Vitamin d derivatives

• US 20040019023A1
• Filed: 07/21/2003
• Published: 01/29/2004
• Est. Priority Date: 06/15/2000
• Status: Active Grant

• Current Assignee: Chugai Seiyaku Kabushiki Kaisha (Roche Holding AG)
• Original Assignee: Chugai Seiyaku Kabushiki Kaisha (Roche Holding AG)
• Inventors: Kawase, Akira, Emura, Takashi, Shimizu, Kazuki, Ohmori, Masayuki, Morikawa, Kazumi
• Granted Patent: US 7,985,744 B2
• Time in Patent Office: Days
• US Class Current: 514/167
• CPC Class Codes: A61K 31/592 9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
• CPC Class Codes: A61K 31/593 9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: C07C 235/06 having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2602/24 the ring system containing nine carbon atoms, e.g. perhydroindane
• 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
• CPC Class Codes: C07D 295/185 from aliphatic carboxylic acids
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896
• CPC Class Codes: C07J 7/00 Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms C07J5/00 takes precedence
• CPC Class Codes: C07J 9/00 Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The object of the present invention is to provide vitamin D derivatives that have excellent physiological activities as medicines, particularly as therapeutic agents for skin diseases such as psoriasis, and that have a reduced hypercalcemic effect.

The present invention provides a vitamin D derivative of Formula (1):

wherein

X represents an oxygen atom or a sulfur atom;

m represents a number of 1 to 3;

R₁ and R₂ each represent a hydrogen atom or an alkyl group;

R₄ and R₅ each represent a hydrogen atom or a hydroxyl group, etc.;

R₃ represents —YR₈, etc.;

R₆ represents a hydrogen atom, etc.; and

R₇ represents a hydrogen atom, etc.

Claims

1. A vitamin D derivative of Formula (1):

2. The vitamin D derivative according to claim 1, wherein in formula (1), X represents an oxygen atom or a sulfur atom, m represents a number of 1 to 3, R₁ and R₂ each represent a hydrogen atom or a C₁-C₄ alkyl group, R₄ and R₅ each represent a hydrogen atom or a hydroxyl group, or R₄ and R₅ together form a double bond between the 16- and 17-positions, R₃ represents —

YR₈ (wherein Y represents an oxygen atom or a sulfur atom, R₈ represents a hydrogen atom, a linear or branched C₁-C₁₅ alkyl group which may be substituted with a fluorine atom or a cyclic C₃-C₁₀ alkyl group, or a cyclic C₃-C₁₅ alkyl group which may be substituted with a fluorine atom) or —

NR₉R₁₀ (wherein R₉ and R₁₀ each represent a hydrogen atom, a linear or branched C₁-C₁₅ alkyl group which may be substituted with a fluorine atom or a cyclic C₃-C₁₀ alkyl group, or a cyclic C₃-C₁₅ alkyl group which may be substituted with a fluorine atom, or R₉ and R₁₀ form a 3- to 10-membered ring together with the nitrogen atom when R₄ and R₅ together form a double bond between the 16- and 17-positions), R₆ represents a hydrogen atom or a hydroxyl group, and R₇ represents a hydrogen atom.

3. The vitamin D derivative according to claim 1, wherein in formula (1), X represents an oxygen atom or a sulfur atom, m represents a number of 1 to 2, R₁ and R₂ each represent a hydrogen atom or a methyl group, R₄ and R₅ simultaneously represent a hydrogen atom, R₄ represents a hydrogen atom while R₅ represents a hydroxyl group, or R₄ and R₅ together form a double bond between the 16- and 17-positions, R₃ represents —

YR₈ (wherein Y represents an oxygen atom or a sulfur atom, R₈ represents a hydrogen atom, a linear or branched C₁-C₁₀ alkyl group which may be substituted with a fluorine atom or a cyclic C₃-C₈ alkyl group, or a cyclic C₃-C₁₂ alkyl group which may be substituted with a fluorine atom) or —

NR₉R₁₀ (wherein R₉ and R₁₀ each represent a hydrogen atom, a linear or branched C₁-C₁₀ alkyl group which may be substituted with a fluorine atom or a cyclic C₃-C₈ alkyl group, or a cyclic C₃-C₁₂ alkyl group which may be substituted with a fluorine atom, or R₉ and R₁₀ form a 3- to 10-membered ring together with the nitrogen atom when R₄ and R₅ together form a double bond between the 16- and 17-positions), R₆ represents a hydroxyl group, and R₇ represents a hydrogen atom.

4. The vitamin D derivative according to claim 1, wherein in formula (1), X represents an oxygen atom or a sulfur atom, m represents a number of 1 to 2, R₁ and R₂ each represent a hydrogen atom or a methyl group, R₄ and R₅ each represent a hydrogen atom, or R₄ and R₅ together form a double bond between the 16- and 17-positions, R₃ represents —

YR₈ (wherein Y represents an oxygen atom or a sulfur atom, R₈ represents a hydrogen atom, a linear or branched C₁-C₈ alkyl group which may be substituted with a fluorine atom or a cyclic C₃-C₈ alkyl group, or a cyclic C₃-C₈ alkyl group which may be substituted with a fluorine atom) or —

NR₉R₁₀ (wherein R₉ and R₁₀ each represent a hydrogen atom, a linear or branched C₁-C₈ alkyl group which may be substituted with a fluorine atom or a cyclic C₃-C₈ alkyl group, or a cyclic C₃-C₈ alkyl group which may be substituted with a fluorine atom, or R₉ and R₁₀ form a 3- to 8-membered ring together with the nitrogen atom when R₄ and R₅ together form a double bond between the 16- and 17-positions), R₆ represents a hydroxyl group, and R₇ represents a hydrogen atom.

5. The vitamin D derivative according to claim 1, wherein in formula (1), X represents an oxygen atom or a sulfur atom, m represents a number of 1 to 2, R₁ and R₂ each represent a hydrogen atom or a methyl group, R₃ represents —

YR₈ (wherein Y represents an oxygen atom or a sulfur atom, R₈ represents a hydrogen atom, a linear or branched C₁-C₈ alkyl group which may be substituted with a fluorine atom or a cyclic C₃-C₆ alkyl group, or a cyclic C₃-C₈ alkyl group which may be substituted with a fluorine atom), R₄ and R₅ each represent a hydrogen atom, or R₄ and R₅ together form a double bond between the 16- and 17-positions, R₆ represents a hydroxyl group, and R₇ represents a hydrogen atom.

6. The vitamin D derivative according to claim 1, wherein in formula (1), X represents an oxygen atom or a sulfur atom, m represents 1, R₁ and R₂ each represent a hydrogen atom or a methyl group, R₄ and R₅ each represent a hydrogen atom, or R₄ and R₅ together form a double bond between the 16- and 17-positions, R₃ represents —

NR₉R₁₀ (wherein R₉ and R₁₀ each represent a hydrogen atom, a linear or branched C₁-C₈ alkyl group which may be substituted with a fluorine atom or a cyclic C₃-C₆ alkyl group, or a cyclic C₃-C₈ alkyl group which may be substituted with a fluorine atom, or R₉ and R₁₀ form a 3- to 6-membered ring together with the nitrogen atom when R₄ and R₅ together form a double bond between the 16- and 17-positions), R₆ represents a hydroxyl group, and R₇ represents a hydrogen atom.

7. The vitamin D derivative according to claim 1, wherein in formula (1), X represents an oxygen atom or a sulfur atom, m represents a number of 1 to 2, R₁ and R₂ each represent a hydrogen atom or a methyl group, R₃ represents —

OR₈ (wherein R₈ represents a branched C₃-C₈ alkyl group), R₄ and R₅ each represent a hydrogen atom, or R₄ and R₅ together form a double bond between the 16- and 17-positions, R₆ represents a hydroxyl group, and R₇ represents a hydrogen atom.

8. The vitamin D derivative according to claim 1, wherein in formula (1), X represents an oxygen atom or a sulfur atom, m represents a number of 1 to 2, R₁ and R₂ each represent a hydrogen atom or a methyl group, R₃ represents —

SR₈ (wherein R₈ represents a branched C₃-C₈ alkyl group), R₄ and R₅ each represent a hydrogen atom, or R₄ and R₅ together form a double bond between the 16- and 17-positions, R₆ represents a hydroxyl group, and R₇ represents a hydrogen atom.

9. The vitamin D derivative according to claim 1, wherein in formula (1), X represents an oxygen atom or a sulfur atom, m represents 1, R₁ and R₂ each represent a hydrogen atom or a methyl group, R₃ represents —

NR₉R₁₀ (wherein R₉ represents a hydrogen atom or a linear or branched C₁-C₄ alkyl group, R₁₀ represents a linear or branched C₁-C₈ alkyl group which may be substituted with a fluorine atom), R₄ and R₅ each represent a hydrogen atom, or R₄ and R₅ together form a double bond between the 16- and 17-positions, R₆ represents a hydroxyl group, and R₇ represents a hydrogen atom.

10. The vitamin D derivative according to claim 1, wherein in formula (1), X represents an oxygen atom, m represents a number of 1 to 2, R₁ and R₂ each represent a hydrogen atom or a methyl group, R₃ represents —

OR₈ (wherein R₈ represents a branched C₆-C₈ alkyl group), R₄ and R₅ each represent a hydrogen atom, or R₄ and R₅ together form a double bond between the 16- and 17-positions, R₆ represents a hydroxyl group, and R₇ represents a hydrogen atom.

11. The vitamin D derivative according to claim 1, wherein in formula (1), X represents an oxygen atom, m represents a number of 1 to 2, R₁ and R₂ each represent a hydrogen atom or a methyl group, provided that one of R₁ and R₂ should represent a methyl group, R₃ represents —

OR₈ (wherein R₈ represents a branched C₆-C₈ alkyl group), R₄ and R₅ together form a double bond between the 16- and 17-positions, R₆ represents a hydroxyl group, and R₇ represents a hydrogen atom.

12. The vitamin D derivative according to claim 1, wherein in formula (1), X represents an oxygen atom, m represents 1, R₁ and R₂ each represent a hydrogen atom or a methyl group, provided that one of R₁ and R₂ should represent a methyl group, R₃ represents —

NR₉R₁₀ (wherein R₉ represents a hydrogen atom or a methyl group, R₁₀ represents a linear or branched C₁-C₄ alkyl group which may be substituted with a fluorine atom), R₄ and R₅ together form a double bond between the 16- and 17-positions, R₆ represents a hydroxyl group, and R₇ represents a hydrogen atom.

13. The vitamin D derivative according to claim 1, wherein in formula (1), X represents an oxygen atom, m represents 1, R₁ and R₂ each represent a hydrogen atom or a methyl group, provided that one of R₁ and R₂ should represent a methyl group, R₃ represents —

NR₉R₁₀ (wherein R₉ represents a hydrogen atom, R₁₀ represents a propyl group which may by substituted with a fluorine atom), R₄ and R₅ together form a double bond between the 16- and 17-positions, R₆ represents a hydroxyl group, and R₇ represents a hydrogen atom.

21. A pharmaceutical composition comprising the vitamin D derivative according to any one of claims 1 to 20.

22. A therapeutic agent for skin diseases, which comprises the vitamin D derivative according to any one of claims 1 to 20 as an active ingredient.

23. The therapeutic agent for skin diseases according to claim 22, wherein the skin disease is psoriasis.

26. A method of treating skin diseases, which comprises the step of administering to a patient in need of such reaction a therapeutically effective amount of the vitamin D derivative according to claim 1.

27. The method according to claim 26, wherein the skin disease is psoriasis.

14. 1α

,3β

-Dihydroxy-20(S)-(1-ethyl-1-methylpropoxycarbonylmethoxy)-9,10-secopregna-5,7,10(19),16-tetraene.

15. 1α

,3β

-Dihydroxy-20(S)-(1-isopropyl-2-methylpropoxycarbonylmethoxy)-9,10-secopregna-5,7,10(19),16-tetraene.

16. 1α

,3β

-Dihydroxy-20(S)-(1,1-dimethylbutoxycarbonylmethoxy)-9,10-secopregna-5,7,10(19),16-tetraene.

17. 1α

,3β

-Dihydroxy-20(S)-(1,1-dimethylhexyloxycarbonylmethoxy)-9,10-secopregna-5,7,10(19),16-tetraene.

18. 1α

,3β

-Dihydroxy-20(S)-{2-(1-ethyl-1-methylpropoxycarbonyl)ethoxy}-9,10-secopregna-5,7,10(19),16-tetraene.

19. {(1α

,3β

-Dihydroxy-9,10-secopregna-5,7,10(19),16-tetraen-20(S)-yl)oxy}-N-(2,2,3,3,3-pentafluoropropyl)acetamide.

20. 1α

,3β

-Dihydroxy-20(S)-(1-ethyl-1-methylpropoxycarbonylmethoxy)-9,10-secopregna-5,7,10(19)-triene.

24. A method of carbonylating a compound of Formula (2):

25. The method according to claim 24, wherein the organoaluminum reagent has Formula (4):

(R₁₅)_nAlW_3-n 

 

(4)

wherein

n represents an integer of 1 to 3, R₁₅ represents an alkyl group, an aryl group, an alkenyl group or an alkynyl group, and W represents a halogen atom.