Claims for Patent: 4,447,424

Summary for Patent: 4,447,424

Title:	Steroid derivatives
Abstract:	Novel 19-nor steroids and 19-nor-D-homo-steroids of the formula ##STR1## wherein R1 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, R2 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═A group at position 3 is selected from the group consisting of C--O, ketal, which may be open or closed ##STR2## --C═NOH, --C--NOAlK3 and C--CH2, AlK1, AlK2 and AlK3 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):	Jean G. Teutsch, Germain Costerousse, Daniel Philibert, Roger Deraedt
Assignee:	Population Council Inc
Application Number:	US06/386,967
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 R1 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, R2 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═A group at position 3 is selected from the group consisting of C═O, ketal, ##STR101## >C═NOH, >C═NOAlK3 and CH2, AlK1, ALK2 and AlK3 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 R2 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 R2 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, R5 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, R6 may be the same as R5 and may be selected from the same group of members as R5 or --OH,R3 and R4 are individually selected from the group consisting of hydrogen, --OH,--OAlk4, --OCOAlk5, alkenyl and alkynyl of 2 to 8 carbon atoms, ##STR104## and --CN wherein Alk4,Alk5, and Alk8 are selected from the group consisting of alkyl of 1 to 8 carbon atoms and aralkyl of 7 to 15 carbon atoms, Alk6 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 Alk7 is alkyl of 1 to 8 carbon atoms and R3 and R4 form the group ##STR105## and Z1 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 Z2 is alkyl of 1 to 8 carbon atoms. 5. A composition of claim 4 wherein the D ring is saturated, R5 and R6 are hydrogen and n is 1. 6. A composition of claim 1 wherein the C═A group is C═O. 7. A composition of claim 1 wherein R1 is a hydrocarbon of 1 to 18 carbon atoms containing at least one nitrogen atom. 8. A composition of claim 7 wherein R1 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 R1 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 R1 is aryl or aralkyl containing the group ##STR106## wherein R7 and R8 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 R1 is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, ##STR107## 12. A composition of claim 1 wherein R1 contains an oxidized nitrogen atoms. 13. A composition of claim 1 wherein the active compound is selected from the group consisting of 11.sub.β -[4-(N,N-dimethylaminoethoxy)-phenyl]-17.sub.α (prop-1-ynyl)-Δ4,9 -estradiene-17.sub.β -ol-3-one, 11β-[4-(N,N-dimethylamino)-phenyl]-17.sub.α -(prop-1-ynyl)-Δ4,9 -estradiene-17.sub.β -ol-3-one, N-oxide of 11β[4-(N,N-dimethylamino)-phenyl]-21 chloro-19-nor-Δ4,9 -pregnadiene-20-yne-17β-ol-3-one, N-oxide of 9α,10α-epoxy-11β[4-(N,N-dimethylamino)-phenyl]-21-chloro 19-nor-17α-Δ4 -pregnene-20-yne-17β-ol-3-one-11β-[4(N,N-dimethylamino)-phenyl]-17α-(prop-2-ynyl)-Δ4,9 -estradiene-17β-ol-3-one, N-oxide of 11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9 -estradiene-17β-ol-3-one and their non-toxic, pharmaceutically acceptable acid addition salts. 14. The composition of claim 1 wherein the active compound is 11β-/4-(N,N-dimethylamino)phenyl/17α-(prop-1-ynyl)Δ4,9 estradiene-17β-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 R1 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, R2 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═A group at position 3 is selected from the group consisting of C═O, ketal, ##STR109## >C═NOH, >C═NOAlK3 and CH2, AlK1, AlK2 and AlK3 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 R2 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 R2 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,R5 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, R6 may be the same as R5 and may be selected from the same group of members as R5 or --OH, R3 and R4 are individually selected from the group consisting of hydrogen, --OH, --OAlK4, --OCOAlK5,alkenyl and alkynyl of 2 to 8 carbon atoms, ##STR112## and --CN wherein AlK4, AlK5 and AlK8 are selected from the group consisting of alkyl of 1 to 8 carbon atoms and aralkyl of 7 to 15 carbon atoms, AlK6, 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 AlK7 is alkyl of 1 to 8 carbon atoms and R3 and R4 form the group ##STR113## and Z1 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 Z2 is alkyl of 1 to 8 carbon atoms. 25. A method of claim 24 wherein the D ring is saturated, R5 and R6 are hydrogen and n is 1. 26. A method of claim 15 wherein the C═A group is C═O. 27. A method of claim 15 wherein R1 is hydrocarbon of 1 to 18 carbon atoms containing at least one nitrogen atom. 28. A method of claim 27 wherein R1 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 R1 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 R1 is aryl or aralkyl containing the group ##STR114## wherein R7 and R8 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 R1 is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, ##STR115## 32. A method of claim 15 wherein R1 contains an oxidized nitrogen atom. 33. The method of claim 15 wherein the active compound is selected from the group consisting of 11β-[4-(N,N-dimethylaminoethoxy)-phenyl]-17α-(prop-1-ynyl)-.DELTA.4,9- estradiene-17β-ol-3-one, 11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9 -estradiene-17β-ol-3-one, N-oxide of 11β-[4,N,N-dimethylamino)-phenyl]-21-chloro-19-nor-Δ4,9 -pregnadiene-20-yne-17β-ol 3-one, N-oxide of 9α,10α-epoxy-11β-[4-(N,N-dimethylamino)-phenyl]-21-chloro-19-nor-17α-Δ4 -pregnene-20-yne-17β-ol-3-one, 11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-2-ynyl)-Δ.sup.4,9 -estradiene-17β-ol-3-one, N-oxide of 11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9 -estradiene-17β-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 11β-[4-(N,N-dimethylaminoethoxy)-phenyl]-17α-(prop-1-ynyl)-.DELTA.4,9 -estradiene-17β-ol-3-one, 11β-[4-N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9 -estradiene-17β-ol-3-one, N-oxide of 11β-[4-N,N-dimethylamino)-phenyl]-21-chloro-19-nor-Δ4,9 -pregnadiene-20-yne-17β-ol-3-one, N-oxide of 9α,10α-epoxy-11β-[4-(N,N-dimethylamino)-phenyl]-21-chloro-19-nor-17α-Δ4 -pregnene-20-yne-17β-ol-3-one, 11β-[4-N,N-dimethylamino)-phenyl]-17α-(prop-2-ynyl)-Δ.sup.4,9 -estradiene-17β-ol-3-one, N-oxide of 11β[4-(N,N-dimethylamino)phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9 -estradiene-17β-ol-3-one and their non-toxic, pharmaceutically acceptable acid addition salts. 35. The method of claim 15 wherein the active compound is 11β-/4-(N,N-dimethylamino)phenyl/17α-(prop-1-ynyl)Δ4,9 estradiene-17β ol-3-one. 36. The method of claim 16 wherein the active compound is 11β-/4-(N,N-dimethylamino)phenyl/17α-(prop-1-ynyl)Δ4,9 estradiene 17β ol-3-one.