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Claims for Patent: 4,447,424

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Claims for Patent: 4,447,424

Title: Steroid derivatives
Abstract:Novel 19-nor steroids and 19-nor-D-homo-steroids of the formula ##STR1## wherein R.sub.1 is an organic radical of 1 to 18 carbon atoms containing at least one atom selected from the group consisting of nitrogen, phosphorous and silicon with the atom immediately adjacent to the 11-carbon atom being carbon, R.sub.2 is a hydrocarbon of 1 to 8 carbon atoms, X is selected from the group consisting of a pentagonal ring and a hexagonal ring optionally substituted and optionally containing a double bond, B and C together form a double bond or an epoxy group, the C.dbd.A group at position 3 is selected from the group consisting of C--O, ketal, which may be open or closed ##STR2## --C.dbd.NOH, --C--NOAlK.sub.3 and C--CH.sub.2, AlK.sub.1, AlK.sub.2 and AlK.sub.3 are selected from the group consisting of alkyl of 1 to 8 carbon atoms and aralkyl of 7 to 15 carbon atoms and their non-toxic, pharmaceutically acceptable acid addition salts having anti-glucocorticoid activity and a process for their preparation.
Inventor(s): Teutsch; Jean G. (Pantin, FR), Costerousse; Germain (Saint-Maurice, FR), Philibert; Daniel (La Varenne Saint Hilaire, FR), Deraedt; Roger (Pavillons sous Bois, FR)
Assignee: Roussel Uclaf (Paris, FR)
Application Number:06/386,967
Patent Claims: 1. An antiprogestomimetic composition comprising an anti-progestomimetically effective amount of at least one compound selected from the group consisting of 19-nor steroids and 19-nor-D-homo-steroids of the formula ##STR100## wherein R.sub.1 is an organic radical of 1 to 18 carbon atoms containing at least one atom selected from the group consisting of nitrogen, phosphorous and silicon with the atom immediately adjacent to the 11-carbon atom being carbon, R.sub.2 is a hydrocarbon of 1 to 8 carbon atoms, X is selected from the group consisting of a pentagonal ring and a hexagonal ring optionally substituted and optionally containing a double bond, B and C together form a double bond or an epoxy group, the ring C.dbd.A group at position 3 is selected from the group consisting of C.dbd.O, ketal, ##STR101## >C.dbd.NOH, >C.dbd.NOAlK.sub.3 and CH.sub.2, AlK.sub.1, ALK.sub.2 and AlK.sub.3 are selected from the group consisting of alkyl of 1 to 8 carbon atoms and aralkyl of 7 to 15 carbon atoms and their non-toxic, pharmaceutically acceptable acid addition salts and an inert carrier.

2. A composition of claim 1 wherein B and C form a double bond.

3. A composition of claim 1 wherein R.sub.2 is methyl.

4. A composition of claim 1 wherein X and the carbons to which it is attached form the ring of the formula ##STR102## wherein R.sub.2 has the above definition, the dotted line in the 16,17-position is an optional double bond, Y is the group ##STR103## n is 1 or 2, R.sub.5 is selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms, alkenyl and alkynyl of 2 to 8 carbon atoms, aryl of 6 to 14 carbon atoms and aralkyl of 7 to 15 carbon atoms, R.sub.6 may be the same as R.sub.5 and may be selected from the same group of members as R.sub.5 or --OH,R.sub.3 and R.sub.4 are individually selected from the group consisting of hydrogen, --OH,--OAlk.sub.4, --OCOAlk.sub.5, alkenyl and alkynyl of 2 to 8 carbon atoms, ##STR104## and --CN wherein Alk.sub.4,Alk.sub.5, and Alk.sub.8 are selected from the group consisting of alkyl of 1 to 8 carbon atoms and aralkyl of 7 to 15 carbon atoms, Alk.sub.6 is selected from the group consisting of optionally substituted alkyl of 1 to 8 carbon atoms and aralkyl of 7 to 15 carbon atoms and Alk.sub.7 is alkyl of 1 to 8 carbon atoms and R.sub.3 and R.sub.4 form the group ##STR105## and Z.sub.1 is selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms and acyl of an organic carboxylic acid of 1 to 8 carbon atoms and Z.sub.2 is alkyl of 1 to 8 carbon atoms.

5. A composition of claim 4 wherein the D ring is saturated, R.sub.5 and R.sub.6 are hydrogen and n is 1.

6. A composition of claim 1 wherein the C.dbd.A group is C.dbd.O.

7. A composition of claim 1 wherein R.sub.1 is a hydrocarbon of 1 to 18 carbon atoms containing at least one nitrogen atom.

8. A composition of claim 7 wherein R.sub.1 is a primary, secondary or tertiary alkyl of 1 to 8 carbon atoms containing at least one heteroatom of the group consisting of nitrogen, sulfur and oxygen at least one being nitrogen or substituted with a heterocycle containing at least one nitrogen atom.

9. A composition of claim 7 wherein R.sub.1 is heterocycle containing at least one nitrogen atom optionally substituted with an alkyl of 1 to 8 carbon atoms.

10. A composition of claim 7 wherein R.sub.1 is aryl or aralkyl containing the group ##STR106## wherein R.sub.7 and R.sub.8 are alkyl of 1 to 8 carbon atoms or primary, secondary or tertiary alkyl of 1 to 8 carbon atoms containing at least one heteroatom of the group consisting of nitrogen, sulfur and oxygen of which at least one is nitrogen or substituted with a heterocycle containing at least one nitrogen atom.

11. A composition of claim 10 wherein R.sub.1 is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, ##STR107##

12. A composition of claim 1 wherein R.sub.1 contains an oxidized nitrogen atoms.

13. A composition of claim 1 wherein the active compound is selected from the group consisting of 11.sub..beta. -[4-(N,N-dimethylaminoethoxy)-phenyl]-17.sub..alpha. (prop-1-ynyl)-.DELTA..sup.4,9 -estradiene-17.sub..beta. -ol-3-one, 11.beta.-[4-(N,N-dimethylamino)-phenyl]-17.sub..alpha. -(prop-1-ynyl)-.DELTA..sup.4,9 -estradiene-17.sub..beta. -ol-3-one, N-oxide of 11.beta.[4-(N,N-dimethylamino)-phenyl]-21 chloro-19-nor-.DELTA..sup.4,9 -pregnadiene-20-yne-17.beta.-ol-3-one, N-oxide of 9.alpha.,10.alpha.-epoxy-11.beta.[4-(N,N-dimethylamino)-phenyl]-21-chloro 19-nor-17.alpha.-.DELTA..sup.4 -pregnene-20-yne-17.beta.-ol-3-one-11.beta.-[4(N,N-dimethylamino)-phenyl]- 17.alpha.-(prop-2-ynyl)-.DELTA..sup.4,9 -estradiene-17.beta.-ol-3-one, N-oxide of 11.beta.-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-(prop-1-ynyl)-.DELTA..su p.4,9 -estradiene-17.beta.-ol-3-one and their non-toxic, pharmaceutically acceptable acid addition salts.

14. The composition of claim 1 wherein the active compound is 11.beta.-/4-(N,N-dimethylamino)phenyl/17.alpha.-(prop-1-ynyl).DELTA..sup.4 ,9 estradiene-17.beta.-ol-3-one.

15. A method of inducing menses in warm-blooded animals comprising administering to warm-blooded animals, when progesterone plays a physiologically essential role, an anti-progestomimetically effective amount of at least one compound selected from the group consisting of 19-nor steroids and 19-nor-D-homo-steroids of the formula ##STR108## wherein R.sub.1 is an organic radical of 1 to 18 carbon atoms containing at least one atom selected from the group consisting of nitrogen, phosphorous and silicon with the atom immediately adjacent to the 11-carbon atom being carbon, R.sub.2 is a hydrocarbon of 1 to 8 carbon atoms, X is selected from the group consisting of a pentagonal ring and a hexagonal ring optionally substituted and optionally containing a double bond, B and C together form a double bond or an epoxy group, the ring C.dbd.A group at position 3 is selected from the group consisting of C.dbd.O, ketal, ##STR109## >C.dbd.NOH, >C.dbd.NOAlK.sub.3 and CH.sub.2, AlK.sub.1, AlK.sub.2 and AlK.sub.3 are selected from the group consisting of alkyl of 1 to 8 carbon atoms and aralkyl of 7 to 15 carbon atoms and their non-toxic, pharmaceutically acceptable acid addition salts.

16. A method of claim 15 comprising administering to women an antiprogestomimetically effective amount of at least one compound of claim 1 during the luteal phase.

17. A method of claim 16 wherein the compound is administered at the end of luteal phase.

18. A method of claim 15 of interrupting pregnancy comprising administering to warm-blooded animals an antiprogestomimetically effective amount of at least one compound of claim 1.

19. A method of claim 15 wherein the compound is administered orally or locally.

20. A method of claim 16 wherein the compound is administered orally or locally.

21. A method of claim 15 wherein the compound is administered during 1 to 5 days.

22. A method of claim 15 wherein B and C form a double bond.

23. A method of claim 15 wherein R.sub.2 is methyl.

24. A method of claim 15 wherein X and the carbons to which it is attached from the ring of the formula ##STR110## wherein R.sub.2 has the above definition, the dotted line in the 16,17 position is an optional bond, Y is the group ##STR111## n is 1 or 2,R.sub.5 is selected from the group consisting of hydrogen, alkyl or 1 to 8 carbon atoms, alkenyl and alkynyl of 2 to 8 carbon atoms, aryl of 6 to 14 carbon atoms and aralkyl of 7 to 15 carbon atoms, R.sub.6 may be the same as R.sub.5 and may be selected from the same group of members as R.sub.5 or --OH, R.sub.3 and R.sub.4 are individually selected from the group consisting of hydrogen, --OH, --OAlK.sub.4, --OCOAlK.sub.5,alkenyl and alkynyl of 2 to 8 carbon atoms, ##STR112## and --CN wherein AlK.sub.4, AlK.sub.5 and AlK.sub.8 are selected from the group consisting of alkyl of 1 to 8 carbon atoms and aralkyl of 7 to 15 carbon atoms, AlK.sub.6, is selected from the group consisting of optionally substituted alkyl of 1 to 8 carbon atoms and aralkyl of 7 to 15 carbon atoms and AlK.sub.7 is alkyl of 1 to 8 carbon atoms and R.sub.3 and R.sub.4 form the group ##STR113## and Z.sub.1 is selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms and acyl of an organic carboxylic acid of 1 to 8 carbon atoms and Z.sub.2 is alkyl of 1 to 8 carbon atoms.

25. A method of claim 24 wherein the D ring is saturated, R.sub.5 and R.sub.6 are hydrogen and n is 1.

26. A method of claim 15 wherein the C.dbd.A group is C.dbd.O.

27. A method of claim 15 wherein R.sub.1 is hydrocarbon of 1 to 18 carbon atoms containing at least one nitrogen atom.

28. A method of claim 27 wherein R.sub.1 is a primary, secondary or tertiary alkyl of 1 to 8 carbon atoms containing at least one heteroatom of the group consisting of nitrogen, sulfur and oxygen at least one being nitrogen or substituted with a heterocycle containing at least one nitrogen atom.

29. A method of claim 27 wherein R.sub.1 is heterocycle containing at least one nitrogen atom optionally subustituted with an alkyl of 1 to 8 carbon atoms.

30. A method of claim 27 wherein R.sub.1 is aryl or aralkyl containing the group ##STR114## wherein R.sub.7 and R.sub.8 are alkyl of 1 to 8 carbon atoms or primary, secondary or tertiary alkyl of 1 to 8 carbon atoms containing at least one heteroatom of the group consisting of nitrogen, sulfur and oxygen of which at least one is nitrogen or substituted with a heterocycle containing at least one nitrogen atom.

31. A method of claim 30 wherein R.sub.1 is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, ##STR115##

32. A method of claim 15 wherein R.sub.1 contains an oxidized nitrogen atom.

33. The method of claim 15 wherein the active compound is selected from the group consisting of 11.beta.-[4-(N,N-dimethylaminoethoxy)-phenyl]-17.alpha.-(prop-1-ynyl)-.DEL TA..sup.4,9- estradiene-17.beta.-ol-3-one, 11.beta.-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-(prop-1-ynyl)-.DELTA..su p.4,9 -estradiene-17.beta.-ol-3-one, N-oxide of 11.beta.-[4,N,N-dimethylamino)-phenyl]-21-chloro-19-nor-.DELTA..sup.4,9 -pregnadiene-20-yne-17.beta.-ol 3-one, N-oxide of 9.alpha.,10.alpha.-epoxy-11.beta.-[4-(N,N-dimethylamino)-phenyl]-21-chloro -19-nor-17.alpha.-.DELTA..sup.4 -pregnene-20-yne-17.beta.-ol-3-one, 11.beta.-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-(prop-2-ynyl)-.DELTA..su p.4,9 -estradiene-17.beta.-ol-3-one, N-oxide of 11.beta.-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-(prop-1-ynyl)-.DELTA..su p.4,9 -estradiene-17.beta.-ol-3-oneand their non-toxic, pharmaceutically acceptable acid addition salts.

34. The method of claim 16 wherein the active compound is selected from the group consisting of 11.beta.-[4-(N,N-dimethylaminoethoxy)-phenyl]-17.alpha.-(prop-1-ynyl)-.DEL TA..sup.4,9 -estradiene-17.beta.-ol-3-one, 11.beta.-[4-N,N-dimethylamino)-phenyl]-17.alpha.-(prop-1-ynyl)-.DELTA..sup .4,9 -estradiene-17.beta.-ol-3-one, N-oxide of 11.beta.-[4-N,N-dimethylamino)-phenyl]-21-chloro-19-nor-.DELTA..sup.4,9 -pregnadiene-20-yne-17.beta.-ol-3-one, N-oxide of 9.alpha.,10.alpha.-epoxy-11.beta.-[4-(N,N-dimethylamino)-phenyl]-21-chloro -19-nor-17.alpha.-.DELTA..sup.4 -pregnene-20-yne-17.beta.-ol-3-one, 11.beta.-[4-N,N-dimethylamino)-phenyl]-17.alpha.-(prop-2-ynyl)-.DELTA..sup .4,9 -estradiene-17.beta.-ol-3-one, N-oxide of 11.beta.[4-(N,N-dimethylamino)phenyl]-17.alpha.-(prop-1-ynyl)-.DELTA..sup. 4,9 -estradiene-17.beta.-ol-3-one and their non-toxic, pharmaceutically acceptable acid addition salts.

35. The method of claim 15 wherein the active compound is 11.beta.-/4-(N,N-dimethylamino)phenyl/17.alpha.-(prop-1-ynyl).DELTA..sup.4 ,9 estradiene-17.beta. ol-3-one.

36. The method of claim 16 wherein the active compound is 11.beta.-/4-(N,N-dimethylamino)phenyl/17.alpha.-(prop-1-ynyl).DELTA..sup.4 ,9 estradiene 17.beta. ol-3-one.
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