Vitamin-D amide derivatives

• US 5,811,562 A
• Filed: 11/20/1996
• Issued: 09/22/1998
• Est. Priority Date: 03/23/1994
• Status: Expired due to Fees

• Current Assignee: Research Institute For Medicine and Chemistry Incorporated
• Original Assignee: Research Institute For Medicine and Chemistry Incorporated
• Inventors: Hesse, Robert Henry, Setty, Sundara Katugam Srinivasasetty
• Primary Examiner(s): Clardy, S. Mark
• Assistant Examiner(s): PRYOR, ALTON NATHANIEL
• Application Number:
  US08/704,613
• Time in Patent Office: 671 Days
• Field of Search: 552/653, 546/226, 514/167
• US Class Current: 552/653
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• 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: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/18 of the parathyroid hormones
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/02 : Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• 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

The present invention relates to compounds of general formula (I) ##STR1## where R¹ and R², which may be the same or different, each represent a hydrogen atom or an aliphatic, cycloaliphatic, araliphatic or aryl group or together with the nitrogen atom to which they are attached form a heterocyclic group; R³ represents a methyl group having α- or β-configuration; one of R^a and R^b represents a hydroxy group or protected hydroxy group and the other represents a hydrogen atom; Y represents a valence bond or an alkylene group containing up to 3 carbon atoms; 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 separation of cell modulating and calcaemic activities coupled with enhanced duration of activity.

Claims

1. Compounds of general formula (I) ##STR13## where R¹ and R², which may be the same or different, each represent a hydrogen atom or an aliphatic, cycloaliphatic, araliphatic or aryl group or together with the nitrogen atom to which they are attached form a heterocyclic group;

R³ represents a methyl group having α

- or β

-configuration;

one of R^a and R^b represents a hydroxy group or protected hydroxy group and the other represents a hydrogen atom;

Y represents a valence bond or an alkylene group containing up to 3 carbon atoms; and

A= represents a cyclohexylidene moiety characteristic of the A-ring of a 1α

-hydroxylated vitamin D or analogue thereof.

2. Compounds as claimed in claim 1 in which R¹ and R² are each selected from hydrogen atoms, lower alkyl, lower cycloalkyl, C_6-12 aryl C_1-4 alkyl and optionally substituted C_6-12 aryl groups.

3. Compounds as claimed in claim 2 in which R¹ and R² are each selected from methyl, ethyl, isopropyl and phenyl groups.

4. Compounds as claimed in claim 1 in which R¹ R² N-represents a heterocyclic group comprising one or more 5- and/or 6-membered rings and optionally containing one or more further heteroatoms selected from O, N and S.

5. Compounds as claimed in claim 4 in which R¹ R² N-represents piperidino or morpholino.

6. Compounds as claimed in claim 1 in which one of R^a and R^b represents a protected hydroxy group wherein the protecting group is a lower alkyl group optionally interrupted by one or more oxygen atoms.

7. Compounds as claimed in claim 1 in which A= represents one of the groups ##STR14## where R⁴ and R⁵ are each selected from hydrogen atoms and O-protecting groups.

8. Compounds as claimed in claim 7 in which R⁴ and R⁵ represent etherifying silyl groups.

9. Compounds as claimed in claim 7 in which R⁴ and R⁵ are selected from hydrogen atoms and metabolically labile etherifying or esterifying groups.

10. Compounds as claimed in claim 1 wherein A= represents one of the groups ##STR15##

11. 20,20-Dimethyl, 20-methylene and 20-spirocyclopropyl analogues of compounds as claimed in claim 1.

12. Pharmaceutical compositions comprising an active compound as claimed in claim 1 in admixture with one or more physiologically acceptable carriers or excipients.

13. A method of treatment of a human or animal subject to promote treatment of osteoporosis, wound healing, suppression of parathyroid hormone or neoplastic disease, infection, bone disease, autoimmune disease, host-graft reaction, transplant rejection, inflammatory disease, neoplasia, hyperplasia, myopathy, enteropathy, spondylitic heart disease, dermatological disease, rheumatoid arthritis, psoriatic arthritis, or secondary hyperparathyroidism, comprising administration to said subject of an effective amount of an active compound as claimed in claim 1.