20-position modified pharmaceutically active vitamin D series compounds

• US 5,585,368 A
• Filed: 06/24/1993
• Issued: 12/17/1996
• Est. Priority Date: 06/24/1992
• Status: Expired due to Fees

• Current Assignee: Schering Ag (Merck & Co., Inc.)
• Original Assignee: Schering Ag (Merck & Co., Inc.)
• Inventors: Thieroff-Ekerdt, Ruth, Haberey, Martin, Kirsch, Gerald, Steinmeyer, Andreas, Wiesinger, Herbert, Neef, Gunter, Schwarz, Katica
• Primary Examiner(s): PRIOR, KIMBERLY
• Application Number:
  US08/080,841
• Time in Patent Office: 1,272 Days
• Field of Search: 552/653, 514/167
• US Class Current: 514/167
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• 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: C07C 45/30 with halogen containing compounds, e.g. hypohalogenation
• CPC Class Codes: C07C 45/305 with halogenochromate reagents, e.g. pyridinium chlorochromate
• CPC Class Codes: C07C 49/517 containing ether groups, groups, groups, or groups
• CPC Class Codes: C07C 49/753 containing ether groups, groups, groups, or groups
• CPC Class Codes: C07C 69/013 Esters of alcohols having the esterified hydroxy group bound to a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896

Abstract

The invention relates to vitamin D derivatives, modified in 20-position, of general formula I ##STR1## in which X, Y, Z, R₁, R₂ as well as R₃ have the meaning indicated in the description, process for their production and their use as agents for treatment of hyperproliferative diseases of the skin.

Claims

1. A vitamin D compound of the formula ##STR51## in which Y means a hydrogen atom, an alkanoyl group of 1 to 9 carbon atoms, or an aroyl group, wherein each Y is chosen independently;

Z means a hydrogen atom, a hydroxyl group or an alkanoyloxy group of 1 to 9 carbon atoms,

X means a hydrogen atom or both X'"'"'s together mean an exocyclic methylene group,

R₁ and R₂ together mean a methylene group or together with carbon atom 20 form a cyclopropyl unit,

R₃ means a linear or branched alkyl group of 1 to 5 carbon atoms or a trifluoromethyl group, or the two R₃ group together with carbon atom 25 form a cyclopropyl or cyclopentyl ring;

L means the grouping ##STR52## in which A represents an oxygen atom, and B represents an alkylene group --(CH₂)_n --, in which n=1, 2, 3, 4, 5 or 6, or

L means grouping ##STR53## in which D represents a direct bond, a methylene bridge or a 1,2-ethenediyl bridge (E-double bond) between carbon atoms 20 and 22, E and F respectively represent a hydrogen atom, or together a second bond (E-double bond), and

G represents a direct bond or an alkylene group --(CH₂)_n --, in which n=1, 2, 3, 4, 5 or 6 or a corresponding alkylene group in which a methylene group is replaced by an oxygen atom.

2. A vitamin D compound according to claim 1, wherein each Y is a hydrogen atom or alkanoyl radical of a saturated alkanecarboxylic acid or benzoyl and Z is a hydroxyl group or an alkanoyloxy radical of a saturated alkanecarboxylic acid or benzoyloxy.

3. A vitamin D compound according To claim 1, wherein each R₃ is a methyl, ethyl or propyl group or the two R₃ groups together with carbon atom 25 form a cyclopropyl or cyclopentyl ring.

4. A vitamin D compound according to claim 1, wherein both Y'"'"'s each stand for a hydrogen atom, Z stands for a hydroxyl group and R³ each stand for a methyl, ethyl or propyl group.

5. A vitamin D compound of claim 1 wherein R₁ and R₂ collectively are methylene or with the carbon atom 20 form a cyclopropyl group, Z is a hydroxyl group or an alkanoyloxy group and each R₃ group is a methyl, ethyl or propyl group.

6. A vitamin D compound of claim 5 wherein Y and Z are hydroxyl groups.

7. A vitamin D compound of claim 6 wherein the two X groups collectively are methylene.

8. A vitamin D compound according to claim 1, wherein L is the grouping --CH₂ --A--B-- wherein A is oxa.

9. A vitamin D compound according to claim 1, wherein Z is a hydroxy group.

10. A compound according to claim 1, wherein

R₁ and R₂ together a methylene group and both X each a hydrogen;

R₁ and R₂ together a methylene group and both X together a methylene group;

R₁ and R₂ together with C(20) a cyclopropyl ring and both X together a methylene group;

or

R₁ and R₂ together with C(20) a cyclopropyl ring and both X each a hydrogen.

11. A vitamin D compound according to claim 1, wherein each X is a hydrogen atom or both X together are a methylene group and the 17 position side chain is one of the following:

##STR54##

12. A vitamin D compound according to claim 1, which is

(5Z,7E)-(1S,3R)-20,21-methylene-23-oxa-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol;

(5Z,7E)-(1S,3R)-26,27-dimethyl-20,21-methylene-23-oxa-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol;

(5Z,7E)-(1S,3R)-26,27-diethyl-20,21-methylene-23-oxa-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol;

(5Z,7E)-(1S,3R)-24-(3-hydroxy-3-methylbutyl)-20,21-methylene-23-oxa-9,10-secochola-5,7,10(19)-triene-1,3-diol;

or

(5Z,7E)-(1S,3R)-24-(3-ethyl-3hydroxypentyl)-20,21-methylene-23-oxa-9,10-secochola-5,7,10(19)-triene-1,3-diol.

13. The vitamin D compound according to claim 1, which is (5Z,7E)-(1S,3R)-26,27-Diethyl-20,21-methylen-23-oxa-9,10-secocholesta-5,7,10(19)-trien-1,3,25triol.

14. A pharmaceutical preparation comprising a compound according to claim 1, and a pharmaceutically compatible vehicle.

15. The pharmaceutical preparation according to claim 14, wherein the vehicle is suitable for topical use.