27-hydroxyrapamycin and derivatives thereof

• US 5,256,790 A
• Filed: 01/27/1993
• Issued: 10/26/1993
• Est. Priority Date: 08/13/1992
• Status: Expired due to Term

• Current Assignee: Wyeth (Pfizer Inc.)
• Original Assignee: American Home Products Corporation (Pfizer Inc.)
• Inventors: Nelson, Frances C.
• Primary Examiner(s): Cintins, Marianne M.
• Assistant Examiner(s): Peabody, John
• Application Number:
  US08/009,605
• Time in Patent Office: 272 Days
• Field of Search: 540/456, 514/291
• US Class Current: 514/291
• CPC Class Codes: C07D 498/16 Peri-condensed systems
• CPC Class Codes: C07D 498/18 Bridged systems

Abstract

This invention provides a compound of formula I, ##STR1## and 27-substituted derivatives thereof which are useful as immunosuppressive, antiinflammatory, antifungal, antitumor, and antiproliferative agents. The compound depicted by formula I is named 27-hydroxyrapamycin, and may also be referred to as 27-deoxo-27-hydroxyrapamycin.

Claims

1. A compound of the formula ##STR22## wherein R¹ is ##STR23## and R² 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, --SO₃ H, --PO₃ H, and --CO₂ H;

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 which is 27-hydroxyrapamycin-27-ester with acetic acid.

3. A compound of the formula ##STR24## wherein R¹ is ##STR25## and R² is a mono-, di-, poly-, or per-fluorinated alkyl group of 1-10 carbon atoms.

4. A compound of the formula ##STR26## wherein R¹ is ##STR27## R² is ##STR28## 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 ##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;

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;

or a pharmaceutically acceptable salt thereof.

5. A compound of the formula ##STR30## wherein R² is ##STR31## R³ is hydrogen, alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, --(CH₂)_q CO₂ R⁶, --(CH₂)_r NR⁷ CO₂ R⁸, 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 --CO₂ H;

R⁴ and R⁷ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or arylalkyl of 7-10 carbon atoms;

R⁵, R⁶, and R⁸ 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 --CO₂ H;

m is 0-4;

n is 0-4;

p is 1-2;

q is 0-4;

r is 0-4;

wherein R³, R⁴, m, and n are independent in each of the ##STR32## subunits when p=2;

or a pharmaceutically acceptable salt thereof.

6. A compound of the formula ##STR33## wherein R¹ is alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, --CH₂ YX, --C(CH₃)₂ YX, --CH(CH₃)YX, or L;

Y is O or S;

X is --CH₃, --(CH₂)_n CH₃, --CH₂ Ar, --(CH₂)₂ OCH₃, --CH₂ CCl₃, --CH(CH₃)₂, or --CH₂ CH₂ SiMe₃ ;

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.

7. A compound of the formula ##STR34## wherein R is ##STR35## R¹ and R² are each hydrogen or alkyl of 1-3 carbon atoms or R¹ and R² 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.

8. A compound of the formula ##STR36## wherein R¹ is --CONHSO₂ --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, --SO₃ H, --PO₃ H, and --CO₂ 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, --SO₃ H, --PO₃ H, or --CO₂ H;

or a pharmaceutically acceptable salt thereof.

9. A compound of the formula ##STR37## wherein R is --SO₂ R¹ ;

R¹ 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 --NHCOR² ; and

R² is lower alkyl containing 1 to 6 carbon atoms;

or a pharmaceutically acceptable salt thereof.

10. A method of inducing immunosuppression which comprises administering an immunosuppressive effective amount of a compound of formula II, ##STR38## wherein R¹ is ##STR39## and R² 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, --SO₃ H, --PO₃ H, and --CO₂ H;

or a pharmaceutically acceptable salt thereof;

or of formula III, ##STR40## wherein R¹ is ##STR41## and R² is a mono-, di-, poly-, or per-fluorinated alkyl group of 1-10 carbon atoms;

or of formula IV, ##STR42## wherein R¹ is ##STR43## R² is ##STR44## 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 ##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;

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;

or a pharmaceutically acceptable salt thereof;

or of formula VI, ##STR46## wherein R² is ##STR47## R³ is hydrogen, alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, --(CH₂)_q CO₂ R⁶, --(CH₂)_r NR⁷ CO₂ R⁸, 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 --CO₂ H;

R⁴ and R⁷ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or arylalkyl of 7-10 carbon atoms;

R⁵, R⁶, and R⁸ 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 --CO₂ H;

m is 0-4;

n is 0-4;

p is 1-2;

q is 0-4;

r is 0-4;

wherein

R³, R⁴, 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 R¹ is alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, --CH₂ YX, --C(CH₃)₂ YX, --CH(CH₃)YX, or L;

Y is O or S;

X is --CH₃, --(CH₂)_n CH₃, --CH₂ Ar, --(CH₂)₂ OCH₃, --CH₂ CCl₃, --CH(CH₃)₂, or --CH₂ CH₂ SiMe₃ ;

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## R¹ and R² are each hydrogen or alkyl of 1-3 carbon atoms or R¹ and R² 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 R¹ is --CONHSO₂ --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, --SO₃ H, --PO₃ H, and --CO₂ 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, --SO₃ H, --PO₃ H, or --CO₂ H;

or a pharmaceutically acceptable salt thereof;

or of formula X, ##STR53## wherein R is --SO₂ R¹ ;

R¹ 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 --NHCOR² ; and

R² is lower alkyl containing 1 to 6 carbon atoms;

or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition which comprises an effective amount of a compound of formula II, ##STR54## wherein R¹ is ##STR55## and R² 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, --SO₃ H, --PO₃ H, and --CO₂ H;

or a pharmaceutically acceptable salt thereof;

or of formula III, ##STR56## wherein R¹ is ##STR57## and R² is a mono-, di-, poly-, or per-fluorinated alkyl group of 1-10 carbon atoms;

or of formula IV, ##STR58## wherein R¹ is ##STR59## R² is ##STR60## 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 ##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;

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;

or a pharmaceutically acceptable salt thereof;

or of formula VI, ##STR62## wherein R² is ##STR63## R³ is hydrogen, alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, --(CH₂)_q CO₂ R⁶, --(CH₂)_r NR⁷ CO₂ R⁸, 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 --CO₂ H;

R⁴ and R⁷ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or arylalkyl of 7-10 carbon atoms;

R⁵, R⁶, and R⁸ 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 --CO₂ H;

m is 0-4;

n is 0-4;

p is 1-2;

q is 0-4;

r is 0-4;

wherein R³, R⁴, 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 R¹ is alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, --CH₂ YX, --C(CH₃)₂ YX, --CH(CH₃)YX, or L;

Y is O or S;

X is --CH₃, --(CH₂)_n CH₃, --CH₂ Ar, --(CH₂)₂ OCH₃, --CH₂ CCl₃, --CH(CH₃)₂, or --CH₂ CH₂ SiMe₃ ;

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## R¹ and R² are each hydrogen or alkyl of 1-3 carbon atoms or R¹ and R² 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 R¹ is --CONHSO₂ --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, --SO₃ H, --PO₃ H, and --CO₂ 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, --SO₃ H, --PO₃ H, or --CO₂ H;

or a pharmaceutically acceptable salt thereof;

or of formula X, ##STR69## wherein R is --SO₂ R¹ ;

R¹ 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 --NHCOR² ; and

R² is lower alkyl containing 1 to 6 carbon atoms;

or a pharmaceutically acceptable salt thereof,

and a pharmaceutically acceptable carrier.