JP5722883B2 - 1−(置換ベンジル)−5−トリフルオロメチル−2−(1h)ピリドン化合物及びその塩、並びにその製造方法及びその用途 - Google Patents
1−(置換ベンジル)−5−トリフルオロメチル−2−(1h)ピリドン化合物及びその塩、並びにその製造方法及びその用途 Download PDFInfo
- Publication number
- JP5722883B2 JP5722883B2 JP2012512189A JP2012512189A JP5722883B2 JP 5722883 B2 JP5722883 B2 JP 5722883B2 JP 2012512189 A JP2012512189 A JP 2012512189A JP 2012512189 A JP2012512189 A JP 2012512189A JP 5722883 B2 JP5722883 B2 JP 5722883B2
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- JP
- Japan
- Prior art keywords
- benzyl
- trifluoromethylpyridin
- amino
- group
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- -1 1- (Substituted benzyl) -5-trifluoromethyl-2- (1H) pyridone compound Chemical class 0.000 title claims description 29
- 150000003839 salts Chemical class 0.000 title claims description 10
- 238000004519 manufacturing process Methods 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims description 46
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 7
- 230000003510 anti-fibrotic effect Effects 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 125000003277 amino group Chemical group 0.000 claims description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 6
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- RBNPOMFGQQGHHO-UWTATZPHSA-N D-glyceric acid Chemical compound OC[C@@H](O)C(O)=O RBNPOMFGQQGHHO-UWTATZPHSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000001506 calcium phosphate Substances 0.000 claims description 4
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 4
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 4
- 235000019800 disodium phosphate Nutrition 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- 239000001488 sodium phosphate Substances 0.000 claims description 4
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 4
- TUEOKAUVWSUGTM-UHFFFAOYSA-N 1-[[2-(2-hydroxyethylamino)phenyl]methyl]-5-(trifluoromethyl)pyridin-2-one Chemical compound OCCNC1=CC=CC=C1CN1C(=O)C=CC(C(F)(F)F)=C1 TUEOKAUVWSUGTM-UHFFFAOYSA-N 0.000 claims description 3
- KPEAHORULBBAST-UHFFFAOYSA-N 1-[[2-(2-morpholin-4-ylethylamino)phenyl]methyl]-5-(trifluoromethyl)pyridin-2-one Chemical compound C1=C(C(F)(F)F)C=CC(=O)N1CC1=CC=CC=C1NCCN1CCOCC1 KPEAHORULBBAST-UHFFFAOYSA-N 0.000 claims description 3
- PVZOBZBTBBRLCV-UHFFFAOYSA-N 1-[[2-(2-piperazin-1-ylethylamino)phenyl]methyl]-5-(trifluoromethyl)pyridin-2-one Chemical compound C1=C(C(F)(F)F)C=CC(=O)N1CC1=CC=CC=C1NCCN1CCNCC1 PVZOBZBTBBRLCV-UHFFFAOYSA-N 0.000 claims description 3
- DNEGGUHDBWIXTQ-UHFFFAOYSA-N 1-[[2-[2-(4-methylpiperazin-1-yl)ethylamino]phenyl]methyl]-5-(trifluoromethyl)pyridin-2-one Chemical compound C1CN(C)CCN1CCNC1=CC=CC=C1CN1C(=O)C=CC(C(F)(F)F)=C1 DNEGGUHDBWIXTQ-UHFFFAOYSA-N 0.000 claims description 3
- MSQBSVGGJQOWLG-UHFFFAOYSA-N 1-[[4-(2-hydroxyethylamino)phenyl]methyl]-5-(trifluoromethyl)pyridin-2-one Chemical compound C1=CC(NCCO)=CC=C1CN1C(=O)C=CC(C(F)(F)F)=C1 MSQBSVGGJQOWLG-UHFFFAOYSA-N 0.000 claims description 3
- VNKMYPVPVYHVQO-UHFFFAOYSA-N 1-[[4-(2-morpholin-4-ylethylamino)phenyl]methyl]-5-(trifluoromethyl)pyridin-2-one Chemical compound C1=C(C(F)(F)F)C=CC(=O)N1CC(C=C1)=CC=C1NCCN1CCOCC1 VNKMYPVPVYHVQO-UHFFFAOYSA-N 0.000 claims description 3
- NQJQDEKDVRSXRX-UHFFFAOYSA-N 1-[[4-(2-piperazin-1-ylethylamino)phenyl]methyl]-5-(trifluoromethyl)pyridin-2-one Chemical compound C1=C(C(F)(F)F)C=CC(=O)N1CC(C=C1)=CC=C1NCCN1CCNCC1 NQJQDEKDVRSXRX-UHFFFAOYSA-N 0.000 claims description 3
- AZDHTDFJNVIJKZ-UHFFFAOYSA-N 1-[[4-(2-piperidin-1-ylethylamino)phenyl]methyl]-5-(trifluoromethyl)pyridin-2-one Chemical compound C1=C(C(F)(F)F)C=CC(=O)N1CC(C=C1)=CC=C1NCCN1CCCCC1 AZDHTDFJNVIJKZ-UHFFFAOYSA-N 0.000 claims description 3
- NERAVCLHOBGTNX-UHFFFAOYSA-N 1-[[4-(3-morpholin-4-ylpropylamino)phenyl]methyl]-5-(trifluoromethyl)pyridin-2-one Chemical compound C1=C(C(F)(F)F)C=CC(=O)N1CC(C=C1)=CC=C1NCCCN1CCOCC1 NERAVCLHOBGTNX-UHFFFAOYSA-N 0.000 claims description 3
- USDXDYDHRLSSFC-UHFFFAOYSA-N 1-[[4-[2-(2-hydroxyethoxy)ethylamino]phenyl]methyl]-5-(trifluoromethyl)pyridin-2-one Chemical compound C1=CC(NCCOCCO)=CC=C1CN1C(=O)C=CC(C(F)(F)F)=C1 USDXDYDHRLSSFC-UHFFFAOYSA-N 0.000 claims description 3
- TZZHDSPYUVLLNZ-UHFFFAOYSA-N 1-[[4-[2-(4-methylpiperazin-1-yl)ethylamino]phenyl]methyl]-5-(trifluoromethyl)pyridin-2-one Chemical compound C1CN(C)CCN1CCNC(C=C1)=CC=C1CN1C(=O)C=CC(C(F)(F)F)=C1 TZZHDSPYUVLLNZ-UHFFFAOYSA-N 0.000 claims description 3
- QQIYZFHTOAXUGX-UHFFFAOYSA-N 1-[[4-[3-(4-methylpiperazin-1-yl)propylamino]phenyl]methyl]-5-(trifluoromethyl)pyridin-2-one Chemical compound C1CN(C)CCN1CCCNC(C=C1)=CC=C1CN1C(=O)C=CC(C(F)(F)F)=C1 QQIYZFHTOAXUGX-UHFFFAOYSA-N 0.000 claims description 3
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 claims description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- ZTVZLYBCZNMWCF-PHDIDXHHSA-N (2r)-2-azaniumyl-4-[[(3r)-3-azaniumyl-3-carboxylatopropyl]disulfanyl]butanoate Chemical class OC(=O)[C@H](N)CCSSCC[C@@H](N)C(O)=O ZTVZLYBCZNMWCF-PHDIDXHHSA-N 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- BJEPYKJPYRNKOW-UWTATZPHSA-N (R)-malic acid Chemical compound OC(=O)[C@H](O)CC(O)=O BJEPYKJPYRNKOW-UWTATZPHSA-N 0.000 claims description 2
- JVTAAEKCZFNVCJ-REOHCLBHSA-M (S)-lactate Chemical compound C[C@H](O)C([O-])=O JVTAAEKCZFNVCJ-REOHCLBHSA-M 0.000 claims description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 claims description 2
- SJJCQDRGABAVBB-UHFFFAOYSA-M 1-hydroxy-2-naphthoate Chemical compound C1=CC=C2C(O)=C(C([O-])=O)C=CC2=C1 SJJCQDRGABAVBB-UHFFFAOYSA-M 0.000 claims description 2
- PWJNDVAKQLOWRZ-UHFFFAOYSA-N 1-hydroxynaphthalene-2-sulfonic acid Chemical compound C1=CC=C2C(O)=C(S(O)(=O)=O)C=CC2=C1 PWJNDVAKQLOWRZ-UHFFFAOYSA-N 0.000 claims description 2
- AOTQGWFNFTVXNQ-UHFFFAOYSA-N 2-(1-adamantyl)acetic acid Chemical compound C1C(C2)CC3CC2CC1(CC(=O)O)C3 AOTQGWFNFTVXNQ-UHFFFAOYSA-N 0.000 claims description 2
- NLBSQHGCGGFVJW-UHFFFAOYSA-N 2-carboxyethylphosphonic acid Chemical compound OC(=O)CCP(O)(O)=O NLBSQHGCGGFVJW-UHFFFAOYSA-N 0.000 claims description 2
- RIOSJKSGNLGONI-UHFFFAOYSA-N 2-phenylbenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1C1=CC=CC=C1 RIOSJKSGNLGONI-UHFFFAOYSA-N 0.000 claims description 2
- DVLFYONBTKHTER-UHFFFAOYSA-M 3-(N-morpholino)propanesulfonate Chemical compound [O-]S(=O)(=O)CCCN1CCOCC1 DVLFYONBTKHTER-UHFFFAOYSA-M 0.000 claims description 2
- ODHCTXKNWHHXJC-GSVOUGTGSA-N 5-oxo-D-proline Chemical compound OC(=O)[C@H]1CCC(=O)N1 ODHCTXKNWHHXJC-GSVOUGTGSA-N 0.000 claims description 2
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 claims description 2
- ODHCTXKNWHHXJC-UHFFFAOYSA-N 5-oxoproline Chemical compound OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- CKLJMWTZIZZHCS-UHFFFAOYSA-N Aspartic acid Chemical compound OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N Cysteine Chemical class SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 2
- CKLJMWTZIZZHCS-UWTATZPHSA-N D-aspartic acid Chemical compound OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 claims description 2
- 150000008558 D-cysteines Chemical class 0.000 claims description 2
- LEVWYRKDKASIDU-QWWZWVQMSA-N D-cystine Chemical class OC(=O)[C@H](N)CSSC[C@@H](N)C(O)=O LEVWYRKDKASIDU-QWWZWVQMSA-N 0.000 claims description 2
- 229930195713 D-glutamate Natural products 0.000 claims description 2
- WHUUTDBJXJRKMK-GSVOUGTGSA-N D-glutamic acid Chemical compound OC(=O)[C@H](N)CCC(O)=O WHUUTDBJXJRKMK-GSVOUGTGSA-N 0.000 claims description 2
- JVTAAEKCZFNVCJ-UWTATZPHSA-N D-lactic acid Chemical compound C[C@@H](O)C(O)=O JVTAAEKCZFNVCJ-UWTATZPHSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-LWMBPPNESA-L D-tartrate(2-) Chemical compound [O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-L 0.000 claims description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- ZTVZLYBCZNMWCF-WDSKDSINSA-N L,L-homocystine zwitterion Chemical class OC(=O)[C@@H](N)CCSSCC[C@H](N)C(O)=O ZTVZLYBCZNMWCF-WDSKDSINSA-N 0.000 claims description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 2
- 150000008538 L-cysteines Chemical class 0.000 claims description 2
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical class [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 claims description 2
- 229930195714 L-glutamate Natural products 0.000 claims description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- QLZHNIAADXEJJP-UHFFFAOYSA-N Phenylphosphonic acid Chemical class OP(O)(=O)C1=CC=CC=C1 QLZHNIAADXEJJP-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- JIMXXGFJRDUSRO-UHFFFAOYSA-M adamantane-1-carboxylate Chemical compound C1C(C2)CC3CC2CC1(C(=O)[O-])C3 JIMXXGFJRDUSRO-UHFFFAOYSA-M 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 2
- 235000011010 calcium phosphates Nutrition 0.000 claims description 2
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 claims description 2
- FDKLLWKMYAMLIF-UHFFFAOYSA-N cyclopropane-1,1-dicarboxylic acid Chemical compound OC(=O)C1(C(O)=O)CC1 FDKLLWKMYAMLIF-UHFFFAOYSA-N 0.000 claims description 2
- LEVWYRKDKASIDU-UHFFFAOYSA-N cystine Chemical class OC(=O)C(N)CSSCC(N)C(O)=O LEVWYRKDKASIDU-UHFFFAOYSA-N 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- 235000019797 dipotassium phosphate Nutrition 0.000 claims description 2
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims description 2
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N glutamic acid Chemical compound OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 2
- ZTVZLYBCZNMWCF-UHFFFAOYSA-N homocystine Chemical class [O-]C(=O)C([NH3+])CCSSCCC([NH3+])C([O-])=O ZTVZLYBCZNMWCF-UHFFFAOYSA-N 0.000 claims description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-L malate(2-) Chemical compound [O-]C(=O)C(O)CC([O-])=O BJEPYKJPYRNKOW-UHFFFAOYSA-L 0.000 claims description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 claims description 2
- ZIYVHBGGAOATLY-UHFFFAOYSA-N methylmalonic acid Chemical compound OC(=O)C(C)C(O)=O ZIYVHBGGAOATLY-UHFFFAOYSA-N 0.000 claims description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 2
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 2
- XTEGVFVZDVNBPF-UHFFFAOYSA-L naphthalene-1,5-disulfonate(2-) Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1S([O-])(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-L 0.000 claims description 2
- PSZYNBSKGUBXEH-UHFFFAOYSA-M naphthalene-1-sulfonate Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-M 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- XUYJLQHKOGNDPB-UHFFFAOYSA-N phosphonoacetic acid Chemical compound OC(=O)CP(O)(O)=O XUYJLQHKOGNDPB-UHFFFAOYSA-N 0.000 claims description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 150000003147 proline derivatives Chemical class 0.000 claims description 2
- MGNVWUDMMXZUDI-UHFFFAOYSA-N propane-1,3-disulfonic acid Chemical compound OS(=O)(=O)CCCS(O)(=O)=O MGNVWUDMMXZUDI-UHFFFAOYSA-N 0.000 claims description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 claims description 2
- 229960001860 salicylate Drugs 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- 235000011008 sodium phosphates Nutrition 0.000 claims description 2
- AGGIJOLULBJGTQ-UHFFFAOYSA-N sulfoacetic acid Chemical compound OC(=O)CS(O)(=O)=O AGGIJOLULBJGTQ-UHFFFAOYSA-N 0.000 claims description 2
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 claims description 2
- 229910000391 tricalcium phosphate Inorganic materials 0.000 claims description 2
- 235000019731 tricalcium phosphate Nutrition 0.000 claims description 2
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- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 2
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P13/00—Drugs for disorders of the urinary system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Description
1−(4−ニトロベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(4−アミノベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(4−((3−モルホリノプロピル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(4−((3−(ピペリジン−1−イル)プロピルアミノ)ベンジル)−5−トリフルオロメチルピリジン−2−(1H)−オン;
1−(4−((3−(4−メチルピペラジン−1−イル)プロピル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(4−((2−ヒドロキシエチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン-2(1H)−オン;
1−(4−((2−(ピペリジン−1−イル)エチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン-2(1H)−オン;
1−(4−((2−モルホリノエチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−((4−((2−(4−メチルピペラジン−1−イル)エチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(4−((2−(ピペラジン−1−イル)エチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(4−((2−(4−(2−ヒドロキシエチル)ピペラジン)エチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(4−((2−(4−メチルピペラジン−1−イル)エチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−((4−(アセチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(2,6−ジクロロベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(4−フルオロベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(2−ニトロベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(2−アミノベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(3−クロロベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(4−メトキシベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(2−フルオロベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(2−((2−ヒドロキシエチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(2−((2−−(ピペラジン−1−イル)エチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(2−((2−(4−メチルピペラジン−1−イル)エチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(2−アセチルアミノ)ベンジル−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(2−((2−モルホリノエチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(4−((2−(2−ヒドロキシエトキシ)エチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
反応式IV
1−(4−ニトロベンジル)−5−トリフルオロメチルピリジン−2(1H)−オンの製造
1−(4−アミノベンジル)−5−トリフルオロメチルピリジン−2(1H)−オンの製造
1−(4−((3−モルホリノプロピル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オンの製造
1−(4−((3−(ピペリジニル−1−イル)プロピルアミノ)ベンジル)−5−トリフルオロメチルピリジン−2−(1H)−オンの製造
1−(4−((3−(4−メチルピペラジン−1−イル)プロピル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オンの製造
1−(4−((2−ヒドロキシエチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オンの製造
1−(4−((2(−ピペリジン−1−イル)エチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オンの製造
1−(4−((2−ヒドロキシエチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン0.31g(1mmol)をジクロロメタン30mLに溶解し、塩化チオニル0.22mL及びトリエチルアミン0.44mLを加え、撹拌しながら室温で2時間反応させ、カラムクロマトグラフィーにより分離し、石油エーテル:酢酸エチル=3:1で溶出し、白色固体0.24gを得た。EI−MS(m/z):330[M]+。1H−NMR(CDCl3,300MHz)δppm:3.485〜3.525(t,2H,−CH2−),3.689〜3.728(t,2H,−CH2−),4.181(br,1H,−NH−),5.020(s,2H,−CH2−),6.612〜6.656(m,3H,Ar−H),7.167〜7.195(d,2H,J=8.4Hz, Ar−H),7.385〜7.426(dd,1H,J=2.7Hz,9.6Hz,Ar−H),7.623(s,1H,Ar−H)。
1−(4−((2−クロロエチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン0.24g(0.7mmol)をアセトニトリル30mLに溶解し、ピペリジン0.37g(4.2mmol)を加え、撹拌しながら27時間還流反応させた。反応終了後、ろ過し、減圧で溶剤を蒸発乾固し、カラムクロマトグラフィーにより分離し、酢酸エチル:メタノール=10:1で溶出し、黄色固体0.27gを得た。m.p.:83.6〜85.5℃。EI−MS(m/z):379[M]+。1H−NMR(CDCl3,300MHz)δppm:1.672(s,2H,−CH2−),1.872(s,4H,−CH2−),2.817〜3.112(br,6H,−CH2−),3.542(s,2H,−CH2−),5.012(s,2H,−CH2−),5.174(br,1H,−NH−),6.618〜6.649(d,1H,J=9.3Hz,Ar−H),6.698〜6.726(d,2H,J=8.4Hz,Ar−H),7.152〜7.181(d,1H,J=8.7Hz,Ar−H),7.386〜7.427(dd,1H,J=
2.7Hz,9.6Hz,Ar−H),7.627(s,1H,Ar−H)。
1−(4−((2−モルホリノエチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オンの製造
1−((4−((2−(4−メチルピペラジン−1−イル)エチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オンの製造
1−(4−((2−(ピペラジン−1−イル)エチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オンの製造
1−(4−((2−(4−(2−ヒドロキシエチル)ピペラジン−1−イル)エチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オンの製造
1−(4−((2−(4−メチルピペラジン−1−イル)エチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン二塩酸塩の製造
1−((4−(アセチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2−(1H)−オンの製造
1−(2,6−ジクロロベンジル)−5−トリフルオロメチルピリジン−2(1H)−オンの製造
1−(4−フルオロベンジル)−5−トリフルオロメチルピリジン−2(1H)−オンの製造
1−(2−ニトロベンジル)−5−トリフルオロメチルピリジン−2(1H)−オンの製造
1−(2−アミノベンジル)−5−トリフルオロメチルピリジン−2(1H)−オンの製造
1−(3−クロロベンジル)−5−トリフルオロメチルピリジン−2(1H)−オンの製造
1−(4−メトキシベンジル)−5−トリフルオロメチルピリジン−2(1H)−オンの製造
1−(2−フルオロベンジル)−5−トリフルオロメチルピリジン−2(1H)−オンの製造
1−(2−((2−ヒドロキシエチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オンの製造
1−(2−((2−−(ピペラジン−1−イル)エチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オンの製造
1−(4−((2−ヒドロキシエチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン2.2gをジクロロメタン40mLに溶解し、塩化チオニル1.7g及びトリエチルアミン1.2gを加え、室温で10時間反応させ、カラムクロマトグラフィーにより分離し、白い固体1.5gを得た。m.p.:93.5〜95.0℃。EI−MS(m/z):330[M]+。1H−NMR(CDCl3,300MHz):δppm:3.483〜3.543(t,2H,−CH2−),3.628〜3.672(t,2H,−CH2−),5.089(s,2H,−CH2−),5.737〜5.753(1H,−NH−),6.618〜6.757(m,3H,Ar−H),7.206〜7.235(dd,1H,J=1.2Hz,7.5Hz,Ar−H),7.250〜7.307(dd,1H,J=8.1Hz,,9.0Hz,Ar−H),7.732(s,1H,Ar−H)。
1−(2−((2クロロエチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン0.33g(1mmol)をアセトニトリル20mLに溶解し、無水ピペラジン0.53g(6mmol)及び触媒量のヨウ化ナトリウムを加え、20時間還流反応させ、ろ過し、ろ液をカラムクロマトグラフィーにより分離し、メタノールで溶出し、1−(2−((2−ピペラジン−1−イル)エチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン0.26gを黄色油状物として得た。EI−MS(m/z):380[M]+。1H−NMR(CDCl3,300MHz):δppm:2.434(s,4H,−CH2−),2.575〜2.615(t,2H,−CH2−),2.839〜2.853(d,4H,−CH2),3.181〜3.200(d,2H,−CH2−),5.153(s,2H,−CH2−),5.275(s,1H,−NH−),6.636〜6.740(m,3H,Ar−H),7.150〜7.174(d,1H,J=7.2Hz,Ar−H),7.283〜7.309(m,1H,Ar−H),7.426〜7.458(d,1H,J=9.6Hz,Ar−H),7.632(s,1H,Ar−H)。
1−(2−((2−(4−メチルピペラジン−1−イル)エチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オンの製造
1−(2−アセチルアミノ)ベンジル−5−トリフルオロメチルピリジン−2(1H)−オンの製造
1−(2−((2−モルホリノエチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オンの製造
1−(4−((2−(2−ヒドロキシエトキシ)エチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オンの製造
化合物のNIH3T3線維芽細胞に対する抑制試験
チアゾリルブルー(MTT)方法を用いた。5%仔ウシ血清含有DMEM培地で細胞を培養し、細胞を3×104/mlの細胞懸濁液に調製した。96穴ウェルプレートのウェル毎に100μl接種した。細胞が壁に付着した後、異なる濃度の化合物とフルオロフェニドン(fluorofenidone,AKF−PD)を含む1%仔ウシ血清含有培地に交換した。各濃度毎に3個の穴を設置し、それぞれ薬剤を投与する48、72時間後、ウェル毎にMTT溶液(培地を5mg/mlに調製し、ろ過した後、日光を避けて保存した。)100μlを加えた。4時間後、MTTを吸い出し、次いでウェル毎にMTT溶液が溶解されたDMSO150μlを加えた。10分後、MTTが全部溶解してから、マイクロプレートリーダーでOD値を測定した。抑制率に基づいて、フルオロフェニドン及び試験化合物のIC50値を算出した。両者のIC50値から、試験化合物の活性及びフルオロフェニドン活性の倍数を算出した。倍数とプレート上のフルオロフェニドンのIC50値に基づいて、試験化合物の相対IC50値を算出した。
ラットの一側尿管結紮腎線維化モデルに対する化合物3の治療効果の観察
1、実験薬品
化合物3は、本発明の方法に従って合成した。
体重が188−213gの雄SDラット9匹を、湖南斯莱克実験動物有限責任会社から購入した。実験動物は毎日12時間の光照を与え、飼料は上海斯莱克実験動物有限責任会社から購入し、飲用水は中南大学の実験動物学部から提供した。
(1)ランダム化:9匹のラットをランダムに3群に分け、それぞれの群は正常群(n=3)、モデル群(n=3)、化合物3 15mg/kg治療群(n=3)であり、ラット3匹を一つのケージに入れた。実験動物は2日適応性飼養を行った。
ラット1匹ごとに0.35ml/100gで10%抱水クロラールを腹腔内注射して麻酔し、後にラット固定板に固定した。まず、水で背中の皮膚を浸潤した後、皮膚を引っ張り、外科用ハサミで皮膚に隣接して脱毛し、普通の消毒を行った。左肋骨縁の下1.0cmと脊柱の中線に接した0.8cmとが交わった箇所に縦方向に1.0cmの切り口を形成し、連続する層を分離して腎左部及び輸尿管左部を暴露し、腎左部下端で4.0縫い糸で輸尿管左部を結紮し、更にその下方1cmの箇所で再結紮した。結紮点間の輸尿管を分離し、ゲンタマイシンの生理食塩液で腹腔を洗い、漏れ及び出血の有無を検査した後、一層づつ後腹膜の各層及び背中の皮膚を縫合した。
(a)CMC−Na粉末に適度な量の0.9%生理食塩水を加え、濃度0.5%のCMC−Na溶液を調製した。以下の各群薬物は、0.5%のCMC−Na溶液を溶剤として調製した。
(b)正常群:0.5%CMC−Na 6ml/kg.dを毎日1回、胃内投与した。
(c)モデル群:0.5%CMC−Na 6ml/kg.dを毎日1回、胃内投与した。
(d)化合物3 15mg/kg治療群:6ml/kg.dを毎日1回、胃内投与した。
手術後第11日目に、各群ラットに10%抱水クロラール(0.7−0.9ml/100g)麻酔を致死するまで腹腔内注射し、得られた閉塞側腎組織を4%ホルムアルデヒドで固定し、パラフィン中に埋め込み、4μm厚スライスを作製し、HE染色とMasson染色を行った。
腎組織のHE染色スライスについて、腎小管間質の左上側、右上側、左下側、右下側及び中間の5箇所の視野を低倍鏡で観察し,腎間質損傷の8の指標(腎小管上皮細胞空泡変性、腎小管拡張、腎小管萎縮、紅細胞管型、蛋白管型、間質水腫、間質線維化、間質炎性細胞浸潤)に基づいて評価し、その平均値を算出して、このサンプルの腎小管間質損傷指数とした。評点基準の参考文献: Radford MG Jr, Donadio JV Jr, Bergstralh EJ, et al. Predicting renal outcome in IgA nephropathy . J Am Soc Nephrol,1997, 8(2):199-207。
腎組織Masson染色スライスを取り、400倍の光学顕微鏡でそれぞれのサンプルについてランダムに20視野を観察し、視野内における青色染色のパーセントを計算した。半定量評点後、平均値を決定した。非陽性染色が0点;<25%が1点;25−50%が2点;50−75%が3点;>75%が4点である。評点基準の参考文献:Lin SL, Chen RH, Chen YM, et al. Pentoxifylline Attenuates Tubulointerstitial Fibrosis by Blocking Smad3/4-Activated Transcription and Profibrogenic Effects of Connective Tissue GroWth Factor. J Am Soc Nephrol.2005, 16: 2702-2713。
1.HE染色腎間質損傷の病理評点の結果
正常群と比べて、☆p<0.05,☆☆p<0.01;☆☆☆p<0.001;
モデル群と比べて、*p<0.05,**p<0.01,***p<0.001;
正常群と比べて,☆p<0.05,☆☆p<0.01;☆☆☆p<0.001;
モデル群と比べて,*p<0.05,** p<0.01,***p<0.001;
化合物3は15mg/kgで有効に腎臓線維化を治療することができる。
Claims (6)
- 式(XIII)の構造を有する、1−置換ベンジル−5−トリフルオロメチル−2−(1H)ピリドン化合物及びその製薬上許容される塩。
XIII
式中、R1〜R4、R12はH、NO2、ヒドロキシ基、アミノ基、ハロゲン原子、C1−C6アルコキシ基、NR10R11、OR13、C(O)R14、O−C(O)R14、C1−C6アルキル基、C1−C6ハロゲン置換アルキル基、C2−C6アルケニル基、カルボキシル基、カルボン酸エステルから選択される。;R1〜R4、R12は同時にHではなく、R14はC1−C6アルキル基から選択される;NR10R11 の構造において、R10及びR11はH、C1−C6ヒドロキシアルキル基、C1−C6アルコキシアルキル基、又は構造式XIVから選択され、且つR10とR11は同時にHではない。;R 13 はヒドロキシアルキル基、アルコキシアルキル基から選択される;R1〜R4、R12の少なくとも1つはNR 10 R 11 である;
構造式XIV中、R5はH、C1−C6アルキル基、C1−C6ハロゲン置換アルキル基、C1−C6ヒドロキシアルキル基、C2−C6アルケニル基から選択される。;R6〜R9はH、C1−C6アルコキシ基、=O、C1−C4アルキル基、C1−C4ハロゲン置換アルキル基、C1−C4ヒドロキシアルキル基、C2−C4アルケニル基から選択される。;XはN、CHから選択される。;YはN、O、CHから選択される(但し、YがOの場合、R5は存在しない。)。;nは1〜6である。 - 塩酸塩、硫酸塩、リン酸塩、過塩素酸塩、メタンスルホン酸塩、トリフルオロメタンスルホン酸塩、ギ酸塩、酢酸塩、プロピオン酸塩、酪酸塩、マイレン酸塩、コハク酸塩、トリフルオロ酢酸塩、コハク酸塩、サリチル酸塩、DL−アスパラギン酸塩、D−アスパラギン酸塩、L−アスパラギン酸塩、DL−グルタミン酸塩、D−グルタミン酸塩、L−グルタミン酸塩、グリセリン酸塩、コハク酸塩、ステアリン酸塩、DL−酒石酸塩、D−酒石酸塩、L−酒石酸塩、(±)マンデル酸塩、(R)−(−)マンデル酸塩、(S)−(+)−マンデル酸塩、クエン酸塩、粘液酸塩、マロン酸塩、安息香酸塩、DL−リンゴ酸塩、D−リンゴ酸塩、L−リンゴ酸塩、半リンゴ酸塩、1−アダマンタン酢酸塩、1−アダマンタンカルボン酸塩、フラビアン酸塩、スルホ酢酸塩、(±)−乳酸塩、L−(+)−乳酸塩、D−(−)−乳酸塩、パモ酸塩、D−α−ガラクツロン酸塩、グリセリン酸塩、DL−シスチン塩、D−シスチン塩、L−シスチン塩、DL−ホモシスチン塩、D−ホモシスチン塩、L−ホモシスチン塩、DL−システイン塩、D−システイン塩、L−システイン塩、(4S)−ヒドロキシ−L−プロライン、シクロプロパン−1,1−ジカルボン酸塩、2,2−メチルマロン酸塩、チロシン塩、プロライン塩、フマル酸塩、1−ヒドロキシ−2ナフタレンカルボン酸塩、ホスホノ酢酸塩、炭酸塩、炭酸水素塩、3−ホスホノプロピオン酸塩、DL−ピログルタミン酸塩、D−ピログルタミン酸塩及びL−ピログルタミン酸塩、トルエンスルホン酸塩、ベンゼンスルホン酸塩、エタンスルホン酸塩、(±)カンファースルホン酸塩、ナフタリンスルホン酸塩、1R−(−)−カンファースルホン酸塩、1S−(+)−カンファースルホン酸塩、1,5−ナフタレンジスルホン酸塩、1,2−エタンジスルホン酸塩、1,3−プロパン二スルホン酸塩、3−(N−モルフォリノ)プロパンスルホン酸塩、ビフェニルスルホン酸塩、イセチオン酸塩及び1−ヒドロキシ−2−ナフタレンスルホン酸塩、リン酸二水素塩、リン酸二水素カリウム塩、リン酸二カリウム塩、リン酸カリウム塩、リン酸水素ナトリウム塩、リン酸二ナトリウム塩、リン酸ナトリウム塩、リン酸二水素ナトリウム塩、リン酸カルシウム塩、第三リン酸カルシウム塩及びヘキサフルオロリン酸塩、ビニルホスホン酸塩、2−カルボキシエチルホスホン酸塩及びフェニルホスホン酸塩である、請求項1に記載の1−置換ベンジル−5−トリフルオロメチル−2−(1H)ピリドン化合物の製薬上許容できる塩。
- R1〜R4、R12の1つがNR10R11 である場合に、残りの置換基がHである、請求項1に記載の1−置換ベンジル−5−トリフルオロメチル−2−(1H)ピリドン化合物。
- 化合物は、
1−(4−((3−モルホリノプロピル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(4−((3−(ピペリジン−1−イル)プロピルアミノ)ベンジル)−5−トリフルオロメチルピリジン−2−(1H)−オン;
1−(4−((3−(4−メチルピペラジン−1−イル)プロピル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(4−((2−ヒドロキシエチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(4−((2−(ピペリジン−1−イル)エチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(4−((2−モルホリノエチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−((4−((2−(4−メチルピペラジン−1−イル)エチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(4−((2−(ピペラジン−1−イル)エチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(4−((2−(4−(2−ヒドロキシエチル)ピペラジン)エチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(4−((2−(4−メチルピペラジン−1−イル)エチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(2−((2−ヒドロキシエチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(2−((2−(ピペラジン−1−イル)エチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(2−((2−(4−メチルピペラジン−1−イル)エチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(2−((2−モルホリノエチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
である、請求項1記載の1−置換ベンジル−5−トリフルオロメチル−2−(1H)ピリドン化合物。 - 1−((4−(アセチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
1−(2−アセチルアミノ)ベンジル−5−トリフルオロメチルピリジン−2(1H)−オン;又は
1−(4−((2−(2−ヒドロキシエトキシ)エチル)アミノ)ベンジル)−5−トリフルオロメチルピリジン−2(1H)−オン;
である、1−置換ベンジル−5−トリフルオロメチル−2−(1H)ピリドン化合物。 - 請求項1〜5のいずれかに記載の1−置換ベンジル−5−トリフルオロメチル−2−(1H)ピリドン化合物又は該化合物及びその製薬上許容される添加剤を含む、抗線維化薬物。
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JP6186434B2 (ja) | 2012-07-18 | 2017-08-23 | サンシャイン・レイク・ファーマ・カンパニー・リミテッドSunshine Lake Pharma Co.,Ltd. | 窒素複素環誘導体及びその医薬品への応用 |
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