22-Thiavitamin D.sub.3 derivatives

• US 5,824,811 A
• Filed: 10/01/1996
• Issued: 10/20/1998
• Est. Priority Date: 04/11/1994
• Status: Expired due to Term

• Current Assignee: Chugai Seiyaku Kabushiki Kaisha (Roche Holding AG)
• Original Assignee: Chugai Seiyaku Kabushiki Kaisha (Roche Holding AG)
• Inventors: Kawase, Akira, Kubodera, Noboru
• Primary Examiner(s): Robinson, Allen J.
• Assistant Examiner(s): BADIO, BARBARA P
• Application Number:
  US08/718,499
• Time in Patent Office: 749 Days
• Field of Search: 552/653, 552/533, 552/560, 552/582, 514/167
• US Class Current: 552/653
• 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: C07J 31/006 not covered by C07J31/003
• CPC Class Codes: C07J 51/00 Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
• CPC Class Codes: C07J 71/0042 Nitrogen only

Abstract

Compounds of the general formula: ##STR1## wherein R₁ represents a C1-10 alkyl group which may be substituted by one or more hydroxyl groups, R₂ represents a hydrogen atom or a hydroxyl group, and R₃ represents a hydrogen atom or a hydroxyl group; their intermediates; as well as synthesis processes of these compounds and intermediates are disclosed. The compounds of this invention, vitamin D derivatives substituted by sulfur atoms at the 22-position have a strong inhibitory effect against proliferation of keratinocytes.

Claims

1. A compound of the general formula (I):

##STR21## wherein R₁ represents a C1-10 alkyl group which may be substituted by one or more hydroxyl groups provided that the terminal carbon atom of R₁ group is a primary carbon atom or a secondary carbon atom, or R₁ is an unsubstituted alkyl group or an alkyl group substituted by 2 or more hydroxyl groups, R₂ represents a hydrogen atom or a hydroxyl group, and R₃ represents a hydrogen atom or a hydroxyl group.

2. A compound according to claim 1 wherein R₃ is a hydroxyl group.

3. A compound according to claim 2 wherein R₁ is a C1-10 alkyl group substituted by two or more hydroxyl groups.

4. A compound according to claim 1 of the general formula (II):

##STR22## wherein R₁ represents a C1-10 alkyl group which may be substituted by one or more hydroxyl groups provided that the terminal carbon atom of R₁ group is a primary carbon atom or a secondary carbon atom, or R₁ is an unsubstituted alkyl group or an alkyl group substituted by 2 or more hydroxyl groups, and R₂ represents a hydrogen atom or a hydroxyl group.

5. A compound according to claim 4 wherein R₁ is a C1-10 alkyl group substituted by two or more hydroxyl groups.

6. A compound according to claim 5 wherein R₁ is a group of the general formula (III):

##STR23## wherein R₄ and R₅, which may be the same or different, each represents a hydrogen atom or a hydroxyl group provided that the both are not hydroxyl groups, m represents an integer of 1 through 4, and n represents an integer of 0 through 2.

7. A compound according to claim 1 wherein R₂ is a hydrogen atom.

8. A compound according to claim 6 wherein R₂ is a hydrogen atom.

9. A compound according to claim 6 wherein the 20-position is in R-configuration.

10. A compound according to claim 6 wherein the 20-position is in S-configuration.

11. A compound of the general formula (I):

##STR24## wherein R₁ represents a C1-10 alkyl group which may be substituted by one or more hydroxyl groups, R₂ represents a hydroxyl group, and R₃ represents a hydrogen atom or a hydroxyl group.

12. A compound according to claim 11 wherein R₃ is a hydroxyl group.

13. A compound according to claim 11 wherein R₁ is a C_1-10 alkyl group substituted by one or more hydroxyl groups.

14. A compound according to claim 11 of the general formula (II):

##STR25## wherein R₁ represents a C_1-10 alkyl group which may be substituted by one or more hydroxyl groups, and R₂ represents a hydrogen atom or a hydroxyl group.

15. A compound according to claim 11 wherein R₁ is a C_1-10 alkyl group substituted by one or more hydroxyl groups.

16. A compound according to claim 11 wherein the 20-position is in R-configuration.

17. A compound according to claim 11 wherein the 20-position is in S-configuration.

18. A compound according to claim 11 wherein R₁ is a group of the general formula (III):

##STR26## wherein R₄ and R₅, which may be the same or different, each represents a hydrogen atom or a hydroxyl group provided that the both are not hydroxyl groups, m represents an integer of 1 through 4, and n represents an integer of 0 through 2.

19. A compound according to claim 18 wherein the 20-position is in R-configuration.

20. A compound according to claim 18 wherein the 20-position is in S-configuration.

21. A compound according to claim 18 wherein the R₄ and R₅ are hydrogen atoms.

22. A compound of the formula (I):

##STR27## wherein R₂ represents a hydrogen atom or a hydroxyl group, R₃ represents a hydrogen atom or a hydroxyl group, and R₁ is a straight chain C_1-10 alkyl group which may be substituted by one or more hydroxyl groups, a branched chain C_1-10 alkyl group which may be substituted by two or more hydroxyl groups, or a group of the formula (III);

##STR28## wherein R₄ represents a hydroxyl group and R₅ represents a hydrogen atom, m represents an integer of 1 through 4, and n represents an integer of 0 through 2.

23. A compound of the formula (I):

##STR29## wherein R₂ represents a hydrogen atom or a hydroxyl group, R₃ represents a hydrogen atom or a hydroxyl group, and R₁ is selected from the group consisting of 3-hydroxy-3-methylbutyl, 2-hydroxy-3-methylbutyl, 4-hydroxy-3-methylbutyl, 2,3-dihydroxy-3-methylbutyl, 2,4-dihydroxy-3-methylbutyl, 3,4-dihydroxy-3-methylbutyl, 3-hydroxy-3-ethylpentyl, 2-hydroxy-3-ethylpentyl, 4-hydroxy-3-ethylpentyl, 2,3-dihydroxy-3-ethylpentyl, 2,4-dihydroxy-3-ethylpentyl, 3,4-dihydroxy-3-ethylpentyl, 4-hydroxy-4-methylpentyl, 3-hydroxy-4-methylpentyl, 5-hydroxy-4-methylpentyl, 3,4-dihydroxy-4-methylpentyl, 3,5-dihydroxy-4-methylpentyl, 4,5-dihydroxy-4-methylpentyl, 3-hydroxy-3-(n-propyl)hexyl, 4-hydroxy-3-(n-propyl)hexyl, 2-hydroxy-3-(n-propyl)hexyl, 2,3-dihydroxy-3-(n-propyl)hexyl, 3,4-dihydroxy-3-(n-propyl)hexyl, 2,4-dihydroxy-3-(n-propyl)hexyl, 3-hydroxy-4-ethylhexyl, 4-hydroxy-4-ethylhexyl, 5-hydroxy-4-ethylhexyl, 3,4-dihydroxy-4-ethylhexyl, 3,5-dihydroxy-4-ethylhexyl, 4,5-dihydroxy-4-ethylhexyl, 4-hydroxy-5-methylhexyl, 5-hydroxy-5-methylhexyl, 6-hydroxy-5-methylhexyl, 4,5-dihydroxy-5-methylhexyl, 4,6-dihydroxy-5-methylhexyl, 5,6-dihydroxy-5-methylhexyl, 5-hydroxy-6-methylheptyl, 6-hydroxy-6-methylheptyl, 7-hydroxy-6-methylheptyl, 5,6-dihydroxy-6-methylheptyl, 5,7-dihydroxy-6-methylheptyl, 6,7-dihydroxy-6-methylheptyl, 4-hydroxy-5-ethylheptyl, 5-hydroxy-5-ethylheptyl, 6-hydroxy-5-ethylheptyl, 4,5-dihydroxy-5-ethylheptyl, 4,6-dihydroxy-5-ethylheptyl, 5,6-dihydroxy-5-ethylheptyl, 3-hydroxy-4-(n-propyl)heptyl, 4-hydroxy-4-(n-propyl)heptyl, 5-hydroxy-4-(n-propyl)heptyl, 3,4-dihydroxy-4-(n-propyl)heptyl, 3,5-dihydroxy-4-(n-propyl)heptyl and 4,5-dihydroxy-4-(n-propyl)heptyl groups, preferably 3-hydroxy-3-methylbutyl, 2,3-dihydroxy-3-methylbutyl, 3,4-dihydroxy-3-methylbutyl, 3-hydroxy-3-ethylpentyl, 2,3-dihydroxy-3-ethylpentyl, 3,4-dihydroxy-3-ethylpentyl, 4-hydroxy-4-methylpentyl, 3,4-dihydroxy-4-methylpentyl and 4,5-dihydroxy-4-methylpentyl.

24. A compound according to claim 23 wherein R₁ is selected from the group consisting of 3-hydroxy-3-methylbutyl, 3-hydroxy-3-ethylpentyl and 4-hydroxy-4-methylpentyl.

25. A compound selected from the group consisting of 1α

,3β

-Dihydroxy-20(R)-(4-hydroxy-4-methylpentylthio)-9,10-secopregna-5,7,10(19)-triene;

1α

,3β

-Dihydroxy-20(R)-(3-ethyl-3-hydroxypentylthio)-9,10-secopregna-5,7,10(19)-triene; and

20(S)-(3-Ethyl-3-hydroxypentylthio)-1α

, 3β

,16α

-trihydroxy-9,10-secopregna-5,7,10(19)-triene.

26. A compound of the general formula (VI):

##STR30## wherein R₆ and R₇, which may be the same or different, each represents a hydrogen atom or a protective group, and R₈ represents a C1-10 alkyl group which may be substituted.

27. A compound according to claim 26 wherein the protective group is an acyl or a substituted silyl group, and R₈ is a C1-10 alkyl group substituted by one or more hydroxyl groups.

28. A compound according to claim 27 wherein R₈ is a group of the general formula (III):

##STR31## wherein R₄ and R₅, which may be the same or different, each represents a hydrogen atom or a hydroxyl group provided that the both are not hydroxyl groups, m represents an integer of 1 through 4, and n represents an integer of 0 through 2.

29. A compound according to claim 26 of the general formula (X):

##STR32## wherein R₁₂ and R₁₃, which may be the same or different, each represents a hydrogen atom or a protective group, and R₁₄ represents a C1-10 alkyl group which may be substituted.

30. A compound according to claim 29 wherein the protective group is an acyl or a substituted silyl group, and R₁₄ is a C1-10 alkyl group substituted by one or more hydroxyl groups.

31. A compound of the general formula (XI):

##STR33## wherein R₁₅ and R₁₆, which may be same or different, each represents a hydrogen atom or a protective group, and A₁ represents --CHOH-- or --CO--.

32. A compound according to claim 31 wherein the protective group is a substituted silyl group.

33. A compound according to claim 31 of the general formula (XII):

##STR34## wherein R₁₇ and R₁₈, which may be the same or different, each represents a hydrogen atom or a protective group, and A₂ represents --CHOH-- or --CO--.

34. A compound of the general formula (XIII):

##STR35## wherein R₁₉ and R₂₀, which may be the same or different, each represents a hydrogen atom or a protective group, R₂₁ represents a C1-10 alkyl group which may be substituted, and A₃ represents --CHOH-- or --CO--.

35. A compound according to claim 34 wherein the protective group is a substituted silyl group, and R₂₁ is a C1-10 alkyl group substituted by one or more hydroxyl groups.

36. A compound according to claim 35 wherein R₂₁ is a group of the general formula (III):

##STR36## wherein R₄ and R₅, which may be the same or different, each represents a hydrogen atom or a hydroxyl group provided that the both are not hydroxyl groups, m represents an integer of 1 through 4, and n represents an integer through 0 to 2.

37. A compound according to claim 34 of the general formula (XIV):

##STR37## wherein R₂₂ and R₂₃, which may be the same or different, each represents a hydrogen atom or a protective group, R₂₄ represents a C1-10 alkyl group which may be substituted, and A₄ represents --CHOH-- or --CO--.

38. A process for preparing a compound of the general formula (XVI):

##STR38## wherein R₂₅ represents a C1-10 alkyl group which may be substituted by one or more hydroxyl groups, R₂₆ and R₂₇, which may be the same or different, each represents a hydrogen atom or a protective group, and R₂₈ represents a hydrogen atom or a hydroxyl group, said process comprising the step of subjecting a compound of the general formula (XV);

##STR39## wherein R₂₅, R₂₆, R₂₇ and R₂₈ are as defined above, to a light irradiation reaction and a thermal isomerization reaction.

39. A process for preparing a compound of the general formula (VI):

##STR40## wherein R₆ and R₇, which may be the same or different, each represents a hydrogen atom or a protective group, and R₈ represents a C1-10 alkyl group which may be substituted, said process comprising the step of reacting a compound of the general formula (IV);

##STR41## wherein R₆ and R₇ are as defined above, with a compound of the general formula (V);

space="preserve" listing-type="equation">R.sub.8 --SH (V)

wherein R₈ is as defined above, under reducing conditions.

40. A process for preparing a compound of the general formula (IX):

##STR42## wherein R₉ and R₁₀, which may be the same or different, each represents a hydrogen atom or a protective group, and R₁₁ represents a C1-10 alkyl group which may be substituted, said process comprising the step of reacting a compound of the general formula (VII);

##STR43## wherein R₉ and R₁₀ are as defined above, with a compound of the general formula (VIII);

space="preserve" listing-type="equation">R.sub.11 --SH (VIII)

wherein R₁₁ is as defined above, under basic conditions.