Silyl ethers of rapamycin

• US 5,120,842 A
• Filed: 04/01/1991
• Issued: 06/09/1992
• Est. Priority Date: 04/01/1991
• Status: Expired due to Term

• Current Assignee: American Home Products Corporation (Pfizer Inc.)
• Original Assignee: American Home Products Corporation (Pfizer Inc.)
• Inventors: Failli, Amedeo A., Steffan, Robert J.
• Primary Examiner(s): BOND, ROBERT
• Application Number:
  US07/678,380
• Time in Patent Office: 435 Days
• Field of Search: 540/452, 540/456, 514/63, 514/183, 514/321, 514/291, 546/90
• US Class Current: 540/452
• 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896

Abstract

A compound of the structure ##STR1## wherein R¹ is --SiR³ R⁴ R⁵ ;

R² is hydrogen or --SiR³ R⁴ R⁵ ; and

R³, R⁴, and R⁵ are each, independently, alkyl, alkenyl, aralkyl, triphenylmethyl, or phenyl which by virtue of its immunosuppressive activity is useful in treating transplantation rejection, host vs. graft disease, autoimmune diseases and diseases of inflammation; by virtue of its antitumor activity is useful in treating solid tumors; and by virtue of its antifungal activity is useful in treating fungal infections. This invention also provides a method of using rapamycin 42-[O-[(1,1-dimethylethyl)-dimethylsilyl] ether for the preparation of 31-substituted rapamycin derivatives.

Claims

1. A compound of the formula ##STR3## wherein R¹ is --SiR³ R⁴ R⁵ ;

R² is hydrogen or --SiR³ R⁴ R⁵ ; and

R³, R⁴, and R⁵ are each, independently, alkyl of 1-8 carbon atoms, alkenyl of 1-8 carbon atoms, phenylalkyl of 7-10 carbon atoms, triphenylmethyl, or phenyl.

2. A compound of claim 1 in which R² is hydrogen.

3. A compound of claim 1 in which R² is hydrogen and R³, R⁴, and R⁵ are alkyl of 1-8 carbon atoms.

4. A compound of claim 1 in which R³, R⁴, and R⁵ are alkyl of 1-8 carbon atoms.

5. A compound of claim 1 which is rapamycin 42-O-[(1,1-dimethylethyl)dimethylsilyl]ether.

6. A compound of claim 1 which is rapamycin 31,42-bis-O-[(1,1-dimethylethyl)dimethylsilyl]ether.

7. A method of using rapamycin 42-O-[(1,1-dimethylethyl)-dimethylsilyl]ether for the preparation of a 31-acylated rapamycin which comprises reacting rapamycin 42-[O-[(1,1-dimethylethyl)-dimethylsilyl]ether with an acylating agent to give an intermediate in which the 31-alcohol of rapamycin has reacted with the acylating agent and the 42-position is protected as the 42-[O-[(1,1-dimethylethyl)dimethylsilyl]ether;

and subsequent hydrolysis of the 42-silyl ether to provide the 31-acylated rapamycin.

8. A compound which is rapamycin 42-[O-[(1,1-Dimethylethyl)dimethylsilyl]ether-31-acetate.

9. A compound which is rapamycin-31-acetate.