2-alkylidene-19-nor-vitamin D compounds

• US 5,936,133 A
• Filed: 09/10/1998
• Issued: 08/10/1999
• 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: Sicinski, Rafal R., Deluca, Hector F.
• Primary Examiner(s): Lambkin, Deborah C.
• Application Number:
  US09/151,113
• Time in Patent Office: 334 Days
• Field of Search: 568/828, 568/670, 568/14, 560/126, 560/128, 556/436, 556/437, 556/482
• US Class Current: 568/828
• CPC Class Codes: A61P 11/06 Antiasthmatics
• 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 17/16 Emollients or protectives, e.g. against radiation
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• 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: ##STR1## 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 low intestinal calcium transport activity and 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. A compound having 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, where R₆ and R₈, which may be the same or different, are each selected from the group consisting of hydrogen, alkyl, hydroxyalkyl and fluoroalkyl, or when taken together represent the group --(CH₂)_x -- where x is an integer from 2 to 5.

2. The compound of claim 1 where Y₁ and Y₂ are both t-butyldimethylsilyl, and R₆ and R₈ are both hydrogen.

3. A compound having the formula:

##STR12## 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, and where R₆ and R₈, which may be the same or different, are each selected from the group consisting of hydrogen, alkyl, hydroxyalkyl and fluoroalkyl, or where taken together represent the group --(CH₂)_x -- where x is an integer from 2 to 5, and where R₇ is an alkyl.

4. The compound of claim 3 where Y₁ and Y₂ are both t-butyldimethylsilyl, and R₆ and R₈ are both hydrogen, and R₇ is methyl.

5. A compound having the formula:

##STR13## 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, and where R₆ and R₈, which may be the same or different, are each selected from the group consisting of hydrogen, alkyl, hydroxyalkyl and fluoroalkyl, or when taken together represent the group --(CH₂)_x -- where x is an integer from 2 to 5.

6. The compound of claim 5 where Y₁ and Y₂ are both t-butyldimethylsilyl, and R₆ and R₈ are both hydrogen.

7. A compound having the formula:

##STR14## 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, where R₆ and R₈, which may be the same or different, are each selected from the group consisting of 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 R₇ is an alkyl.

8. The compound of claim 7 where Y₁ and Y₂ are both t-butyldimethylsilyl, R₆ and R₈ are both hydrogen, and R₇ is methyl.

9. A compound having the formula:

##STR15## 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, and where R₆ and R₈, which may be the same or different, are each selected from the group consisting of hydrogen, alkyl, hydroxyalkyl and fluoroalkyl, or when taken together represent the group --(CH₂)_x -- where x is an integer from 2 to 5.

10. The compound of claim 9 where Y₁ and Y₂ are both t-butyidimethylsilyl, and R₆ and R₈ are both hydrogen.

11. A compound having the formula:

##STR16## 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, and where R₆ and R₈, which may be the same or different, are each selected from the group consisting of hydrogen, alkyl, hydroxyalkyl and fluoroalkyl, or when taken together represent the group --(CH₂)_x -- where x is an integer from 2 to 5.

12. The compound of claim 11 where Y₁ and Y₂ are both t-butyidimethylsilyl, and R₆ and R₈ are both hydrogen.