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US 2012/0059188 A9Published application
Halogenated analogues of anti-fibrotic agents
AssigneesThe University of Melbourne, Fibrotech Therapeutics Pty Ltd
InventorsDarren James Kelly, Spencer John Williams, Steven Zammit
Life of this patent
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Abstract
The present invention relates to halogenated compounds of formula (I) with the substituents as described within the specification. The compounds may be useful as anti-fibrotic agents. The present invention also relates to methods for their preparation.
Claims25
A compound of Formula (I)
- or a pharmaceutically acceptable salt or prodrug thereof, wherein:
- T is a single bond, a double bond or a triple bond;
- R1, R4, and R5 are each independently selected from the group consisting of:
- H, halogen, OH, NO2, CN, NH2, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted C1-C10 heteroalkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted C2-C12 heterocycloalkyl, optionally substituted C2-C12 heterocycloalkenyl, optionally substituted C6-C18 aryl, optionally substituted C1-C18 heteroaryl, optionally substituted C1-C12 alkyloxy, optionally substituted C2-C12 alkenyloxy, optionally substituted C2-C12 alkynyloxy, optionally substituted C1-C10 heteroalkyloxy, optionally substituted C3-C12 cycloalkyloxy, optionally substituted C3-C12 cycloalkenyloxy, optionally substituted C1-C12 heterocycloalkyloxy, optionally substituted C1-C12 heterocycloalkenyloxy, optionally substituted C6-C18 aryloxy, optionally substituted C1-C18 heteroaryloxy, optionally substituted C1-C12 alkylamino, SR11, SO3H, SO2NR11R12, SO2R11, SONR11R12, SOR11, COR11, COOH, COOR11, CONR11R12, NR11COR12, NR11COOR12, NR11SO2R12, NR11CONR12R13, NR11R12, and acyl;
- at least one of R2 and R3 is selected from the group consisting of C1-C12 alkyloxy containing at least one halogen atom, C2-C12 alkenyloxy containing at least one halogen atom, C2-C12 alkynyloxy containing at least one halogen atom, and C3-C12 cycloalkyloxy containing at least one halogen atom and the other R2 or R3 is selected from the group consisting of optionally substituted C1-C12, alkyloxy, optionally substituted C2-C12 alkenyloxy, optionally substituted C2-C12 alkynyloxy and optionally substituted C3-C12 cycloalkyloxy;
- or R2 and R3 are combined to form —O—X—O— where X is optionally substituted C1-12 alkyl containing at least one halogen atom;
- R6 and R7 are present when T is a single bond or a double bond but not when T is a triple bond, each R6 and R7 being independently selected from the group consisting of:
- H, NO2, CN, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted C1-C10 heteroalkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted C2-C12 heterocycloalkyl, optionally substituted C2-C12 heterocycloalkenyl, optionally substituted C6-C18 aryl, optionally substituted C1-C18 heteroaryl, optionally substituted C1-C12 alkyloxy, optionally substituted C2-C12 alkenyloxy, optionally substituted C2-C12 alkynyloxy, optionally substituted C1-C10 heteroalkyloxy, optionally substituted C3-C12 cycloalkyloxy, optionally substituted C3-C12 cycloalkenyloxy, optionally substituted C1-C12, heterocycloalkyloxy, optionally substituted C1-C12 heterocycloalkenyloxy, optionally substituted C6-C18 aryloxy, optionally substituted C1-C18 heteroaryloxy, optionally substituted C1-C12 alkylamino, SR11, SO3H, SO2NR11R12, SO2R11, SONR11R12, SOR11, COR11, COOH, COOR11, CONR11R12, NR11COR12, NR11COOR12, NR11SO2R12, NR11CONR12R13, NR11R12, and acyl;
- R8 is selected from the group consisting of:
- H, a N-protecting group, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted C1-C10 heteroalkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted C1-C12 heterocycloalkyl, optionally substituted C1-C12 heterocycloalkenyl, optionally substituted C6-C18 aryl, and optionally substituted C1-C18 heteroaryl;
- R9 is COOH;
- R10 is selected from the group consisting of:
- H, halogen, OH, NO2, CN, NH2, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted C1-C10 heteroalkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted C2-C12 heterocycloalkyl, optionally substituted C2-C12 heterocycloalkenyl, optionally substituted C6-C18 aryl, optionally substituted C1-C18 heteroaryl, optionally substituted C1-C12 alkyloxy, optionally substituted C2-C12 alkenyloxy, optionally substituted C2-C12 alkynyloxy, optionally substituted C1-C10 heteroalkyloxy, optionally substituted C3-C12 cycloalkyloxy, optionally substituted C3-C12 cycloalkenyloxy, optionally substituted C1-C12 heterocycloalkyloxy, optionally substituted C1-C12 heterocycloalkenyloxy, optionally substituted C6-C18 aryloxy, optionally substituted C1-C18 heteroaryloxy, optionally substituted C1-C12 alkylamino, SR11, SO3H, SO2NR11R12, SO2R11, SONR11R12, SOR11, COR11, COOH, COOR11, CONR11R12, NR11COR12, NR11COOR12, NR11SO2R12, NR11CONR12R13, NR11R12, and acyl;
- each R11, R12 and R13 is independently selected from the group consisting of H, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted C1-C10 heteroalkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted C1-C12 heterocycloalkyl, optionally substituted C1-C12 heterocycloalkenyl, optionally substituted C6-C18 aryl, and optionally substituted C1-C18 heteroaryl;
- and
- m is an integer selected from the group consisting of 0, 1, 2, 3, and 4.
13 more elements
A compound of Formula (III)
- or a pharmaceutically acceptable salt or prodrug thereof, wherein:
- R1, R4, and R5 are each independently selected from the group consisting of:
- H, halogen, OH, NO2, CN, NH2, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted C1-C10 heteroalkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted C2-C12 heterocycloalkyl, optionally substituted C2-C12 heterocycloalkenyl, optionally substituted C6-C18 aryl, optionally substituted C1-C18 heteroaryl, optionally substituted C1-C12 alkyloxy, optionally substituted C2-C12 alkenyloxy, optionally substituted C2-C12 alkynyloxy, optionally substituted C1-C10 heteroalkyloxy, optionally substituted C3-C12 cycloalkyloxy, optionally substituted C3-C12 cycloalkenyloxy, optionally substituted C1-C12 heterocycloalkyloxy, optionally substituted C1-C12 heterocycloalkenyloxy, optionally substituted C6-C18 aryloxy, optionally substituted C1-C18 heteroaryloxy, optionally substituted C1-C12 alkylamino, SR11, SO3H, SO2NR11R12, SO2R11, SONR11R12, SOR11, COR11, COOH, COOR11, CONR11R12, NR11COR12, NR11COOR12, NR11SO2R12, NR11CONR12R13, NR11R12, and acyl;
- provided that at least one of R1, R2, R3, R4, and R5 contains a halogen atom;
- R2 is selected from the group consisting of optionally substituted C1-C12 alkyloxy containing at least one halogen atom, optionally substituted C2-C12 alkenyloxy, optionally substituted C2-C12 alkynyloxy and optionally substituted C3-C12 cycloalkyloxy;
- R6 and R7 are each independently selected from the group consisting of:
- H, NO2, CN, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted C1-C10 heteroalkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted C2-C12 heterocycloalkyl, optionally substituted C2-C12 heterocycloalkenyl, optionally substituted C6-C18 aryl, optionally substituted C1-C18 heteroaryl, optionally substituted C1-C12 alkyloxy, optionally substituted C2-C12 alkenyloxy, optionally substituted C2-C12 alkynyloxy, optionally substituted C1-C10 heteroalkyloxy, optionally substituted C3-C12 cycloalkyloxy, optionally substituted C3-C12 cycloalkenyloxy, optionally substituted C1-C12 heterocycloalkyloxy, optionally substituted C1-C12 heterocycloalkenyloxy, optionally substituted C6-C18 aryloxy, optionally substituted C1-C18 heteroaryloxy, optionally substituted C1-C12 alkylamino, SR11, SO3H, SO2NR11R12, SO2R11, SONR11R12, SOR11, COR11, COOH, COOR11, CONR11R12, NR11COR12, NR11COOR12, NR11SO2R12, NR11CONR12R13, NR11R12, and acyl
- R8 is selected from the group consisting of:
- H, a N-protecting group, optionally substituted C1-C12alkyl, optionally substituted C2-C12alkenyl, optionally substituted C2-C12alkynyl, optionally substituted C1-C10heteroalkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C3-C12cycloalkenyl, optionally substituted C1-C12 heterocycloalkyl, optionally substituted C1-C12 heterocycloalkenyl, optionally substituted C6-C18aryl, and optionally substituted C1-C18heteroaryl;
- R9 is COOH,
- R10 is selected from the group consisting of:
- H, halogen, OH, NO2, CN, NH2, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted C1-C10 heteroalkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted C2-C12 heterocycloalkyl, optionally substituted C2-C12 heterocycloalkenyl, optionally substituted C6-C18 aryl, optionally substituted C1-C18 heteroaryl, optionally substituted C1-C12 alkyloxy, optionally substituted C2-C12 alkenyloxy, optionally substituted C2-C12 alkynyloxy, optionally substituted C1-C10 heteroalkyloxy, optionally substituted C3-C12 cycloalkyloxy, optionally substituted C3-C12 cycloalkenyloxy, optionally substituted C1-C12 heterocycloalkyloxy, optionally substituted C1-C12 heterocycloalkenyloxy, optionally substituted C6-C18 aryloxy, optionally substituted C1-C18 heteroaryloxy, optionally substituted C1-C12 alkylamino, SR11, SO3H, SO2NR11R12, SO2R11, SONR11R12, SOR11, COR11, COOH, COOR11, CONR11R12, NR11COR12, NR11COOR12, NR11SO2R12, NR11CONR12R13, NR11R12, and acyl;
- each R11, R12 and R13 is independently selected from the group consisting of H, optionally substituted C1-C12alkyl, optionally substituted C2-C12alkenyl, optionally substituted C2-C12alkynyl, optionally substituted C1-C10heteroalkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C3-C12cycloalkenyl, optionally substituted C1-C12 heterocycloalkyl, optionally substituted C1-C12 heterocycloalkenyl, optionally substituted C6-C18aryl, and optionally substituted C1-C18heteroaryl;
- and
- m is an integer selected from the group consisting of 0, 1, 2, 3, and 4.
12 more elements
(canceled)
(canceled)
21-25. (canceled)
A compound of Formula (V)
- or a pharmaceutically acceptable salt or prodrug thereof, wherein:
- R1, R4, and R5 are each independently selected from the group consisting of:
- H, halogen, OH, NO2, CN, NH2, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted C1-C10 heteroalkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted C2-C12 heterocycloalkyl, optionally substituted C2-C12 heterocycloalkenyl, optionally substituted C6-C18 aryl, optionally substituted C1-C18 heteroaryl, optionally substituted C1-C12 alkyloxy, optionally substituted C2-C12 alkenyloxy, optionally substituted C2-C12 alkynyloxy, optionally substituted C1-C10 heteroalkyloxy, optionally substituted C3-C12 cycloalkyloxy, optionally substituted C3-C12 cycloalkenyloxy, optionally substituted C1-C12 heterocycloalkyloxy, optionally substituted C1-C12 heterocycloalkenyloxy, optionally substituted C6-C18 aryloxy, optionally substituted C1-C18 heteroaryloxy, optionally substituted C1-C12 alkylamino, SR11, SO3H, SO2NR11R12, SO2R11, SONR11R12, SOR11, COR11,COOH, COOR11, CONR11R12, NR11COR12, NR11COOR12, NR11SO2R12, NR11CONR12R13, NR11R12, and acyl;
- provided that at least one of R1, R2, R3, R4, and R5 contains a halogen atom;
- R8 is selected from the group consisting of H, an N-protecting group, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted C1-C10 heteroalkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted C1-C12 heterocycloalkyl, optionally substituted C1-C12 heterocycloalkenyl, optionally substituted C6-C18aryl, and optionally substituted C1-C18 heteroaryl;
- R9 is selected from the group consisting of:
- COOR11, CONR11R12, and NR11R12;
- R10 is selected from the group consisting of:
- H, halogen, OH, NO2, CN, NH2, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted C1-C10 heteroalkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted C2-C12 heterocycloalkyl, optionally substituted C2-C12 heterocycloalkenyl, optionally substituted C6-C18 aryl, optionally substituted C1-C18 heteroaryl, optionally substituted C1-C12 alkyloxy, optionally substituted C2-C12 alkenyloxy, optionally substituted C2-C12 alkynyloxy, optionally substituted C1-C10 heteroalkyloxy, optionally substituted C3-C12 cycloalkyloxy, optionally substituted C3-C12 cycloalkenyloxy, optionally substituted C1-C12 heterocycloalkyloxy, optionally substituted C1-C12 heterocycloalkenyloxy, optionally substituted C6-C18 aryloxy, optionally substituted C1-C18 heteroaryloxy, optionally substituted C1-C12 alkylamino, SR11, SO3H, SO2NR11R12, SO2R11, SONR11R12, SOR11, COR11, COOH, COOR11, CONR11R12, NR11COR12, NR11COOR12, NR11SO2R12, NR11CONR12R13, NR11R12;
- and acyl;
- each R11, R12 and R13 is independently selected from the group consisting of H, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted C1-C10 heteroalkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted C1-C12 heterocycloalkyl, optionally substituted C1-C12 heterocycloalkenyl, optionally substituted C6-C18 aryl, and optionally substituted C1-C18 heteroaryl;
- and
- m is an integer selected from the group consisting of 0, 1, 2, 3, and 4.
10 more elements
27-36. (canceled)
38-48. (canceled)
Dependencies are inferred from the claim text.