9, 10-SECOPREGNANE DERIVATIVE AND PHARMACEUTICAL

• US 20100016263A1
• Filed: 06/01/2007
• Published: 01/21/2010
• Est. Priority Date: 06/02/2006
• Status: Active Grant

• Current Assignee: Nippon Shinyaku Company Limited
• Original Assignee: Nippon Shinyaku Company Limited
• Inventors: Shirai, Masaaki, Fujieda, Hiroki, Yasufuku, Shoji, Otsu, Hironori
• Granted Patent: US 8,796,246 B2
• Time in Patent Office: Days
• US Class Current: 514/167
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• 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

A main object of the invention is to provide a novel useful vitamin D₃ derivative, which has an excellent vitamin D₃ activity and, as compared with conventional vitamin D₃ derivatives, has a relatively small amount of influence on the systemic calcium metabolism. The invention includes a 9,10-secopregnane derivative of the following general formula [1] and a pharmaceutical composition containing it as active ingredient.

In the general formula [1], the following partial structure between the 16-position and the 17-position means a single bond or a double bond:

Y is a single bond, an alkylene, an alkenylene or phenylene; R¹ and R² are the same or different, each represents hydrogen, an alkyl or a cycloalkyl; or R¹ and R², taken together with the adjacent carbon atom, form a cycloalkyl; R³ is hydrogen or methyl; Z is hydrogen, hydroxy or —NR¹¹R¹².

Claims

1. A 9,10-secopregnane derivative of general formula [1]:

wherein the following partial structure between the 16-position and the 17-position means a single bond or a double bond;

Y represents (1) a single bond, (2) an alkylene having 1 to 5 carbon atoms and optionally substituted with 1 to 3 substituents selected from of halogen, hydroxy and oxo, (3) an alkenylene having 2 to 5 carbon atoms, or (4) phenylene;

R¹ and R² are the same or different, and each represents (1) hydrogen, (2) an alkyl having 1 to 6 carbon atoms and optionally substituted with I to 3 halogens, or (3) a cycloalkyl having 3 to 8 carbon atoms;

or R¹ and R², taken together with the adjacent carbon atom, form a cycloalkyl having 3 to 8 carbon atoms;

R³ represents hydrogen or methyl;

Z represents hydrogen, hydroxy or —

NR¹¹R¹², wherein R¹¹ represents hydrogen or an alkyl having 1 to 6 carbon atoms; and

R¹² represents (1) an alkyl having 1 to 6 carbon atoms and optionally substituted with hydroxy, or (2) an alkylsulfonyl having 1 to 6 carbon atoms;

R^a and R^b are both hydrogens, or R^a and R^b, taken together, form methylene;

R^c and R^d are the same or different, and each represents hydrogen or methyl, or R^c and R^d, taken together, form methylene;

provided that compounds where (1) R¹ and R², taken together, form methylene, (2) R^c and R^d are hydrogens, and (3) the partial structure between the 16-position and the 17-position is a single bond are excluded;

or a pharmaceutically acceptable salt thereof.

2. The 9,10-secopregnane derivative or the pharmaceutically acceptable salt thereof as claimed in claim 1, wherein Z is hydroxy.

3. The 9,10-secopregnane derivative or the pharmaceutically acceptable salt thereof as claimed in claim 1, wherein Y is an alkylene having 1 to 5 carbon atoms, or an alkenylene having 2 to 5 carbon atoms.

4. The 9,10-secopregnane derivative or the pharmaceutically acceptable salt thereof as claimed in claim 1, wherein R¹ and R² are the same or different, each is an alkyl having 1 to 6 carbon atoms and optionally substituted with 1 to 3 halogens.

5. The 9,10-secopregnane derivative or the pharmaceutically acceptable salt thereof as claimed in claim 1, wherein R³ is a methyl.

6. The 9,10-secopregnane derivative or the pharmaceutically acceptable salt thereof as claimed in claim 1, wherein Z is hydroxy, Y is ethylene or ethenylene, R¹ and R² are the same or different, each is methyl, trifluoromethyl or ethyl, and R³ is methyl.

7. The 9,10-secopregnane derivative or the pharmaceutically acceptable salt thereof as claimed in claim 1, which is a compound of the following (1) to (16):

(1) (1S,3R,20S)-20-(4-hydroxy-4-methylpentanoyloxy)-9,10-secopregna-5Z,7E,10(19),16-tetraene-1,3-diol,

(2) (1R,3R,20S)-19-nor-20-(4-hydroxy-4-methylpentanoyloxy)-9,10-secopregna-5Z,7E-diene-1,3-diol,

(3) (1R,3R,20S)-2-methylene-19-nor-20-(4-hydroxy-4-methylpentanoyloxy)-9,10-secopregna-5Z,7E-diene-1,3-diol,

(4) (1R,3R,20S)-19-nor-20-[(2E)-4-ethyl-4-hydroxyhex-2-enoyloxy]-9,10-secopregna-5Z,7E-diene-1,3-diol,

(5) (1R,3R,20S)-19-nor-20-(5,5,5-trifluoro-4-hydroxy-4-methylpentanoyloxy)-9,10-secopregna-5Z,7E-diene-1,3-diol,

(6) (1R,3R,20S)-2-methylene-19-nor-20-(5,5,5-trifluoro-4-hydroxy-4-methylpentanoyloxy)-9,10-secopregna-5Z,7E-diene-1,3-diol,

(7) (1R,3R,20S)-2-methylene-19-nor-20-[(2E)-4-ethyl-4-hydroxyhex-2-enoyloxy]-9,10-secopregna-5Z,7E-diene-1,3-diol,

(8) (1R,3R,20S)-19-nor-20-(4-hydroxy-4-methylpentanoyloxy)-9,10-secopregna-5Z,7E,16-triene-1,3-diol,

(9) (1R,3R,20S)-19-nor-20-(5,5,5-trifluoro-4-hydroxy-4-methylpentanoyloxy)-9,10-secopregna-5Z,7E,16-triene-1,3-diol,

(10) (1R,3R,20S)-19-nor-2-methylene-20-(4-hydroxy-4-methylpentanoyloxy)-9,10-secopregna-5Z,7E,16-triene-1,3-diol,

(11) (1S,3R,20S)-20-(5,5,5-trifluoro-4-hydroxy-4-methylpentanoyloxy)-9,10-secopregna-5Z,7E,10(19),16-tetraene-1,3-diol,

(12) (1R,2α

,3R,20S)-2-methyl-19-nor-20-(4-hydroxy-4-methylpentanoyloxy)-9,10-secopregna-5Z,7E-diene-1,3-diol,

(13) (1R,2β

,3R,20S)-2-methyl-19-nor-20-(4-hydroxy-4-methylpentanoyloxy)-9,10-secopregna-5Z,7E-diene-1,3-diol,

(14) (1R,3R,20S)-2-methyl-19-nor-20-(5,5,5-trifluoro-4-hydroxy-4-methylpentanoyloxy)-9,10-secopregna-5Z,7E-diene-1,3-diol,

(15) (1R,3R,20S)-2-methyl-19-nor-20-[(2E)-4-ethyl-4-hydroxyhex-2-enoyloxy]-9,10-secopregna-5Z,7E-diene-1,3-diol,

(16) (1R,3R,20S)-19-nor-2-methyl-20-(4-hydroxy-4-methylpentanoyloxy)-9,10-secopregna-5Z,7E,16-triene-1,3-diol.

8. A pharmaceutical composition, comprising a 9,10-secopregnane derivative or a pharmaceutically acceptable salt thereof of claim 1 and a pharmaceutically acceptable carrier.

9. A method of treating dyskeratosis, which comprises administering an effective amount of a 9,10-secopregnane derivative or a pharmaceutically acceptable salt thereof of claim 1 to a patient in need thereof.

10. A method of treating psoriasis vulgaris, which comprises administering an effective amount of a 9,10-secopregnane derivative or a pharmaceutically acceptable salt thereof of claim 1 to a patient in need thereof.

11. A 9,10-secopregnane derivative or a pharmaceutically acceptable salt thereof, which is a compound of the following (1) to (5):

(1) (1S,3R,20S)-20-(5-hydroxy-5-ethylheptanoyloxy)-9,10-secopregna-5Z,7E,10(19)-triene-1,3-diol,

(2) (1S,3R,20S)-20-[(4R)-5,5,5-trifluoro-4-hydroxy-4-methylpentanoyloxy]-9,10-secopregna-5Z,7E,10(19)-triene-1,3-diol,

(3) (1S,3R,20S)-20-[(4S)-5,5,5-trifluoro-4-hydroxy-4-methylpentanoyloxy]-9,10-secopregna-5Z,7E,10(19)-triene-1,3-diol,

(4) (1S,3R,20S)-20-(6,6,6-trifluoro-5-hydroxy-5-methylhexanoyloxy)-9,10-secopregna-5Z,7E,10(19)-triene-1,3-diol,

(5) (1S,3R,20S)-20-(5,5,5-trifluoro-4-hydroxy-4-methyl-3-oxopentanoyloxy)-9,10-secopregna-5Z,7E,10(19)-triene-1,3-diol.

12. A pharmaceutical composition, comprising a 9,10-secopregnane derivative or a pharmaceutically acceptable salt thereof of claim 11 and a pharmaceutically acceptable carrier.

13. A method of treating dyskeratosis, which comprises administering an effective amount of a 9,10-secopregnane derivative or a pharmaceutically acceptable salt thereof of claim 11 to a patient in need thereof.

14. A method of treating psoriasis vulgaris, which comprises administering an effective amount of a 9,10-secopregnane derivative or a pharmaceutically acceptable salt thereof of claim 11 to a patient in need thereof.