Rapamycin derivatives

Claim 1

A method for preventing or treating acute or chronic organ or tissue transplant rejection, or transplant vasculopathies in a subject in need of such treatment, which comprises administering to said subject an effective amount of a compound of formula I wherein R 1 is alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, benzyl, alkoxybenzyl, or chlorobenzyl; R 2 is selected from formula II or formula III: wherein R 3 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, hydroxyarylalkyl, hydroxyaryl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, alkylcarbonyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, alkylcarbonylaminoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl, carbalkoxyalkyl, or alkylsilyl; R 4 is H, methyl or together with R 3 forms C 2-6 alkylene; R 5 is R 6 O—CH 2 —, wherein R 6 is H, alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalkylcarbonyl, aminoalkylcarbonyl, formyl, arylalkyl, hydroxyarylalkyl, hydroxyaryl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, alkylcarbonyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy-carbonylaminoalkyl, alkylcarbonylaminoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl, or carbalkoxyalkyl; R 7 CO—, wherein R 7 is H, alkyl, hydroxy, alkoxy, aryloxy, amino, alkylamino, or N,N-disubstituted-amino wherein the substituents are alkyl, aryl, or arylalkyl; R 8 NCH—, wherein R 8 is alkyl, aryl, amino, alkylamino, arylamino, hydroxy, alkoxy, or arylsulfonylamino; or Y is O, (H, OH), or (H, C 1-4 alkoxy); and X is OH or H; wherein “alk” or “alkyl” refers to a C 1-10 aliphatic substituent optionally interrupted by an oxy linkage; and “ar” or “aryl” refers phenyl, benzyl, tolyl, and pyridyl, provided that, when X is OH, R 1 is alkyl and R 2 is a residue of formula 11, then R 3 is other than H.

Claim 2

A method for preventing or treating acute or chronic organ or tissue transplant rejection, or transplant vasculopathies in a subject in need of such treatment, which comprises administering to said subject an effective amount of a compound of formula I wherein R 1 is alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, benzyl, alkoxybenzyl, or chlorobenzyl; R 2 is selected from formula II or formula III: wherein R 3 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, hydroxyarylalkyl, hydroxyaryl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, alkylcarbonyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, alkylcarbonylaminoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl, carbalkoxyalkyl, or alkylsilyl; R 4 is H, methyl or together with R 3 forms C 2-6 alkylene; R 5 is R 6 O—CH 2 —, wherein R 6 is H, alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalkylcarbonyl, aminoalkylcarbonyl, formyl, arylalkyl, hydroxyarylalkyl, hydroxyaryl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, alkylcarbonyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy-carbonylaminoalkyl, alkylcarbonylaminoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl, or carbalkoxyalkyl; R 7 CO—, wherein R 7 is H, alkyl, hydroxy, alkoxy, aryloxy, amino, alkylamino, or N,N-disubstituted-amino wherein the substituents are alkyl, aryl, or arylalkyl; R 8 NCH—, wherein R 8 is alkyl, aryl, amino, alkylamino, arylamino, hydroxy, alkoxy, or arylsulfonylamino; or Y is O, (H, OH), or (H, C 1-4 alkoxy); and X is OH or H; wherein “alk” or “alkyl” refers to a C 1-10 aliphatic substituent optionally interrupted by an oxy linkage; and “ar” or “aryl” refers phenyl, benzyl, tolyl, and pyridyl, provided that, when X is OH, R 1 is alkyl and R 2 is a residue of formula 11, then R 3 is other than H.

Claim 15

A method for treating smooth muscle cell proliferation and migration leading to vessel intimal thickening in a subject in need of such treatment, which comprises administering to said subject an effective amount of a compound of formula I wherein R 1 is alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, benzyl, alkoxybenzyl, or chlorobenzyl; R 2 is selected from formula II or formula III: wherein R 3 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, hydroxyarylalkyl, hydroxyaryl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, alkylcarbonyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, alkylcarbonylaminoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl, carbalkoxyalkyl, or alkylsilyl; R 4 is H, methyl or together with R 3 forms C 2-6 alkylene; R 5 is R 6 O—H 2 —, wherein R 5 is H, alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalkylcarbonyl, aminoalkylcarbonyl, formyl, arylalkyl, hydroxyarylakyl, hydroxyaryl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, alkylcarbonyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy-carbonylaminoalkyl, alkylcarbonylaminoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl, or carbalkoxyalkyl; R 7 CO—, wherein R 7 is H, allyl, hydroxy, alkoxy, aryloxy, amino, alkylamino, or N,N-disubstituted-amino wherein the substituents are alkyl, aryl, or arylalkyl; R 8 NCH—, wherein R 8 is alkyl, aryl, amino, alkylamino, arylamino, hydroxy, alkoxy, or arylsulfonylamino; or Y is O, (H, )H), or (H, C 1-4 alkoxy); and X is OH or H; wherein “alk” or “alkyl” refers to a C 1-10 aliphatic substituent optionally interrupted by an oxy linkage; and “arm or “aryl” refers phenyl, benzyl, tolyl, and pyridyl, provided that, when X is OH, R 1 is alkyl and R 2 is a residue of formula II, then R 3 is other than H.

Claim 16

A method for treating smooth muscle cell proliferation and migration leading to vessel intimal thickening in a subject in need of such treatment, which comprises administering to said subject an effective amount of a compound of formula I wherein R 1 is alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, benzyl, alkoxybenzyl, or chlorobenzyl; R 2 is selected from formula II or formula III: wherein R 3 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, hydroxyarylalkyl, hydroxyaryl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, alkylcarbonyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, alkylcarbonylaminoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl, carbalkoxyalkyl, or alkylsilyl; R 4 is H, methyl or together with R 3 forms C 2-6 alkylene; R 5 is R 6 O—H 2 —, wherein R 5 is H, alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalkylcarbonyl, aminoalkylcarbonyl, formyl, arylalkyl, hydroxyarylakyl, hydroxyaryl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, alkylcarbonyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy-carbonylaminoalkyl, alkylcarbonylaminoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl, or carbalkoxyalkyl; R 7 CO—, wherein R 7 is H, allyl, hydroxy, alkoxy, aryloxy, amino, alkylamino, or N,N-disubstituted-amino wherein the substituents are alkyl, aryl, or arylalkyl; R 8 NCH—, wherein R 8 is alkyl, aryl, amino, alkylamino, arylamino, hydroxy, alkoxy, or arylsulfonylamino; or Y is O, (H, )H), or (H, C 1-4 alkoxy); and X is OH or H; wherein “alk” or “alkyl” refers to a C 1-10 aliphatic substituent optionally interrupted by an oxy linkage; and “arm or “aryl” refers phenyl, benzyl, tolyl, and pyridyl, provided that, when X is OH, R 1 is alkyl and R 2 is a residue of formula II, then R 3 is other than H.