RU2002135308A - UREA DERIVATIVES (TIO), INHIBITING FACTOR VIIA, THEIR PRODUCTION AND APPLICATION - Google Patents

Claims (10)

1. The compound of formula I

in which m = 0, 1, 2, 3 or 4; n is 0, 1, 2 or 3; A is halogen; X represents sulfur or oxygen; R ^{1 is} selected from hydrogen, hydroxy, (C ₁ -C ₁₂ ) alkoxycarbonyl, (C ₆ -C ₁₄ ) aryl- (C ₁ -C ₄ ) alkoxycarbonyl and (C ₆ -C ₁₄ ) aryloxycarbonyl, in which all aryl groups are unsubstituted or substituted by one or more identical or different substituents selected from (C ₁ -C ₁₂ ) -alkyl, halogen or (C ₁ -C ₁₂ ) -alkoxy; R ^{2 is} selected from hydrogen, (C ₁ -C ₁₂ ) -alkyl, (C ₆ -C ₁₄ ) -aryl, (C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₄ ) -alkyl, R ²⁰ - ( C ₁ -C ₁₂ ) -alkyl, R ²⁰ - (C ₆ -C ₁₄ ) -aryl and R ²⁰ - (C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₄ ) -alkyl in which R ^{20 is} selected from hydroxycarbonyl, aminocarbonyl, (C ₁ -C ₁₂ ) alkoxycarbonyl and (C ₆ -C ₁₄ ) aryl- (C ₁ -C ₄ ) alkoxycarbonyl; R ³ selected from hydrogen, cyano, hydroxy and (C ₁ -C ₁₂ ) -alkyl; R ^{4 is} selected from (C ₁ -C ₁₂ ) -alkyl, (C ₆ -C ₁₄ ) -aryl, (C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₄ ) -alkyl, Het and Het- (C ₁ -C ₄ ) -alkyl in which the alkyl, aryl and Het groups are unsubstituted or substituted by one or more identical or different substituents R ¹⁰ ; R ^{5 is} selected from hydrogen, (C ₁ -C ₁₂ ) -alkyl, (C ₆ -C ₁₄ ) -aryl, (C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₄ ) -alkyl, Het, Het- (C ₁ -C ₄ ) -alkyl, (C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₄ ) -alkylaminocarbonyl and Het- (C ₁ -C ₄ ) -alkylaminocarbonyl, in which alkyl, aryl and Het groups unsubstituted or substituted by one or more identical or different substituents R ¹⁰ ; or R ⁴ and R ^5, together with the carbon atom to which they are bonded, form a saturated or unsaturated 3-8 membered ring, which is a carbocyclic ring or a heterocyclic ring containing 1, 2 or 3 identical or different ring heteroatoms selected from nitrogen oxygen and sulfur, and which may be condensed to one or two saturated or unsaturated carbocyclic or heterocyclic ring systems containing from 5 to 10 ring atoms, of which 1, 2 or 3 may be the same or different ring ring heteroatoms selected from nitrogen, oxygen and sulfur, in which the resulting R ⁴ (R ⁵ ) C group is unsubstituted or substituted with one or more identical or different R ¹⁰ substituents; R ^{6 is} selected from hydrogen, hydroxy, (C ₁ -C ₈ ) alkoxy and (C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₄ ) alkoxy; R ^{10 is} selected from (C ₁ -C ₁₂ ) -alkyl, (C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₈ ) -alkoxy, (C ₁ -C ₄ ) -alkoxy- (C ₂ -C ₄ ) -alkoxy, (C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₄ ) -alkoxy, (C ₆ -C ₁₄ ) aryloxy, Het-hydroxy, Het- (C ₁ -C ₄ ) -alkoxy, (C ₆ -C ₁₄ ) -aryl, Het, Het- (C ₁ -C ₄ ) -alkyl, trifluoromethoxy, trifluoromethyl, halogen, oxo, hydroxy, amino, (C ₁ - C ₁₂ ) -alkylcarbonylamino, aminocarbonylamino, (C ₆ -C ₁₄ ) -arylcarbonylamino, Het-carbonylamino, (C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₄ ) -alkylcarbonylamino, Het- (C ₁ -C ₄ ) -alkylcarbonylamino, (C ₁ -C ₈ ) -alkylcarbonyl, (C ₆ -C ₁₄ ) -arylcarbonyl, (C ₁ -C ₈ ) -alkylaminocarbonyl, (C ₆ -C ₁₄ ) -arylaminocarbonyl, (C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₄ ) -alkylaminocarbonyl, Het-aminocarbonyl, Het- (C ₁ -C ₄ ) -alkylaminocarbonyl, aminocarbonyl, (C ₁ -C ₈ ) -alkoxycarbonyl, hydroxycarbonyl, cyano, nitro, amidino, acetimino, three - ((C ₁ -C ₄ ) -alkyl) ammonio, (C ₁ -C ₈ ) -alkylamino, di - ((C ₁ -C ₈ ) -alkyl) amino, hydroxycarbonylmethoxy, (C ₁ -C ₈ ) -alkylsulfonyl, (C ₆ -C ₁₄ ) -aryl sulfonyl, (C ₁ -C ₈ ) -alkylaminosulfonyl, (C ₆ -C ₁₄ ) -arylaminosulfonyl, (C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₄ ) -alkylaminosulfonyl, Het-aminosulfonyl , Het- (C ₁ -C ₄ ) -alkylamino-sulfonyl, (C ₁ -C ₈ ) -alkylsulfonylamino, (C ₆ -C ₁₄ ) -arylsulfonylamino, (C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₄ ) alkylsul phonylamino, Het-sulfonylamino and Het- (C ₁ -C ₄ ) -alkylsulfonylamino, in which the (C ₁ -C ₁₂ ) -alkylcarbonylamino, representing R ¹⁰ , is unsubstituted or substituted in the alkyl group with a substituent selected from amino, hydroxy and (C ₁ -C ₄ ) -alkoxy, and in which (C ₁ -C ₁₂ ) -alkyl and (C ₁ -C ₈ ) -alkoxy representing R ¹⁰ are unsubstituted or substituted with one or more identical or different substituents selected from (C ₁ -C ₈₎ alkoxycarbonyl, hydroxycarbonyl, and aminocarbonyl, wherein all aryl and Het groups in a group R ¹⁰ are unsubstituted or substituted with one or more odi What are the or different substituents selected from halogen, nitro, oxo, hydroxy, (C ₁ -C ₈₎ -alkyl, (C ₁ -C ₈₎ -alkoxy, (C ₁ -C ₄₎ -alkoxy- (C ₂ -C ₄ ) -alkoxy, (C ₆ -C ₁₄ ) -aryloxy, (C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₄ ) -alkoxy, Het-hydroxy, Het- (C ₁ -C ₄ ) -alkoxy , (C ₆ -C ₁₄ ) -aryl, (C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₄ ) -alkyl, Het, Het- (C ₁ -C ₄ ) -alkyl, trifluoromethyl, cyano, trifluoromethoxy , (C ₁ -C ₈ ) -alkylsulfonyl, (C ₁ -C ₈ ) -alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, amino, (C ₁ -C ₈ ) -alkylamino, di ((C ₁ -C ₈ ) -alkyl) amino , (C ₁ -C ₈₎ -alkilkarbonilamino, (C ₆ -C ₁₄₎ -aryl- (C ₁ -C ₄₎ -alkilkarbonilamino, (C ₆ -C ₁₄₎ -arilkarbonilamino, Het-ct onilamino, Het- (C ₁ -C ₄₎ -alkilkarbonilamino and (C ₁ -C ₈₎ alkylcarbonyl, wherein (C ₁ -C ₈₎ -alkyl and (C ₁ -C ₈₎ -alkoxy representing a substituent on the aryl or a Het group in the R ¹⁰ group, unsubstituted or substituted by one or more identical or different substituents selected from (C ₁ -C ₈ ) alkoxycarbonyl, hydroxycarbonyl and aminocarbonyl, provided that when the R ¹⁰ substituent is attached to an alkyl group, it is not may be (C ₁ -C ₈ ) alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, (C ₁ -C ₈ ) alkylaminocarbonyl or (C ₁ -C ₈ ) alkylaminosulfonyl, and when R ¹⁰ is attached to an alkyl group, it cannot represent (C ₁ -C ₈ ) -alkyl substituted with one or more identical or different substituents selected from (C ₁ -C ₈ ) -alkoxycarbonyl, hydroxycarbonyl and aminocarbonyl; Het represents a residue of a saturated or unsaturated, monocyclic or bicyclic, 3-10 membered heterocyclic ring system containing 1, 2 or 3 identical or different ring heteroatoms selected from nitrogen, oxygen and sulfur; in all stereoisomeric forms and their mixtures in any ratio and its physiologically tolerated salts. 2. The compound of formula I according to claim 1, where X is oxygen, in all stereoisomeric forms and their mixtures in any ratio, as well as its physiologically tolerated salts. 3. The compound of formula I according to claims 1 and / or 2, where R ¹ represents hydrogen, hydroxy or (C ₁ -C ₄ ) alkoxycarbonyl, in all stereoisomeric forms and their mixtures in any ratio, as well as its physiologically tolerated salts. 4. The compound of formula I according to one or more of claims 1 to 3, where R ² represents hydrogen, in all stereoisomeric forms and their mixtures in any ratio, as well as its physiologically tolerated salts. 5. The compound of formula I according to one or more of claims ^{1 to 4} , where R ⁶ is hydrogen or hydroxy, in all stereoioomer forms and their mixtures in any ratio, as well as its physiologically tolerated salts. 6. The compound of formula I according to one or more of claims 1 to 5, where n is 0, R ³ is hydrogen, R ⁵ is methyl, ethyl or phenyl, where the phenyl group is unsubstituted or substituted by one or more identical or different R ¹⁰ substituents; in all stereoisomeric forms and their mixtures in any ratio, as well as its physiologically tolerated salts. 7. A method of obtaining a compound of formula I according to one or more of claims 1 to 6, comprising binding compounds of formulas II, III and IV to form a (thio) urea bridge between groups G ¹ and G ² in formulas II and III, and also an amide bond between the COZ group in formula II and the NH ₂ group in formula IV

where either G ^{2 is} selected from iso (thio) cyanato, (C ₁ -C ₆ ) -alkoxycarbonylamino, trichloromethylcarbonylamino and azolyl-N- (thio) carbonylamino, where these groups contain a group R ⁶ and G ¹ represents NHz, or G ^{1 is} selected from iso (thio) cyanato, (C ₁ -C ₆ ) -alkoxycarbonylamino, trichloromethylcarbonylamino and azolyl-N- (thio) carbonylamino, G ² represents NHR ⁶ , Z in the compound of formula III represents a hydroxy or nucleophilic substitution leaving group, R ⁰ in the compound of formula II represents the group R ¹ NH -C (= NH) - or its protected form, or its precursor group, and m, n, A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the meanings indicated in claims 1 -6, but in which functional groups may also be present in protected form or in the form of precursor groups. 8. A pharmaceutical composition comprising at least one compound of formula I according to one or more of claims 1 to 6 and / or its physiologically tolerable salt and a pharmaceutically acceptable carrier. 9. The compound of formula I according to one or more of claims 1 to 6 and / or its physiologically tolerated salt, for use as an inhibitor of factor VIIa. 10. The compound of formula I according to one or more of claims 1 to 6 and / or its physiologically tolerable salt for inhibiting or reducing blood coagulation or inflammatory reaction, or for use in the treatment of cardiovascular disorders, thromboembolic diseases or restenoses.