Water soluble rapamycin esters

A method of treating or inhibiting transplant rejection or graft vs. host disease in a mammal in need thereof, which comprises providing to said mammal an effective amount of a compound having the strucure

• 6
• wherein
• R1 and R2 are each, independently, hydrogen or —CO(CR3R4)b(CR5R6)dCR7R8R9;
• R3 and R4 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, trifluoromethyl, or —F;
• R5 and R6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR3R4)fOR10, —CF3, —F, or —CO2R11;
• R7 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR3R4)fOR10, —CF3, —F, or —CO2R11;
• R8 and R9 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR3R4)fOR10, —CF3, —F, or —CO2R11;
• R10 is hydrogen or —COCH2—S—CH2CH2—(O—CH2—CH2)n—OCH3;
• R11 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, or phenylalkyl of 7-10 carbon atoms;
• b=0-6;
• d=0-6;
• f=0-6;
• n=5-450;
• with the proviso that R1 and R2 are both not hydrogen and further provided that either R1 or R2 contains at least one —(CR3R4)fOR10 group in which R10 is —COCH2—S—CH2CH2—(O—CH2—CH2)n—OCH3, or a pharmaceutically acceptable salt thereof.

A method of treating or inhibiting a solid tumor in a mammal in need thereof, which comprises providing to said mammal a compound having the structure

• 7
• wherein
• R1 and R2 are each, independently, hydrogen or —CO(CR3R4)b(CR5R6)dCR7R8R9;
• R3 and R4 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, trifluoromethyl, or —F;
• R5 and R6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR3R4)fOR10, —CF3, —F, or —CO2R11;
• R7 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR3R4)fOR10, —CF3, —F, or —CO2R11;
• R8 and R9 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR3R4)fOR10, —CF3, —F, or —CO2R11;
• R10 is hydrogen or —COCH2—S—CH2CH2—(O—CH2—CH2)n—OCH3;
• R11 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, or phenylalkyl of 7-10 carbon atoms;
• b=0-6;
• d=0-6;
• f=0-6;
• n=5-450;
• with the proviso that R1 and R2 are both not hydrogen and further provided that either R1 or R2 contains at least one —(CR3R4)fOR10 group in which R10 is —COCH2—S—CH2CH2—(O—CH2—CH2)n—OCH3, or a pharmaceutically acceptable salt thereof.

A method of treating or inhibiting a fungal infection in a mammal in need thereof, which comprises providing to said mammal an effective amount of a compound having the structure

• 8
• wherein
• R1 and R2 are each, independently, hydrogen or —CO(CR3R4)b(CR5R6)dCR7R8R9;
• R3 and R4 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, trifluoromethyl, or —F;
• R5 and R6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR3R4)fOR10, —CF3, —F, or —CO2R11;
• R7 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR3R4)fOR10, —CF3, —F, or —CO2R11;
• R8 and R9 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR3R4)fOR10, —CF3, —F, or —CO2R11;
• R10 is hydrogen or —COCH2—S—CH2CH2—(O—CH2—CH2)n—OCH3;
• R11 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, or phenylalkyl of 7-10 carbon atoms;
• b=0-6;
• d=0-6;
• f=0-6;
• n=5-450;
• with the proviso that R1 and R2 are both not hydrogen and further provided that either R1 or R2 contains at least one —(CR3R4)fOR10 group in which R10 is —COCH2—S—CH2CH2—(O—CH2—CH2)n—OCH3, or a pharmaceutically acceptable salt thereof.

A method of treating or inhibiting rheumatoid arthritis in a mammal in need thereof, which comprises providing to said mammal an effective amount of a compound having the structure

• 9
• wherein
• R1 and R2 are each, independently, hydrogen or —CO(CR3R4)b(CR5R6)dCR7R8R9;
• R3 and R4 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, trifluoromethyl, or —F;
• R5 and R6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR3R4)fOR10, —CF3, —F, or —CO2R11;
• R7 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR3R4)fOR10, —CF3, —F, or —CO2R11;
• R8 and R9 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR3R4)fOR10, —CF3, —F, or —CO2R11;
• R10 is hydrogen or —COCH2—S—CH2CH2—(O—CH2—CH2)n—OCH3;
• R11 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, or phenylalkyl of 7-10 carbon atoms;
• b=0-6;
• d=0-6;
• f=0-6;
• n=5-450;
• with the proviso that R1 and R2 are both not hydrogen and further provided that either R1 or R2 contains at least one —(CR3R4)fOR10 group in which R10 is —COCH2—S—CH2CH2—(O—CH2—CH2)n—OCH3, or a pharmaceutically acceptable salt thereof.

A method of treating or inhibiting multiple sclerosis in a mammal in need thereof, which comprises providing to said mammal an effective amount of a compound having the structure

• 10
• wherein
• R1 and R2 are each, independently, hydrogen or —CO(CR3R4)b(CR5R6)dCR7R8R9;
• R3 and R4 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, trifluoromethyl, or —F;
• R5 and R6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR3R4)fOR10, —CF3, —F, or —CO2R11;
• R7 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR3R4)fOR10, —CF3, —F, or —CO2R11;
• R8 and R9 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR3R4)fOR10, —CF3, —F, or —CO2R11;
• R10 is hydrogen or —COCH2—S—CH2CH2—(O—CH2—CH2)n—OCH3;
• R11 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, or phenylalkyl of 7-10 carbon atoms;
• b=0-6;
• d=0-6;
• f=0-6;
• n=5-450;
• with the proviso that R1 and R2 are both not hydrogen and further provided that either R1 or R2 contains at least one —(CR3R4)fOR10 group in which R10 is —COCH2—S—CH2CH2—(O—CH2—CH2)n—OCH3, or a pharmaceutically acceptable salt thereof.

A method of treating or inhibiting restenosis in a mammal in need thereof, which comprises providing to said mammal an effective amount of a compound having the structure

• 11
• wherein
• R1 and R2 are each, independently, hydrogen or —CO(CR3R4)b(CR5R6)dCR7R8R9;
• R3 and R4 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, trifluoromethyl, or —F;
• R5 and R6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR3R4)fOR10, —CF3, —F, or —CO2R11;
• R7 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR3R4)fOR10, —CF3, —F, or —CO2R11;
• R8 and R9 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR3R4)fOR10, —CF3, —F, or —CO2R11;
• R10 is hydrogen or —COCH2—S—CH2CH2—(O—CH2—CH2)n—OCH3;
• R11 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, or phenylalkyl of 7-10 carbon atoms;
• b=0-6;
• d=0-6;
• f=0-6;
• n=5-450;
• with the proviso that R1 and R2 are both not hydrogen and further provided that either R1 or R2 contains at least one —(CR3R4)fOR10 group in which R10 is —COCH2—S—CH2CH2—(O—CH2—CH2)n—OCH3, or a pharmaceutically acceptable salt thereof.

A method of treating or inhibiting pulmonary inflammation in a mammal in need thereof, which comprises providing to said mammal an effective amount of a compound having the structure

• 12
• wherein
• R1 and R2 are each, independently, hydrogen or —CO(CR3R4)b(CR5R6)dCR7R8R9;
• R3 and R4 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, trifluoromethyl, or —F;
• R5 and R6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR3R4)fOR10, —CF3, —F, or —CO2R11;
• R7 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR3R4)fOR10, —CF3, —F, or —CO2R11;
• R8 and R9 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR3R4)fOR10, —CF3, —F, or —CO2R11;
• R10 is hydrogen or —COCH2—S—CH2CH2—(O—CH2—CH2)n—OCH3;
• R11 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, or phenylalkyl of 7-10 carbon atoms;
• b=0-6;
• d=0-6;
• f=0-6;
• n=5-450;
• with the proviso that R1 and R2 are both not hydrogen and further provided that either R1 or R2 contains at least one —(CR3R4)fOR10 group in which R10 is —COCH2—S—CH2CH2—(O—CH2—CH2)n—OCH3, or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition which comprises a compound having the structure

• 13
• wherein
• R1 and R2 are each, independently, hydrogen or —CO(CR3R4)b(CR5R6)dCR7R8R9;
• R3 and R4 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, trifluoromethyl, or —F;
• R5 and R6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR3R4)fOR10, —CF3, —F, or —CO2R11;
• R7 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR3R4)fOR10, —CF3, —F, or —CO2R11;
• R8 and R9 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR3R4)fOR10, —CF3, —F, or —CO2R11;
• R10 is hydrogen or —COCH2—S—CH2CH2—(O—CH2—CH2)n—OCH3;
• R11 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, or phenylalkyl of 7-10 carbon atoms;
• b=0-6;
• d=0-6;
• f=0-6;
• n=5-450;
• with the proviso that R1 and R2 are both not hydrogen and further provided that either R1 or R2 contains at least one —(CR3R4)fOR10 group in which R10 is —COCH2—S—CH2CH2—(—CH2—CH2)n—OCH3, or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier.