Claims for Patent: 4,386,085

Summary for Patent: 4,386,085

Title:	Novel steroids
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, ##STR2## --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 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:	US06/338,077
Patent Claims:	1. A compound selected form the group consisting of 19-nor steroids and 19-nor-D-homo-steroids of the formula ##STR99## 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, ##STR100## --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. 2. A compound of claim 1 wherein B and C form a double bond. 3. A compound of claim 1 or 2 wherein R2 is methyl. 4. A compound of claim 1, 2 or 3 wherein X and the carbons to which it is attached form the ring of the formula ##STR101## wherein R2 has the above definition, the dotted line in the 16,17-position is an optional double bond, Y is the group ##STR102## n is 1 or 2, R5 is selected from the group consisting of hydrogen 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 are 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, ##STR103## 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 ##STR104## 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 compound of claim 4 wherein the D ring is saturated, R5 and R6 are hydrogen and n is 1. 6. A compound of claim 1 wherein the C═A group is C═O. 7. A compound of claim 1 wherein R1 is a hydrocarbon of 1 to 18 carbon atoms containing at least one nitrogen atom. 8. A compound 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 compound 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 compound of claim 7 wherein R1 is aryl or aralkyl containing the group ##STR105## 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 compound of claim 10 wherein R1 is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, ##STR106## 12. A compound of claim 1 wherein R1 contains an oxidized nitrogen atom. 13. A compound of claim 1 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. 14. A process for the preparation of a compound of claim 1 comprising reacting a compound of the formula ##STR107## wherein K is a ketone blocked in the form of a ketal, thioketal, oxime or methyloxime and R1, R2 and X have the above definitions with a dehydration agent capable of freeing the ketone group to form a compound of the formula ##STR108## and either reacting the latter with a ketalization agent to obtain a compound of the formula ##STR109## or reacting the compound of formula IA ' with NH2 OH or NH2 OAlK3 wherein AlK3 has the above definition to obtain a compound of the formula ##STR110## wherein R is hydrogen or AlK3 or reacting a compound of formula IA ' with a reducing agent capable of selectively reducing the 3-keto group to obtain a compound of the formula ##STR111## and reacting the latter with an etherification agent capable of introducing AlK1 to obtain a compound of the formula ##STR112## or reacting the compound of formula ID ' with an esterification agent capable of introducing COAlK2 to obtain a compound of the formula ##STR113## or transforming the compound of formula IA ' by known methods to a compound wherein the C═A group is CH2 -- and optionally reacting a compound of formula IA ', IB ', IC ', ID ', IE ' or IF ' with an acid to form the corresponding acid addition salt or with an oxidation agent to obtain when R1 is a radical containing a nitrogen atom a compound having in the 11β-position a radical wherein the nitrogen atom is in the oxide form and B and C optionally form an epoxide bridge or when R1 does not contain a nitrogen atom, a compound where B and C form an epoxide bridge and when the compound contains the nitrogen oxide and the B and C group form an epoxide bridge, selectively reducing the oxidized nitrogen atom in R1 and optionally reacting the latter with an acid to form the acid addition salt. 15. A process of claim 16 wherein X and the carbons to which it is attached form the ring of the formula ##STR114## wherein R2 has the above definition, the dotted line in the 16,17-position is an optional double bond, Y is the group ##STR115## 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, ##STR116## 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 carbons atoms and R3 and R4 form the group ##STR117## 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. 16. A process for the preparation of a compound of the formula ##STR118## wherein R1, R2 and X have the definition of claim 1 and K is selected from the group consisting of ketal, thioketal, oxime and methyloxime wherein a compound of the formula ##STR119## is reacted with a compound selected from the group consisting of LiCu (R1)2, LiR1 and R1 Mg Hal wherein R1 has the above definition and Hal is a halogen in the presence of a cuprous halide. 17. A process for the preparation of a compound of the formula ##STR120## wherein R1, R2 and K have the above definitions, R3 ' is selected from the group consisting of --OH and ORc, Rc is the residue AlK4 of an ether group or COAlK5 of an ester group, AlK4 and AlK5 having the above definitions, and R4 ' is hydrogen or alkenyl or alkynyl of 2 to 8 carbon atoms comprising reacting a compound of the formula ##STR121## with a compound selected from the group consisting of LiCu(R1)2, R1 Li and R1 Mg Hal wherein R1 and Hal have the above definitions in the presence of a cuprous halide to obtain a compound of the formula ##STR122## and either reducing the latter to obtain the corresponding 17-ol compound or with an appropriate magnesium to obtain the corresponding 17α-substituted-17β-ol steroid or with an organometallic derivative such as a lithium or potassium derivative to obtain the corresponding 17α-substituted-17β-ol steroid or with a cyanuration agent to obtain the corresponding 17α-ol-17β-cyano steroid, protecting the hydroxy group and reacting the latter with an organometallic compound as discussed above to obtain the corresponding 17α-substituted-17β-ol steroid and in the case of one of the compounds obtained is 17-hydroxylated, reacting it with an etherification agent or esterification agent and in the case when one of the compounds contains a 17 substituent with a triple bond reacting the latter with a reducing agent to obtain the corresponding ethylenic derivative. 18. A compound selected from the group consisting of ##STR123## wherein R1, R2 and X have the definition of claim 1 and K is selected from the group consisting of ketal, thioketal, oxime and methyloxime. 19. A compound of claim 18 selected from the group consisting of 3,3-[1,2-ethanediyl-bisoxy]-11β-[4-trimethylsilylphenyl]-17α-(prop-1-ynyl)-Δ9 -estrene-5α,17β-diol, 3,3-[1,2-ethanediyl-bisoxy]-11β-(4-pyridyl)-17α-(prop-1-ynyl)-.DELTA.9 -estrene-5α,17β-diol, 3,3-[1,2-ethanediyl-bisoxy]-11β-[3-(N,N-dimethylamino)-propyl]-17.alpha.-(prop-1-ynyl)-Δ9 -estrene-5α,17β-diol, 3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-(prop-1-ynyl)-Δ9 -estrene-5α,17β-diol, 3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylaminoethoxy)-phenyl]-17α-(prop-1-ynyl)-Δ9 -estrene-5α,17β-diol, 3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-21-chloro-19-nor-17α-Δ9 -pregnene-20-yne-5α,17β-diol and 3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-(prop-2-ynyl)-Δ9 -estrene-5α,17β-diol, 3,3-/1,2-ethane dilyl-bisoxy/-5α, 10α-epoxy-17α-(prop-1-ynyl)Δ9(11) -estrene-17β-ol. 20. An antiglucocorticoid composition comprising an antiglucocorticoidally effective amount of at least one compound of claim 1 and an inert carrier. 21. A composition of claim 20 wherein B and C form a double bond. 22. A composition of claim 20 wherein R2 is methyl. 23. A composition of claim 20 wherein X and the carbons to which it is attached form the ring of the formula ##STR124## wherein R2 has the above definition, the dotted line in the 16,17-position is an optional double bond, Y is the group ##STR125## n is 1 or 2, R5 is selected from the group consisting of hydrogen 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, ##STR126## 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 to 7 to 15 carbon atoms and AlK7 is alkyl of 1 to 8 carbon atoms and R3 and R4 form the group ##STR127## 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. 24. A composition of claim 23 wherein the D ring is saturated, R5 and R6 are hydrogen and n is 1. 25. A composition of claim 20 wherein the C═A group is C═O. 26. A composition of claim 20 wherein R1 is a hydrocarbon of 1 to 18 carbon atoms containing at least one nitrogen atom. 27. A composition of claim 26 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. 28. A composition of claim 26 wherein R1 is heterocycle containing at least one nitrogen atom optionally substituted with an alkyl of 1 to 8 carbon atoms. 29. A composition of claim 26 wherein R1 is aryl or aralkyl containing the group ##STR128## 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. 30. A composition of claim 29 wherein R1 is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, ##STR129## 31. A composition of claim 20 wherein R1 contains an oxidized nitrogen atom. 32. The composition of claim 20 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. 33. A method of inducing antiglucocorticoid activity in warm-blooded animals comprising administering to warm-blooded animals an antiglucocorticoidally effective amount of at least one compound of claim 1. 34. A method of claim 33 wherein B and C form a double bond. 35. A method of claim 33 wherein R2 is methyl. 36. A method of claim 33 wherein X and the carbons to which it is attached form the ring of the formula ##STR130## wherein R2 has the above definition, the dotted line in the 16,17-position is an optional double bond, Y is the group ##STR131## n is 1 or 2, R5 is selected from the group consisting of hydrogen 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, ##STR132## 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 ##STR133## 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. 37. A method of claim 36 wherein the D ring is saturated, R5 and R6 are hydrogen and n is 1. 38. A method of claim 33 wherein the C═A group is C═O. 39. A method of claim 33 wherein R1 is a hydrocarbon of 1 to 18 carbon atoms containing at least one nitrogen atom. 40. A method of claim 39 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. 41. A method of claim 39 wherein R1 is heterocycle containing at least one nitrogen atom optionally substituted with an alkyl of 1 to 8 carbon atoms. 42. A method of claim 39 wherein R1 is aryl or aralkyl containing the group ##STR134## 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. 43. A method of claim 42 wherein R1 is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, ##STR135## 44. A method of claim 33 wherein R1 contains an oxidized nitrogen atom. 45. A compound of claim 1 selected from the group consisting of 11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9 -estradiene-17β-ol-3-one and its non-toxic, pharmaceutically-acceptable acid addition salts. 46. A method of claim 33 wherein the compound is selected from the group consisting of 11β-[4,-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9 -estradiene-17β-ol-3-one and its non-toxic, pharmaceutically acceptable acid addition salts.