Patent EA-003325-B1 (EA)
Title: Novel 17-haligenated 19-nor steroids, method and intermediates for preparing same, use as medicines and pharmaceutical compositions containing same
Inventor: BOUALI YASMINA
IPC: C07J41/00
Filed: 1999-06-22
Abstract: 1. Compound of general formula (I): in which: R1 represents a carbon atom, methyl, ethyl, COCH3, COEt, COPh, or CH2Ph, R2 represents methyl, X represents a halogen atom, Y represents a simple bond, O, NH, S, SO or SO2, Z represents a hydrogen atom or a halogen atom, n is 2, 3, 4 or 5, or R3 and R4, identical or different, represent a hydrogen atom or an alkyl having 1 to 6 carbon atoms, or R3 and R4 form together with a nitrogen atom with which they are bonded one of the following heterocycles: unsubstituted or substituted by methyl, the dotted lines represent optionally a second bond and addition salts thereof with bases and acids. 2. The compounds of general formula (I) according to claim 1 and the addition salts thereof, in which X is a fluorine atom in the alpha position and the dotted lines are not a second bond. 3. The compounds of general formula (I) according to claim 1 or 2 and the addition salts thereof, in which R1 represents a hydrogen atom, R2 represents methyl and Z represents either an hydrogen atom or a chlorine atom, Y represents an oxygen atom, and the dotted lines are not a second bond. 4. The compounds of general formula (I) according to claims 1 to 3 and the addition salts thereof, in which X is a fluorine atom in the alpha position, R1 represents a hydrogen atom, R2 represents methyl Y represents an oxygen atom, Z represents either an hydrogen atom or a chlorine atom, n is 2 or 3, or R3 and R4, identical or different, represent a hydrogen atom or an alkyl radical having 1 to 6 carbon atoms, or R3 and R4 form together with a nitrogen atom with which they are bonded one of the following heterocycles: the dotted lines are not a second bond. 5. A compound of claim 1 selected from the group consisting of: 17-alpha-fluoro-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol, 17-alpha-fluoro-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol hydcrochloride, 17-alpha-fluoro-11-beta-[4-[2-(1-diethylamino)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol, 17-alpha-fluoro-11-beta-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol, 4-chloro-17-alpha-fluoro-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-3-ol, 17-iodo-11-beta-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10),16-tetraen-3-ol, 17-alpha-fluoro-11-beta-[4-[2-(4-methyl-1-piperidinyl)ethoxy]-phenyl]-estra-1,3,5(10)-trien-3-ol, 17-alpha-fluoro-11-beta-[4-[2-(4-methyl-1-piperidinyl)ethoxy]-phenyl]-estra-1,3,5(10)-trien-3-ol hydrochloride, 17-alpha-fluoro-3-methoxy-11-beta-[4-[2-(1-piperidinyl)ethoxy]-phenyl]-estra-1,3,5(10)-triene, 17-alpha-fluoro-3-methoxy-11-beta-[4-[2-(1-pyrrolidinyl)ethoxy]-phenyl]-estra-1,3,5(10)-triene, 17-alpha-fluoro-3-methoxy-1-beta-[4-[2-(diethylamino)ethoxy]-phenyl]-estra-1,3,5(10)-triene, (11-beta)-17-chloro-11-[4-[2-(1-piperidinyl)ethoxy]-phenyl]-estra-1,3,5(10),16-tetraen-3-ol, 17-alpha-chloro-11-beta-[4-[2-(1-piperidinyl)ethoxy]-phenyl]-estra-1,3,5(10)-trien-3-ol, 17-iodo-11beta-[4-[2-(1-piperidinyl)ethoxy]-phenyl]-estra-1,3,5(10),16-tetraen-3-ol hydrochloride, 17-alpha-fluoro-11beta-(4-(2-(1-piperidinyl)ethoxy]-phenyl]-estra-1,3,5(10)-trien-3-ol lactate. 6. A method for preparing compounds of general formula (I) as defined in claim 1, wherein the compound of formula (II) in which R2 and Z are as defined in claim 1, RA represents one of the following groups: in which Y, n, R3 and R4 are as defined in claim 1, and Hal represents a halogen atom are subjected after possible protection and/or activation of hydroxyl groups to an action of a) an agent reducing a keto group in position 17 to obtain a compound of formula (IIIa): b) then a halogenation agent to obtain a compound of formula of (I'a) : corresponding to certain compounds of formula (I), when RA represents -Ph-Y-(CH2)n-NR3R4, wherein the compounds of formulae (II), (IIIa) and (I'a) protected or not are subjected, if desire or necessary, to one or plurality of the following reactions: - deprotection of the protected hydroxyl group(s), - acylation/alkylation of the protected hydroxyl group(s), - action to HN3R4, optionally in the form of a salt, if RA represents -Ph-Y-(CH2)n-Hal or an activated group -Ph-Y-(CH2)n-OH, - salification. 7. A method for preparing compounds of general formula (I) as defined in claim 1, wherein the compound of formula (II) in which R2 and Z are as defined in claim 1, RA represents one of the following groups: in which Y, n, R3 and R4 are as defined in claim 1, and Hal represents a halogen atom are subjected after possible protection and/or activation of hydroxyl groups to an action of a) hydrazine to obtain a compound of formula (IIIb): b) then a halogenation agent to obtain a compound of formula of (I'b) : corresponding to certain compounds of formula (I), when RA represents -Ph-Y-(CH2)n-NR3R4, wherein the compounds of formulae (II), (IIIa) and (I'b) protected or not are subjected, if desire or necessary, to one or plurality of the following reactions: - deprotection of the protected hydroxyl group(s), - acylation/alkylation of the protected hydroxyl group(s), - action to HNR3R4, optionally in the form of a salt, if RA represents -Ph-Y-(CH2)n-Hal or an activated group -Ph-Y-(CH2)n-OH, - salification. 8. The method according to claim 6 or 7 of general formula (I) as defined in claim 2, in which X represents a fluorine atom in the 17 alpha position, and dotted lines are not a second bond, wherein the halogenation agent represents -perfluoro 1-butane sulfonylflouride (FSO2C4F9). 9. Use of the compounds of general formula (I) according to claim 1, or pharmaceutically acceptable addition salts thereof with acids or bases as medicaments. 10. Use of the compounds of general formula (I) according to any one of claims 2 to 4, or pharmaceutically acceptable addition salts thereof with acids as medicaments. 11. Use of the compounds according to claim 5, or pharmaceutically acceptable addition salts with acids as medicaments. 12. Pharmaceutical compositions, comprising one or a plurality of compounds according to any one of claims 1 to 5, or pharmaceutically acceptable addition salts thereof with acids and bases as medicaments. 13. Compounds of general formula (I'a) or (I'b) as defined in claim 6 or 7 as intermediates. 14. Compounds of general formula (IIIb) as defined in claim 7 as intermediates. 15. Use of the compounds of formula (I) according to claims 1 to 5 for preparing a medicament of hormone replacement for treating menopause or perimenopause with low estrogen activity or without activity at the uterine level. 16. Use according to claim 15, wherein the medicament for treating or prophylaxis osteoporosis. 17. A medicament comprising at least one compound according to claim 5 for treating or prophylaxis osteoporosis. 18. A medicament comprising at least one compound according to claim 5 to strengthen cardiovascular protection.