Patent EA-003133-B1 (EA)
Title: NOVEL 19-NOR STEROIDS SUBSTITUTED IN POSITION 11beta, PREPARATION METHOD AND INTERMEDIATES, APPLICATION AS MEDICINES AND PHARMACEUTICAL CONTAINING THEM
Inventor: NIQUE FRANCOIS
IPC: C07J43/00
Filed: 1998-11-16
Abstract: 1. A compound of general formula (I) wherein R1 is hydrogen atom or radical acyl, R2 is radical (C1-C4) alkyl X is halogen atom or hydrogen atom, n is an integer from 3,4 or 5, R3 and R4 are (C1-C4) alkyl, and R3 and R4 forms together with the linked nitrogen atom, a group of pyrrolidinyl or piperidinyl. R5 means OH and R6 means H, (C1-C4) alkyl, optionally substituted with 1 or 3 halogen atoms, or R5 and R6 form together with carbon, they are linked with, furanyl or dihydrofuranyl group, forming together oxogroup, and pharmaceutically acceptable acid addition salts. 2. A compound of formula (I') according to claim 1, wherein X' means chlorine, bromine or hydrogen, n' is 3, R'3, R'4, R'5 and R'6 have values, indicated in claim 1 for R3, R4, R5 and R6 and pharmaceutically acceptable acid addition salts. 3. Compounds according to claim 1 or 2, where X is chlorine. 4. Compounds according to any of claims 1-3, where X is hydrogen. 5. Compounds of formula (I) or (I') according to any of claims 1-4 which are brought below; 3-hydroxy-11(-[4-[3-(1-piperidinyl)propyl]phenyl]-estra-1,3,5 (10)-trien-17-one; 3-hydroxy-11(-[4-[3-(1-pyrrolidinyl)propyl]phenyl-estra-1,3,5 (10)-trien-17-one; 3-hydroxy-11(-[4-[3-(diethylamino)propyl]phenyl]-estra-1,3,5( 10)-trien-17-one; 4-chloro-3-hydroxy-11(-[4-[3-(1- piperidinyl)propyl]phenyl]-estra-1,3,5(10)-trien-17-one; 4-chloro-3-hydroxy-11(-[4-[3(1-pyrrolidinyl)propyl]phenyl]-estra-1,3,5(10)-trien- 17-one; 11(-[4-[3-( pyrrolidinyl)propyl]phenyl]-estra-1,3,5(10)-trien-3,17(-diol; 11(-[4-[3-( dimethylamino)propyl]phenyl]-estra-1,3,5(10)-trien-3,17(-diol; 11(-4-[3-(1-piperidinyl)propyl]phenyl]-estra -1,3,5(10)-trien-3-17(-diol; 4-chloro-11(-[4-[3-(1-pyrrolidinyl)propyl]phenyl]-estra-1,3,5(10)-trie n-3,17(-diol; 4-chloro-11(-[4-[3(piperidinyl)propyl]phenyl]-estra-1,3,5(10)-trien-3, 17(-diol; 11(-4-[3-(1-piperidinyl)propyl]phenyl]-estra -1,3,5(10)-trien-3-17(-diol; 4-chloro-11(-[4-[3-(diethylamino)propyl]phenyl]-estra-1,3,5(10)-trien- 3,17(-diol; 17(-methyl-11(-4-[3-(1-piperidinyl)propyl]phenyl]-estra -1,3,5(10)-trien-3-17(-diol; 4-chloro-17(-methyl-11(-4-[3-(1-piperidinyl)propyl]phenyl]-estra -1,3,5(10)-trien-3-17(-diol; (17R)-11(-[4-[3-(diethylamino)propyl]phenyl] spiro (estra-1,3,5(10)-trien- 17,2' (5'H) - furan)- 3-ol; (17R)-4',5'-dihydro-11(4-[3-(diethylamino)propyl]phenyl] spiro (estra-1,3,5(10)-trien- 17,2' (5'H)-furan)-3-ol; 6. A method of preparation of compounds of formula (I) according to claim 1, wherein a compound of formula (II): where R2, R5, and R6 have values indicated in claim 1, and K means protecting group for a functional 3-ketogroup, is subjected to the following reactions: a) reaction of compound of formula (III): wherein P means a protecting group for a functional alcoholic group and n is an integer, equal to 3, 4 or 5, after by request, removing of protecting groups from one or several protected reactive functional groups, to obtain a compound of formula (IIIa): wherein P' has the same values as P, and is also hydrogen; b) reaction, by request, of halogenating agent, to obtain a compound of formula (IIIb): wherein Hal is halogen atom; c) reaction of aromatizing agent of (A) cycle with the compounds of formulas (IIIa) and (IIIb), if desirable, after protection or activation of functional group OH, then reaction with base, to obtain the compounds of formula (IV): wherein P'' has the same values as P', and can be in addition an activating group; X has the values indicated in claim 1; d) reaction of amine of formula (V) where R3 and R4 have the values indicated in claim 1, compound being able to be as a salt, to obtain some compounds of formula (I), compounds of formulas (IIIa), (IIIb), (IV) and (I) if necessary in corresponding order being subjected to one or several reactions: - introduction/removing of protecting groups in case of OH group or groups; - alkylation/acylation of OH group or groups; - reacting of reducing agent, when R3 and R6 form together an oxogroup; - reacting of organometallic compound or compound CF3SiMe3 on compounds of formula (IV) or (I), wherein R5 and R6 form together an oxogroup; - reacting of reducing agent of double bond when R5 and R6 form furanyl together with carbon atom, they are linked with; - reacting of lactonization agent on compounds of formulas (IV), or (I) where R5 and R6 form together an oxogroup. - salification. 7. The use of compounds of formulas (I) according to claim 1, and pharmaceutically acceptable acid and base addition salts thereof. 8. The use of compounds of formulas (I) or (I') according to any of claims 2-5, and pharmaceutically acceptable acid and base addition salts, as a drug. 9. The use of compounds according to claim 5, and pharmaceutically acceptable acid and base addition salts. 10. Pharmaceutical compositions, comprising one or several compounds according to any of claims 1-5. 11. Compounds of general formulas (IIIa), (IIIb), (IV) according to claim 6 as an intermediate products.