P-terphenyl compounds

A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient,

• wherein the compound is of the formula (I):
• wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12 and R13 are each independently hydrogen, hydroxy, halogen, carboxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, optionally substituted lower alkenyloxy, optionally substituted lower alkylthio, optionally substituted lower alkoxycarbonyl, optionally substituted acyloxy, optionally substituted lower alkylsulfonyl, optionally substituted lower alkylsulfonyloxy, optionally substituted lower alkylsulfinyl, nitro, cyano, formyl, optionally substituted amino, optionally substituted carbamoyl, optionally substituted sulfamoyl or optionally substituted heterocyclyl,
• X is —O—, —CH2—, —NR14— wherein R14 is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl or acetyl, or —S(O)p— wherein p is an integer of 0 to 2,
• Y is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl or optionally substituted heterocyclyl, and Y may optionally be substituted lower alkoxy when X is —CH2— and may optionally be substituted lower alkoxycarbonyl, optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl when X is —O— or —NR14—,
• R1 and R4, R1 and R2, R2 and R3, R4 and R5, R6 and R7, R8 and R9, R10 and R11, R12 and R13, R11 and —X—Y, or R13 and —X—Y taken together may form a 5- or 6-membered ring which may contain one or more of O, S or NR15 wherein R15 is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted arylsulfonyl and which may optionally be substituted,
• excluding compounds wherein one or more of R6, R7, R8 and R9 are halogen and the others are hydrogen, compounds wherein all of R6, R7, R8 and R9 are halogen and compounds wherein all of R2–R13 are hydrogen, halogen or cyano,
• provided that R1 is not hydrogen, fluorine, optionally substituted lower alkyl or optionally substituted lower alkoxy, all of R2, R3, R4, R5 and R12 are hydrogen, or R13 is not hydrogen or halogen when R6, R7, R8 and R9 are all simultaneously hydrogen,
• and further provided that R1 is not methyl or acetyloxy, R13 is not hydrogen, optionally substituted lower alkoxycarbonyl or optionally substituted carbamoyl, or —X—Y is not methoxy when at least one of R6, R7, R8 and R9 is a substituent other than hydrogen,
• and excluding a compound of the formula (I′):
• wherein R1 is hydrogen or hydroxy and R13′ is hydroxy or methoxy.

An immunosuppressive composition comprising a compound of the formula (I″):

• wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R1, R12 and R13 are each independently hydrogen, hydroxy, halogen, carboxy, optionally substituted lower alkyl optionally substituted, lower alkoxy, optionally substituted lower alkenyl, optionally substituted lower alkenyloxy, optionally substituted lower alkylthio, optionally substituted lower alkoxycarbonyl, optionally substituted acyloxy, optionally substituted lower alkylsulfonyl, optionally substituted lower alkylsulfonyloxy, optionally substituted lower alkylsulfinyl, nitro, cyano, formyl, optionally substituted amino, optionally substituted carbamoyl, optionally substituted sulfamoyl or optionally substituted heterocyclyl,
• X is —O—, —CH2—, —NR14— wherein R14 is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl or acetyl, or —S(O)p— wherein p is an integer of 0 to 2,
• Y is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl or optionally substituted heterocyclyl, and Y may optionally be substituted lower alkoxy when X is —CH2— and may optionally be substituted lower alkoxycarbonyl, optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl when X is —O— or —NR14—,
• R1 and R4, R1 and R2, R2 and R3, R4 and R5, R6 and R7, R8 and R9, R10 and R11, R12 and R13, R11 and —X—Y, or R13 and —X—Y taken together may form a 5- or 6-membered ring which may contain one or more of O, S or NR15 wherein R15 is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl or optionally substituted arylsulfonyl and which may optionally be substituted,
• excluding a compound of the formula (I′):
• wherein R1′ is hydrogen or hydroxy and R13′ is hydroxy or methoxy;
• or a pharmaceutically acceptable salt or hydrate thereof, and
• a pharmaceutically acceptable excipient.

A process for producing a compound of the formula (I) or a pharmaceutically acceptable salt thereof:

• wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12 and R13 are each independently hydrogen, hydroxy, halogen, carboxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, optionally substituted lower alkenyloxy, optionally substituted lower alkylthio, optionally substituted lower alkoxycarbonyl, optionally substituted acyloxy, optionally substituted lower alkylsulfonyl, optionally substituted lower alkylsulfonyloxy, optionally substituted lower alkylsulfinyl, nitro, cyano, formyl, optionally substituted amino, optionally substituted carbamoyl, optionally substituted sulfamoyl or optionally substituted heterocyclyl,
• X is —O—, —CH2—, —NR14— wherein R14 is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl or acetyl, or —S(O)p— wherein p is an integer of 0 to 2,
• Y is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl or optionally substituted heterocyclyl, and Y may optionally be substituted lower alkoxy when X is —CH2— and may optionally be substituted lower alkoxycarbonyl, optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl when X is —O— or —NR14—,
• R1 and R4, R1 and R2, R2 and R3, R4 and R5, R6 and R7, R8 and R9, R10 and R11 R12 and R13, R11 and —X—Y, or R13 and —X—Y taken together may form a 5- or 6-membered ring which may contain one or more of O, S or NR15 wherein R15 is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted arylsulfonyl and which may optionally be substituted,
• excluding compounds wherein one or more of R6, R7, R8 and R9 are halogen and the others are hydrogen, compounds wherein all of R6, R7, R8 and R9 are halogen and compounds wherein all of R2–R13 are hydrogen, halogen or cyano,
• provided that R1 is not hydrogen, fluorine, optionally substituted lower alkyl or optionally substituted lower alkoxy, all of R2, R3, R4, R5 and R12 are hydrogen, or R13 is not hydrogen or halogen when R6, R7, R8 and R9 are all simultaneously hydrogen,
• and further provided that R1 is not methyl or acetyloxy, R13 is not hydrogen, optionally substituted lower alkoxycarbonyl or optionally substituted carbamoyl, or —X—Y is not methoxy when at least one of R6, R7, R8 and R9 is a substituent other than hydrogen, and excluding a compound of the formula (I′):
• wherein R1′ is hydrogen or hydroxy and R13′ is hydroxy or methoxy;
• said process comprising reacting a compound of the formula (II):
• with a compound of the formula (III):
• wherein, in the formulas (II) and (III), R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12 and R13 are each described above;
• either of A and Z is dihydroxyborane, di(lower)alkoxyborane, di(lower)alkylborane,
• and the other is halogen or —OSO2(CqF2q+1)— wherein q is an integer of 1 to 4, or reacting a compound of the formula (II′):
• with a compound of the formula (III′):
• wherein, in the formulas (II′) and (III′), R1–R13, X and Y are the same as defined above and A and Z are the same as defined in the above formulas (II) and (III).

A compound of the formula (I):

• wherein R1 is hydrogen, halogen, optionally substituted lower alkenyloxy, optionally substituted lower alkylsulfonyloxy, optionally substituted amino or optionally substituted sulfamoyl,
• R2 is hydrogen, halogen or lower alkyl having 1 to 3 carbon atoms,
• R3 is hydrogen or halogen,
• R4 is hydrogen, lower alkyl, lower alkoxy or halogen,
• R5 is hydrogen, lower alkoxycarbonyl or carboxy,
• R6 is hydrogen, lower alkyl or halogen,
• R7 is hydrogen, lower alkyl or lower alkoxy,
• R8 is hydrogen, lower alkyl or lower alkoxy,
• R9 is hydrogen, hydroxy, carboxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, optionally substituted lower alkoxycarbonyl, optionally substituted lower alkylsulfonyloxy, formyl, optionally substituted carbamoyl or optionally substituted amino,
• R10 is hydrogen,
• R11 is hydrogen or halogen,
• R12 is hydrogen,
• R13 is hydrogen, hydroxy, halogen, carboxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted acyloxy, optionally substituted lower alkylsulfonyloxy, formyl or optionally substituted amino,
• X is —O—, —NH—, —NMe- or —SO2—,
• Y is lower alkyl optionally substituted with lower alkoxycarbonyl, aryl, lower alkylaryl, halogenoaryl, lower alkoxyaryl, heterocyclyl or acyl;
• or lower alkenyl optionally substituted with hydroxy, halogen or aryl,
• and R1 and R4 or R8 and R9 taken together may form a 5- or 6-membered ring which contains one or more of 0,
• excluding compounds wherein one or more of R6, R7, R8 and R9 are halogen and the others are hydrogen and compounds wherein all of R2—R13 are hydrogen,
• provided that R1 is not hydrogen or fluorine, all of R2, R3, R4, R5 and R12 are hydrogen, or R13 is not hydrogen or halogen when R6, R7, R8 and R9 are an simultaneously hydrogen,
• and further provided that R3 is not hydrogen or —X—Y is not methoxy when at least one of R6, R7, R8 and R9 is a substituent other than hydrogen, and excluding a compound of the formula (I′):
• wherein R1′, is hydrogen or hydroxy and R13 is hydroxy or methoxy;
• or a pharmaceutically acceptable salt thereof.

A compound of the formula (I):

• wherein R1 is hydrogen, hydroxy, halogen, optionally substituted lower alkoxy, optionally substituted alkenyloxy, optionally substituted lower alkylsulfonyloxy, optionally substituted amino or optionally substituted sulfamoyl,
• R2 is hydrogen, halogen or lower alkyl having 1 to 3 carbon atoms,
• R3 is hydrogen or halogen,
• R4 is hydrogen, lower alkyl, lower alkoxy or halogen,
• R5 is hydrogen, lower alkoxycarbonyl or carboxy,
• R6 is hydrogen, lower alkyl or halogen,
• R7 is hydrogen, lower alkyl or lower alkoxy,
• R8 is hydrogen, lower alkyl or lower alkoxy,
• R9 is hydrogen, hydroxy, carboxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, optionally substituted lower alkoxycarbonyl, optionally substituted lower alkylsulfonyloxy, formyl, optionally substituted carbamoyl or optionally substituted amino,
• R10 is hydrogen,
• R11 is hydrogen or halogen,
• R12 is hydrogen,
• R13 is hydrogen, hydroxy, halogen, carboxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted acyloxy, optionally substituted lower alkylsulfonyloxy, formyl or optionally substituted amino,
• X is —O—, —NH—, —NMe- or —SO2—,
• Y is lower alkyl optionally substituted with aryl;
• or lower alkenyl,
• and R1 and R4 or R8 and R9 taken together may form a 5- or 6-membered ring which contains one or more of O,
• excluding compounds wherein one or more of R6, R7, R8 and R9 are halogen and the others are hydrogen and compounds wherein all of R2–R13 are hydrogen, provided that R1 is not hydrogen, fluorine or optionally substituted lower alkoxy, all of R2, R3, R4, R5 and R12 are hydrogen, or R13 is not hydrogen or halogen when R6, R7, R8 and R9 are all simultaneously hydrogen, and further provided that R13 is not hydrogen or —X—Y is not methoxy when at least one of R6, R7, R8 and R9 is a substituent other than hydrogen, and excluding a compound of the formula (I′):
• wherein R1′ is hydrogen or hydroxy and R13′ is hydroxy or methoxy;
• or a pharmaceutically acceptable salt or hydrate thereof.

A compound of the formula (I):

• wherein R1, R2, R1, R4, R5, R6, R7, R1, R9, R10, R11, R12 and R13 are each independently hydrogen, hydroxy, halogen, carboxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, optionally substituted lower alkenyloxy, optionally substituted lower alkylthio, optionally substituted lower alkoxycarbonyl, optionally substituted acyloxy, optionally substituted lower alkylsulfonyl, optionally substituted lower alkylsulfonyloxy, optionally substituted lower alkylsulfinyl, nitro, cyano, formyl, optionally substituted amino, optionally substituted carbamoyl, optionally substituted sulfamoyl or optionally substituted heterocyclyl,
• X is —O—, —CH2—, —NR14— wherein R14 is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl or acetyl, or —S(O)p— wherein p is an integer of 0 to 2,
• Y is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl or optionally substituted heterocyclyl, and Y may be optionally substituted lower alkoxy when X is —CH2— and may be optionally substituted lower alkoxycarbonyl, optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl when X is —O— or —NR14—, R1 and R4, R1 and R2, R2 and R3, R4 and R5, R6 and R7, R8 and R9, R10 and R11, R12 and R13, R11 and —X—Y, or R13 and —X—Y taken together may form a 5- or 6-membered ring which may contain one or more of O, S or NR5 wherein R15 is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted arylsulfonyl and which may optionally be substituted, excluding compounds wherein one or more of R6, R7, R8 and R9 are halogen and the others are hydrogen, compounds wherein all of R6, R7, R1 and R9 are halogen and compounds wherein all of R2–R13 are hydrogen, halogen or cyano, provided that R1 is not hydrogen, fluorine, optionally substituted lower alkyl or optionally substituted lower alkoxy, all of R2, R3, R4, R1 and R12 are hydrogen, and R13 is not hydrogen or halogen when R6, R7, R8 and R9 are all simultaneously hydrogen, and further provided that R1 is not methyl or acetyloxy, R13 is not hydrogen, optionally substituted lower alkoxycarbonyl or optionally substituted carbamoyl, and —X—Y is not methoxy when at least one of R6, R7, R8 and R9 is a substituent other than hydrogen, and excluding a compound of the formula (I′):
• wherein R1′ is hydrogen or hydroxy and R13 is hydroxy or methoxy;
• or a pharmaceutically acceptable salt thereof.

A compound of the formula (I):

• wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R1, R12 and R13 are each independently hydrogen, hydroxy, carboxy, optionally substituted lower alkoxy, optionally substituted lower alkenyl, optionally substituted lower alkenyloxy, optionally substituted lower alkylthio, optionally substituted lower alkoxycarbonyl, optionally substituted acyloxy, optionally substituted lower alkylsulfonyl, optionally substituted lower alkylsulfonyloxy, optionally substituted lower alkylsulfinyl, nitro, formyl, optionally substituted amino, optionally substituted carbamoyl, optionally substituted sulfamoyl or optionally substituted heterocyclyl,
• X is —O—, —CH2—, —NR14— wherein R14 is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl or acetyl, or —S(O)p— wherein p is an integer of 0 to 2,
• Y is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl or optionally substituted heterocyclyl, and Y may optionally be substituted lower alkoxy when X is —CH2— and may optionally be substituted lower alkoxycarbonyl, optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl when X is —O— or —NR14—,
• R1 and R4, R1 and R2, R2 and R3, R4 and R5, R6 and R7, R8 and R9, R10 and R111, R12 and R13, R11 and —X—Y, or R13 and —X—Y taken together may form a 5- or 6-membered ring which may contain one or more of O, S or NR15 wherein R15 is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted arylsulfonyl and which may optionally be substituted,
• excluding compounds wherein all of R2–R1 3 are hydrogen,
• provided that R1 is not hydrogen or optionally substituted lower alkoxy, all of R2, R3, R4, R5 and R12 are hydrogen, or R13 is not hydrogen when R6, R7, R8 and R9 are all simultaneously hydrogen,
• and further provided that R1 is not acetyloxy, R13 is not hydrogen, optionally substituted lower alkoxycarbonyl or optionally substituted carbamoyl, or —X—Y is not methoxy when at least one of R6, R7, R8 and R9 is a substituent other than hydrogen, and excluding a compound of the formula (I′):
• wherein R1′ is hydrogen or hydroxy and R13′ is hydroxy or methoxy;
• or a pharmaceutically acceptable salt thereof.

An immunosuppressive composition comprising a compound of the formula (I″):

• wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12 and R13 are each independently hydrogen, hydroxy, carboxy, optionally substituted lower alkoxy, optionally substituted lower alkenyl, optionally substituted lower alkenyloxy, optionally substituted lower alkylthio, optionally substituted lower alkoxycarbonyl, optionally substituted acyloxy, optionally substituted lower alkylsulfonyl, optionally substituted lower alkylsulfonyloxy, optionally substituted lower alkylsulfinyl, nitro, formyl, optionally substituted amino, optionally substituted carbamoyl, optionally substituted sulfamoyl or optionally substituted heterocyclyl,
• X is —O—, —CH2—, —NR14— wherein R14 is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl or acetyl, or —S(O)p— wherein p is an integer of 0 to 2,
• Y is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl or optionally substituted heterocyclyl, and Y may optionally be substituted lower alkoxy when X is —CH2— and may optionally be substituted lower alkoxycarbonyl, optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl when X is —O— or —NR14—,
• R1 and R4, R1 and R2, R2 and R3, R4 and R5, R6 and R7, R8 and R9, R10 and R11, R12 and R13, R11 and —X—Y, or R13 and —X—Y taken together may form a 5- or 6-membered ring which may contain one or more of O, S or NR1 5 wherein R15 is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl or optionally substituted arylsulfonyl and which may optionally be substituted,
• excluding a compound of the formula (I′):
• wherein R1′ is hydrogen or hydroxy and R13′ is hydroxy or methoxy;
• or a pharmaceutically acceptable salt thereof, and
• a pharmaceutically acceptable excipient.

A compound of the formula (I):

• wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12 and R13 are each independently hydrogen, hydroxy, halogen, carboxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, optionally substituted lower alkenyloxy, optionally substituted lower alkylthio, optionally substituted lower alkoxycarbonyl, optionally substituted acyloxy, optionally substituted lower alkylsulfonyl, optionally substituted lower alkylsulfonyloxy, optionally substituted lower alkylsulfinyl, nitro, cyano, formyl, optionally substituted amino, optionally substituted carbamoyl, optionally substituted sulfamoyl or optionally substituted heterocyclyl,
• X is —O—, —CH2—, —NR14— wherein R14 is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl or acetyl, or —S(O)p— wherein p is an integer of 0 to 2,
• Y is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl or optionally substituted heterocyclyl, and Y may optionally be substituted lower alkoxy when X is —CH2— and may optionally be substituted lower alkoxycarbonyl, optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl when X is —O— or —NR14—,
• R1 and R4, R1 and R2, R2 and R3, R4 and R5, R6 and R7, R8 and R9, R10 and R1 R12 and R13, R11 and —X—Y, or R13 and —X—Y taken together may form a 5- or 6-membered ring which may contain one or more of O, S or NR15 wherein R15 is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted arylsulfonyl and which may optionally be substituted,
• excluding compounds wherein one or more of R6, R7, R8 and R9 are halogen and the others are hydrogen, compounds wherein all of R6, R7, R8 and R9 are halogen and compounds wherein all of R2–R1 3 are hydrogen, halogen or cyano,
• provided that R1 is not hydrogen, fluorine, optionally substituted lower alkyl or optionally substituted lower alkoxy, all of R2, R3, R4, R5 and R12 are hydrogen, or R13 is not hydrogen or halogen when R6, R7, R8 and R9 are all simultaneously hydrogen, and further provided that R1 is not methyl or acetyloxy, R13 is not hydrogen, optionally substituted lower alkoxycarbonyl or optionally substituted carbamoyl, or —X—Y is not methoxy when at least one of R6, R7, R8 and R9 is a substituent other than hydrogen, and excluding a compound of the formula (I′):
• wherein R1′ is hydrogen or hydroxy and R13′ is hydroxy or methoxy;
• or a pharmaceutically acceptable salt thereof.