DK2474533T3 - Preparation of 1- (substituted benzyl) -5-TRIFLUOROMETYL-2- (1H) pyridone compounds and their salts and their use - Google Patents
Preparation of 1- (substituted benzyl) -5-TRIFLUOROMETYL-2- (1H) pyridone compounds and their salts and their use Download PDFInfo
- Publication number
- DK2474533T3 DK2474533T3 DK10780057.5T DK10780057T DK2474533T3 DK 2474533 T3 DK2474533 T3 DK 2474533T3 DK 10780057 T DK10780057 T DK 10780057T DK 2474533 T3 DK2474533 T3 DK 2474533T3
- Authority
- DK
- Denmark
- Prior art keywords
- pyridin
- trifluoromethyl
- benzyl
- amino
- trifluorometyl
- Prior art date
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- 150000003839 salts Chemical class 0.000 title claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 title claims 2
- 238000002360 preparation method Methods 0.000 title description 58
- -1 1- (substituted benzyl) -5-trifluoromethyl-2 (1H) pyridone compounds Chemical class 0.000 claims description 46
- 150000001875 compounds Chemical class 0.000 claims description 40
- OSBVVTNMGMJFNM-UHFFFAOYSA-N 1-[(4-aminophenyl)methyl]-5-(trifluoromethyl)pyridin-2-one Chemical compound C1=CC(N)=CC=C1CN1C(=O)C=CC(C(F)(F)F)=C1 OSBVVTNMGMJFNM-UHFFFAOYSA-N 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- ILVHBYJGIOLNMU-UHFFFAOYSA-N 1-[(2-aminophenyl)methyl]-5-(trifluoromethyl)pyridin-2-one Chemical compound NC1=CC=CC=C1CN1C(=O)C=CC(C(F)(F)F)=C1 ILVHBYJGIOLNMU-UHFFFAOYSA-N 0.000 claims description 7
- FQHNXBPWRWVCFE-UHFFFAOYSA-N 1-[(4-nitrophenyl)methyl]-5-(trifluoromethyl)pyridin-2-one Chemical compound C1=CC([N+](=O)[O-])=CC=C1CN1C(=O)C=CC(C(F)(F)F)=C1 FQHNXBPWRWVCFE-UHFFFAOYSA-N 0.000 claims description 6
- 230000002300 anti-fibrosis Effects 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 6
- 239000011734 sodium Substances 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
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
- 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 5
- 229910019142 PO4 Inorganic materials 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 239000010452 phosphate Substances 0.000 claims description 5
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 5
- 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
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 4
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-L malate(2-) Chemical compound [O-]C(=O)C(O)CC([O-])=O BJEPYKJPYRNKOW-UHFFFAOYSA-L 0.000 claims description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 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
- 125000000171 (C1-C6) haloalkyl group Chemical group 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
- YVLRQILTVNOKDC-UHFFFAOYSA-N 1-[[4-[2-[4-(2-hydroxyethyl)piperazin-1-yl]ethylamino]phenyl]methyl]-5-(trifluoromethyl)pyridin-2-one Chemical compound C1CN(CCO)CCN1CCNC(C=C1)=CC=C1CN1C(=O)C=CC(C(F)(F)F)=C1 YVLRQILTVNOKDC-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
- XUJNEKJLAYXESH-UHFFFAOYSA-N Cysteine Chemical class SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 3
- 150000008558 D-cysteines Chemical class 0.000 claims description 3
- 150000008538 L-cysteines Chemical class 0.000 claims description 3
- 235000019797 dipotassium phosphate Nutrition 0.000 claims description 3
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 3
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 3
- 235000019800 disodium phosphate Nutrition 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001488 sodium phosphate Substances 0.000 claims description 3
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 2
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-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
- 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
- HNKRYZAGBVUXNZ-UHFFFAOYSA-N 1-[[4-[2-(4-methylpiperazin-1-yl)ethylamino]phenyl]methyl]-5-(trifluoromethyl)pyridin-2-one;dihydrochloride Chemical compound Cl.Cl.C1CN(C)CCN1CCNC(C=C1)=CC=C1CN1C(=O)C=CC(C(F)(F)F)=C1 HNKRYZAGBVUXNZ-UHFFFAOYSA-N 0.000 claims description 2
- SJJCQDRGABAVBB-UHFFFAOYSA-N 1-hydroxy-2-naphthoic acid Chemical compound C1=CC=CC2=C(O)C(C(=O)O)=CC=C21 SJJCQDRGABAVBB-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
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-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-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
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 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
- CKLJMWTZIZZHCS-UWTATZPHSA-N D-aspartic acid Chemical compound OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-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
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-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
- 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
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 2
- 239000002253 acid Substances 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
- 229940077388 benzenesulfonate Drugs 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 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
- 239000001506 calcium phosphate Substances 0.000 claims description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 2
- 235000011010 calcium phosphates Nutrition 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
- 239000003814 drug Substances 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
- FCQJEPASRCXVCB-UHFFFAOYSA-L flavianate Chemical compound C1=C(S([O-])(=O)=O)C=C2C([O-])=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FCQJEPASRCXVCB-UHFFFAOYSA-L 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
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 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
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 2
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 2
- 229950005216 napadisilate Drugs 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
- 235000021317 phosphate Nutrition 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
- 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
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 2
- 125000001493 tyrosinyl group Chemical class [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 claims description 2
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims 3
- 229940049920 malate Drugs 0.000 claims 2
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims 1
- FFFHZYDWPBMWHY-GSVOUGTGSA-N D-Homocysteine Chemical class OC(=O)[C@H](N)CCS FFFHZYDWPBMWHY-GSVOUGTGSA-N 0.000 claims 1
- FFFHZYDWPBMWHY-UHFFFAOYSA-N HOMOCYSTEINE Chemical class OC(=O)C(N)CCS FFFHZYDWPBMWHY-UHFFFAOYSA-N 0.000 claims 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical class OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 claims 1
- 101001043818 Mus musculus Interleukin-31 receptor subunit alpha Proteins 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 claims 1
- IWEDIXLBFLAXBO-UHFFFAOYSA-N dicamba Chemical group COC1=C(Cl)C=CC(Cl)=C1C(O)=O IWEDIXLBFLAXBO-UHFFFAOYSA-N 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 34
- 238000001914 filtration Methods 0.000 description 30
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 27
- 239000000706 filtrate Substances 0.000 description 27
- 238000001704 evaporation Methods 0.000 description 26
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- 238000004440 column chromatography Methods 0.000 description 21
- 238000010992 reflux Methods 0.000 description 21
- 239000003480 eluent Substances 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 18
- 239000000047 product Substances 0.000 description 17
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
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- 229960003073 pirfenidone Drugs 0.000 description 14
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 238000001035 drying Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 241000700159 Rattus Species 0.000 description 9
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- 235000020188 drinking water Nutrition 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 229950007655 esilate Drugs 0.000 description 1
- BNKAXGCRDYRABM-UHFFFAOYSA-N ethenyl dihydrogen phosphate Chemical compound OP(O)(=O)OC=C BNKAXGCRDYRABM-UHFFFAOYSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000007519 figuring Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- ZTVZLYBCZNMWCF-UHFFFAOYSA-N homocystine Chemical class [O-]C(=O)C([NH3+])CCSSCCC([NH3+])C([O-])=O ZTVZLYBCZNMWCF-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- ISTFUJWTQAMRGA-UHFFFAOYSA-N iso-beta-costal Natural products C1C(C(=C)C=O)CCC2(C)CCCC(C)=C21 ISTFUJWTQAMRGA-UHFFFAOYSA-N 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000013059 nephrectomy Methods 0.000 description 1
- 125000004971 nitroalkyl group Chemical group 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- CMPQUABWPXYYSH-UHFFFAOYSA-N phenyl phosphate Chemical compound OP(O)(=O)OC1=CC=CC=C1 CMPQUABWPXYYSH-UHFFFAOYSA-N 0.000 description 1
- XUYJLQHKOGNDPB-UHFFFAOYSA-N phosphonoacetic acid Chemical compound OC(=O)CP(O)(O)=O XUYJLQHKOGNDPB-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011158 quantitative evaluation Methods 0.000 description 1
- 230000036647 reaction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 210000000574 retroperitoneal space Anatomy 0.000 description 1
- 230000036573 scar formation Effects 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 210000004926 tubular epithelial cell Anatomy 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910043502 | 2009-05-25 | ||
| PCT/CN2010/073131 WO2010135976A1 (zh) | 2009-05-25 | 2010-05-24 | 1-（取代苄基）-5-三氟甲基-2-（1h）吡啶酮化合物及其盐，其制备方法及其用途 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DK2474533T3 true DK2474533T3 (en) | 2015-05-18 |
Family
ID=43222161
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK10780057.5T DK2474533T3 (en) | 2009-05-25 | 2010-05-24 | Preparation of 1- (substituted benzyl) -5-TRIFLUOROMETYL-2- (1H) pyridone compounds and their salts and their use |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US8377932B2 (https=) |
| EP (1) | EP2474533B1 (https=) |
| JP (1) | JP5722883B2 (https=) |
| KR (1) | KR101478133B1 (https=) |
| CN (1) | CN102149683B (https=) |
| AU (1) | AU2010252451B2 (https=) |
| DK (1) | DK2474533T3 (https=) |
| ES (1) | ES2536200T3 (https=) |
| WO (1) | WO2010135976A1 (https=) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102099036B (zh) | 2008-06-03 | 2015-05-27 | 英特芒尼公司 | 用于治疗炎性疾患和纤维化疾患的化合物和方法 |
| JP5924984B2 (ja) * | 2012-03-06 | 2016-05-25 | 国立大学法人東京農工大学 | トリフルオロメチルピリジノン化合物およびその製造方法 |
| BR112014030284B1 (pt) | 2012-07-18 | 2021-11-30 | Sunshine Lake Pharma Co., Ltd | Composto, composição farmacêutica, e, uso de um composto ou de uma composição farmacêutica |
| AR092742A1 (es) | 2012-10-02 | 2015-04-29 | Intermune Inc | Piridinonas antifibroticas |
| KR20150018127A (ko) * | 2013-08-09 | 2015-02-23 | 삼성전자주식회사 | 디스플레이 장치 및 그 방법 |
| US9902712B2 (en) | 2013-12-19 | 2018-02-27 | Sunshine Lake Pharma Co., Ltd. | Nitrogenous heterocyclic derivatives and their application in drugs |
| MX382781B (es) | 2014-04-02 | 2025-03-13 | Intermune Inc | Piridinonas anti-fibroticas. |
| CN106466318B (zh) * | 2015-08-21 | 2019-01-01 | 中南大学 | 1-杂环取代苄基吡啶酮类化合物在制备治疗糖尿病肾病药物中的应用 |
| CN107663167A (zh) * | 2016-10-19 | 2018-02-06 | 广州南新制药有限公司 | 1‑（取代苄基）‑5‑三氟甲基‑2(1h)‑吡啶酮盐酸盐的晶型及制备方法 |
| CN107652228B (zh) * | 2016-10-28 | 2020-04-14 | 广州南新制药有限公司 | 抗肾纤维化药物1-（取代苄基）-5-三氟甲基-2(1h)-吡啶酮盐酸盐的合成方法 |
| CN113456642B (zh) * | 2021-07-09 | 2022-09-06 | 中南大学 | 一种美氟尼酮在制备治疗急性肾损伤药物中的应用 |
| WO2023168649A1 (zh) * | 2022-03-10 | 2023-09-14 | 广州南新制药有限公司 | 一种美氟尼酮盐酸盐的制备方法 |
| WO2023168650A1 (zh) * | 2022-03-10 | 2023-09-14 | 广州南新制药有限公司 | 一种美氟尼酮晶型的制备方法 |
Family Cites Families (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3839346A (en) | 1972-12-18 | 1974-10-01 | Affiliated Med Res | N-substituted pyridone and general method for preparing pyridones |
| US4052509A (en) | 1972-12-18 | 1977-10-04 | Affiliated Medical Research, Inc. | Method for reducing serum uric acid levels |
| US4042699A (en) | 1972-12-18 | 1977-08-16 | Affiliated Medical Research, Inc. | Method for reducing serum glucose levels |
| GB8523126D0 (en) * | 1985-09-19 | 1985-10-23 | Ici Plc | Aryl pyridones |
| GB8621217D0 (en) | 1986-09-03 | 1986-10-08 | Ici Plc | Chemical compounds |
| GB8825314D0 (en) | 1988-10-28 | 1988-11-30 | Ici Plc | Chemical compounds |
| GB9006479D0 (en) | 1989-04-17 | 1990-05-23 | Ici Plc | Novel compounds |
| US5310562A (en) | 1989-11-22 | 1994-05-10 | Margolin Solomon B | Composition and method for reparation and prevention of fibrotic lesions |
| US5518729A (en) | 1989-11-22 | 1996-05-21 | Margolin; Solomon B. | Compositions and methods for reparation and prevention of fibrotic lesions |
| US5716632A (en) | 1989-11-22 | 1998-02-10 | Margolin; Solomon B. | Compositions and methods for reparation and prevention of fibrotic lesions |
| US5238906A (en) | 1990-11-27 | 1993-08-24 | Sumitomo Chemical Company, Limited | Pyridone derivatives and use |
| DE4343528A1 (de) | 1993-12-16 | 1995-06-22 | Schering Ag | Zweifach heterocyclisch substituierte Benzole und Pyridine, Verfahren zu ihrer Herstellung und ihre Verwendung als Schädlingsbekämpfungsmittel |
| ATE448784T1 (de) * | 2002-02-14 | 2009-12-15 | Pharmacia Corp | Substituierte pyridinone als modulatoren für p38 map kinase |
| CN1218942C (zh) * | 2002-06-11 | 2005-09-14 | 中南大学湘雅医学院 | 抗纤维化吡啶酮化合物及其生产工艺方法 |
| US7166603B2 (en) * | 2003-07-23 | 2007-01-23 | Bristol-Myers Squibb Co. | Dihydropyrimidone inhibitors of calcium channel function |
| GB0324159D0 (en) * | 2003-10-15 | 2003-11-19 | Glaxo Group Ltd | Novel compounds |
| CN100358872C (zh) | 2003-11-14 | 2008-01-02 | 上海睿星基因技术有限公司 | 吡啶酮衍生物及其应用 |
| DE102004027359A1 (de) | 2004-06-04 | 2005-12-29 | Abbott Gmbh & Co. Kg | Pyridin-2-onverbindungen und deren Verwendung |
| ES2600460T3 (es) | 2005-05-10 | 2017-02-09 | Intermune, Inc. | Derivados de piridona-2-ona como moduladores del sistema de proteína cinasa activada por estrés |
| CN101237869A (zh) * | 2005-05-10 | 2008-08-06 | 英特芒尼公司 | 用于调节应激-活化蛋白激酶系统的吡啶酮衍生物 |
| WO2007053610A2 (en) | 2005-11-01 | 2007-05-10 | The Regents Of The University Of California | Methods of treating atrial fibrillation wtih pirfenidone |
| KR20080076968A (ko) | 2005-11-23 | 2008-08-20 | 인터뮨, 인크. | 스트레스-활성화 단백질 키나제 시스템을 조절하는 방법 |
| CN101235030A (zh) * | 2007-01-30 | 2008-08-06 | 中南大学 | 1-取代-5-三氟甲基-2-(1h)吡啶酮化合物、制备方法及其用途 |
| US20090118135A1 (en) | 2007-06-08 | 2009-05-07 | The Burnham Institute | Methods and compounds for regulating apoptosis |
| CN101371833A (zh) | 2007-08-23 | 2009-02-25 | 中南大学 | 1-芳基-2(1h)-吡啶酮类化合物在制备治疗皮肤瘙痒药物中的应用 |
| CN102099036B (zh) | 2008-06-03 | 2015-05-27 | 英特芒尼公司 | 用于治疗炎性疾患和纤维化疾患的化合物和方法 |
| AP2011005824A0 (en) | 2009-01-26 | 2011-08-31 | Intermune Inc | Methods for treating acute myocardial infarctions and associated disorders. |
| WO2010135470A1 (en) | 2009-05-19 | 2010-11-25 | Intermune, Inc. | Pifenidone derivatives for treating bronchial asthma |
-
2010
- 2010-05-24 KR KR1020117030958A patent/KR101478133B1/ko not_active Expired - Fee Related
- 2010-05-24 EP EP10780057.5A patent/EP2474533B1/en not_active Not-in-force
- 2010-05-24 US US13/322,153 patent/US8377932B2/en not_active Expired - Fee Related
- 2010-05-24 ES ES10780057.5T patent/ES2536200T3/es active Active
- 2010-05-24 JP JP2012512189A patent/JP5722883B2/ja not_active Expired - Fee Related
- 2010-05-24 AU AU2010252451A patent/AU2010252451B2/en not_active Ceased
- 2010-05-24 DK DK10780057.5T patent/DK2474533T3/en active
- 2010-05-24 WO PCT/CN2010/073131 patent/WO2010135976A1/zh not_active Ceased
- 2010-05-24 CN CN2010800025776A patent/CN102149683B/zh active Active
Also Published As
| Publication number | Publication date |
|---|---|
| AU2010252451B2 (en) | 2014-04-03 |
| CN102149683A (zh) | 2011-08-10 |
| AU2010252451A1 (en) | 2011-12-15 |
| KR101478133B1 (ko) | 2014-12-31 |
| ES2536200T3 (es) | 2015-05-21 |
| KR20120060785A (ko) | 2012-06-12 |
| EP2474533B1 (en) | 2015-02-25 |
| EP2474533A1 (en) | 2012-07-11 |
| WO2010135976A1 (zh) | 2010-12-02 |
| JP5722883B2 (ja) | 2015-05-27 |
| US8377932B2 (en) | 2013-02-19 |
| HK1166791A1 (en) | 2012-11-09 |
| JP2012527488A (ja) | 2012-11-08 |
| EP2474533A4 (en) | 2012-11-14 |
| CN102149683B (zh) | 2013-10-02 |
| US20120129859A1 (en) | 2012-05-24 |
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