CN88101782A - 抗心律不齐药 - Google Patents
抗心律不齐药 Download PDFInfo
- Publication number
- CN88101782A CN88101782A CN88101782.5A CN88101782A CN88101782A CN 88101782 A CN88101782 A CN 88101782A CN 88101782 A CN88101782 A CN 88101782A CN 88101782 A CN88101782 A CN 88101782A
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- benzazepines
- tetrahydrochysene
- pharmaceutically acceptable
- 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.)
- Granted
Links
- 239000003416 antiarrhythmic agent Substances 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 61
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 238000002360 preparation method Methods 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 31
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 13
- -1 alkyl sulfonic acid acid anhydride Chemical class 0.000 claims description 11
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 8
- 235000015320 potassium carbonate Nutrition 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 150000001805 chlorine compounds Chemical class 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- NBNBICNWNFQDDD-UHFFFAOYSA-N sulfuryl dibromide Chemical compound BrS(Br)(=O)=O NBNBICNWNFQDDD-UHFFFAOYSA-N 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 65
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 22
- 230000009467 reduction Effects 0.000 description 20
- 238000009834 vaporization Methods 0.000 description 20
- 230000008016 vaporization Effects 0.000 description 20
- 238000004458 analytical method Methods 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 238000003756 stirring Methods 0.000 description 18
- 238000005406 washing Methods 0.000 description 17
- 239000002904 solvent Substances 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 11
- 235000019441 ethanol Nutrition 0.000 description 11
- 238000001035 drying Methods 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 206010003119 arrhythmia Diseases 0.000 description 8
- 230000006793 arrhythmia Effects 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
- 230000008020 evaporation Effects 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 235000017550 sodium carbonate Nutrition 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 230000006837 decompression Effects 0.000 description 5
- 210000002837 heart atrium Anatomy 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 230000003288 anthiarrhythmic effect Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000005917 acylation reaction Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 210000003205 muscle Anatomy 0.000 description 3
- 235000009518 sodium iodide Nutrition 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- OBCFOPGCTNULTG-UHFFFAOYSA-N 1-(2-chloroethoxy)-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(OCCCl)C=C1 OBCFOPGCTNULTG-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 208000003663 ventricular fibrillation Diseases 0.000 description 2
- HXEURDRGGNKAJL-UHFFFAOYSA-N 2-[4-(methanesulfonamido)phenyl]ethyl methanesulfonate Chemical compound CS(=O)(=O)NC1=CC=C(CCOS(C)(=O)=O)C=C1 HXEURDRGGNKAJL-UHFFFAOYSA-N 0.000 description 1
- ZXNMIUJDTOMBPV-UHFFFAOYSA-N 2-chloroethyl 4-methylbenzenesulfonate Chemical compound CC1=CC=C(S(=O)(=O)OCCCl)C=C1 ZXNMIUJDTOMBPV-UHFFFAOYSA-N 0.000 description 1
- CIIGWOXXOUVEAD-UHFFFAOYSA-N 2-chloroethyl benzenesulfonate Chemical compound ClCCOS(=O)(=O)C1=CC=CC=C1 CIIGWOXXOUVEAD-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical class OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 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 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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229960001413 acetanilide Drugs 0.000 description 1
- 230000036982 action potential Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000002763 arrhythmic effect Effects 0.000 description 1
- 230000001746 atrial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000011928 denatured alcohol Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000037024 effective refractory period Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 230000005496 eutectics Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000012447 hatching Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 210000003540 papillary muscle Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 230000009090 positive inotropic effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 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 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 210000005245 right atrium Anatomy 0.000 description 1
- 210000005241 right ventricle Anatomy 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- ZPHGMBGIFODUMF-UHFFFAOYSA-N thiophen-2-ylmethanol Chemical compound OCC1=CC=CS1 ZPHGMBGIFODUMF-UHFFFAOYSA-N 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000013022 venting Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
-
- 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
- A61P9/06—Antiarrhythmics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/06—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
- C07D233/08—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms with alkyl radicals, containing more than four carbon atoms, directly attached to ring carbon atoms
- C07D233/12—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms with alkyl radicals, containing more than four carbon atoms, directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D233/16—Radicals substituted by nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Cardiology (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)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Saccharide Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Apparatus For Radiation Diagnosis (AREA)
- Diaphragms For Electromechanical Transducers (AREA)
- Magnetic Resonance Imaging Apparatus (AREA)
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Abstract
式(I)化合物或其药物上可接受的盐为抗心律不齐药,式(I)为:
式中:R1是H,C1-C4烷基或C1-C4烷氧基;
X是0,或直接连键;
R2和R3彼此相同或不同,各自为C1-C4烷基,其前提是:当X是时,R2和R3相同。
Description
本发明涉及某些用作抗心律不齐药物的苯并吖庚因氨磺酰类化合物及其中间体。
本发明抗心律不齐化合物可以延长心肌和传导组织的动作电位时间,因此可以增强对早期刺激的不应性。所以按照Vaughan Williams分类法(Anti-Arrhythmic Action,E.M.Vaughan Williams,Academic Press,1980),这类化合物属于Ⅲ型抗心律不齐药。无论是在体内还是体外,它们对心房,心室及传导组织均有效,因此可用于预防和治疗包括心房和心室纤维颤动在内的各种心室和心室上心律不齐。由于它们不改变脉冲传导速度,因此,与现有药物(多为Ⅰ型)相比,更不易突然引起或加重心律不齐,而且更不易产生神经病学付作用。其中某些化合物还具有一定的增强收缩力的作用,因此特别有利于治疗心脏收缩功能受损的患者。
本发明提供了结构式如下的化合物及其药物上可接受的盐:
R2和R3(彼此相同或不同)各自是C1-C4烷基,其前提是:当X是-NHCO-时,R2和R3相同。这些式(Ⅰ)化合物是抗心律不齐药。
可取的烷基和烷氧基是甲基和甲氧基。
R1最好是H,甲基或甲氧基,最佳者为H。R2和R3最好相同,并且最好是甲基。X最好是0或直接连键。
其最佳化合物中,R1是H,R2和R3是甲基,X是0或直接连键。
最好的一种化合物结构式为:
将这类化合物命名为下式,即1,2,4,5-四氢-3H-3-苯并吖庚因的衍生物:
另外,本发明还包括下式中间体:
式中:R1如式(Ⅰ)所定义,并且(a)X的定义如式(Ⅰ)所述,Ra和Rb彼此相同,为-NO2或-NH2,或者(b)X是0或直接连键,Ra是-NO2,Rb是-NH2。
下列式(B)和式(C)中间体也属于本发明的范畴,式(B)为:
式中Rc是-NO2,-NH2或-NHSO2(C1-C4烷基);式(C)为:
式中R2如式(Ⅰ)所定义。
按下列反应式所述,将相应的二氨基化合物酰化,可以制得式中R2和R3彼此相同的式(Ⅰ)化合物:
该酰化反应的经典反应条件为:于适宜的有机溶剂中(如:二氯甲烷,吡啶,或N-甲基吗啉),在约室温下,在任意的酸受体存在下(如:三乙胺,碳酸钾,碳酸氢钠,吡啶或N-甲基吗啉)进行。事实上,最好采用C1-C4烷磺酸酐或磺酰氯为酰化剂,在吡啶或N-甲基吗啉(由于这些化合物既可以起溶剂的作用又可以起酸受体的作用)中进行该酰化反应。显然,必须使用至少两个当量的酰化剂。然后可按惯用方法分离并纯化式(Ⅰ)产物。
按下列制备实施例详细描述的惯用方法,可制得式(Ⅱ)起始原料。其合成路线反应式如下:
(a)按下列路线可制得式中X是氧或直接连键的式(Ⅱ)起始原料:
其中R1如式(Ⅰ)所定义,X是0或直接连键。
在上述反应式的第二步中,最好采用碘化钠作催化剂,但并非必须。也可以选用除卤素之外的其它离去基团,如:甲磺酰氧基、苯磺酰氧基或甲苯磺酰氧基。最好加入像碳酸钾这样的酸受体。另外也可采用像碳酸钠或碳酸氢钠这样的酸受体。
(b)通过下列路线也可制得式中X是0或直接连键的式(Ⅱ)起始
其中R1如式(Ⅰ)所定义,X是0或直接连键。
(c)按下列路线可制得式中X是-NHCO-的式(Ⅱ)起始原料:
其中R1如式(Ⅰ)所定义。
通过下列概括性反应式,可制得式中X是0或直接连键,而R2和R3彼此相同或不同的式(Ⅰ)化合物:
显然,这一方法也可以用于制备式中烷磺酰氨基相同或不同的式(Ⅰ)化合物。
在上述化合物中,R1,R2,R3的定义如式(Ⅰ)所述,X是氧或直接连键,Q是离去基团。典型的离去基团包括:氯,溴,碘,甲磺酰氧基,苯磺酰氧基,甲苯磺酰氧基。
该反应的经典反应条件为:在酸受体存在下(如:三乙胺,碳酸氢钠,碳酸氢钾,碳酸钠,或碳酸钾)在适宜的有机溶剂中(如:乙醇,甲醇或乙腈,在高至回流温度下进行该反应。产物可以按惯用方法分离和纯制。
在制备实施例1和18至21中,介绍了7-甲磺酰氨基-1,2,4,5-四氢-3H-3-苯并吖庚因的制备。在倒数第二步,采用适宜的烷磺酰氯,可制得类似的高级烷磺酰氨基衍生物(Ⅲ)。起始原料(Ⅳ)既是已知化合物(见:欧洲专利0245997),但也可按本领域训练有素的人员所熟知的惯用方法制得。
式(Ⅰ)化合物的药物上可以接受的盐包括由酸形成的酸加成盐,该酸形成含药物上可接受的阴离子的非毒性酸加成盐,如:盐酸盐,氢溴酸盐,氢碘酸盐,硫酸盐或硫酸氢盐,磷酸盐或磷酸氢盐,乙酸盐,马来酸盐,富马酸盐,乳酸盐,酒石酸盐,柠檬酸盐,葡糖酸盐,苯甲酸盐,甲磺酸盐,苯磺酸盐和对甲苯磺酸盐。该化合物也可形成金属盐,其中最好是碱土金属盐或碱金属盐。最好是钠盐和钾盐。这类盐可用惯用方法制得。
为了评价本发明化合物对心房不应性的影响,将豚鼠右心房置于含生理盐水的浴液中,一端联接于力传感器,用场电极,以1Hz刺激组织。采用每第8个基础刺激(S1)后引入早期刺激(S2)的方法,测量有效不应期。S1S2相加的间期逐渐增加,直到S2再次引出一次扩增反应。这称之为ERP,此时确定增加ERP 25%(ED25)所需化合物的浓度。用在生理盐水中孵育的豚鼠左乳头肌也可测定其ERP。一端用双极电极刺激肌肉,并在另一端用单极表面电极记录扩增电图。如上所述,用外刺激技术测定ERP通过测定刺激现象和电图峰之间的间期(即:脉冲沿肌肉长度传导的时间,可从数字储存示波器上得出传导时间。
将外刺激技术用于麻醉或失去知觉的狗,在其心房或右心室仍保持恒速博动的同时,也可测得心房和心室的ERP。
式(Ⅰ)化合物可以单独服用。但是,一般与根据预定给药途径和常规制药方法选定的药物载体混合服用。这类化合物既可以给患有心律不齐的病人服用,也可以作为预防药给有心律不齐倾向的病人服用。例如,可以含像淀粉或乳糖这类赋形剂的片剂口服,或者以单一成份胶囊或与赋形剂混合服用,或者以含香料或着色剂的酏剂或混悬剂的形式服用。也可以经胃肠道外注射给药,如:静脉,肌肉或皮下注射。就胃肠道外给药而言,最好采用含其他溶质的无菌水溶液剂型,例如加入足量的盐或葡萄糖以使之成等渗溶液。
就治疗或预防人心脏病用药而言(如:心室和心室上心律不齐,包括心房和心室纤维颤动),按照要求,对成人(70Kg)来说,式(Ⅰ)化合物的口服剂量应为:每天1-75mg,每天分多至4次服用。静脉给药的剂量,按照要求应为:每单一剂量0.5-10mg。对严重心律不齐者,为使之心律尽快恢复正常,最好采用静脉给药。因此,对于典型的成人患者,在适当的药用载体中,每片或每粒胶囊应含1-25mg活性化合物。按照临床经治者所掌握的具体情况,根据受治患者的体重和病情,可以改变用药剂量和方法。
因此,本发明提供了包括前述定义的式(Ⅰ)化合物或其药物上可接受的盐,及其药物上可接受的稀释剂或载体的药物组合物。
本发明还提供了一种预防或减缓人类心律不齐病的方法,该方法包括给所说的人服用有效量的式(Ⅰ)化合物或其药物上可接受的盐,或如上所述的药物组合物。
因此,本发明还提供了用作医药,特别是用作抗心律不齐药的式(Ⅰ)化合物或其药物上可以接受的盐。
本发明还提供了式(Ⅰ)化合物或其药物上可以接受的盐在制备预防或减缓心律不齐药物中的应用。
下列实施例详细地说明了式(Ⅰ)化合物的制备过程,其中所有温度均以℃为单位;
实施例1
7-甲磺酰胺基-3-(2-〔4-甲磺酰胺基苯氧基〕乙基)-1,2,4,5-四氢-3H-3-苯并吖庚因,游离碱和盐酸盐
方法(A)(游离碱)
将甲磺酸酐(0.2ml)加到冷至0℃的7-氨基-3-(2-〔4-氨基苯氧基〕乙基)-1,2,4,5-四氢-3H-3-苯并吖庚因(0.37g)的吡啶(30ml)溶液中,然后将该混合物于室温搅拌72小时。减压蒸掉溶剂,将残留物溶于二氯甲烷中,用碳酸氢钠水溶液洗3次,用盐水洗3次。将有机层干燥(Na2SO4),过滤,减压蒸馏,得到一油状物,后者经硅胶柱层析分离,用含甲醇(0%至5%)的二氯甲烷洗脱。合并含产物馏份,蒸发,得到一半固体产物,经用醚研磨,过滤,干燥,得到无形粉末状标题化合物,0.19g,m.p.不确定。
元素分析%:
实验值:C,53.05;H,6.1;N,8.9;
计算值:C20H27N3O5S2:C,53.0;H,6.00;N,9.3.
1H-N.m.r.(CDCl3):δ=7.2(d,2H);7.05(q,2H);7.00(s,1H);6.9(d,2H);4.1(t,2H);3.00(t,2H);3.00(s,3H);2.95(s,3H);2.9(m,4H);2.8(m,4H).
于室温下,在乙醇中,使用甲磺酰氯和三乙胺也可重复上述反应,并得出相似的结果。
方法(B)(盐酸盐)
用多于45分钟的时间,将甲磺酰氯(70.3g)滴加到搅拌着的,冷至0℃的7-氨基-3-(2-〔4-氨基苯氧基〕乙基)-1,2,4,5-四氢-3H-3-苯并吖庚因(83g)的N-甲基吗啉(700ml)溶液中。将反应物温热至15℃,再另加入甲磺酰氯(14.6g)。从大量的沉淀中倾出溶剂,倾出液倒入水(3000ml)中,用乙酸乙酯(2×500ml)提取水溶液。将沉淀物溶于合并过的有机提取液中,用水(2×500ml)洗涤,干燥(MgSO4),减压蒸馏。将所得到的油溶于2.5M氢氧化钠(400ml)的甲醇(500ml)中,于40℃搅拌半小时。减压蒸掉甲醇,水层用二氯甲烷洗涤2次。用水(1000ml)稀释水层,并用浓盐酸调至pH6.5,将所得沉淀轧碎,过滤,用水洗涤,然后于60℃真空干燥,得到产物110.4g,产物经工业用含甲醇酒精(1100ml)和甲醇(1320ml)重结晶,得到标题化合物73.5g,m.p.221℃。
元素分析%:
实验值:C,48.9;H,5.8;N,8.6;S,13.0;
计算值:C20H27N3O5S2.HCl:C,49.0;H,5.8;N,8.6;S,13.1.
实施例2
7-甲磺酰胺基-3-(4-甲磺酰胺基苯乙基)-1,2,4,5-四氢-3H-3-苯并吖庚因
按照与实施例1方法(A)相似的方法,除反应时间为18小时外,用甲磺酸酐酰化相应的二胺化合物,可制得标题化合物,m.p.184-7℃。检测溶解物并经1H-n.m.r.图谱定性。
元素分析%:-
实验值:C,53.9;H,6.0;N,9.3;
计算值:C20H27N3O4S2.1/10 CH2Cl2:C,54.1;H,6.15;N,9.4.
1H-N.m.r.(DMSO d6):δ=9.55(br s,2H);7.1(q,4H);7.05(d,1H);6.95(s,1H);6.90(d,1H);2.95(s,6H);2.8(br s,4H);2.65(m,8H).
实施例3
7-甲磺酰胺基-3-〔2-(4-甲磺酰胺基-2-甲氧基苯甲酰胺基)乙基〕-1,2,4,5-四氢-3H-3-苯并吖庚因
将甲磺酰氯(0.155ml)滴加到冷至0℃的7-氨基-3-〔2-(4-氨基-2-甲氧基苯甲酰胺基)乙基〕-1,2,4,5-四氢-3H-3-苯并吖庚因的吡啶溶液中,并将该反应混合物于室温下再搅拌18小时。减压蒸除溶剂,并将残留物溶于二氯甲烷中,用碳酸氢钠水溶液洗涤3次,用盐水洗涤3次。将有机层干燥(Na2SO4),过滤,蒸发,得到一油状物,薄层层析表明,其中有一些未反应的起始原料存在。因此,将该油状物溶于吡啶中,用甲磺酰氯(0.05ml)处理之,并将该反应混合物在室温搅拌72小时。减压蒸除溶剂,将残留物溶于二氯甲烷中,用碳酸氢钠水溶液洗涤3次,用盐水洗涤3次。将有机层干燥(Na2SO4),过滤,蒸发,得到一油状物。然后将所得油状物经硅胶柱层析分离,用含甲醇(0%至5%)的二氯甲烷洗脱,合并含产物的馏份,减压蒸发,得到无色泡沫状标题化合物0.32g。
元素分析%:-
实验值:C,51.7;H,6.0;N,10.6;
计算值:C22H30N4O6S2:C,51.7;H,5.9;N,11.0.
1H-N.m.r.(CDCl3)δ=8.4(br s,1H);8.25(d,1H);7.1(d,1H);7.05(s,2H);7.0(d,1H);6.8(d,1H);4.0(s,3H);3.6(m,2H);3.1(s,3H);3.05(s,3H);2.95(br s,4H);2.7(br s,6H).
实施例4
7-甲磺酰胺基-3-〔2-(4-甲磺酰胺基-3-甲基苯氧基)乙基〕-1,2,4,5-四氢-3H-3-苯并吖庚因
将甲磺酰氯(0.18ml)滴加到冷至0℃的7-氨基-3-〔2-(4-氨基-3-甲基苯氧基)乙基〕-1,2,4,5-四氢-3H-3-吖庚因(0.36g)的吡啶(30ml)溶液中,将该反应混合物于室温下搅拌72小时。减压蒸掉溶剂,将残留物溶于二氯甲烷中,用饱和碳酸氢钠水溶液洗涤3次,用盐水洗涤3次。将有机层干燥(Na2SO4),过滤,减压蒸发得到一油状物,将该油用二氯甲烷研磨得到一固体。该固体用乙醇/乙酸乙酯重结晶,得到标题化合物0.28g,m.p.173-174℃。
元素分析%:
实验值:C,54.3;H,6.3;N,8.7;
计算值:C21H29N3O5S2:C,53.9;H,6.25;N,9.0.
1H-N.m.r.(DMSO d6):δ=7.15(d,1H);7.05(d,1H);6.95(s,1H);6.90(d,1H);6.85(d,1H);6.75(dd,1H);4.05(t,2H);2.95(s,3H);2.90(s,3H);2.85(t,2H);2.8(br s,4H);2.7(br s,4H);2.3(s,3H).
实施例5(实施例2的另一方法)
7-甲磺酰胺基-3-(4-甲磺酰胺基苯乙基)-1,2,4,5-四氢-3H-3-苯并吖庚因的制备
将7-甲磺酰胺基-1,2,4,5-四氢-3H-3-苯并吖庚因(0.21g),4-〔2-(甲磺酰氧基)乙基〕甲磺酰苯胺(0.26g)(见欧洲专利申请书0245997,制备7)和三乙胺(0.12ml),在乙醇中,于回流温度下加热24小时。减压除去溶剂,将残留物溶于二氯甲烷中,依次用碳酸氢钠水溶液,盐水和水洗涤。用Na2SO4干燥有机层,减压蒸发。残留物经硅胶柱层析分离,用含甲醇(0%至5%)的二氯甲烷洗脱,合并含产物的馏份,蒸发,得到一固体,经重结晶,得到标题化合物0.05g,m.p.190-193℃。
元素分析%:
实验值:C,55.1;H,6.3;N,9.4;
计算值:C20H27N3O4S2:C,54.9;H,6.2;N,9.6.
下列制备过程详细地说明了前述实施例中某些起始原料的制备。所有的温度均以℃为单位;
制备1:
(参见J.Het.Chem.,p.779,vol.8,1971)
7-硝基-1,2,4,5-四氢-3H-3-苯并吖庚因
将1,2,4,5-四氢-3H-3-苯并吖庚因(1g)(参见:P.Ruggli et al.,Helv.Chem.Acta,18,1388〔1935〕)缓慢地滴加到搅拌着的冷至-10℃的发烟硝酸(25ml,比重为1.5g/ml)。在-10℃连续搅拌1小时,然后将该反应混合物倒在冰上,过滤收集沉淀,干燥,得到标题化合物的硝酸盐1.4g。取样在水中重结晶,m.p.203-204℃。
元素分析%:
实验值:C,46.9;H,5.4;N,16.6;
计算值:C10H12N2O2.HNO3:C,47.05;H,5.1;N,16.5.
将一部分上述硝酸盐混悬于水中,冷却,用5M氢氧化钠中和,过滤收集沉淀,用水重结晶,干燥,得到标题化合物0.6g,m.p.53-56℃。
元素分析%:
实验值:C,62.9;H,6.45;N,14.8.
计算值:C10H12N2O2:C,62.5;H,6.3;N,14.6.
备制2
7-硝基-3-(2-〔4-硝基苯氧基)乙基)-1,2,4,5-四氢-3H-3-苯并吖庚因
将7-硝基-1,2,4,5-四氢-3H-3-苯并吖庚因(0.7g)2-〔4-硝基苯氧基〕乙基氯(0.73g)(见:C.A.〔1955〕,49,3163e),碘化钠(0.5g),碳酸钾,在乙腈(50ml)中,加热回流3天。冷却后,减压蒸除溶剂,将残留物溶于乙酸乙酯中,依次用水(一次),碳酸钠(一次),盐水(两次)洗涤。将有机层干燥(Na2SO4),减压蒸发,得到一油状物,后者经硅胶柱层析分离,用含甲醇(0%至5%)的二氯甲烷洗脱。合并含产物的馏份,减压蒸发,得到橙色油状产物1.0g。
元素分析%:
实验值:C,60.5;H,5.5;N,11.9;
计算值:C18H19N3O5:C,60.5;H,5.4;N,11.8.
制备3
7-硝基-3-(4-硝基苯乙基)-1,2,4,5-四氢-3H-3-苯并吖庚因半水合
与制备2类似,通过7-硝基-1,2,4,5-四氢-3H-3-苯并吖庚因(0.5g)与4-硝基苯乙基溴(0.6g)反应,回流18小时后,得到油状标题化合物0.29g。
元素分析%:
实验值:C,61.7;H,5.5;N,12.1;
计算值:C18H19N3O4.1/2H2O:C,61.7;H,5.75;N,12.0.
制备4
7-氨基-3-(2-〔4-氨基苯氧基〕乙基)-1,2,4,5-四氢-3H-3-苯并吖庚因
在含5%Pd/c的乙酸乙酯中,在氢气压下〔344.7kPa(50p.s.i.)〕,将7-硝基-3-(2-〔4-硝基苯氧基〕乙基)-1,2,4,5-四氢-3H-3-苯并吖庚因(0.42g)于室温下搅拌4小时。然后滤除催化剂,减压蒸发滤液,得到油状标题化合物0.3g,不用进一步纯化便可直接使用。
1H-N.m.r.(CDCl3):δ=6.9(d,1H);6.7(q,4H);6.45(q,2H);4.05(t,2H);2.95(t,2H);2.80(m,8H).
制备5
7-氨基-3-(4-氨基苯乙基)-1,2,4,5-四氢-3H-3-苯并吖庚因
以类似于制备4的方法,通过将相应的二硝基化合物氢化,制得了标题化合物。
1H-N.m.r.(CDCl3):δ=7.02(d,2H);6.9(d,1H);6.65(d,2H);6.5(s,1H);6.45(d,1H);2.9(br s,4H);2.7(br s,8H).
制备6
2-甲磺酰氧乙基叠氮
将甲磺酰氯(5.7g)的二氯甲烷(20ml)溶液滴加到搅拌着的2-叠氮乙醇(4.3g)和三乙胺(5.0g)的二氯甲烷(80ml)溶液中。于室温下搅拌2小时后,用水洗涤该反应混合物,干燥(MgSO4),减压蒸发至干,得到黄色油状标题化合物7g,无须进一步纯化便可直接使用。
1H-N.m.r.(CDCl3):δ=4.25(t,2H);3.5(t,2H);3.0(s,3H).
制备7
3-(2-叠氮乙基)-7-硝基-1,2,4,5-四氢-3H-3-苯并吖庚因
将7-硝基-1,2,4,5-四氢-3H-3-苯并吖庚因(1.1g),2-甲磺酰氧乙基叠氮(0.92g),碳酸钾(0.76g),在乙腈中加热回流18小时。减压蒸除溶剂,将残留物溶于乙酸乙酯中,然后用碳酸钠水溶液洗涤3次,用盐水洗3次。将有机层干燥,过滤,减压蒸发,得到一油状物,后者经硅胶柱层析分离,用乙酸乙酯/己烷(1∶1)洗脱。合并含产物的馏份,蒸发,得到油状标题化合物0.65(无须纯制便可使用)。
I.R.γ=2100cm-1(叠氮基)
1H-N.m.r.(CDCl3):δ=8.05(d,1H);8.05(s,1H);7.3(d,1H);3.4(t,2H);3.1(m,4H);2.75(m,6H).
制备8
3-(2-氨乙基)-7-硝基-1,2,4,5-四氢-3H-3-苯并吖庚因
充氮下,将三苯基磷(0.71g)加到3-(2-叠氮乙基)-7-硝基-1,2,4,5-四氢-3H-3-苯并吖庚因(0.68g)的无水四氢呋喃溶液中,然后将该反应混合物于室温搅拌18小时,于50℃加热5小时。冷却后加入水,将该混合物于室温搅拌3天。然后减压蒸掉溶剂,用2M的盐酸稀释残留物,并用乙酸乙酯洗3次。用5M的氢氧化钠使水层碱化(pH=12),用乙酸乙酯提取3次。合并后3次有机提取液,干燥(Na2SO4),过滤,减压蒸发,得到油状标题化合物0.56g,无须进一步纯制便可使用。
制备9
7-硝基-3-(2-〔2-甲氧基-4-硝基苯甲酰胺基〕乙基)-1,2,4,5-四氢-3H-3-苯并吖庚因
将2-甲氧基-4-硝基苯甲酰氯(0.56g)的二氯甲烷溶液滴加到搅拌着的冷至0℃的3-(2-氨乙基)-7-硝基-1,2,4,5-四氢-3H-3-苯并吖庚因(0.56g)的二氯甲烷溶液中,并于室温连续搅拌1小时。然后减压蒸除溶剂,用醚研磨残留物,过滤。将沉淀物混悬于碳酸钠水溶液中,用二氯甲烷提取3次。合并有机层,然后用盐水洗3次,干燥(Na2SO4),过滤,减压蒸发。残留物经硅胶柱层析分离,用含甲醇(0%至2%)二氯甲烷洗脱。合并含产物的馏份,减压蒸发,得到标题化合物0.55,m.p.138-140℃。
元素分析%:
实验值:C,58.05;H,5.5;N,13.1;
计算值:C20H22N4O6:C,58.0;H,5.35;N,13.5.
制备10
7-氨基-3-(2-〔4-氨基-2-甲氧基苯甲酰胺基〕乙基)-1,2,4,5-四氢-3H-3-苯并吖庚因
在氢气压〔344.7kPa(50p.s.i.)〕,室温条件下,将7-硝基-3-(2-〔2-甲氧基-4-硝基苯甲酰胺基〕乙基)-1,2,4,5-四氢-3H-苯并吖庚因(0.52g)在乙醇/甲醇溶液中搅拌3小时。然后滤除催化剂,减压蒸发滤液,得到泡沫状标题化合物0.42g,天须进一步纯制便可直接使用。
1H-N.m.r.(CDCl3):δ=8.4(br s,1H);8.1(d,1H);6.95(d,1H);6.5(s,2H);6.45(d,1H);6.35(q,1H);6.25(d,1H);4.0(s,2H);3.95(s,3H);3.6(s,2H);2.9(m,4H);2.7(m,2H).
制备11
2-甲氧基-4-硝基苯甲酰氯
(J.Chem.Soc.,1917,111,220.)
将于二氯甲烷(10ml)中的草酰氯(0.81ml)滴加到2-甲氧基-4-硝基苯甲酸-水合物(1g)和DMF(1滴)的二氯甲烷溶液中,在放气停止后,将该反应混合物在室温搅拌1小时。然后减压蒸除溶剂,得到一油状物,用冷却的乙酸乙酯/己烷结晶,得到标题化合物0.7g。
该低熔化合物不经进一步纯制便可直接使用。
制备12
2-(4-硝基苯氧基)乙基氯
将4-硝基苯酚(139g,1mole),2-(苯磺酰氧基)乙基氯(220.5g,1mole-参见:Ber(1920),53,1836)和无水碳酸钾(138g,1mole)置于甲乙酮(“MEK”-1000ml)中,然后将该混合物搅拌回流16小时。冷却后,将该混合物倒入水中,分离有机层,再用甲乙酮提取两次,合并有机层,干燥(MgSO4),过滤,蒸发。所得固体用乙醇结晶,得到标题化合物(165.8g),m.p.60℃。
元素分析%:
实验值:C,47.65;H,4.0;N,7.0;
计算值:C8H8ClNO3:C,47.7;H,4.0;N,7.0.
制备13
4-(2-氯乙氧基)-2-甲基乙酰苯胺
Annalen,259,217(1890).
将4-羟基-2-甲基乙酰苯胺(33g),2-甲苯磺酰氧基乙基氯(46.9g)和碳酸钾(23.6g)的混合物在丁酮-2-中加热回流6小时。然后将该反应混合物冷却,用水稀释,过滤收集沉淀,水洗,用乙醇重结晶,得到标题化合物22g,m.p.127-129℃。
元素分析%:
实验值:C,58.0;H,6.2;N,6.15;
计算值:C11H14ClNO2:C,58.2;H,6.3;N,6.4.
制备14
3-〔2-(4-乙酰氨基-3-甲基苯氧基)乙基〕-7-硝基-1,2,4,5-四氢-3H-3-苯并吖庚因
将7-硝基-1,2,4,5-四氢-3H-3-苯并吖庚因(1.69g),2-甲基-4-(2-氯乙氧基)乙酰苯胺(2g),碳酸钾(1.21g),碘化钠(1.32g),在乙腈中加热回流5天。冷却后,减压除去溶剂,并用碳酸钠溶液稀释残留物,用二氯甲烷提取3次。合并有机提取液,用盐水洗涤3次,干燥(Na2SO4),蒸发,得到一种半固体,后者用醚研磨得到一固体。该固体经乙酸乙酯/己烷重结晶,得到标题化合物1.6g,m.p.132-134℃。
元素分析%:
实验值:C,65.9;H,6.7;N,11.0;
计算值:C21H25N3O4:C,65.8;H,6.6;N,11.0.
制备15
3-〔2-(4-氨基-3-甲基苯氧基)乙基〕-7-硝基-1,2,4,5-四氢-3H-3-苯并吖庚因二盐酸盐
将3-〔2-(4-乙酰氨基-3-甲基苯氧基)乙基〕-7-硝基-1,2,4,5-四氢-3H-3-苯并吖庚因(1g)在6M的盐酸中(20ml),于90℃,搅拌18小时。冷却后,过滤收集沉淀,并用乙醇重结晶,得到标题化合物0.65g,m.p.253-256℃。
元素分析%:
实验值:C,53.9;H,6.6;N,9.1;
计算值:C19H23N3O2.2HCl.1/2H2O.1/2C2H5OH*:C,53.8;H,6.3;
*经鉴定,样品中含1/2摩尔乙醇,并经1H-n.m.r.定性。
1H-N.m.r.(CDCl3)δ=8.0(s,1H);8.0(d,1H);7.5(d,1H);7.3(d,1H);6.9(s,1H);6.9(q,2H);4.1(t,2H);3.05(m,6H);2.8(br s,4H);2.25(s,3H);2.2(s,3H).
制备16
3-〔2-(4-氨基-3-甲基苯氧基)乙基〕-7-硝基-1,2,4,5-四氢-3H-3-苯并吖庚因
将3-〔2-(4-氨基-3-甲基苯氧基)乙基〕-7-硝基-1,2,4,5-四氢-3H-3-苯并吖庚因二盐酸盐半水合物(0.62g)溶于饱和碳酸钠水溶液(20ml)中,并用乙酸乙酯(30ml)提取3次。合并有机提取液,干燥(Na2SO4),减压蒸发,得到油状标题化合物0.5g,不经进一步纯制便可直接使用。
制备17
7-氨基-3-〔2-(4-氨基-3-甲基苯氧基)乙基)-1,2,4,5-四氢-3H-3-苯并吖庚因
氢气压(344.7kPa(50p.s.i.)〕下,在乙酸乙酯(20ml)和含5%Pd/c(0.075g)的甲醇中,于室温下,将3-〔2-(4-氨基-3-甲基苯氧基)乙基〕-7-硝基-1,2,4,5-四氢-3H-3-苯并吖庚因(0.5g)搅拌3小时。然后过滤除去催化剂,减压蒸发滤液,得到油状标题化合物0.385g,无须进一步纯化便可直接使用。
1H-N.m.r.(CDCl3):δ=6.9(d,1H);6.7(s,1H);6.6(s,2H);6.5(s,2H);4.05(t,2H);2.95(t,2H);2.8(m,8H);2.2(s,3H).
制备18
3-叔丁氧羰基-7-硝基-1,2,4,5-四氢-3H-3-苯并吖庚因
将二叔丁基二羧酸酐(2.18g)的无水二氯甲烷(15ml)溶液滴加到搅拌着的冷至0℃的7-硝基-1,2,4,5-四氢-3H-3-苯并吖庚因(1.92g)的无水二氯甲烷(40ml)溶液中。于室温下搅拌18小时后,减压除去溶剂,得到一油状物,将后者溶于二氯甲烷中,然后依次用碳酸氢钠水溶液洗两次,用1M的盐酸洗三次,最后用盐水洗两次。将该二氯甲烷溶液干燥(Na2SO4),减压蒸发,得到一油状物,后者用己烷研磨,得到题目化合物,得量2.33g,m.p.106-108℃。
元素分析%:
实验值:C,61.7;H,7.0;N,9.6;
计算值:C15H20N2O4:C,61.6;H,6.9;N,9.6.
制备19
7-氨基-3-叔丁氧基羰基-1,2,4,5-四氢-3H-3-苯并吖庚因
在氢气压下(50.p.s.i.,相当于344.7kPa),在含5%Pd/c(0.21g)的乙醇(20ml)和甲醇(20ml)溶液中,将3-叔丁氧羰基-7-硝基-1,2,4,5-四氢-3H-3-苯并吖庚因(2.1g)溶液搅拌3小时。过滤除去催化剂,蒸掉溶剂,得到油状标题化合物2.0g。
该油状物的样品(100mg)经硅胶层析分离,用含甲醇(0%至2%)的二氯甲烷洗脱。合并含产物的馏份,减压蒸发,得到低熔点固体状(~30℃)标题化合物58mg。
元素分析%:
实验值:C,69.0;H,8.6;N,10.3;
计算值:C15H22N2O2:C,68.7;H,8.45;N,10.7.
制备20
7-甲磺酰胺基-3-叔丁氧羰基-1,2,4,5-四氢-3H-3-苯并吖庚因
将甲磺酰氯(0.56ml)滴加到冷至0℃的7-氨基-3-叔丁氧羰基-1,2,4,5-四氢-3H-3-苯并吖庚因(1.9g)的吡啶(40ml)溶液中。于室温下连续搅拌18小时。蒸除溶剂,得到一油状物,将该油溶于二氯甲烷中,用碳酸氢钠水溶液洗3次,用盐水洗3次,然后干燥(Na2SO4),减压蒸发。残留物经硅胶柱层析分离,用含甲醇(0%至5%)的二氯甲烷洗脱。合并含产物的馏份,减压蒸发,得到一半固体状产物,后者与醚研磨,得到风力式。
标题化合物1.2g,m.p.153-154℃。
元素分析%:
实验值:C,56.6;H,7.05;N,8.2;
计算值:C16H24N2O4S:C,56.45;H,7.1;N,8.2.
制备21
7-甲磺酰胺基-1,2,4,5-四氢-3H-3-苯并吖庚因
将3-叔丁氧羰基-7-甲磺酰胺基-1,2,4,5-四氢-3H-3-苯并吖庚因(0.6g)和98%的甲酸(10ml)一起在室温下搅拌2小时。减压蒸掉溶剂,得到一油状物,后者用碳酸氢钠水溶液碱化。减压蒸发该水溶液,并用热异丙醇研磨该残留物。倾出异丙醇,减压蒸发,得到一固体,用乙酸乙酯/己烷重结晶,得到标题化合物0.22g。
元素分析%:
实验值:C,54.7;H,7.0;N,11.4;
计算值:C11H16N2O2S:C,55.0;H,6.7;N,11.7.
Claims (11)
2、权利要求1所述方法,其特征在于该方法在酸受体存在下进行。
3、权利要求2所述方法,其特征在于所说酸受体是吡啶,N-甲基吗啉,三乙胺,碳酸钾或碳酸氢钠。
4、前述权利要求中任一权项所述方法,其特征在于用甲磺酰氯或甲磺酸酐进行该反应。
5、权利要求4所述方法,其特征在于:由7-氨基-3-(2-〔4-氨基苯氧基〕乙基)-1,2,4,5-四氢-3H-3-苯并吖庚因与甲磺酰氯或甲磺酸酐反应,制得7-甲磺酰胺基-3-(2-〔4-甲磺酰胺基苯氧基〕乙基)-1,2,4,5-四氢-3H-3-苯并吖庚因。
6、制备具有式(Ⅰ″)化合物或其药物上可接受的盐的方法;其特征在于由式(Ⅲ)化合物与式(a)化合物反应,继之任意地将式(Ⅰ″)产物转化成药物上可接受的盐,式(Ⅰ″)为:
式中:R1是H,C1-C4烷基或C1-C4烷氧基;
R2和R3彼此相同或不同,各自为C1-C4烷基;
X是0或直接连键;
式(Ⅲ)为:
其中R2如前所述,
式(a)为:
其中R1,R3和X如前所述,Q是离去基团。
7、权利要求6所述方法,其特征在于所说离去基团是氯,溴,碘,甲磺酰氧基,苯甲磺酰氧基或甲苯磺酰氧基。
8、权利要求6或7所述方法,其特征在于该方法在酸受体存在下进行。
9、权利要求8所述方法,其特征在于所说酸受体是三乙胺。
10、前述权利要求中任一权项所述方法,其特征在于R1是H,甲基或甲氧基,并且R2和R3是甲基。
11、制备药用组合物的方法,其特征在于:分别将权利要求1和6所述式(Ⅰ′)或(Ⅰ″)化合物,或其药物上可接受的盐与药物上可接受的稀释剂或载体混合。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB878707120A GB8707120D0 (en) | 1987-03-25 | 1987-03-25 | Antiarrhythmic agents |
GB8707120 | 1987-03-25 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN88101782A true CN88101782A (zh) | 1988-11-02 |
CN1023644C CN1023644C (zh) | 1994-02-02 |
Family
ID=10614606
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN88101782A Expired - Fee Related CN1023644C (zh) | 1987-03-25 | 1988-03-25 | 抗心律不齐药化合物的制备方法 |
Country Status (28)
Country | Link |
---|---|
US (1) | US4891372A (zh) |
EP (1) | EP0284384B1 (zh) |
JP (1) | JPH0662573B2 (zh) |
KR (1) | KR900006099B1 (zh) |
CN (1) | CN1023644C (zh) |
AT (1) | ATE58726T1 (zh) |
AU (1) | AU583763B2 (zh) |
CA (1) | CA1294273C (zh) |
DD (1) | DD280965A5 (zh) |
DE (1) | DE3861147D1 (zh) |
DK (1) | DK170890B1 (zh) |
ES (1) | ES2021142B3 (zh) |
FI (1) | FI85468C (zh) |
GB (1) | GB8707120D0 (zh) |
GR (1) | GR3001507T3 (zh) |
HU (1) | HU199124B (zh) |
IE (1) | IE61070B1 (zh) |
IL (1) | IL85822A (zh) |
MX (1) | MX10867A (zh) |
MY (1) | MY103245A (zh) |
NO (1) | NO168421C (zh) |
NZ (1) | NZ224017A (zh) |
PH (1) | PH24074A (zh) |
PL (1) | PL153455B1 (zh) |
PT (1) | PT87048B (zh) |
SU (1) | SU1579456A3 (zh) |
YU (1) | YU47191B (zh) |
ZA (1) | ZA882103B (zh) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4906634A (en) * | 1988-03-08 | 1990-03-06 | Schering A.G. | Novel N-[4-(aminosubstituted)phenyl]methanesulfonamides and their use as cardiovascular agents |
US4966967A (en) * | 1989-09-15 | 1990-10-30 | Berlex Laboratories, Inc. | 3,4,5,6-tetrahydro-2H-1,7,4-benzodioxazonines as cardiovascular agents |
US5206240A (en) * | 1989-12-08 | 1993-04-27 | Merck & Co., Inc. | Nitrogen-containing spirocycles |
US5112824A (en) * | 1989-12-08 | 1992-05-12 | Merck & Co., Inc. | Benzofuran compounds as class III antiarrhythmic agents |
US5032598A (en) * | 1989-12-08 | 1991-07-16 | Merck & Co., Inc. | Nitrogens containing heterocyclic compounds as class III antiarrhythmic agents |
US5215989A (en) * | 1989-12-08 | 1993-06-01 | Merck & Co., Inc. | Nitrogen-containing heterocyclic compounds as class III antiarrhythmic agents |
US5032604A (en) * | 1989-12-08 | 1991-07-16 | Merck & Co., Inc. | Class III antiarrhythmic agents |
US5382587A (en) * | 1993-06-30 | 1995-01-17 | Merck & Co., Inc. | Spirocycles |
US5403846A (en) * | 1993-11-22 | 1995-04-04 | Merck & Co., Inc. | Spirocycles |
US5439914A (en) * | 1994-02-18 | 1995-08-08 | Merck & Co., Inc. | Spirocycles |
US6083991A (en) | 1997-06-04 | 2000-07-04 | University Of Florida Research Foundation, Inc. | Anti-arrhythmic composition and methods of treatment |
FR2920773B1 (fr) * | 2007-09-11 | 2009-10-23 | Servier Lab | Derives de 1,2,4,5-tetrahydro-3h-benzazepines, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR148F (zh) * | 1962-01-24 | |||
US3478149A (en) * | 1962-01-24 | 1969-11-11 | Mead Johnson & Co | Therapeutic compositions and methods employing sulfonamidophenethanolamines |
US4233217A (en) * | 1968-03-11 | 1980-11-11 | Pennwalt Corporation | Substituted 1,2,4,5-tetrahydro-3H, 3 benzazepines |
CA974989A (en) * | 1968-03-11 | 1975-09-23 | Wallace And Tiernan Inc. | Process for preparing 1,2,4,5-tetrahydro-3h,3-benzazepines and products obtained thereby |
US3758692A (en) * | 1969-04-14 | 1973-09-11 | Mead Johnson & Co | Ylamines sympathomimetic process and compositions employing sulfonamidophenalk |
US3574741A (en) * | 1969-04-14 | 1971-04-13 | Mead Johnson & Co | Sulfonamidophenalkylamines |
BE757005A (fr) * | 1969-10-02 | 1971-04-02 | Bristol Myers Co | Phenethanolamines substituees et procede pour leur preparation |
US4210749A (en) * | 1974-11-12 | 1980-07-01 | Pennwalt Corporation | Substituted 1,2,4,5-tetrahydro-3H,3 benzazepines |
US4581370A (en) * | 1983-07-12 | 1986-04-08 | Schering A.G. | Antiarrhythmic imidazoliums |
DE3566886D1 (en) * | 1984-05-04 | 1989-01-26 | Upjohn Co | N-(aminoalkylphenyl)sulfonamides their preparation and therapeutic use |
DK180485D0 (da) * | 1985-04-22 | 1985-04-23 | Novo Industri As | Nitrogenholdige forbindelser |
EP0204349A3 (de) * | 1985-06-01 | 1990-01-03 | Dr. Karl Thomae GmbH | Neue heteroaromatische Aminderivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
-
1987
- 1987-03-25 GB GB878707120A patent/GB8707120D0/en active Pending
-
1988
- 1988-03-21 US US07/170,499 patent/US4891372A/en not_active Expired - Lifetime
- 1988-03-22 MY MYPI88000297A patent/MY103245A/en unknown
- 1988-03-23 PL PL1988271379A patent/PL153455B1/pl unknown
- 1988-03-23 IL IL85822A patent/IL85822A/xx not_active IP Right Cessation
- 1988-03-23 CA CA000562151A patent/CA1294273C/en not_active Expired - Lifetime
- 1988-03-23 FI FI881392A patent/FI85468C/fi not_active IP Right Cessation
- 1988-03-23 PT PT87048A patent/PT87048B/pt not_active IP Right Cessation
- 1988-03-24 ZA ZA882103A patent/ZA882103B/xx unknown
- 1988-03-24 NZ NZ224017A patent/NZ224017A/xx unknown
- 1988-03-24 KR KR1019880003152A patent/KR900006099B1/ko not_active IP Right Cessation
- 1988-03-24 EP EP88302597A patent/EP0284384B1/en not_active Expired - Lifetime
- 1988-03-24 MX MX1086788A patent/MX10867A/es unknown
- 1988-03-24 DK DK160488A patent/DK170890B1/da not_active IP Right Cessation
- 1988-03-24 DD DD88313961A patent/DD280965A5/de not_active IP Right Cessation
- 1988-03-24 DE DE8888302597T patent/DE3861147D1/de not_active Expired - Lifetime
- 1988-03-24 ES ES88302597T patent/ES2021142B3/es not_active Expired - Lifetime
- 1988-03-24 SU SU4355570A patent/SU1579456A3/ru active
- 1988-03-24 IE IE88488A patent/IE61070B1/en not_active IP Right Cessation
- 1988-03-24 YU YU59688A patent/YU47191B/sh unknown
- 1988-03-24 AU AU13571/88A patent/AU583763B2/en not_active Ceased
- 1988-03-24 NO NO881314A patent/NO168421C/no not_active IP Right Cessation
- 1988-03-24 PH PH36682A patent/PH24074A/en unknown
- 1988-03-24 AT AT88302597T patent/ATE58726T1/de not_active IP Right Cessation
- 1988-03-25 CN CN88101782A patent/CN1023644C/zh not_active Expired - Fee Related
- 1988-03-25 HU HU881530A patent/HU199124B/hu not_active IP Right Cessation
- 1988-03-25 JP JP63071710A patent/JPH0662573B2/ja not_active Expired - Fee Related
-
1991
- 1991-02-26 GR GR91400225T patent/GR3001507T3/el unknown
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