ES2200324T3 - Nuevos derivados de pirimidina con actividad antisecretora, su procedimiento de preparacion, y composiciones farmaceuticas que los contienen. - Google Patents
Nuevos derivados de pirimidina con actividad antisecretora, su procedimiento de preparacion, y composiciones farmaceuticas que los contienen.Info
- Publication number
- ES2200324T3 ES2200324T3 ES98911242T ES98911242T ES2200324T3 ES 2200324 T3 ES2200324 T3 ES 2200324T3 ES 98911242 T ES98911242 T ES 98911242T ES 98911242 T ES98911242 T ES 98911242T ES 2200324 T3 ES2200324 T3 ES 2200324T3
- Authority
- ES
- Spain
- Prior art keywords
- methyl
- pyrimidine
- phenyl
- tetrahydro
- amino
- 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 - Lifetime
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 10
- 238000000034 method Methods 0.000 title description 98
- 238000002360 preparation method Methods 0.000 title description 27
- 230000000694 effects Effects 0.000 title description 14
- -1 1-naphthyl-methyl Chemical group 0.000 claims abstract description 199
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 52
- 239000001257 hydrogen Substances 0.000 claims abstract description 52
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 34
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 17
- 150000003230 pyrimidines Chemical class 0.000 claims abstract description 17
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 15
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 14
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 13
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 9
- 229910052736 halogen Chemical group 0.000 claims abstract description 9
- 150000002367 halogens Chemical group 0.000 claims abstract description 9
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims abstract description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 4
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims abstract description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 4
- 125000004372 methylthioethyl group Chemical group [H]C([H])([H])SC([H])([H])C([H])([H])* 0.000 claims abstract description 4
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 208
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 claims description 16
- 108010083204 Proton Pumps Proteins 0.000 claims description 15
- MXMLBPWGHPXZRW-UHFFFAOYSA-N [2-(4-fluoroanilino)-5-methyl-6-(1-methyl-3,4-dihydro-1h-isoquinolin-2-yl)pyrimidin-4-yl]methanol Chemical compound C1CC2=CC=CC=C2C(C)N1C(C(=C(CO)N=1)C)=NC=1NC1=CC=C(F)C=C1 MXMLBPWGHPXZRW-UHFFFAOYSA-N 0.000 claims description 10
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 9
- FEOTVFZHCHZXJX-UHFFFAOYSA-N 2-[2-(4-fluoroanilino)-5,6-dimethylpyrimidin-4-yl]-1-methyl-3,4-dihydro-1h-isoquinolin-6-ol Chemical compound C1CC2=CC(O)=CC=C2C(C)N1C(C(=C(C)N=1)C)=NC=1NC1=CC=C(F)C=C1 FEOTVFZHCHZXJX-UHFFFAOYSA-N 0.000 claims description 7
- IQXXEPZFOOTTBA-UHFFFAOYSA-N 1-benzylpiperazine Chemical compound C=1C=CC=CC=1CN1CCNCC1 IQXXEPZFOOTTBA-UHFFFAOYSA-N 0.000 claims description 6
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 5
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 5
- HAASDWOKLDBJAK-UHFFFAOYSA-N [2-(4-fluoroanilino)-4-methyl-6-(1-methyl-3,4-dihydro-1h-isoquinolin-2-yl)pyrimidin-5-yl]methanol Chemical compound C1CC2=CC=CC=C2C(C)N1C(C(=C(C)N=1)CO)=NC=1NC1=CC=C(F)C=C1 HAASDWOKLDBJAK-UHFFFAOYSA-N 0.000 claims description 5
- 239000000654 additive Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 101100079984 Caenorhabditis elegans nhr-9 gene Proteins 0.000 claims description 3
- 208000008469 Peptic Ulcer Diseases 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 3
- 239000013037 reversible inhibitor Substances 0.000 claims description 2
- PFRMYBINSXRVBK-UHFFFAOYSA-N 4-(3,4-dihydro-1H-isoquinolin-2-yl)-5,6-dimethyl-2-(4-methyl-1,3-thiazol-2-yl)-2H-pyrimidin-1-amine Chemical compound CC=1C(=NC(N(C=1C)N)C=1SC=C(N=1)C)N1CC2=CC=CC=C2CC1 PFRMYBINSXRVBK-UHFFFAOYSA-N 0.000 claims 1
- MELAICPHFIDWPI-LUTIACGYSA-N [2-(4-fluoroanilino)-5-methyl-6-(1-methyl-3,4-dihydro-1h-isoquinolin-2-yl)pyrimidin-4-yl]methyl (2s)-2-amino-3-methylbutanoate Chemical compound N=1C(N2C(C3=CC=CC=C3CC2)C)=C(C)C(COC(=O)[C@@H](N)C(C)C)=NC=1NC1=CC=C(F)C=C1 MELAICPHFIDWPI-LUTIACGYSA-N 0.000 claims 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 276
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 234
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 156
- 238000005481 NMR spectroscopy Methods 0.000 description 150
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 123
- 239000000243 solution Substances 0.000 description 115
- 229940086542 triethylamine Drugs 0.000 description 78
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 64
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 46
- 238000005160 1H NMR spectroscopy Methods 0.000 description 46
- 238000002844 melting Methods 0.000 description 46
- 230000008018 melting Effects 0.000 description 46
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 41
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 37
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 239000002253 acid Substances 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 27
- 230000002829 reductive effect Effects 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 23
- 239000007787 solid Substances 0.000 description 22
- 239000011541 reaction mixture Substances 0.000 description 21
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 20
- 239000012044 organic layer Substances 0.000 description 18
- 239000000203 mixture Substances 0.000 description 16
- 239000000725 suspension Substances 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 14
- SCFDZWASOUFVBE-UHFFFAOYSA-N 2-(2-chloro-5,6-dimethylpyrimidin-4-yl)-1-methyl-3,4-dihydro-1h-isoquinoline Chemical compound C1CC2=CC=CC=C2C(C)N1C1=NC(Cl)=NC(C)=C1C SCFDZWASOUFVBE-UHFFFAOYSA-N 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 12
- 239000010410 layer Substances 0.000 description 12
- BORJVRHSXJQZQT-UHFFFAOYSA-N 2-(2-chloro-5,6-dimethylpyrimidin-4-yl)-3,4-dihydro-1h-isoquinoline Chemical compound CC1=NC(Cl)=NC(N2CC3=CC=CC=C3CC2)=C1C BORJVRHSXJQZQT-UHFFFAOYSA-N 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 238000002156 mixing Methods 0.000 description 10
- UWYZHKAOTLEWKK-UHFFFAOYSA-N tetrahydro-isoquinoline Natural products C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 10
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 229960000381 omeprazole Drugs 0.000 description 8
- DYXPYDSFGXASRO-UHFFFAOYSA-N 2-[2-(4-fluoroanilino)-5,6-dimethylpyrimidin-4-yl]-1-methyl-3,4-dihydro-1h-isoquinolin-7-ol Chemical compound C1CC2=CC=C(O)C=C2C(C)N1C(C(=C(C)N=1)C)=NC=1NC1=CC=C(F)C=C1 DYXPYDSFGXASRO-UHFFFAOYSA-N 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 7
- BFXIDUSEHNCLTP-UHFFFAOYSA-N 2,4-dichloro-5,6-dimethylpyrimidine Chemical compound CC1=NC(Cl)=NC(Cl)=C1C BFXIDUSEHNCLTP-UHFFFAOYSA-N 0.000 description 6
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- SZXBQTSZISFIAO-ZETCQYMHSA-N (2s)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)OC(C)(C)C SZXBQTSZISFIAO-ZETCQYMHSA-N 0.000 description 5
- SCPUERXVEBRZMV-UHFFFAOYSA-N 2,4-dichloro-6-(methoxymethyl)-5-methylpyrimidine Chemical compound COCC1=NC(Cl)=NC(Cl)=C1C SCPUERXVEBRZMV-UHFFFAOYSA-N 0.000 description 5
- DQXIHLOJSHOJMV-UHFFFAOYSA-N 2-[2-chloro-6-(methoxymethyl)-5-methylpyrimidin-4-yl]-1-methyl-3,4-dihydro-1h-isoquinoline Chemical compound COCC1=NC(Cl)=NC(N2C(C3=CC=CC=C3CC2)C)=C1C DQXIHLOJSHOJMV-UHFFFAOYSA-N 0.000 description 5
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 210000004051 gastric juice Anatomy 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- ZYJPUMXJBDHSIF-NSHDSACASA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZYJPUMXJBDHSIF-NSHDSACASA-N 0.000 description 4
- NRHPBXWENYCPFC-UHFFFAOYSA-N 2-[2-chloro-6-(methoxymethyl)-5-methylpyrimidin-4-yl]-3,4-dihydro-1h-isoquinoline Chemical compound COCC1=NC(Cl)=NC(N2CC3=CC=CC=C3CC2)=C1C NRHPBXWENYCPFC-UHFFFAOYSA-N 0.000 description 4
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 4
- FSCCJTKQQGRDAT-UHFFFAOYSA-N 6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline Chemical compound CC1NCCC2=CC(OC)=CC=C21 FSCCJTKQQGRDAT-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 4
- ATDWJOOPFDQZNK-UHFFFAOYSA-N N-acetyltyramine Chemical compound CC(=O)NCCC1=CC=C(O)C=C1 ATDWJOOPFDQZNK-UHFFFAOYSA-N 0.000 description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 4
- 239000012346 acetyl chloride Substances 0.000 description 4
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 4
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- PZTJJIUPKAYECR-UHFFFAOYSA-N n-(4-chloro-5,6-dimethylpyrimidin-2-yl)-4-methyl-1,3-thiazol-2-amine Chemical compound CC1=CSC(NC=2N=C(Cl)C(C)=C(C)N=2)=N1 PZTJJIUPKAYECR-UHFFFAOYSA-N 0.000 description 4
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 230000002441 reversible effect Effects 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- YXLCLPJXNVPJQL-UHFFFAOYSA-N 1-methoxy-1-methyl-3,4-dihydro-2h-isoquinoline Chemical compound C1=CC=C2C(OC)(C)NCCC2=C1 YXLCLPJXNVPJQL-UHFFFAOYSA-N 0.000 description 3
- QPILYVQSKNWRDD-UHFFFAOYSA-N 1-methyl-1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2C(C)NCCC2=C1 QPILYVQSKNWRDD-UHFFFAOYSA-N 0.000 description 3
- QLJDWNGVIXFBPK-UHFFFAOYSA-N 2-[[4,5-dimethyl-6-(1-methyl-3,4-dihydro-1h-isoquinolin-2-yl)pyrimidin-2-yl]amino]-5-fluorophenol Chemical compound C1CC2=CC=CC=C2C(C)N1C(C(=C(C)N=1)C)=NC=1NC1=CC=C(F)C=C1O QLJDWNGVIXFBPK-UHFFFAOYSA-N 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
- ICGYBJNONRDZOP-UHFFFAOYSA-N 2-morpholin-4-ium-4-ylacetic acid;chloride Chemical compound Cl.OC(=O)CN1CCOCC1 ICGYBJNONRDZOP-UHFFFAOYSA-N 0.000 description 3
- WKVJGLBBPPFCGD-UHFFFAOYSA-N 2-piperidin-1-ium-1-ylacetic acid;chloride Chemical compound Cl.OC(=O)CN1CCCCC1 WKVJGLBBPPFCGD-UHFFFAOYSA-N 0.000 description 3
- KIIKGHGBAFSTOE-UHFFFAOYSA-N 4-(5,8-dimethoxy-1-methyl-3,4-dihydro-1h-isoquinolin-2-yl)-n-(4-fluorophenyl)-5,6-dimethylpyrimidin-2-amine;hydrochloride Chemical compound Cl.C1CC=2C(OC)=CC=C(OC)C=2C(C)N1C(C(=C(C)N=1)C)=NC=1NC1=CC=C(F)C=C1 KIIKGHGBAFSTOE-UHFFFAOYSA-N 0.000 description 3
- VMIDQQQAEQXCDJ-UHFFFAOYSA-N 7-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline Chemical compound C1CNC(C)C2=CC(OC)=CC=C21 VMIDQQQAEQXCDJ-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 150000001263 acyl chlorides Chemical class 0.000 description 3
- 230000001262 anti-secretory effect Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- MDTAQVYGCCBSQV-UHFFFAOYSA-N n-(4-fluorophenyl)-4-(5-methoxy-1-methyl-3,4-dihydro-1h-isoquinolin-2-yl)-5,6-dimethylpyrimidin-2-amine;hydrochloride Chemical compound Cl.C1CC=2C(OC)=CC=CC=2C(C)N1C(C(=C(C)N=1)C)=NC=1NC1=CC=C(F)C=C1 MDTAQVYGCCBSQV-UHFFFAOYSA-N 0.000 description 3
- UYXOVNNIRHAKPN-UHFFFAOYSA-N n-(4-fluorophenyl)-4-(7-methoxy-1-methyl-3,4-dihydro-1h-isoquinolin-2-yl)-5,6-dimethylpyrimidin-2-amine;hydrochloride Chemical compound Cl.CC1C2=CC(OC)=CC=C2CCN1C(C(=C(C)N=1)C)=NC=1NC1=CC=C(F)C=C1 UYXOVNNIRHAKPN-UHFFFAOYSA-N 0.000 description 3
- VTSRQYDCXGTZMF-UHFFFAOYSA-N n-(4-fluorophenyl)-4-[1-(methoxymethyl)-3,4-dihydro-1h-isoquinolin-2-yl]-5,6-dimethylpyrimidin-2-amine Chemical compound C1CC2=CC=CC=C2C(COC)N1C(C(=C(C)N=1)C)=NC=1NC1=CC=C(F)C=C1 VTSRQYDCXGTZMF-UHFFFAOYSA-N 0.000 description 3
- 229940117803 phenethylamine Drugs 0.000 description 3
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- HHGRZHRHYAEMKG-RQPQIBMQSA-N [2-[2-(4-fluoroanilino)-5,6-dimethylpyrimidin-4-yl]-1-methyl-3,4-dihydro-1h-isoquinolin-7-yl] (2s)-2-amino-3-methylbutanoate;dihydrochloride Chemical compound Cl.Cl.CC1C2=CC(OC(=O)[C@@H](N)C(C)C)=CC=C2CCN1C(C(=C(C)N=1)C)=NC=1NC1=CC=C(F)C=C1 HHGRZHRHYAEMKG-RQPQIBMQSA-N 0.000 description 1
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- 239000012047 saturated solution Substances 0.000 description 1
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- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
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- 229960003010 sodium sulfate Drugs 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR19970010863 | 1997-03-27 | ||
| KR19970010862 | 1997-03-27 | ||
| KR9710863 | 1997-03-27 | ||
| KR9710862 | 1997-03-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2200324T3 true ES2200324T3 (es) | 2004-03-01 |
Family
ID=26632616
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES98911242T Expired - Lifetime ES2200324T3 (es) | 1997-03-27 | 1998-03-24 | Nuevos derivados de pirimidina con actividad antisecretora, su procedimiento de preparacion, y composiciones farmaceuticas que los contienen. |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US6352993B1 (OSRAM) |
| EP (1) | EP1015444B1 (OSRAM) |
| JP (1) | JP3176379B2 (OSRAM) |
| KR (1) | KR100278857B1 (OSRAM) |
| CN (1) | CN1118464C (OSRAM) |
| AR (1) | AR012181A1 (OSRAM) |
| AT (1) | ATE241613T1 (OSRAM) |
| AU (1) | AU720385B2 (OSRAM) |
| BR (1) | BR9808070A (OSRAM) |
| CA (1) | CA2284795C (OSRAM) |
| DE (1) | DE69815126T2 (OSRAM) |
| DK (1) | DK1015444T3 (OSRAM) |
| ES (1) | ES2200324T3 (OSRAM) |
| HU (1) | HUP0000851A3 (OSRAM) |
| IN (1) | IN188411B (OSRAM) |
| PT (1) | PT1015444E (OSRAM) |
| RU (1) | RU2203894C2 (OSRAM) |
| TR (1) | TR199902383T2 (OSRAM) |
| TW (1) | TW542831B (OSRAM) |
| UY (1) | UY24938A1 (OSRAM) |
| WO (1) | WO1998043968A1 (OSRAM) |
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| KR100272471B1 (ko) | 1998-11-17 | 2000-11-15 | 김선진 | 신규의 피리미딘 유도체 및 그의 제조방법 |
| US6852739B1 (en) | 1999-02-26 | 2005-02-08 | Nitromed Inc. | Methods using proton pump inhibitors and nitric oxide donors |
| AR038368A1 (es) | 2002-02-01 | 2005-01-12 | Novartis Ag | Compuestos n-pirimidin-2-il-aminas sustituidas como inhibidores de ige, una composicion farmaceutica y el uso de dichos compuestos para la preparacion de un medicamento |
| EP1534278A4 (en) | 2002-08-01 | 2006-09-06 | Nitromed Inc | NITROSED PROTONATE PUMP INHIBITORS, COMPOSITIONS AND USE METHOD |
| JP2006528640A (ja) * | 2003-07-22 | 2006-12-21 | ニューロジェン・コーポレーション | 置換ピリジン−２−イルアミン類縁体 |
| WO2005039506A2 (en) * | 2003-10-24 | 2005-05-06 | Exelixis, Inc. | P70s6 kinase modulators and method of use |
| US20080280944A1 (en) | 2003-11-03 | 2008-11-13 | Paula Fernstrom | Imidazo[1,2-A]Pyridine Derivatives For The Treatment Of Silent Gastro-Esophageal Reflux |
| KR101122376B1 (ko) * | 2005-03-09 | 2012-03-26 | 주식회사유한양행 | 신규의 5,6-다이메틸피리미딘 유도체 및 그의 제조방법 |
| US20090124645A1 (en) * | 2005-10-14 | 2009-05-14 | Neurosearch A/S | Novel Pyrimidine-2,4-Diamine Derivatives and their Use as Modulators of Small-Conductance Calcium-Activated Potassium Channels |
| JP4946482B2 (ja) | 2007-02-08 | 2012-06-06 | 船井電機株式会社 | 緩衝用梱包材及びｔｖ受像機の緩衝用梱包材 |
| US8367684B2 (en) * | 2007-06-13 | 2013-02-05 | Valeant Pharmaceuticals International | Derivatives of 4-(N-azacycloalkyl) anilides as potassium channel modulators |
| MY153606A (en) | 2008-08-05 | 2015-02-27 | Daiichi Sankyo Co Ltd | Imidazopyridin-2-one derivatives |
| GB0908394D0 (en) | 2009-05-15 | 2009-06-24 | Univ Leuven Kath | Novel viral replication inhibitors |
| GB0913636D0 (en) | 2009-08-05 | 2009-09-16 | Univ Leuven Kath | Novel viral replication inhibitors |
| MX2013005478A (es) | 2010-11-15 | 2013-08-29 | Univ Leuven Kath | Compuestos heterociclicos condensados antivirales. |
| JP5980236B2 (ja) | 2011-02-25 | 2016-08-31 | ユーハン・コーポレイションＹＵＨＡＮ Ｃｏｒｐｏｒａｔｉｏｎ | ジアミノピリミジン誘導体及びその製造方法 |
| EP2836486B1 (en) * | 2012-02-17 | 2017-10-04 | AbbVie Inc. | Diaminopyrimidines useful as inhibitors of the human respiratory syncytial virus (rsv) |
| KR102080782B1 (ko) | 2012-05-29 | 2020-02-27 | 모멘티브 퍼포먼스 머티리얼즈 게엠베하 | 이소시아네이토 실란의 제조 |
| NZ708909A (en) | 2012-11-21 | 2019-11-29 | Ptc Therapeutics Inc | Substituted reverse pyrimidine bmi-1 inhibitors |
| MX2015011898A (es) | 2013-03-13 | 2016-05-05 | Genentech Inc | Compuestos de pirazolo y usos de los mismos. |
| EP3039015B1 (en) | 2013-08-30 | 2019-10-30 | PTC Therapeutics, Inc. | Substituted pyrimidine bmi-1 inhibitors |
| EP3055301B1 (en) * | 2013-10-07 | 2019-11-20 | Kadmon Corporation, LLC | (2-(5-isoindolin-2-yl)pyrimidin-4-yl)-amine derivatives as rho kinase inhibitors for treating autoimmune diseases |
| EP3071553A4 (en) | 2013-11-21 | 2017-08-02 | PTC Therapeutics, Inc. | Substituted pyridine and pyrazine bmi-1 inhibitors |
| CN107206004A (zh) | 2014-10-22 | 2017-09-26 | 德克萨斯大学系统董事会 | 靶向盘状结构域受体1的小分子抑制剂及其用途 |
| CN105669642B (zh) * | 2014-11-19 | 2020-06-09 | 江苏天士力帝益药业有限公司 | 一种盐酸洛氟普啶的制备方法 |
| UA125377C2 (uk) * | 2016-01-04 | 2022-03-02 | Мерк Сероно С.А. | L-валінат карбоксамідного похідного гідроксипропілтіазолідину та його сольова форма, кристалічна поліморфна форма |
| CN110461833A (zh) * | 2017-04-05 | 2019-11-15 | 拜耳作物科学股份公司 | 2-氨基-5-氧基烷基嘧啶衍生物及其用于防治不希望的植物生长的用途 |
| AU2019340402B2 (en) | 2018-08-17 | 2025-04-03 | Ptc Therapeutics, Inc. | Method for treating pancreatic cancer |
| CN114685369B (zh) * | 2022-05-17 | 2024-02-02 | 河南省科学院高新技术研究中心 | 一种利用离子液体制备1-甲基-1,2,3,4-四氢异喹啉的方法 |
Family Cites Families (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4000138A (en) | 1966-03-31 | 1976-12-28 | Imperial Chemical Industries Limited | Organic compounds and compositions containing them |
| GB1182584A (en) | 1966-03-31 | 1970-02-25 | Ici Ltd | Pyrimidine derivates and the use thereof as fungicides |
| US3980781A (en) | 1966-03-31 | 1976-09-14 | Imperial Chemical Industries Limited | Fungicidal composition and method containing 2-amino-pyrimidines |
| US4044136A (en) | 1972-09-09 | 1977-08-23 | Pfizer Inc. | Aminoquinazoline therapeutic agents |
| GB1383409A (en) | 1972-09-09 | 1974-02-12 | Pfizer Ltd | Derivatives of 2-amino- and 4-amino-quinazoline and pharmaceutical compositions containing them |
| US3956495A (en) | 1973-10-30 | 1976-05-11 | Eli Lilly And Company | 2,4-Diaminoquinazolines as antithrombotic agents |
| US4755218A (en) | 1985-12-31 | 1988-07-05 | Monsanto Company | Haloacyl 1-substituted-1,2,3,4-tetrahydro-isoquinolines as herbicide antidotes |
| GB8621425D0 (en) * | 1986-09-05 | 1986-10-15 | Smith Kline French Lab | Compounds |
| IL88507A (en) * | 1987-12-03 | 1993-02-21 | Smithkline Beckman Intercredit | 2,4-diaminoquinazolines, process for their preparation and pharmaceutical compositions comprising them |
| US4966622A (en) | 1988-04-12 | 1990-10-30 | Ciba-Geigy Corporation | N-phenyl-N-pyrimidin-2-ylureas |
| HU206337B (en) * | 1988-12-29 | 1992-10-28 | Mitsui Petrochemical Ind | Process for producing pyrimidine derivatives and pharmaceutical compositions |
| DE3901448A1 (de) | 1989-01-19 | 1990-07-26 | Basf Ag | Emulsionscopolymerisate |
| ES2081863T3 (es) | 1989-03-22 | 1996-03-16 | Ciba Geigy Ag | Plaguicidas. |
| GB8910722D0 (en) | 1989-05-10 | 1989-06-28 | Smithkline Beckman Intercredit | Compounds |
| CA2015981A1 (en) * | 1989-05-10 | 1990-11-10 | Thomas H. Brown | Compounds |
| GB9012592D0 (en) | 1990-06-06 | 1990-07-25 | Smithkline Beecham Intercredit | Compounds |
| ATE124694T1 (de) | 1990-11-06 | 1995-07-15 | Pfizer | Chinazolinderivate um die antitumorwirkung zu verbessern. |
| HUT65177A (en) | 1991-04-17 | 1994-05-02 | Pfizer | Process for producing antitumor activity enhancing pyrimidine derivatives and pharmaceutical preparations containing them |
| US5276186A (en) | 1992-03-11 | 1994-01-04 | Ciba-Geigy Corporation | Process for the production of guanidine derivatives |
| KR0144833B1 (ko) * | 1992-12-28 | 1998-07-15 | 김태훈 | 신규의 퀴나졸린 유도체 및 그의 제조방법 |
| DE69432019T2 (de) * | 1993-08-12 | 2003-11-27 | Astrazeneca Ab, Soedertaelje | Amidin-derivate mit stickstoffoxid-synthease-aktivität |
| DE69408750T2 (de) | 1993-08-26 | 1998-07-23 | Ono Pharmaceutical Co | 4-Aminopyrimidin Derivate |
| RU2153494C2 (ru) | 1993-10-12 | 2000-07-27 | Дзе Дюпон Мерк Фармасьютикал Компани | 1-n-алкил-n-арилпиримидинамины, способ лечения заболеваний, фармацевтическая композиция |
| WO1996005177A1 (en) | 1994-08-13 | 1996-02-22 | Yuhan Corporation | Novel pyrimidine derivatives and processes for the preparation thereof |
| AU712970B2 (en) * | 1996-05-04 | 1999-11-18 | Yuhan Corporation | Process for preparation of pyrimidine derivatives |
-
1998
- 1998-03-23 IN IN724DE1998 patent/IN188411B/en unknown
- 1998-03-24 AU AU65239/98A patent/AU720385B2/en not_active Ceased
- 1998-03-24 EP EP98911242A patent/EP1015444B1/en not_active Expired - Lifetime
- 1998-03-24 BR BR9808070-9A patent/BR9808070A/pt not_active Application Discontinuation
- 1998-03-24 DK DK98911242T patent/DK1015444T3/da active
- 1998-03-24 AT AT98911242T patent/ATE241613T1/de not_active IP Right Cessation
- 1998-03-24 DE DE69815126T patent/DE69815126T2/de not_active Expired - Fee Related
- 1998-03-24 RU RU99122603/04A patent/RU2203894C2/ru not_active IP Right Cessation
- 1998-03-24 WO PCT/KR1998/000058 patent/WO1998043968A1/en active IP Right Grant
- 1998-03-24 TR TR1999/02383T patent/TR199902383T2/xx unknown
- 1998-03-24 PT PT98911242T patent/PT1015444E/pt unknown
- 1998-03-24 US US09/381,814 patent/US6352993B1/en not_active Expired - Fee Related
- 1998-03-24 CN CN98803765A patent/CN1118464C/zh not_active Expired - Fee Related
- 1998-03-24 ES ES98911242T patent/ES2200324T3/es not_active Expired - Lifetime
- 1998-03-24 HU HU0000851A patent/HUP0000851A3/hu unknown
- 1998-03-24 JP JP54148798A patent/JP3176379B2/ja not_active Expired - Fee Related
- 1998-03-24 CA CA002284795A patent/CA2284795C/en not_active Expired - Fee Related
- 1998-03-26 UY UY24938A patent/UY24938A1/es not_active IP Right Cessation
- 1998-03-26 AR ARP980101380A patent/AR012181A1/es unknown
- 1998-03-27 TW TW087104605A patent/TW542831B/zh not_active IP Right Cessation
- 1998-03-27 KR KR1019980010754A patent/KR100278857B1/ko not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| HUP0000851A1 (hu) | 2001-04-28 |
| RU2203894C2 (ru) | 2003-05-10 |
| KR19980080789A (ko) | 1998-11-25 |
| WO1998043968A1 (en) | 1998-10-08 |
| AU720385B2 (en) | 2000-06-01 |
| CN1118464C (zh) | 2003-08-20 |
| JP3176379B2 (ja) | 2001-06-18 |
| EP1015444A1 (en) | 2000-07-05 |
| AU6523998A (en) | 1998-10-22 |
| UY24938A1 (es) | 2001-01-31 |
| EP1015444B1 (en) | 2003-05-28 |
| CA2284795A1 (en) | 1998-10-08 |
| CA2284795C (en) | 2004-01-20 |
| PT1015444E (pt) | 2003-10-31 |
| ATE241613T1 (de) | 2003-06-15 |
| DK1015444T3 (da) | 2003-08-18 |
| DE69815126T2 (de) | 2004-04-08 |
| JP2000513014A (ja) | 2000-10-03 |
| TR199902383T2 (xx) | 2000-06-21 |
| AR012181A1 (es) | 2000-09-27 |
| BR9808070A (pt) | 2000-03-08 |
| CN1251586A (zh) | 2000-04-26 |
| US6352993B1 (en) | 2002-03-05 |
| KR100278857B1 (ko) | 2001-01-15 |
| TW542831B (en) | 2003-07-21 |
| IN188411B (OSRAM) | 2002-09-21 |
| DE69815126D1 (de) | 2003-07-03 |
| HUP0000851A3 (en) | 2002-04-29 |
| HK1026418A1 (en) | 2000-12-15 |
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