Patent EA-002271-B1 (EA)
Title: TRICYCLIC COMPOUNDS HAVING ACTIVITY SOECIFIC FOR INTEGRINS, PARTICULARLY alpha v beta 3 INTEGRINS, METHOD FOR PREPARING SAME, INTERMEDIATES THEREFOR, USE OF SAID COMPOUNDS AS DRUGS, AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
Inventor: BERNARD SERGE
IPC: C07B61/00
Filed: 1997-03-20
Abstract: 1. A compound of general formula (I)   wherein R1 is -O-[A]-[B]-COR6, wherein R6 is -OH, C1-C6alkoxy, -O-CH2-CH(OH)-CH2OH, [A] is C1-C6alkylene, optionally substituted with oxo group, [B] is -CH(Z)- or a single bond; Z is -NHCO2Rc, or -NHSO2Rc, wherein Rc is phenyl(C1-C4)alkyl-, quinolinyl, or pyridinylimidazolyl-(C1-C4)alkyl, R2 and R3, identical or different, represent either a hydrogen atom, a hydroxyl radical, an C1-C6-alkoxy radical or R2 and R3 form together the group -O-(C1-C3-alkylene)-O- or -O-C(Ph)2-O, G is -NH-C-(=X)-NH2, wherein X is S, O or NH, or radical -NH-Het', wherein Het' is imidazole, optionally substituted with oxo, pyrimidin, diazepine or benzimidazole of formulae   wherein p is 2, 3 or 4, the dotted lines are an optional second bond and their addition salts with acids and bases and their esters, R1, R2 and R3 can be in 8, 9, or 10 position of tricycle. 2. A compound of general formula (I) of Claim 1, corresponding to general formula (I'):   wherein R' is the group -O-[A']-[B]-COR6, wherein [A'] is bivalent C1-C6-alkylene group, and [B] and R6 have the meanings, mentioned in Claim 1, G has the meaning, mentioned in Claim 1, R'2 and R'3 represent a hydrogen atom or methoxyradical , the dotted lines are an optional second bond and their addition salts with acids and bases and their esters. 3. The compounds of general formula (I) of Claim 1 or 2, wherein R6 is selected from the group consisting of -OH, -OCH3, -OCH2CH3, -O(CH2)-CH(OH)-CH2OH, and their addition salts with acids and bases and their esters. 4. The compounds of general formula (I) of Claim 1, 2 or 3, wherein R1 is -O-CH(Z)-COOH, and their addition salts with acids and bases and their esters. 5. The compounds of general formula (I) of Claims 1-4, wherein (Z) is -NH-CO2-Rc, wherein Rc has the meanings, mentioned in Claim 1, and their addition salts with acids and bases and their esters. 6. The compounds of general formula (I) of one of Claims 1-5, characterized in that G is NH-(Het'), and (Het') has the meanings, mentioned in Claim 1. 7. The compounds of general formula (I) of Claim 6, wherein G is the following heterocycles:   wherein p is integer 2, 3 or 4, and their addition salts with acids and bases and their esters. 8. The compounds of general formula (I) of Claim 6 or 7, wherein G is   wherein p is integer 2, 3 or 4, and their addition salts with acids and bases and their esters. 9. The compounds of formula (I) as it is determined in Claim 1 with the names of: -4-((4-((aminoiminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulen-yl)oxy)butyric acid, -5-((4-((aminoiminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulen-yl)oxy)pentanoic acid, -5-((4-((aminoiminomethyl)hydrazono)-8,10-dimethoxy-1,2,3,4,5,6-hexahydro-9-benz(e)azulen-yl)oxy)pentanoic acid, -6-((4-((aminoiminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)hexanoic acid, -7-((4-((aminoiminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)heptanoic acid, -5-((9,10-dimethoxy-1,2,3,4,5,6-hexahydro-4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-8-benz(e)azulenyl)oxy)pentanoic acid, ethyl 5-((4-((aminoiminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)pentanoate hydrochloride, -4-((4-((aminoiminomethyl)hydrazono)-8,9-dimethoxy-1,2,3,4,5,6-hexahydro-10-benz(e)azulenyl)oxy)butyric acid, -5-((4-((aminoiminomethyl)hydrazono)-8,9-dimethoxy-1,2,3,4,5,6-hexahydro-10-benz(e)azulenyl)oxy)pentanoic acid, -5-((4-(((amino)carbonyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)pentanoic acid, -5-((4-(((amino)thiocarbonyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)pentanoic acid, -4-((4-((aminoiminomethyl)hydrazono)-8,10-dimethoxy-1,2,3,4,5,6-hexahydro-9-benz(e)azulenyl)oxy)butyric acid, -6-((4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)hexanoic acid, -5-((4-((aminoiminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-3,3-dimethyl-4-oxopentanoic acid, -5-((4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-3,3-dimethyl-4-oxopentanoic acid, -5-((4-((aminoiminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)pentanoic acid hydrochloride, -4-((4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)butyric acid, -5-((8-((-aminoiminomethyl)hydrazono)-6,7,8,9,10,11-hexahydroazuleno(5,6-d)-1,3-benzodioxol-4-yl)oxy)pentanoic acid, -5-((8-((aminoiminomethyl)hydrazono)-2,2-diphenyl-6,7,8,9,10,11-hexahydroazuleno(4,5-e)-(1,3)-benzodioxol-4-yl)oxy)pentanoic acid, -4-((9,10-dimethoxy-4-((1,4,5,6-tetrahydro-2-pyrimidinyl)hydrazono)-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)butyric acid, -2-((4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)ethanoic acid, -3-((4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)propanoic acid, -4-((4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)butyric acid, -O-[4-[(4,5-dihydro-1H-imidazol-2-yl)hydrazono]-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz[e]azulenyl]-N-[(phenylmethoxy)carbonyl]-DL-homoserine, -O-[4[(4,5-dihydro-1H-imidazol-2-yl)hydrazono]-1,2,3,4,5,6-hexahydro-8-benz[e]azulenyl]-N-[(phenylmethoxy)carbonyl]-DL-homoserine, -O--[4-[(1,2,3,4-tetrahydro-6-pyrimidinyl)hydrazono]-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz[e]azulenyl]-N-[(phenylmethoxy)carbonyl]-DL-homoserine, -(2,3-dihydroxypropyl) ester of O-(9,10-dimethoxy-1,2,3,4,5,6-hexahydro-4-((1,4,5,6-tetrahydro-2-pyrimidinyl)hydrazono]-8-benz(e)azulenyl]-N-[(phenylmethoxy)carbonyl]-DL-homoserine, -O-[4-[(4,5-dihydro-1H-imidazol-2-yl)hydrazono]-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl]-N-[(8-quinolinyl)sulphonyl]-DL-homoserine, -monohydrochloride of O-[4-[(4,5-dihydro-1H-imidazol-2-yl)hydrazono]-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)-azulenyl]-N-[[3-[4-(3-pyridinyl)-1H-imidazol-1-yl]propoxy]carbonyl]-DL-homoserine, -5-[[4-[(4,5-dihydro-4-oxo-1H-imidazol-2-yl)hydrazono]-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl]oxy]pentanoic acid, -O-[9,10-dimethoxy-1,2,3,4,5,6-hexahydro-4-[(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl)hydrazono]-8-benz(e)-azulenyl]-N-[(phenylmethoxy)carbonyl]-DL-homoserine, -O-[9,10-dimethoxy-1,2,3,4,5,6-hexahydro-4-[(3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl)hydrazono]-8-benz(e)azulenyl]-N-[(phenylmethoxy)carbonyl]-DL-homoserine. 10. A method for obtaining the compound of formula (I) determined in Claim 1, characterized in that the compound of formula (II)   wherein R2 and R3 have the meanings determined in Claim 1, with the exception of the hydroxyl value, are subjected either to the action of a compound of formula (Fl) in the presence of a base   or a compound of formula (F'1) in the presence of a phosphine and of diethylazodicarboxylate:   in which Hal is a halogen atom, [A], [B] and R6 are as described previously, [B] also being able to represent the   group, P being a protective group of the amine function, in order to obtain a compound of formula (IIIa):   the obtained compound of formula (IIIa) is treated with a compound of formula (F3): H2N-G (F3) wherein G has the meanings determined in Claim 1, in order to obtain a compound of formula (IVa), corresponding to several products of formula (I):   which are subjected, if appropriate, in a suitable order, to one or more of the following reactions: - the action of a base or an acid in order to cleave the ester and to obtain the corresponding acid, - the action of a reducing agent suitable for partially or totally reducing the unsaturations, - the action of a dealkylation agent, - to the action of a deprotection agent of the NH-P function in beta position of COR6 when [B] represents the CH-NHP group, - to the formation of the NH-SO2Rc, NH-CO2Rc group from the corresponding amine in beta position of COR6, in order to obtain the corresponding compounds of formula (I) which are subjected if appropriate to the action of an acid or a base in order to obtain the corresponding salts or to the action of an esterification agent in order to obtain the corresponding esters. 11. Preparation process of the compounds of formula (I) as defined in Claim 1, characterized in that beforehand a compound of formula (II) is subjected to the action of a compound of formula (F3) in order to obtain a compound of formula (IIIc):   which compound is subjected if appropriate after protection of G to the action of a compound of formula (F1), (F'1), then if appropriate to a deprotection reaction of G, in order to obtain the corresponding compounds of formula (IVa) which is then subjected, if appropriate, to the different reactions as defined in Claim 10, the compounds of formulae (II), (F1), (F'1), (F3, (IVa) being as defined in Claim 10. 12. Preparation process of the compounds of formula (II) as defined in Claim 10, wherein R2 and R3 are hydrogen atoms and OH is in position 8, 9 or 10, characterized in that (i) a compound of formula (a):   in which O-(Alk) is in meta- or para- position of the alkylcarboxylic group, (Alk) being as defined in Claim 1, is subjected to the action of a halogenation agent in order to obtain the corresponding acylhalide, (ii) which is subjected to the action of a reagent of formula (b):   in which R(I) and R(II), identical or different, represent an alkyl group containing 1 to 6 carbon atoms, or R(I) and R(II) together with the nitrogen atom to which they are linked. represent a saturated or unsaturated heterocycle with 5 or 6 members optionally containing another heteroatom chosen from O and N, in order to obtain a compound of formula (c):   (iii) which is subjected to the action of a halogenation agent in order to obtain a compound of formula (d):   in which Hal1_ repre