MX2008009180A - Combination therapy with parp inhibitors - Google Patents

Abstract

The present invention describes benzimidazole derivatives of Formula (I) which constitute potent PARP inhibitors in combination with radiotherapy or in combination with other chemotherapeutic agents.

Description

COMBINATION THERAPY WITH PARP INHIBITORS This application claims the priority of U.S. Provisional Patent Application Serial No. 60 / 867,518 filed on November 28, 2006, U.S. Provisional Patent Application Serial No. 60 / 829,261 filed on December 12, 2006. October 2006, United States Provisional Patent Application Serial No. 60 / 850,042 filed on October 6, 2006, United States Provisional Patent Application Serial No. 60 / 804,112 filed on June 7, 2006. 2006, and United States Provisional Patent Application Serial No. 60 / 759,445 filed January 17, 2006 which are incorporated herein by reference. Field of the Invention The invention relates to compositions comprising drugs having anti-cancer additive activity and methods for treatment using the combinations. BACKGROUND OF THE INVENTION Poly (ADP-ribose) polymerase (PARP) or poly (ADP-ribose) synthase (PARS) have an essential role in facilitating DNA repair (DNA) to control transcription of RNA (RNA for its acronym in English), to mediate cell death, and to regulate the immune response. These actions target PARP inhibitors for a broad spectrum of disorders. PARP inhibitors have demonstrated efficacy in numerous disease models, particularly in models of reperfusion injury by ischemia, inflammatory disease, degenerative diseases, protection from adverse effects of cytoxic compounds, and potentiation of cytotoxic cancer therapy. PARP has also been indicated in retroviral infection and in this way inhibitors may have use in anti-retroviral therapy. PARP inhibitors have been effective in preventing reperfusion injury due to ischemia in models of myocardial infarction, stroke, other neural traumas, organ transplantation, as well as reperfusion of the eyes, kidney, intestines and skeletal muscle. Inhibitors have been effective in inflammatory diseases such as arthritis, gout, inflammatory bowel disease, central nervous system (CNS) inflammation such as MS and allergic encephalitis, sepsis, septic shock, hemorrhagic shock, pulmonary fibrosis and uveitis. PARP inhibitors have also shown benefit in various models of degenerative diseases including diabetes (as well as complications) and Parkinson's disease. PARP inhibitors can improve liver toxicity after an overdose of acetaminophen, cardiac and kidney toxicities from doxorubicin-based and platinum-based antineoplastic agents, as well as secondary skin damage by sulfur mustards. In several cancer models, PARP inhibitors have been shown to enhance radiation and chemotherapy by increasing the apoptosis of cancer cells, by limiting tumor growth, by decreasing metastasis, and by prolonging the survival of animals carrying tumors. The present invention describes benzimidazole derivatives of the Formula (I) which constitute potent PARP inhibitors in combination with radiotherapy or in combination with other chemotherapeutic agents. Brief Description of the Invention In its principle embodiment, the present invention provides a PARP inhibitor of the formula (I) (D or a therapeutically acceptable salt thereof, wherein Ri. R2 and R3 are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro , NRARB, and (NRARB) carbonyl; A is a non-aromatic ring of 4, 5, 6, 7 or 8 members containing 1 or 2 nitrogen atoms and, optionally, a sulfur or oxygen atom, wherein the ring is not aromatic is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl , heteroaryl, heteroarylalkyl, hydroxy, hydroxyalkyl, nitro, NRCRD (NRcRD) alkyl, (NRcRD) carbonyl, (NRcRD) carbonylalkyl, and (NRcRD) sulfonyl; and RA, RB, RC and RD are independently selected from the group consisting of hydrogen, alkyl and alkylcarbonyl; in combination with radiotherapy or a cytotoxic agent selected from the group consisting of temozolomide, irinotecan, cisplatin, carboplatin, and topotecan. Brief Description of the Drawings Figure 1 shows the data generated from the simple or combined administration of the compound, 2- (N-propylpiperidin-4-yl) benzimidazole-4-carboxamide and radiotherapy.

Figure 2 shows the data generated from the single or combined administration of A-861695 and TMZ in rats with murine melanoma. Figure 3 shows the data generated from the simple or combined administration of A-861695 and TMZ in rats with orthotopic gliosarcoma. Figure 4 shows the data generated from the single or combined administration of A-861695 and carboplatin in the xenograft model of breast carcinoma MX-1 in scid mice. Figure 5 shows the data generated from the single or combined administration of A-861695 and cisplatin in the xenograft model of breast carcinoma MX-1 in nude mice. Figure 6 shows the data generated from the simple or combined administration of valproic acid and radiotherapy. Figure 7 shows the survival rate of mice with intra-cerebellar medulloblastoma xenografts after they have been treated with TMZ and ABT-888 in combination and as single agents. Figure 8 shows the survival rate of mice with intra-cerebellar medulloblastoma xenografts after they have been treated with TMZ and ABT-888 in combination and as single agents. Figure 9 shows the results of administration of different amounts of combinations of TMZ and ABT-888 for HSB T cell ALL. Figure 10 shows the results of administration of different amounts of combinations of TMZ and ABT-888 for ALL of pre-B JM1. Figure 11 shows the results of administration of different amounts of combinations of TMZ and ABT-888 for primary AML P115 cells. Detailed Description of the Invention In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula (I), or a therapeutically acceptable salt thereof, and a cytotoxic agent selected from the group consisting of temozolomide (TMZ), irinotecan, cisplatin, carbopyatin, and topotecan. In another embodiment, the present invention provides a pharmaceutical composition comprising 2 - [(2R) -2-methylpyrrolidin-2-yl] -1H-benzimidazole-4-carboxamide, or a therapeutically acceptable salt thereof, and an agent cytotoxic selected from the group consisting of temozolomide, irinotecan, cisplatin, carboplatin, and topotecan. In another embodiment, the present invention provides a pharmaceutical composition comprising 2- (N-propylpiperidin-4-yl) benzimidazole-4-carboxamide, or a therapeutically acceptable salt thereof, and a cytotoxic agent selected from the group consisting of temozolomide , irinotecan, cisplatin, carboplatin, and topotecan In another embodiment, the present invention provides for the administration of a compound of Formula (I) in combination with a cytotoxic agent selected from the group consisting of temozolomide, irinotecan, cisplatin, carboplatin, and topotecan In another embodiment, the present invention provides for the administration of a compound of the formula (I) selected from the group consisting of 2- (N-propylpiperidin-4-yl) benzimidazole-4-carboxamide and 2 - [(2R) -2 -methylpyrrolidin-2-yl] -1H-benzimidazole-4-carboxamide, or a therapeutically acceptable salt thereof, and a cytotoxic agent selected from the group consisting of temozolomide, rinotecan, cisplatin, carboplatin, and topotecan. In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of the formula (I), or a therapeutically acceptable salt thereof, used in combination with radiotherapy. In another embodiment, the present invention provides a pharmaceutical composition comprising 2 - [(2R) -2-methylpyrrolidin-2-yl] -1H-benzimidazole-4-carboxamide, or a therapeutically acceptable salt thereof, used in combination with radiotherapy. In another embodiment, the present invention provides a pharmaceutical composition comprising 2- (N-propylpiperidin-4-yl) benzimidazole-4-carboxamide, or a therapeutically acceptable salt thereof, used in combination with radiotherapy. In another embodiment, the present invention provides for the administration of a compound of Formula (I) in combination with radiotherapy.

In another embodiment, the present invention provides for the administration of a compound of the formula (I) selected from the group consisting of 2- (N-propylpiperidin-4-yl) benzimidazole-4-carboxamide and 2 - [(2R) -2 -methylpyrrolidin-2-yl] -1H-benzimidazole-4-carboxamide, or a therapeutically acceptable salt thereof, and radiotherapy. In another embodiment, the present invention provides a method for treating cancer in a mammal that needs to be recognized for such a treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of the formula (I) or a therapeutically acceptable salt thereof and a cytotoxic agent selected from the group consisting of temozolomide, irinotecan, cisplatin, carboplatin, and topotecan. In another embodiment, the present invention provides a method of treating cancer in a mammal in need of recognition of such a treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a therapeutically acceptable salt thereof and radiotherapy. . In another embodiment, the present invention provides a method of treating cancer in a mammal in need of recognition of such a treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) selected from the group consisting of 2- ( N-propylpiperidin-4-yl) benzimidazole-4-carboxamide and 2 - [(2R) -2-methylpyrrolidin-2-yl] -1H-benzimidazole-4-carboxamide, or a therapeutically acceptable salt thereof, and an agent cytotoxic selected from the group consisting of temozolomide, irinotecan, cisplatin, carboplatin, and topotecan. In another embodiment, the present invention provides a method of treating cancer in a mammal in need of recognition of such a treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) selected from the group consisting of 2- ( N-propylpiperidin-4-yl) benzimidazole-4-carboxamide and 2 - [(2R) -2-methylpyrrolidin-2-yl] -1H-benzimidazole-4-carboxamide, or a therapeutically acceptable salt thereof, and radiotherapy. In another embodiment, the present invention provides a method for inhibiting tumor growth in a mammal that needs to be recognized for such a treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a therapeutically acceptable salt thereof. , and a cytotoxic agent selected from the group consisting of temozolomide, irinotecan, cisplatin, carboplatin, and topotecan. In another embodiment, the present invention provides a method for inhibiting tumor growth in a mammal that needs to be recognized for such a treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a therapeutically acceptable salt thereof. , and radiotherapy. In another embodiment, the present invention provides a method for inhibiting tumor growth in a mammal that needs to be recognized for such a treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) selected from the group consisting of - (N-propylpiperidin-4-yl) benzimidazole-4-carboxamide and 2 - [(2R) -2-methylpyrrolidin-2-yl] -1H-benzimidazole-4-carboxamide, or a therapeutically acceptable salt thereof, and radiotherapy. In another embodiment, the present invention provides a method for inhibiting tumor growth in a mammal that needs to be recognized for such a treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) selected from the group consisting of - (N-propylpiperidin-4-yl) benzimidazole-4-carboxamide and 2 - [(2R) -2-methylpyrrolidin-2-yl] -1 H -benzimidazole-4-carboxamide, or a therapeutically acceptable salt thereof, and a cytotoxic agent selected from the group consisting of temozolomide, irinotecan, cisplatin, carboplatin, and topotecan. In its principle embodiment, this invention provides a composition for treating leukemia comprising a PARP inhibitor of the formula (I) (D or a therapeutically acceptable salt thereof, wherein R-i. R2 and R3 are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, NRARB, and (NRARB) carbonyl; A is a non-aromatic ring of 4, 5, 6, 7 or 8 members containing 1 or 2 nitrogen atoms and, optionally, a sulfur or oxygen atom, wherein the non-aromatic ring is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkoxy, haloalkyl, halogen, heterocycle, heterocycloalkyl, heteroaryl, heteroarylalkyl, hydroxy, hydroxyalkyl, nitro, NRCRD (NRcRD) alkyl, (NRcRD) carbonyl, (NRcRo) carbonylalkyl, and (NRcRD) sulfonyl; and RA, RB, RC and RD are independently selected from the group consisting of hydrogen, alkyl and alkylcarbonyl; in combination with radiotherapy or a cytotoxic agent selected from the group consisting of temozolomide, irinotecan, cisplatin, carboplatin, and topotecan. In another embodiment, this invention provides a composition for treating CNS tumors comprising a PARP inhibitor of the formula (I) (I) or a therapeutically acceptable salt thereof, wherein Ri, R2 and R3 are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, NRARB, and (NRARB) carbonyl; A is a non-aromatic ring of 4, 5, 6, 7 or 8 members containing 1 or 2 nitrogen atoms and, optionally, a sulfur or oxygen atom, wherein the non-aromatic ring is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkoxy, haloalkyl, halogen, heterocycle, heterocycloalkyl, heteroaryl, heteroarylalkyl, hydroxy, hydroxyalkyl, nitro, NRCRD (NRcRD) alkyl, (NRcRD) carbonyl, (NRcRD) carbonylalkyl, and (NRcRD) sulfonyl; and RA, RB, RC and RD are independently selected from the group consisting of hydrogen, alkyl and alkylcarbonyl; in combination with radiotherapy or a cytotoxic agent selected from the group consisting of temozolomide, irinotecan, cisplatin, carboplatin, and topotecan. In another embodiment, the present invention provides a method for treating leukemia in a mammal comprising administering thereto a compound of formula (I), or a therapeutically acceptable salt thereof, and a cytotoxic agent selected from the group consisting of temozolomide ( TMZ), irinotecan, cisplatin, carboplatin, and topotecan. In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of the formula (I), or a therapeutically acceptable salt thereof, and a cytotoxic agent selected from the group consisting of temozolomide (TMZ), irinotecan, cisplatin, carboplatin , and topotecan. In another embodiment, the present invention provides a pharmaceutical composition for treating leukemia comprising 2 - [(2R) -2-methylpyrrolidin-2-yl] -1H-benzimidazole-4-carboxamide, or a therapeutically acceptable salt thereof, and a cytotoxic agent selected from the group consisting of temozolomide, irinotecan, cisplatin, carboplatin, and topotecan.

In another embodiment, the present invention provides a pharmaceutical composition for treating CNS tumors comprising 2 - [(2R) -2-methylpyrrolidin-2-yl] -1H-benzimidazole-4-carboxamide, or a therapeutically acceptable salt thereof. , and a cytotoxic agent selected from the group consisting of temozolomide, irinotecan, cisplatin, carboplatin, and topotecan. In another embodiment, the present invention provides a method for treating leukemia in a mammal comprising administering the same 2- (N-propylpiperidin-4-yl] benzimidazole-4-carboxamide), or a therapeutically acceptable salt thereof, and a cytotoxic agent selected from the group consisting of temozolomide, irinotecan, cisplatin, carboplatin, and topotecan. In another embodiment, the present invention provides a method for treating CNS tumors in a mammal comprising administering thereto 2- (N-propylpiperidin-4-yl) benzimidazole-4-carboxamide, or a therapeutically acceptable salt thereof, and a cytotoxic agent selected from the group consisting of temozolomide, irinotecan, cisplatin, carboplatin, and topotecan In another embodiment, the present invention provides a method of treating leukemia in a mammal comprising administering to the same a compound of the formula (I) selected from the group consisting of 2- (N-propylpiperidin-4-yl) benzimidazole-4-carboxamide and 2 - [(2R) -2-methylpyrrolidin-2-yl] -1H-benzimidazole-4-carboxamide, or a salt Therapeutically acceptable thereof, and a cytotoxic agent selected from the group consisting of temozolomide, irinotecan, cisplatin, carboplatin, and topotecan, In another embodiment, the present invention provides a pharmaceutical composition for treating leukemia in a mammal comprising a compound of Formula (I), or a therapeutically acceptable salt thereof, used in combination with radiotherapy. In another embodiment, the present invention provides a pharmaceutical composition for treating leukemia in a mammal comprising 2 - [(2R) -2-methylpyrrolidin-2-yl] -1H-benzimidazole-4-carboxamide, or a therapeutically acceptable salt thereof. same, used in combination with radiotherapy. In another embodiment, the present invention provides a pharmaceutical composition for treating leukemia comprising 2- (N-propylpiperidin-4-yl) benzimidazole-4-carboxamide, or a therapeutically acceptable salt thereof, used in combination with radiotherapy. In another embodiment, the present invention provides a method for treating leukemia in a mammal comprising administering thereto a compound of Formula (I) in combination with radiotherapy. In another embodiment, the present invention provides a method for treating leukemia in a mammal comprising administering thereto a compound of formula (I) selected from the group consisting of 2- (N-propylpiperidin-4-yl) benzimidazo I -4 -carboxamide and 2 - [(2R) -2-methylpyrrolidin-2-yl] -1 H -benzimidazole-4-carboxamide, or a therapeutically acceptable salt thereof, and radiotherapy. In another embodiment, the present invention provides a method for treating leukemia in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of the Formula (I) or a therapeutically acceptable salt thereof and a cytotoxic agent selected from the group consisting of of temozolomide, irinotecan, cisplatin, carboplatin, and topotecan. In another embodiment, the present invention provides a method for treating leukemia in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of Formula (I) or a therapeutically acceptable salt thereof and radiotherapy. In another embodiment, the present invention provides a method for treating leukemia in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of Formula (I) selected from the group consisting of 2- (N-propylpiperidin-4-yl). ) benzimidazole-4-carboxamide and 2 - [(2R) -2-methylpyrrolidin-2-yl] -1H-benzimidazole-4-carboxamide, or a therapeutically acceptable salt thereof, and a cytotoxic agent selected from the group consisting of temozolomide, irinotecan, cisplatin, carboplatin, and topotecan. In another embodiment, the present invention provides a method for treating leukemia in a mammal comprising administering thereto a therapeutically acceptable amount of a compound of Formula (I) selected from the group consisting of 2- (N-propylpiperidin-4-yl). benzimidazole-4-carboxamide and 2 - [(2R) -2-methylpyrrolidin-2-yl] -1H-benzimidazole-4-carboxamide, or a therapeutically acceptable salt thereof, and radiotherapy. Definitions Own valences are maintained for all portions and combinations thereof of the compounds of this invention. As used throughout this specification and the appended claims, the following terms have the following meanings: The term "leukemia," as used herein, means acute myelogenous leukemia, lymphocytic leukemia, or chronic myeloid leukemia. The term "A-861695", and the term "ABT-888" as used herein, is the compound 2 - [(2R) -2-methylpyrrolidin-2-yl] -1H-benzimidazole-4-carboxamide. The term "ABT-472", as used herein, means the compound 2- (N-propylpiperidin-4-yl) benzimidazole-4-carboxamide.

The term "alkenyl" as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl and 3-decenyl. The term "alkoxy" as used herein, means an alkyl group, as defined herein, attached to the main molecular moiety through an oxygen atom.

Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy. The term "alkoxyalkyl" as used herein, means at least one alkoxy group, as defined herein, attached with the major molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl. The term "alkoxycarbonyl" as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl. The term "alkoxycarbonylalkyl" as used herein, means an alkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. The term "alkyl" as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. The term "alkylcarbonyl" as used herein means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl and 1-oxopentyl. The term "alkylcarbonyloxy" as used herein means an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy. The term "alkylthio" as used herein, means an alkyl group, as defined herein, appended to the major molecular moiety through a sulfur atom. Representative examples of alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, and hexylthio. The term "alkylthioalkyl" as used herein, means an alkylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylthioalkyl include, but are not limited to, methylthiomethyl and 2- (ethylthio) ethyl. The term "alkynyl" as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl. The term "aryl", as used herein, means a phenyl group or a naphthyl group. The aryl groups of the present invention may be optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy , cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NRERF, and (NRERF) carbonyl. The term "arylalkyl" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, 1-methyl-3-phenylpropyl, and 2-naphth-2-ylethyl. The term "cancer", as used herein, means growth of tumor cells that interfere with the growth of healthy cells. The term "carbonyl" as used herein means a group -C (O) -. The term "carboxy" as used herein means a group -CO2H. The term "CNS tumor", as used herein, means a tumor of the central nervous system (CNS), including brainstem glioma, craniopharyngioma, medulloblastoma, and meningioma. The term "cyano" as used herein, means a -CN group. The term "cycloalkyl" as used herein, means a saturated cyclic hydrocarbon group containing from 3 to 8 carbons, examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The cycloalkyl groups of the present invention are optionally substituted with 1, 2, 3 or 4 substituents selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl. , halogen, hydroxy, hydroxyalkyl, mercapto, oxo, -NRERF, and (NRERF) carbonyl. The term "cycloalkylalkyl" as used herein, means a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl. The term "cytotoxic agent" as used herein, means a substance that is potentially genotoxic, oncogenic, mutagenic, teratogenic or in any form dangerous to cells; commonly used to refer to antineoplastic drugs that selectively damage or destroy dividing cells. The term "formyl" as used herein means a group -C (O) H.

The term "halo" or "halogen" as used herein means -Cl, -Br, -I or -F. The term "haloalkoxy" as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy. The term "haloalkyl" as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl. The term "heteroaryl" as used herein means a monocyclic heteroaryl ring or a bicyclic heteroaryl ring. The monocyclic heteroaryl ring is a 5- or 6-membered ring. The 5-membered ring has two double bonds and contains one, two, three or four heteroatoms independently selected from the group consisting of N, O and S. The 6-membered ring has three double bonds and contains one, two, three or four heteroatoms independently selected from the group consisting of N, O and S. The bicyclic heteroaryl ring consists of the 5- or 6-membered heteroaryl ring fused with a phenyl group or the 5- or 6-membered heteroaryl ring is fused with another heteroaryl ring of 5 or 6 members The nitrogen heteroatoms contained within the heteroaryl can optionally be oxidized with the N-oxide. Heteroaryl is connected to the main molecular portion through any carbon atom contained within the heteroaryl while maintaining the valence itself. Representative examples of heteroaryl include, but are not limited to, benzothienyl, benzoxadiazolyl, cinol inyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl. , pyrrolyl, pyridinium N-oxide, quinolinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, and triazinyl. The heteroaryl groups of the present invention are substituted with 0, 1, 2, 3 or 4 substituents independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy, cyano, formyl, haloalkoxy , haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NRERF, and (NRERF) carbonyl. The term "heteroarylalkyl" as used herein, means a heteroaryl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heteroarylalkyl include, but are not limited to, pyridinylmethyl. The term "heterocycle" or "heterocyclic" as used herein means a monocyclic or bicyclic heterocyclic ring. The monocyclic heterocyclic ring consists of a 3, 4, 5, 6, 7 or 8 member ring containing at least one heteroatom independently selected from O, N and S. The 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of consists of O, N and S. The 5-membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The 6 or 7 member ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. The bicyclic heterocyclic ring consists of a monocyclic heterocyclic ring fused to a cycloalkyl group or the monocyclic heterocyclic ring fused to a phenyl or ring group monocyclic heterocyclic fused to another monocyclic heterocyclic ring. The heterocycle is connected to the main molecular portion through any carbon or nitrogen atom contained within the heterocycle while maintaining its own valence. Representative examples of heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazole inyl, isothiazole idin i what, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidyl, pyrazolinyl, pt Razol idinilo, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, thiadiazolinyl, iazol TIAD idinilo, thiazolinyl, you azo I id ini I, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholino-sulfone), thiopyranyl and trityanil. The heterocycles of this invention are substituted with 0, 1, 2, or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NRERF, and (NRERF) carbonyl. The term "heterocycloalkyl" as used herein, means a heterocycle, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. The term "hydroxy" as used herein, means an -OH group. The term "hydroxyalkyl" as used herein, means at least one hydroxy group, as defined herein, is attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl. The term "mammal", as used herein, means a particular class of vertebrates. The term "mercapto" as used herein, means a -SH group. The term "nitro" as used herein, means a group -NO2. The term "non-aromatic" as used herein, means that a non-aromatic 4-membered ring contains zero double bonds, a non-aromatic 5-membered ring contains zero or a double bond, a non-aromatic ring of 6, 7 or 8 members contains zero, one, or two double bonds. The term "NRARB" as used herein, means two groups, RA and RB, which are attached to the main molecular portion through a nitrogen atom. RA and RB are each independently hydrogen, alkyl and alkylcarbonyl. Representative examples of NRARB include, but are not limited to, amino, methylamino, acetylamino, and acetylmethylamino. The term "(NRARB) carbonyl" as used herein, means a NRARB group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of (NRARB) carbonyl include, but are not limited to, aminocarbonyl, (methylamino) carbonyl, (dimethylamino) carbonyl, and (ethylmethylamino) carbonyl. The term "NRCRD" as used herein, means two groups, Rc and RD, which are attached to the main molecular portion through a nitrogen atom. Rc and RD are each independently hydrogen, alkyl and alkylcarbonyl. Representative examples of NRCRD include, but are not limited to, amino, methylamino, acetylamino and acetylmethylamino. The term "(NRcRD) carbonyl" as used herein means a group NRCRD, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of (NRcRD) carbonyl include, but are not limited to, aminocarbonyl, (methylamino) carbonyl, (dimethylamino) carbonyl and (ethylmethylamino) carbonyl. The term "(NRcRD) carbonylalkyl" as used herein, means a group (NRcRD) carbonyl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. The term "(NRcRD) sulfonyl" as used herein means a group NRCRD, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of (NRcRD) sulfonyl include, but are not limited to, aminosulfonyl, (methylamino) sulfonyl, (dimethylamino) sulfonyl, and (ethylmethylamino) sulfonyl. The term "NRERF" as used herein, means two groups, RE and RF, which are attached to the main molecular portion through a nitrogen atom. RE and RF are each independently hydrogen, alkyl and alkylcarbonyl. Representative examples of NRERF include, but are not limited to, amino, methylamino, acetylamino, and acetylmethylamino. The term "(NRERF) carbonyl" as used herein, means a NRERF group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of (NRERF) carbonyl include, but are not limited to, aminocarbonyl, (methylamino) carbonyl, (dimethylamino) carbonyl, and (ethylmethylamino) carbonyl. The term "oxo" as used herein, means a portion = O. The term "radiotherapy" as used herein, means exposure to radiation of a radioactive substance used in the treatment of a disease (especially cancer). The term or abbreviation "TMZ", as used herein, means temozolomide.

The term "treat" as used herein, means at least to support and preferably reverse the course of a disease or adverse physiological event. Compounds of the present invention can exist as stereoisomers, wherein asymmetric and chiral centers are present. The stereoisomers are designated (R) or (S) depending on the configuration of substituents around the chiral carbon atom. The terms (R) and (S) used herein are configurations as defined in the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Puré Appl. Chem., (1976), 45: 13-30, incorporated herein by reference. The present invention contemplates various stereoisomers and mixtures thereof and are specifically included within the scope of this invention. Stereoisomers include enantiomers, diastereomers, and mixtures of enantiomers or diastereomers. The individual stereoisomers of compounds of the present invention can be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well known to those of ordinary skill in the art. These resolution methods are exemplified by (1) binding of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and release of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers in chiral chromatographic columns. When used in the above or other treatments, a therapeutically effective amount of one of the compounds of the present invention may be employed as an amphoteric ion (zwitterion) or as a pharmaceutically acceptable salt. By a "therapeutically effective amount" of the compound of the invention is meant a sufficient amount of the compound to treat or prevent a disease or disorder enhanced by a PARP inhibitor at a reasonable benefit / risk ratio applicable to any medical treatment. It will be understood, however, that the total daily use of the compounds and compositions of the present invention will be decided by the attending physician within the scope of the medical judgment that probes it. The specific therapeutically effective dose level for a particular patient will depend on a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition used, the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or that match the specific compound used; and similar factors well known in the medical arts. For example, it is well within the skill of the art to start dose of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. By "pharmaceutically acceptable salt" is meant those salts which are, within the scope of medical judgment probing it, suitable for use in contact with the tissues of human and lower animals without undue toxicity, irritation, allergic response and the like and are provided. with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the present invention or separately by reacting the free base of a compound of the present invention with a suitable acid. Representative acids include, but are not limited to, acetic, citric, aspartic, benzoic, benzenesulfonic, butyric, fumaric, hydrochloric, hydrobromic, hydroiodic, lactic, maleic, methanesulfonic, pamoic, pectinic, pivalic, propionic, succinic, tartaric, phosphorus, glutamic and p-toluenesulfonic. Also, groups containing basic nitrogen can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides; dialkyl sulfate such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides such as benzyl and phenethyl bromides and others. In this way soluble or dispersible products in oil or water are obtained. A compound of the present invention can be administered as a pharmaceutical composition containing a compound of the present invention in combination with one or more pharmaceutically acceptable excipients. A "pharmaceutically acceptable carrier or excipient" refers to a semi-solid, non-toxic solid or liquid filler, diluent, encapsulating material or auxiliary formulation of any type. The compositions may be administered parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, drops or transdermal patch), rectally, or buccally. The term "parenteral" as used herein refers to modes of administration that include infusion and intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection. Pharmaceutical compositions for parenteral injection comprise sterile aqueous or non-aqueous pharmaceutically acceptable solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution within dispersions or sterile injectable solutions just before use. Examples of suitable carriers, diluents, solvents or aqueous and non-aqueous vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethyl cellulose and suitable mixtures thereof, vegetable oils (such as olive oil). , and injectable organic esters such as ethyl oleate. The proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants (surfactants). These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. The prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol-sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be caused by the inclusion of agents that retard absorption, such as aluminum monostearate and gelatin. Compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. The liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The compositions present in the form of a liposome may contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are phospholipids and phosphatidylcholines (lecithins), both natural and synthetic. Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 er seq. The total daily doses of the compositions of the invention that are administered to a human or other mammalian host in single or divided doses may be in amounts, for example, of 0.0001 to 300 mg / kg of body weight per day and more usually of 1 at 300 mg / kg of body weight. The dose, from 0.0001 to 300 mg / kg of body weight, can be given twice a day. Compounds of the present invention were named by ACD / ChemSketch version 5.06 (developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada) or were given names that appear to be consistent with the ACD nomenclature.

Determination of Biological Activity Inhibition of PARP Nicotinamide Dinucleotide [2,5 ', 8-3H] adenine and streptavidin SPA beads were purchased from Amersham Biosiences (UK) Poly (ADP-Ribose) Human Recombinant Polymerase (PARP) purified from Coli and 6-Biotin-17-NAD + were purchased from Trevigen, Gaithersburg, MD. NAD +, Histone, aminobenzamide, 3-amino-benzamide and Tern Thymus DNA (dsDNA) were purchased from Sigma, St. Louis, MO. The MCAT sequence containing stem loop oligonucleotide was obtained from Qiagen. The oligos were dissolved at 1 mM in annealing buffer containing 10 mM Tris-HCl pH 7.5, 1 mM EDTA and 50 mM NaCl, incubated for 5 minutes at 95 ° C, and followed by annealing at 45 ° C for 45 minutes. . Histone H1 (95% electrophoretically pure) was purchased from Roche, Indianapolis, IN. Biotinylated histone H1 was prepared by treating the protein with Sulfo-NHS-LC-Biotin from Pierce Rockford, IL. The biotinylation reaction was conducted by adding 3 equivalents slowly or intermittently from 10 mM Sulfo-NHS-LC-Biotin to 100 μM Histone H1 in phosphate buffered saline, pH 7.5, at 4 ° C with gentle vortex for 1 minute followed by subsequent incubation at 4 ° C for 1 hour. Streptavidin-coated microplates (FlashPlate Plus) were purchased from Perkin Elmer, Boston, MA.

The PARP1 assay was conducted in a PARP assay buffer containing 50 mM Tris pH 8.0, 1 mM DTT, 4 mM MgCl 2. The PARP reactions contained 1.5 μM [3 H] -NAD + (1.6 uCi / mmol), 200 nM of biotinylated histone H1, 200 nM of sIDNA, and 1 nM of enzyme PARP. Self-reactions using SPA-based bead detection were carried out in 100 μl volumes in 96-well white plates. Reactions were initiated by adding 50 μl of a 2X NAD + substrate mixture to 50 μl of a 2X enzyme mixture containing PARP and DNA. These reactions were terminated by the addition of 150 μl of 1.5 mM benzamide (-1000 times its IC50). 170 μl of interrupted reaction mixtures were transferred to Streptavidin Instant Plates, incubated for 1 hour, and counted using a TopCount microplate scintillation counter. The K data were determined from the inhibition curves at various substrate concentrations and are shown in Table 1 for representative compounds of the present invention. Table 1 PARP Inhibition The following examples are presented to provide what is believed to be the most useful and readily understood description of the methods and conceptual aspects of this invention. In Vivo Trial This study was done in nude mice that carry HCT-116 tumors in the leg. Three days (-3) before the radiotherapy began, the mice were implanted i.p. (intraperitoneal) with OMPs that supplies A-620223 at 0, 6.25, 12.5 or 25 mg / kg / day for 14 days. Beginning on day 0 the mice received radiation treatment (2 Gy / day) for 10 doses only or in combination with the 3 different doses of 2- (N-propylpiperidin-4-yl) benzimidazole-4-carboxamide. As can be seen from the data presented in Figure 1, the combination of the compound, 2- (N-propylpiperidin-4-yl) benzimidazole-4-carboxamide, with radiotherapy resulted in a significant improvement in tumor size reduction when it is compared to the administration of radiotherapy or compound only as a monotherapy. In vivo assay This study was done in mice with murine melanoma B16F10. The mice were divided into six treatment groups with 8-10 mice per group. See figure two for treatment groups. The B16F10 cells were injected s.c. in 6 mice / C57BL on day 0. The dosing was started on day one. A-861695 p.o. (oral or buccal), b.i.d. (twice a day) on days 1-14. On days 3-7, temozolomide (TMZ) p.o. (oral or buccal), q.d. (every day) (for groups that received both TMZ and A-861695, TMZ was given two hours after A-861695 was administered). As can be seen from the data presented in Figure 2, A-861695, administered orally, significantly enhances the efficacy of TMZ in a dose-dependent manner. The combination of A-861695 at 25, 12.5 or 3.1 mg / kg / day p.o., divided b.i.d., in combination with TMZ at 62.5 mg / kg / day (p.o., q.d. X5) provides significantly more efficacy with TMZ monotherapy. In vivo assay This study was conducted with 344 Fisher rats. 9L is a transplantable rat glioma cell line that produces orthotopic gliosarcoma in 344 Fisher rats. Since 9L is orthotopically implanted, this model can be used to assess the ability of a compound to be effective in an environment where the drug must cross the blood-brain barrier. Agents such as TMZ, which cross the blood-brain barrier, are more effective in this model than agents that do not. Rats were randomized into treatment groups (11-12 rats per group) of vehicle, TMZ (17.5 mg / kg / day, po, qd), and A-861695 (5, 18 and 50 mg / kg / day, po, bid) + TMZ (17.5 mg / kg, po, qd). The treatment of A-861695 begins on day 3 after the tumor cell inoculation and is continued for 13 days. TMZ was administered from day 4 to 8. Tumor growth was monitored longitudinally using an enhanced magnetic resonance imaging (MRI). The survival of the animal was evaluated based on the humanitarian euthanasia of rats that show signs of irreversible disease. The results are shown in Figure 3. When combined with TMZ, A-861695 significantly potentiates its antitumor activity. A-861695 at 50 mg / kg / day in combination with a reduced tumor volume of TMZ (on day 14) by 63%, which was 44% better than TMZ alone (p <; 0.005). The dose combination of 18 mg / kg / day or 50 mg / kg / day of A-861695 with TMZ also significantly prolonged animal survival (p <0.005, Log-rank test). The pharmacokinetic profile of A-861695 was evaluated in rats bearing tumor with a drug concentration measured in the plasma as well as in brain and tumor tissues. After multiple doses of A-861695 (50 mg / kg / day), the compound concentration 2 hours after dosing (close to Cmax) was 1.36 ± 0.16 μg / mL, 0.72 ± 0.12 μg / g, and 3.00 ± 0.16 μg / g, in plasma, brain, and tumor tissues, respectively. A-861695 presents improved bioavailability in brain tissue compared to other PARP inhibitors. The co-administration of TMZ does not alter the PK plasma profile of A-861695. In vivo Assay The MX-1 breast carcinoma xenograft model in scid mice is used to test the ability of A-861695 to enhance the effectiveness of platinum-based agents. This cell line is derived from a 29-year-old female with a poorly differentiated breast carcinoma. MX-1 is sensitive to cytotoxic agents. Carboplatin, an anti-cancer drug containing second-generation platinum, is currently the standard of care for treating cancers of the lung, ovaries, and head and neck. MX-1 tumors are sensitive to carboplatin. Therefore, carboplatin is administered at lower doses of 5, 10 and 15 mg / kg / day until an appropriate experimental window is obtained to allow the examination of potentiation with PARP inhibitors. Mice were randomized into treatment groups of 8-10 mice per group. The tumors were compared in size to -200 mm3 on day 16. A-861695 was administered at 25 mg / kg / day sc, via osmotic minipumps on day 14 (OMPs) starting on day 17. Carboplatin ip was given, on day 20, 24 and 27. The data presented in Figure 4 are means ± SEM of 8-10 mice per treatment group. As a simple agent, carboplatin produced a tumor-dependent inhibition of the dose. A-861695 administered at 25 mg / kg / day via OMPs for 14 days caused a pronounced potentiation of carboplatin at 10 and 15 mg / kg / day as reflected by tumor volumes. The carboplatin / PARP combination of 10 mg / kg / day returned tumor volumes from day 26, whereas carboplatin monotherapy only delayed tumor growth. In vivo assay In this study the efficacy of A-861695 in combination with cisplatin was evaluated in the xenograft model of breast carcinoma MX-1 in nude mice. The tumors were compared in size to 100 mm3 on day 16 and the PARP inhibitor therapy (p.o., b.i.d. x8) was started on the same day. A single dose of cisplatin at 6.0 mg / kg / day was administered i.p. on day 18. The data, shown in Figure 5, are means ± S.E.M. of mice by treatment groups. A-861695 induced a pronounced enhancement of cisplatin activity. A-861695 at 5, 25 and 50 mg / kg / day in combination with cisplatin showed an increase in cures (8/9, 8/9 and 6/9 animals, respectively, cures defined as non-measurable tumors at the end of the trial ), whereas cisplatin monotherapy had only 3/9 cures. This dose response study showed that maximal potentiation was achieved at 5 mg / kg / day of A-861695. The Applicants have also found that the HDAC inhibitor such as valproic acid can be used to reduce the size of the tumor. Valproic acid crosses the blood-brain barrier and also studies and is safely tolerated in children. Valproic acid as a simple therapeutic agent has been used as an anti-tumor agent for adult and pediatric tumors, including neuroblastomas and gliomas. The Applicants have found that valproic acid can improve the effects of radiation therapy (see Figure 6). The PARP inhibitor A-861695 also crosses the blood-brain barrier and can work well in combination with valproic acid. DOSAGE The dosage of the compounds to form (I) such as 2 - [(2R) -2-methylpyrrolidin-2-yl] -1H-benzimidazole-4-carboxamide in humans has been studied by the Applicants. The following table, shown in Table 2, has been used by the Requesters when ABT-888 and temozolomide are administered. This protocol for dosing can be followed by up to 12 cycles. Table 2 The following scheme at the dose scale, shown in Table 3, was used by the Applicants at doses of temozolomide. All patients were initiated with dose level 1. Patients with leukemia were dosed at a level below the dose level under the study for patients with CNS / solid tumors. Table 4 shows the dose adjustment of temozolomide in patients with tumors in the CNS / solids. Table 5 shows the dose adjustment of temozolomide in patients with leukemia. Table 3 Table 4 Table 5 Protocol therapy to continue if ANC > 500 / μl and platelet count > 20,000 / μl per day 28 If ANC > 500 / μl and platelet count > 20,000 / μl per day 42 - > reduce TMZ by day 25 mg / m2 / day If ANC < 500 / μl and platelet count < 20,000 / μl per day 42 - > Bone marrow < 25% of downloads Retrace therapy to ANC > 500 / μl and platelet count > 20,000 / μl Reduce TMZ by 25 mg / m2 / day Additional In Vivo Studies The percentage survival rate of mice with intra-cerebellar medulloblastoma xenografts after they have been treated with TMZ and ABT-888 are shown in Figure 7 and 8. Time is in days. The results of administration and improvement of the in vivo activity of different amounts of combinations of TMZ and ABT-888 for the HSB ALL T cell; JM1 pre-B ALL; and primary AML cells P115; they are shown in Figures 9-11. These data show the improvement of TMZ toxicity by ABT-888.

Claims (10)

1. CLAIMS 1. A PARP inhibitor of the formula (I) 0) or a therapeutically acceptable salt thereof, characterized in that Ri, R2 and R3 are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro , NRARB, and (NRARB) carbonyl; A is a non-aromatic ring of 4, 5, 6, 7 or 8 members containing 1 or 2 nitrogen atoms and, optionally, a sulfur or oxygen atom, wherein the non-aromatic ring is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkoxy, haloalkyl, halogen, heterocycle, heterocycloalkyl, heteroaryl, heteroarylalkyl, hydroxy, hydroxyalkyl, nitro, NRCRD (NRcRD) alkyl, (NRcRD) carbonyl, (NRcRD) carbonylalkyl, and (NRcRD) sulfonyl; and RA, RB, RC and RD are independently selected from the group consisting of hydrogen, alkyl and alkylcarbonyl; in combination with radiotherapy or a cytotoxic agent selected from the group consisting of temozolomide, irinotecan, cisplatin, carboplatin, and topotecan.
2. 2. The combination according to claim 1, characterized in that the PARP inhibitor of the formula (I) is 2 - [(2R) -2-methylpyrrolidin-2-yl] -1H-benzimidazole-4-carboxamide.
3. 3. The combination according to claim 1, characterized in that the cytotoxic agent is temozolomide.
4. A method for treating leukemia in a mammal, characterized in that it comprises administering thereto a PARP inhibitor of the formula (I), or a therapeutically acceptable salt thereof, and a cytotoxic agent selected from the group consisting of temozolomide (TMZ) , irinotecan, cisplatin, carboplatin, and topotecan.
5. 5. The method according to claim 4, characterized in that the PARP inhibitor of the formula (I) is 2 - [(2R) -2-methylpyrrolidin-2-yl] -1H-benzimidazole-4-carboxamide. The method according to claim 4, characterized in that the PARP inhibitor of the formula (I) is 2 - [(2R) -2-methylpyrrolidin-2-yl] -1H-benzimidazole-4-carboxamide and the agent cytotoxic is temozolomide. A method for treating CNS tumors in a mammal, characterized in that it comprises administering thereto a PARP inhibitor of the formula (I), or a therapeutically acceptable salt thereof, and a cytotoxic agent selected from the group consisting of temozolomide ( TMZ), irinotecan, cisplatin, carboplatin, and topotecan. The method according to claim 7, characterized in that the PARP inhibitor of the formula (I) is 2 - [(2R) -2-methylpyrrolidin-2-yl] -1H-benzimidazole-4-carboxamide. The method according to claim 7, characterized in that the PARP inhibitor of the formula (I) is 2 - [(2R) -2-methylpyrrolidin-2-yl] -1H-benzimidazole -4 -carboxamide and the agent cytotoxic is temozolomide. The method according to claim 7, characterized in that the PARP inhibitor of the formula (I) is 2- (N-propylpyperidin-4-yl) benzimidazole-4-carboxamide.