Vitamin D analogues

• US 6,013,814 A
• Filed: 10/20/1998
• Issued: 01/11/2000
• Est. Priority Date: 07/23/1993
• Status: Expired due to Fees

• Current Assignee: Research Institute For Medicine and Chemistry Incorporated
• Original Assignee: Research Institute For Medicine and Chemistry Incorporated
• Inventors: Ramgopal, Malathi, Reddy, Gaddam Subba, Hesse, Robert Henry, Setty, Sundara Katugam Srinivasasetty
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): COLEMAN, BRENDA LIBBY
• Application Number:
  US09/175,311
• Time in Patent Office: 448 Days
• Field of Search: 552/10, 552/4, 514/151, 514/63, 514/236.2, 514/319, 514/359, 544/132, 546/14, 546/205, 548/255
• US Class Current: 552/10
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 9/12 Antihypertensives
• 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 249/04 1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles

Abstract

The present invention relates to novel 1α-hydroxy vitamin D derivatives in which the 17-position side chain carries an azide or optionally substituted 1,2,3-triazole group, including compounds of general formula (I) where R¹ represents a methyl group having α- or β-configuration; W represents a valence bond or a C_1-5 alkylene group; X represents azide or an optionally substituted triazole group; and A═ represents a cyclohexylidene moiety characteristic of the A-ring of a 1α-hydroxylated vitamin D or analogue thereof. Active compounds of the invention exhibit cell modulating activity while exhibiting a substantial lack of calcaemic effect.

Claims

1. A compound of formula (I) ##STR10## where R¹ represents a methyl group having α

- or β

- configuration or a dimethyl, methylene or spirocyclopropyl group;

W represents a valence bond or a C_1-5 alkylene group;

X represents azide; and

A═

represents a group selected from the group consisting of ##STR11## where R⁶ and R⁷, which may be the same or different, each represent a hydrogen atom or an O-protecting group which is an etherifying group which is a tri(C_1-6 alkyl)silyl, tri-(C_6-12 aryl)silyl or mixed C_1-6 alkyl-C_6-12 arylsilyl group, a C_1-6 alkyl group optionally interrupted by an oxygen atom or a tetrahydropyranyl group or is an esterifying group which is a C_1-6 alkanoyl group, an aroyl group containing 7-15 carbon atoms, a C_1-6 alkane sulphonyl group optionally substituted with a halogen atom or a p-toluene sulphonyl group.

2. A compound as claimed in claim 1 wherein W represents a valence bond, a methylene, ethylene or trimethylene group.

3. A compound as claimed in claim 1 wherein R⁶ and R⁷ are hydrogen atoms.

4. A compound as claimed in claim 1 wherein A═

represents one of the groups selected from the group consisting of ##STR12##

5. The compound of claim 1 which is 20α

-(3-azidopropyl)-1α

,3β

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

6. The compound of claim 1 which is 20α

-azido-1α

,3β

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

7. A process for the preparation of a compound of formula (I) as defined in claim 1 which comprises one or more of:

A) isomerising a 5,6-trans isomer of formula (I) to a corresponding 5,6-cis isomer, followed if necessary and/or desired by removal of any O-protecting groups;

B) hydroxylating a 1-unsubstituted-5,6-trans analogue of a compound of formula (I) to prepare a 5,6-trans isomer of formula (I), followed if necessary and/or desired by isomerisation and/or removal of any O-protecting group;

C) reacting a compound containing a precursor for the desired 17-position side chain in one or more stages and with one or more reactants serving to form the desired side chain, followed if necessary and/or desired by isomerisation and/or removal of any O-protecting groups; and

D) reacting a compound of formula (I) to modify the substitution pattern about the A═

group, followed if necessary and/or desired by isomerisation and/or removal of any O-protecting groups.

8. A process as claimed in claim 7 wherein a compound of formula (III) ##STR13## (where L represents a leaving group) or a precursor therefor is reacted with a source of azide ions.