26,27-Homologated-20-EPI-2alkyl-19-nor-vitamin D compounds

• US 6,316,642 B1
• Filed: 03/31/2000
• Issued: 11/13/2001
• Est. Priority Date: 03/17/1997
• Status: Expired due to Fees

• 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 NAIM
• Application Number:
  US09/541,470
• Time in Patent Office: 592 Days
• Field of Search: 514/167, 552/653
• US Class Current: 552/653
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• 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

This invention provides a novel class of vitamin D related compounds, namely, 2-alkyl-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 is selected from the group consisting of alkyl, hydroxyalkyl and fluoroalkyl, and where the group R represents any of the typical side chains known for vitamin D type compounds. These 2-substituted compounds, especially the 2α-methyl and the 2α-methyl-20S derivatives, 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. 19-nor-26,27-dihomo-20(S)-2α

-methyl-1α

,25-dihydroxyvitamin D₃ having the formula

2. 19-nor-26,27-dihomo-20(S)-2β

-methyl-1α

,25-dihydroxyvitamin D₃ having the formula

3. 19-nor-26,27-dimethylene-20(S)-2α

-methyl-1α

,25-dihydroxyvitamin D3 having the formula

4. 19-nor-26,27-dimethylene-20(S)-2β

-methyl-1α

,25-dihydroxyvitamin D₃ having the formula

5. A pharmaceutical composition containing at least one compound selected from the group consisting of 19-nor-26,27-dihomo-20(S)-2α

-methyl-1α

,25-dihydroxyvitamin D₃, 19-nor-26,27-dihomo-20(S)-2β

-methyl-1α

,25-dihydroxyvitamin D₃, 19-nor-26,27-dimethylene-20(S)-2α

-methyl-1α

,25-dihydroxyvitamin D₃, and 19-nor-26,27-dimethylene-20(S)-2β

-methyl-1α

,25-dihydroxyvitamin D₃, together with a pharmaceutically acceptable excipient.

6. The pharmaceutical composition of claim 5 containing 19-nor-26,27-dihomo-20(S)-2α

-methyl-1α

,25-dihydroxyvitamin D₃ having the formula

in an amount from about 0.01 μ

g/gm to about 100 μ

g/gm of the composition.

7. The pharmaceutical composition of claim 5 containing 19-nor-26,27-dihomo-20(S)-2β

-methyl-1α

,25-dihydroxyvitamin D₃ having the formula

in an amount from about 0.01 μ

g/gm to about 100 μ

g/gm of the composition.

8. The pharmaceutical composition of claim 5 containing 19-nor-26,27-dihomo-20(S)-2α

-methyl-1α

,25-dihydroxyvitamin D₃ having the formula

in an amount from about 0.01 μ

g/gm to about 100 μ

g/gm of the composition.

9. The pharmaceutical composition of claim 5 containing 19-nor-26,27-dimethlene-20(S)-2β

-methyl-1α

,25-dihydroxyvitamin D₃ having the formula

in an amount from about 0.01 μ

g/gm to about 100 μ

g/gm of the composition.

10. The pharmaceutical composition of claim 5 containing 19-nor-26,27-dihomo-20(S)-2α

-methyl-1α

,25-dihydroxyvitamin D₃ having the formula

in an amount from about 0.01 μ

g/gm to about 100 μ

g/gm of the composition.

11. The pharmaceutical composition of claim 5 containing 19-nor-26,27-dihomo-20(S)-2β

-methyl-1α

,25-dihydroxyvitamin D₃ having the formula

in an amount from about 0.01 μ

g/gm to about 100 μ

g/gm of the composition.

12. The pharmaceutical composition of claim 5 containing 19-nor-26,27-dihomo-20(S)-2α

-methyl-1α

,25-dihydroxyvitamin D₃ having the formula

in an amount from about 0.01 μ

g/gm to about 100 μ

g/gm of the composition.

13. The pharmaceutical composition of claim 5 containing 19-nor-26,27-dihomo-20(S)-2β

-methyl-1α

,25-dihydroxyvitamin D₃ having the formula

in an amount from about 0.01 μ

g/gm to about 100 μ

g/gm of the composition.