Patent EA-000965-B1 (EA)
Title: Novel nor-pregnanes for inducing hypothalamic effects
Inventor: JENNINGS-WHITE CLIVE L
IPC: C07J53/00
Filed: 1996-06-07
Abstract: 1. A pharmaceutical composition suitable for nasal administration in an individual, said composition comprising an 19-norpregnane steroid and a pharmaceutically acceptable carrier, wherein said steroid has the formula:   wherein P1 is oxo, α- or β-hydroxy, α- or β-acetoxy, α- or β-propionoxy, α- or β alkoxy of 1-6 carbon atoms, α- or β-acyloxy of 1-6 carbon atoms, or α- or β-benzyloxy; "a", "b", "c", "d", "e", "f", "g", "h", "i", "j", "m" and "n" are alternative sites for optional double bonds, and "k" may be absent or present with "j" to form a triple bond; P2 is a hydroxy, hydrogen, alkoxy of 1 to 6 carbon atoms, or P2 is absent; P3 is oxo, hydrogen, hydroxy, alkoxy of 1-6 carbon atoms or halo; P4 is methyl or ethyl; P5 is hydrogen, methyl or halo; P6 is hydrogen or methyl; R and R' are independently, hydrogen or halo, or are absent. 2. A method of altering an autonomic function of an individual, said method comprising: providing a 19-nor-pregnane of the formula   wherein P1 is oxo, α- or β-hydroxy, α- or β-acetoxy, α- or β-propionoxy, α- or β alkoxy of 1-6 carbon atoms, α- or β-acyloxy of 1-6 carbon atoms, or α- or β-benzyloxy; "a", "b", "c", "d", "e", "f", "g", "h", "i", "j", "m" and "n" are alternative sites for optional double bonds, and "k" may be absent or present with "j" to form a triple bond; P2 is a hydroxy, hydrogen, alkoxy of 1 to 6 carbon atoms, or P2 is absent; P3 is oxo, hydrogen, hydroxy, alkoxy of 1-6 carbon atoms or halo; P4 is methyl or ethyl; P5 is hydrogen, methyl or halo; P6 is hydrogen or methyl; R' and R" are independently, hydrogen or halo, or are absent; on the surface of nasal neuroepithelial cell of said individual wherein said cell is a part of tissue other than olfactory epithelia; and  administering said 19-nor pregnane derivative within a nasal passage of said individual such that said 19-nor-pregnane derivative binds specifically to said receptor 3. The method of claim 2 wherein said neuroepithelial cell is located within a vomeronasal organ of said individual. 4. The method of any of claims 2-3 wherein the amount of said 19-nor-pregnane derivative that is administered is at least about 100 picograms, but no more than about 100 micrograms. 5. The method of claim 2 wherein the amount of said 19-nor-pregnane derivative that is administered is at least about 1 nanograms, but no more than about 10 micrograms. 6. The method of claim 5 wherein the amount of said 19-nor-pregnane derivative that is administered is at least about 10 nanograms, but no more than about 1 microgram. 7. The method of any of claims 2-5 further comprising preparing a pharmaceutical composition of said pregnane derivative dissolved in a pharmaceutically acceptable carrier. 8. A 19-nor-pregnane of the formula   wherein P1 is oxo, α- or β-hydroxy, α- or β-acetoxy, α- or β-propionoxy, α- or β alkoxy of 1-6 carbon atoms, α- or β-acyloxy of 1-6 carbon atoms, or α- or β-benzyloxy; "a", "b", "c", "d", "e", "f", "g", "h", "i", "j", "m" and "n" are alternative sites for optional double bonds, and "k" may be absent or present with "j" to form a triple bond; P2 is a hydroxy, hydrogen, alkoxy of 1 to 6 carbon atoms, or P2 is absent; P3 is oxo, hydrogen, hydroxy, alkoxy of 1-6 carbon atoms or halo; P4 is methyl or ethyl; P5 is hydrogen, methyl or halo; P6 is hydrogen or methyl; R' and R" are independently, hydrogen or halo, or are absent; with the provisos that when P3 and P6 are hydrogen, "f", "n", "h" and "g" are absent, P4 is methyl and R' and R" are not halo, then: i) when P1 is oxo, "c" is present and P2 and P5 are hydrogen, then either of "j" or "i" cannot be present alone, or "m" and "j" cannot be present together, or "i" and "j" cannot be present together, or "m", "j" and "k" cannot be present together, and at least one of "i", "j", "k" or "m" must be present;  ii) when P1 is OH, and "a", "d" and "e" are present, and P5 is hydrogen, then any of "j", "i", or "m" cannot be present alone, or "j" and "k" cannot be present together, or "i" and "j" cannot be present together, or "m", "j" and "k" cannot be present together, and at least one of "i", "j", "k" and "m" must be present; iii) when P1 is β-OH, "c" is present and P2 and P5 are hydrogen, then "i" and "j" cannot be present together, or "m", "j", and "k" cannot be present together; iv) when P, is -OMe, "d" and "b" are present, then either of "j" and "i" cannot be present alone; v) when P1 is oxo, "d" is present, and P5 is hydrogen, "i" cannot be present alone or "j" and "k" cannot be present together. 9. The compound according to claim 8, 19-norpregna-4,20-dien-3-β-ol. 10. The compound according to claim 8, 19-norpregna-1,3,5(10),16,20-pentaen-3-ol. 11. The compound according to claim 8, 19-norpregna-5-(10),20-dien-3-one. 12. The compound according to claim 8, 19-norpregna-5(10),20-dien-3-ol. 13. The compound according to claim 8, 19-norpregna-4,20-dien-10β-ol-3-one. 14. The compound according to claim 8, 19-norpregna-4,9(10),20-trien-3-one. 15. The compound according to claim 8, 19-norpregn-1,3,5(10),16-tetraene-6-one-20-yn-3-yl acetate. 16. The compound according to claim 8,19-norpregna-l,3,5(10),16-tetraene-3,6-β-diol-20-yne. 17. The compound according to claim 8, 19-norpregna-1,3,5(10),17-tetraene-3-ol. 18. The compound according to claim 8, 19-norpregna-1,3,5(10),6,17-pentaen-3-ol. 19. The compound according to claim 8, 19-norpregna-1,3,5(10),6,8,17-hexaen-3-ol. 20. The compound according to claim 8, 19-norpregna-1,3,5(10),7,16-pentaen-3-ol. 21. The compound according to claim 8, 19-norpregna-2,5(10),16-trien-3-yl methyl ether. 22. The compound according to claim 8, 19-norpregna-4,16-dien-3-one. 23. The compound according to claim 8, 19-norpregna-5(10),16-dien-3-one. 24. The compound according to claim 8, 19-norpregna-4,16-dien-10β-ol-3-one. 25. The compound according to claim 8, 19-norpregna-2-5(10)-dien-3-yl methyl ether. 26. The compound according to claim 8, 19-norpregna-5(10),-en-3-one. 27. The compound according to claim 8, 19-norpregna-4-en-10β-ol-3-one. 28. The compound according to claim 8, 19-norpregna-4,17-dien-10β-ol-3-one. 29. A method of alkylating a steroid having a 17-halo-16-ene D-ring comprising the step of contacting said steroid with trialkylborane in the presence of a catalytic amount of Pd(II), to produce a 17-alkyl-16-ene steroid product.