1,3-dihydroxy-20,20-cycloalkyl-vitamin D3analogs

• US 6,492,353 B1
• Filed: 09/03/1998
• Issued: 12/10/2002
• Est. Priority Date: 09/08/1997
• Status: Expired due to Fees

• Current Assignee: Syntec Incorporated (Atos SE), Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Syntec Incorporated (Atos SE), Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Manchand, Percy Sarwood, Uskokovic, Milan Radoje
• Primary Examiner(s): QAZI, SABIHA NAIM
• Application Number:
  US09/148,018
• Time in Patent Office: 1,559 Days
• Field of Search: 552/653, 514/167
• US Class Current: 514/167
• CPC Class Codes: A61K 31/593 9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 401/00 Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation

Abstract

This invention relates to 1,3-dihydroxy-20,20-dialkyl-vitamin D₃ analogs of Formula (I):

compositions comprising the analogs, methods of preparing the analogs and methods of treatment of osteoporosis, secondary hyperparathyroidism, cancer and autoimmune diseases using such analogs.

Claims

1. A compound selected from the group of compounds represented by Formula (I)

wherein

X is hydrogen or ═

CH₂;

R¹ and R² together with C20 form a (C₃-C₆)cycloalkyl or (C₃-C₆)cyclofluoroalkyl;

R³ and R⁴ are, independently of each other, a (C₁-C₄)alkyl or (C₁-C₄)fluoroalkyl, or R³ and R⁴ together with C25 form a (C₃-C₆)cycloalkyl or (C₃-C₆)cyclofluoroalkyl;

A is a single or a double bond; and

B is a triple bond.

2. The compound of claim 1, wherein:

B is a triple bond.

3. The compound of claim 2, wherein:

R¹ and R² together with C20 form a (C₃-C₆)cycloalkyl;

R³ and R⁴ are, independently of each other, a (C₁-C₄)alkyl or a (C₁-C₄)fluoroalkyl;

X is ═

CH₂; and

A is a single bond.

4. The compound of claim 3, wherein:

R¹ and R² together with C20 form a cyclopropyl group; and

R³ and R⁴ are, independently of each other, methyl, ethyl, trifluoromethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl.

5. The compound of claim 4, wherein R³ and R⁴ are methyl namely, 1,25-dihydroxy-23-yne-20,21,28-cyclopropyl-cholecalciferol.

6. The compound of claim 4, wherein R³ and R⁴ are trifluoromethyl, namely 1,25-dihydroxy-23-yne-26,27-hexafluoro-20,21,28-cyclopropyl-cholecalciferol.

7. The compound of claim 2, wherein:

R¹ and R² together with C20 form a (C₃-C₆)cycloalkyl;

R³ and R⁴ are, independently of each other, a (C₁-C₄)alkyl or a (C₁-C₄)fluoroalkyl;

X is hydrogen; and

A is a single bond.

8. The compound of claim 7, wherein:

R¹ and R² together with C20 form a cyclopropyl group; and

R³ and R⁴ are, independently of each other, methyl, ethyl, trifluoromethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl.

9. The compound of claim 8, wherein R³ and R⁴ are methyl, namely 1,25-dihydroxy-23-yne-20,21,28-cyclopropyl-19-nor-cholecaliferol.

10. The compound of claim 8, wherein R³ and R⁴ are trifluoromethyl, namely 1,25-dihydroxy-23-yne-26,27-hexafluoro-20,21,28-cyclopropyl-19-nor-cholecaliferol.

11. The compound of claim 2, wherein:

R¹ and R² together with C20 form a (C₃-C₆)cycloalkyl;

R³ and R⁴ are, independently of each other, a (C₁-C₄)alkyl or a (C₁-C₄)fluoroalkyl;

X is ═

CH₂; and

A is a double bond.

12. The compound of claim 11, wherein:

R¹ and R² together with C20 form a cyclopropyl group; and

R³ and R⁴ are, independently of each other, methyl, ethyl, trifluoromethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl.

13. The compound of claim 2, wherein:

R¹ and R² together with C20 form a (C₃-C₆)cycloalkyl;

R³ and R⁴ are, independently of each other, a (C₁-C₄)alkyl or a (C₁-C₄)fluoroalkyl;

X is H₂; and

A is a double bond.

14. The compound of claim 13, wherein:

R¹ and R²together with C20 form a cyclopropyl group; and

R³ and R⁴ are, independently of each other, methyl, ethyl, trifluoromethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl.

15. The compound of claim 1, wherein:

A is a double bond; and

B is a double bond.

16. The compound of claim 15, wherein:

R¹ and R² together with C20 form a (C₃-C₆)cycloalkyl;

R³ and R⁴ are, independently of each other, a (C₁-C₄)alkyl or a (C₁-C₄)fluoroalkyl; and

X is ═

CH₂.

17. The compound of claim 16, wherein:

R¹ and R² together with C20 form a cyclopropyl group; and

R³ and R⁴ are, independently of each other, methyl, ethyl, trifluoromethyl, 11-difluoroethyl or 2,2,2-trifluoroethyl.

18. The compound of claim 15, wherein:

R¹ and R² together with C20 form a (C₃-C₆)cycloalkyl;

R³ and R⁴ are, independently of each other, a (C₁-C₄)alkyl or a (C₁-C₄)fluoroalkyl; and

X is H₂.

19. The compound of claim 18, wherein:

R¹ and R² together with C20 form a cyclopropyl group; and

R³ and R⁴ are, independently of each other, methyl, ethyl, trifluoromethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl.

20. The compound of claim 1, wherein:

A is a single bond; and

B is a cis double bond.

21. The compound of claim 20, wherein:

R¹ and R² together with C20 form a (C₃-C₆)cycloalkyl;

R³ and R⁴ are, independently of each other, a (C₁-C₄)alkyl or a (C₁-C₄)fluoroalkyl; and

X is ═

CH₂.

22. The compound of claim 21, wherein:

R¹ and R² together with C20 form a cyclopropyl group; and

R³ and R⁴ are, independently of each other, methyl, ethyl, trifluoromethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl.

23. The compound of claim 22, wherein R³ and R⁴ are trifluoromethyl namely, 1,25-dihydroxy-23-(Z)-ene-26,27-hexafluoro-20,21,28-cyclopropyl-cholecalciferol.

24. The compound of claim 20, wherein:

R¹ and R² together with C20 form a (C₃-C₆)cycloalkyl;

R³ and R⁴ are, independently of each other, a (C₁-C₄)alkyl or a (C₁-C₄)fluoroalkyl; and

X is H₂.

25. The compound of claim 24, wherein:

R¹ and R² together with C20 form a cyclopropyl group; and

R³ and R⁴ are, independently of each other, methyl, ethyl, trifluoromethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl.

26. The compound of claim 25, wherein R³ and R⁴ are trifluoromethyl namely, 1,25-dihydroxy-23-(Z)-ene-26,27-hexafluoro-20,21,28-cyclopropyl-19-nor-cholecalciferol.

30. A pharmaceutical composition comprising an effective amount of a compound of claim 1.

27. A method of treating osteoporosis via administration of a therapeutically effective amount of a compound of Formula (I)

wherein

X is hydrogen or ═

CH₂;

R¹ and R² together with C20 form a (C₃-C₆)cycloalkyl or (C₃-C₆)cyclofluoroalkyl;

R³ and R⁴ are, independently of each other, a (C₁-C₄)alkyl or (C₁-C₄)fluoroalkyl, or R³ and R⁴ together with C25 form a (C₃-C₆)cycloalkyl or (C₃-C₆)cyclofluoroalkyl;

A is a single or a double bond; and

B is a triple bond;

or a prodrug thereof.

28. A method of treating leukemia, colon cancer, breast cancer or prostate cancer via administration of a therapeutically effective amount of a compound of Formula (I)

wherein

X is hydrogen or ═

CH₂;

R¹ and R² together with C20 form a (C₃-C₆)cycloalkyl or (C₃-C₆)cyclofluoroalkyl;

R³ and R⁴ are, independently of each other, a (C₁-C₄)alkyl or (C₁-C₄)fluoroalkyl, or R³ and R⁴ together with C25 form a (C₃-C₆)cycloalkyl or (C₃-C₆)cyclofluoroalkyl;

A is a single or a double bond; and

B is a triple bond;

or a prodrug thereof.

29. A method of treating secondary hyperparathyroidism via administration of a therapeutically effective amount of a compound of Formula (I)

wherein

X is hydrogen or ═

CH₂;

R¹ and R² together with C20 form a (C₃-C₆)cycloalkyl or (C₃-C₆)cyclofluoroalkyl;

R³ and R⁴ are, independently of each other, a (C₁-C₄)alkyl or (C₁-₄)fluoroalkyl, or R³ and R⁴ together with C25 form a (C₃-C₆)cycloalkyl or (C₃-C₆)cyclofluoroalkyl;

A is a single or a double bond; and

B is a triple bond;

or a prodrug thereof.