# US 8,541,412 B2 · Dihydroindolone compounds, a process for their preparation and pharmaceutical compositions containing them > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,541,412 B2 - Document ID: US8541412B2 - Status: Granted - Kind: B2 - Application number: 13/373,016 - Filed: 2011-11-02 - Published: 2012-02-23 - Granted: 2013-09-24 - Earliest claimed: 2009-08-04 - Assignees: Les Laboratoires Servier - Applicants: Jean-Claude Ortuno; Alexis Cordi; Imre Fejes; Vincent Lacoste; Pauline Lacoste - Inventors: Jean-Claude Ortuno; Alexis Cordi; Jean-Michel Lacoste; Imre Fejes - Web page: https://patentgrep.com/patent/US8541412B2 ## CPC - C07D 417/14: containing three or more hetero rings - A61P 35/00: Antineoplastic agents - A61P 35/04: specific for metastasis - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - C07D 401/12: linked by a chain containing hetero atoms as chain links - C07D 401/14: containing three or more hetero rings - C07D 403/12: linked by a chain containing hetero atoms as chain links - C07D 403/14: containing three or more hetero rings - C07D 413/14: containing three or more hetero rings - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract Compounds of formula (I): wherein: m and n represent 1 or 2, A represents a pyrrolyl group, X represents a C(O), S(O) or SO2 group, R1 and R2 represent an alkyl group or, together with the nitrogen atom carrying them, form a heterocyclic group, R3 and R4, together with the atoms carrying them, form a heterocyclic group, R5 represents a hydrogen atom or an alkyl group, R6 represents a hydrogen atom or a halogen atom. Medicinal products containing the same which are useful in treating cancer. ## Claims ### Claim 1 A method of treating a condition selected from cancers of the colon, breast, liver, kidneys, brain, esophagus, melanomas, melanomas, cancers of the ovary, small cell lung cancers, cancers of the prostate and pancreas, and sarcomas in a subject in need thereof comprising administration of an effective amount of a compound selected from those of formula (I): wherein: m represents 1 or 2, n represents 1 or 2, A represents a pyrrolyl group which is unsubstituted or substituted by 1 to 3 linear or branched (C1-C6)alkyl groups, X represents a C(O), S(O) or SO2 group, R1 and R2, which are the same or different, each represent a linear or branched (C1-C6)alkyl group, or R1 and R2, together with the nitrogen atom carrying them, form a heterocyclic group, R3 and R4, together with the atoms carrying them, form a heterocyclic group, R5 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group, R6 represents a hydrogen atom or a halogen atom, it being understood that: a “heterocyclic group” means a mono- or bi-cyclic group which may contain from 5 to 8 members, which may contain from one to three hetero atoms selected from nitrogen, oxygen and sulphur, and which may contain one or more unsaturated bonds, wherein the heterocyclic group is optionally substituted by one or more groups selected from linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkenyl, oxo, hydroxy, linear or branched (C1-C6)alkoxy, aryl, arylalkyl and arylalkenyl, “aryl” means a phenyl group which is optionally substituted by one or more groups selected from halogen atoms and linear or branched (C1-C6)alkyl groups, the notation representing, the exocyclic double bond at the 3-position of the indolone ring means that the double bond is of configuration Z or E, its optical and geometric isomers, and addition salts thereof with a pharmaceutically acceptable acid or base. ### Claim 2 (depends on 1) The method of claim 1, wherein R1 and R2, together with the nitrogen atom carrying them, form a morpholinyl group, in and n have the value 1, R5 and R6 represent a hydrogen atom and A represents a 1H-pyrrol-2,4-yl group. ### Claim 3 (depends on 1) The method of claim 1, wherein the compound of formula (I) is 3-[(3-{[4-(4-morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione, or an optical or geometric isomer, or addition salt thereof with a pharmaceutically acceptable acid or base. ### Claim 4 (depends on 1) The method of claim 1, wherein the compound of formula (I) is 3-[((3Z)-3-{[4-(4-morpholinylmethyl)-1H-pyrrol2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione, or an addition salt thereof with a pharmaceutically acceptable acid or base. ### Claim 5 A method of treating a condition selected from cancers of the colon, breast, liver, kidneys, brain, esophagus, melanomas, myelomas, cancers of the ovary, small cell lung cancers, cancers of the prostate and pancreas, and sarcomas in a subject in need thereof comprising administration of an effective amount of a compound selected from those of formula (I): wherein: m represents 1 or 2, n represents 1 or 2, A represents a pyrrolyl group which is unsubstituted or substituted by 1 to 3 linear or branched (C1-C6)alkyl groups, X represents a C(O), S(O) or SO2 group, R1 and R2, which are the same or different, each represent a linear or branched (C1-C6)alkyl group, or R1 and R2, together with the nitrogen atom carrying them, form a heterocyclic group, R3 and R4, together with the atoms carrying them, form a heterocyclic group, R5 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group, R6 represents a hydrogen atom or a halogen atom, it being understood that: a “heterocyclic group” means a mono- or bi-cyclic group which may contain from 5 to 8 members, which may contain from one to three hetero atoms selected from nitrogen, oxygen and sulphur, and which may contain one or more unsaturated bonds, wherein the heterocyclic group is optionally substituted by one or more groups selected from linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkenyl, oxo, hydroxy, linear or branched (C1-C6)alkoxy, aryl, arylalkyl and Arylalkenyl, “aryl” means a phenyl group which is optionally substituted by one or more groups selected from halogen atoms and linear or branched (C1-C6)alkyl groups, the notation representing the exocyclic double bond at the 3-position of the indolone ring means that the double bond is of configuration Z or E, its optical and geometric isomers, and addition salts thereof with a pharmaceutically acceptable acid or base and an anticancer agent selected from genotoxic agents, mitotic poisons, antimetabolites, proteasome inhibitors and kinase inhibitors. ### Claim 6 (depends on 5) The method of claim 5, wherein R1 and R2, together with the nitrogen atom carrying them, form a morpholinyl group, m and n have the value 1, R5 and R6 represent a hydrogen atom and A represents a 1H-pyrrol-2,4-yl group. ### Claim 7 (depends on 5) The method of claim 5, wherein the compound of formula (I) is 3-[(3-{[4-(4-morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione, or an optical or geometric isomer, or addition salt thereof with a pharmaceutically acceptable acid or base. ### Claim 8 (depends on 5) The method of claim 5, wherein the compound of formula (I) is 3-[((3Z)-3-{[4-(4-morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione, or an addition salt thereof with a pharmaceutically acceptable acid or base. ### Claim 9 A method of treating a condition selected from cancers of the colon, breast, liver, kidneys, brain, esophagus, melanomas, myelomas, cancers of the ovary, small cell lung cancers, cancers of the prostate and pancreas, and sarcomas in a subject in need thereof comprising administration of an effective amount of a compound selected from those of formula (I): wherein: m represents 1 or 2, n represents 1 or 2, A represents a pyrrolyl group which is unsubstituted or substituted by 1 to 3 linear or branched (C1-C6)alkyl groups, X represents a C(O), S(O) or SO2 group, R1 and R2, which are the same or different, each represent a linear or branched (C1-C6)alkyl group, or R1 and R2, together with the nitrogen atom carrying them, form a heterocyclic group, R3 and R4, together with the atoms carrying them, form a heterocyclic group, R5 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group, R6 represents a hydrogen atom or a halogen atom, it being understood that: a “heterocyclic group” means a mono- or bi-cyclic group which may contain from 5 to 8 members, which may contain from one to three hetero atoms selected from nitrogen, oxygen and sulphur, and which may contain one or more unsaturated bonds, wherein the heterocyclic group is optionally substituted by one or more groups selected from linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkenyl, oxo, hydroxy, linear or branched (C1-C6)alkoxy, aryl, arylalkyl and arylalkenyl, “aryl” means a phenyl group which is optionally substituted by one or more groups selected from halogen atoms and linear or branched (C1-C6)alkyl groups, the notation representing the exocyclic double bond at the 3-position of the indolone ring means that the double bond is of configuration Z or E, its optical and geometric isomers, and addition salts thereof with a pharmaceutically acceptable acid or base in combination with radiotherapy. ### Claim 10 (depends on 9) The method of claim 9, wherein R1 and R2, together with the nitrogen atom carrying them, form a morpholinyl group, m and n have the value 1, R5 and R6 represent a hydrogen atom and A represents a 1H-pyrrol-2,4-yl group. ### Claim 11 (depends on 9) The method of claim 9, wherein the compound of formula (I) is 3-[(3-{[4-(4-morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-2oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione, or an optical or geometric isomer, or addition salt thereof with a pharmaceutically acceptable acid or base. ### Claim 12 (depends on 9) The method of claim 9, wherein the compound of formula (I) is 3-[((3Z)-3-{[4-(4-morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione, or an addition salt thereof with a pharmaceutically acceptable acid or base.