RU2002129354A - Ethylenediamine derivatives - Google Patents

Claims (21)

1. The compound represented by General formula (1) Q ¹ -Q ² -C (= O) -N (R ¹ ) -Q ³ -N (R ² ) -T ¹ -Q ⁴ (1) where R ¹ and R ² independently from each other represent a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group; Q ¹ represents a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group, which may be a substituted, saturated or unsaturated 5- or 6-membered heterocyclic group, which may be a substituted, saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group, which may be substituted, or a saturated or unsaturated bicyclic or tricyclic fused heterocyclic group which may be substituted; Q ² represents a single bond, an unbranched or branched alkylene group having 1-6 carbon atoms, a unbranched or branched alkenylene group having 2-6 carbon atoms, a unbranched or branched alkynylene group having 2-6 carbon atoms, an —N group (R ³ ) -, where R ³ means a hydrogen atom or an alkyl group, the group —N (R ⁴ ) - (CH ₂ ) _m -, where R ⁴ means a hydrogen atom or an alkyl group and m is an integer from 1 to 6, saturated or unsaturated 5- or 6-membered divalent cyclic hydrocarbon a group which may be substituted, saturated or unsaturated 5- or 6-membered divalent heterocyclic group, which may be substituted, saturated or unsaturated divalent bicyclic or tricyclic condensed hydrocarbon group, which may be substituted, or saturated or unsaturated divalent bicyclic or tricyclic condensed a heterocyclic group which may be substituted; Q ³ represents a group

in which R ⁵ , R ⁶ , R ⁷ and R ⁸ independently represent a hydrogen atom, a hydroxyl group, a halogen atom, a haloalkyl group, a cyano group, a cyanoalkyl group, an acyl group, an acylalkyl group, an alkyl group, an alkenyl group, an alkynyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, carbamoylalkyl nuyu group, N-alkylcarbamoylalkyl group, N, N-dialkylcarbamoylalkyl group, aryl group, aralkyl group, heteroaryl group or heteroarylalkyl group or the following group:

in which Q ⁵ means an alkylene group having 1-8 carbon atoms, or an alkenylene group having 2-8 carbon atoms, and R ⁹ and R ¹⁰ are substituents on the carbon atom (s) of the ring containing Q ⁵ and independently of the other is a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom, a haloalkyl group, a cyano group, a cyanoalkyl group, an amino group, an aminoalkyl group, an N-alkylaminoalkyl group, an N, N-dialkylaminoalkyl group, an acyl group, an acylalkylalkyl th group, acylamino group which may be substituted, alkoxyimino group, hydroxyimino, atsilaminoalkilnuyu group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, alkoksikarbonilalkilaminogruppu, karboksialkilaminogruppu, alkoxycarbonylamino alkoksikarbonilaminoalkilnuyu group, carbamoyl group, N -alkylcarbamoyl group which may have a substituent in the alkyl group, N An N-dialkylcarbamoyl group which may have a substituent on the alkyl group, an N-alkenylcarbamoyl group, an N-alkenylcarbamoylalkyl group, an N-alkenyl-N-alkylcarbamoyl group, an N-alkenyl-N-alkylcarbamoylalkyl group, an N-alkoxycarbamoylalkyl group An N-alkoxycarbamoyl group, an N-alkoxycarbamoylalkyl group, an N-alkyl-N-alkoxycarbamoylalkyl group, a carbazoyl group which may be substituted with 1-3 alkyl groups, an alkylsulfonyl group, an alkylsulfonylalkyl group, a 3-6 membered nitrogen containing a heterocyclic carbonyl group which may be substituted, a carbamoylalkyl group, an N-alkylcarbamoylalkyl group, which may have a substituent in the alkyl group, an N, N-dialkylcarbamoylalkyl group, which may have a substituent in the alkyl group, a carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N-dialkylcarbamoyloxyalkyl group, a 3-6 membered nitrogen containing heterocyclic carbonyloxyalkyl group which may be substituted, a 3-6 membered nitrogen containing heterocyclic ring bonilalkilnuyu group which may be substituted, an aryl group, an aralkyl group, heteroaryl group, heteroarylalkyl group, alkylsulfonylamino group, arylsulfonylamino group, alkilsulfonilaminoalkilnuyu group arilsulfonilaminoalkilnuyu group alkilsulfonilaminokarbonilnuyu group arilsulfonilaminokarbonilnuyu group alkilsulfonilaminokarbonilalkilnuyu group arilsulfonilaminokarbonilalkilnuyu group, an oxo group, carbamoyloxy group, aralkyloxy group karboksialkiloksigruppu, acyloxy ny, or acyloxyalkyl group, or R ⁹ and R ¹⁰ together with each other, denote an alkylene group having 1-5 carbon atoms, alkenylene group having 2-5 carbon atoms, alkylenedioxy group having 1-5 carbon atoms or carbonyldioxy; Q ⁴ represents an aryl group which may be substituted, an arylalkenyl group which may be substituted, a heteroaryl group which may be substituted, a heteroarylalkenyl group which may be substituted, saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group, which may be substituted, or a saturated or unsaturated bicyclic or tricyclic fused heterocyclic group which may be substituted; and T ¹ represents a carbonyl or sulfonyl group; its salt, solvate or N-oxide. 2. The compound, its salt, MES or N-oxide according to claim 1, where the group Q ⁴ in the formula (1) is any one of the following groups:

where R ¹¹ and R ¹² independently represent a hydrogen atom, a cyano group, a halogen atom, an alkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group, an acyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group or a phenyl group, which may be substituted with a cyano group, a hydroxyl group, a halogen atom, an alkyl group or an alkoxy group, and R ¹³ and R ¹⁴ independently represent a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group, a carbamoyl group a group, an alkoxycarbonyl group, an amidino group or an alkoxycarbonylalkyl group;

where R ¹⁵ , R ¹⁶ and R ¹⁷ independently represent a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group, an acyl group, a carbamoyl group, an alkoxycarbonyl group, an amidino group or an alkoxycarbonylalkyl group;

where X ¹ represents CH ₂ , CH, NH, NOH, N, O or S and R ¹⁸ , R ¹⁹ and R ²⁰ independently represent a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl a group, an acyl group, a carbamoyl group, an alkoxycarbonyl group, an amidino group or an alkoxycarbonylalkyl group;

where X ² represents NH, N, O or S, X ³ represents N, C or CH, X ⁴ represents N, C or CH and R ²¹ and R ²² independently represent a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group, an acyl group a group, a carbamoyl group, an alkoxycarbonyl group, an amidino group or an alkoxycarbonylalkyl group; and

where N indicates that any of the carbon atoms of the ring substituted by R ²³ has already been replaced by a nitrogen atom, and R ²³ , R ²⁴ and R ²⁵ independently represent a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group a group, an acyl group, a carbamoyl group, an alkoxycarbonyl group, an amidino group or an alkoxycarbonylalkyl group. 3. The compound, its salt, MES or N-oxide according to claim 1 or 2, where the group Q ⁴ in the formula (1) represents

where R ¹¹ , R ¹² and R ¹³ all represent hydrogen atoms and R ¹⁴ represents a halogen atom or an ethynyl group;

where R ¹⁵ and R ¹⁶ both represent hydrogen atoms and R ¹⁷ represents a halogen atom or an ethynyl group;

where X ¹ represents NH, NOH, N, O or S, R ¹⁸ represents a hydrogen atom, R ¹⁹ represents a hydrogen or halogen atom and R ²⁰ represents a halogen atom, an alkyl or ethynyl group;

where X ² represents NH, O or S, X ³ represents N, C or CH, R ⁴ represents N, C or CH, R ²¹ represents a hydrogen atom and R ²² represents a halogen atom or an ethynyl group; or

where N indicates that any of the carbon atoms of the ring substituted by R ²³ has already been replaced by a nitrogen atom, and R ²³ and R ²⁴ both represent hydrogen atoms, and R ²⁵ represents a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a haloalkyl group. 4. The compound, its salt, MES or N-oxide according to any one of claims 1 to 3, where the group Q ¹ in the formula (1) represents a saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group, which may be substituted, or saturated or an unsaturated bicyclic or tricyclic fused heterocyclic group which may be substituted, and the Q ² group is a single bond. 5. The compound, its salt, solvate or N-oxide according to any one of claims ¹ to ⁴ , where the group Q ¹ in the formula (1) is a thienopyridyl group, which may be a substituted, tetrahydrothienopyridyl group, which may be a substituted, thiazolopyridyl group which may be substituted, a tetrahydrothiazolopyridyl group which may be substituted, a thiazolopyridazinyl group which may be substituted, a tetrahydrothiazolopyridazinyl group which may be substituted, a pyranothiazolyl group which may be substituted a further dihydropyranothiazolyl group which may be substituted, a furopyridyl group which may be substituted, a tetrahydrofuropyridyl group which may be substituted, an oxazolopyridyl group, which may be substituted, tetrahydrooxazolopyridyl group, which may be substituted, pyrrolopyridyl group dihydropyrrolopyridyl group which may be substituted, tetrahydropyrrolopyridyl group which may be substituted, pyrrolopyrimidyl a group which may be substituted, a dihydropyrrolopyrimidyl group which may be substituted, an oxazolopyridazinyl group, which may be substituted, a tetrahydrooxazolopyridazinyl group, which may be substituted, a pyrrolothiazolyl group, which may be substituted, a dihydropyrrolothiarolazole group, which may be a substituted dihydropyrrolothiarolazole group, which may be which may be substituted, a dihydropyrroloxazolyl group, which may be substituted, a benzothiazolyl group, which may be substituted, a tetrahydrobenzothiazolyl group, which may be substituted, a 4,5,6,7-tetrahydro-5,6-tetramethylene-thiaolopyridazinyl group, which may be substituted, or a 5, b-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl group which may be substituted, and Q ² represents a single bond. 6. The compound, its salt, MES or N-oxide according to any one of claims 1 to 3, where the group Q ¹ in the formula (1) represents a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group, which may be substituted, or a saturated or unsaturated 5- or 6-membered heterocyclic group which may be substituted, and the Q ² group is a saturated or unsaturated 5- or 6-membered divalent cyclic hydrocarbon group which may be substituted, or a saturated or unsaturated 5- or 6 membered divalent hetero a cyclic group which may be substituted. 7. The compound, its salt, MES or N-oxide according to any one of claims 1 to 6, where the group Q ³ in the formula (1) represents

where Q ⁵ , R ⁹ and R ¹⁰ have the same meanings as defined above. 8. The compound, its salt, MES or N-oxide according to any one of claims 1 to 7, where the group T ¹ in the formula (1) represents a carbonyl group. 9. The compound, its salt, MES or N-oxide according to any one of claims 1 to 8, where the group Q ⁴ in the formula (1) is 4-chlorostyryl, 4-fluorostyryl, 4-bromo-styryl, 4-ethynylstyryl, 6- chloro-2-naphthyl, 6-fluoro-2-naphthyl, 6-bromo-2-naphthyl, 6-ethynyl-2-naphthyl, 7-chloro-2-naphthyl, 7-fluoro-2-naphthyl, 7-bromo 2-naphthyl, 7-ethynyl-2-naphthyl, 5-chloroindol-2-yl, 5-fluorindol-2-yl, 5-bromindol-2-yl, 5-ethynylindol-2-yl, 5-methylindol-2- sulphonic, 5-chloro-4-fluorindol-2-yl, 6-chloroindol-2-yl, 6-fluorindol-2-yl, 6-bromindol-2-yl, 6-ethynylindol-2-yl 6-methylindol-2-yl, 5-chlorobenzothiophen-2-yl, 5-fluorobenzothiophen-2-yl, 5-bromobenzothiophen-2-yl, 5-ethynylbenzothiophen-2-yl, 5-methylbenzothiophen-2-yl, 5 -chloro-4-fluorobenzothiophen-2-yl, 6-chlorobenzothiophen-2-yl, 6-fluorobenzothiophen-2-yl, 6-bromobenzothiophen-2-yl, 6-ethynylbenzothiophen-2-yl, 6-methylbenzothiophen-2-yl 5-chlorobenzofuran-2-yl, 5-fluorobenzofuran-2-yl, 5-bromobenzofuran-2-yl, 5-ethynylbenzofuran-2-yl, 5-methylbenzofuran-2-yl, 5-chloro-4-fluorobenzofuran-2 -yl, 6-chlorobenzofuran-2-yl, 6-fluorobenzofuran-2-yl, 6- rombenzofuran-2-yl, 6-ethynylbenzofuran-2-yl, 6-methylbenzofuran-2-yl, 6-chloroquinolin-2-yl, 6-fluoroquinolin-2-yl, 6-bromoquinolin-2-yl, 6-ethynylquinoline- 2-yl, 7-chloroquinolin-3-yl, 7-fluoroquinolin-3-yl, 7-bromoquinolin-3-yl, 7-ethynylquinolin-3-yl, 7-chloroisoquinolin-3-yl, 7-fluoroisoquinolin-3- a methyl, 7-bromoisoquinolin-3-yl or 7-ethynylisoquinolin-3-yl group. 10. The compound, its salt, MES or N-oxide according to any one of claims 1 to 9, where the group Q ³ in the formula (1) represents

where n is an integer from 1 to 8, R ⁹ represents a hydrogen atom and R ¹⁰ represents a hydrogen atom, a hydroxyl group, an alkyl group, a halogen atom, a hydroxyimino group, an N-alkylaminoalkyl group, an N, N-dialkylaminoalkyl group, an acyl group, an acylamino group, which may be substituted, an acylaminoalkyl group, an alkoxy group, an alkoxyalkyl group, a hydroxyalkyl group, a carboxyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an alkoxycarbonylamino group, a carbamoyl group, an N-alkylcarb a methyl group which may have a substituent in the alkyl group, an N, N-dialkylcarbamoyl group, which may have a substituent in alkyl groups, an N-alkenylcarbamoyl group, an N-alkenylcarbamoylalkyl group, an N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N -alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group which may be substituted by 1-3 alkyl groups, alkylsulfonyl group, alkylsulfonyl th group, a 3-6 membered nitrogen containing heterocyclic carbonyl group which may be substituted, a 3-6 membered nitrogen containing heterocyclic carbonyloxyalkyl group, which may be substituted, carbamoylalkyl group, N, N-dialkylcarbamoyloxyalkyl group, N-alkylcarbamoylalkyl have a substituent in the alkyl group, an N, N-dialkylcarbamoylalkyl group which may have a substituent in the alkyl groups, an alkylsulfonylamino group, an alkylsulfonylaminoalkyl group, an oxo group, or tsiloksigruppu. 11. A medicament containing a compound, its salt, solvate or N-oxide according to any one of claims 1 to 10 as an active ingredient. 12. An inhibitor of activated blood coagulation factor X containing the compound, its salt, solvate or N-oxide according to any one of claims 1 to 10 as an active ingredient. 13. An anticoagulant containing the compound, its salt, solvate or N-oxide according to any one of claims 1 to 10 as an active ingredient. 14. An agent for the prevention and / or treatment of thrombosis or embolism containing the compound, its salt, solvate or N-oxide according to any one of claims 1 to 10 as an active ingredient. 15. Means for the prevention and / or treatment of cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Burger disease, deep vein thrombosis, disseminated intravascular coagulation syndrome, thrombosis after valve or joint replacement, thrombosis and reocclusion after angioplasty, systemic inflammatory response syndrome (SIRS), multiple organ disease syndrome (MODS), blood clots during extracorporeal circulation, or blood clotting her collection. 16. A pharmaceutical composition comprising a compound, a salt thereof, a solvate or N-oxide according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier. 17. The use of the compound, its salt, MES or N-oxide according to any one of claims 1 to 10 for the manufacture of a medicinal product. 18. A method for treating thrombosis or embolism, which comprises administering a compound, a salt, solvate or N-oxide thereof according to any one of claims 1 to 10. 19. A method for the treatment of cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Burger disease, deep vein thrombosis, disseminated intravascular coagulation syndrome, thrombosis after valve or joint replacement, thrombosis and reocclusion after angioplasty syndrome, inflammatory reaction (SIRS), multiple organ disease syndrome (MODS), blood clots during extracorporeal circulation, or blood clotting during collection, including m administration of a compound, a salt, solvate or N-oxide according to any one of claims 1-10. 20. The compound represented by the following General formula (4): NH (R ¹ ) -Q ³ -N (R ² ) -T ¹ -Q ⁴ (4), where R ¹ , R ² and T ¹ have the same meanings as defined above, Q ⁴ represents a saturated or unsaturated bicyclic or tricyclic hydrocarbon group, which may be substituted, or a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group, which may be substituted , and Q ³ represents

where Q ⁵ , R ⁹ and R ¹⁰ have the same meanings as defined above, its salt, MES or N-oxide. 21. The compound represented by the following general formula (9): Q ¹ -Q ² -C (= O) -N (R ¹ ) -Q ³ -NHR ² , (9) where R ¹ and R ² have the same meanings as defined above, Q ¹ represents a saturated or unsaturated bicyclic or tricyclic heterocyclic group which may be substituted, Q ² represents a single bond and Q ³ represents

where Q ⁵ , R ⁹ and R ¹⁰ have the same meanings as defined above, its salt, MES or N-oxide.