US2006009438A2PendingUtilityA2

Modified, hydroxy-substituted aromatic structures having cytoprotective activity

Assignee: UNIV WASHINGTONPriority: Nov 3, 2000Filed: Oct 22, 2004Published: Jan 12, 2006

Est. expiryNov 3, 2020(expired)· nominal 20-yr term from priority

A61P 9/10A61P 31/18A61P 9/00A61P 43/00A61P 39/00A61P 37/04A61P 25/18A61P 25/28A61P 25/08A61P 27/02A61P 25/14A61P 27/06A61P 27/12A61P 25/00A61P 25/16A61P 21/04C07J 1/0059C07J 1/00C07J 1/007A61K 31/565

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Claims

Abstract

Abstract of the Disclosure The present invention is directed to a process for conferring cytoprotection on a population of cells which comprises administering to that population of cells a compound comprising a hydroxy-substituted aromatic ring structure and a non-fused polycyclic, hydrophobic substituent attached thereto. In particular, the present invention is directed to such a process wherein the administered compound is phenolic, such as a steriod (e.g., estrogen), and has a non-fused polycyclic, hydrophobic substituent attached to the hydroxy-substituted A-ring thereof.

Claims

exact text as granted — not AI-modified

1. A process for treating a cytodegenerative disease comprising administering to a subject in need thereof a compound having cytoprotective activity comprising a hydroxy-substituted aromatic ring structure and a non-fused polycyclic, hydrophobic substituent attached thereto.

2. The process of claim 1 wherein the compound has the formula:

wherein n is 1 or 2, R 1 is a non-fused polycyclic substituent, and R 2 and R 3 are independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted hydrocarbyl.

3. The process of claim 2 wherein R 2 and R 3 are bound to different carbon atoms, and further wherein R 2 and R 3 and the carbon atoms to which they are attached form a fused ring.

4. The process of claim 3 wherein said compound has the formula:

wherein: R 1 and R x are independently selected from the group consisting of a non-fused, polycyclic hydrophobic substituent, hydrogen, and substituted or unsubstituted alkyl, with the proviso that at least one of R 1 and R x is a non-fused, polycyclic hydrophobic substituent; R 13 is hydrogen or substituted or unsubstituted alkyl; and, R z is hydrogen, hydroxy, substituted or unsubstituted alkyl, or oxo.

5. The process of claim 4 wherein said non-fused polycyclic, hydrophobic substituent is adamantyl.

6. The process of claim 5 wherein R z is oxo.

7. The process of claim 6 wherein said compound has the formula:

and wherein R x are as defined in claim 4 .

8. The process of claim 7 wherein R x is hydrogen or methyl.

9. The process of claim 8 wherein the compound has the formula:

wherein R 1 is as defined in claim 8 .

10. The process of claim 8 wherein the compound has the formula:

wherein R 1 is as defined in claim 8 .

11. The process of claim 4 wherein said compound has the formula:

wherein R 1 and R x are as defined in claim 4 .

12. The process of claim 11 wherein R 1 is adamantyl and R x is hydrogen, methyl or methylpropyl.

13. The process of claim 12 wherein the compound has the formula:

wherein R 1 is as defined in claim 12 .

14. The process of claim 12 wherein the compound has the formula:

wherein R 1 is as defined in claim 12 .

15. The process of claim 12 wherein the compound has the formula:

wherein R 1 is as defined in claim 12 .

16. The process of claim 1 wherein the non-fused polycyclic, hydrophobic substituent is bicyclic.

17. The process of claim 16 wherein said substituent is selected from the group consisting of bicyclo[2.2.1]heptanyl and bicyclo[3.2.1]octanyl.

18. The process of claim 1 wherein the nonfused polycyclic, hydrophobic substituent is tricyclic.

19. The process of claim 18 wherein said substituent is adamantyl.

20. The process of claim 1 wherein the hydroxy-substituted, aromatic ring structure is polycyclic.

21. The process of claim 20 wherein the polycyclic ring structure is steroidal.

22. The process of claim 21 wherein the steroidal structure is phenolic.

23. The process of claim 22 wherein said polycyclic phenol is selected from the group consisting of estradiol, estratrienol and estrone.

24. The process of claim 23 wherein said polycyclic phenol is an estrone.

25. The process of claim 24 , wherein said estrone is selected from 2-(1-adamantyl)-3-hydroxyestra-1,3,5(10)-trien-17-one, and 2-(1-adamantyl)-3-hydroxy-4-methylestra-1,3,5(10)-trien-17-one.

26. The process of claim 23 wherein said polycyclic phenol is an estradiol.

27. The process of claim 26 wherein said estradiol is selected from the group consisting of (17 β)-2-(1-adamantyl)-estra-1,3,5(10)-triene-3,17-diol, (17 α)-2-(1-adamantyl)-estra-1,3,5(10)-triene-3,17-diol, (17 β)-2-(1-adamantyl)-4-(1-methylpropyl)estra-1,3,5(10)-triene-3,17-diol, (17 α)-2-(1-adamantyl)-4-(1-methylpropyl)estra-1,3,5(10)-triene-3,17-diol, or an enantiomer thereof.

28. The process of claim 21 wherein the steroidal structure is catecholic.

29. The process of claim 28 wherein said polycyclic catechol is selected from the group consisting of 2-hydroxy-(17β)-estradiol, 2-hydroxy-(17 α)-estradiol, or an enantiomer thereof.

30. The process of claim 1 comprising administering a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier, excipient or diluent.

31. The process of claim 1 wherein said subject is an animal.

32. The process of claim 1 wherein said subject is a human.

33. A process for conferring cytoprotection on a population of cells, the process comprising administering to the population of cells a compound having cytoprotective activity comprising a hydroxy-substituted aromatic ring structure and a non-fused polycyclic, hydrophobic substituent attached thereto.

34. The process of claim 33 comprising administering a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier, excipient or diluent.

35. The process of claim 34 wherein said cells are neurons.

36. A compound having cytoprotective activity, the compound having the formula:

wherein:
the compound optionally has one or more unsaturated bonds in conjugation with the aromatic A-ring between C-6 and C-7, C-8 and C-9 or C-9 and C-11, with the proviso that when C-8 or C-9 is unsaturated, R y is not bound thereto;
n ranges from 1 to 3;
R 1 is a non-fused polycyclic, hydrophobic substituent;
R x is selected from the group consisting of hydrogen and substituted or unsubstituted alkyl;
R y and R v are independently selected from hydrogen, substituted or unsubstituted alkyl, halo, amido, sulfate, and nitrate;
p and q range from 1 to 3;
R 13 is hydrogen or substituted or unsubstituted hydrocarbyl, halo, amido, sulfate or nitrate;
R z is hydrogen, hydroxy, substituted or unsubstituted alkyl, or oxo; and,
t ranges from 1 to 3;
with the proviso that when the compound has the following structure:

R x is not hydrogen.

37. The compound of claim 36 wherein R 1 is adamantyl.

38. The compound of claim 37 wherein a single R z substituent is present on the D-ring at the C-17 position.

39. The compound of claim 38 wherein R z is oxo, or alpha or beta hydroxy.

40. The compound of claim 39 wherein R x and R 13 are methyl.

41. The compound of claim 40 wherein the configurations at C-8, C-9, C-13 and C-14 are alpha, beta, alpha, and beta, respectively.

42. The compound of claim 39 wherein R x is hydrogen and R 13 is methyl.

43. The process of claim 1 wherein said cytodegenerative disease is selected from Alzheimer&#39;s disease, Parkinson&#39;s disease, Huntington&#39;s disease, multiple sclerosis, amyotrophic lateral sclerosis, stroke, ischemia, ophthalmologic diseases, cerebral vascular hemorrhage, hemorrhage, dementias, drug-induced brain damage and other systemic or acute degenerative diseases characterized by necrotic or apoptotic cell death.

44. The process of claim 43 wherein said cytodegenerative disease is an ophthalmologic disease selected from macular degeneration, lens or retinal degeneration, cataracts and glaucoma.

45. The process of claim 43 comprising administering said compound to a population of cells within ophthalmic tissue of said subject.

46. The process of claim 33 wherein said cells are within ophthalmic tissue.

47. A process for treating an ophthalmologic disease comprising administering to a subject in need thereof a compound having cytoprotective activity comprising a hydroxy-substituted aromatic ring structure and a non-fused polycyclic, hydrophobic substituent attached thereto.

48. The process of claim 47 wherein said compound has the formula:

wherein: n is 1 or 2; R 1 and R x are independently selected from the group consisting of a non-fused, polycyclic hydrophobic substituent, hydrogen, and substituted or unsubstituted alkyl, with the proviso that at least one of R 1 and R x is a non-fused, polycyclic hydrophobic substituent; R 13 is hydrogen or substituted or unsubstituted alkyl; and, R z is hydrogen, hydroxy, substituted or unsubstituted alkyl, or oxo.

49. The process of claim 48 wherein said ophthalmologic disease is selected from macular degeneration, lens or retinal degeneration, cataracts and glaucoma.

50. The process of claim 48 comprising administering said compound to a population of cells within ophthalmic tissue of said subject.

51. The process of claim 50 wherein said compound has the structure

wherein R 1 is as defined in claim 50 .

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