RU2002100067A - VIIA FACTOR INHIBITORS - Google Patents

Claims (10)

1. The compound of formula I

where r is 0, 1, 2 or 3; s is 0, 1, 2, 3 or 4; t is 0, 1 or 2; R ^{1 is} selected from the group consisting of hydrogen, R ¹¹ —CO— and R ¹² —SO ₂ - R ^{11 is} selected from the group consisting of hydrogen, (C ₁ -C ₈ ) -alkyl, (C ₆ -C ₁₄ ) -aryl, (C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₄ ) -alkyl, Het-, Het- (C ₁ -C ₄ ) -alkyl-, (C ₁ -C ₈ ) -alkyloxy-, (C ₆ -C ₁₄ ) -aryloxy-, (C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₄ ) -alkyloxy-, amino, (C ₁ -C ₈ ) -alkylamino, (C ₆ -C ₁₄ ) -arylamino and (C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₄ ) -alkylamino, where all of these groups are unsubstituted or substituted with one or more identical or different substituents R ⁴⁰ ; R ^{12 is} selected from the group consisting of (C ₁ -C ₈ ) -alkyl, (C ₆ -C ₁₄ ) -aryl, (C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₄ ) -alkyl-, Het- , Het- (C ₁ -C ₄ ) -alkyl-, di ((C ₁ -C ₈ ) -alkyl) amino and di ((C ₆ -C ₁₄ ) aryl (C ₁ -C ₄ ) -alkyl) amino, where all of these groups are unsubstituted or substituted by one or more identical or different substituents R ⁴⁰ ; R ² is hydrogen, R ²¹ (R ²² ) CH-, R ²³ -Het- (CH ₂ ) _k -, R ²³ (R ²⁴ ) N- (CH ₂ ) _m -D- (CH ₂ ) _n - or R ²⁵ (R ²⁶ ) N-CO- (CH ₂ ) _p -D- (CH ₂ ) _q -, where D is the divalent residue-C (R ³¹ ) (R ³² ) -, divalent (C ₆ -C ₁₄ ) -arylene residue or divalent residue obtained from the aromatic group Het containing from 5 to 10 atoms in the cycle, of which 1, 2, 3 or 4 are the same or different cyclic heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and the numbers k, m, n, p and q, which are independent of each other and may be the same or different, are 0, 1, 2, 3, 4 or 5, provided that if D is —C (R ³¹ ) (R ³² ) - the sum m + n cannot be equal to 0 and the sum p + q cannot be equal to 0; R ²¹ and R ²² , which are independent of each other, and may be the same or different, are selected from the group consisting of hydrogen, (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-, where all these groups are unsubstituted or substituted by one or more identical or different substituents from a group comprising R ⁴⁰ , (C ₁ -C ₈ ) -alkylamino, di - ((C ₁ -C ₈ ) -alkyl) amino, (C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₄ ) -alkylamino, (C ₆ -C ₁₄ ) -arylamino, aminocarbonyl- and aminocarbonyl- (C ₁ -C ₈ ) -alkyl-, or R ²¹ and R ^22, together with the carbon atom to which they are bonded, form a saturated or unsaturated 3-8 membered carbocyclic structure, which may be fused to one or two cyclic systems representing heteroaromatic rings containing from 5 to 10 atoms in the cycle, of which 1, 2 or 3 are the same or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and / or (C ₆ -C ₁₀ ) carbocyclic aromatic structures, where the resulting group R ²¹ R ²² CH- is unsubstituted or substituted one or more identical or different substituents selected from the group consisting of R ⁴⁰ , (C ₁ -C ₈ ) -alkylamino, di - ((C ₁ -C ₈ ) -alkyl) amino, (C ₆ -C ₁₄ ) aryl- (C ₁ -C ₄ ) -alkylamino, (C ₆ -C ₁₄ ) arylamino, aminocarbonyl- and aminocarbonyl- (C ₁ -C ₈ ) -alkyl-; R ²³ represents hydrogen, R ²⁷ —SO ₂ - or R ²⁸ —CO—; R ^{24 is} selected from the group consisting of hydrogen, (C ₁ -C ₈ ) -alkyl, (C ₆ -C ₁₄ ) -aryl and (C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₄ ) -alkyl-; R ²⁵ and R ²⁶ , which are independent from each other, and may be the same or different, are selected from the group consisting of hydrogen, (C ₁ -C ₈ ) -alkyl, (C ₆ -C ₁₄ ) -aryl, (C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₄ ) -alkyl-, Het- and Het- (C ₁ -C ₄ ) -alkyl-, where all these groups are unsubstituted or substituted by one or more identical or different substituents R ⁴⁰ ; R ^{27 is} selected from the group consisting of (C ₁ -C ₈ ) -alkyl, (C ₆ -C ₁₄ ) -aryl, (C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₄ ) -alkyl-, Het- , Het- (C ₁ -C ₄ ) -alkyl, amino, (C ₁ -C ₈ ) -alkylamino, di - ((C ₁ -C ₈ ) -alkyl) amino, (C ₆ -C ₁₄ ) -arylamino- and (C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₄ ) -alkylamino, wherein all of these groups are unsubstituted or substituted with one or more identical or different substituents R ⁴⁰ ; R ^{28 is} selected from the group consisting of R ²⁷ , (C ₁ -C ₈ ) -alkyloxy, (C ₆ -C ₁₄ ) aryloxy and (C ₆ -C ₁₄ ) aryl- (C ₁ -C ₄ ) - alkyloxy-, where all these groups are unsubstituted or substituted with one or more identical or different substituents R ⁴⁰ ; R ³¹ and R ³² , which are independent from each other, and may be the same or different, are selected from the group consisting of hydrogen, (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-, where all these groups are unsubstituted or substituted by one or more identical or different substituents R ⁴⁰ ; R ^{40 is} selected from the group consisting of halogen, hydroxy, (C ₁ -C ₈ ) -alkyloxy, (C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₈ ) -alkyloxy, (C ₆ -C ₁₄ ) -aryloxy-, (C ₁ -C ₈ ) -alkyl, (C ₆ -C ₁₄ ) -aryl, (C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₈ ) -alkyl-, (C ₁ -C ₈ ) -alkylsulfonyl-, trifluoromethyl, acetylamino-, amino, amidino, guanidino, oxo, nitro and cyano, where the groups R ⁴⁰ are independent from each other and may be the same or different; R ⁹¹ , R ⁹² and R ⁹³ , which are independent from each other, and may be the same or different, are selected from the group consisting of hydrogen, (C ₁ -C ₈ ) -alkyl, (C ₆ -C ₁₄ ) -aryl, (C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₄ ) -alkyl-, Het- and Het- (C ₁ -C ₄ ) -alkyl-; R ^{94 is} selected from the group consisting of (C ₁ -C ₄ ) -alkyl, (C ₆ -C ₁₄ ) -aryl, amino, nitro, halogen, trifluoromethyl, hydroxy, (C ₁ -C ₄ ) -alkyloxy, where the groups R ⁹⁴ are independent of each other and may be the same or different; R ^{95 is} selected from the group consisting of amidino, guanidino, ((C ₁ -C ₄ ) -alkyl) hydroxycarbonylamidino, ((C ₁ -C ₄ ) -alkyl) hydroxycarbonylguanidino- and hydroxyamidino; R ^{96 is} selected from the group consisting of hydrogen, R ⁹⁸ - (C ₁ -C ₈ ) -alkyl-, R ⁹⁸ - (C ₆ -C ₁₄ ) aryl-, R ⁹⁸ - (C ₆ -C ₁₄ ) aryl- (C ₁ -C ₄ ) -alkyl-, R ⁹⁸ -Het- and R ⁹⁸ -Het- (C ₁ -C ₄ ) -alkyl-; R ^{97 is} selected from the group consisting of R ⁹⁹ - (C ₁ -C ₈ ) -alkyl-, R ⁹⁹ - (C ₆ -C ₁₄ ) aryl, R ⁹⁹ - (C ₆ -C ₁₄ ) aryl- (C ₁ - C ₄ ) -alkyl-, R ⁹⁹ -Het- and R ⁹⁹ -Het- (C ₁ -C ₄ ) -alkyl-; R ⁹⁸ and R ⁹⁹ , which are independent from each other, and may be the same or different, are selected from the group consisting of hydroxycarbonyl, (C ₁ -C ₈ ) alkyloxycarbonyl, (C ₆ -C ₁₄ ) aryloxycarbonyl, (C ₆ -C ₁₄ ) -aryl- (C ₁ -C ₄ ) -alkyloxycarbonyl-, aminocarbonyl-, (C ₁ -C ₈ ) -alkylaminocarbonyl-, tetrazolyl, P (O) (OH) ₂ , -S (O ) ₂ OH and -S (O) ₂ NH ₂ ; Het means a saturated, partially unsaturated or aromatic monocyclic or bicyclic heterocyclic structure containing from 3 to 10 atoms in the cycle, of which 1, 2, 3 or 4 are the same or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; in all its stereoisomeric forms, as well as their mixtures in any proportions, and its physiologically acceptable salts. 2. The compound of formula I according to claim 1, in which R ¹¹ denotes (C ₁ -C ₈ ) -alkyl, (C ₆ -C ₁₀ ) -aryl or (C ₁ -C ₈ ) -alkyloxy-, in all its stereoisomeric forms, as well as mixtures thereof in any proportions, and its physiologically acceptable salts. 3. The compound of formula I according to claim 1 and / or 2, in which r is 0 or 1, t is 0 or 1, s is 0, 1 or 2, and R ⁹⁵ is amidino, ((C ₁ -C ₄ ) -alkyl) hydroxycarbonylamidino- or hydroxyamidino-, in all its stereoisomeric forms, as well as mixtures thereof in any proportions, and its physiologically acceptable salts. 4. The compound of formula I according to any one of claims 1 to 3, in which R ⁹⁶ is hydrogen, R ⁹⁷ is R ⁹⁴ - (C ₁ -C ₈ ) -alkyl- and R ⁹⁹ is hydroxycarbonyl-, (C ₁ -C ₈ ) -alkyloxycarbonyl-, (C ₆ -C ₁₀ ) -aryl- (C ₁ -C ₄ ) -alkyloxycarbonyl-, aminocarbonyl- or (C ₁ -C ₈ ) -alkylaminocarbonyl-, in all its stereoisomeric forms, as well as mixtures thereof in any proportions, and its physiologically acceptable salts. 5. The compound of formula I according to any one of claims 1 to ⁴ , in which R ² denotes R ²¹ (R ²² ) CH-, R ²³ -Het- (CH ₂ ) _k - or R ²³ R ²⁴ N- (CH ₂ ) _m -D- (CH ₂ ) _n -, a D is a divalent residue C (P ³¹ ) (R ³² ) -, a divalent phenylene residue or a divalent residue derived from the aromatic monocyclic group Het, in all its stereoisomeric forms, as well as their mixtures in any proportions, and its physiologically acceptable salts. 6. The compound of formula I according to any one of claims 1 to 5, where r is 1; s is 0 or 1; t is 0; R ¹ is allyloxycarbonyl; R ² is R ²¹ (R ²² ) -, R ²³ -Het- (CH ₂ ) _k - or R ²³ (R ²⁴ ) N- (CH ₂ ) _m -D- (CH ₂ ) _n -; D represents a divalent residue —C (R ³¹ ) (R ³² ) -, a divalent phenylene residue or a divalent residue derived from an aromatic monocyclic group Het; R ⁹⁴ is halogen; R ⁹⁵ is amidino or ((C ₁ -C ₄ ) -alkyl) hydroxycarbonylamidino and is attached at the 4-position of the phenyl ring in formula I; R ⁹¹ , R ⁹² , R ⁹³ and R ⁹⁶ are hydrogen; R ⁹⁷ is R ⁹⁹ —CH ₂ —CH ₂ -; R ⁹⁹ is hydroxycarbonyl or ((C ₁ -C ₄ ) alkyl) hydroxycarbonyl; in all its stereoisomeric forms, as well as their mixtures in any proportions, and its physiologically acceptable salts. 7. A method of producing a compound according to one or more of claims 1 to 6, comprising reacting compounds of formulas II, III and IV

where the groups R ¹ , R ² , R ⁹¹ , R ⁹² , R ⁹³ , R ⁹⁴ , R ⁹⁵ , R ⁹⁶ , R ⁹⁷ and r, s and t have the definitions specified in claims 1-6, or the functional groups are present in the form precursor groups, or in protected form, and Y ¹ and Y ² are hydroxyl or nucleophilic substitution leaving groups. 8. A pharmaceutical preparation comprising at least one compound of formula I according to one or more of claims 1 to 6, and / or its physiologically acceptable salts 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 acceptable salts, 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 acceptable salts, for inhibiting or reducing blood coagulation or an inflammatory response, or for use in the treatment or prevention of cardiovascular diseases, thromboembolic diseases or repeated stenosis.