20-methyl-substituted vitamin D derivatives

• US 5,446,035 A
• Filed: 09/16/1994
• Issued: 08/29/1995
• Est. Priority Date: 12/13/1991
• Status: Expired due to Fees

• Current Assignee: Schering Ag (Merck & Co., Inc.)
• Original Assignee: Schering Ag (Merck & Co., Inc.)
• Inventors: Thieroff-Ekerdt, Ruth, Haberey, Martin, Kirsch, Gerald, Steinmeyer, Andreas, Wiesinger, Herbert, Neef, Gunter, Schwarz, Katica
• Primary Examiner(s): Mars, Howard T.
• Assistant Examiner(s): Kestler, Kimberly J.
• Application Number:
  US08/307,081
• Time in Patent Office: 347 Days
• Field of Search: 552/653, 514/167
• US Class Current: 514/167
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/14 for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• 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 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

Abstract

New 20-methyl-substituted vitamin D derivatives of general formula I ##STR1## are described in which

R¹ means a hydrogen atom, a hydroxy group or an alkanoyloxy group with 1 to 12 carbon atoms or a benzoyloxy group,

R² means a hydrogen atom or an alkanoyl group with 1 to 12 carbon atoms or a benzoyl group and

R³ means a saturated or unsaturated, straight-chain or branched hydrocarbon radical with up to 18 C atoms, which optionally contains carbocyclic structures, optionally substituted with one or more hydroxy, oxo, amino group(s) and/or one or more halogen atom(s) as well as optionally exhibits one or more oxygen, sulfur and/or nitrogen atom(s) as a bridging link or links in the hydrocarbon radical, and a process for their production.

Relative to calcitriol, the new compounds exhibit a greatly improved induction of cell differentiation (HL-60) and are suitable for the production of pharmaceutical agents.

Claims

1. A 20-Methyl-substituted vitamin D compound of formula I ##STR8## wherein R¹ is a hydrogen atom, a hydroxy group, a C₁ -C₁₂ -alkanoyloxy group, or a benzoyloxy group;

R² is a hydrogen atom, a C₁ -C₁₂ -alkanoyl group, or a benzoyl group; and

R³ is a saturated or unsaturated, straight-chain or branched C₁ -C₁₈ -hydrocarbon group, which group optionally contains a C_3-10 -cycloalkyl or -cycloalkenyl moiety, said hydrocarbon group optionally being substituted with at least one of hydroxy, oxo, amino or halogen, and in which at least one carbon atom is optionally replaced by an oxygen, sulfur or nitrogen atom.

2. A 20-methyl-substituted vitamin D compound according to claim 1, wherein R³ is ##STR9## R is C₁ -C₄ -alkyl, C₁ -C₄ -hydroxyalkyl, or C₁ -C₄ -alkoxy.

4. A topical pharmaceutical composition, comprising a compound according to claim 1 and a pharmacologically compatible vehicle.

5. A pharmaceutical composition, comprising a compound of claim 1 and a pharmacologically compatible vehicle.

6. A pharmaceutical composition according to claim 5, wherein the vehicle is compatible with oral administration.

7. A pharmaceutical composition according to claim 5, wherein the vehicle is compatible with intravenous administration.

3. 1α

,25-dihydroxy-20,26,27-trimethyl-23-oxa-vitamin D₃ ;

1(S),3(R)-dihydroxy-20-(5-hydroxy-5-methyl-hexa-1E,3E-dien-1-yl)-20-methyl-9,10-secopregna-5Z, 7E,10(19)-triene;

1α

,25-dihydroxy-20-methyl-vitamin D₃ ;

1α

,25-dihydroxy-20-methyl-24-homo-vitamin D₃ ;

1α

,24(S)-dihydroxy-20-methyl-vitamin D₃ ;

1α

,25-dihydroxy-20-methyl-23-oxa-vitamin D₃ ;

1α

,25-dihydroxy-20-methyl-23 -dehydro-vitamin D₃ ;

1α

,25-dihydroxy-20,26,27-trimethyl-23-dehydro-vitamin D₃ ;

1α

,24(R),25-trihydroxy-20-methyl-vitamin D₃ ;

1α

,24(S),25-trihydroxy-20-methyl-vitamin D₃ ;

1α

,25-dihydroxy-20-methyl-24-oxo-vitamin D₃ ;

(5Z,7E)-(1S,3R)-20-methyl-20-vinyl-9,10-secopregna-5,7,10(19) -triene-1,3-diol;

(5Z,7E)-(1S,3R)-20-ethyl-20-methyl-9,10-secopregna-5,7,10(19) -triene-1,3-diol;

or

(5Z,7E)-(1S,3R)-20-hydroxymethyl-20-methyl-9,10-secopregna-5,7,10(19)-triene-1,3-diol.