.

Pharmaceutical Business Intelligence

  • Anticipate P&T budget requirements
  • Evaluate market entry opportunities
  • Find generic sources and suppliers
  • Predict branded drug patent expiration

► Plans and Pricing

Upgrade to enjoy subscriber-only features like email alerts and data export. See the Plans and Pricing

DrugPatentWatch Database Preview

Details for Patent: 4,547,493

« Back to Dashboard

Details for Patent: 4,547,493

Title: Novel 11.beta.-substituted-19-nor-steroids
Abstract:Novel 19-nor-steroids of the formula ##STR1## wherein R.sub.1 is an organic group of 1 to 18 carbon atoms optionally containing at least one heteroatom with the atom immediately adjacent the 11-carbon atom being carbon, R.sub.2 is a hydrocarbon of 1 to 8 carbon atoms, X is the remainder of a pentagonal or hexagonal ring optionally substituted and optionally containing one unsaturated bond, the A and B rings are selected from the group consisting of ##STR2## R' and R" are individually selected from the group consisting of hydrogen, --CN and alkyl of 1 to 4 carbon atoms with at least one being other than hydrogen, R.sub.x is selected from the group consisting of hydrogen and OR.sub.e R.sub.e is selected from the group consisting of hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms and acyl, R.sub.a may be in the E or Z positions as indicated by the wavy line and is selected from the group consisting of ##STR3## and acyloxy, R.sub.a ' and R.sub.a " are alkyl of 1 to 4 carbon atoms or taken together with the nitrogen atom form a heterocycle of 5 to 6 chain members optionally containing another heteroatom with the proviso that when A and B are ##STR4## R.sub.1 contains at least one nitrogen, phosphorus or silicium atom and when A and B are ##STR5## R.sub.1 is not a linear alkyl and their non-toxic, pharmaceutically acceptable acid addition salts having a remarkable antigluococorticoid activity, their preparation and novel intermediates.
Inventor(s): Teutsch; Jean-Georges (Pantin, FR), Torelli; Vesperto (Maisons-Alfort, FR), Deraedt; Roger (Pavillons-sous-Bois, FR), Philibert; Daniel (La Varenne-Saint-Hilaire, FR)
Assignee: Roussel Uclaf (Paris, FR)
Filing Date:Jun 06, 1983
Application Number:06/501,373
Claims:1. A compound selected from the group consisting of 19-nor-steroids of the formula ##STR610## wherein R.sub.1 is an organic group of 1 to 18 carbon atoms optionally containing at least one atom selected from the group consisting of oxygen, sulfur, nitrogen, phosphorus and silicon with the atom immediately adjacent the 11-carbon atom being carbon, R.sub.2 is a hydrocarbon of 1 to 8 carbon atoms, X is the remainder of a pentagonal or hexagonal ring optionally substituted and optionally containing one unsaturated bond, the A and B rings are selected from the group consisting of ##STR611## R' and R" are individually selected from the group consisting of hydrogen, --CN and alkyl of 1 to 4 carbon atoms with at least one being other than hydrogen, R.sub.x is selected from the group consisting of hydrogen and OR.sub.e, R.sub.e is selected from the group consisting of hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms and acyl, R.sub.a may be in the E or Z positions as indicated by the wavy line and is selected from the group consisting of ##STR612## and acyloxy R.sub.a ' and R.sub.a " are alkyl of 1 to 4 carbon atoms or taken together with the nitrogen atom form a heterocycle of 5 to 6 chain members optionally containing another heteroatom with the proviso that when A and B are ##STR613## R.sub.1 contains at least one nitrogen, phosphorus or silicium atom and when A and B are ##STR614## R.sub.1 is not a linear akyl and their non-toxic, pharmaceutically acceptable acid addition salts.

2. A compound of claim 1 wherein X is ##STR615## wherein R.sub.2 has the definition of claim 1, the dotted line in the 16,17-position indicates an optional double bond, Y is ##STR616## 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 is selected from the group consisting of hydrogen, --OH, 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 and R.sub.3 and R.sub.4 are individually selected from the group consisting of hydrogen, --OH, --OAlK.sub.4, ##STR617## alkenyl and alkynyl of 2 to 8 carbon atoms, ##STR618## or R.sub.3 and R.sub.4 together with the carbon atoms are ##STR619## or ##STR620## AlK.sub.4, AlK.sub.6 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 are selected from the group consisting of alkyl of 1 to 8 carbon atoms, optionally substituted and aralkyl of 7 to 15 carbon atoms, AlK.sub.7 and Z.sub.2 are alkyl of 1 to 8 carbon atoms and Z.sub.1 is selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms and acyl of 1 to 8 carbon atoms.

3. A compound of claim 2 wherein the D ring does not contain unsaturation, n is 1 and R.sub.5 and R.sub.6 is hydrogen.

4. A compound of claim 1 or 2 wherein R.sub.3 is --OH or ##STR621## AlK.sub.5 is alkyl of 1 to 8 carbon atoms or aralkyl of 7 to 15 carbon atoms and R.sub.4 is alkenyl or alkynyl of 2 to 4 carbon atoms.

5. A compound of claim 1 or 2 wherein R.sub.1 is aryl or aralkyl carrying an amino of the formula ##STR622## 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 --O--, --S-- or --N-- with at least one being nitrogen or substituted with a heterocycle containing at least one nitrogen atom.

6. A compound of claim 1 or 2 wherein R.sub.1 is selected from the group consisting of 2-pyridyl, 3-pyridyl and 4-pyridyl, ##STR623##

7. A compound of claim 1 or 2 wherein R.sub.1 is selected from the group consisting of thienyl, furyl, cycloalkyl of 3 to 6 carbon atoms and phenyl optionally substituted with at least one member of the group consisting of --OH, halogen, --CF.sub.3, alkyl and alkoxy of 1 to 8 carbon atoms and alkylthio of 1 to 8 carbon atoms optionally oxidixed to sulfoxide or sulfone and A and B rings are not ##STR624##

8. A compound of claim 1 or 2 wherein R.sub.1 is phenyl substituted with a member of the group consisting of chlorine, fluorine, methylthio, methylsulfonyl, methoxy, --OH and allyloxy.

9. A compound of claim 1 or 2 wherein the A and B rings are ##STR625## wherein R' and R" are both methyl or both --CN or one is hydrogen and the other is methyl or --CN.

10. A compound of claim 1 or 2 wherein A and B rings are ##STR626## wherein R.sub.a is morpholino or acetoxy.

11. A compound of claim 1 selected from the group consisting of 2,2-dimethyl-11.beta.-(4-dimethylaminophenyl)-17.alpha.-(prop-1-ynyl)-.DEL TA..sup.4,9 -estradiene-17.beta.-ol-3-one, 2,2-dicyano-11.beta.-(4-dimethylaminophenyl)-17.alpha.-(prop-1-ynyl)-.DELT A..sup.4,9 -estradiene-17.beta.-ol-3-one, 2,.alpha.-methyl-11.beta.-(4-dimethylaminophenyl)-17.alpha.-(prop-1-ynyl)- .DELTA..sup.4,9 -estradiene-17.beta.-ol-3-one, 2.beta.-methyl-11.beta.-(4-dimethylaminophenyl)-.DELTA..sup.4,9 -estradiene-17.beta.-ol-3-one, 2-cyano-11.beta.-(4-dimethylaminophenyl)-17.alpha.-(prop-1-ynyl)-.DELTA..s up.4,9 -estradiene-17.beta.-ol-3-one and their non-toxic, pharmaceutically acceptable acid addition salts.

12. A compound of claim 1 selected from the group consisting of 11.beta.-(4-dimethylaminophenyl)-17.alpha.-(prop-1-ynyl)-.DELTA..sup.1,3,5 (10) -estratriene-3-; 17.beta.-diol, 11.beta.-(4-dimethylaminophenyl)-17.beta.-acetoxy-17.alpha.-(prop-1-ynyl)- .DELTA..sup.1,3,5(10) -estratriene-3-ol, 3-methoxy-11.beta.-(4-dimethylaminophenyl)-17.alpha.-(prop-1-ynyl)-.DELTA. .sup.1,3,5(10) -estratriene-17.beta.-ol, 3-methoxy-11.beta.-(4-dimethylaminophenyl)-17.beta.-acetoxy-17.alpha.-(pro p-1-ynyl)-.DELTA..sup.1,3,5(10) -estratriene and their non-toxic, pharmaceutically acceptable acid addition salts.

13. A compound of claim 1 selected from the group consisting of 11.beta.-(3-methoxyphenyl)-17.alpha.-(prop-1-ynyl)-.DELTA..sup.5(10) -estrene-17.beta.-ol-3-one, E isomer of 11.beta.-(3-methoxyphenyl)-17.alpha.-(prop-1-enyl)-.DELTA..sup.5(10) -estrene-17.beta.-ol-3-one, 11.beta.-(4-dimethylaminophenyl)-17.alpha.-(prop-1-ynyl)-.DELTA..sup.5(10) -estrene-17.beta.-ol-3-one and their non-toxic, pharmaceutically acceptable acid addition salts.

14. A compound of claim 1 selected from the group consisting of 2-(acetyloxymethylene)-11.beta.-(4-dimethylaminophenyl)-17.alpha.-(prop-1- ynyl)-.DELTA..sup.4,9 -estradiene-17.beta.-ol-3-one, 2-(4-morpholinomethylene)-11.beta.-(4-dimethylaminophenyl)-17.alpha.-(prop -1-ynyl)-.DELTA..sup.4,9 -estradiene-17.beta.-ol-3-one and their non-toxic, pharmaceutically acceptable acid addition salts.

15. A compound of claim 1 selected from the group consisting of 11.beta.-(4-dimethylaminophenyl)-17.alpha.-(prop-1-ynyl)-isoxazolo[4,5-b]- .DELTA..sup.4,9 -estradiene-17.beta.-ol and its non-toxic, pharmaceutically acceptable acid addition salts.

16. A compound of claim 1 selected from the group consisting of 11.beta.-[4-(2-dimethylaminoethoxy)-phenyl]-.DELTA..sup.1,3,5(10) -estratriene-3, 17.beta.-diol, 11.beta.-[4-(2-dimethylaminoethoxy)-phenyl]-.DELTA..sup.1,3,5(10) -estratriene-17.beta.-ol, 3-(2-dimethylaminoethoxy)-11.beta.-phenyl-.DELTA..sup.1,3,5(10) -estratriene-17.beta.-ol and their non-toxic, pharmaceutically acceptable acid addition salts.

17. A compound of the formula ##STR627## wherein R.sub.1, R.sub.2 and X have the definition of claim 1.

18. An antiglucocorticoidal composition comprising an antiglucocorticoidally effective amount of at least one compound of claim 1 and an inert pharmaceutically carrier.

19. A composition of claim 18 wherein X is ##STR628## wherein R.sub.2 has the definition of claim 1, the dotted line in the 16,17-position indicates an optional double bond, Y is ##STR629## 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 is selected from the group consisting of hydrogen, --OH, 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 and R.sub.3 and R.sub.4 are individually selected from the group consisting of hydrogen, --OH, --OAlK.sub.4, ##STR630## alkenyl and alkynyl of 2 to 8 carbon atoms, ##STR631## or R.sub.3 and R.sub.4 together with the carbon atoms are ##STR632## or ##STR633## 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 are selected from the group consisting of alkyl of 1 to 8 carbon atoms, optionally susbituted and aralkyl of 7 to 15 carbon atoms, AlK.sub.7 and Z.sub.2 are alkyl of 1 to 8 carbon atoms and Z.sub.1 is selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms and acyl of 1 to 8 carbon atoms.

20. A composition of claim 18 wherein the D ring does not contain unsaturation, n is 1 and R.sub.5 and R.sub.6 are hydrogen.

21. A composition of claim 18 wherein R.sub.3 is --OH or ##STR634## AlK.sub.5 is alkyl of 1 to 8 carbon atoms or aralkyl of 7 to 15 carbon atoms and R.sub.4 is alkenyl or alkynyl of 2 to 4 carbon atoms.

22. A composition of claim 18 wherein R.sub.1 is aryl or aralkyl carrying an amino of the formula ##STR635## 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 --O--, --S-- or --N-- with at least one being nitrogen or substituted with a heterocycle containing at least one nitrogen atom.

23. A composition of claim 18 wherein R.sub.1 is selected from the group consisting of 2-pyridyl, 3-pyridyl and 4-pyridyl, ##STR636##

24. A composition of claim 18 wherein R.sub.1 is selected from the group consisting of thienyl, furyl, cycloalkyl of 3 to 6 carbon atoms and phenyl optionally substituted with at least one member of the group consisting of --OH, halogen, --CF.sub.3, alkyl and alkoxy of 1 to 8 carbon atoms and alkylthio of 1 to 8 carbon atoms optionally oxidized to sulfoxide or sulfone and A and B rings are not ##STR637##

25. A composition of claim 18 wherein R.sub.1 is phenyl substituted with a member of the group consisting of chlorine, fluorine, methylthio, methylsulfonyl, methoxy, --OH and allyloxy.

26. A composition of claim 18 wherein the A and B rings are: ##STR638## wherein R' and R" are both methyl or both --CN or one is hydrogen and the other is methyl or --CN.

27. A composition of claim 18 wherein A and B are ##STR639## wherein R.sub.a is morpholino or acetoxy.

28. A method of inducing antiglucocorticoidal activity in warm-blooded animals comprising administering to warm-blooded animals an antiglucocorticoidally effective amount of at least one compound of claim 1.

29. A method of claim 28 wherein X is ##STR640## wherein R.sub.2 has the definition of claim 1, the dotted line in the 16,17-position indicates an optional double bond, Y is ##STR641## 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 is selected from the group consisting of hydrogen, --OH, 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 and R.sub.3 and R.sub.4 are individually selected from the group consisting of hydrogen, --OH, --OAlK.sub.4, ##STR642## alkenyl and alkynyl of 2 to 8 carbon atoms, ##STR643## or R.sub.3 and R.sub.4 together with the carbon atoms are ##STR644## or ##STR645## AlK.sub.4, AlK.sub.6 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 are selected from the group consisting of alkyl 1 to 8 carbon atoms optionally substitued and aralkyl of 7 to 15 carbon atoms, AlK.sub.7 and Z.sub.2 are alkyl of 1 to 8 caron atoms and Z.sub.1 is selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms and acyl of 1 to 8 carbon atoms.

30. A method of claim 28 wherein the D ring does not contain unsaturation, n is 1 and R.sub.5 and R.sub.6 are hydrogen.

31. A method of claim 28 wherein R.sub.3 is --OH or ##STR646## AlK.sub.5 is alkyl of 1 to 8 carbon atoms or aralkyl of 7 to 15 carbon atoms and R.sub.4 is alkenyl or alkynyl of 2 to 4 carbon atoms.

32. A method of claim 28 wherein R.sub.1 is aryl or aralkyl carrying an amino of the formula ##STR647## 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 --O--, --S-- or --N-- with at least one being nitrogen or substituted with a heterocycle containing at least one nitrogen atom.

33. A method of claim 28 wherein R.sub.1 is selected from the group consisting of 2-pyridyl, 3-pyridyl and 4-pyridyl, ##STR648##

34. A method of claim 28 and wherein R.sub.1 is selected from the group consisting of thienyl, furyl, cycloalkyl of 3 to 6 carbon atoms and phenyl optionally substituted with at least one member of the group consisting of --OH, halogen, --CF.sub.3, alkyl and alkoxy of 1 to 8 carbon atoms and alkylthio of 1 to 8 carbon atoms optionally oxidized to sulfoxide or sulfone and A and B rings are not ##STR649##

35. A method of claim 28 wherein R.sub.1 is phenyl substituted with a member of the group consisting of chlorine, fluorine, methylthio, methylsulfonyl, methoxy, --OH and allyloxy.

36. A method of claim 28 wherein the A and B rings are ##STR650## wherein R' and R" are both methyl or both --CN or one is hydrogen and the other is methyl or --CN.

37. A method of claim 28 wherein A and B are ##STR651## wherein R.sub.a is morpholino or acetoxy.

38. A method of claim 28 wherein the compound is selected from the group consisting of 2,2-dimethyl-11.beta.-(4-dimethylaminophenyl)-17.alpha.-(prop-1-ynyl)-.DEL TA..sup.4,9 -estradiene-17.beta.-ol-3-one, 2,2-dicyano-11.beta.-(4-dimethylaminophenyl)-17.alpha.-(prop-1-ynyl)-.DELT A..sup.4,9 -estradiene-17.beta.-ol-3-one, 2.alpha.-methyl-11.beta.-(4-dimethylaminophenyl)-17.alpha.-(prop-1-ynyl)-. DELTA..sup.4,9 -estradiene-17.beta.-ol-3-one, 2.beta.-methyl-11.beta.-(4-dimethylaminophenyl)-.DELTA..sup.4,9 -estradiene-17.beta.-ol-3-one, 2-cyano-11.beta.-(4-dimethylaminophenyl)-17.alpha.-(prop-1-ynyl)-.DELTA..s up.4,9 -estradiene-17.beta.-ol-3-one and their non-toxic, pharmaceutically acceptable acid addition salts.

39. A method of claim 28 wherein the compound is selected from the group consisting of 11.beta.-(4-dimethylaminophenyl)-17.alpha.-(prop-1-ynyl)-.DELTA..sup.1,3,5 (10) -estratriene-3,17.beta.-diol, 11.beta.-(4-dimethylaminophenyl)-17.beta.-acetoxy-17.alpha.-(prop-1-ynyl)- .DELTA..sup.1,3,5(10) -estratriene-3-ol, 3-methoxy-11.beta.-(4-dimethylaminophenyl)-17.alpha.-(prop-1-ynyl)-.DELTA. .sup.1,3,5(10) -estratriene-17.beta.-ol, 3-methoxy-11.beta.-(4-dimethylaminophenyl)-17.beta.-acetoxy-17.alpha.-(pro p-1-ynyl)-.DELTA..sup.1,3,5(10) -estratriene and their non-toxic, pharmaceutically acceptable acid addition salts.

40. A metuod of claim 28 wherein the compound is selected from the group consisting of 11.beta.-(3-methoxyphenyl)-17.alpha.-(prop-1-ynyl)-.DELTA..sup.5(10) -estrene-17.beta.-ol-3-one, E isomer of 11.beta.-(3-methoxyphenyl)-17.alpha.-(prop-1-enyl)-.DELTA..sup.5(10) -estrene-17.beta.-ol-3-one, 11.beta.-(4-dimethylaminophenyl)-17.alpha.-(prop-1-ynyl)-.DELTA..sup.5(10) -estrene-17.beta.-ol-3-one and its non-toxic, pharmaceutically acceptable acid addition salts.

41. A method of claim 28 wherein the compound is selected from the group consisting of 2-(acetyloxy methylene)-11.beta.-(4-dimethylaminophenyl)-17.alpha.-(prop-1-ynyl)-.DELTA ..sup.4,9 -estradiene-17.beta.-ol-3-one, 2-(4-morpholinomethylene)-11.beta.-(4-dimethylaminophenyl)-17.alpha.-(prop -1-ynyl)-.DELTA..sup.4,9 -estradiene-17.beta.-ol-3-one and their non-toxic, pharmaceutically acceptable acid addition salts.

42. A method of claim 28 wherein the compound is selected from the group consisting of 11.beta.-(4-dimethylaminophenyl)-17.alpha.-(prop-1-ynyl)-isoxazolo[4,5-b]- .DELTA..sup.4,9 -estradiene-17.beta.-ol and its non-toxic, pharmaceutically acceptable acid addition salts.

43. A method of claim of claim 28 wherein the compound is selected from the group consisting of 11.beta.-[4-(2-dimethylaminoethoxy)-phenyl]-.DELTA..sup.1,3,5(10) -estratriene-3,17.beta.-diol, 11.beta.-[4-(2-dimethylaminoethoxy)-phenyl]-.DELTA..sup.1,3,5(10) -estratriene-17.beta.-ol, 3-(2-dimethylaminoethoxy)-11.beta.-phenyl-.DELTA..sup.1,3,5(10) -estratriene-17.beta.-ol and their non-toxic, pharmaceutically acceptable acid addition salts.

44. A method of inducing contraception or interruption of pregnancy in warm-blooded animals comprising administering to female warm-blooded animals a sufficient amount of at least one compound of claim 1 to interrupt pregnancy or to induce contraception.
« Back to Dashboard

For more information try a trial or see the database preview and plans and pricing

Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verifification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.

`abc