Aminoheterocyclic derivatives as antithrombotic or anticoagulant

• US 5,965,559 A
• Filed: 03/26/1997
• Issued: 10/12/1999
• Est. Priority Date: 09/26/1994
• Status: Expired due to Fees

• Current Assignee: Astrazeneca UK Limited (Astrazeneca PLC)
• Original Assignee: Zeneca Incorporated (Astrazeneca PLC)
• Inventors: Stocker, Andrew, Faull, Alan Wellington, Mayo, Colette Marie, Preston, John
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): COLEMAN, BRENDA LIBBY
• Application Number:
  US08/817,031
• Time in Patent Office: 930 Days
• Field of Search: 514/252, 514/256, 514/275, 544/295, 544/323, 544/329
• US Class Current: 514/252.11
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• 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
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings

Abstract

The invention concerns compounds of formula (I), wherein each of G¹, G² and G⁶ is CH or n; m is 1 or 2; R¹ includes hydrogen, halogeno and (1-4C)alkyl; M¹ is a group of formula: NR² -L¹ -T¹ R³, in which R² and R³ together form a (1-4C)alkylene group, L¹ includes (1-4C)alkylene, and T¹ is CH or N; A may be a direct link; M² is a group of the formula: (T² R⁴)_r -L² T³ R⁵ in which R is 0 or 1, each of T² and T³ is CH or N, each of R⁴ and R⁵ is hydrogen or (1-4C)alkyl, or R⁴ and R⁵ together form a (1-4C)alkylene group, and L² includes (1-4C)alkylene; M³ may be a direct link to X; X includes sulphonyl; and Q includes naphthyl and a heterocycle moiety; or a pharmaceutically-acceptable salt thereof; processes for their preparation, pharmaceutical compositions containing them and their use as antithrombotic or anticoagulant agents.

Claims

1. A compound of the formula I wherein:

each of G¹ and G³ is CH and G² is N, or each of G¹ and G² is CH and G³ is N;

m is 1 or 2;

each R¹ is independently selected from hydrogen, amino, halogeno, cyano, (1-4C)alkyl and (1-4C)alkoxy;

M¹ is a group of the formula

space="preserve" listing-type="equation">NR.sup.2 -L.sup.1 -T.sup.1 R.sup.3

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

L¹ is (1-4C)alkylene, and

T¹ is CH or N,

and wherein 1 or 2 methylene groups within L¹ and the rings formed when R² and R³ are linked optionally bears a (1-4C)alkyl substituent;

A is a direct link to the carbonyl group, or A is (1-4C)alkylene;

M² is a group of the formula

space="preserve" listing-type="equation">(T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which r is 0 or 1,

T² is N,

T³ is N,

R⁴ is hydrogen or (1-4C)alkyl,

R⁵ is hydrogen or (1-4C)alkyl,

or R⁴ and R⁵ together form a (1-4C)alkylene, methylenecarbonyl or carbonylmethylene group, or R⁴ is a (2-3C)alkylene group which is linked to a methylene group within L² forming a 5- or 6-membered ring involving R⁴ and T², or R⁵ is a (2-3C)alkylene group which is linked to a methylene group within L² forming a 5- or 6-membered ring involving R⁵ and T³,

L² is (1-4C)alkylene or (1-3C)alkylene-carbonyl, and, when r is 1, L² may also be carbonyl-(1 -3C)alkylene,

and wherein 1 or 2 methylene groups within L² and the rings formed when R⁴ and R⁵,

R⁴ and L² or R⁵ and L² are linked optionally bears a substituent selected from the group consisting of oxo, carboxy, (1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin- 1 -ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl, 4-(1-4C)alkylpiperazin-1-ylcarbonyl, N-phenylcarbamoyl, N-(1-4C)alkyl-N-phenylcarbamoyl, N-[phenyl-(1-3C)alkyl]carbamoyl, N-(1-4C)alkyl-N-[phenyl-(1-3C)alkyl]carbamoyl, N-[hydroxy-(2-3C)alkyl]carbamoyl, N-(1-4C)alkyl-N-[hydroxy(2-3C)alkyl]carbamoyl, N-[(1-4C)alkoxy-(2-3C)alkyl]carbamoyl, N-(1-4C)alkyl-N-[(1-4C)alkoxy-(2-3C)alkyl]carbamoyl, N-[carboxy-(1-3C)alkyl]carbamoyl, N-(1-4C)alkyl-N-[carboxy-(1 -3C)alkyl]carbamoyl, N-[carboxy-(1-3C)alkyl]-N-[hydroxy-(2-3C)alkyl]carbamoyl, N-[carboxy-(1-3C)alkyl]-N-[(1-4C)alkoxy-(2-3C)alkyl]carbamoyl, N-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]carbamoyl, N-(1-4C)alkyl-N-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]carbamoyl, N-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]-N-[hydroxy-(2-3C)alkyl]carbamoyl, N-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]-N-[( 1-4C)alkoxy-(2-3C)alkyl]carbamoyl, (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, pyrrolidin-1-ylcarbonyl-(1-4C)alkyl, piperidinocarbonyl-(1-4C)alkyl, morpholinocarbonyl-(1-4C)alkyl, piperazin-1-ylcarbonyl-(1-4C)alkyl, 4-(1-4C)alkylpiperazin-1-ylcarbonyl-(1-4C)alkyl, N-phenylcarbamoyl-(1-4C)alkyl, N-[phenyl-(1-3C)alkyl]carbamoyl-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl and phenyl-(1-4C)alkyl,

and wherein any heterocyclic group in said substituent optionally bears 1 or 2 substituents selected from the group consisting of (1-4C)alkyl, (1-4C)alkoxy, carboxy, (1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl,

and wherein any phenyl or phenylene group in M² optionally bears 1 or 2 substituents selected from the group consisting of halogeno, trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy;

M³ is a direct link to X, or M³ is a group of the formula

space="preserve" listing-type="equation">L.sup.3 -(NR.sup.6).sub.s

in which s is 0 or 1,

R⁶ is hydrogen or (1-4C)alkyl, or R⁵ and R⁶ together form a (1-4C)alkylene, methylenecarbonyl or carbonylmethylene group, or R⁶ is a (2-3C)alkylene group which is linked to a methylene group within L³ forming a 5- or 6-membered ring involving NR⁶,

L³ is (1-4C)alkylene or carbonyl-(1-3C)alkylene, and, when s is 1, L³ may also be (1-3C)alkylene-carbonyl,

and wherein 1 or 2 methylene groups within L³ and the rings formed when R⁵ and R⁶ or R⁶ and L³ are linked optionally bears a substituent selected from the group consisting of oxo, carboxy, (1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl, 4-(1-4C)alkylpiperazin-1-ylcarbonyl, N-phenylcarbamoyl, N-(1-4C)alkyl-N-phenylcarbamoyl, N-[phenyl-(1-3C)alkyl]carbamoyl, N-(1-4C)alkyl-N-[phenyl-(1-3C)alkyl]carbamoyl, (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, pyrrolidin-1-ylcarbonyl-(1-4C)alkyl, piperidinocarbonyl-(1-4C)alkyl, morpholinocarbonyl-(1-4C)alkyl, piperazin-1-ylcarbonyl-(1-4C)alkyl, 4-(1-4C)alkylpiperazin-1-ylcarbonyl-(1-4C)alkyl, N-phenylcarbamoyl-(1-4C)alkyl, N-[phenyl-(1-3C)alkyl]carbamoyl-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl and phenyl-(1-4C)alkyl,

and wherein any heterocyclic group in said substituent optionally bears 1 or 2 substituents selected from the group consisting of (1-4C)alkyl, (1-4C)alkoxy, carboxy, (1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl and N,N-di-( 1-4C)alkylcarbamoyl,

and wherein any phenyl or phenylene group in M³ optionally bears 1 or 2 substituents selected from the group consisting of halogeno, trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy;

X is oxy, thio, sulphinyl, sulphonyl, sulphonylamino, methylene, (1-4C)alkylmethylene or di-(1-4C)alkylmethylene, or, when T³ is CH and M³ is a direct link to X, X may also be aminosulphonyl or oxycarbonyl; and

Q is phenyl, naphthyl, phenyl-(1-4C)alkyl, phenyl-(2-4C)alkenyl, phenyl-(2-4C)alkynyl, (5-7C)cycloalkyl or a heterocyclic moiety containing up to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur, and Q optionally bears 1, 2 or 3 substituents selected from the group consisting of hydroxy, amino, halogeno, cyano, trifluoromethyl, nitro, carboxy, carbamoyl, formyl, formimidoyl, formohydroximoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkylcarbamoyl, (1-4C)alkylamino, di-(1-4C)alkylamino, (2-4C)alkanoylamino, (2-4C)alkanoyl, (2-4C)alkanoimidoyl, (2-4C)alkanohydroximoyl, phenyl, heteroaryl, phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl, heteroaryloxy, heteroarylthio, heteroarylsulphinyl, heteroarylsulphonyl, benzyl and benzoyl,

and wherein said heteroaryl substituent or the heteroaryl group in a heteroaryl-containing substituent comprises a 5- or 6-membered monocyclic heteroaryl ring containing up to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur,

and wherein said phenyl, heteroaryl, phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl, heteroaryloxy, heteroarylthio, heteroarylsulphinyl, heteroarylsulphonyl, benzyl or benzoyl substituent optionally bears 1, 2, 3 or 4 substituents selected from the group consisting of halogeno, trifluoromethyl, cyano, trifluoromethoxy, nitro, (1-4C)alkyl, (1-4C)alkoxy, hydroxy, amino, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkylcarbamoyl, (1-4C)alkylamino, di-(1-4C)alkylamino, (2-4C)alkanoylamino and tetrazolyl;

or a pharmaceutically-acceptable salt thereof.

2. A compound of the formula I as claimed in claim 1 wherein

m is 1 or 2;

each R¹ is independently selected from hydrogen, amino, fluoro, chloro, bromo, cyano, methyl, ethyl and methoxy;

M¹ is a group of the formula

space="preserve" listing-type="equation">NR.sup.2 -L.sup.1 -T.sup.1 R.sup.3

in which R² and R³ together form an ethylene group,

L¹ is methylene or ethylene, and

T¹ is CH or N,

and wherein 1 or 2 methylene groups within L¹ and the ring formed when R² and R³ are linked optionally bears a substituent selected from the group consisting of methyl and ethyl;

A is a direct link to the carbonyl group or A is methylene;

M² is a group of the formula

space="preserve" listing-type="equation">(T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which r is 0 or 1,

T² is N,

T³ is N,

R⁴ is hydrogen, methyl or ethyl,

R⁵ is hydrogen, methyl or ethyl,

or R⁴ and R⁵ together form a methylene, ethylene, trimethylene or methylenecarbonyl group, or R⁴ is an ethylene group which is linked to a methylene group within L² forming a 5- or 6-membered ring involving R⁴ and T², and

L² is methylene, ethylene, trimethylene or methylenecarbonyl,

and wherein 1 or 2 methylene groups within L² and the ring formed when R⁴ and R⁵ are linked optionally bears a substituent selected from the group consisting of oxo, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, methyl, ethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, hydroxymethyl, methoxymethyl and benzyl,

and wherein the pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl or 4-methylpiperazin-1-ylcarbonyl substituent optionally bears a methyl or ethyl substituent;

M³ is a direct link to X, or M³ is a group of the formula

space="preserve" listing-type="equation">L.sup.3 -(NR.sup.6).sub.s

in which s is 1,

R⁶ is hydrogen

and L³ is carbonylmethylene or carbonylethylene;

X is thio, sulphinyl, sulphonyl, or methylene; and

Q is phenyl, naphthyl, benzyl, phenethyl, styryl, 2-phenylethynyl, dibenzofuranyl, biphenylyl, pyridylphenyl or pyridylthienyl, and Q optionally bears 1, 2 or 3 substituents selected from the group consisting of hydroxy, amino, fluoro, chloro, bromo, iodo, cyano, trifluoromethyl, nitro, carboxy, carbamoyl, methoxycarbonyl, ethoxycarbonyl, methyl, ethyl, methoxy and ethoxy;

or a pharmaceutically-acceptable salt thereof.

3. A compound of the formula I as claimed in claim 1 wherein

m is 1 or 2;

each R¹ is independently selected from hydrogen, amino, chloro, methyl and ethyl;

M¹ is a group of the formula

space="preserve" listing-type="equation">NR.sup.2 -L.sup.1 -T.sup.1 R.sup.3

in which R² and R³ together form an ethylene group,

L¹ is ethylene, and

T¹ is CH or N;

A is a direct link to the carbonyl group or A is methylene;

M² is a group of the formula

space="preserve" listing-type="equation">(T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which r is 0 or 1,

T² is N,

T³ is N,

R⁴ is hydrogen,

R⁵ is hydrogen,

or R⁴ and R⁵ together form an ethylene group, or R⁴ is an ethylene group which is linked to a methylene group within L² forming a 5- or 6-membered ring involving R⁴ and T², and

L² is methylene or ethylene,

and wherein 1 or 2 methylene groups within L² and the ring formed when R⁴ and R⁵ are linked optionally bears a substituent selected from the group consisting of carboxy, methoxycarbonyl, ethoxycarbonyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, methyl, ethyl and benzyl,

and wherein the pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl or 4-methylpiperazin-1-ylcarbonyl substituent optionally bears a methyl or ethyl substituent;

M³ is a direct link to X, or M³ is a group of the formula

space="preserve" listing-type="equation">L.sup.3 -(NR.sup.6).sub.s

in which s is 1,

R⁶ is hydrogen and

L³ is carbonylmethylene;

X is sulphonyl; and

Q is phenyl, naphthyl, benzyl, phenethyl, styryl, 2-phenylethynyl, dibenzofuranyl, biphenylyl, pyridylphenyl or pyridylthienyl, and Q optionally bears 1 or 2 substituents selected from the group consisting of fluoro, chloro, bromo, iodo, methyl, ethyl, methoxy and ethoxy;

or a pharmaceutically-acceptable salt thereof.

4. A compound of the formula I as claimed in claim 1 wherein

each of G¹ and G² is CH and G³ is N;

m is 1;

R¹ is hydrogen;

M¹ is a group of the formula

space="preserve" listing-type="equation">NR.sup.2 -L.sup.1 -T.sup.1 R.sup.3

in which R² and R³ together form an ethylene group,

L¹ is methylene or ethylene, and

T¹ is CH or N,

and wherein 1 or 2 methylene groups within L¹ and the ring formed when R² and R³ are linked optionally bears a substituent selected from the group consisting of methyl and ethyl;

A is a direct link to the carbonyl group or A is methylene;

M² is a group of the formula

space="preserve" listing-type="equation">(T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which r is 1,

T² is N,

T³ is N,

R⁴ is hydrogen, methyl or ethyl,

R⁵ is hydrogen, methyl or ethyl,

or R⁴ and R⁵ together form a methylene, ethylene or trimethylene group, or R⁴ is an ethylene group which is linked to a methylene group within L² forming a 5- or 6-membered ring involving R⁴ and T², and

L² is methylene, ethylene or trimethylene,

and wherein 1 or 2 methylene groups within L² and the ring formed when R⁴ and R⁵ are linked optionally bears a substituent selected from the group consisting of oxo, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, methyl, ethyl and benzyl,

and wherein the pyrrolidin-1-ylcarbonyl or piperidinocarbonyl substituent optionally bears one or two methyl or ethyl substituents;

M³ is a direct link to X, or M³ is a group of the formula

space="preserve" listing-type="equation">L.sup.3 -(NR.sup.6).sub.s

in which s is 1,

R⁶ is hydrogen and

L³ is carbonylmethylene or carbonylethylene;

X is sulphonyl; and

Q is 3- or 4-biphenylyl which optionally bears, in the ring attached to X, 1 or 2 substituents selected from the group consisting of hydroxy, fluoro, chloro, bromo, cyano, trifluoromethyl, methyl, ethyl, methoxy and ethoxy and which optionally bears in the terminal phenyl group up to 4 substituents selected from the group consisting of fluoro, chloro, bromo, trifluoromethyl, cyano, trifluoromethoxy, methyl, ethyl, methoxy and ethoxy;

or a pharmaceutically-acceptable salt thereof.

5. A compound of the formula I as claimed in claim 1 wherein

each of G¹ and G² is CH and G³ is N;

m is 1;

R¹ is hydrogen;

M¹ is a group of the formula

space="preserve" listing-type="equation">NR.sup.2 -L.sup.1 -T.sup.1 R.sup.3

in which R² and R³ together form an ethylene group,

L¹ is methylene or ethylene, and

T¹ is CH or N,

and wherein 1 or 2 methylene groups within L¹ and the ring formed when R² and R³ are linked optionally bears a substituent selected from the group consisting of methyl and ethyl;

A is a direct link to the carbonyl group or A is methylene;

M² is a group of the formula

space="preserve" listing-type="equation">(T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which r is 1,

T² is N,

T³ is N,

R⁴ is hydrogen, methyl or ethyl,

R⁵ is hydrogen, methyl or ethyl,

or R⁴ and R⁵ together form a methylene, ethylene or trimethylene group, or R⁴ is an ethylene group which is linked to a methylene group within L² forming a 5- or 6-membered ring involving R⁴ and T², and

L² is methylene, ethylene or trimethylene,

and wherein 1 or 2 methylene groups within L² and the ring formed when R⁴ and R⁵ are linked optionally bears a substituent selected from the group consisting of oxo, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, methyl, ethyl and benzyl,

and wherein the pyrrolidin-1-ylcarbonyl or piperidinocarbonyl substituent optionally bears one or two methyl or ethyl substituents;

M³ is a direct link to X, or M³ is a group of the formula

space="preserve" listing-type="equation">L.sup.3 -(NR.sup.6).sub.s

in which s is 1,

R⁶ is hydrogen and

L³ is carbonylmethylene or carbonylethylene;

X is sulphonyl; and

Q is benzyl, phenethyl, styryl or 2-phenylethynyl which optionally bears 1, 2 or 3 substituents selected from the group consisting of fluoro, chloro, bromo, cyano, trifluoromethyl, methyl, ethyl, methoxy and ethoxy;

or a pharmaceutically-acceptable salt thereof.

6. A compound of the formula I as claimed in any one of claims 1 to 5 wherein A is a direct link to the carbonyl group.

7. A compound of the formula I as claimed in claim 1 wherein M² is a group of the formula

8. A compound of the formula I as claimed in any one of claims 1 to 5 wherein M³ is a direct link to X.

9. A compound of the formula I as claimed in claim 1 or claim 2 wherein X is sulphonyl.

10. A compound of the formula I as claimed in claim 1 or claim 7 wherein Q is phenyl, naphthyl or phenyl-(1-4C)alkyl which optionally bears 1, 2 or 3 substituents selected from the group consisting of hydroxy, halogeno, cyano, trifluoromethyl, (1-4C)alkyl, (1-4C)alkoxy, phenyl, phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl, benzyl and benzoyl, and wherein the phenyl group in a phenyl-containing substituent optionally bears 1 or 2 substituents selected from the group consisting of halogeno, (1-4C)alkyl and (1-4C)alkoxy.

11. A compound as claimed in claim 1 of the formula Ia ##STR7## wherein G¹ is CH and G² is N;

m is 1;

R¹ is hydrogen;

M¹ is a group of the formula

space="preserve" listing-type="equation">NR.sup.2 -L.sup.1 -T.sup.1 R.sup.3

in which R² and R³ together form an ethylene group,

L¹ is ethylene, and

T¹ is CH or N;

A is a direct link to the carbonyl group;

M² is a group of formula

space="preserve" listing-type="equation">(T.sub.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which r is 1,

T² is N,

T³ is N,

R⁴ is hydrogen,

R⁵ is hydrogen,

or R⁴ and R⁵ together form an ethylene group, and

L is ethylene,

and wherein 1 methylene group within L² optionally bears a substituent selected from carboxy, ethoxycarbonyl, N-methylcarbamoyl, piperidinocarbonyl, methyl and benzyl;

M³ is a direct link to X, or M³ is a group of the formula

space="preserve" listing-type="equation">L.sup.3 -(NR.sup.6).sub.s

in which s is 1,

R⁶ is hydrogen and

L³ is carbonylmethylene;

X is sulphonyl; and

Q is 2-naphthyl which optionally bears 1 or 2 substituents selected from the group consisting of fluoro, chloro, bromo, trifluoromethyl, methyl, methoxy and ethoxy;

or a pharmaceutically-acceptable acid-addition salt thereof.

12. A compound of the formula I as claimed in claim 1 selected from

1-[(E-4-chlorostyrylsulphonyl]-4-[1-(4-pyrimidinyl)piperidin-4-ylcarbonyl]piperazine;

1-(2-naphthylsulphonyl)-4-[1-(4-pyrimidinyl)piperidin-4-ylcarbonyl]- piperazine;

1 -(6-chloronaphth-2-ylsulphonyl)-4-[1 -(4-pyrimidinyl)piperidin-4-ylcarbonyl]piperazine; and

4-[1-(2-aminopyrimidin-4-yl)piperidin-4-ylcarbonyl]-1-(6-chloronaphth-2-ylsulphonyl)piperazine;

and pharmaceutically-acceptable salts thereof.

13. A process for the preparation of an aminoheterocyclic derivative of the formula I or of the formula Ia, or a pharmaceutically-acceptable salt thereof, as claimed in claim 1 or claim 11 which comprises:

(a) for the production of those compounds of the formula I or formula Ia wherein M² is a group of the formula

space="preserve" listing-type="equation">(T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which T² is N and r is 1, the reaction of an acid of the formula II, or a reactive derivative thereof, ##STR8## with an amine of the formula

space="preserve" listing-type="equation">HNR.sup.4 -L.sup.2 -T.sup.3 R.sup.5 -M.sup.3 -X-Q;

(b) for the production of those compounds of the formula I or formula Ia wherein M² is a group of the formula

space="preserve" listing-type="equation">(T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which T³ is N, and wherein M³ is a direct link to X, the reaction of an amine of formula III ##STR9## with a compound of the formula Z-X-Q wherein Z is a displaceable group;

(c) for the production of those compounds of the formula I or formula Ia wherein M¹ is a group of the formula

space="preserve" listing-type="equation">NR.sup.2 -L.sup.1 -T.sup.1 R.sup.3

in which T¹ is N, and wherein A is a direct link to the carbonyl group, the reaction of an amine of the formula IV ##STR10## with an acid of the formula

space="preserve" listing-type="equation">HO.sub.2 C-M.sup.2 -M.sup.3 -X-Q

or a reactive derivative thereof;

(d) for the production of those compounds of the formula I or formula Ia wherein M is a group of the formula

space="preserve" listing-type="equation">(T.sup.2 R.sup.4).sub.r L.sup.2 -T.sup.3 R.sup.5

in which T³ is N, and wherein M³ is a group of the formula

space="preserve" listing-type="equation">L.sup.3 -(NR.sup.6).sub.s

in which L³ is carbonylmethylene, the reaction of an amine of the formula III with an acid of the formula

space="preserve" listing-type="equation">HO.sub.2 C-CH.sub.2 -(NR.sup.6).sub.s -X-Q

or a reactive derivative thereof;

(e) for the production of those compounds of the formula I or formula Ia wherein M² is a group of the formula

space="preserve" listing-type="equation">(T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which T³ is N, and wherein M³ is a direct link to X and X is carbonylamino, the reaction of an amine of the formula III with an isocyanate of the formula

space="preserve" listing-type="equation">OCN-X-Q;

(f) the reaction of a compound of the formula V ##STR11## wherein Z is a displaceable group, with an amine of the formula

space="preserve" listing-type="equation">HNR.sup.2 -L.sup.1 -T.sup.1 R.sup.3 -A-CO-M.sup.2 -M.sup.3 -X-Q

(g) for the production of those compounds of the formula I or formula Ia wherein M², M³ or Q bears a carboxy or carboxy-containing group, the hydrolysis of a compound of the formula I wherein M², M³ or Q bears a (1-4C)alkoxycarbonyl group;

(h) for the production of those compounds of the formula I or formula Ia wherein M², M³ or Q bears a carbamoyl, N-alkylcarbamoyl or N N-dialkylcarbamoyl group, the reaction of a compound of the formula I wherein M², M³ or Q bears a carboxy group, or a reactive derivative thereof, with ammonia or an appropriate alkylamine or dialkylamine;

or

(i) for the production of those compounds of the formula I or formula Ia wherein Q bears a hydroxy group, the dealkylation of a compound of the formula Ia wherein Q bears a (1-4C)alkoxy group;

and optionally the reaction of the compound thus obtained with a suitable acid or base using a conventional procedure to form a pharmaceutically-acceptable salt of a compound of the formula Ia;

and optionally carrying out one of the aforesaid procedures using an optically active starting material, or carrying out a resolution of a racemic form of said compound using a conventional procedure, to obtain an optically active form of a compound of the formula I.

14. A pharmaceutical composition which comprises a compound of the formula I or of the formula Ia, or a pharmaceutically-acceptable salt thereof, as claimed in claim 1 or claim 11, together with a pharmaceutically-acceptable diluent or carrier.

15. A method of producing an anticoagulant or antithrombotic effect in a warm blooded animal in need thereof, said method comprising administrating to said animal an anticoagulant or antithrombotic effective amount of a compound according to claim 1.

16. A method of producing a Factor Xa enzyme inhibitory effect in a warm blooded animal in need thereof, said method comprising administering to said animal a Factor Xa enzyme inhibitory effective amount of a compound according to claim 1.

17. A method of selectively producing a Factor Xa enzyme inhibitory effect in a warm blooded animal in need thereof, without inhibiting, or inhibiting to a lesser extent, the enzyme thrombin, said method comprising administering to said animal an amount of a compound according to claim 1 which is effective to inhibit Factor Xa enzyme while having no, or a lesser, inhibitory effect on the enzyme thrombin.

18. A method treating a Factor Xa enzyme mediated disease or medical condition in a warm blooded animal in need of such treatment, said method comprising administering to said animal a Factor Xa enzyme inhibitory effective amount of a compound according to claim 1.

19. A method treating a thrombosis mediated disease or medical condition in a warm blooded animal in need of such treatment, said method comprising administering to said animal an antithrombotic effective amount of a compound according to claim 1.

20. A method treating a coagulation disorder in a warm blooded animal in need of such treatment, said method comprising administering to said animal an anticoagulation effective amount of a compound according to claim 1.

21. A method treating a warm blooded animal having a thrombosis or embolism involving Factor Xa mediated coagulation, said method comprising administering to said animal an anticoagulation effective amount of a compound according to claim 1.

22. A method of producing an anticoagulant effect ex vivo in a biological sample suspected to contain Factor Xa enzyme, said method comprising introducing into said biological sample an anticoagulant-effective amount of a compound according to claim 1.

23. The method of claim 22 wherein said biological sample is whole blood.