Claims
- 1. An 11.beta.-aryl-4-estrene of formula I having progesterone antagonist activity ##STR18## wherein X is an oxygen atom, the hydroxyimino grouping >N.about.OH or two hydrogen atoms,
- R.sup.1 is hydrogen or a methyl group,
- R.sup.2 is a hydroxy group, a C.sub.1 -C.sub.10 alkoxy or C.sub.1 -C.sub.10 alkanoyloxy group,
- R.sup.3 is hydrogen, 1-propinyl, 2-propenyl, the grouping (--CH.sub.2).sub.n CH.sub.2 Z, wherein
- n is 0, 1, 2, 3, 4 or 5,
- Z is hydrogen, cyano or the radical --OR.sup.5, wherein R.sup.5 is H, C.sub.1 -C.sub.10 alkyl or C.sub.1 -C.sub.10 alkanoyl,
- the grouping --(CH.sub.2).sub.m C.tbd.C--Y, wherein
- m is 0, 1 or 2 and
- Y is hydrogen, fluorine, chlorine, bromine or iodine atom; or a C.sub.1 -C.sub.10 hydroxyalkyl, C.sub.1 -C.sub.10 alkoxyalkyl, or C.sub.1 -C.sub.10 alkanoyloxyalkyl radical, the grouping --(CH.sub.2).sub.p --CH.dbd.CH--(CH.sub.2).sub.k CH.sub.2 R.sup.6,
- wherein
- p is 0 or 1,
- k is 0, 1 or 2, and
- R.sup.6 means a hydrogen atom, a hydroxy group, a C.sub.1 -C.sub.4 alkoxy or C.sub.1 -C.sub.4 alkanoyloxy radical,
- or else R.sup.2 and R.sup.3 together stand for a radical of the formula ##STR19## wherein x=1 or 2, R.sup.4 is hydrogen; cyano; chlorine; fluorine; bromine; iodine; trialkylsilyl; trialkylstannyl; a straight-chain or branched, saturated or unsaturated C.sub.1-8 hydrocarbyl, C.sub.1-8 alkanoyl or C.sub.1-8 alkoxyalkyl radical; an amino group ##STR20## in which R.sup.7 and R.sup.8, each independently of one another, is hydrogen or a C.sub.1 -C.sub.4 alkyl group;
- a corresponding amine oxide ##STR21## a grouping --OR.sup.9 or --S(O).sub.i R.sup.9, wherein i is 0, 1 or 2,
- R.sup.9 means hydrogen, a methyl, ethyl, propyl, isopropyl, methoxyphenyl, allyl or a 2-dimethylaminoethyl group;
- a heteroaryl radical for the formula I.alpha. ##STR22## wherein A is a nitrogen, oxygen or sulfur atom,
- --B--D--E-- is the element sequence --C--C--C--, --N--C--C-- or --C--N--C--, and
- R.sup.10 is hydrogen; cyano; chlorine; fluorine; bromine; iodine;
- trialkylsilyl; trialkylstannyl; a straight-chain or branched, saturated or unsaturated C.sub.1-8 hydrocarbyl, C.sub.1-8 alkanoyl or C.sub.1-8 alkoxyalkyl radical; an amino group ##STR23## or the radical --OR.sup.9 or --S(O).sub.i R.sup.9, wherein R.sup.7, R.sup.8, R.sup.9 and i each independently has one of the meanings already indicated;
- a heteroaryl radical of formula I.beta. ##STR24## wherein A is a nitrogen atom,
- --B--D--E-- is the element sequence --C--C--C--, --N--C--C--, --C--N--C-- or
- --C--C--N--, and
- R.sub.10 has the meaning already indicated;
- or a phenyl radical of formula I.tau. ##STR25## wherein R.sup.10 has the meaning already indicated, or a pharmacologically compatible addition salt thereof.
- 2. A compound of claim 1, wherein R.sup.3 is 2-propenyl.
- 3. A compound of claim 1, wherein R.sup.3 is 3-hydroxy-1Z-propenyl.
- 4. A compound of claim 1, wherein R.sup.3 is 1-propinyl.
- 5. A compound of claim 1, wherein R.sup.4 is 4-(3-furyl)-phenyl.
- 6. A compound of claim 1, wherein R.sup.4 is 4-(3-pyridinyl)phenyl.
- 7. A compound of claim 1, wherein R.sup.4 is 4-(3-pyridyl)phenyl.
- 8. A compound of claim 1, wherein R.sup.4 is 4-(5-pyrimidinyl)phenyl.
- 9. A compound of claim 1, wherein R.sup.4 is 4-vinylphenyl.
- 10. A compound of claim 1, wherein R.sup.4 is 4-(1-hydroxyethyl)phenyl.
- 11. 11.beta.-�4-(dimethylamino)phenyl!-17.beta.-hydroxy-17.alpha.-(1-propinyl)-4-estren-3-one;
- 11.beta.-(4-acetylphenyl)-17.beta.-hydroxy-4-estren-3-one;
- 11.beta.-(4-acetylphenyl)-17.beta.-hydroxy-17.alpha.-(1-propinyl)-4-estren-3-one;
- 11.beta.-(4-acetylphenyl)-17.beta.-hydroxy-17.alpha.-(3-hydroxy-1Z-propenyl)-4-estren-3-one;
- 11.beta.-�4-(dimethylamino)phenyl!-17.beta.-hydroxy-17.alpha.-(3-hydroxy-1Z-propenyl)-4-estren-3-one;
- 11.beta.-�4-(3-furyl)phenyl!-17.beta.-hydroxy-17.alpha.-(1-propinyl)-4-estren-3-one;
- 11.beta.-�4-(3-furyl)phenyl!-17.beta.-hydroxy-17.alpha.-(3-hydroxy-1Z-propenyl)-4-estren-3-one;
- 11.beta.-�4-(5-pyrimidinyl)phenyl!-17.beta.-hydroxy-17.alpha.-(1-propinyl)-4-estren-3-one;
- 11.beta.-�4-(5-pyrimidinyl)phenyl!-17.beta.-hydroxy-17.alpha.-(3-hydroxy-1Z-propenyl)-4-estrene-3-one;
- 11.beta.-�4-3-pyridyl)phenyl!-17.beta.-(hydroxy-17.alpha.-(1-propinyl)-4-estren-3-one;
- 11.beta.-�4-(3-pyridyl)phenyl!-17.beta.-(hydroxy-17.alpha.-(3-hydroxy-1Z-propenyl)-4-estren-3-one;
- 11.beta.-�4-(4-cyanophenyl)phenyl!-17.beta.-hydroxy-17.alpha.-(1-propinyl)-4-estren-3-one;
- 11.beta.-�4-(4-cyanophenyl)phenyl!-17.beta.-hydroxy-17.alpha.-(3-hydroxy-1Z-propenyl)-4-estren-3-one;
- 11.beta.-(4-vinylphenyl)-17.beta.-hydroxy-17.alpha.-(3-hydroxy-1Z-propenyl)-4-estren-3-one;
- 11.beta.-(4-vinylphenyl)-17.beta.-hydroxy-17.alpha.-(1-propinyl)-4-estren-3-one;
- 11.beta.-�4-(1-hydroxyethyl)phenyl!-17.beta.-hydroxy-17.alpha.-(3-hydroxy-1Z-propenyl)-4-estren-3-one;
- 11.beta.-�4-(1-hydroxyethyl)phenyl!-17.beta.-hydroxy-17.alpha.-(1-propinyl)-4-estren-3-one;
- 11.beta.-�4-(dimethylamino)phenyl!-17.beta.-hydroxy-17.alpha.-methoxymethyl-4-estren-3-one;
- 11.beta.-�4-(dimethylamino)phenyl!-17.beta.-hydroxy-17.alpha.-cyanomethyl-4-estren-3-one;
- (11.beta.,17.beta.)-4',5'-dihydro-11-�4-(dimethylamino)phenyl!-spiro�estr-4-ene-17,2'(3'H)-furan!-3-one;
- (11.beta.,17.beta.)-3',4'-dihydro-11-�4-(dimethylamino)phenyl!-spiro�estr-4-ene-17,2'(5'H)-furan!-3,5'-dione;
- (11.beta.,17.beta.)-11-�4-(dimethylamino)phenyl!spiro�estr-4-ene-17,2'(5'H)-furan!-3-one;
- 11.beta.-�4-(dimethylamino)phenyl!-17.alpha.-(1-propinyl)-4-estren-17.beta.-ol;
- 17.beta.-hydroxy-3-oxo-11.beta.-�4-(3-pyridinyl)phenyl!-4-estren-17.alpha.-acetonitrile;
- (E)-17.beta.-hydroxy-3-(hydroxyimino)-11.beta.-�4-(3-pyridinyl)phenyl!-4-estren-17.alpha.-acetonitrile;
- (Z)-17.beta.-hydroxy-3-(hydroxyimino)-11.beta.-�4-(3-pyridinyl)phenyl!-4-estren-17.alpha.-acetonitrile;
- 17.beta.-hydroxy-17.alpha.-(2-propenyl)-11.beta.-�4-(3-pyridinyl)phenyl!-4-estren-3-one;
- 17.beta.-hydroxy-17.alpha.-(methoxymethyl)-11.beta.-�4-(3-pyridinyl)phenyl!-4-estren-3-one;
- 11.beta.-(4-ethylphenyl)-17.beta.-hydroxy-17.alpha.-(1-propinyl)-4-estren-3-one;
- (Z)-11.beta.-(4-ethylphenyl)-17.beta.-hydroxy-17.alpha.-(3-hydroxy-1-propenyl)-4-estren-3-one;
- (Z)-11.beta.-�4-(2-furanyl)phenyl!-17.beta.-hydroxy-17.alpha.-(3-hydroxyl-1-propenyl)4-estren-3-one;
- 11.beta.-(4-ethylphenyl)-17.beta.-hydroxy-17.alpha.-methyl)-4-estren-3-one;
- (Z)-17.beta.-hydroxy-17.alpha.-(3-hydroxy-1-propenyl)-11.beta.-(4-methylphenyl)-4-estren-3-one; and
- (11.beta.,17.beta.)-11-�4-(5-pyrimidinyl)phenyl!spiro�estr-4-en-17,2'(3'H)-furan!-3-one, each a compound of claim 1.
- 12. 11.beta.-�4-(Dimethylamino)phenyl!-17.beta.-hydroxy-17.alpha.-(3-hydroxy-1Z-propenyl)-4-estren-3-one, a compound of claim 11.
- 13. A compound of claim 1, wherein X is an oxygen atom.
- 14. A compound of claim 1, wherein R.sup.4 is 4-acetylphenyl.
- 15. A compound of claim 1, wherein R.sup.4 is 4-dimethylaminophenyl.
- 16. A compound of claim 1, wherein R.sup.4 is 4-ethylphenyl.
- 17. A compound of claim 1, wherein R.sup.4 is 4-(4-cyanophenyl)phenyl.
- 18. A pharmaceutical preparation comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
- 19. A pharmaceutical preparation comprising a compound of claim 12 and a pharmaceutically acceptable excipient.
- 20. A method of inducing an antigestagenic effect, comprising administering an antigestagenically effective amount of a compound of claim 1.
- 21. A method of inducing abortion, comprising administering an effective amount of a compound of claim 1.
- 22. A method of post-coital birth control, comprising administering an effective amount of a compound of claim 1.
- 23. A method of treating endometriosis, hormonal irregularities, or hormone dependent tumors, comprising administering an effective amount of a compound of claim 1.
- 24. A method of treating disorders caused by an excess of glucocorticoids being present in the body, comprising administering an effective amount of a compound of claim 1.
- 25. A method of claim 24, wherein said disorder is glaucoma or a side effect of glucocorticoid therapy for treatment of a disease.
- 26. A method of claim 25, wherein the disease is Cushing's syndrome, adiposity, arterioschlerosis, hypertension, osteoporosis, diabetes or insomnia.
- 27. A method of inducing an antimineralocorticoid effect, comprising administering an effective amount of a compound of claim 1.
- 28. A method of treating disorders in which reduction of the amount of androgens present in the body is desirable, comprising administering an effective amount of a compound of claim 1.
- 29. A method of claim 28, wherein said disorders are prostate hypertrophy, prostate carcinoma, hirsutism, androgenic alopecia, acne or seborrhea.
- 30. A process for the production of 11.beta.-aryl-4-estrenes of general formula I ##STR26## wherein X is an oxygen atom, the hydroxyimino grouping >N.about.OH or two hydrogen atoms,
- R.sup.1 is hydrogen or a methyl group,
- R.sup.2 is a hydroxy group, a C.sub.1 -C.sub.10 alkoxy or C.sub.1 -C.sub.10 alkanoyloxy group,
- R.sup.3 is hydrogen, the grouping --(CH.sub.2).sub.n CH.sub.2 Z, wherein
- n is 0, 1, 2, 3, 4 or 5,
- Z is hydrogen, cyano or the radical --OR.sup.5 wherein R.sup.5 is H, C.sub.1 -C.sub.10 alkyl or C.sub.1 -C.sub.10 alkanoyl,
- the grouping --(CH.sub.2).sub.m C.tbd.C--Y, wherein
- m is 0, 1 or 2 and
- Y is hydrogen, fluorine, chlorine, bromine or iodine atom,
- a C.sub.1 -C.sub.10 hydroxyalkyl, C.sub.1 -C.sub.10 alkoxyalkyl, C.sub.1 -C.sub.10 alkanoyloxyalkyl, the grouping --(CH.sub.2).sub.p --CH.dbd.CH--(CH.sub.2).sub.k CH.sub.2 R.sup.6, wherein
- p is 0 or 1,
- k is 0, 1 or 2 and
- R.sup.6 means a hydrogen atom, a hydroxy group, a C.sub.1 -C.sub.4 alkoxy or C.sub.1 -C.sub.4 alkanoyloxy radical,
- or else R.sup.2 and R.sup.3 together stand for a radical of the formula ##STR27## wherein x=1 or 2; R.sup.4 is hydrogen; cyano; chlorine; fluorine; bromine; iodine; trialkylsilyl; trialkylstannyl; a straight-chain or branched, saturated or unsaturated C.sub.1-8 hydrocarbyl, C.sub.1-8 alkanoyl or C.sub.1-8 alkoxyalkyl radical; an amino group ##STR28## in which R.sup.7 and R.sup.8, each independently of one another, is hydrogen or a C.sub.1 -C.sub.4 alkyl group;
- a corresponding amine oxide ##STR29## a grouping --OR.sup.9 or --S(O).sub.i R.sup.9, wherein i is 0, 1 or 2,
- R.sup.9 means hydrogen, a methyl, ethyl, propyl, isopropyl, methoxyphenyl, allyl or a 2-dimethylaminoethyl group;
- a heteroaryl radical of the formula I.alpha. ##STR30## wherein A is an nitrogen, oxygen or sulfur atom,
- --B--D--E-- is the element sequence --C--C--C--,
- --N--C--C-- or --C--N--C--, and
- R.sup.10 is hydrogen; cyano; chlorine; fluorine; bromine; iodine; trialkylsilyl; trialkylstannyl; a straight-chain or branched, saturated or unsaturated C.sub.1-8 hydrocarbyl, C.sub.1-8 alkanoyl or C.sub.1-8 alkoxyalkyl radical; an amino group ##STR31## or the radical --OR.sup.9 or --S(O).sub.i R.sup.9, wherein R.sup.7, R.sup.8, R.sup.9, and i each independently having one of the meanings already indicated;
- a heteroaryl radical of formula I.beta. ##STR32## wherein A is a nitrogen atom,
- --B--D--E-- is the element sequence --C--C--C--,
- --N--C--C--, --C--N--C-- or --C--C--N--, and
- R.sup.10 has the meaning already indicated;
- or a phenyl radical of formula I.tau. ##STR33## wherein R.sup.10 has the meaning already indicated, or a pharmacologically compatible addition salt thereof with acid, comprising
- converting by heating in the presence of acid, a compound of general formula II ##STR34## wherein R.sup.1 and R.sup.4 have the meanings indicated in formula I,
- A is for a .beta.-hydroxy group or the radical OR.sup.2 and
- B is for an .alpha.-hydrogen atom, an .alpha.-position radical
- R.sup.3 or
- A and B together are a keto oxygen, into a compound of formula Ia ##STR35## wherein R.sup.1, A and B have the meanings indicated in formula II and R.sup.4' has the same meaning as R.sup.4 in formula I, provided that R.sup.4 is stable under said reaction conditions;
- producing a compound of formula III ##STR36## wherein Z is a keto group protected in the form of a dithioketal, by either
- (1)
- (a) optionally oxidizing the 17-hydroxy group to the 17-keto group in the compound of general formula Ia, if, in said compound Ia, A is a .beta.-hydroxy group and B is an .alpha.-hydrogen atom,
- b) converting the 3-keto group into a dithioketal, and all other optionally present keto groups are also ketalized, or else first b) and then a) are performed,
- c) when R.sup.4' in the 3-thioketalized compound stands for a methoxy or a hydroxy group and R.sup.4 in the finally desired compound of general formula I is not a methoxy or hydroxy group, converting the hydroxy compound, optionally after cleavage of the methoxy compound, into a corresponding perfluoroalkyl sulfonic acid compound, wherein -alkyl- is a C.sub.1 -C.sub.4 alkyl radical, and from the latter either
- directly by reaction with a corresponding substituted tin(trialkyl) compound R.sup.4" --Sn(alkyl).sub.3, or with a corresponding substituted boron compound R.sup.4" --BL.sub.2, wherein L is hydroxy or alkyl, wherein R.sup.4" is identical with R.sup.4 of general formula I or represents a tautomer precursor of R.sup.4 and alkyl is C.sub.1 -C.sub.4 alkyl radical, or
- indirectly by reaction with a compound substituted in the 4 position of the 11.beta.-phenyl radical with a tin(trialkyl) radical, wherein alkyl is C.sub.1 -C.sub.4, which was obtained by reaction of the perfluoroalkyl sulfonate compound with Sn.sub.2 alkyl.sub.6, and further treatment of the 11.beta.-(4-trialkylstannyl)-phenyl compound with a compound R.sup.4" --Y, in which R.sup.4" is identical with R.sup.4 of general formula I or represents a tautomer precursor of R.sup.4 and Y is a starting group, in the presence of a transition metal catalyst, and
- d) if R.sup.2 and R.sup.3 in the compound of formula I are not a hydroxy group or a hydrogen atom, or R.sup.2 and R.sup.3 together are not a keto oxygen atom, introducing the desired substituents R.sup.2 and R.sup.3 on the C 17 atom of the steroid skeleton of the compound of formula III; or
- (1) performing step d) first and then step c); cleaving protecting groups;
- optionally alkylating or acylating free hydroxy groups; optionally
- converting the 3-keto group with hydroxylaminohydrochloride into a 3-hydroxyimino grouping >N.about.OH, or
- the converting the 3-keto group into the dihydro compound; and
- optionally producing a pharmaceutically compatible addition salt thereof with an acid.
- 31. A process according to claim 30, wherein the heating is conducted at a temperature of 80.degree.-120.degree. C.
- 32. A process according to claim 30, wherein the heating is conducted in the presence of a mineral acid.
- 33. A process according to claim 30, wherein the heating is conducted in the presence of an organic acid.
- 34. A process according to claim 33, wherein the heating is conducted in the presence of p-toluenesulfonic acid.
Priority Claims (1)
Number |
Date |
Country |
Kind |
39 21 059.6 |
Jun 1989 |
DEX |
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Parent Case Info
This application is a continuation of application Ser. No. 07/541,806, filed Jun. 21, 1990, now abandoned.
US Referenced Citations (8)
Foreign Referenced Citations (5)
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196 707 |
Jun 1983 |
EPX |
277 089 |
Jan 1988 |
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Mar 1988 |
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308 345 |
Sep 1988 |
EPX |
404283 |
Dec 1990 |
EPX |
Continuations (1)
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Number |
Date |
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Parent |
541806 |
Jun 1990 |
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