Synthesis and use of dual tyrosyl-DNA phosphodiesterase I (TDP1)- topoisomerase I (TOP1) inhibitors
AssigneePurdue Research Foundation
InventorsMark S. Cushman, Trung X. Nguyen, Martin M. Conda-Sheridan, Yves G. Pommier
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Abstract
The invention described herein pertains to the synthesis and use of certain N-substituted indenoisoquinoline compounds which inhibit the activity Tyrosyl-DNA Phosphodiesterase I (Tdp1) or Topoisomerase I (Top1) or both, or otherwise demonstrate anticancer activity. Also disclosed are novel N-substituted indenoisoquinoline compounds and pharmaceutical compositions comprising the novel N-substituted indenoisoquinoline compounds.
Claims7
A method for treating cancer comprising the step of administering a therapeutically effective amount of a compound of formula
- or a pharmaceutically acceptable salt thereof,
- wherein:
- RT is amino, Ra is 3-carboxymethylamino and Rd is hydrogen;
- or
- RT is amino, Ra is 3-amino and Rd is 9-methoxy;
- or
- RT is amino, Ra is 3-nitro and Rd is 8-methoxy;
- or
- RT is amino, Ra is 3-nitro and Rd is 7-methoxy;
- or
- RT is amino, Ra is 3-iodo and Rd is hydrogen;
- or
- RT is dimethylamino, Ra is 3-iodo and Rd is 9-methoxy;
- or
- RT is dimethylamino, Ra is 3-cyano and RQ is hydrogen;
- or
- RT is amino, Ra is 3-amino and Rd is hydrogen;
- or
- RT is amino, Ra is 3-nitro and Rd is 9-methoxy;
- or
- RT is amino, Ra is 3-iodo and Rd is 9-methoxy;
- to a patient in need of relief from said cancer.
A method for treating cancer comprising the step of administering a therapeutically effective amount of a compound of the formula
- or a pharmaceutically acceptable salt thereof,
- wherein:
- n is 1,2,3,4,5,6,7,8,9, 11, or 12,
- Ra represents 1-4 substituents each of which is independently selected from the group consisting of hydrogen, halo, hydroxy, optionally substituted (1-4C)alkyl, optionally substituted (1-4C)alkoxy, cyano, nitro, optionally substituted alkylthio, optionally substituted alkylsulfonyl, carboxylic acid and derivatives thereof, and sulfonic acid and derivatives thereof;
- or Ra represents 2-4 substituents where 2 of said substituents are adjacent substituents and are taken together with the attached carbons to form an optionally substituted heterocycle, and where any remaining substituents are each independently selected from the group consisting of hydrogen, halo, hydroxy, optionally substituted (1-4C)alkyl, optionally substituted (1-4C)alkoxy, cyano, nitro, optionally substituted (1-4C)alkylthio, optionally substituted (1-4C)alkylsulfonyl, carboxylic acid and derivatives thereof, and sulfonic acid and derivatives thereof;
- and
- Rd represents 1-4 substituents each of which is independently selected from the group consisting of hydrogen, halo, hydroxy, optionally substituted (1-4C)alkyl, optionally substituted (1-4C)alkoxy, cyano, nitro, optionally substituted (1-4C)alkylthio, optionally substituted (1-4C) alkylsulfonyl, phenyl (which may bear one or more amino, hydroxyl, halo, thiol, (1-6C)alkyl or halo(1-6C)alkyl substituents), carboxylic acid and derivatives thereof, and sulfonic acid and derivatives thereof;
- or Rd represents 2-4 substituents where 2 of said substituents are adjacent substituents and are taken together with the attached carbons to form an optionally substituted heterocycle, and where any remaining substituents are each independently selected from the group consisting of hydrogen, halo, hydroxy, optionally substituted (1-4C)alkyl, optionally substituted d-4C)alkoxy, cyano, nitro, optionally substituted (1-4C)alkylthio, optionally substituted (1-4C)alkylsulfonyl, carboxylic acid and derivatives thereof, and sulfonic acid and derivatives thereof;
- and
- Rs is (1-6C)alkyl, (3-7C)cycloalkyl or phenyl, which phenyl may bear one or more amino, hydroxyl, halo, thiol, (1-6C)alkyl or halo(1-6C)alkyl substituents;
- to a patient in need of relief from said cancer.
A method for treating cancer comprising the step of administering a therapeutically effective amount of a compound of the formula
- or a pharmaceutically acceptable salt thereof,
- wherein:
- RT is dimethylamino, Ra is 3-cyano and Rd is 8,9-methylenedioxy;
- or
- RT is 4-morpholinyl, Ra is 3-cyano and Rd is hydrogen;
- or
- RT is imidazolyl, Ra is 3-cyano and Rd is hydrogen;
- to a patient in need of relief from said cancer.
Dependencies are inferred from the claim text.