8β-hydrocarbyl-substituted estratrienes for use as selective estrogens

A method for

• in-vitro treatment of male infertility;
• in-vivo treatment of male infertility;
• in-vitro treatment of female infertility;
• in-vivo treatment of female infertility;
• hormone replacement therapy in a patient in need of replacement of estrogen;
• therapy of osteoporosis;
• treatment of arteriosclerosis:
• or treatment of benign prostate hyperplasia;
• comprising administering to a subject in need thereof an effective amount of an 8β-substituted estra-1,3,5(10)-triene compound of formula I′
• in which
• R2 means a hydrogen atom, a halogen atom;
• a radical R18— or R18—O—, in which R18 means a hydrogen atom or a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 6 carbon atoms or, a trifluoromethyl group;
• a group R19SO2—O—, in which R19 is an R20R21N, in which R20 and R21, independently of one another, mean a hydrogen atom, a C1-C5-alkyl radical, a group C(O)R22, in which R22 represents an optionally substituted, straight-chain or branched-chain, saturated or unsaturated in up to three places, an optionally partially or completely halogenated hydrocarbon radical with up to 10 carbon atoms, an optionally substituted C3-C7-cycloalkyl radical, an optionally substituted C4-C15-cycloalkylalkyl radical or an optionally substituted aryl, heteroaryl or aralkyl radical, or R20R21N means a polymethylenimino radical with 4 to 6 C atoms or a morpholino radical;
• R3 means a group R18′—O—, R19SO2—O— or —O—C(O)R22, in which R18′ is a atom or a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 6 carbon atoms, a trifluoromethyl group, or an aryl heteroaryl or aralkyl radical;
• R6 and R7 each mean a hydrogen atom or together an additional bond;
• R6′ and R7′, are each independently a hydrogen atom, a halogen atom, a group R18—O—, R19SO2—O— or —R22;
• R8 means a branched-chain, optionally partially or completely halogenated alkyl radical with up to 5 carbon atoms, or a straight chain or branched chain, optionally partially or completely halogenated alkenyl radical with up to 5 carbon atoms, an
• R9 means a hydrogen atom, a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 5 carbon atoms, or together with R11 means an additional bond;
• R11 means a hydrogen atom or together with R9 or together with R12 means an additional bond;
• R11′ means a hydrogen atom, a halogen atom, a saturated or unsaturated, optionally partially or completely halogenated (F, Cl) hydrocarbon radical, which has a maximum linear chain length of 4 carbon atoms, or a group —X—R18″, in which X is an oxygen or sulfur atom, and R18″ is an alkyl radical with 1 to 3 carbon atoms;
• R12 means a hydrogen atom or together with R11 means an additional bond;
• R14 means a hydrogen atom or together with R15 means an additional bond;
• R15 means a hydrogen atom or together with R14 or together with R16 means an additional bond;
• R16 means a hydrogen atom or together with R15 means an additional bond;
• R15′ and R16′, independently of one another, mean a hydrogen atom, a halogen atom, a group R18—O—, R19SO2—O— or —R22;
• R17 and R17′ each mean a hydrogen atom and a halogen atom;
• a hydrogen atom and a benzyloxy group;
• a hydrogen atom and a group R19SO2—O—;
• a group R18 and a group —C(O)R22 or —O—C(O)R22;
• a group R18—O— and a group R18—;
• a group R18—O— and a group —O—C(O)R22;
• or
• R17 and R17′ together mean a group ═CR23R24, in which R23 and R24, independently of one another, represent a hydrogen atom and a halogen atom, or together an oxygen atom,
• wherein said administration of the compound of formula I′ achieves a selective effect on estrogen receptor beta.

A method according for the treatment of hot flashes, sleep disturbances, irritability mood swings, incontinence, or vaginal atrophy comprising administering to a subject in need thereof an effective amount of an 8β-substituted estra-1,3,5(10)-triene compound of formula I′

• in which
• R2 means a hydrogen atom, a halogen atom;
• a radical R18 or R18—O—, in which R18 means a hydrogen atom or a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 6 carbon atoms or, a trifluoromethyl group;
• a group R19SO2—O—, in which R19 is an R20R21N, in which R20 and R21, independently of one another, mean a hydrogen atom, a C1-C5-alkyl radical, a group C(O)R22, in which R22 represents an optionally substituted, straight-chain or branched-chain, saturated or unsaturated in up to three places, an optionally partially or completely halogenated hydrocarbon radical with up to 10 carbon atoms, an optionally substituted C3-C7-cycloalkyl radical, an optionally substituted C4-C15-cycloalkylalkyl radical or an optionally substituted aryl, heteroaryl or aralkyl radical, or R20R21N means a polymethylenimino radical with 4 to 6 C atoms or a morpholino radical;
• R3 means a group R18′—O—, R19SO2—O— or —O—C(O)R22, in which R18′ is a hydrogen atom or a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 6 carbon atoms, a trifluoromethyl group, or an aryl, heteroaryl or aralkyl radical;
• R6 and R7 each mean a hydrogen atom or together an additional bond;
• R6′ and R7′, are each independently a hydrogen atom, a halogen atom, a group R18—O—, R19SO2—O— or —R22;
• R8 means a branched-chain, optionally partially or completely halogenated alkyl radical with up to 5 carbon atoms, or a straight chain or branched chain, optionally partially or completely halogenated alkenyl radical with up to 5 carbon atoms, an ethinyl or pro-1-inyl radical;
• R9 means a hydrogen atom, a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 5 carbon atoms, or together with R11 means an additional bond;
• R11 means a hydrogen atom or together with R9 or together with R12 means an additional bond;
• R11′ means a hydrogen atom, a halogen atom, a saturated or unsaturated, optionally partially or completely halogenated (F, Cl) hydrocarbon radical, which has a maximum linear chain length of 4 carbon atoms, or group —X—R18″, in which X is an oxygen or sulfur atom, and R18″ is an alkyl radical with 1 to 3 carbon atoms;
• R12 means a hydrogen atom or together with R11 means an additional bond;
• R14 means a hydrogen atom or together with R15 means an additional bond;
• R15 means a hydrogen atom or together with R14 or together with R16 means an additional bond;
• R16 means a hydrogen atom or together with R15 mean an additional bond;
• R15′ and R16′, independently of one another, mean a hydrogen atom, a halogen atom, a group R18—O—, R19SO2—O— or —R22;
• R17 and R17′ each mean a hydrogen atom;
• a hydrogen atom and a halogen atom;
• a hydrogen atom and an benzyloxy group;
• a hydrogen atom and a group R19SO2O—;
• a group R18 and a group —C(O)R22 or —O—C(O)R22;
• a group R18—O— and a group R18—;
• a group R18—O— and a group —O—C(O)R22;
• or
• R17 and R17′ together a group ═CR23 R24, in which R23 and R24, independently of one another, represent a hydrogen atom and a halogen atom, or together an oxygen atom,
• wherein said administration of the compound of formula I′ achieves a selective effect on estrogen receptor beta.

A compound having partial formula II or II′

• in which R8 represents a straight-chain or branched-chain, optionally partially or completely halogenated alkyl or alkenyl radical with up to 5 carbon atoms, or an ethinyl- or prop-1-inyl radical, and in addition to the aromatic A-ring, one or more double bonds can be present in the B-, C- and/or D-ring in positions 6(7);
• 9(11);
• 11(12);
• 14(15) and 15(16), and substituents at carbon atoms 6, 7, 11, 15, 16 and 17 can be respectively in α- or β-position.