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Claims for Patent: 4,386,085

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Claims for Patent: 4,386,085

Title: Novel steroids
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.dbd.O, ketal, ##STR2## --C.dbd.NOH, --C.dbd.NOAlK.sub.3 and .dbd.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: Roussell Uclaf (Paris, FR)
Application Number:06/338,077
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 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.dbd.O, ketal, ##STR100## --C.dbd.NOH, --C.dbd.NOAlK.sub.3 and .dbd.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.

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

3. A compound of claim 1 or 2 wherein R.sub.2 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 R.sub.2 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, R.sub.5 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, R.sub.6 may be the same as R.sub.5 and may be selected from the same group of members are 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, ##STR103## 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 ##STR104## 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 compound of claim 4 wherein the D ring is saturated, R.sub.5 and R.sub.6 are hydrogen and n is 1.

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

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

8. A compound 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 compound 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 compound of claim 7 wherein R.sub.1 is aryl or aralkyl containing the group ##STR105## 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 compound of claim 10 wherein R.sub.1 is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, ##STR106##

12. A compound of claim 1 wherein R.sub.1 contains an oxidized nitrogen atom.

13. A compound of claim 1 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..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. 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 R.sub.1, R.sub.2 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 I.sub.A ' with NH.sub.2 OH or NH.sub.2 OAlK.sub.3 wherein AlK.sub.3 has the above definition to obtain a compound of the formula ##STR110## wherein R is hydrogen or AlK.sub.3 or reacting a compound of formula I.sub.A ' 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 AlK.sub.1 to obtain a compound of the formula ##STR112## or reacting the compound of formula I.sub.D ' with an esterification agent capable of introducing COAlK.sub.2 to obtain a compound of the formula ##STR113## or transforming the compound of formula I.sub.A ' by known methods to a compound wherein the C.dbd.A group is CH.sub.2 -- and optionally reacting a compound of formula I.sub.A ', I.sub.B ', I.sub.C ', I.sub.D ', I.sub.E ' or I.sub.F ' with an acid to form the corresponding acid addition salt or with an oxidation agent to obtain when R.sub.1 is a radical containing a nitrogen atom a compound having in the 11.beta.-position a radical wherein the nitrogen atom is in the oxide form and B and C optionally form an epoxide bridge or when R.sub.1 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 R.sub.1 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 R.sub.2 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, 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, ##STR116## 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 carbons atoms and R.sub.3 and R.sub.4 form the group ##STR117## 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.

16. A process for the preparation of a compound of the formula ##STR118## wherein R.sub.1, R.sub.2 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 (R.sub.1).sub.2, LiR.sub.1 and R.sub.1 Mg Hal wherein R.sub.1 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 R.sub.1, R.sub.2 and K have the above definitions, R.sub.3 ' is selected from the group consisting of --OH and OR.sub.c, R.sub.c is the residue AlK.sub.4 of an ether group or COAlK.sub.5 of an ester group, AlK.sub.4 and AlK.sub.5 having the above definitions, and R.sub.4 ' 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(R.sub.1).sub.2, R.sub.1 Li and R.sub.1 Mg Hal wherein R.sub.1 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 17.alpha.-substituted-17.beta.-ol steroid or with an organometallic derivative such as a lithium or potassium derivative to obtain the corresponding 17.alpha.-substituted-17.beta.-ol steroid or with a cyanuration agent to obtain the corresponding 17.alpha.-ol-17.beta.-cyano steroid, protecting the hydroxy group and reacting the latter with an organometallic compound as discussed above to obtain the corresponding 17.alpha.-substituted-17.beta.-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 R.sub.1, R.sub.2 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]-11.beta.-[4-trimethylsilylphenyl]-17.alpha.-(p rop-1-ynyl)-.DELTA..sup.9 -estrene-5.alpha.,17.beta.-diol, 3,3-[1,2-ethanediyl-bisoxy]-11.beta.-(4-pyridyl)-17.alpha.-(prop-1-ynyl)-. DELTA..sup.9 -estrene-5.alpha.,17.beta.-diol, 3,3-[1,2-ethanediyl-bisoxy]-11.beta.-[3-(N,N-dimethylamino)-propyl]-17.alp ha.-(prop-1-ynyl)-.DELTA..sup.9 -estrene-5.alpha.,17.beta.-diol, 3,3-[1,2-ethanediyl-bisoxy]-11.beta.-[4-(N,N-dimethylamino)-phenyl]-17.alp ha.-(prop-1-ynyl)-.DELTA..sup.9 -estrene-5.alpha.,17.beta.-diol, 3,3-[1,2-ethanediyl-bisoxy]-11.beta.-[4-(N,N-dimethylaminoethoxy)-phenyl]- 17.alpha.-(prop-1-ynyl)-.DELTA..sup.9 -estrene-5.alpha.,17.beta.-diol, 3,3-[1,2-ethanediyl-bisoxy]-11.beta.-[4-(N,N-dimethylamino)-phenyl]-21-chl oro-19-nor-17.alpha.-.DELTA..sup.9 -pregnene-20-yne-5.alpha.,17.beta.-diol and 3,3-[1,2-ethanediyl-bisoxy]-11.beta.-[4-(N,N-dimethylamino)-phenyl]-17.alp ha.-(prop-2-ynyl)-.DELTA..sup.9 -estrene-5.alpha.,17.beta.-diol, 3,3-/1,2-ethane dilyl-bisoxy/-5.alpha., 10.alpha.-epoxy-17.alpha.-(prop-1-ynyl).DELTA..sup.9(11) -estrene-17.beta.-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 R.sub.2 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 R.sub.2 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, R.sub.5 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, 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, ##STR126## 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 to 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 ##STR127## 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.

24. A composition of claim 23 wherein the D ring is saturated, R.sub.5 and R.sub.6 are hydrogen and n is 1.

25. A composition of claim 20 wherein the C.dbd.A group is C.dbd.O.

26. A composition of claim 20 wherein R.sub.1 is a hydrocarbon of 1 to 18 carbon atoms containing at least one nitrogen atom.

27. A composition of claim 26 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.

28. A composition of claim 26 wherein R.sub.1 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 R.sub.1 is aryl or aralkyl containing the group ##STR128## 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.

30. A composition of claim 29 wherein R.sub.1 is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, ##STR129##

31. A composition of claim 20 wherein R.sub.1 contains an oxidized nitrogen atom.

32. The composition of claim 20 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-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 R.sub.2 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 R.sub.2 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, R.sub.5 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, 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, ##STR132## 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 ##STR133## 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.

37. A method of claim 36 wherein the D ring is saturated, R.sub.5 and R.sub.6 are hydrogen and n is 1.

38. A method of claim 33 wherein the C.dbd.A group is C.dbd.O.

39. A method of claim 33 wherein R.sub.1 is a hydrocarbon of 1 to 18 carbon atoms containing at least one nitrogen atom.

40. A method of claim 39 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.

41. A method of claim 39 wherein R.sub.1 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 R.sub.1 is aryl or aralkyl containing the group ##STR134## 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.

43. A method of claim 42 wherein R.sub.1 is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, ##STR135##

44. A method of claim 33 wherein R.sub.1 contains an oxidized nitrogen atom.

45. A compound of claim 1 selected from the group consisting 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 its non-toxic, pharmaceutically-acceptable acid addition salts.

46. A method of claim 33 wherein the compound is selected from the group consisting of 11.beta.-[4,-(N,N-dimethylamino)-phenyl]-17.alpha.-(prop-1-ynyl)-.DELTA..s up.4,9 -estradiene-17.beta.-ol-3-one and its non-toxic, pharmaceutically acceptable acid addition salts.
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