26,27-homologated-20-EPI-2-alkylidene-19-nor-vitamin D compounds

• US 6,392,071 B1
• Filed: 03/31/2000
• Issued: 05/21/2002
• Est. Priority Date: 03/17/1997
• Status: Expired due to Term

• Current Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Original Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Inventors: DeLuca, Hector F., Sicinski, Rafal R.
• Primary Examiner(s): Qazi, Sabiha
• Application Number:
  US09/540,686
• Time in Patent Office: 781 Days
• Field of Search: 514/167, 553/653
• US Class Current: 552/653
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 13/08 of the prostate
• 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 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/10 Anti-acne agents
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 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 3/10 for hyperglycaemia, e.g. antidiabetics
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 5/18 of the parathyroid hormones
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• 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: Y02P 20/55 : Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

This invention provides a novel class of vitamin D related compounds, namely, the 2-alkylidene-19-nor-vitamin D derivatives, as well as a general method for their chemical synthesis. The compounds have the formula:

where Y₁ and Y₂, which may be the same or different, are each selected from the group consisting of hydrogen and a hydroxy-protecting group, R₆ and R₈, which may be the same or different, are each selected from hydrogen, alkyl, hydroxyalkyl and fluoroalkyl, or when taken together represent the group —(CH₂)_x— where x is an integer from 2 to 5, and where the group R represents any of the typical side chains known for vitamin D type compounds. These 2-substituted compounds are characterized by relatively high intestinal calcium transport activity and relatively high bone calcium mobilization activity resulting in novel therapeutic agents for the treatment of diseases where bone formation is desired, particularly low bone turnover osteoporosis. These compounds also exhibit pronounced activity in arresting the proliferation of undifferentiated cells and inducing their differentiation to the monocyte thus evidencing use as anti-cancer agents and for the treatment of diseases such as psoriasis.

Claims

1. 20(S)-1α

,25-dihydroxy-2-methylene-26,27-dihomo-19-norvitamin D₃.

2. 20(S)-26,27-dimethylene-25-methoxy-2-methylene-19-norvitamin D₃.

3. 20(S)-1α

,25-dihydroxy-26,27-dimethylene-2-methylene-19-norvitamin D₃.

4. 20(S)-26,27-dimethylene-1α

-hydroxy-2-methylene-24-dehydro-19-norvitamin D₃.

5. A pharmaceutical composition containing at least one compound selected from the group consisting of

20(S)-1α

,25-dihydroxy-2-methylene-26,27-dihomo-19-norvitamin D₃,

20(S)-26,27-dimethylene-25-methoxy-2-methylene-19-norvitamin D₃,

20(S)-1α

,25-dihydroxy-26,27-dimethylene-2-methylene-19-norvitamin D₃, and

20(S)-26,27-dimethylene-1α

-hydroxy-2-methylene-24-dehydro-19-norvitamin D₃, together with a pharmaceutically acceptable excipient.

6. The pharmaceutical composition of claim 5 containing 20(S)-1α

,25-dihydroxy-2-methylene-26,27-dihomo-19-norvitamin D₃ in an amount from about 0.1 μ

g to about 50 μ

g.

7. The pharmaceutical composition of claim 5 containing 20(S)-26,27-dimethylene-25-methoxy-2-methylene-19-norvitamin D₃ in an amount from about 0.1 μ

g to about 50 μ

g.

8. The pharmaceutical composition of claim 5 containing 20(S)-1α

,25-dihydroxy-26,27-dimethylene-2-methylene-19-norvitamin D₃ in an amount of from about 0.1 μ

g to about 50 μ

g.

9. The pharmaceutical composition of claim 5 containing 20(S)-26,27-dimethylene-1α

-hydroxy-2-methylene-24-dehydro-19-norvitamin D₃ in an amount from about 0.1 μ

g to about 50 μ

g.