514/218
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 237/20 Nitrogen atoms nitro radicals C07D237/12
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings

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.

Claims

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, 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)SO_{2, N(R}⁷)CO, C(R⁶)₂S, C(R⁶)₂SO, C(R⁶)₂SO₂, C(R⁶)₂—

C(R⁶)₂, C(R⁶)₂CO or C(R⁶)₂O.

2. The compound according to claim 1 wherein:

each of G¹ and G² is CH;

m is 1; and

R¹ is hydrogen;

L¹ is (1-4C)alkylene,

T¹ is CH or N, and

R² and R³ together form a (1-4C)alkylene group,

and wherein 1 or 2 methylene groups within L¹ and the ring formed when R² and R³ are linked optionally bears 1 or 2 (1-4C)alkyl substituents,

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;

when T¹ is CH or N, X¹ is a group of the formula SO₂, CH₂, CO, CH₂O, CH₂S, CH₂SO₂, COCH₂ or SO₂CH₂, or, when T¹ is CH, X¹ is, in addition, a group of the formula O, S, OCH₂ or SCH₂;

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 —

L²—

Y¹ or of the formula —

L²—

Y² wherein L² is (1-4C)alkylene, Y¹ 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 Y² 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 —

X³—

L²—

Y² wherein X³ is a group of the formula CONH, CON(Me), CH₂O or O, L² is methylene, ethylene or trimethylene and Y² 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 —

X³—

L³—

Y¹ wherein X³ is a group of the formula CONH, CH₂O, O or NH, L³ is ethylene or trimethylene and Y¹ 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;

X² is a group of the formula SO₂, CH₂, CO, NHSO₂, N(R⁷)SO₂, NHCO, N(R⁷)CO, CH₂SO₂, CH₂CH₂ or CH₂CO wherein R⁷ is (1-4C)alkyl or a group of the formula —

X⁴—

Q wherein X⁴ is SO₂ and Q has any of the meanings defined hereinafter;

or X² 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 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.

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.

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.

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.

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.

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.

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 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.

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.

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, 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.

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.

12. A pharmaceutical composition which comprises a compound or a pharmaceutically acceptable salt thereof as claimed in claim 8, and a pharmaceutically acceptable carrier.

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

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, SO_2, 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.