Amide esters of rapamycin

• US 5,118,677 A
• Filed: 05/20/1991
• Issued: 06/02/1992
• Est. Priority Date: 05/20/1991
• Status: Expired due to Term

• Current Assignee: Wyeth (Pfizer Inc.)
• Original Assignee: American Home Products Corporation (Pfizer Inc.)
• Inventors: Caufield, Craig E.
• Primary Examiner(s): BOND, ROBERT
• Application Number:
  US07/703,240
• Time in Patent Office: 379 Days
• Field of Search: 540/456, 514/183, 514/321
• US Class Current: 514/183
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07D 498/18 Bridged systems

Abstract

A compound of the structure ##STR1## wherein R¹ and R² are each independently, hydrogen or ##STR2## X is --(CH₂)_m -- or --Ar--; R³ and R⁴ are each, independently, hydrogen, alkyl, --(CH₂)_n --Ar, --(CH₂)_p --NR⁵ R⁶, or --(CH₂)_p --N⁺ R⁵ R⁶ R⁷ Y^- ; R⁵ and R⁶ are each, independently, hydrogen, alkyl, or --(CH₂)_n --Ar; Ar is an optionally substituted group selected from ##STR3## in which the optional substituents are selected from the group consisting of alkyl, aralkyl, alkoxy, cyano, halo, nitro, carbalkoxy, or perfluoroalkyl; R⁷ is alkyl; Y is a halide, sulfate, phosphate, or p-toluenesulfonate anion; m=1-6; n=1-6; p=1-6; with the proviso that R¹ and R² are not both hydrogen; or a pharmaceutically acceptable salt thereof, 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 ##STR9## wherein R¹ and R² are each independently, hydrogen or ##STR10## X is --(CH₂)_m -- or --Ar--;

R³ and R⁴ are each, independently, hydrogen, alkyl of 1-12 carbon atoms, --(CH₂)_n --Ar, --(CH₂)_p --NR⁵ R⁶, or --(CH₂)_p --N⁺ R⁵ R⁶ R⁷ Y^- ;

R⁵ and R⁶ are each, independently, hydrogen, alkyl of 1-12 carbon atoms, or --(CH₂)_n --Ar;

Ar is an optionally mono- or di- substituted group selected from ##STR11## in which the optional substituents are selected from the group consisting of 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, or perfluoroalkyl of 1-6 carbon atoms;

R⁷ is alkyl of 1-6 carbon atoms;

Y is a halide, sulfate, phosphate, or p-toluenesulfonate anion;

m=1-6;

n=1-6;

p=1-6;

with the proviso that R¹ and R² are not both hydrogen;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 in which X is --(CH₂)_m --.

3. A compound according to claim 1 in which X is --(CH₂ 2)_m -- and R³ and R⁴ are alkyl of 1-6 carbon atoms.

4. A compound according to claim 1 in which X is --(CH₂)_m --, R³ is hydrogen, and R⁴ is and Ar is --(CH₂)_n --Ar.

5. A compound according to claim 1 which is rapamycin 42-ester with 4-(dimethylamino)-4-oxobutanoic acid.

6. A compound according to claim 1 which is rapamycin 31,42-diester with 4-oxo-4-[[2-(2-pyridinyl)ethyl]amino]butanoic acid or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 6 which is rapamycin 31,42-diester with 4-oxo-4-[[2-(2-pyridinyl)ethyl]amino]butanoic acid dihydrochloride.

8. A compound according to claim 1 which is rapamycin 31,42-diester with 2-[2-[(3-carboxy-1oxopropyl)amino]ethyl]-1-methyl-pyridinium iodide.

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

9. 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 ##STR12## wherein R¹ and R² are each independently, hydrogen or ##STR13## X is --(CH₂)_m -- or --Ar--;

R³ and R⁴ are each, independently, hydrogen, alkyl of 1-12 carbon atoms, --(CH₂)_n --Ar, --(CH₂)_p --NR⁵ R⁶, or --(CH₂)_p --N⁺ R⁵ R⁶ R⁷ Y^- ;

R⁵ and R⁶ are each, independently, hydrogen, alkyl of 1-12 carbon atoms, or --(CH₂)_n --Ar;

Ar is an optionally mono- or di- substituted group selected from ##STR14## in which the optional substituents are selected from the group consisting of 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, or perfluoroalkyl of 1-6 carbon atoms;

R⁷ is alkyl of 1-6 carbon atoms;

Y is a halide, sulfate, phosphate, or p-toluenesulfonate anion;

m=1-6;

n=1-6;

p=1-6;

with the proviso that R¹ and R² are not both hydrogen;

or a pharmaceutically acceptable salt thereof.