18-substituted-19-nor-vitamin D compounds

• US 6,359,152 B2
• Filed: 05/15/2001
• Issued: 03/19/2002
• Est. Priority Date: 07/21/1997
• Status: Expired due to Fees

• Current Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Original Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Inventors: Cai, Zu Y., DeLuca, Hector F.
• Primary Examiner(s): QAZI, SABIHA NAIM
• Application Number:
  US09/855,859
• Publication Number:
  US 20010051617A1
• Time in Patent Office: 308 Days
• Field of Search: 549/458, 549/459
• US Class Current: 549/459
• 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: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

This invention provides a novel class of vitamin D compounds, namely, 13-ethyl and 13-vinyl-18,19-dinor-vitamin D derivatives, as well as a general method for their chemical synthesis. The compounds have the formula:

where Y₁ and Y₂, which may be the same or different, are each selected from the group consisting of hydrogen and a hydroxy-protecting group, R₆ is selected from the group consisting of an ethyl or vinyl radical, and where the group R represents any of the typical side chains known for vitamin D type compounds. These 18-substituted compounds are characterized by minimal intestinal calcium transport activity and minimal bone calcium mobilization activity resulting in novel therapeutic agents for the treatment of secondary hyperparathyroidism. These compounds also exhibit pronounced activity in arresting the proliferation of undifferentiated cells and inducing their differentiation to the monocyte thus evidencing use as anti-cancer agents and for the treatment of diseases such as psoriasis.

Claims

1. A compound having the formula:

where R is represented by the structure;

where the stereochemical center at carbon 20 may have the R or S configuration, and where Z is selected from Y, —

OY, —

CH₂OY, —

C≡

CY and —

CH═

CHY, where the double bond may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, —

COR⁵ and a radical of the structure;

where m and n, independently, represent the integers from 0 to 5, where R¹ is selected from hydrogen, deuterium, hydroxy, protected hydroxy, fluoro, trifluoromethyl, and C_1-5-alkyl, which may be straight chain or branched and, optionally, bear a hydroxy or protected-hydroxy substituent, and where each of R³ and R⁴ is methyl, and where R², is selected from deuterium, deuteroalkyl, hydrogen, fluoro, trifluoromethyl and C_1-5 alkyl, which may be straight-chain or branched, and optionally, bear a hydroxy or protected-hydroxy substituent, and where R¹ and R², taken together, represent an oxo group, or an alkylidene group, ═

CR²R³, or the group —

(CH₂)_p—

, where p is an integer from 2 to 5, and where R⁵ represents hydrogen, hydroxy, protected hydroxy, or C_1-5 alkyl and wherein any of the CH-groups at positions 20, 22, or 23 in the side chain may be replaced by a nitrogen atom, or where any of the groups —

CH(CH₃)—

, —

CH(R³)—

, or —

CH(R²)—

at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom, and X is an acyl group.

2. The compound of claim 1 where X is represented by QCO—

where Q represents hydrogen or a hydrocarbon radical of from 1 to 18 carbons that may be straight chain, cyclic, branched, saturated or unsaturated.

3. The compound of claim 1 where the acyl group is selected from the group consisting of an alkaynoyl group or an alkenoyl group.

4. The compound of claim 1 where the acyl group is CH₃CO—

.