Patent EA-002116-B1 (EA)
Title: 4-halogenated steroids, preparation thereof, intermediates, application as medicines and pharmaceutical compositions
Inventor: BOUALI YAMINA
IPC: A61K31/56
Filed: 1998-04-08
Abstract: 1. Compounds of general formula (I):   wherein R1 is a hydrogen atom or a radical --(CH2)m--CH2-CO2H, in which m is 0, 1, 2 or 3, R2 is an alkyl of 1 to 6 carbon atoms, D is a residue of a 5 membered ring, optionally substituted, X is a halogen atom, Y is selected from the group consisting of --O--, --S--, --SO--, --SO2, n is an interger of 2 to 5, R3 and R4 identical or different, are a hydrogen atom, (C1-C6)-alkyl, linear, ramified or cyclic, optionally comprising an unsaturated fragment, or R3 and R4 form together with a nitrogen atom, with which they are bond, a saturated C4-C7 heterocycle comprising optionally a sulphur atom, as well as its addition salts with acids or bases. 2. Compounds of general formula (I) of claim 1 wherein (D) is a residue of a 5 membered circle of formula:   wherein R2 has the meaning as claimed in claim 1, R5 R6, identical or different, are a hydrogen atom, a OH group or an alkyl radical of 1 to 6 carbon atoms, or R5 R6 form together with a carbon atom one of the following cycles:   or R5 R6 form together an oxo-group is or =N-OH, as well as its addition salts with acids or bases. 3. Compounds of general formula (I) of claim 1claim 1 corresponding to general formula (I'):   wherein X' is chlorine or bromine atom, n' is an integer from 2 to 5, R'3 and R'4, identical or different, are an alkyl radical of 1 to 6 carbon atoms or R'3 and R'4 form together with a nitrogen atom with which they are bond, a saturated C4-C7 heterocycle comprising optionally a sulphur atom, and R'5 and R'6 have the definitions of R5 and R6 of claim 2, as well as its addition salts with acids or bases. 4. Compounds of general formula (I') as in claim 3 wherein R'5 and R'6, identical or different, are a hydrogen atom or an alkyl radical of 1 to 6 carbon atoms or R'5 and R'6 form together with a carbon atom one of the following cycles:   or R'5 and R'6 form together an oxo-group as well as its addition salts with acids or bases. 5. Compounds of general formula (I') as in claim 3 or 4 wherein X' is chlorine atom, n is 2, R'3 and R'4, identical or different, are an alkyl radical of 1 to 6 carbon atoms or R'3 and R'4 form together with a nitrogen atom the following saturated heterocycles:   R'5 and R'6, identical or different, are a hydrogen atom or an alkyl radical of 1 to 6 carbon atoms or R'5 and R'6 form together with a carbon atom one of the following cycles:   or R'5 and R'6 form together an oxo-group and also additive salts thereof with bases or acids. 6. Compounds of formulae (I) and (I') as claimed in one of claims 1 to 5 selected from the group consisting of: - 4-chloro-3-hydroxy-11.beta.-[4-[2-(diethylamino)ethoxy]phenyl]-estra-1,3,5(10)-trien-17-one,  - 4-chloro-3-hydroxy-11.beta.-[4-[2-(dimethylamino)ethoxy]phenyl]-estra-1,3,5(10)-trien-17-one, - 4-chloro-3-hydroxy-11.beta.-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-17-one, - 4-chloro-3-hydroxy-11.beta.-[4-[2-(1-pyrrolidinyl)ethoxy] phenyl]-estra-1,3,5(10)-trien-17-one, - 4-bromo-3-hydroxy-11.beta.-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-17-one, - 4-chloro-11.beta.-[4-[2-(dimethylamino)ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - 4-chloro-11.beta.-[4-[2-(diethylamino)ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - 4-chloro-11.beta.-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - 4-bromo-11.beta.-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - 4-chloro-11.beta.-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - 4-chloro-11.beta.-[4-[2-(diethylamino)ethoxy]phenyl]-19-nor-17alpha-pregna-1,3,5(10)-trien-20-yne-17beta-diol, - 4-chloro-11.beta.-[4-[3-(1-piperidinyl)propoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - 4-chloro-11.beta.-[4-[4-(1-piperidinyl)butoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - 4-chloro-11.beta.-[4-[5-(1-piperidinyl)pentyloxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - gamma lactone (17alpha)-4-chloro-3,17beta-dihydroxy-11.beta.-[4-[2-(diethylamino)ethoxy]phenyl]-19-nor-pregna-1,3,5(10)-triene-21-carboxylic acid, - gamma lactone (17alpha)-4-chloro-3,17beta-dihydroxy-11.beta.-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-19-nor-pregna-1,3,5(10)-triene-21-carboxylic acid, - gamma lactone (17alpha)-4-chloro-3,17beta-dihydroxy-11.beta.-[4-[2-(1-piperidinyl)ethoxy]phenyl]-19-nor-pregna-1,3,5(10)-triene-21-carboxylic acid, - gamma lactone (17alpha)-4-chloro-3,17beta-dihydroxy-11.beta.-[4-[3-(1-piperidinyl)propoxy]phenyl]-19-nor-pregna-1,3,5(10)-triene-21-carboxylic acid, - gamma lactone (17alpha)-4-chloro-3,17beta-dihydroxy-11.beta.-[4-[4-(1-piperidinyl)butoxy]phenyl]-19-nor-pregna-1,3,5(10)-triene-21-carboxylic acid, - gamma lactone (17alpha)-4-chloro-3,17beta-dihydroxy-11.beta.-[4-[5-(1-piperidinyl)pentyloxy]phenyl]-19-nor-pregna-1,3,5(10)-triene-21-carboxylic acid, - (17beta)-4-chloro-11.beta.-[4-[2-(diethylamino)ethoxy]phenyl]-spiro[estra-1,3,5(10)-triene-17,2'(5'H)furan]-3-ol, - (17beta)-4-chloro-11.beta.-[4-[2-(1-piperidinyl)ethoxy]phenyl]-spiro[estra-1,3,5(10)-triene-17,2'(5'H)furan]-3-ol, - (17beta)-4-chloro-11.beta.-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-spiro[estra-1,3,5(10)-triene-17,2'(5'H)furan]-3-ol, - (17beta)-4-chloro-4',5'-dihydro-11.beta.-[4-[2-(1-piperidinyl)ethoxy]phenyl]-spiro[estra-1,3,5(10)-triene-17,2'(3'H)furan]-3-ol, - (17beta)-4-chloro-11.beta.-[4-[3-(1-piperidinyl)propoxy]phenyl]-spiro[estra-1,3,5(10)-triene-17,2'(5'H)furan]-3-ol, - (17beta)-4-chloro-4',5'-dihydro-11.beta.-[4-[3-(1-piperidinyl) propoxy]phenyl]-spiro[estra-1,3,5(10)-triene-17,2'(3'H) furan]-3-ol, - (17beta)-4-chloro-11.beta.-[4-[4-(1-piperidinyl)butoxy]phenyl]-spiro[estra-1,3,5(10)-triene-17,2'(5'H)furan]-3-ol, - (17beta)-4-chloro-4',5'-dihydro-11.beta.-[4-[4-(1-piperidinyl)-butoxy]phenyl]-spiro[estra-1,3,5(10)-triene-17,2'(3'H)furan]-3-ol, - 4-chloro-11.beta.-[4-[2-(diethylamino)ethoxy]phenyl]-17alpha-methyl-estra-1,3,5(10)-triene-3,17beta-diol, - 4-chloro-17alpha-methyl-11.beta.-[4-[2-(1-piperidinyl)ethoxy] phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - 4-chloro-17alpha-methyl-11.beta.-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - 11.beta.-[4-[2-[2-aza-bicyclo(2.2.1)hept-2-yl]ethoxy] phenyl]-4-chloro-17alpha-methyl-estra-1,3,5(10)-triene-3,17beta-diol, - 11.beta.-[4-[2-[2-aza-bicyclo(2.2.1)hept-2-yl]ethoxy] phenyl]-4-chloro-estra-1,3,5(10)-triene-3,17beta-diol, - 4-chloro-11.beta.-[4-[2-[methyl(1-methylethyl)amino]ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - 4-chloro-11.beta.-[4-[2-(tetrahydro-(1H)-1,4-thiazin-4-yl)ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - 4-chloro-11.beta.-[4-[2-[ethyl(propyl)amino]ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - 4-chloro-11.beta.-[4-[2-[ethyl(methyl)amino]ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - 4-chloro-11.beta.-[4-[2-[(1,1-dimethyl-2-propynyl)amino]ethoxy] phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - 4-chloro-11.beta.-[4-[2-[hexahydro-1H-azepin-1-yl)ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - 4-chloro-11.beta.-[4-[2-[cyclohexyl(methyl)amino]ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - 4-chloro-11.beta.-[4-[2-[butyl(ethyl)amino]ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - 4-chloro-11.beta.-[4-[2-(1-azetidinyl)ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - 4-chloro-11.beta.-[4-[2-[ethyl(2-propenyl)amino]ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - 4-chloro-11.beta.-[4-[2-[cyclopentyl(methyl)amino]ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - 4-chloro-11.beta.-[4-[2-(dipropylamino)ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - 4-chloro-11.beta.-[4-[2-(3-thiazolidinyl)ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - 4-chloro-11.beta.-[4-[2-[ethyl(1-methylethyl)amino]ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - 4-chloro-11.beta.-[4-[2-[methyl(propyl)amino]ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - 4-chloro-11.beta.-[4-[2-[butyl(methyl)amino]ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - 4-chloro-11.beta.-[4-[2-[methyl(2-propynyl)amino]ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - 4-chloro-11.beta.-[4-[2-(4-methyl-1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - 4-chloro-11.beta.-[4-[2-(1-piperidinyl)ethylthio]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - 4-chloro-11.beta.-[4-[2-(1-piperidinyl)ethylsulfinyl]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, - acide 4-[4-chloro-11beta-[4-[2-(diethylamino)ethoxy]phenyl] l7beta-hydroxy-estra-1,3,5(10)-trien-3-yl-oxy]-butanoic acid, -oxime 4-chloro-3-hydroxy-11beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-17-one, - 4-[[2-[4-(4-chloro-3,17beta-dihydroxy-estra-1,3,5(10)-trien-11beta-yl)phnoxy]ethyl]ethylamino]-butanoic acid. 7. A compound of formula (I) or (I') as defined in any one of claims 1 to 5, the name of which follows: 4-chloro-11.beta.-[4-[2-(diethylamino)ethoxy]phenyl]-estra-1,3,5 (10)-triene-3,17beta-diol, as well as its addition salts with acids. 8. Process for preparing compounds of general formula (I) as claimed in claims 1 or 2, wherein the compound of general formula (II):   in which: D and R2 have values as defined in claim 1, R7 is one of the following groups:   in which: n, Y, R3 and R4 have values as defined in claim 1, wherein, P is a protection group, Hal is a halogene,  are subjected to an action of halogenation agent to obtain a compound of formula (III):   which is subjected to an action of aromatisation agent of the cycle A, then to an action with the base to  obtain a compound o formula (IV), corresponding to some copmpounds of general formula (I):   wherein the compounds of formulae (I), (III) or (IV), when desired and if necessary, in an appropriate sequence are subjected to one or a plurality of the following reactions: - protection of compounds, in which R7 is a -Ph-YH group, - removal of the protection groups in compounds, in which R7 is a -Ph-YH group, - action by the compound of fo