# US 8,569,378 B2 · p27 protein inducer > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,569,378 B2 - Document ID: US8569378B2 - Status: Granted - Kind: B2 - Application number: 12/669,944 - Filed: 2008-07-18 - Published: 2011-01-13 - Granted: 2013-10-29 - Earliest claimed: 2007-07-20 - Assignees: Toshiyuki Sakai; Chugai Seiyaku Kabushiki Kaisha - Applicants: Toshiyuki Sakai; Hitoshi Iikura; Ikumi Hyoudoh; Toshihiro Aoki; Noriyuki Furuichi; Masayuki Matsushita; Fumio Watanabe; Sawako Ozawa; Masahiro Sakaitani; Pil-Su Ho; Yasushi Tomii; Kenji Takanashi; Naoki Harada - Inventors: Toshiyuki Sakai; Hitoshi Iikura; Ikumi Hyoudoh; Toshihiro Aoki; Noriyuki Furuichi; Masayuki Matsushita; Fumio Watanabe; Sawako Ozawa; Masahiro Sakaitani; Pil-Su Ho; Yasushi Tomii; Kenji Takanashi; Naoki Harada - Web page: https://patentgrep.com/patent/US8569378B2 ## CPC - C07D 405/14: containing three or more hetero rings - A61P 19/02: for joint disorders, e.g. arthritis, arthrosis - A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] - A61P 35/00: Antineoplastic agents - A61P 35/02: specific for leukemia - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - C07D 407/04: directly linked by a ring-member-to-ring-member bond - C07D 409/04: directly linked by a ring-member-to-ring-member bond - C07D 409/12: linked by a chain containing hetero atoms as chain links - C07D 413/12: linked by a chain containing hetero atoms as chain links - C07D 417/04: directly linked by a ring-member-to-ring-member bond - C07D 417/12: linked by a chain containing hetero atoms as chain links - C07D 417/14: containing three or more hetero rings - C07D 491/052: the oxygen-containing ring being six-membered - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The present invention provides a p27 protein inducing agent comprising a compound represented by general formula (11) below or pharmaceutically acceptable salt thereof as an active ingredient: wherein G1, G2, G3 and G8 are each independently selected from —N═ etc., Ring G6 is selected from divalent aryl etc., A is selected from amino etc., G4 is selected from oxygen etc., G5 is selected from oxygen etc., G7 is selected from —CH2— etc., and R2 is selected from C1-6 alkyl etc. ## Claims ### Claim 1 A method of treating rheumatism or inflammation in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound represented by general formula (1) below or a pharmaceutically acceptable salt thereof: wherein: X is a heteroaryl group or R3R4NCO—; Y1 and Y2 are each independently —N═ or —CR11═; Y3 and Y4 may be the same or different, and are each —CR12═; A is a group represented by general formula (2) below or a group represented by general formula (3) below: R1 is a hydrogen atom, a halogen atom, a cyano group, a C1-6 alkyl group, a C2-7 alkenyl group, a carbamoyl group or a C2-7 alkynyl group where the C2-7 alkynyl group may optionally be substituted with a C1-4 acyl group; R2 is a C1-6 alkyl group optionally substituted with a halogen atom; R3, R4, R6, R7, R9 and R10 are each independently a hydrogen atom, a C1-6 alkoxy group, a C3-8 cycloalkyl group or a C1-6 alkyl group where the C1-6 alkyl group may optionally be substituted with a group selected from a cyano group, a halogen atom, a hydroxy group, a C1-6 alkoxy group and —NR13R14; the combination of R3 and R4, combination of R6 and R7, and combination of R9 and R10 may form, together with the nitrogen atom to which they are bonded, a 4- to 6-membered heterocyclic group having at least one nitrogen atom; R5, R8, R13 and R14 are each independently a hydrogen atom or a C1-6 alkyl group; R11 is a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-4 acyl group, a C1-4 acyloxy group or —NR15R16; R12 is a hydrogen atom, a halogen atom or a C1-6 alkyl group; and R15 and R16 are each independently a hydrogen atom or a C1-4 acyl group. ### Claim 2 (depends on 1) The method according to claim 1, wherein R1 is a hydrogen atom, a halogen atom or a C1-6 alkyl group. ### Claim 3 (depends on 1) The method according to claim 1, wherein R5 or R8 is a hydrogen atom. ### Claim 4 (depends on 1) The method according to claim 1, wherein R3, R4, R6, R7, R9 and R10 are each independently a hydrogen atom or a C1-6 alkyl group. ### Claim 5 (depends on 1) The method according to claim 1, wherein X is a thiazol-2-yl group, a pyrimidin-2-yl group, a 2-pyridyl group or R3R4NCO— where R3 and R4 have the same definitions as above. ### Claim 6 (depends on 5) The method according to claim 5, wherein both R3 and R4 are a methyl group. ### Claim 7 (depends on 1) The method according to claim 1, wherein R2 is a C1-6 alkyl group optionally substituted with a fluorine atom. ### Claim 8 (depends on 7) The method according to claim 7, wherein R2 is —CH3, —CH2F or —CH2CH3. ### Claim 9 (depends on 1) The method according to claim 1, wherein the compound represented by general formula (1) is selected from: dimethylcarbamic acid 3-{3-(aminosulfonyl)aminobenzyl}-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-{3-(aminosulfonyl)aminobenzyl}-6-fluoro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-{3-(aminosulfonyl)aminobenzyl}-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-(3-aminosulfonylamino-2-fluoro-benzyl)-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-{2-fluoro-3-(aminosulfonyl)aminobenzyl}-6-fluoro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-{3-(aminosulfonyl)aminobenzyl}-6-iodo-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-{3-(aminosulfonyl)aminobenzyl}-6-methyl-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-{3-(aminosulfonyl)aminobenzyl}-6-cyano-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-{3-(aminosulfonyl)aminobenzyl}-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-{3-(aminosulfonyl)aminobenzyl}-6-fluoro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-{3-(aminosulfonyl)aminobenzyl}-6-chloro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-(3-aminosulfonylamino-2-fluoro-benzyl)-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl ester, 3-{2-fluoro-3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-6-chloro-2-oxo-2H-1-benzopyran, 3-{2-fluoro-3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-6-methyl-2-oxo-2H-1-benzopyran, 3-{2-chloro-3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran, dimethylcarbamic acid 4-methyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 6-fluoro-4-methyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-(3-(N-methylsulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-(3-methylaminosulfonylamino-2-fluoro-benzyl)-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 6-fluoro-4-methyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 6-iodo-4-methyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 6-methyl-4-methyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 6-cyano-4-methyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 4-methyl-3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 4-methyl-3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-6-fluoro-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 4-methyl-3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-6-chloro-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 4-methyl-3-{6-(methylaminosulfonyl)aminopyridin-2-ylmethyl}-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 4-methyl-3-{6-(methylaminosulfonyl)aminopyridin-2-ylmethyl}-6-fluoro-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 4-methyl-3-{6-(methylaminosulfonyl)aminopyridin-2-ylmethyl}-6-chloro-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-(3-methylaminosulfonylamino-2-fluoro-benzyl)-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-(3-methylaminosulfonylaminobenzyl)-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-(3-methylaminosulfonylaminobenzyl)-6-fluoro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 6-chloro-4-fluoromethyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-(3-methylaminosulfonylamino-2-fluoro-benzyl)-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl ester, 3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-6-fluoro-2-oxo-2H-1-benzopyran, 3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-fluoromethyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-6-chloro-2-oxo-2H-1-benzopyran, 3-{3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-6-chloro-2-oxo-2H-1-benzopyran, 3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-6-methyl-2-oxo-2H-1-benzopyran, dimethylcarbamic acid 6-chloro-4-methyl-3-{3-(dimethylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-yl ester, 3-{2-fluoro-3-(dimethylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, dimethylcarbamic acid 3-(3-(N-(2-cyanoethyl)sulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-(3-(N-(2-hydroxyethyl)sulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-(3-(N-(2-methoxyethyl)sulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-(3-(N-(2-aminoethyl)sulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester hydrochloride, dimethylcarbamic acid 3-(3-(N—(N′-methyl-2-aminoethyl)methylsulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester hydrochloride, dimethylcarbamic acid 3-(3-(N-2,2,2-trifluoroethyl-sulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-(3-(N-methoxysulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-(3-carbamoylmethanesulfonylamino-benzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-(3-methylcarbamoylmethanesulfonylamino-benzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, 2-{2-fluoro-3-[4-methyl-2-oxo-7-(pyrimidin-2-yloxy)-2H-1-benzopyran-3-ylmethyl]phenylsulfamoyl}-N-methyl-acetamide, dimethylcarbamic acid 3-(3-dimethylcarbamoylmethanesulfonylamino-benzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, 2-{2-fluoro-3-[4-methyl-2-oxo-7-(thiazol-2-yloxy)-2H-1-benzopyran-3-ylmethyl]phenylsulfamoyl}-N-methyl-acetamide, 3-{2-methyl-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-(ethylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-(isopropylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-fluoro-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-(cyclopropylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-fluoro-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-chloro-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-ethyl-6-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-(cyclopropylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-(cyclopropylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-(methylaminosulfonyl)amino-3-chloropyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-6-chloro-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-(cyclopropylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-6-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-(methylaminosulfonyl)amino-3-chloropyridin-4-ylmethyl}-4-methyl-6-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(5-fluoropyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(4-chloropyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(2,4-dimethoxypyrimidin-6-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(benzothiazol-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(5-bromothiazol-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(5-fluoropyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(4-chloropyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(2,4-dimethoxypyrimidin-6-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(benzothiazol-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(5-bromothiazol-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyrazin-2-yloxy)-2-oxo-2H-1-benzopyran, and 3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyridin-2-yloxy)-2-oxo-2H-1-benzopyran.