Carbamates of rapamycin

• US 5,118,678 A
• Filed: 04/17/1991
• Issued: 06/02/1992
• Est. Priority Date: 04/17/1991
• Status: Expired due to Term

• Current Assignee: Wyeth (Pfizer Inc.)
• Original Assignee: American Home Products Corporation (Pfizer Inc.)
• Inventors: Musser, John H., Vogel, Robert L., Kao, Wenling
• Primary Examiner(s): BOND, ROBERT
• Application Number:
  US07/686,728
• Time in Patent Office: 412 Days
• Field of Search: 540/456, 540/452, 514/183, 514/321, 514/63
• US Class Current: 514/183
• CPC Class Codes: C07D 498/18 Bridged systems

Abstract

A compound of the structure ##STR1## wherein R¹ and R² are each, independently, hydrogen or --CONH(CR³ R⁴)_n --X;

R³ and R⁴ are each, independently, hydrogen, alkyl, aralkyl, cycloalkyl, halogen, or trifluoromethyl;

X ix hydrogen, lower alkyl, cycloalkyl, trifluoromethyl, nitro, alkoxy, carboalkoxy, aralkyl, halo, dialkylamino, thioalkyl, or Y;

Y is a phenyl group which may be optionally mono-, di-, or tri- substituted with a group selected from alkyl, aralkyl, alkoxy, cyano, halo, nitro, carbalkoxy, trifluoromethyl, dialkylamino, or alkylthio;

n=0-5;

with the proviso that R¹ and R² are not both hydrogen and when n=0, X is lower alkyl, cycloalkyl, aralkyl, or Y;

or a pharmaceutically acceptable salt thereof when X is dialkylamino, 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.

Claims

1. A compound of the formula ##STR3## wherein R¹ and R² are each, independently, hydrogen or --CONH(CR³ R⁴)_n --X;

R³ and R⁴ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, phenylalkyl of 7-10 carbon atoms, cycloalkyl of 3-8 carbon atoms, halogen, or trifluoromethyl;

X is hydrogen, lower alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, trifluoromethyl nitro, alkoxy of 1-6 carbon atoms, carboalkoxy of 2-7 carbon atoms, phenylalkyl of 7-10 carbon atoms, halo, dialkylamino of 1-6 carbon atoms per alkyl group, thioalkyl of 1-6 carbon atoms, or Y;

Y is a phenyl group which may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, phenylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, dialkylamino of 1-6 carbon atoms per alkyl group, or alkylthio of 1-6 carbon atoms;

n=0-5;

with the proviso that R¹ and R² are not both hydrogen and when n=0, X is lower alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, phenylalkyl of 7-10 carbon atoms, or Y;

or a pharmaceutically acceptable salt thereof when X is dialkylamino of 1-6 carbon atoms per alkyl group.

2. A compound of claim 1 where R¹ is hydrogen.

3. A compound of claim 1 where R² is hydrogen.

4. A compound of claim 1 where n is 0 and X is Y.

5. A compound of claim 1 where R² is hydrogen, n is 0, and X is Y.

6. A compound of claim 1 where n is 0, X is Y, and Y is phenyl, 4-fluorophenyl, 2,4-diflurophenyl, 4-nitrophenyl, or 4-methylphenyl.

7. A compound of claim 1 which is rapamycin 42-ester with (4-fluorophenyl)carbamic acid.

8. A compound of claim 1 which is rapamycin 42-ester with phenylcarbamic acid.

9. A compound of claim 1 which is rapamycin-31,42-diester with [4(trifluoromethyl)phenyl]carbamic acid.

10. A compound of claim 1 which is rapamycin-42-ester with [4-(trifluoromethyl)phenyl]carbamic acid.

11. A compound of claim 1 which is rapamycin-31,42-diester with (4-nitrophenyl)carbamic acid.

12. A compound of claim 1 which is rapamycin-42-ester with (4-nitrophenyl)carbamic acid.

13. A compound of claim 1 which is rapamycin-31,42-diester with (4-methylphenyl)carbamic acid.

14. A compound of claim 1 which is rapamycin-42-ester with (4-methylphenyl)carbamic acid.

15. A compound of claim 1 which is rapamycin-42-ester with (2,4-difluorophenyl)carbamic acid.

16. A compound of claim 1 which is rapamycin-31,42-diester with (2,4-difluorophenyl)carbamic acid.

17. A compound of claim 1 which is rapamycin-31,42-diester with phenylcarbamic acid.

18. A compound of claim 1 which is rapamycin-31,42-diester with (4-fluorophenyl)carbamic acid.

19. A compound of claim 1 which is rapamycin-31-ester with (2,4-difluorophenyl)carbamic acid.

22. A pharmaceutical composition for use as an immunosuppressive agent comprising an immunosuppressive amount of a compound of claim 1.

23. A composition as claimed in claim 22 in unit dosage form.

20. A compound which is rapamycin-42-tert-butyldimethylsilyl ether-31-ester with (2,4-difluorophenyl)carbamic acid.

21. A method of treating transplantation rejection, host vs. draft disease, autoimmune diseases, and diseases of inflammation in a mammal by administering an effective amount of a compound having the formula ##STR4## wherein R¹ and R² are each, independently, hydrogen or --CONH(CR³ R⁴)_n --X;

R³ and R⁴ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, phenylalkyl of 7-10 carbon atoms, cycloalkyl of 3-8 carbon atoms, halogen, or trifluoromethyl;

X is hydrogen, lower alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, trifluoromethyl nitro, alkoxy of 1-6 carbon atoms, carboalkoxy of 2-7 carbon atoms, phenylalkyl of 7-10 carbon atoms, halo, dialkylamino of 1-6 carbon atoms per alkyl group, thioalkyl of 1-6 carbon atoms, or Y;

Y is a phenyl group which may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, phenylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, dialkylamino of 1-6 carbon atoms per alkyl group, or alkylthio of 1-6 carbon atoms;

n=0-5;

with the proviso that R¹ and R² are not both hydrogen and when n=0, X is lower alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, phenylalkyl of 7-10 carbon atoms, or Y;

or a pharmaceutically acceptable salt thereof when X is dialkylamino of 1-6 carbon atoms per alkyl group.