CN1008061B - 不同的二氢呲啶混合物的制备工艺 - Google Patents
不同的二氢呲啶混合物的制备工艺Info
- Publication number
- CN1008061B CN1008061B CN85109017A CN85109017A CN1008061B CN 1008061 B CN1008061 B CN 1008061B CN 85109017 A CN85109017 A CN 85109017A CN 85109017 A CN85109017 A CN 85109017A CN 1008061 B CN1008061 B CN 1008061B
- Authority
- CN
- China
- Prior art keywords
- group
- alkyl
- nitro
- cyano group
- component
- 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
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 30
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title claims description 6
- 239000003814 drug Substances 0.000 claims abstract description 7
- -1 pyrrole radicals Chemical class 0.000 claims description 40
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 claims description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 11
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 239000011737 fluorine Substances 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 claims description 4
- XBLVHTDFJBKJLG-UHFFFAOYSA-N Ethyl nicotinate Chemical compound CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 claims description 4
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- VKQFCGNPDRICFG-UHFFFAOYSA-N methyl 2-methylpropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)C)C1C1=CC=CC=C1[N+]([O-])=O VKQFCGNPDRICFG-UHFFFAOYSA-N 0.000 claims description 4
- 229960001783 nicardipine Drugs 0.000 claims description 4
- 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 claims description 4
- 229960001597 nifedipine Drugs 0.000 claims description 4
- 229960000227 nisoldipine Drugs 0.000 claims description 4
- 229960005425 nitrendipine Drugs 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000006225 propoxyethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- YFGOPWVRHFJVNI-KOFBORESSA-N (4R,4aR,7S,7aR,12bS)-9-aminooxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-ol Chemical compound O[C@H]([C@@H]1O2)C=C[C@H]3[C@]4([H])N(C)CC[C@]13C1=C2C(ON)=CC=C1C4 YFGOPWVRHFJVNI-KOFBORESSA-N 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 125000006713 (C5-C10) cycloalkyl group Chemical group 0.000 claims description 2
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 2
- LYTMVABTDYMBQK-UHFFFAOYSA-N 2-benzothiophene Chemical compound C1=CC=CC2=CSC=C21 LYTMVABTDYMBQK-UHFFFAOYSA-N 0.000 claims description 2
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 claims description 2
- UEBKKWPCSFJRJC-UHFFFAOYSA-N 4-oxochromene-2-sulfonic acid Chemical compound C1=CC=C2OC(S(=O)(=O)O)=CC(=O)C2=C1 UEBKKWPCSFJRJC-UHFFFAOYSA-N 0.000 claims description 2
- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 150000001491 aromatic compounds Chemical class 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 claims description 2
- OTAFHZMPRISVEM-UHFFFAOYSA-N chromone Chemical compound C1=CC=C2C(=O)C=COC2=C1 OTAFHZMPRISVEM-UHFFFAOYSA-N 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- OBISXEJSEGNNKL-UHFFFAOYSA-N dinitrogen-n-sulfide Chemical compound [N-]=[N+]=S OBISXEJSEGNNKL-UHFFFAOYSA-N 0.000 claims description 2
- 229960003580 felodipine Drugs 0.000 claims description 2
- 239000012530 fluid Substances 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 150000002390 heteroarenes Chemical class 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 229960000715 nimodipine Drugs 0.000 claims description 2
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 2
- XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 125000005306 thianaphthenyl group Chemical group 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 claims 1
- 239000007787 solid Substances 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 3
- 230000000304 vasodilatating effect Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 230000008485 antagonism Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 239000007924 injection Substances 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 206010047139 Vasoconstriction Diseases 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 230000025033 vasoconstriction Effects 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000012895 dilution Substances 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 230000010412 perfusion Effects 0.000 description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- 241000700199 Cavia porcellus Species 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 239000004141 Sodium laurylsulphate Substances 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 210000000709 aorta Anatomy 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 210000004351 coronary vessel Anatomy 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 210000002837 heart atrium Anatomy 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 229960003511 macrogol Drugs 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 210000000115 thoracic cavity Anatomy 0.000 description 2
- 230000024883 vasodilation Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000008051 alkyl sulfates Chemical class 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 239000002969 artificial stone Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- UBAZGMLMVVQSCD-UHFFFAOYSA-N carbon dioxide;molecular oxygen Chemical compound O=O.O=C=O UBAZGMLMVVQSCD-UHFFFAOYSA-N 0.000 description 1
- 230000003683 cardiac damage Effects 0.000 description 1
- 230000002612 cardiopulmonary effect Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 229920005610 lignin Polymers 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 239000004531 microgranule Substances 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 230000002572 peristaltic effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- CTYRPMDGLDAWRQ-UHFFFAOYSA-N phenyl hydrogen sulfate Chemical compound OS(=O)(=O)OC1=CC=CC=C1 CTYRPMDGLDAWRQ-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- 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
-
- 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
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Epidemiology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
一种有效治疗循环紊乱疾患的组合物，其包括式(I)与(II)的混合物。
式中各种基团已呈于说明书中。(I)是影响收结力的而(II)是血管舒张的，尽管化合体中的各组分应表示出拮抗性，但它们药力反而加强。
Description
本发明是关于有增加血管收缩力和防止心绞痛作用的活性化合物的组合物（含有增加血管收缩力的二氢吡啶-组分A和有舒张血管作用的二氢吡啶-组分B）的制备工艺及其在医药方面的用途。
所述增加血管收缩力的二氢吡啶（组分A）的化学结构通式（Ⅰ）如下：
式中：
R-代表（C5-C10）环烷基或
-苯基、萘基、噻吩基、呋喃基、吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、喹唑啉基、喹噁啉基、硫茚基、异硫茚基、色酮基、硫代色酮基、色烯基、硫代色烯基、苯并噁二唑基或苯并噻二唑基，上述基团也可以被如下基团中最多三个相同或不相同的基团取代：氟、氯、溴、硝基、氰基、三氟甲基、一氟（C1-C4）烷氧基、多氟（C1-C4）烷氧基、羟基、氨基、C1-C4烷基胺基、二（C1-C4）烷基胺基、苯基、噻吩基、吡啶基、苄基、邻苄基、或-SOn-苄基、（n＝0-2），芳族化合物和杂芳族化合物也可以依次被如下基团单取代到三取代：氟、氯、溴、氰基、硝基、羟基、三氟甲基、三氟甲氧基、氨基、C1-C4烷基胺基、二（C1-C4）烷基胺基、甲氧基、甲基硫醇基。
R1-代表直链、支链或环状的饱和或不饱和的烃基，这些烃基的碳原子数最大为14，这些烃基的链里也可以最多被三个氧和/或硫原子所间隔，同时也可以被如下基团单取代或多取代：氟、氯、溴、硝基、羟
基、氰基或三（C1-C4）三烷基甲硅烷基，
R2，R4可以是相同或不相同的，并代表：
-氢，
-氨基，
-氰基，
-甲酰基或
-直链、支链的（C1-C4）烷基或链烯基，这些烃基中的每一个都可以被羟基取代，
R3-代表氢或
-直链、支链或环状（C1-C6）烷基或链烯基，这些基团中的每一个链里可以被最多二个氧原子所间隔，而且可以被如下基团单取代或多取代：氟、氯、氰基、羟基、氨基、吗啡代，
R5-代表氢、氰基、硝基，或者
R4和R5一起形成如下的环：
n是1或2，
可特别提及以下化合物：
1.4-二氢-2.6-二甲基-5-硝基-4-（2-三氟甲基苯基）-吡啶-3-羧酸甲酯（BAyK8644）和2-甲基-4-（4-氧代-2-苯基-4H-硫代色烯-8-基）-5-氧代-1.4.5.7-四氢呋喃-〔3，4-b〕吡啶-3-羧酸乙酯。
这些化合物的制备在西德专利（西德公开说明书）DE-OS 3206671，3311005和3311003中已经叙述过。
作为使血管舒张的二氢吡啶（组份B），其化学结构通式（Ⅱ）
如下：
式中
R1-代表甲基、乙基、异丙基或正丙氧基乙基，
R2-代表甲基、乙基、异丙基、异丁基、正癸基、正丙氧基乙基，甲氧基乙基、三氟甲基甲基、或基团C6H5CH2N（CH3）-CH2-CH2-，
R3-代表氰基、羟甲基或甲基，
X-代表2-硝基、3-硝基、2-氯、2，3-二氯或2，3-＝N-O-N＝基团，下表中的化合物是特别好的：
尼群地平，尼卡地平，尼索地平，非洛地平，尼非地平，尼莫地平，表中№13产品和达早地平将要详述。这些化合物的制备在如下的专利说明书中已叙述过，它们是：美国专利说明书3485847，欧洲专利说明书7293，西德专利公开说明书2407115，2549568，2117571，2949464，2949491。
由于钙的反作用和增加血管收缩力的二氢吡啶二者被结合于同一受体，肯定会予料到两个组份的结合会使单个组份的活性减弱。
然而，在适当的条件下，组份A和组份B构成的组合物会显示出完全惊人的活性：可以增加血管的收缩和舒张的能力，特别是增加冠状动脉扩张的能力。组合物包含1到10%重的组份A和0.1到100%重的组份B，较好是0.1到10%重的组份B。
本发明是关于增加血管收缩力的消旋二氢吡啶和可增加血管舒张能力的有光学活性的二氢吡啶构成的组合物;是关于有增加血管舒张能力的消旋二氢吡啶和增加血管收缩力的有光学活性的二氢吡啶构成的组合物;也是关于有光学活性的可使血管增加收缩能力的二氢吡啶和有光学活性的能使血管舒张的二氢吡啶构成的组合物。
组合物的制备可以通过将单个组份分别溶解在可溶介它们的惰性溶剂里，然后再将这些溶液按一定比例混合。
作为惰性溶剂可以提及的是，醇类，如乙醇或乙二醇，例如，聚乙烯二醇，特别是二甲亚砜。
正如已经谈到的本发明的组合物可以用来控制一些疾病，特别是循环系统和心脏的疾病，例如，心脏局部缺血病，心脏损坏和高血压病。
活性化合物的组合物用已知的方法可以做成通常的配方，如用适
合于药物的惰性、无毒的赋形剂和溶剂可以做成药片、膜片、糖衣、药丸、药粒、氣溶胶、糖浆、乳剂、悬浮液和溶液。从治疗上考虑，活性化合物在所有情况下都应约为全部混合物重量的0.01到90%，即这个数量完全可以达到剂量范围的要求。
制备这些配方的药物时，可以在活性化合物的组合物里添加溶剂和/或赋形剂，可以使用也可以不使用乳化剂和/或分散剂，例如当使用水作稀释剂时，有机溶剂可以用作辅助溶剂，但也可以不用它。
所说的辅助材料的例子可以提及：
水、无毒的有机溶剂，如正构烷烃（石油馏份），植物油（如花生油、芝麻油），醇类（如乙醇、甘油）和二元醇类（如丙烯二醇，聚乙烯二醇），固体赋形剂如，天然石粉（如高岭土、氧化铝、滑石、白垩）、合成石粉（如高分散的硅胶和硅酸盐）、糖（如蔗糖、乳糖、葡萄糖），乳化剂（如聚氧乙烯脂肪酸酯、聚氧乙烯脂肪醇醚、烷基硫酸盐和芳基硫酸盐），分散剂（如木质素、亚硫酸盐废液、甲基纤维素、淀粉和聚乙烯醇吡咯酮）和润滑剂（如硬脂酸镁、滑石、硬脂酸和十二烷基硫酸钠）。
一般方法使用这些药物都是有效的，较好是口服或非肠道使用，特别好的是经舌或静脉注射。当然，在口服使用情况下除有所提到的赋形剂外，还要添加柠檬酸钠、碳酸钙、砱酸二钙以及各种添加物，如淀粉，较好是土豆淀粉，明胶等。此外，在制作片剂时，可以同时使用多种润滑剂，如硬脂酸镁、十二烷基硫酸钠、滑石。在制作口服液体悬浮液和/或甘香酒剂时，除上述辅助材料外活性化合物的组合物中可加入各种香料改进剂和着色剂。
不经肠道使用，在用适宜的液体赋形剂时可以使用活性化合物组合物的溶液。
本发明复合物对心脏和脉管的效果，在单独注入试验的豚鼠心脏时已经检测出来（根据Opie.L，生理学杂志180（1965），529-541）。用于这个试验的是重250到350克，心脏患白化病的豚鼠。敲击动物的头部将其杀死，打开胸腔，将金属套管连结到暴露的主动脉上并打开左前心房。将心脏和肺脏分离出胸腔，通过主动脉套管将心肺连结到注入设备同时开动注入设备。将肺脏从其根部分离出来。注入介质使用克雷布斯-享瑟勒特溶液（118.5毫摩尔/升的氯化钠，4.75毫摩尔/升的氯化钾，1.19毫摩尔/升的硫酸镁，25毫摩尔/升的碳酸氢钠，0.013毫摩尔/升的NaEDTA）氯化钙的浓度根据需要可以改变，一般是1.2毫摩尔/升，添加10毫摩尔/升的葡萄糖溶液作为能量供给物质。注入前，溶液要过滤到没有微粒。用卡波金气体（95%O2，5%CO2，保持PH为7.4）处理溶液。在32℃通过蠕动泵以不变的速率（10毫升/分）注入心脏。
为了测量心脏的功能，充满液体的乳胶袋（通过液柱与压力传感器相连）经过左前心房进入左心室，在高速记录器上记录下等体积收缩的情况。
注入压力作为测量冠状动脉的阻力通过压力传感器记录下来。在这样的条件下，注入压力的降低表示冠状动脉的膨胀，左心室压力的升高表示心脏可收缩性的增加。在分离出心脏前，将适当稀度的本发明复合物灌注到注入系统。
列入下表中作为例子的组合物，在分离出的经过灌注的豚鼠心脏上有增加冠状动脉血管收缩力的效果。
组合物 收缩程度 注入压力
组份 组份 与参照物比较 百分数增加（+）
A B 降低（-）
组合物1
BAy K8644：尼非地平 +38 -18
（100毫克分子/升）（100毫摩尔/升）
复合物2
BAy K8644：尼索地平 +32 -21
（100毫克分子/升）（100毫摩尔/升）
复合物3
BAy K8644：尼卡地平 +18 -17
（100毫克分子/升）（200毫摩尔/升）
复合物4
BAy K8644：尼群地平 +47 -24
（30毫克分子/升）（90毫摩尔/升）
组合物1到4的制备如下：
组合物1
3.6×10-3克的BAy K8644溶解在1毫升的二甲亚砜里，然后将3.6×10-3克的尼非地平溶解在1毫升的二甲亚砜里，接着将这两种溶液再按1∶1的比例混合在一起，最后倒入0.9%氯化钠溶液将混合物适当地稀释以备灌注。
组合物2
3.6×10-3克的BAy K8644溶解在1毫升的二甲亚砜里，然后将3.9×10-3克的尼索地平溶解在1毫升的二甲亚砜里，接着将这两种溶液再按1∶1的比例混合在一起，最后倒入0.9%氯化钠溶液将混合物适当的稀释以备灌注。
组合物3
3.6×10-3克的BAy K8644溶解在1毫升的二甲亚砜里，然后将9.3×10-3克的尼卡地平溶解在1毫升的二甲亚砜里，接着将这两种溶液按1∶1的比例混合在一起，最后倒入0.9%的氯化钠溶液适应的稀释以备灌注。
组合物4
1×10-3克的BAy K8644溶解在1毫升的二甲亚砜里，然后将3.2×10-3克的尼群地平溶解在1毫升的二甲亚砜里，接着将这两种溶液按1∶1的比例混合在一起，最后倒入0.9%的氯化钠溶液适当稀释以备灌注。
当然，本发明并不限于说明书和例子的所作的解释，在本发明的精神和范围之内的实施方案将浮现在本技术领域里熟练的技术人员心中。
Claims (4)
1、一种制备含有通式(Ⅰ)的和通式(Ⅱ)的二氢吡啶混合物的方法，其中通式(Ⅰ)的二氢吡啶作为A组分，
式中：
R-代表(C5-C10)环烷基或
-苯基、萘基、噻吩基、呋喃基、吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、喹唑啉基、喹噁啉基、硫茚基、异硫茚基、色酮基、硫代色酮基、色烯基、硫代色烯基、苯并噁二唑基或苯并噻二唑基，上述基团也可以被如下基团中最多三个相同或不相同的基团取代：氟、氯、溴、硝基、氰基、三氟甲基、一氟(C1-C4)烷氧基、多氟(C1-C4)烷氧基、羟基、氨基、C1-C4烷基胺基、二(C1-C4)烷基胺基、苯基、噻吩基、吡啶基、苄基、邻苄基、或-SOn-苄基、(n=0-2)，芳族化合物和杂芳族化合物也可以依次被如下基团单取代到三取代：氟、氯、溴、氰基、硝基、羟基、三氟甲基、三氟甲氧基、氨基、C1-C4烷基胺基、二(C1-C4)烷基胺基、甲氧基、甲基硫醇基，
R1-代表直链、支链或环状的饱和或不饱和的烃基，这些烃基的碳原子数最大为14，这些烃基的链里也可以最多被三个氧和/或硫原子所间隔，同时也可以被如下基团单取代或多取代：氟、氯、溴、硝基、羟基、氰基或三(C1-C4)三烷基甲硅烷基，
R2，R4可以是相同或不相同的，并代表：
-氢，
-氨基，
-氰基，
-甲酰基或
-直链、支链的(C1-C4)烷基或链烯基，这些烃基中的每一个都可以被羟基取代，
R3-代表氢或
-直链、支链或环状(C1-C6)烷基或链烯基，这些基团中的每一个链里可以被最多二个氧原子所间隔，而且可以被如下基团单取代或多取代：氟、氯、氰基、羟基、氨基、吗啡代，
R5-代表氢、氰基、硝基，或者
R4和R5一起形成如下的环：
n是1或2，
而通式(Ⅱ)的二氢吡啶作为B组
式中
R1-代表甲基、乙基、异丙基或正丙氧基乙基，
R2-代表甲基、乙基、异丙基、异丁基、正癸基、正丙氧基乙基，甲氧基乙基、三氟甲基甲基、或基团C6H5CH2N(CH3)-CH2-CH2-，
R3-代表氰基、羟甲基或甲基，
X-代表2-硝基、3-硝基、2-氯、2，3-二氯或2，3-=N-O-N=基团，其方法的特征在于将1到10份重量的A组分与0.1到100份重量的B组分溶于惰性有机溶剂中，然后将该溶液混合，再添加通常的辅助材料和/或赋形剂。
2、根据权利要求1的所述制备混合物的方法，其中它含有下列化合物作为组分A，1，4-二氢-2，6-二甲基-5-硝基-4-（2-三氟甲基苯基）-吡啶-3-羧酸甲酯和/或2-甲基-4-（4-氧代-2-苯基-4H-硫代色烯-8-基）-5-氧代-1，4，5，7-四氢呋喃-[3，4-b]吡啶-3-羧酸乙酯。
3、根据权利要求1和2所述制备混合物的方法，其中它含有由下列基团构成二氢吡啶的组分B，尼群地平、尼卡地平、尼索地平、非洛地平、尼非地平、尼莫地平、PM200-100或达早地平。
4、一种制备药剂的方法，其特征在于将权利要求1到3的方法制得的混合物与常用的流体或固体辅助材料和/或赋形剂混合形成肠内或肠胃外系统剂形的药剂。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3447170.7 | 1984-12-22 | ||
| DE19843447170 DE3447170A1 (de) | 1984-12-22 | 1984-12-22 | Mischung unterschiedlicher dihydropyridine, verfahren zu ihrer herstellung sowie ihre verwendung in arzneimitteln |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN85109017A CN85109017A (zh) | 1986-08-27 |
| CN1008061B true CN1008061B (zh) | 1990-05-23 |
Family
ID=6253729
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN85109017A Expired CN1008061B (zh) | 1984-12-22 | 1985-12-11 | 不同的二氢呲啶混合物的制备工艺 |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US4895855A (zh) |
| EP (1) | EP0186027A3 (zh) |
| JP (1) | JPS61155326A (zh) |
| CN (1) | CN1008061B (zh) |
| AU (1) | AU585916B2 (zh) |
| CA (1) | CA1251139A (zh) |
| DE (1) | DE3447170A1 (zh) |
| DK (1) | DK597285A (zh) |
| FI (1) | FI855085A (zh) |
| GR (1) | GR853099B (zh) |
| IL (1) | IL77391A (zh) |
| NO (1) | NO855174L (zh) |
| NZ (1) | NZ214627A (zh) |
| PH (1) | PH23019A (zh) |
| PT (1) | PT81739B (zh) |
| ZA (1) | ZA859745B (zh) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5001139A (en) * | 1987-06-12 | 1991-03-19 | American Cyanamid Company | Enchancers for the transdermal flux of nivadipine |
| US5455253A (en) * | 1992-10-20 | 1995-10-03 | Zeneca Limited | Heterocyclic derivatives |
| US6082358A (en) * | 1998-05-05 | 2000-07-04 | 1263152 Ontario Inc. | Indicating device for aerosol container |
| US6518279B2 (en) * | 1999-03-04 | 2003-02-11 | Abbott Laboratories | Cyclopentanone dihydropyridine compounds useful as potassium channel openers |
| KR102484846B1 (ko) * | 2015-11-27 | 2023-01-05 | 한림제약(주) | 벤조피란 유도체의 정제방법, 이의 결정형 및 상기 결정형의 제조방법 |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3932646A (en) * | 1971-04-10 | 1976-01-13 | Farbenfabriken Bayer Ag | Pharmaceutical compositions containing unsymmetrical esters of 1,4-dihydropyridine 3,5-dicarboxylate |
| US3911123A (en) * | 1972-03-06 | 1975-10-07 | Bayer Ag | Pharmaceutical compositions utilizing 2-amino-1,4-dihydropyridine derivatives and method of effecting coronary vessel dilation and treating hypertension in humans and animals utilizing said compounds |
| US4284634A (en) * | 1975-07-02 | 1981-08-18 | Fujisawa Pharmaceutical Co., Ltd. | 1,4-Dihydropyridine derivatives, and pharmaceutical method of the same |
| DE2752820A1 (de) * | 1977-11-26 | 1979-05-31 | Bayer Ag | Neue nitrosubstituierte 1,4-dihydropyridine, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel |
| SE429652B (sv) * | 1978-06-30 | 1983-09-19 | Haessle Ab | 2.6-dimetyl-4-(2.3-diklorfenyl)-1.4-dihydropyridin-3.5-dikarboxylsyra-3-metylester-5-etylester |
| DE3212736A1 (de) * | 1982-04-06 | 1983-10-13 | Bayer Ag, 5090 Leverkusen | Verwendung von dihydropyridinen in arzneimitteln mit salidiuretischer wirkung |
| DE3307422A1 (de) * | 1983-03-03 | 1984-09-06 | Bayer Ag, 5090 Leverkusen | Fluessigzubereitungen von dihydropyridinen, ein verfahren zu ihrer herstellung, sowie ihre verwendung bei der bekaempfung von erkrankungen |
| DE3317872A1 (de) * | 1983-05-17 | 1984-11-22 | Basf Ag, 6700 Ludwigshafen | Oral verabreichbares arzneimittel |
| DE3427402A1 (de) * | 1984-07-25 | 1986-01-30 | Bayer Ag, 5090 Leverkusen | Neues kombinationspraeparat, verfahren zu seiner herstellung und seine verwendung als arzneimittel |
| DE3419131A1 (de) * | 1984-05-23 | 1985-11-28 | Bayer Ag, 5090 Leverkusen | Dihydropyridinkombinationspraeparate und verfahren zu ihrer herstellung |
| DE3424342A1 (de) * | 1984-07-03 | 1986-01-09 | Bayer Ag, 5090 Leverkusen | 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridin-3,5-dicarbonsaeure-isopropyl-(2-(3-trifluormethylphenoxy)-ethyl)-ester, mehrere verfahren zu seiner herstellung sowie seine verwendung in arzneimitteln |
| DE3447169A1 (de) * | 1984-12-22 | 1986-07-03 | Bayer Ag, 5090 Leverkusen | Optisch aktive nitrodihydropyridine, verfahren zur herstellung und ihre verwendung in arzneimitteln |
| 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. |
-
1984
- 1984-12-22 DE DE19843447170 patent/DE3447170A1/de not_active Withdrawn
-
1985
- 1985-12-06 US US06/806,160 patent/US4895855A/en not_active Expired - Fee Related
- 1985-12-09 EP EP85115636A patent/EP0186027A3/de not_active Withdrawn
- 1985-12-11 CN CN85109017A patent/CN1008061B/zh not_active Expired
- 1985-12-16 AU AU51286/85A patent/AU585916B2/en not_active Ceased
- 1985-12-17 PH PH33203A patent/PH23019A/en unknown
- 1985-12-19 IL IL77391A patent/IL77391A/xx unknown
- 1985-12-19 FI FI855085A patent/FI855085A/fi not_active Application Discontinuation
- 1985-12-19 NO NO855174A patent/NO855174L/no unknown
- 1985-12-19 NZ NZ214627A patent/NZ214627A/xx unknown
- 1985-12-20 GR GR853099A patent/GR853099B/el unknown
- 1985-12-20 CA CA000498231A patent/CA1251139A/en not_active Expired
- 1985-12-20 PT PT81739A patent/PT81739B/pt unknown
- 1985-12-20 DK DK597285A patent/DK597285A/da not_active Application Discontinuation
- 1985-12-20 ZA ZA859745A patent/ZA859745B/xx unknown
- 1985-12-20 JP JP60285854A patent/JPS61155326A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| AU5128685A (en) | 1986-06-26 |
| CA1251139A (en) | 1989-03-14 |
| PT81739A (en) | 1986-01-01 |
| FI855085A0 (fi) | 1985-12-19 |
| ZA859745B (en) | 1986-08-27 |
| EP0186027A2 (de) | 1986-07-02 |
| NZ214627A (en) | 1989-06-28 |
| PT81739B (en) | 1987-10-06 |
| FI855085A (fi) | 1986-06-23 |
| DK597285D0 (da) | 1985-12-20 |
| PH23019A (en) | 1989-03-03 |
| EP0186027A3 (de) | 1988-11-02 |
| DK597285A (da) | 1986-06-23 |
| CN85109017A (zh) | 1986-08-27 |
| DE3447170A1 (de) | 1986-07-03 |
| AU585916B2 (en) | 1989-06-29 |
| JPS61155326A (ja) | 1986-07-15 |
| NO855174L (no) | 1986-06-23 |
| IL77391A (en) | 1989-01-31 |
| GR853099B (zh) | 1986-04-18 |
| US4895855A (en) | 1990-01-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6291490B1 (en) | Methods and compositions for treating conditions caused by excessive calcium influx in cells using optically pure (-) amlodipine | |
| US8129426B2 (en) | Water-soluble artemisinin derivatives, their preparation methods, the pharmaceutical compositions and the use thereof | |
| RU2464271C1 (ru) | Способ получения производного диамина | |
| CN1041595A (zh) | 新蒿属素衍生物，其制法及其作为抗原虫剂的应用， | |
| EP1262182A2 (en) | Methods and compositions for treating hypertension, angina and other disorders using optically pure(-) amlodipine | |
| RU2004111601A (ru) | Пиперидиновые производные и их применение в качестве модуляторов активности р ецепторов хемокина (в частности ccr5) | |
| CN1008061B (zh) | 不同的二氢呲啶混合物的制备工艺 | |
| CN1152685C (zh) | 内皮素受体拮抗剂在制备治疗肥胖的药物方面的用途 | |
| CN1328453A (zh) | 含索他洛尔右旋和左旋异构体混合物的药物组合物 | |
| CN87106996A (zh) | 喹啉基化合物，它们的制备方法和以其作为有效药物组分的抗癌剂 | |
| CN1192121A (zh) | 钙通道的调整 | |
| CN1224354A (zh) | 肺循环改善剂 | |
| JPS61155369A (ja) | 光学活性のニトロジヒドロピリジン類 | |
| CN1070909A (zh) | 硫脲衍生物和含该硫脲衍生物的抗微生物剂和抗溃疡剂 | |
| KR20040058266A (ko) | 메트포르민 및 4-옥소부탄산의 조합물을 포함하여이루어지는 약제학적 조성물 및 당뇨병을 치료하기 위한이의 용도 | |
| CN1127342C (zh) | 降低眼压的药物 | |
| CN112274642A (zh) | Ck2抑制剂在制备类风湿关节炎治疗药物中的应用 | |
| JPS60233057A (ja) | ４‐（ニトロフエニル）‐テトラヒドロピリジン類 | |
| CN1110556A (zh) | 含3-苯甲酰基-3，7-二氮杂双环[3.3.1]壬烷的药物 | |
| CN109966299B (zh) | 吲哚生物碱治疗过敏性鼻炎的应用及其药物组合物 | |
| US5441962A (en) | Method for treating hyperlipemia | |
| CN116444482B (zh) | 噻吩-2-羧酸衍生物、其制备方法及医药用途 | |
| EP0040489A1 (en) | Mixtures, salts, packages and pharmaceutical compositions containing 5-(2-hydroxypropoxy)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid or a derivative thereof and an H2 receptor antagonist antihistamine | |
| US5126372A (en) | Excretion of nonprotein nitrogen into the intestine by prostanoic acid derivatives | |
| KR870007178A (ko) | 4-아미노 아릴디히드로피리딘 락톤, 이 화합물의 제조방법 및 의약품에 있어서 이들의 용도 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C13 | Decision | ||
| GR02 | Examined patent application | ||
| AD01 | Patent right deemed abandoned | ||
| C20 | Patent right or utility model deemed to be abandoned or is abandoned |