HU199454B - Process for producing dihydropyridine derivatives and pharmaceutical compositions comprising these compounds as active ingredient - Google Patents
Process for producing dihydropyridine derivatives and pharmaceutical compositions comprising these compounds as active ingredient Download PDFInfo
- Publication number
- HU199454B HU199454B HU874578A HU457887A HU199454B HU 199454 B HU199454 B HU 199454B HU 874578 A HU874578 A HU 874578A HU 457887 A HU457887 A HU 457887A HU 199454 B HU199454 B HU 199454B
- Authority
- HU
- Hungary
- Prior art keywords
- formula
- methyl
- phenyl
- compound
- substituted
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims description 145
- 238000000034 method Methods 0.000 title claims description 30
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 7
- 125000004925 dihydropyridyl group Chemical class N1(CC=CC=C1)* 0.000 title claims description 4
- 239000004480 active ingredient Substances 0.000 title description 6
- 229940085304 dihydropyridine derivative selective calcium channel blockers with mainly vascular effects Drugs 0.000 title description 4
- -1 amidinoacetic acid ester Chemical class 0.000 claims description 103
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 47
- 150000003839 salts Chemical class 0.000 claims description 34
- 238000002360 preparation method Methods 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 239000002253 acid Substances 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 16
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 claims description 15
- 125000005843 halogen group Chemical group 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 239000007858 starting material Substances 0.000 claims description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 239000012458 free base Substances 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 8
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 8
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 8
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 7
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 7
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 6
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 6
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- AZVXJAWDAQYTEB-UHFFFAOYSA-N 2-amino-3-(1-benzhydrylazetidin-3-yl)-4-(2,3-dichlorophenyl)-6-methyl-5-propan-2-ylpiperidine-3,5-dicarboxylic acid Chemical compound C=1C=CC(Cl)=C(Cl)C=1C1C(C(C)C)(C(O)=O)C(C)NC(N)C1(C(O)=O)C(C1)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 AZVXJAWDAQYTEB-UHFFFAOYSA-N 0.000 claims description 3
- VMKJYXINEWTAEI-UHFFFAOYSA-N 2-amino-3-(1-benzhydrylpiperidin-3-yl)-6-methyl-4-(3-nitrophenyl)-5-propan-2-ylpiperidine-3,5-dicarboxylic acid Chemical compound C=1C=CC([N+]([O-])=O)=CC=1C1C(C(C)C)(C(O)=O)C(C)NC(N)C1(C(O)=O)C(C1)CCCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 VMKJYXINEWTAEI-UHFFFAOYSA-N 0.000 claims description 3
- ZUSWDTWYONAOPH-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]hydrazine;hydrochloride Chemical group [Cl-].[NH3+]NC1=CC=CC=C1C(F)(F)F ZUSWDTWYONAOPH-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 3
- JKGFDIUOKNLPCB-UHFFFAOYSA-N 2-amino-3-(1-benzhydrylazetidin-3-yl)-5-ethyl-6-methyl-4-(3-nitrophenyl)piperidine-3,5-dicarboxylic acid Chemical compound C=1C=CC([N+]([O-])=O)=CC=1C1C(CC)(C(O)=O)C(C)NC(N)C1(C(O)=O)C(C1)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 JKGFDIUOKNLPCB-UHFFFAOYSA-N 0.000 claims description 2
- LFXNFCPJTVNECS-UHFFFAOYSA-N 2-amino-3-(1-benzhydrylazetidin-3-yl)-6-methyl-4-(3-nitrophenyl)-5-propan-2-ylpiperidine-3,5-dicarboxylic acid Chemical compound C=1C=CC([N+]([O-])=O)=CC=1C1C(C(C)C)(C(O)=O)C(C)NC(N)C1(C(O)=O)C(C1)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 LFXNFCPJTVNECS-UHFFFAOYSA-N 0.000 claims description 2
- FWPPGCUUNGPTHT-UHFFFAOYSA-N 2-amino-3-(1-benzhydrylpyrrolidin-3-yl)-5-hexyl-6-methyl-4-(3-nitrophenyl)piperidine-3,5-dicarboxylic acid Chemical compound C=1C=CC([N+]([O-])=O)=CC=1C1C(CCCCCC)(C(O)=O)C(C)NC(N)C1(C(O)=O)C(C1)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 FWPPGCUUNGPTHT-UHFFFAOYSA-N 0.000 claims description 2
- IFEDVZDFHCQPAC-UHFFFAOYSA-N 2-amino-3-(1-benzhydrylpyrrolidin-3-yl)-6-methyl-4-(3-nitrophenyl)-5-propan-2-ylpiperidine-3,5-dicarboxylic acid Chemical compound C=1C=CC([N+]([O-])=O)=CC=1C1C(C(C)C)(C(O)=O)C(C)NC(N)C1(C(O)=O)C(C1)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 IFEDVZDFHCQPAC-UHFFFAOYSA-N 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 3
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 claims 1
- VPZLJTBUEKHFQM-UHFFFAOYSA-N 6-amino-5-ethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid Chemical compound CCOC(=O)C1=C(N)NC(C)=C(C(O)=O)C1C1=CC=CC([N+]([O-])=O)=C1 VPZLJTBUEKHFQM-UHFFFAOYSA-N 0.000 claims 1
- 125000003277 amino group Chemical group 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- MPFLRYZEEAQMLQ-UHFFFAOYSA-N dinicotinic acid Chemical compound OC(=O)C1=CN=CC(C(O)=O)=C1 MPFLRYZEEAQMLQ-UHFFFAOYSA-N 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- 238000002474 experimental method Methods 0.000 description 29
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 25
- 238000001819 mass spectrum Methods 0.000 description 21
- 239000000203 mixture Substances 0.000 description 21
- 239000002904 solvent Substances 0.000 description 20
- 239000000243 solution Substances 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 238000000862 absorption spectrum Methods 0.000 description 9
- 230000036772 blood pressure Effects 0.000 description 9
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 229960001597 nifedipine Drugs 0.000 description 8
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- MLIREBYILWEBDM-UHFFFAOYSA-N anhydrous cyanoacetic acid Natural products OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 description 7
- 230000003276 anti-hypertensive effect Effects 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 229960001783 nicardipine Drugs 0.000 description 6
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- 235000008247 Echinochloa frumentacea Nutrition 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 240000004072 Panicum sumatrense Species 0.000 description 5
- 101100438134 Rattus norvegicus Cabs1 gene Proteins 0.000 description 5
- WDJHALXBUFZDSR-UHFFFAOYSA-M acetoacetate Chemical compound CC(=O)CC([O-])=O WDJHALXBUFZDSR-UHFFFAOYSA-M 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- MLIREBYILWEBDM-UHFFFAOYSA-M 2-cyanoacetate Chemical compound [O-]C(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-M 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 235000008504 concentrate Nutrition 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- MMAJXKGUZYDTHV-UHFFFAOYSA-N 1-benzhydrylazetidin-3-ol Chemical compound C1C(O)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 MMAJXKGUZYDTHV-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229940127291 Calcium channel antagonist Drugs 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 208000029078 coronary artery disease Diseases 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- WASQWSOJHCZDFK-UHFFFAOYSA-N diketene Chemical compound C=C1CC(=O)O1 WASQWSOJHCZDFK-UHFFFAOYSA-N 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- KSZGPBFUBSHVTO-UHFFFAOYSA-N (1-benzhydrylazetidin-3-yl) 2-cyanoacetate Chemical compound C1C(OC(CC#N)=O)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 KSZGPBFUBSHVTO-UHFFFAOYSA-N 0.000 description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 2
- AVUDXLOVIBJFQA-UHFFFAOYSA-N 1-benzhydrylazetidin-3-one Chemical compound C1C(=O)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 AVUDXLOVIBJFQA-UHFFFAOYSA-N 0.000 description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- WDJHALXBUFZDSR-UHFFFAOYSA-N Acetoacetic acid Natural products CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 210000000709 aorta Anatomy 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000000480 calcium channel blocker Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- BIWOSRSKDCZIFM-UHFFFAOYSA-N piperidin-3-ol Chemical compound OC1CCCNC1 BIWOSRSKDCZIFM-UHFFFAOYSA-N 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- 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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Endocrinology (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Saccharide Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP24025486 | 1986-10-09 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HUT47268A HUT47268A (en) | 1989-02-28 |
| HU199454B true HU199454B (en) | 1990-02-28 |
Family
ID=17056752
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HU874578A HU199454B (en) | 1986-10-09 | 1987-10-09 | Process for producing dihydropyridine derivatives and pharmaceutical compositions comprising these compounds as active ingredient |
Country Status (19)
| Country | Link |
|---|---|
| US (1) | US4772596A (en, 2012) |
| EP (2) | EP0266922B1 (en, 2012) |
| JP (1) | JPS63253082A (en, 2012) |
| KR (1) | KR920004483B1 (en, 2012) |
| CN (1) | CN1017897B (en, 2012) |
| AT (2) | ATE94162T1 (en, 2012) |
| AU (1) | AU600038B2 (en, 2012) |
| CA (1) | CA1309098C (en, 2012) |
| DE (2) | DE3751978T2 (en, 2012) |
| DK (1) | DK170891B1 (en, 2012) |
| ES (2) | ES2059391T3 (en, 2012) |
| FI (1) | FI90543C (en, 2012) |
| GR (1) | GR3022301T3 (en, 2012) |
| HU (1) | HU199454B (en, 2012) |
| IE (1) | IE63111B1 (en, 2012) |
| NO (1) | NO170084C (en, 2012) |
| NZ (1) | NZ222106A (en, 2012) |
| RU (1) | RU1831476C (en, 2012) |
| ZA (1) | ZA877518B (en, 2012) |
Families Citing this family (31)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2671349B1 (fr) * | 1991-01-09 | 1993-04-23 | Lafon Labor | Nouveaux derives de 1,4-dihydropyridine, leur procede de preparation et composition therapeutique les contenant. |
| US5310917A (en) * | 1991-09-13 | 1994-05-10 | Merck & Co., Inc. | Process for the preparation of 4-substituted-1,4-dihydropydrines |
| IL152021A0 (en) * | 2000-04-11 | 2003-04-10 | Sankyo Co | Pharmaceutical compositions containing pyridine derivatives |
| AU2001284413A1 (en) * | 2000-08-30 | 2002-03-13 | Sankyo Company Limited | Medicinal compositions for preventing or treating heart failure |
| TWI341312B (en) | 2002-12-24 | 2011-05-01 | Sankyo Co | Optical active dihydropyridine derivatives |
| JP4546726B2 (ja) * | 2002-12-24 | 2010-09-15 | 宇部興産株式会社 | 光学活性なジヒドロピリジン誘導体 |
| BRPI0406987A (pt) * | 2003-01-31 | 2006-01-10 | Sankyo Co | Medicamento para a prevenção e/ou tratamento de arteriosclerose, medicamentos para a inibição de proliferação de células do músculo liso vascular, de formação de neoìntima dos vasos sanguìneos e de remodelação vascular, medicamento para a prevenção de restenose que segue intervenção coronária percutânea, e, medicamentos para a profilaxia e/ou tratamento de hipertensão ou doenças causadas por hipertensão ou doenças causadas por hipertensão, de doenças cardìacas, de angina do peito, de infarto miocárdico, de arritmia, de morte súbita, de insuficiência cardìaca, de hipertrofia cardìaca, de doenças renais, de nefropatia diabética, de glomerulonefrite, de nefrosclerose, de doenças cerebrovasculares, de infarto cerebral, e de hemorragia cerebral |
| JP4629973B2 (ja) * | 2003-09-22 | 2011-02-09 | 第一三共株式会社 | 光学活性シクロプロピルアミン誘導体およびその製造方法 |
| EP1693364B1 (en) * | 2003-12-12 | 2015-05-20 | Daiichi Sankyo Company, Limited | Intermediates for the production of optically active cyclopropylamine derivatives and process for the production of the intermediates |
| JP2008543862A (ja) * | 2005-06-15 | 2008-12-04 | エラン ファーマ インターナショナル リミテッド | ナノ粒子アゼルニジピン製剤 |
| BRPI0612674B8 (pt) * | 2005-06-27 | 2021-05-25 | Daiichi Sankyo Co Ltd | preparação farmacêutica, uso de um antagonista do receptor de angiotensina ii e um bloqueador do canal de cálcio |
| CN100352818C (zh) * | 2005-09-23 | 2007-12-05 | 四川科伦药业股份有限公司 | 一种改进的制备阿折地平的方法 |
| TW200736245A (en) * | 2005-11-29 | 2007-10-01 | Sankyo Co | Acid addition salts of optically active dihydropyridine derivatives |
| TW200806648A (en) * | 2005-11-29 | 2008-02-01 | Sankyo Co | Acid addition salts of dihydropyridine derivatives |
| TWI399223B (zh) * | 2006-09-15 | 2013-06-21 | Daiichi Sankyo Co Ltd | 奧美沙坦酯及氨氯地平之固體劑型 |
| JP2008290989A (ja) * | 2007-05-28 | 2008-12-04 | Ube Ind Ltd | ジヒドロピリジン誘導体の酸付加塩を含有する医薬 |
| JP2008290988A (ja) * | 2007-05-28 | 2008-12-04 | Ube Ind Ltd | 光学活性なジヒドロピリジン誘導体の酸付加塩を含有する医薬 |
| IT1391113B1 (it) * | 2008-09-30 | 2011-11-18 | Dipharma Francis Srl | Procedimento per la preparazione di azelnidipina cristallina |
| JP5463051B2 (ja) * | 2009-02-17 | 2014-04-09 | 相模化成工業株式会社 | １，４―ジヒドロピリジン誘導体の製造法 |
| CN101863879B (zh) * | 2009-04-16 | 2012-12-19 | 四川科伦药物研究有限公司 | 一种α晶型阿折地平的制备方法 |
| JP2011006379A (ja) * | 2009-05-26 | 2011-01-13 | Tokuyama Corp | ｛２−アミノ−１，４−ジヒドロ−６−メチル−４−（３−ニトロフェニル）−３，５−ピリジンジカルボン酸３−（１−ジフェニルメチルアゼチジン−３−イル）エステル５−イソプロピルエステル｝（アゼルニジピン）の再結晶方法、アゼルニジピンのイソプロピルアルコール付加体、およびアゼルニジピンの製造方法 |
| JP2011105649A (ja) * | 2009-11-18 | 2011-06-02 | Daito Kk | アゼルニジピンの結晶 |
| JP5637710B2 (ja) * | 2010-03-24 | 2014-12-10 | 株式会社トクヤマ | ｛２−アミノ−１，４−ジヒドロ−６−メチル−４−（３−ニトロフェニル）−３，５−ピリジンジカルボン酸３−（１−ジフェニルメチルアゼチジン−３−イル）エステル５−イソプロピルエステル｝の製造方法 |
| JP2012020970A (ja) * | 2010-07-15 | 2012-02-02 | Tokuyama Corp | ｛２−アミノ−１，４−ジヒドロ−６−メチル−４−（３−ニトロフェニル）−３，５−ピリジンジカルボン酸３−（１−ジフェニルメチルアゼチジン−３−イル）エステル５−イソプロピルエステル｝の製造方法 |
| EP2703398B1 (en) * | 2011-04-29 | 2017-12-13 | Xuanzhu Pharma Co., Ltd. | 1,4-dihydropyridine -3,5-dicarboxylate derivatives, preparation methods and uses thereof |
| JP5917034B2 (ja) * | 2011-07-15 | 2016-05-11 | ニプロ株式会社 | カルシウムブロッカーを含有する固形医薬組成物 |
| RU2570752C2 (ru) | 2011-08-26 | 2015-12-10 | Вокхардт Лимитед | Способы лечения сердечно-сосудистых нарушений |
| CN102329259B (zh) * | 2011-10-21 | 2013-09-18 | 南京工业大学 | (1-二苯甲基-3-吖丁啶醇)氰基乙酸酯的制备方法 |
| CN102382104A (zh) * | 2011-11-21 | 2012-03-21 | 山东新华制药股份有限公司 | α晶型阿折地平的制备方法 |
| CN103319457B (zh) * | 2012-03-20 | 2016-01-27 | 北京晶润宏达医药科技有限公司 | 阿折地平γ晶型的制备方法 |
| WO2017063307A1 (zh) * | 2015-10-13 | 2017-04-20 | 山东轩竹医药科技有限公司 | 1，4-二氢吡啶-3，5-二羧酸酯衍生物的制备方法及中间体 |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1670827C3 (de) * | 1967-03-20 | 1974-10-24 | Bayer Ag, 5090 Leverkusen | 4-(2'-Nitrophenyl)-2,6-dimethyl-3,5-dicarbmethoxy-1,4-dihydropyridin |
| ZA7152B (en) * | 1970-01-24 | 1971-10-27 | Bayer Ag | New pharmaceutically active 1,4-dihydropyridines |
| US3935223A (en) * | 1972-03-06 | 1976-01-27 | Bayer Aktiengesellschaft | 2-Amino-1,4-dihydropyridine derivatives |
| GB1455502A (en) * | 1973-02-20 | 1976-11-10 | Yamanouchi Pharma Co Ltd | 1,4-dihydropyridine derivatives |
| JPS55301A (en) * | 1978-02-14 | 1980-01-05 | Yamanouchi Pharmaceut Co Ltd | 1,4-dihydropyridine-3,5-dicarboxylic ester derivative and its preparation |
| JPS57171968A (en) * | 1981-04-17 | 1982-10-22 | Kyowa Hakko Kogyo Co Ltd | 1,4-dihydropyridine derivative |
| JPS5970666A (ja) * | 1982-10-15 | 1984-04-21 | Kyowa Hakko Kogyo Co Ltd | １，４−ジヒドロピリジン誘導体 |
| DE3244178A1 (de) * | 1982-11-30 | 1984-05-30 | Bayer Ag, 5090 Leverkusen | 1,4-dihydropyridinderivate, verfahren zu ihrer herstellung sowie ihre verwendung in arzneimitteln |
| EP0125803A3 (en) * | 1983-04-27 | 1987-01-21 | FISONS plc | Pharmaceutically active dihydropyridines |
| GB8314744D0 (en) * | 1983-05-27 | 1983-07-06 | Fujisawa Pharmaceutical Co | 2 6-disubstituted-1 4-dihydropyridine derivative |
| US4603135A (en) * | 1983-10-17 | 1986-07-29 | Takeda Chemical Industries, Ltd. | Substituted piperazinyl alkyl esters of 2-amino-4-aryl-1,4-dihydro-6-alkyl-3,5-pyridinedicarboxylates |
| ES8708211A1 (es) * | 1985-06-14 | 1987-10-01 | Sankyo Co | Un procedimiento para la preparacion de nuevos derivados de 4-(fenil sustituido)-1,4-dihidropiridina. |
-
1987
- 1987-10-05 US US07/105,388 patent/US4772596A/en not_active Expired - Lifetime
- 1987-10-06 KR KR1019870011142A patent/KR920004483B1/ko not_active Expired
- 1987-10-07 ZA ZA877518A patent/ZA877518B/xx unknown
- 1987-10-08 RU SU874203529A patent/RU1831476C/ru active
- 1987-10-08 JP JP62254085A patent/JPS63253082A/ja active Granted
- 1987-10-09 DE DE3751978T patent/DE3751978T2/de not_active Expired - Lifetime
- 1987-10-09 AU AU79537/87A patent/AU600038B2/en not_active Expired
- 1987-10-09 AT AT87308976T patent/ATE94162T1/de not_active IP Right Cessation
- 1987-10-09 CA CA000548953A patent/CA1309098C/en not_active Expired - Lifetime
- 1987-10-09 HU HU874578A patent/HU199454B/hu unknown
- 1987-10-09 AT AT92202251T patent/ATE146169T1/de not_active IP Right Cessation
- 1987-10-09 DE DE87308976T patent/DE3787346T2/de not_active Expired - Lifetime
- 1987-10-09 IE IE270687A patent/IE63111B1/en not_active IP Right Cessation
- 1987-10-09 NO NO874219A patent/NO170084C/no unknown
- 1987-10-09 EP EP87308976A patent/EP0266922B1/en not_active Expired - Lifetime
- 1987-10-09 EP EP92202251A patent/EP0529702B1/en not_active Expired - Lifetime
- 1987-10-09 NZ NZ222106A patent/NZ222106A/xx unknown
- 1987-10-09 ES ES87308976T patent/ES2059391T3/es not_active Expired - Lifetime
- 1987-10-09 CN CN87107150A patent/CN1017897B/zh not_active Expired
- 1987-10-09 DK DK529987A patent/DK170891B1/da not_active IP Right Cessation
- 1987-10-09 FI FI874451A patent/FI90543C/fi not_active IP Right Cessation
- 1987-10-09 ES ES92202251T patent/ES2097859T3/es not_active Expired - Lifetime
-
1997
- 1997-01-16 GR GR970400061T patent/GR3022301T3/el unknown
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| HU90 | Patent valid on 900628 |