27-hydroxyrapamycin and derivatives thereof

A compound of the formula ##STR26## wherein R.sup.1 is ##STR27## R.sup.2 is ##STR28## X is --(CH.sub.2).sub.m -- or --Ar--;

• R.sup.3 and R.sup.4 are each, independently, hydrogen, alkyl of 1-12 carbon atoms, --(CH.sub.2).sub.n --Ar, --(CH.sub.2).sub.p --NR.sup.5 R.sup.6, or --(CH.sub.2).sub.p --N.sup.+ R.sup.5 R.sup.6 R.sup.7 Y.sup.- ;
• R.sup.5 and R.sup.6 are each, independently, hydrogen, alkyl of 1-12 carbon atoms, or --(CH.sub.2).sub.n --Ar;
• Ar is an optionally mono- or di-substituted group selected from ##STR29## in which the optional substituents are selected from the group consisting of alkyl of 1-6 carbon atoms, arylalkyl 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;
• R.sup.7 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;
• or a pharmaceutically acceptable salt thereof.

A compound of the formula ##STR30## wherein R.sup.2 is ##STR31## R.sup.3 is hydrogen, alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, --(CH.sub.2).sub.q CO.sub.2 R.sup.6, --(CH.sub.2).sub.r NR.sup.7 CO.sub.2 R.sup.8, carbamylalkyl of 2-3 carbon atoms, aminoalkyl of 1-4 carbon atoms, hydroxyalkyl of 1-4 carbon atoms, guanylalkyl of 2-4 carbon atoms, mercaptoalkyl of 1-4 carbon atoms, alkylthioalkyl of 2-6 carbon atoms, indolylmethyl, hydroxyphenylmethyl, imidazoylmethyl or phenyl which is optionally mono-, di-, or tri-substituted with a substituent selected from alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, or --CO.sub.2 H;

• R.sup.4 and R.sup.7 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or arylalkyl of 7-10 carbon atoms;
• R.sup.5, R.sup.6, and R.sup.8 are each, independently, alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, fluorenylmethyl, or phenyl which is optionally mono-, di-, or tri-substituted with a substituent selected from alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, or --CO.sub.2 H;
• m is 0-4;
• n is 0-4;
• p is 1-2;
• q is 0-4;
• r is 0-4;
• wherein R.sup.3, R.sup.4, m, and n are independent in each of the ##STR32## subunits when p=2;
• or a pharmaceutically acceptable salt thereof.

A compound of the formula ##STR33## wherein R.sup.1 is alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, --CH.sub.2 YX, --C(CH.sub.3).sub.2 YX, --CH(CH.sub.3)YX, or L;

• Y is O or S;
• X is --CH.sub.3, --(CH.sub.2).sub.n CH.sub.3, --CH.sub.2 Ar, --(CH.sub.2).sub.2 OCH.sub.3, --CH.sub.2 CCl.sub.3, --CH(CH.sub.3).sub.2, or --CH.sub.2 CH.sub.2 SiMe.sub.3 ;
• L is tetrahydrofuran-2-yl, tetrahydrothiophen-2-yl, tetrahydrothiopyran-2-yl, tetrahydropyran-2-yl, 4-methoxytetrahydropyran-2-yl, 4-methoxytetrahydrothiopyran-2-yl, or 4-methoxytetrahydrothiopyran-2-yl S,S dioxide;
• and
• n=1-5.

A compound of the formula ##STR36## wherein R.sup.1 is --CONHSO.sub.2 --Ar;

• and
• Ar is phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, quinoxalyl, thienyl, thionaphthyl, furyl, benzofuryl, benzodioxyl, benzoxazolyl, benzoisoxazolyl, or benzodioxolyl;
• wherein the Ar group may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, dialkylamino of 1-6 carbon atoms per alkyl group, alkylthio of 1-6 carbon atoms, --SO.sub.3 H, --PO.sub.3 H, and --CO.sub.2 H;
• or a pharmaceutically acceptable salt thereof when the Ar group contains a basic nitrogen or when the Ar group is substituted by dialklyamino of 1-6 carbon atoms per alkyl group, --SO.sub.3 H, --PO.sub.3 H, or --CO.sub.2 H;
• or a pharmaceutically acceptable salt thereof.

A compound of the formula ##STR37## wherein R is --SO.sub.2 R.sup.1 ;

• R.sup.1 is alkyl, alkenyl, alkynyl containing 1 to 6 carbon atoms;
• or an aromatic moiety selected from the group consisting of phenyl and naphthyl or a heterocyclic moiety selected from the group consisting of thiophenyl and quinolinyl;
• or --NHCOR.sup.2 ;
• and
• R.sup.2 is lower alkyl containing 1 to 6 carbon atoms;
• or a pharmaceutically acceptable salt thereof.

A method of inducing immunosuppression which comprises administering an immunosuppressive effective amount of a compound of formula II, ##STR38## wherein R.sup.1 is ##STR39## and R.sup.2 is alkyl of 1-10 carbon atoms, arylalkyl of 7-10 carbon atoms, or aryl wherein the aryl group may be optionally mono-, di-, or tri- substituted with a group selected from alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, dialkylamino of 1-6 carbon atoms per alkyl group, alkylthio of 1-6 carbon atoms, --SO.sub.3 H, --PO.sub.3 H, and --CO.sub.2 H;

• or a pharmaceutically acceptable salt thereof;
• or of formula III, ##STR40## wherein R.sup.1 is ##STR41## and R.sup.2 is a mono-, di-, poly-, or per-fluorinated alkyl group of 1-10 carbon atoms;
• or of formula IV, ##STR42## wherein R.sup.1 is ##STR43## R.sup.2 is ##STR44## X is --(CH.sub.2).sub.m -- or --Ar--;
• R.sup.3 and R.sup.4 are each, independently, hydrogen, alkyl of 1-12 carbon atoms, --(CH.sub.2).sub.n --Ar, --(CH.sub.2).sub.p --NR.sup.5 R.sup.6, or --(CH.sub.2).sub.p --N.sup.+ R.sup.5 R.sup.6 R.sup.7 Y.sup.- ;
• R.sup.5 and R.sup.6 are each, independently, hydrogen, alkyl of 1-12 carbon atoms, or --(CH.sub.2).sub.n --Ar;
• Ar is an optionally mono- or di- substituted group selected from ##STR45## in which the optional substituents are selected from the group consisting of alkyl of 1-6 carbon atoms, arylalkyl 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;
• R.sup.7 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;
• or a pharmaceutically acceptable salt thereof;
• or of formula VI, ##STR46## wherein R.sup.2 is ##STR47## R.sup.3 is hydrogen, alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, --(CH.sub.2).sub.q CO.sub.2 R.sup.6, --(CH.sub.2).sub.r NR.sup.7 CO.sub.2 R.sup.8, carbamylalkyl of 2-3 carbon atoms, aminoalkyl of 1-4 carbon atoms, hydroxyalkyl of 1-4 carbon atoms, guanylalkyl of 2-4 carbon atoms, mercaptoalkyl of 1-4 carbon atoms, alkylthioalkyl of 2-6 carbon atoms, indolylmethyl, hydroxyphenylmethyl, imidazoylmethyl or phenyl which is optionally mono-, di-, or tri-substituted with a substituent selected from alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, or --CO.sub.2 H;
• R.sup.4 and R.sup.7 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or arylalkyl of 7-10 carbon atoms;
• R.sup.5, R.sup.6, and R.sup.8 are each, independently, alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, fluorenylmethyl, or phenyl which is optionally mono-, di-, or tri-substituted with a substituent selected from alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, or --CO.sub.2 H;
• m is 0-4;
• n is 0-4;
• p is 1-2;
• q is 0-4;
• r is 0-4;
• wherein
• R.sup.3, R.sup.4, m, and n are independent in each of the ##STR48## subunits when p=2;
• or a pharmaceutically acceptable salt thereof;
• or of formula VII, ##STR49## wherein R.sup.1 is alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, --CH.sub.2 YX, --C(CH.sub.3).sub.2 YX, --CH(CH.sub.3)YX, or L;
• Y is O or S;
• X is --CH.sub.3, --(CH.sub.2).sub.n CH.sub.3, --CH.sub.2 Ar, --(CH.sub.2).sub.2 OCH.sub.3, --CH.sub.2 CCl.sub.3, --CH(CH.sub.3).sub.2, or --CH.sub.2 CH.sub.2 SiMe.sub.3 ;
• L is tetrahydrofuran-2-yl, tetrahydrothiophen-2-yl, tetrahydrothiopyran-2-yl, tetrahydropyran-2-yl, 4-methoxytetrahydropyran-2-yl, 4-methoxytetrahydrothiopyran-2-yl, or 4-methoxytetrahydrothiopyran-2-yl S,S dioxide;
• and
• n=1-5;
• or of formula VIII, ##STR50## wherein R is ##STR51## R.sup.1 and R.sup.2 are each hydrogen or alkyl of 1-3 carbon atoms or R.sup.1 and R.sup.2 together with the nitrogen to which they are attached form a saturated heterocyclic ring having 4-5 carbon atoms;
• and
• m=1-3 or a pharmaceutically acceptable salt thereof;
• or of formula IX, ##STR52## wherein R.sup.1 is --CONHSO.sub.2 --Ar;
• and
• Ar is phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, quinoxalyl, thienyl, thionaphthyl, furyl, benzofuryl, benzodioxyl, benzoxazolyl, benzoisoxazolyl, or benzodioxolyl;
• wherein the Ar group may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, dialkylamino of 1-6 carbon atoms per alkyl group, alkylthio of 1-6 carbon atoms, --SO.sub.3 H, --PO.sub.3 H, and --CO.sub.2 H;
• or a pharmaceutically acceptable salt thereof when the Ar group contains a basic nitrogen or when the Ar group is substituted by dialkylamino of 1-6 carbon atoms per alkyl group, --SO.sub.3 H, --PO.sub.3 H, or --CO.sub.2 H;
• or a pharmaceutically acceptable salt thereof;
• or of formula X, ##STR53## wherein R is --SO.sub.2 R.sup.1 ;
• R.sup.1 is alkyl, alkenyl, alkynyl containing 1 to 6 carbon atoms;
• or an aromatic moiety selected from the group consisting of phenyl and naphthyl or a heterocyclic moiety selected from the group consisting of thiophenyl and quinolinyl;
• or --NHCOR.sup.2 ;
• and
• R.sup.2 is lower alkyl containing 1 to 6 carbon atoms;
• or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition which comprises an effective amount of a compound of formula II, ##STR54## wherein R.sup.1 is ##STR55## and R.sup.2 is alkyl of 1-10 carbon atoms, arylalkyl of 7-10 carbon atoms, or aryl wherein the aryl group may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, dialkylamino of 1-6 carbon atoms per alkyl group, alkylthio of 1-6 carbon atoms, --SO.sub.3 H, --PO.sub.3 H, and --CO.sub.2 H;

• or a pharmaceutically acceptable salt thereof;
• or of formula III, ##STR56## wherein R.sup.1 is ##STR57## and R.sup.2 is a mono-, di-, poly-, or per-fluorinated alkyl group of 1-10 carbon atoms;
• or of formula IV, ##STR58## wherein R.sup.1 is ##STR59## R.sup.2 is ##STR60## X is --(CH.sub.2).sub.m -- or --Ar--;
• R.sup.3 and R.sup.4 are each, independently, hydrogen, alkyl of 1-12 carbon atoms, --(CH.sub.2).sub.n --Ar, --(CH.sub.2).sub.p --NR.sup.5 R.sup.6, or --(CH.sub.2).sub.p --N.sup.+ R.sup.5 R.sup.6 R.sup.7 Y.sup.- ;
• R.sup.5 and R.sup.6 are each, independently, hydrogen, alkyl of 1-12 carbon atoms, or --(CH.sub.2).sub.n --Ar;
• Ar is an optionally mono- or di-substituted group selected from ##STR61## in which the optional substituents are selected from the group consisting of alkyl of 1-6 carbon atoms, arylalkyl 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;
• R.sup.7 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;
• or a pharmaceutically acceptable salt thereof;
• or of formula VI, ##STR62## wherein R.sup.2 is ##STR63## R.sup.3 is hydrogen, alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, --(CH.sub.2).sub.q CO.sub.2 R.sup.6, --(CH.sub.2).sub.r NR.sup.7 CO.sub.2 R.sup.8, carbamylalkyl of 2-3 carbon atoms, aminoalkyl of 1-4 carbon atoms, hydroxyalkyl of 1-4 carbon atoms, guanylalkyl of 2-4 carbon atoms, mercaptoalkyl of 1-4 carbon atoms, alkylthioalkyl of 2-6 carbon atoms, indoylmethyl, hydroxyphenylmethyl, imidazoylmethyl or phenyl which is optionally mono-, di-, or tri-substituted with a substituent selected from alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, or --CO.sub.2 H;
• R.sup.4 and R.sup.7 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or arylalkyl of 7-10 carbon atoms;
• R.sup.5, R.sup.6, and R.sup.8 are each, independently, alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, fluorenylmethyl, or phenyl which is optionally mono-, di-, or tri-substituted with a substituent selected from alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, or --CO.sub.2 H;
• m is 0-4;
• n is 0-4;
• p is 1-2;
• q is 0-4;
• r is 0-4;
• wherein R.sup.3, R.sup.4, m, and n are independent in each of the ##STR64## subunits when p=2;
• or a pharmaceutically acceptable salt thereof;
• or of formula VII, ##STR65## wherein R.sup.1 is alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, --CH.sub.2 YX, --C(CH.sub.3).sub.2 YX, --CH(CH.sub.3)YX, or L;
• Y is O or S;
• X is --CH.sub.3, --(CH.sub.2).sub.n CH.sub.3, --CH.sub.2 Ar, --(CH.sub.2).sub.2 OCH.sub.3, --CH.sub.2 CCl.sub.3, --CH(CH.sub.3).sub.2, or --CH.sub.2 CH.sub.2 SiMe.sub.3 ;
• L is tetrahydrofuran-2-yl, tetrahydrothiophen-2-yl, tetrahydrothiopyran-2-yl, tetrahydropyran-2-yl, 4-methoxytetrahydropyran-2-yl, 4-methoxytetrahydrothiopyran-2-yl, or 4-methoxytetrahydrothiopyran-2-yl S,S dioxide;
• and
• n=1-5;
• or of formula VIII, ##STR66## wherein R is ##STR67## R.sup.1 and R.sup.2 are each hydrogen or alkyl of 1-3 carbon atoms or R.sup.1 and R.sup.2 together with the nitrogen to which they are attached form a saturated heterocyclic ring having 4-5 carbon atoms;
• and
• m=1-3 or a pharmaceutically acceptable salt thereof;
• or of formula IX, ##STR68## wherein R.sup.1 is --CONHSO.sub.2 --Ar;
• and
• Ar is phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, quinoxalyl, thienyl, thionaphthyl, furyl, benzofuryl, benzodioxyl, benzoxazolyl, benzoisoxazolyl, or benzodioxolyl;
• wherein the Ar group may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, dialkylamino of 1-6 carbon atoms per alkyl group, alkylthio of 1-6 carbon atoms, --SO.sub.3 H, --PO.sub.3 H, and --CO.sub.2 H;
• or a pharmaceutically acceptable salt thereof when the Ar group contains a basic nitrogen or when the Ar group is substituted by dialkylamino of 1-6 carbon atoms per alkyl group, --SO.sub.3 H, --PO.sub.3 H, or --CO.sub.2 H;
• or a pharmaceutically acceptable salt thereof;
• or of formula X, ##STR69## wherein R is --SO.sub.2 R.sup.1 ;
• R.sup.1 is alkyl, alkenyl, alkynyl containing 1 to 6 carbon atoms;
• or an aromatic moiety selected from the group consisting of phenyl and naphthyl or a heterocyclic moiety selected from the group consisting of thiophenyl and quinolinyl;
• or --NHCOR.sup.2 ;
• and
• R.sup.2 is lower alkyl containing 1 to 6 carbon atoms;
• or a pharmaceutically acceptable salt thereof,
• and a pharmaceutically acceptable carrier.