Vitamin D amide derivatives

• US 5,494,905 A
• Filed: 05/31/1994
• Issued: 02/27/1996
• Est. Priority Date: 11/07/1991
• Status: Expired due to Fees

• Current Assignee: Research Institute For Medicine and Chemistry Incorporated
• Original Assignee: Research Institute For Medicine and Chemistry Incorporated
• Inventors: Setty, Sundara K. S., Reddy, Gaddam S., Hesse, Robert H.
• Primary Examiner(s): Kumar, Shailendra
• Application Number:
  US08/211,722
• Time in Patent Office: 637 Days
• Field of Search: 552/547, 552/501, 552/544, 552/653, 552/505, 514/167, 514/169, 514/319, 564/188, 564/189, 546/205
• US Class Current: 514/167
• CPC Class Codes: A61P 19/10 for osteoporosis
• 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 35/00 Antineoplastic agents
• 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: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention pertains to vitamin D amide derivatives of formula (I). These novel 1α-hydroxy vitamin D derivatives and their 20-epi analogues comprise compounds of formula (I) and corresponding 5,6-trans isomers, where Y represents an alkylene or alkenylene group containing up to four carbon atoms; R¹ and R² independently represent a hydrogen atom or a lower alkyl or cycloalkyl group, or R¹ R² N-- represents a heterocyclic group; and R³ and R⁴ independently represent a hydrogen atom or an 0-protecting group. Active compounds, in which R³ and R⁴ are hydrogen atoms or metabolically labile 0-protecting groups exhibit potent cell modulating effect, but minimal effect on calcium metabolism.

Claims

1. Compounds of general formulae (I) and (II) ##STR6## wherein Y represents an alkylene or alkenylene group containing up to 4 carbon atoms;

R¹ and R², which may be the same or different, each represents a hydrogen atom or a lower alkyl or cycloalkyl group or together with the nitrogen atom to which they are attached form a piperidino group; and

R³ and R⁴, which may be the same or different, each represents a hydrogen atom or an O-protecting group.

2. Compounds as claimed in claim 1 wherein Y represents a group of formula

3. Compounds as claimed in claim 1 wherein Y is a C_2-4 alkylene group.

4. Compounds as claimed in claim 1 wherein at least one of R¹ and R² is other than hydrogen.

5. Compounds as claimed in claim 1 wherein R¹ and R² are selected from hydrogen atoms, methyl and cyclopropyl groups, or R¹ R² N-- represents a piperidino group.

6. Compounds as claimed in claim 1 wherein R³ and R⁴ represent etherifying silyl groups.

7. Compounds as claimed in claim 1 wherein R³ and R⁴ are selected from hydrogen atoms and metabolically labile etherifying or esterifying groups.

10. Pharmaceutical compositions comprising a compound as claimed in claim 7 or in admixture with one or more physiologically acceptable carriers or excipients.

8. The compounds:

1α

,3β

-dihydroxy-9,10-seco-25-azacholesta-5(Z),7,10(19)-trien-24-one;

1α

,3β

-dihydroxy-23,23-bishomo-24-aza-9,10-secosholesta-5(Z), 7,10(19)-trien-24-one;

1α

,3β

-dihydroxy-27-nor-9,10-secocholesta-5(Z), 7,10(19),22,24-pentaene-26-carboxylic acid, 26-dimethyl amide;

N,N-pentamethylene-1α

,3β

-dihydroxy-9,10 -secocholanamide-5(Z), 7,10(19)-triene;

N-cyclopropyl-1α

,3β

-dihydroxy-9,10 -secocholanamide-5(Z), 7,10(19)-triene;

11. A pharmaceutical composition comprising a compound as claimed in claim 8 in admixture with one or more physiologically acceptable carriers or excipients.

9. α

. 3β

-dihydroxy-9,10 -secocholanamide-5(Z), 7,10(19)-triene;

N,N-pentamethylene-1α

,3β

-dihydroxy-9,10 -seco-20 -epi-cholanamide-5(Z),7,10(19-triene; and

corresponding 5(E)-isomers thereof.