Vitamin D.sub.3 analogues having an unsaturated side chain

• US 5,817,648 A
• Filed: 05/08/1996
• Issued: 10/06/1998
• Est. Priority Date: 05/09/1995
• Status: Expired due to Fees

• Current Assignee: Duphar International Research B.V. (Abbott Laboratories Incorporated)
• Original Assignee: Duphar International Research B.V. (Abbott Laboratories Incorporated)
• Inventors: Wojciechowska, Wanda, Halkes, Sebastianus, Kutner, Andrzej, van de Velde, Jan-Paul
• Primary Examiner(s): Dees, Jose G.
• Assistant Examiner(s): PRYOR, ALTON NATHANIEL
• Application Number:
  US08/646,640
• Time in Patent Office: 881 Days
• Field of Search: 514/167, 552/653
• US Class Current: 514/167
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/10 for osteoporosis
• 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 3/02 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: 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: 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: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896
• CPC Class Codes: C07J 51/00 Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00

Abstract

Vitamin D₃ analogues of the formula (I): ##STR1## wherein R₁ is hydrogen or hydroxy, R₂ is hydrogen, (C₁ -C₃) alkyl, phenyl, or trifluoromethyl, R₃ is branched or unbranched (C₁ -C₄) alkyl, cyclopropyl or CF₃, A and B are individually hydrogen or methyl, or A and B together form methylene, X is CH₂ or O, and n is 2 or 3. These compounds are useful for treating various skin and bone disorders and cancers. These compounds are also useful in cosmetic applications and for diagnostic purposes. Compounds of formula (I) are prepared by reacting a C--25 ester compound with an organometallic compound or by coupling a CD ring ester moiety with a Wittig reagent or an enyne compound to form the desired diene or triene system.

Claims

1. A vitamin D compound of the general formula ##STR20## wherein:

R¹ is a hydrogen atom or a hydroxy group,

R₂ is a hydrogen atom or a substituent selected from the group consisting of (C₁ -C₃)alkyl, phenyl and trifluoromethyl,

R₃ is a branched or unbranched (C₁ -C₄)alkyl group, a cyclopropyl group or a CF₃ group,

A and B are each individually hydrogen atoms or methyl groups, or

A and B form together a methylene group,

X is CH₂ or O,

n is 2 or 3.

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

R₁ is a hydroxy group,

R₂ is hydrogen or methyl,

R₃ is methyl, ethyl, isopropyl or cyclopropyl,

X is CH₂,

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

n is 2.

3. A method of preparing a vitamin D compound as claimed in claim 1, characterized in that an ester compound of the general formula ##STR21## wherein:

R₁ '"'"' is a hydrogen atom or a protected hydroxy group,

R₂, A, B, X and n have meanings given in claim 1,

R₄ is a protected hydroxy group, and

R₅ is a (C₁ -C₆)alkyl group;

is reacted with an organometallic compound of the general formula

space="preserve" listing-type="equation">R.sub.3 M(X).sub.p (III)

wherein;

R₃ has the meaning given in claim 1,

X is Cl, Br or I,

M is a metal selected from Li and Mg, and

p is, dependent on the valence of M, 0 or 1;

followed by deprotection.

4. A method of preparing a vitamin D compound as claimed in claim 1, characterized in that an ester compound of the general formula ##STR22## wherein:

R₂, X and n have the meanings given in claim 1,

R₄ '"'"' is an optionally protected hydroxy group, and

R₅ has the meaning given in claim 3;

is reacted with an organometallic compound of the general formula

space="preserve" listing-type="equation">R.sub.3 M(X).sub.p (III)

wherein the symbols have the meanings given in claim 3;

after which the hydrindane compound obtained, having the general formula ##STR23## is deprotected, if R₄ '"'"' is a protected hydroxy group, and then oxidized to the corresponding hydrindane-4-one compound of the general formula ##STR24## which compound of formula VI is then converted either (a) with a Wittig reagent of the general formula ##STR25## wherein;

R₁ '"'"' and R₄ have the meanings given in claim 3, and

A and B have the meanings given in claim 1;

or (b), after enolization and derivatization of the enolic hydroxy group, with an enyne compound of the general formula ##STR26## wherein R₁ '"'"' and R₄ have the above meanings, followed by hydrogenation and isomerization, to produce a compound of the general formula I, wherein A and B form together a methylene group;

followed by deprotection.

5. The method of claim 4, further comprising, before the converting step, protecting the hydroxy group of the compound of formula VI.

6. A vitamin D compound as claimed in claim 2, wherein R₂ is hydrogen, R₃ is methyl, and A and B form together a methylene group.

7. A pharmaceutical composition comprising, in addition to a pharmaceutically acceptable carrier as the active ingredient at least one compound as defined in claim 1 or 2 in an effective amount.

9. A method of preparing a compound of the general formula II, as defined in claim 8, wherein A and B form together a methylene group, characterized in that an ester compound of the general formula ##STR28## wherein:

R₂, X and n have the meanings given in claim 1,

R₅ has the meaning given in claim 3, and

R₆ is a derivatized hydroxy group;

is reacted with an enyne compound of the general formula ##STR29## wherein R₁ '"'"' and R₄ have the meanings given in claim 3;

followed by hydrogenation and isomerization.

10. A method of preparing a compound of the general formula II, as defined in claim 8, characterized in that a ketone of the general formula ##STR30## wherein:

R₂, X and n have the meanings given in claim 5, and

R₅ has the meaning given in claim 3;

is reacted with a Wittig reagent of the general formula ##STR31## wherein;

R₁ '"'"' and R₄ have the meanings given in claim 3, and

A and B have the meanings given in claim 1.

11. A method of preparing a compound of the general formula II as defined in claim 8, characterized in that a compound of the general formula ##STR32## is reacted with a reducing agent, after which the compound obtained, having the general formula ##STR33## is converted with a compound of the general formula ##STR34## wherein:

R₂ has the meaning given in claim 1,

R₅ has the meaning given in claim 3,

R₇ is a substituent selected from the group consisting of branched or unbranched (C₁ -C₄)alkoxy, phenoxy, phenyl or di(C₁ -C₄)alkylamino, and

q is 0 or 1 if n is 1 and q is 0 if n is 2.

12. A method of preparing a compound of the general formula II as defined in claim 8, wherein:

R₂ is hydrogen,

A, B, X and n have the meanings as given in claim 1, and

R₄ and R₅ have the meanings given in claim 3;

characterized in that a compound of the general formula ##STR35## is reacted with a reducing agent, after which the compound obtained, having the general formula ##STR36## is converted with a compound of the general formula ##STR37## wherein;

R₅ has the meaning given in claim 3.

13. A method for the treatment of a number of disorders or diseases in a warm-blooded living being, comprising administering to said being or treating said being with a composition as claimed in claim 7 in a quantity effective for the intended purpose, wherein said disorders or diseases comprise:

osteoporosis, renal osteodystrophy and osteomalacia;

autoimmune diseases;

acne skin aging;

imbalance in the immune system;

inflammatory diseases;

diseases related to abnormal cell differentiation and/or proliferation; and

solid, skin and blood cancers.

14. The method according to claim 13 wherein the inflammatory diseases are selected form the group consisting of rheumatoid arthritis and asthma.

15. A method for the treatment of alopecia comprising administering to a warm-blooded living being or treating said being with a composition as claimed in claim 7 in a quantity effective for the intended purpose.

8. An ester compound of the general formula II:

##STR27## wherein;

R'"'"'₁ is a hydrogen atom or a protected hydroxy group,

R₂ is a hydrogen atom or a substituent selected from the group consisting of (C₁ -C₃)alkyl, phenyl and trifluoromethyl,

R₃ is a branched or unbranched (C₁ -C₄)alkyl group, a cyclopropyl group or CF₃ group,

A and B are each individually hydrogen atoms or methyl groups, or

A and B form together a methylene group,

X is CH₂ or O,

n is 2 or 3

R₄ is a protected hydroxy group, and

R₅ is a (C₁ -C₆)alkyl group.