Patent EA-002623-B1 (EA)
Title: 11beta-HALOGEN-7alpha-SUBSTITUTED ESTRATRIENS, METHOD FOR PRODUCING PHARMACEUTICAL PREPARATIONS CONTAINING SAID 11beta-HALOGEN-7alpha-SUBSTITUTED ESTRATRIENS AND USE OF THE SAME FOR PRODUCING MEDICAMENTS
Inventor: BOLHMANN ROLF
IPC: C07J43/00
Filed: 1998-12-23
Abstract: 1. 11β-halogen-7α-substituted estratrienes of general formula I   wherein R<3> is hydrogen atom, hydrocarbon residue with the number of carbon atoms up to 8 inclusively or the residuum of subformula R<3>'-C(O)-, wherein R<3> is a hydrogen atom or hydrocarbon residue with the number of carbon atoms up to 8 inclusively or the phenyl residuum, R<7> is the residuum of formula -A-B-Z-R<20>, wherein A is direct bond or is benzylidene residue, and methylene group is bound with steroid's carbon atom in 7 position or is a phenylene residue, B is direct-chained or branched alkylene, alkenylene or alkinylene group with 3 to 14 carbon atoms, and Z is -NR<21>-, wherein R<21> is C1-C3alkyl group, and R<20> is hydrogen atom, direct-chained or branched alkyl, alkenyl or alkinyl group with the number of carbon atoms up to 10 inclusively or is one of the following groupings: -D-CnF2n+1, wherein D is direct-chained or branched alkylene, alkenylene or alkinylene group with up to 8 carbon atoms inclusively, and n is an integer 1 to 8, -L-CH=CF-CpF2p+l, wherein L is direct-chained or branched alkylene, alkenylene or alkinylene group with 2 to 7 carbon atoms, and p is integer from 2 to 7, -D-O-(CH2)q-aryl, wherein D has above-mentioned meanings, q is 0, 1, 2 or 3 and aryl is optionally mono- or disubstituted phenyl-, 1- or 2-naphthyl or heteroaryl residue, -D-O-(CH2)r-CnF2n+1, wherein D and n have the above-mentioned meanings, and r is an integer from 1 to 5, or R<20> and R<21> together with nitrogen atom, to which they are attached form saturated or unsaturated heterocycle with 5 or 6 chain members which optionally comprises one or two heteroatoms more, selected from the group, comprising nitrogen, oxygen and sulfur, and which is also optionally substituted, or Z is -SOx- wherein x is 0, 1 or 2, in this case R<20> is direct-chained or branched alkyl, alkenyl or alkinyl group with the number of carbon atoms up to 10 inclusively or is one of the following groupings: -D-CnF2n+1, wherein D is direct-chained or branched alkylene, alkenylene or alkinylene group with up to 8 carbon atoms inclusively, and n is an integer 1 to 8, -L-CH=CF-CpF2p+l, wherein L is direct-chained or branched alkylene, alkenylene or alkinylene group with 2 to 7 carbon atoms, and p is integer from 2 to 7, -D-O-(CH2)q-aryl, wherein D has above-mentioned meanings, q is 0, 1, 2 or 3 and aryl is optionally mono- or disubstituted phenyl-, 1- or 2-naphthyl- or heteroaryl residue, -D-O-(CH2)r-CnF2n+1, wherein D and n have the above-mentioned meanings, and r is an integer from 1 to 5, or Z is -NR<31>-, in this case R<20> is direct-chained or branched alkyl, alkenyl or alkinyl residue with the number of carbon atoms up to 14 inclusively which can be interrupted with one-three heteroatoms -O- and -S- and groupings -NR<32>-, wherein R<32> is hydrogen atom or C1-C3alkyl residue, and/or may be partly fluoridized, or is optionally mono- or disubstituted aryl or heteroaryl residue, optionally mono- or disubstituted C3-C10cycloalkyl residue, optionally mono- or disubstituted C4-C15cycloalkylalkyl residue , optionally mono- or disubstituted C7-C20aralkyl residue, optionally mono- or disubstituted heteroaryl-C1-C6alkyl residue or optionally substituted aminoalkyl residue, and R<31> is residuum of formula -C(O)R<33> or -CH2-R<33>, wherein R<33> is direct-chained or branched alkyl, alkenyl or alkinyl group with the number of carbon atoms up to 14 inclusively, which can be interrupted with one-three heteroatoms -O- and -S- and groupings -NR<32>-, wherein R<32> is hydrogen atom or is C1-C3alkyl residue, and/or may be partly fluoridized, or is optionally mono- or disubstituted aryl or heteroaryl residue, optionally mono- or disubstituted C3-C10cycloalkyl residue , optionally mono- or disubstituted C4-C15cycloalkylalkyl residue , optionally mono- or disubstituted C7-C20aralkyl residue, optionally mono- or disubstituted heteroaryl-C1-C6alkyl residue or optionally substituted aminoalkyl residue or biphenylen residue, with exception of the following compounds: 11β-fluoro-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}estra-1,3,5(10)trien-3,17β-diol; 11β-fluoro-7α-{5-[2-(4,4,5,5,5-pentafluoropentylthiomethyl)pyrrolidin-1-yl]pentyl}estra-1,3,5(10)trien-3,17β-diol; 11β-fluoro-7α-{6-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]hexyl}estra-1,3,5(10)trien-3,17β-diol; 11β-fluoro-7α-{5-[(2S)-2-(4-trifluoromethylphenylthiomethyl)pyrrolidin-1-yl]pentyl}estra-1,3,5(10)trien-3,17β-diol; 11β-fluoro-7α-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)pyrrolidin-1-yl]pentyl}estra-1,3,5(10)trien-3,17β-diol; 11β-fluoro-7α-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentansulfinylmethyl)pyrrolidin-1-yl]pentyl}estra-1,3,5(10)trien-3,17β-diol; 11β-fluoro-7α-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentansulfonylmethyl)pyrrolidin-1-yl]pentyl}estra-1,3,5(10)trien-3,17β-diol, R<11> is fluoro or chloro, R<17> is hydrogen atom or R<17'>-C(O)- subformula residuum, wherein R<17'> is hydrogen atom or hydrocarbon residue with up to 8 carbon atoms inclusively. 2. 11β-halogen-7α-substituted estratrienes as claimed in Claim 1, wherein R<3> is hydrogen atom. 3. 11β-halogen-7α-substituted estratrienes as claimed in Claim 1, wherein R<3> is benzoyl residue. 4. 11β-halogen-7α-substituted estratrienes as claimed in Claim 1, wherein R<11> is fluorine atom. 5. 11β-halogen-7α-substituted estratrienes as claimed in Claim 1, wherein R<17> is hydrogen atom. 6. 11β-halogen-7α-substituted estratrienes as claimed in Claim 1, wherein A is direct bond. 7. 11β-halogen-7α-substituted estratrienes as claimed in Claim 6, wherein R<7> is a residuum of formula -(CH2)s-Z-R<20>, wherein s is integer 3-8, Z is -NR<21>, wherein R<21> is C1-C3alkyl group, R<20> is hydrogen atom, C1-C9alkyl group , or one of the following groupings: -(CH2)m-CnF2n+1, wherein m and n each independently is integer 1 to 8, -(CH2)o-CH=CF-CpF2p+1, wherein o is 1, 2 or 3 and p is integer 2 to 7, -(CH2)m-O-(CH2)q-aryl, wherein m has above-mentioned meanings, q is 0, 1, 2 or 3 and aryl is optionally mono- or disubstituted phenyl or heteroaryl residue, -(CH2)m-O-(CH2)r-CnF2n+l, wherein m and n have above-mentioned meanings, and r is integer 1 to 5. 8. 11β-halogen-7α-substituted estratrienes as claimed in Claim 6, wherein R<7> is a residuum of formula -(CH2)s-Z-R<20>, wherein s is integer 3-8, Z is -NR<21>, wherein R<21> is C1-C3alkyl group, R<20> and R<21 >together with< >nitrogen atom, to which they are attached form saturated or unsaturated heterocycle with 5 or 6 chain members which optionally comprises one or two heteroatoms more, selected from the group, comprising nitrogen, oxygen and sulfur, and which is also optionally substituted. 9. 11β-halogen-7α-substituted estratrienes as claimed in Claim 6, wherein R<7> is a residuum of formula -(CH2)s-Z-R<20>, wherein s is integer 3-8, Z is -SOx- and x is 0, 1 or 2, R<20> is - (CH2)m-O-(CH2)r-CnF2n+1, wherein m and n have above-mentioned meanings, and r is integer 1 to 5. 10 11β-halogen-7α-substituted estratrienes as claimed in Claim 1, wherein R<7> is selected from the group, comprising the following side chains: -(CH2)5N(CH3)(CH2)3C2F5, -(CH2)5N(CH3)(CH2)6C2F5, -(CH2)5N(CH3)(CH2)7C2F5, -(CH2)5N(CH3)(CH2)8C2F5, -(CH2)6N(CH3)(CH2)6C2F5, -(CH2)6N(CH3)(CH2)7C2F5, -(CH2)6N(CH3)(CH2)8C2F5, -(CH2)5N(CH3)(CH2)2C4F9, -(CH2)5N(CH3)(CH2)3C6F13, -(CH2)5N(CH3)(CH2)3C8F17, -(CH2)5N(CH3)(CH2)6C4F9, -(CH2)5N(CH3)(CH2)6C6F13, -(CH2)5N(CH3)(CH2)6C8F17, -(CH2)5N(CH3)H, -(CH2)5N(CH3)(CH2)9H, -(CH2)5N(CH3)CH2CH=CF-C2F5, -(CH2)5N(CH3)CH2CH=CF-C3F7, -(CH2)5N(CH3)CH2CH=CF-C5F11, -(CH2)5N(CH3)CH2CH=CF-C7F15, -(CH2)5-1-pyrrolidinyl, -(CH2)5N(CH3)(CH2)3Ophenyl, -(CH2)5N(CH3)(CH2)3Obenzyl, -(CH2)5N(CH3)(CH2)3O(CH2)3C2F5, -(CH2)9S(CH2)3C2F5, -(CH2)9SO(CH2)3C2F5, -(CH2)9SO2(CH2)3C2F5, -(CH2)5N(CH3)(CH2)3CH(CH3)2, -(CH2)5N(CH3)(CH2)3-pyridyl, -(CH2)5N(CH3)(CH2)3-phenyl, -(CH2)5N(CH3)(CH2)2-p-tolyl, -(CH2)5N(CH3)(CH2)2-p-ethoxyphenyl, -(CH2)5N(CH3)(CH2)3-p-tolyl, -(CH2)5N(CH3)(CH2)3-p-chlorophenyl,  -(CH2)5N(CH3)(CH2)3-O-CH2-phenyl, -(CH2)5N(CH3)(CH2)2-O-p-Br-phenyl, -(CH2)5N(CH3)(CH2)2-O-p-CF3-phenyl. 11. The compounds of general formula I, namely: 11β-fluoro-7α-{5-[methyl-(8,8,9,9,9-pentafluorononyl)amino]pentyl}estra-1,3,5(10)-trien-3,17β-diol, 11β-fluoro-7α-{5-[methylnonylamino]pentyl}estra-1,3,5(10)-trien-3,17β-diol; 11β-fluoro-7α-{5-[methyl-(9,9,10,10,10-pentafluorodecyl)amino]pentyl}estra-1,3,5(10)trien-3,17β-diol; 11β-fluoro-7α-{6-[methyl-(8,8,9,9,9-pentafluorononyl)amino]hexyl}estra-1,3,5(10)-trien-3,17β-diol; 11β-fluoro-7α-{6-[methyl-(9,9,10,10,10-pentafluorodecyl)amino]hexyl}estra-1,3,5(10)-trien-3,17β-diol; 11β-fluoro-7α-(5-(methylamino)pentyl)estra-1,3,5(10)-trien-3,17β-diol; 11β-fluoro-7α-(5-pyrrolidin-1-ylpentyl)estra-1,3,5-(10)-trien-3,17β-diol; 11β-fluoro-7α-{5-[methyl-(4,4,5,5,5-pentafluoropentyl)amino]pentyl}estra-1,3,5(10)-trien-3,17β-diol; 11β-fluoro-7α-{5-[methyl-(4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluorononyl)amino]pentyl}estra-1,3,5(10)-trien-3,17β-diol; 11β-fluoro-7α-{5-[(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoroandecyl)methylamino]pentyl}estra-1,3,5(10)-trien-3,17β-diol; 11β-fluoro-7α-{5-[methyl-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)amino]pentyl}estra-1,3,5(10)-trien-3,17β-diol; 11β-fluoro-7α-{5-[methyl-(7,7,8,8,8-pentafluorooctyl)amino]pentyl}estra-1,3,5(10)-trien-3,17β-diol; 11β-fluoro-7α-{6-[methyl-(7,7,8,8,8-pentafluorooctyl)amino]hexyl}estra-1,3,5(10)-trien-3,17β-diol; 11β-fluoro-7α-{5-[methyl-(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}estra-1,3,5(10)-trien