Compounds and methods of treating transplant rejection

A method for treating transplant rejection in a mammal comprising administering to said mammal an effective amount of a compound of formula:

• 21
• or a pharmaceutically acceptable salt wherein:
• Y is a bond;
• Z is selected from the group consisting of C1-10alkyl, C2-10alkenyl, C2-10alkynyl, hydroxyC1-10alkyl, aryl, heteroaryl, C1-10alkaryl, arylC1-10alkyl, heteroarylC1-10alkyl, C1-10alkoxyC1-10alkyl, C1-10alkylaminoC1-10alkyl, carboxyC1-10alkyl, C1-10dialkylaminoC1-10alkyl, aminoC1-10alkyl, heterocycle, heterocyclC1-10alkyl, R7NH, R7R7N, and carboxyC1-10alkyl, wherein all may optionally be substituted by one or more R5;
• R5 is independently selected from the group selected from hydroxy, C1-10alkyl, C1-10alkoxy, halo, nitro, amino, cyano, C1-10alkylamino, diC1-10alkylamino, acyl, acyloxy, COOH, COOR7, OC(O)R7, CH(OH)R7, NHR7, NR7R7, C(O)NH2, C(O)NHR7, CONR7R7, NHC(O)O-R7, OSO3H, SO3H, SO2NHR7, SO2NR7R7, P(O)(OH)OR7, PO2H2 P(O)(OH)R7, P(O)(OR7)2, P(O)R7(OR7), OPO3H, PO3H2, hydroxymethyl, and cyclic phosphate, wherein when possible, all may be optionally substituted by one or more R6;
• R6 is independently selected from the group consisting of hydroxy, C1-10alkyl, C1-10alkoxy, acyloxy, halo, nitro, amino, cyano, haloC1-10alkyl, C1-10alkylamino, diC1-10Ioalkylamino, acyl, and acyloxy;
• R7 is independently selected from the group consisting of C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10alkoxy, C1-10alkoxycarbonylC1-10alkyl, aryl, carboxyC1-10alkyl, C1-10alkylcarboxyC1-10alkyl, C1-10alkylcarboxyC1-10aryl, heterocycle, heterocyclC1-10alkyl, and heteroaryl, wherein all may be optionally substituted by one or more R8;
• and
• R8 is independently selected from the group consisting of hydroxy, C1-10alkyl, C1-10alkoxy, acyloxy, halo, nitro, amino, cyano, and carboxy;
• wherein two R7 groups may come together to form a 4 to 7 membered ring.

A method for treating transplant rejection in a mammal comprising administering to said mammal an effective amount of a compound of formula

• 25
• or a pharmaceutically acceptable salt wherein:
• Y is
• 26
• Z is selected from the group consisting of C1-10alkyl, C2-10alkenyl, C2-10alkynyl, hydroxyC1-10alkyl, aryl, heteroaryl, C1-10alkaryl, arylC1-10alkyl, heteroarylC1-10alkyl, C1-10alkoxyC1-10alkyl, C1-10alkylaminoC1-10alkyl, carboxyC1-10alkyl, C1-10dialkylaminoC1-10alkyl, aminoC1-10alkyl, heterocycle, heterocyclC1-10alkyl, R7NH, R7R7N, carboxy, carbohydrate group, carbohydrate lactone group, and an alditol group wherein all may optionally be substituted by one or more R5;
• R5 is independently selected from the group selected from hydroxy, C1-10alkyl, C1-10alkoxy, halo, nitro, amino, cyano, C1-10alkylamino, diC1-10alkylamino, acyl, acyloxy, COOH, COOR7, OC(O)R7, CH(OH)R7, NHR7, NR7R7, C(O)NH2, C(O)NHR7, CONR7R7, NHC(O)O-R7, OSO3H, SO3H, SO2NHR7, SO2NR7R7, P(O)(OH)OR7, PO2H2 P(O)(OH)R7, P(O)(OR7)2, P(O)R7(OR7), OPO3H, PO3H2, hydroxymethyl, and cyclic phosphate, wherein when possible, all may be optionally substituted by one or more R6;
• R6 is independently selected from the group consisting of hydroxy, C1-10alkyl, C1-10alkoxy, acyloxy, halo, nitro, amino, cyano, haloC1-10alkyl, C1-10alkylamino, diC1-10Ioalkylamino, acyl, and acyloxy;
• R7 is independently selected from the group consisting of C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10alkoxy, C1-10alkoxycarbonylC1-10alkyl, aryl, carboxyC1-10alkyl, C1-10alkylcarboxyC1-10alkyl, C1-10alkylcarboxyC1-10aryl, heterocycle, heterocyclC1-10alkyl, and heteroaryl, wherein all may be optionally substituted by one or more R8;
• and
• R8 is independently selected from the group consisting of hydroxy, C1-10alkyl, C1-10alkoxy, acyloxy, halo, nitro, amino, cyano, and carboxy;
• wherein two R7 groups may come together to form a 4 to 7 membered ring.

A method for treating or preventing transplantation rejection in a mammal comprising administering by way of an intraluminal stent a compound of the formula

• 31
• or a pharmaceutically acceptable salt wherein:
• Y is
• 32
• Z is selected from the group consisting of C1-6alkyl, C1-6alkoxyC1-6alkyl, C1-6alkylaminoC1-6alkyl, and aminoC1-6alkyl, wherein all may optionally be substituted by one or more R5;
• R5 is independently selected from the group selected from hydroxy, C1-6alkyl, C1-6alkoxy, acyloxy, halo, nitro, amino, cyano, C1-6alkylamino, diC1-6alkylamino, acyl, acyloxy, COOH, COOR7, OC(O)R7, CH(OH)R7, NHR7, NR7R7, C(O)NH2, C(O)NHR7, CONR7R7, NHC(O)O-R7, OSO3H, SO3H, SO2NHR7, SO2NR7R7, P(O)(OH)OR7, P(O)HR7, P(O)(OH)R7, P(OR7)2, P(O)R7(OR7), OPO3H, PO3H2, hydroxymethyl, and cyclic phosphate, wherein when possible, all may be optionally substituted by one or more R6;
• R6 is independently selected from the group consisting of hydroxy, C1-6alkyl, C1-6alkoxy, acyloxy, halo, amino, cyano, haloC1-6alkyl, C1-6alkylamino, diC1-6alkylamino, acyl, and acyloxy;
• R7 is independently selected from the group consisting of C1-6alkyl, C2-10alkenyl, C2-10alkynyl, C1-10alkoxy, C1-10alkoxycarbonylC1-10alkyl, carboxyC1-6alkyl, C1-6alkylcarboxyC1-6alkyl, and heteroaryl, wherein all may be optionally substituted by one or more R8;
• and
• R8 is independently selected from the group consisting of hydroxy, halo, amino, and carboxy.

An intraluminal stent incorporating a compound of the formula

• 34
• or a pharmaceutically acceptable salt wherein:
• Y is
• 35
• Z is selected from the group consisting of C1-6alkyl, C1-6alkoxyC1-6alkyl, C1-6alkylaminoC1-6alkyl, and aminoC1-6alkyl, wherein all may optionally be substituted by one or more R5;
• R5 is independently selected from the group selected from hydroxy, C1-6alkyl, C1-6alkoxy, acyloxy, halo, nitro, amino, cyano, C1-6alkylamino, diC1-6alkylamino, acyl, acyloxy, COOH, COOR7, OC(O)R7, CH(OH)R7, NHR7, NR7R7, C(O)NH2, C(O)NHR7, CONR7R7, NHC(O)O-R7, OSO3H, SO3H, SO2NHR7, SO2NR7R7, P(O)(OH)OR7, P(O)HR7, P(O)(OH)R7, P(OR7)2, P(O)R7(OR7), OPO3H, PO3H2, hydroxymethyl, and cyclic phosphate, wherein when possible, all may be optionally substituted by one or more R6;
• R6 is independently selected from the group consisting of hydroxy, C1-6alkyl, C1-6alkoxy, acyloxy, halo, amino, cyano, haloC1-6alkyl, C1-6alkylamino, diC1-6alkylamino, acyl, and acyloxy;
• R7 is independently selected from the group consisting of C1-6alkyl, C2-10alkenyl, C2-10alkynyl, C1-10alkoxy, C1-10alkoxycarbonylC1-10alkyl, carboxyC1-6alkyl, C1-66alkylcarboxyC1-6alkyl, and heteroaryl, wherein all may be optionally substituted by one or more R8;
• and
• R8 is independently selected from the group consisting of hydroxy, halo, amino, and carboxy.

A method for treating transplant rejection in a mammal comprising administering to said mammal an effective amount of a compound of formula:

• 36
• or a pharmaceutically acceptable salt thereof, in combination or alternation with one or more other agents effective for inhibiting transplant rejection, wherein:
• Y is a bond or
• 37
• R1, R2, R3, and R4 are independently selected from the group consisting of hydrogen, hydroxy, alkoxy, C1-10alkyl, aryl, heteroaryl, C1-10alkaryl, and aryl C1-10alkyl, wherein said alkoxy, C1-10alkyl, aryl, heteroaryl, C1-10alkaryl, and aryl C1-10alkyl may optionally be substituted with one or more of the group selected from C1-10alkyl, halogen, nitro, amino, haloC1-10alkyl, C1-10alkylamino, diC1-10alkylamino, acyl, and acyloxy;
• Z is selected from the group consisting of C1-10alkyl, C2-10alkenyl, C2-10alkynyl, hydroxyC1-10alkyl, aryl, heteroaryl, C1-10alkaryl, arylC1-10alkyl, heteroarylC1-10alkyl, C1-10alkoxyC1-10alkyl, C1-10alkylaminoC1-10alkyl, carboxyC1-10alkyl, C1-10dialkylaminoC1-10alkyl, aminoC1-10alkyl, heterocycle, R7NH, R7R7N, carboxyC1-10alkyl and carboxy, wherein all may optionally be substituted by one or more R5;
• R5 is independently selected from the group selected from hydroxy, C1-10alkyl, C1-10alkoxy, halo, nitro, amino, cyano, C1-10alkylamino, diC1-10alkylamino, acyl, acyloxy, COOH, COOR7, OC(O)R7, CH(OH)R7, NHR7, NR7R7, C(O)NH2, C(O)NHR7, CONR7R7, NHC(O)O-R7, OSO3H, SO3H, SO2NHR7, SO2NR7R7, P(O)(OH)OR7, PO2H2 P(O)(OH)R7, P(O)(OR7)2, P(O)R7(OR7), OPO3H, PO3H2, hydroxymethyl, and cyclic phosphate, wherein when possible, all may be optionally substituted by one or more R6;
• R6 is independently selected from the group consisting of hydroxy, C1-10alkyl, C1-10alkoxy, acyloxy, halo, nitro, amino, cyano, haloC1-10alkyl, C1-10alkylamino, diC1-10alkylamino, acyl, and acyloxy;
• R7 is independently selected from the group consisting of C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10alkoxy, C1-10alkoxycarbonylC1-10alkyl, aryl, carboxyC1-10alkyl, C1-10alkylcarboxyC1-10alkyl, C1-10alkylcarboxyC1-10aryl, heterocycle, heterocyclC1-10alkyl, and heteroaryl, wherein all may be optionally substituted by one or more R8;
• and
• R8 is independently selected from the group consisting of hydroxy, C1-10alkyl, C1-10alkoxy, acyloxy, halo, nitro, amino, cyano, and carboxy;
• wherein two R7 groups may come together to form a 4 to 7 membered ring.

A method for treating transplant rejection in a mammal comprising administering to said mammal an effective amount of a compound of formula:

• 38
• or a pharmaceutically acceptable salt thereof, in combination or alternation with one or more other agents effective for inhibiting transplant rejection, wherein:
• Y is a bond;
• Z is selected from the group consisting of C1-10alkyl, C2-10alkenyl, C2-10alkynyl, hydroxyC1-10alkyl, aryl, heteroaryl, C1-10alkaryl, arylC1-10alkyl, heteroarylC1-10alkyl, C1-10alkoxyC1-10alkyl, C1-10alkylaminoC1-10alkyl, carboxyC1-10alkyl, C1-10dialkylaminoC1-10alkyl, aminoC1-10alkyl, heterocycle, heterocyclC1-10alkyl, R7NH, R7R7N, and carboxyC1-10alkyl, wherein all may optionally be substituted by one or more R5;
• R5 is independently selected from the group selected from hydroxy, C1-10alkyl, C1-10alkoxy, halo, nitro, amino, cyano, C1-10alkylamino, diC1-10alkylamino, acyl, acyloxy, COOH, COOR7, OC(O)R7, CH(OH)R7, NHR7, NR7R7, C(O)NH2, C(O)NHR7, CONR7R7, NHC(O)O-R7, OSO3H, SO3H, SO2NHR7, SO2NR7R7, P(O)(OH)OR7, PO2H2 P(O)(OH)R7, P(O)(OR7)2, P(O)R7(OR7), OPO3H, PO3H2, hydroxymethyl, and cyclic phosphate, wherein when possible, all may be optionally substituted by one or more R6;
• R6 is independently selected from the group consisting of hydroxy, C1-10alkyl, C1-10alkoxy, acyloxy, halo, nitro, amino, cyano, haloC1-10alkyl, C1-10alkylamino, diC1-10alkylamino, acyl, and acyloxy;
• R7 is independently selected from the group consisting of C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10alkoxy, C1-10alkoxycarbonylC1-10alkyl, aryl, carboxyC1-10alkyl, C1-10alkylcarboxyC1-10alkyl, C1-10alkylcarboxyC1-10aryl, heterocycle, heterocyclC1-10alkyl, and heteroaryl, wherein all may be optionally substituted by one or more R8;
• and
• R8 is independently selected from the group consisting of hydroxy, C1-10alkyl, C1-10alkoxy, acyloxy, halo, nitro, amino, cyano, and carboxy;
• wherein two R7 groups may come together to form a 4 to 7 membered ring.

A method for treating transplant rejection in a mammal comprising administering to said mammal an effective amount of a compound of formula

• 42
• or a pharmaceutically acceptable salt, in combination or alternation with one or more other agents effective for inhibiting transplant rejection, wherein:
• Y is
• 43
• Z is selected from the group consisting of C1-10alkyl, C2-10alkenyl, C2-10alkynyl, hydroxyC1-10alkyl, aryl, heteroaryl, C1-10alkaryl, arylC1-10alkyl, heteroarylC1-10alkyl, C1-10alkoxyC1-10alkyl, C1-10alkylaminoC1-10alkyl, carboxyC1-10alkyl, C1-10dialkylaminoC1-10alkyl, aminoC1-10alkyl, heterocycle, heterocyclC1-10alkyl, R7NH, R7R7N, carboxy, carbohydrate group, carbohydrate lactone group, and an alditol group wherein all may optionally be substituted by one or more R5;
• R5 is independently selected from the group selected from hydroxy, C1-10alkyl, C1-10alkoxy, halo, nitro, amino, cyano, C1-10alkylamino, diC1-10alkylamino, acyl, acyloxy, COOH, COOR7, OC(O)R7, CH(OH)R7, NHR7, NR7R7, C(O)NH2, C(O)NHR7, CONR7R7, NHC(O)O-R7, OSO3H, SO3H, SO2NHR7, SO2NR7R7, P(O)(OH)OR7, PO2H2 P(O)(OH)R7, P(O)(OR7)2, P(O)R7(OR7), OPO3H, PO3H2, hydroxymethyl, and cyclic phosphate, wherein when possible, all may be optionally substituted by one or more R6;
• R6 is independently selected from the group consisting of hydroxy, C1-10alkyl, C1-10alkoxy, acyloxy, halo, nitro, amino, cyano, haloC1-10alkyl, C1-10alkylamino, diC1-10alkylamino, acyl, and acyloxy;
• R7 is independently selected from the group consisting of C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10alkoxy, C1-10alkoxycarbonylC1-10alkyl, aryl, carboxyC1-10alkyl, C1-10alkylcarboxyC1-10alkyl, C1-10alkylcarboxyC1-10aryl, heterocycle, heterocyclC1-10alkyl, and heteroaryl, wherein all may be optionally substituted by one or more R8;
• and
• R8 is independently selected from the group consisting of hydroxy, C1-10alkyl, C1-10alkoxy, acyloxy, halo, nitro, amino, cyano, and carboxy;
• wherein two R7 groups may come together to form a 4 to 7 membered ring.