Aminoheterocyclic derivatives as antithrombotic or anticoagulant agents
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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.
132 Citations
11 Claims
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1. An aminoheterocyclic derivative of the formula I
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11)
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2. A compound according to claim 1 wherein:
each of G1 and G2 is CH;
or G1 is CH and G2 is N, or G1 is N and G2 is CH;
m is 1 and R1 is hydrogen;
L1 is (1-4C)alkylene, T1 is CH or N, and R1 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, N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, thiamorpholinocarbonyl, 1-oxothiamorpholinocarbonyl, 1,1-dioxothiamorpholinocarbonyl, piperazin-1-ylcarbonyl and 4-(1-4C)alkylpiperazin-1-ylcarbonyl;
orAr 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, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl and (2-4C)alkanoylamino, and Y2 is selected from carboxy, carbamoyl, (1-4C)alkoxycarbonyl, L-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl and 4-(1-4C)alkylpiperazin-1-ylcarbonyl;
orAr 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, N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl and 4-(1-4C)alkylpiperazin-1-yl;
orAr 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, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl, (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 in this section of particular compounds of the invention;
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, (1A-4C)alkyl and (1-4C)alkoxy;
orQ 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;
orQ is phenyl or phenyl-(1-4C)alkyl which bears 1 substituent selected from heteroaryl, heteroaryloxy, heteroarylthio, heteroarylsulphinyl and heteroarylsulphonyl, wherein the 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 nitrogen, oxygen and sulphur, and wherein said heteroaryl or heteroaryl-containing substituent optionally bears 1 or 2 substituents selected from halogeno, (1-4C)alkyl and (1-4C)alkoxy;
orQ is a heterocyclic moiety containing up to 2 heteroatoms selected from benzofuranyl, quinolyl, tetrahydroquinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, indolyl, benzimidazolyl, indazolyl, benzoxazolyl, benzothiazolyl, dibenzofuranyl and dibenzothienyl, and Q optionally bears 1 or 2 substituents selected from halogeno, cyano, trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy;
orQ is a heterocyclic moiety containing up to 4 heteroatoms selected from furyl, thienyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl, and Q optionally bears 1 or 2 substituents selected from halogeno, cyano, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl;
orQ is a heterocyclic moiety containing up to 2 heteroatoms selected from thienyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl, and Q optionally bears 1 or 2 substituents selected from phenyl, heteroaryl, phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl, heteroaryloxy, heteroarylthio, heteroarylsulphinyl, heteroarylsulphonyl, benzyl and benzoyl, wherein the heteroaryl substituent or the heteroaryl group in a heteroaryl-containing substituent is selected from thienyl, pyridyl, pyrimidinyl, pyrazolyl, oxazolyl and thiazolyl, and wherein said phenyl, phenyl-containing, heteroaryl or heteroaryl-containing substituent optionally bears 1 or 2 substituents selected from halogeno, (I 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.
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3. A compound according to claim 1 or 2 wherein each of G1 and G2 is CH, G1 is CH and G2 is N, or G1 is N and G2 is CH;
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m is 1 and R1 is hydrogen;
L1 is ethylene, T1 is CH or N, and R2 and R3 are independently hydrogen or 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 T, is CH, X1 is, in addition, a group of the formula O;
Ar is 1,2-phenylene, 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, 2-(ethylthio)ethylaminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl and 4-methylpiperazin-1-ylcarbonyl;
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, 1,4-tetrahydroisoquinolinyl, 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 1,2-, 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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4. A compound according to any one of claims 1 to 3 wherein each of G1 and G2 is CH, G1 is CH and G2 is N, or G1 is N and G2 is CH;
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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, N,-dimethylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl and 4-methylpiperazin-1-ylcarbonyl;
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 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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5. A compound according to any one of claims 1 to 4 wherein each of G1 and G2 is CH, G1 is CH;
- and G2 is N, or G1 is N 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, 2-carboxy-1,4-phenylene or 2-piperidinocarbonyl-1,4-phenylene (with the X1 group in the 1-position and the X2 group in the 4-position);
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.
- and G2 is N, or G1 is N and G2 is CH;
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6. A compound according to any one of claims 1 to 5.
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, 2-carboxy-1,4-phenylene or 2-piperidinocarbonyl-1,4-phenylene (with the X1 group in the 1-position and the X2 group in the 4-position);
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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7. A compound according to any one of claims, 1 to 6 which is:
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1-[4-(6-chloronaphth-2-ylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine, 1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-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, 1-{5-(6-bromonaphth-2-ylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoyl}-piperidine, 1-{5-(6-chloronaphth-2-ylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoyl}-piperidine, 1-{5-(4′
-bromo-4-biphenylylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoyl}-piperidine,1-{5-[(E)-4-chlorostyrylsulphonyl]-2-[4-(4-pyridyl)piperazin-ylcarbonyl]benzoyl}piperidine, 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-4yloxy]phenyl}-(E)-styrylsulphonamide, 4-[4-(6-bromonaphth-2-ylsulphonyl)phenoxy]-1-(4-pyridyl)piperidine, 4-[4-(6-bromonaphth-2-ylsulphonyl)bcnzoyl]-1-(4-pyridyl)piperidine, 4-[4-(6-bromonaphth-2-ylthio)benzoyl]-1-(4-pyridyl)piperidine, 1-[4-(6-bromonaphth-2-ylsulphonyl)phenylsulphonyl]-1-(4-pyridyl)piperazine, 6-(bromo-2-(4-(2-pyrimidin-4-yl)aminoethylaminocarbonyl)phenylsulphonyl)naphthalene, 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)benzoyl]-4-(4-pyrimidinyl)-piperazine, 1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(4-pyridazinyl)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]44-pyridyl)piperazine, 1-[4-(6-bromonaphth-2-ylsulphonyl)-2-(2-(ethylthio)-ethylaminocarbonyl)benzoyl]4 (4-pyridyl)piperazine, 1-[5-(6-bromonaphth-2-yisulphonyl)-2-(2-ethylthio)ethylaminocarbonyl)benzoyl]-4-(4-pyridyl)piperazine, 1-[4-(6-bromonaphth-2-ylsulphonyl)-2-(piperidin-1-ylcarbonyl]-4-(4-pyridyl)piperazine, 1-[5-(6-bromonaphth-2-ylsulphonyl)-2-(piperidin-1-ylcarbonyl]-4-(4-pyridyl)piperazine, 1-[4-(4-(3-chlorophenyl)piperazin-1-ylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine, 1-[4-(6-chloro-1,2,3,4-tetrahydroisoquinolin-2-ylsulphonylbenzoyl]-4-(4-pyridyl)piperazine, 1-(4-pyridyl)-(5-(6-methoxyindol-2-ylcarbonylamino)pyrid-2-yloxy)pyrrolidine, 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.
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8. A process for the preparation of an aminoheterocyclic derivative 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 IIIHO2C—
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 VHO—
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 IXZ-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(R)SO2, the reaction, conveniently in the presence of a suitable base, of a sulphonamide of the formula X
with a compound of the formula XIR5-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 XVZ-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(R4)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 XVIIHS-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, (1-4C)alkylsulphonyl, 1-oxothiamorpholino or 1,1-dioxothiamorpholino group or a substituent which contains a (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, 1-oxothiamorpholino or 1,1-dioxothiamorpholino group, 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, phenylsulphonyl, heteroarylsulphinyl or heteroarylsulphonyl group, the oxidation of the corresponding compound of the formula I which contains a thio group. (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, 1-oxothiamorpholino or 1,1-dioxothiamorpholino group, 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, phenylsulphonyl, heteroarylsulphinyl or heteroarylsulphonyl group, 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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9. A pharmaceutical composition which comprises an aminoheterocyclic derivative of the formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 7 and a pharmaceutically acceptable carrier.
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10. The use of an aminoheterocyclic derivative of the formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 7 in the production of a medicament for producing an antithrombiotic or anticoagulant effect.
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11. The use of an aminoheterocyclic derivative of the formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 7 in the production of a medicament for treating coronary artery or cerebro-vascular disease.
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2. A compound according to claim 1 wherein:
Specification
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Current AssigneeAstrazeneca UK Limited (Astrazeneca PLC)
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Original AssigneeZeneca Incorporated (Astrazeneca PLC)
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InventorsStocker, Andrew, Smithers, Michael James, Preston, John
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Application NumberUS10/427,991Publication NumberTime in Patent OfficeDaysField of SearchUS Class Current514/235.8CPC Class CodesA61P 25/00 Drugs for disorders of the ...A61P 7/00 Drugs for disorders of the ...A61P 7/02 Antithrombotic agents; Anti...A61P 9/00 Drugs for disorders of the ...A61P 9/10 for treating ischaemic or a...C07D 213/74 Amino or imino radicals sub...C07D 237/20 Nitrogen atoms nitro radica...C07D 239/42 One nitrogen atom nitro rad...C07D 401/04 directly linked by a ring-m...C07D 401/12 linked by a chain containin...C07D 401/14 containing three or more he...