Vitamin D compounds and method of preparing these compounds

• US 6,075,015 A
• Filed: 05/27/1997
• Issued: 06/13/2000
• Est. Priority Date: 06/04/1993
• Status: Expired due to Fees

• Current Assignee: Duphar International Research B.V. (Abbott Laboratories)
• Original Assignee: Duphar International Research B.V. (Abbott Laboratories)
• Inventors: van de Velde, Jan-Paul, Mourino, Antonio, Dijkstra, Gerhardus D. H., Sestelo, Jose P., Mascarenas, Jose L., Zorgdrager, Jan, Halkes, Sebastianus J.
• Primary Examiner(s): O SULLIVAN, PETER G
• Application Number:
  US08/863,947
• Time in Patent Office: 1,113 Days
• Field of Search: 552/653, 514/167, 514/861, 514/863, 556/443
• US Class Current: 514/167
• CPC Class Codes: C07C 35/32 the condensed ring system being a (4.3.0) system, e.g. indenols
• 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 45/292 with chromium derivatives
• CPC Class Codes: C07C 49/477 having two rings
• CPC Class Codes: C07C 49/513 a keto group being part of a condensed ring system

Abstract

Vitamin D₃ analogues of the formula (I): ##STR1## wherein R₁ is hydrogen or hydroxy, R₂ is (C₁ -C₃)alkyl, hydroxy(C₁ -C₃)alkyl, (C₁ -C₂)alkoxymethyl, (C₂ -C₃)alkenyl, or (C₂ -C₃)alkynyl, R₃ is a branched or unbranched, saturated or unsaturated aliphatic 3- to 5- membered hydrocarbon or oxahydrocarbon biradical, having at least 3 atoms in the main chain and being optionally substituted with one or more substituents selected from epoxy, fluoro and hydroxy, R₄ is sec. or tert. (C₃ -C₆)alkyl or (C₃ -C₆)cycloalkyl, A and B are each individually hydrogen or methyl, or A and B together from methylene. The compounds of the present invention exhibit pharmacotherapeutic activities, including in particular, the treatment of osteoporosis, renal osteodystrophy, osteomalacia, skin disorders such as psoriasis and other hyperproliferative skin diseases, eczema and dermatitis, nmyopathy, leukemia, breast and colon cancer, osteosarcomas, squamous cell carcinomas, melanoma, certain immunological disorders, and transplant rejections. Several methods of synthesis, including reaction of an ester compound of general formula (IX) with an inorganometallic compound of formula (III) followed by deprotection or, alternatively, first finalization of the C₁₇ -side chain are also disclosed.

Claims

1. A vitamin D compound of the formula ##STR25## wherein:

R₁ is hydroxy;

R₂ is CH₃, C₂ H₅, or --CH═

CH₂ ;

R₃ is --(CH₂)₃ or --(CH₂)₄ --;

R₄, which are identical, represent the isopropyl or cyclopropyl group; and

A and B are each individually hydrogen atoms or methyl groups, or A and B form together a methylene group.

2. A vitamin D compound as claimed in claim 1, having the formula I shown in claim 1, wherein:

R₄ is, a cyclopropyl group.

3. A vitamin D compound as claimed in claim 1, having the formula I shown in claim 1, wherein:

R₂ has the meaning given in claim 1; and

R₄ is an isopropyl group.

4. A pharmaceutical composition comprising, in addition to a pharmaceutically acceptable carrier and/or at least one pharmaceutically acceptable auxillary substance, as the active ingredient at least one compound as defined in claim 1, in an effective amount.

5. A composition an claimed in claim 4, in a dosage unit form, for oral, topical (dermal) or parenteral administration, comprising approx. 0.1 μ

g to approx. 0.1 mg active ingredient per dosis unit.

6. A composition for diagnostic purposes comprising, in addition to a compatible, non-toxic carrier and/or at least one auxillary substance, as the active ingredient at least one compound as defined in claim 1, in an effective amount.

7. A cosmetical composition, preferably selected from the group consisting of creams, lipocreams, lotions, ointments, liposomes and gels, comprising in addition to a cosmetically acceptable, non-toxic carrier and/or at least one auxillary substance, as the active ingredient at least one compound as defined in claim 1, in an effective amount.

8. A pharmaceutical composition comprising, in addition to a pharmaceutically acceptable carrier and/or at least one pharmaceutically acceptable auxiliary substance, as the active ingredient at least one compound as defined in claim 2 in a effective amount.

9. A pharmaceutical composition comprising, in addition to pharmaceutically acceptable carrier and/or at least one pharmaceutically acceptable auxiliary substance, as the active ingredient at least one compound as defined in claim 3 in a effective amount.

10. A composition as claimed in claim 8, in a dosage unit form, for oral, topical (dermal) or parenteral administration, comprising approximately 0.1 μ

g to approximately 0.1 mg active ingredient per dosis unit.

11. A composition as claimed in claim 9, in a dosage unit form, for oral, topical (dermal) or parenteral administration, comprising approximately 0.1 μ

g to approximately 0.1 mg active ingredient per dosis unit.

12. A composition for diagnostic purposes comprising, in addition to compatible, non-toxic carrier and/or at least one auxiliary substance, as the active ingredient at least one compound as defined in claim 2 in an effective amount.

13. A composition for diagnostic purposes comprising, in addition to compatible, non-toxic carrier and/or at least one auxiliary substance, as the active ingredient at least one compound as defined in claim 3 in an effective amount.

14. A cosmetical composition, preferably selected from the group consisting of creams, lipocreams, lotions, ointments, liposomes and gels, comprising in addition to a cosmetically acceptable, non-toxic carrier and/or at least one auxiliary substance, as the active ingredient at least one compound as defined in claim 2 in an effective amount.

15. A cosmetical composition, preferably selected from the group consisting of creams, lipocreams, lotions, ointments, liposomes and gels, comprising in addition to a cosmetically acceptable, non-toxic carrier and/or at least one auxiliary substance, as the active ingredient at least one compound as defined in claim 3 in an effective amount.