# US 10,870,633 B2 · Types of C-3 substituted kynurenic acid derivatives with improved neuroprotective activity > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,870,633 B2 - Document ID: US10870633B2 - Status: Granted - Kind: B2 - Application number: 16/082,099 - Filed: 2017-03-03 - Published: 2019-04-11 - Granted: 2020-12-22 - Earliest claimed: 2016-03-04 - Assignees: Szegedi TudomáNyegyetem - Applicants: Szegedi TudomáNyegyetem - Inventors: Ferenc Fülöp; István Szatmári; József Toldi; László Vécsei - Web page: https://patentgrep.com/patent/US10870633B2 ## CPC - C07D 401/14: containing three or more hetero rings - A61P 25/00: Drugs for disorders of the nervous system - C07D 215/48: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen - C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms - C07D 413/06: linked by a carbon chain containing only aliphatic carbon atoms - C07D 413/14: containing three or more hetero rings - A61P 25/06: Antimigraine agents - A61P 25/08: Antiepileptics; Anticonvulsants - A61P 25/16: Anti-Parkinson drugs - A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The invention relates to C-3 substituted kynurenic acid derivatives with the general formula (I) wherein R1 is C1-7alkyl-, R6R7N—C1-7alkyl-, C6-10aryl-C1-7alkyl group; R2 is H or C1-7alkyl group; or R1 and R2 with the nitrogen atom to which they are attached form a saturated or partially saturated 5-7 membered, optionally benzofused heterocyclic ring, optionally comprising additional N, O, S heteroatoms and optionally being substituted; R3 is —OH, C1-7alkyl-O—, —NH2, C1-7alkyl-NH—, C6-10aryl-C1-7alkyl-NH— or —NH— —(CH2)n—NR8R9 group wherein n is an integer from 1 to 3; R4 is H, C1-7alkyl-, C6-10aryl group or a halogen atom; R5 is H or C6-10aryl group; R6 is C1-7alkyl group; R7 is C1-7alkyl group; or R6 and R7 with the nitrogen atom to which they are attached form a saturated or partially saturated 5-7 membered, optionally benzofused heterocyclic ring, optionally comprising additional N, O, S heteroatoms and optionally being substituted; R8 is C1-7alkyl group; R9 is C1-7alkyl group; R8 and R9 with the nitrogen atom to which they are attached form a saturated or partially saturated 5-7 membered, optionally benzofused heterocyclic ring, optionally comprising additional N, O, S heteroatoms and optionally being substituted; and stereoisomers, tautomers and salts thereof. The invention relates to the pharmaceutical preparations comprising the compounds and stereoisomers, tautomers and pharmaceutically acceptable salts. The compounds of the invention have neuroprotective activity, may be used for the prevention and treatment of neurodegeneration, and for slowing down the development of the conditions and diseases associated with a decline in cognitive abilities. ## Claims ### Claim 1 A compound of formula (I) wherein R1 and R2 are C1-7alkyl; or R1 and R2 with the nitrogen atom to which they are attached form a saturated 5-6 membered, optionally benzofused heterocyclic ring; R3 is —NH—(CH2)2—NR8R9; R4 is H, C1-7alkyl-, C6-10 aryl group, or halogen; R5 is H or C6-10aryl group; and R8 and R9 are each independently methyl or ethyl; or a stereoisomer, tautomer, and pharmaceutically acceptable salt thereof. ### Claim 2 A compound selected from the group consisting of: 3-((2-morpholinoethylamino)methyl)-4-hydroxyquinoline-2-carboxylic acid; 3-((2-(dimethyl amino)ethyl amino)(phenyl)methyl)-4-hydroxyquinoline-2-carboxylic acid; 3-((dimethyl amino)methyl)-4-hydroxyquinoline-2-carboxylic acid; 3-((benzyl methyl amino)methyl)-4-hydroxyquinoline-2-carboxylic acid; 4-hydroxy-3-(morpholinomethyl)quinoline-2-carboxylic acid; 4-hydroxy-3-((piperidin-1-yl)methyl)quinoline-2-carboxylic acid; 4-hydroxy-3-((4-methylpiperazin-1-yl)methyl)quinoline-2-carboxylic acid; 4-hydroxy-3-(morpholinomethyl)-6-phenylquinoline-2-carboxylic acid; 7-chloro-4-hydroxy-3-(morpholinomethyl)quinoline-2-carboxylic acid; 4-hydroxy-8-methyl-3-(morpholinomethyl)quinoline-2-carboxylic acid; 3-((1,2,3,4-tetrahydroisoquinoline-2-yl)methyl)-4-hydroxyquinoline-2-carboxylic acid; 3-((1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline-2-yl)methyl)-4-hydroxyquinoline-2-carboxylic acid; 3-((diethyl amino)methyl)-N-(2-(dimethyl amino)ethyl)-4-hydroxyquinoline-2-carboxylic acid amide; N-(2-(dimethyl amino)ethyl)-4-hydroxy-3-((pyrrolidin-1-yl)methyl)quinoline-2-carboxylic acid amide; N-(2-(dimethyl amino)ethyl)-4-hydroxy-3-((piperidine-1-yl)methyl)quinoline-2-carboxylic acid amide; N-(2-(dimethyl amino)ethyl)-4-hydroxy-3-(morpholinomethyl)quinoline-2-carboxylic acid amide; 3-((diethyl amino)methyl)-4-hydroxy-N-(2-(pyrrolidin-1-yl)ethyl)quinoline-2-carboxylic acid amide; 4-hydroxy-N-(2-(pyrrolidin-1-yl)ethyl)-3-((pyrrolidin-1-yl)methyl)quinoline-2-carboxylic acid amide; 4-hydroxy-3-((piperidin-1-yl)methyl)-N-(2-(pyrrolidin-1-yl)ethyl)quinoline-2-carboxylic acid amide; 4-hydroxy-3-(morpholinomethyl)-N-(2-(pyrrolidin-1-yl)ethyl)quinoline-2-carboxylic acid amide; 4-hydroxy-3-(morpholinomethyl)quinoline-2-carboxylic acid methyl ester; 4-hydroxy-3-(morpholinomethyl)quinoline-2-carboxylic acid amide; N-benzyl-4-hydroxy-3-(morpholinomethyl)quinoline-2-carboxylic acid amide; or a stereoisomer, tautomer, and pharmaceutically acceptable salt thereof. ### Claim 3 (depends on 2) The compound according to claim 2, selected from the group consisting of: 4-hydroxy-3-(morpholinomethyl)quinoline-2-carboxylic acid; 3-((1,2,3,4-tetrahydroisoquinoline-2-yl)methyl)-4-hydroxyquinoline-2-carboxylic acid; 3-((1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline-2-yl)methyl)-4-hydroxyquinoline-2-carboxylic acid; N-(2-(dimethyl amino)ethyl)-4-hydroxy-3-(morpholinomethyl)quinoline-2-carboxylic acid amide; 3-((diethyl amino)methyl)-4-hydroxy-N-(2-(pyrrolidin-1-yl)ethyl)quinoline-2-carboxylic acid amide; 4-hydroxy-N-(2-(pyrrolidin-1-yl)ethyl)-3-((pyrrolidin-1-yl)methyl)quinoline-2-carboxylic acid amide; 4-hydroxy-3-(morpholinomethyl)-N-(2-(pyrrolidin-1-yl)ethyl)quinoline-2-carboxylic acid amide; or a stereoisomer, tautomer, and pharmaceutically acceptable salt thereof. ### Claim 4 (depends on 1) A pharmaceutical preparation comprising a compound according to claim 1, or a stereoisomer, tautomer, and pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and/or vehicles. ### Claim 5 (depends on 2) A pharmaceutical preparation comprising a compound according to claim 2, or a stereoisomer, tautomer, and pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and/or vehicles. ### Claim 6 (depends on 1) A method for providing a neuroprotective effect in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound according to claim 1, or a stereoisomer, tautomer, and pharmaceutically acceptable salt thereof. ### Claim 7 (depends on 2) A method for providing a neuroprotective effect in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 2, or a stereoisomer, tautomer, and pharmaceutically acceptable salt thereof. ### Claim 8 (depends on 1) The compound according to claim 1, wherein R1 and R2 are each independently methyl, ethyl, or benzyl; or a stereoisomer, tautomer, and pharmaceutically acceptable salt thereof. ### Claim 9 (depends on 1) The compound according to claim 1, wherein R1 and R2 with the nitrogen atom to which they are attached form morpholinyl, pyrrolidinyl, piperidinyl, or piperazinyl; or a stereoisomer, tautomer, and pharmaceutically acceptable salt thereof. ### Claim 10 (depends on 1) The compound according to claim 1, wherein R1 and R2 with the nitrogen atom to which they are attached form tetrahydroisoquinolinyl; or a stereoisomer, tautomer, and pharmaceutically acceptable salt thereof. ### Claim 11 (depends on 1) The compound according to claim 1, wherein R8 and R9 are both methyl; or a stereoisomer, tautomer, and pharmaceutically acceptable salt thereof. ### Claim 12 (depends on 3) The compound according to claim 3, wherein the compound is 4-hydroxy-3-(morpholinomethyl)quinoline-2-carboxylic acid. ### Claim 13 (depends on 3) The compound according to claim 3, wherein the compound is 3-((1,2,3,4-tetrahydroisoquinoline-2-yl)methyl)-4-hydroxyquinoline-2-carboxylic acid. ### Claim 14 (depends on 3) The compound according to claim 3, wherein the compound is 3-((1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline-2-yl)methyl)-4-hydroxyquinoline-2-carboxylic acid. ### Claim 15 (depends on 3) The compound according to claim 3, wherein the compound is N-(2-(dimethyl amino)ethyl)-4-hydroxy-3-(morpholinomethyl)quinoline-2-carboxylic acid amide. ### Claim 16 (depends on 3) The compound according to claim 3, wherein the compound is 3-((diethyl amino)methyl)-4-hydroxy-N-(2-(pyrrolidin-1-yl)ethyl)quinoline-2-carboxylic acid amide. ### Claim 17 (depends on 3) The compound according to claim 3, wherein the compound is 4-hydroxy-N-(2-(pyrrolidin-1-yl)ethyl)-3-((pyrrolidin-1-yl)methyl)quinoline-2-carboxylic acid amide. ### Claim 18 (depends on 3) The compound according to claim 3, wherein the compound is 4-hydroxy-3-(morpholinomethyl)-N-(2-(pyrrolidin-1-yl)ethyl)quinoline-2-carboxylic acid amide.