CN1049888C - 苯甲酰基胍的制备方法 - Google Patents
苯甲酰基胍的制备方法 Download PDFInfo
- Publication number
- CN1049888C CN1049888C CN90107457A CN90107457A CN1049888C CN 1049888 C CN1049888 C CN 1049888C CN 90107457 A CN90107457 A CN 90107457A CN 90107457 A CN90107457 A CN 90107457A CN 1049888 C CN1049888 C CN 1049888C
- Authority
- CN
- China
- Prior art keywords
- methyl
- benzoylguanidines
- fusing point
- acid
- methylsulfonyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- AJDQRQQNNLZLPM-UHFFFAOYSA-N n-(diaminomethylidene)benzamide Chemical compound NC(N)=NC(=O)C1=CC=CC=C1 AJDQRQQNNLZLPM-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 239000003814 drug Substances 0.000 title description 9
- 238000004519 manufacturing process Methods 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 55
- -1 3-methylsulfonyl-4-(piperidino) benzoylguanidines 4-thiophenyl-3-sulfamyl benzoylguanidines Chemical class 0.000 claims description 39
- 238000000034 method Methods 0.000 claims description 25
- 229910052799 carbon Inorganic materials 0.000 claims description 20
- 239000000460 chlorine Substances 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 11
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 150000002357 guanidines Chemical class 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- BVSDDNGJJYSHEN-UHFFFAOYSA-N CS(=O)(=O)C=1C=C(C(=O)NC(=N)N)C=CC1C=1SC=CC1 Chemical class CS(=O)(=O)C=1C=C(C(=O)NC(=N)N)C=CC1C=1SC=CC1 BVSDDNGJJYSHEN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000002837 carbocyclic group Chemical group 0.000 claims description 2
- 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 2
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims 2
- 239000012434 nucleophilic reagent Substances 0.000 claims 1
- 230000003288 anthiarrhythmic effect Effects 0.000 abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 96
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 74
- 229960004198 guanidine Drugs 0.000 description 41
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 40
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 36
- 238000006243 chemical reaction Methods 0.000 description 26
- 239000013078 crystal Substances 0.000 description 24
- 239000000843 powder Substances 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical class OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 21
- 239000002904 solvent Substances 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 18
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 16
- ZWBQTUAUWSDCKX-UHFFFAOYSA-N 4-chloro-3-methylsulfonylbenzoic acid Chemical compound CS(=O)(=O)C1=CC(C(O)=O)=CC=C1Cl ZWBQTUAUWSDCKX-UHFFFAOYSA-N 0.000 description 15
- 229940095102 methyl benzoate Drugs 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 239000003999 initiator Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- 238000000354 decomposition reaction Methods 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- 238000002425 crystallisation Methods 0.000 description 10
- 235000019441 ethanol Nutrition 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 230000008025 crystallization Effects 0.000 description 9
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 8
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- VCOYRKXQRUGBKS-UHFFFAOYSA-N N.[Cl] Chemical compound N.[Cl] VCOYRKXQRUGBKS-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 7
- IOHPVZBSOKLVMN-UHFFFAOYSA-N 2-(2-phenylethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCC1=CC=CC=C1 IOHPVZBSOKLVMN-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000009835 boiling Methods 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 235000011121 sodium hydroxide Nutrition 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 229960000789 guanidine hydrochloride Drugs 0.000 description 5
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 239000012429 reaction media Substances 0.000 description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000000470 constituent Substances 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- NGBMRUQCUCRKQN-UHFFFAOYSA-N 4-fluoro-3-sulfamoylbenzoic acid Chemical compound NS(=O)(=O)C1=CC(C(O)=O)=CC=C1F NGBMRUQCUCRKQN-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 239000003416 antiarrhythmic agent Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical class ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 230000003203 everyday effect Effects 0.000 description 3
- 208000010125 myocardial infarction Diseases 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 description 2
- LZGZJLJZSAGDKR-UHFFFAOYSA-N 3-chlorosulfonyl-4-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C(S(Cl)(=O)=O)=C1 LZGZJLJZSAGDKR-UHFFFAOYSA-N 0.000 description 2
- XQMRJPIIQVAONW-UHFFFAOYSA-N 4-benzyl-3-methylsulfonylbenzoyl chloride Chemical compound CS(=O)(=O)C1=CC(C(Cl)=O)=CC=C1CC1=CC=CC=C1 XQMRJPIIQVAONW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- JNBCXUUCHANVPD-UHFFFAOYSA-N COC(C1=CC(=C(C=C1)C=1SC=CC1)S(N)(=O)=O)=O Chemical class COC(C1=CC(=C(C=C1)C=1SC=CC1)S(N)(=O)=O)=O JNBCXUUCHANVPD-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 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
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 208000004880 Polyuria Diseases 0.000 description 2
- 208000001871 Tachycardia Diseases 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000012752 auxiliary agent Substances 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 230000005540 biological transmission Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- FTAORUVBXKFVDA-UHFFFAOYSA-N cyclohexylsulfanylcyclohexane Chemical compound C1CCCCC1SC1CCCCC1 FTAORUVBXKFVDA-UHFFFAOYSA-N 0.000 description 2
- KIDLLGOQWUQWEA-UHFFFAOYSA-L disodium 4-chloro-3-sulfinatobenzoate Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=C(Cl)C(S([O-])=O)=C1 KIDLLGOQWUQWEA-UHFFFAOYSA-L 0.000 description 2
- 230000035619 diuresis Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229960001031 glucose Drugs 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- MQEHZIIXZHVUQS-UHFFFAOYSA-N methyl 4-amino-3-methylsulfonylbenzoate Chemical class COC(=O)C1=CC=C(N)C(S(C)(=O)=O)=C1 MQEHZIIXZHVUQS-UHFFFAOYSA-N 0.000 description 2
- NLPRXDKTULOVCK-UHFFFAOYSA-N methyl 4-chloro-3-methylsulfonylbenzoate Chemical class COC(=O)C1=CC=C(Cl)C(S(C)(=O)=O)=C1 NLPRXDKTULOVCK-UHFFFAOYSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- MAGVJLLHDZWQFM-UHFFFAOYSA-N n-chloro-n-methylmethanamine Chemical compound CN(C)Cl MAGVJLLHDZWQFM-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- RINCXYDBBGOEEQ-UHFFFAOYSA-N succinic anhydride Chemical compound O=C1CCC(=O)O1 RINCXYDBBGOEEQ-UHFFFAOYSA-N 0.000 description 2
- 230000006794 tachycardia Effects 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- LNLHPBJXXTZBEZ-UHFFFAOYSA-N (2,3,4,5,6-pentafluorophenyl) 4-sulfamoylbenzoate Chemical class C1=CC(S(=O)(=O)N)=CC=C1C(=O)OC1=C(F)C(F)=C(F)C(F)=C1F LNLHPBJXXTZBEZ-UHFFFAOYSA-N 0.000 description 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- LIHSOKFARJWASE-UHFFFAOYSA-N 1H-imidazole imidazolidine Chemical compound N1CNCC1.N1C=NC=C1 LIHSOKFARJWASE-UHFFFAOYSA-N 0.000 description 1
- RPFXNLAQWORIOK-UHFFFAOYSA-N 2-amino-4-cyclopentyl-3-methylsulfonylbenzoic acid Chemical compound CS(=O)(=O)C1=C(N)C(C(O)=O)=CC=C1C1CCCC1 RPFXNLAQWORIOK-UHFFFAOYSA-N 0.000 description 1
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 description 1
- UWNPAZQRCXOJHK-UHFFFAOYSA-N 3-methylsulfonyl-4-pyrrolidin-1-ylbenzoyl chloride Chemical compound CS(=O)(=O)C1=CC(C(Cl)=O)=CC=C1N1CCCC1 UWNPAZQRCXOJHK-UHFFFAOYSA-N 0.000 description 1
- KUTBMATZUQWFSR-UHFFFAOYSA-N 3-methylsulfonylbenzoic acid Chemical group CS(=O)(=O)C1=CC=CC(C(O)=O)=C1 KUTBMATZUQWFSR-UHFFFAOYSA-N 0.000 description 1
- BWNRMNBZRGLEJR-UHFFFAOYSA-N 4-(benzylamino)-3-methylsulfonylbenzoic acid Chemical compound CS(=O)(=O)C1=CC(C(O)=O)=CC=C1NCC1=CC=CC=C1 BWNRMNBZRGLEJR-UHFFFAOYSA-N 0.000 description 1
- LYBQQYNSZYSUMT-UHFFFAOYSA-N 4-chloro-3-chlorosulfonylbenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C(S(Cl)(=O)=O)=C1 LYBQQYNSZYSUMT-UHFFFAOYSA-N 0.000 description 1
- XTBFOJKVQGWRSR-UHFFFAOYSA-N 4-chloro-3-sulfinobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C(S(O)=O)=C1 XTBFOJKVQGWRSR-UHFFFAOYSA-N 0.000 description 1
- BBYDXOIZLAWGSL-UHFFFAOYSA-N 4-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C=C1 BBYDXOIZLAWGSL-UHFFFAOYSA-N 0.000 description 1
- XFPXGSMHIQZNIG-UHFFFAOYSA-N 4-methoxycarbonyl-2-nitrobenzenesulfonic acid Chemical class C1=C(C(=CC=C1C(=O)OC)S(=O)(=O)O)N(=O)=O XFPXGSMHIQZNIG-UHFFFAOYSA-N 0.000 description 1
- SOSVTEHBZNSARP-UHFFFAOYSA-N 4-sulfamoylbenzoyl chloride Chemical compound NS(=O)(=O)C1=CC=C(C(Cl)=O)C=C1 SOSVTEHBZNSARP-UHFFFAOYSA-N 0.000 description 1
- DFXQXFGFOLXAPO-UHFFFAOYSA-N 96-99-1 Chemical compound OC(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 DFXQXFGFOLXAPO-UHFFFAOYSA-N 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- 244000215068 Acacia senegal Species 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
- 206010002091 Anaesthesia Diseases 0.000 description 1
- XYCNHYYTMFTLLA-UHFFFAOYSA-N C(CCC)OC(C=1CC(C(=O)O)(C=CC1)C)=O.C1(=CC=CC=C1)C(=O)O Chemical compound C(CCC)OC(C=1CC(C(=O)O)(C=CC1)C)=O.C1(=CC=CC=C1)C(=O)O XYCNHYYTMFTLLA-UHFFFAOYSA-N 0.000 description 1
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- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
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- DVLHGMFTRAFHPR-UHFFFAOYSA-N pyrazole-1-carboxamide Chemical compound NC(=O)N1C=CC=N1 DVLHGMFTRAFHPR-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/26—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/65—N-sulfonylisocyanates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- 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
-
- 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
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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
- A61P9/10—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/22—Y being a hydrogen or a carbon atom, e.g. benzoylguanidines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
- C07C311/47—Y being a hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
- C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
- C07C317/42—Y being a hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/64—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton
- C07C323/67—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton containing sulfur atoms of sulfonamide groups, bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
式Ⅰ苯甲酰基胍和它们的药用盐有突出的抗心律失常的药效。其中各基团的意义和制备方法详见说明书。
Description
本发明涉及式I苯甲酰基胍以及它们的药用盐其中，R(1)或R(2)代表R(6)-S(O)n-或
，同时，还代表其它取代基H、F、Cl、Br、I、1-4碳烷基、1-4碳烷氧基、苯氧基，该苯氧基是未取代的或具有1-3个选自氟、氯甲基或甲氧基、以及R(6)-S(O)n或
的取代基，且其中，R(6)代表1-6碳烷基、5-7碳环烷基、环戊基甲基、环己基甲基或苯基，它是未取代的或具有1-3个选自氟、氯、甲基或甲氧基的取代基，且其中，R(7)和R(8)相同或不同，且代表H、1-6碳烷基，或R(7)代表m＝1-4的苯基-(CH2)m-或是未取代的或具有1-2个选自氟、氯、甲基或甲氧基的取代基的苯基，且其中，R(7)和R(8)也可共同成为一个直链的或支化的4-7碳链，其中该链可另外被O、S或NR(9)间隔，且R(9)代表H或甲基，且其中，R(7)和R(8)与它们所结合的氮原子共同形成一个二氢吲哚、四氢喹啉或四氢异喹啉，同时，R(3)、R(4)和R(5)代表氢、1-2碳烷基，或要么R(3)和R(4)可共同形成一个2-4碳亚烷基链，要么R(4)和R(5)可共同形成一个4-7碳亚烷基链，n代表0、1或2。
若取代基R(1)-R(5)含有一个或多个不对称中心，则其S构型和R构型化合物属于本发明范围。这些化合物可以旋光异构体、非对映异构体、消旋化合物或它们的混合物形式存在。
上述所指的烷基既可是直链的，也可是支化的。
式I化合物中优选的是这样的化合物，其中，
R(1)为氟、氯、NR(7)R(8)、R(6)-S(O)n-或苯氧基，
R(2)为R(6)-S(O)n-和R(7)R(8)N-SO2-，同时n为0，1、2，以及
R(3)、R(4)和R(5)为氢，而R(6)、R(7)和R(8)的定义同上，同时优选的还有它们的药用盐。
特别优选的式I化合物中，R(1)为R(7)R(8)N-或R(6)-S(O)n-，其中R(6)为1-3碳烷基或苯基，n＝0，R(7)和R(8)为氢、1-4碳烷基，或R(7)和R(8)共同形成一个(C4-C7)-亚甲基链；R(2)为CH3-SO2-或H2N-SO2-；R(3)、R(4)和R(5)都为氢。同样优选的还有它们的药用盐。
最优选的式I化合物是3-甲基磺酰基-4-(1-哌啶基)-苯甲酰基胍、4-苯硫基-3-氨磺酰基苯甲酰基胍和3-甲磺酰基-4-苯硫基苯甲酰基胍及其它们的药用盐。
式I化合物为取代的酰基胍。
酰基胍的有名酯类的代表是吡嗪衍生物氨氯，它用作在治疗中的免钾利尿药。大量的其它氨氯型化合物在文献中已有叙述，例如二甲基氨氯或乙基异丙基氨氯。
氨氯：R′、R″＝H二甲基氨氯：R′和、R″＝CH3乙基异丙基氨氯：R′＝C2H5，R″＝CH(CH3)2
此外，研究表明，氨氯显示出抗心律失常的性质(CirCulafion79，1257-63(1989))。然而不提倡广泛用作抗心律失常药剂，因为这种药的治疗效果显然是弱的，且伴随出现导致血压下降和排盐利尿的效果，在处理心脏病患者的心律失常时是不希望出这些副作用的。
也可通或对隔离的动物心脏进行实验而观察到氨氯的抗心律失常的性能(Eur。Heart.j.9(Suppl.1)：167(1988)(book of abstracts))。例如从老鼠心脏可发现，采用氨氯可以完全抑制住由人工引起的心室颤动。在这种情况下，上述的氨氯衍生物乙基异丙基氨氯代替氨氯更为有效。
在US 3,780,027中，叙述了其结构与式I化合物相似的酰基胍。它与式I化合物的主要差别在于，它是三取代的苯甲酰基胍，它是通过在市售可得的利尿药如丁尿胺和呋喃苯胺酸的母核上进行衍生而得的，并且在羰基胍基团的2或3位上载有对所希望的排盐利尿作用很重要的氨基基团。同样报导了这些化合物有强的排盐利尿药效。
令人惊异的是，本发明化合物没有不希望的排盐利尿的性能，而有很好的抗心律失常性能。由于具有保护心肌的成分的药理学性能，它们用作抗心律失常的药剂，以预防心肌梗塞和治疗心肌梗塞，并适用于作为治疗心绞痛的克冠酸钠，也可用于预防这些疾病。
本发明进一步涉及制备式I化合物的方法，其特征在于，使式II化合物
与一种III胍衍生物反应
其中，R(1)-R(5)的定义同前，×为一个易于亲核取代的离去基团。
式II活性的酸衍生物，其中×为一个烷氧基，优选为甲氧基、苯氧基、苯硫基、甲硫基、2-吡啶硫基、氮杂环，优选为1-咪唑基，可从羧酸酰氯(式II，×＝Cl)按已知方式有利地制得，而羧酸酰氯本身可从羧酸(式II，×＝OH)按已知方式如与亚硫酰氯反应而制得。
除了式II羧酸酰氯(×＝Cl)外，式II的其它活性羧酸衍生物可从苯甲酸衍生物(式II，X＝OH)按已知方式直接制备，例如式II的甲酯(X＝OCH3)通过在甲醇中用气体HCl处理而制得，式II咪唑烷(Imidazolide)通过用二咪唑羰(Carbonyldiimidazole)处理而制得(X＝1-咪唑基，Staab，Angew.Chem.Int.Ed.Engl.1，351-367(1962))，在三乙胺存在下，在一种惰性溶剂中用Cl-COOC2H5或甲苯磺酰氯处理而制得式II的混合酸酐，还有该苯甲酸经二环己基碳化二亚胺(DCC)处理所得的活性物质。文献J.March，Advanced Organic Chemistry，ThirdEdition(John Wiley & Sons，1985)，S.350给出了一系列适宜的方法，它们适于制备式II活性羧酸衍生物。
另一类制备这样的特定式I化合物，其中R(4)和/或R(5)不为氢的方法为，在苛性钠溶液存在下，使一种式II的酰氯或其它适宜的活性苯甲酸衍生物与3，5-二甲基吡唑-1-烃酰脒-硝酸酯(从Aldrich可得到)反应，然后用氨水或一种胺HNR(4)R(5)处理得到的N-苯甲酰基-3，5-二甲基吡唑-1-烃酰脒衍生物(Methods Enzymol.，25b，558(1972))。
式I活性羧酸衍生物与式III胍衍生物的反应能按已知方式在一种质子传递的或非质子传递的极性但惰性的有机溶剂中进行。在该反应中，在20℃至它们的沸点之间的甲醇或THF适宜于作为溶剂，用于苯甲酸甲酯(式II，X＝oMe)与胍的反应。在多数情况下，化合物II与式III的非盐型胍的反应有利的是在非质子传递的惰性有机溶剂如THF、二甲氧基乙烷、二噁烷中进行。燃而水也可用作式II与式III化合物的反应的溶剂。
当X＝Cl时，有利的是向反应中添加一种缚酸剂例如加过量的胍，以便移去氢卤酸。
一部分作为基础物的式II苯甲酸衍生物和使用的式III胍是已知的，并已在文献中有报道。未知的式II化合物可根据文献已知的方法制备，其中，例如可用4-氯-或4-氟-3-氯-磺酰苯甲酸与氨或一种胺反应，生成3-氨基磺酰基-4-氯-或-氟苯甲酸(IVa)，或与一种弱还原剂如亚硫酸氢钠反应，随后烷基化成一种3-烷基磺酰基-4-氯-或-4-氟苯甲酸(IVb，n＝2)
并按上述变通方法之一使得到的苯甲酸转化成本发明的式I化合物。
式IVa)和b)化合物也可用作其它羧酸的原料化合物，其中R(1)位置上的卤素很适宜于与众多的亲核反应剂如硫醇R(6)-SH或伯胺R(7)R(8)NH进行交换，生成众多的式II苯甲酸衍生物(X＝OH)。按相似的方式，从3-硝基-4-氯苯甲酸出发，通过在4-位上亲核引入一种本发明基团R(1)(与Cl交换)，并转变硝基如还原成NH2，随后烷基化或取代掉，如通过重氮化和Sandmeier-反应，可制得其它的式II苯甲酸衍生物(X＝OH)。
式I苯甲酰胍通常是弱碱，并可与酸成盐。酸加成盐可考虑所有药用酸的盐，如氢卤酸盐尤其是氢氯酸盐、乳酸盐、硫酸盐、柠檬酸盐、酒石酸盐、醋酸盐、磷酸盐、甲磺酸盐、对甲苯磺酸盐。
含有式I化合物的药剂可以以口服、肠胃外、静脉注射、直肠或经吸入等方式给药，其中优选的方式要依病况和临床反应而定。式I化合物可单独或与盖伦氏辅剂混合药用，而且既可制成兽药也可制成人类用药。
适用于所需的药物制剂的那些辅剂是专业人员根据他的专业知识所熟知的。除溶剂、成胶剂、栓剂基础物、片剂辅助物和其它有效成分的载体外，可以使用抗氧化剂、分散剂、乳化剂、消泡剂、矫味剂、防腐剂、助溶剂或色素。
对于口服药剂形式，活性化合物与适用的添加剂如载体、稳定剂或惰性稀释剂混合，并用常规方法制成合适的服用剂型，如片剂、糖衣剂、硬胶囊剂、水剂、醇剂或油剂。可作为惰性载体的有例如阿拉伯树胶、氧化镁、碳酸镁、磷酸钾、乳糖、葡萄糖或淀粉，尤其是玉米淀粉。既可以制成干的也可以是湿的粒剂。举例来说，植物或动物油可用作油状载体或溶剂，如向日葵籽油或鱼肝油。
对于肌肉或静脉内用药，活性化合物根据需要与通常的物质如助溶剂、乳化剂或其它助剂一起，制成溶液剂、悬浮剂或乳剂。考虑用的溶剂有：水、生理食盐溶液或醇，如乙醇、丙醇、甘油，除此之外还有糖溶液如葡萄糖溶液或甘露糖醇溶液，还有上述各种物质形成的混合物。
适于以气溶胶或喷洒剂形式给药的药用制剂是(如)式I有效成分在一种药理上无毒的溶剂、尤其是乙醇或水、或这些溶剂的混合物中所形成的溶液、悬浮液或乳液。根据要求，这些制剂中还可加入其它药用助剂如表面活性剂、乳化剂和稳定剂以及一种燃气。这样的制剂含有有效成分的量通常使浓度为约0.1-10％(重量)，尤其好的是约0.3-3％(重量)。
待给药的式I有效成分的剂量和给药次数取决于所用的化合物的作用强度和作用时效；此外，还取决于待处理的病例的类型和轻重、以及性别、年龄大小、体重和待处理的哺乳动物的各别的药物反应情况。
平均而言，一个约75Kg重的病人每日所需的式I化合物的剂量至少为0.001mg，较好为0.01mg，至最高10mg，较好的最大量为1mg。对急发病例，如刚经过心肌梗塞的病人，更高剂量和首先更频繁的给药次数可能是必要的，例如每天4次给药。尤其对静脉内注射的用药方式而言，一个加强护理的心肌梗塞病人每天用药量多至100mg可能是必要的。
类似于在实施例中给出的步骤，下列本发明化合物或它们的药用盐可以制得：4-甲氧基-3-甲基磺酰基苯甲酰基胍4-异丁氧基-3-甲基磺酰基苯甲酰基胍4-苄氧基-3-甲基磺酰基苯甲酰基胍4-(1-丁硫基)-3-甲基磺酰基苯甲酰基胍4-(1-丁基亚硫酰基)-3-甲基磺酰基苯甲酰基胍4-(1-丁基磺酰基)-氨磺酰基苯甲酰基胍4-(1-丁基磺酰基)-3-甲磺酰基苯甲酰基胍4-(2-氯苯硫基)-3-甲磺酰基苯甲酰基胍4-苯氧基-3-甲磺酰基苯甲酰基胍4-环己硫基-3-甲磺酰基苯甲酰基胍4-环己亚硫酰基-3-甲磺酰基苯甲酰基胍4-环己磺酰基-3-甲磺酰基苯甲酰基胍4-(1-哌啶子基)-3-氨磺酰基苯甲酰基胍4-甲氧基-3-氨磺酰基苯甲酰基胍4-异丁氧基-3-氨磺酰基苯甲酰基胍4-苄氧基-3-氨磺酰基苯甲酰基胍4-(1-丁硫基)-3-氨磺酰基苯甲酰基胍4-(1-丁基亚硫酰基)-3-氨磺酰基苯甲酰基胍4-(2-氯苯硫基)-3-氨磺酰基苯甲酰基胍4-环己硫基-3-氨磺酰基苯甲酰基胍4-环己硫基-3-氨磺酰基苯甲酰基胍4-环己磺酰基-3-氨磺酰基苯甲酰基胍3-异丙基氨磺酰基-4-(1-哌啶子基)-苯甲酰基胍3-(1-丁基氨磺酰基)-4-(1-哌啶子基)-苯甲酰基胍3-(N，N-双-1-丁基氨磺酰基)-4-(1-哌啶子基)-苯甲酰基胍3-(3-甲氧丙基氨磺酰基)-4-(1-哌啶子基)-苯甲酰基胍3-(3，5-二甲基哌啶子基-N-磺酰基)-4-(1-哌啶子基)-苯甲酰基胍3-环戊基氨磺酰基-4-(1-哌啶子基)-苯甲酰基胍4-(3-甲氧基-1-丙基氨基)-3-甲磺酰基苯甲酰基胍4-(3-甲氧基-1-丙基氨基)-3-氨磺酰基苯甲酰基胍4-(N，N-双-1-丁基氨基)-3-甲磺酰基苯甲酰基胍4-(N，N-双-1-丁基氨基)-3-氨磺酰基苯甲酰基胍4-N-五亚甲基氨基-3-甲磺酰基苯甲酰基胍4-N-五亚甲基氨基-3-氨磺酰基苯甲酰基胍4-环戊基氨基-3-甲磺酰基苯甲酰基胍4-环戊基氨基-3-氨磺酰基苯甲酰基胍4-(2-氯苯基氨基)-3-甲磺酰基苯甲酰基胍4-(2-氯苯基氨基)-3-氨磺酰基苯甲酰基胍4-(4-甲氧苯基氨基)-3-甲磺酰基苯甲酰基胍4-(4-甲氧苯基氨基)-3-氨磺酰基苯甲酰基胍4-(N-甲基-N-苯基氨基)-3-甲磺酰基苯甲酰基胍4-(N-甲基-N-苯基氨基)-3-氨磺酰基苯甲酰基胍4-(2，4-二甲氨基)-3-甲磺酰基苯甲酰基胍4-(2，4-二甲氨基)-3-氨磺酰基苯甲酰基胍4-(3-甲基苯基氨基)-3-甲磺酰基苯甲酰基胍4-(3-甲基苯基氨基)-3-氨磺酰基苯甲酰基胍4-(4-甲基苯基硫基)-3-氨磺酰基苯甲酰基胍4-(4-氯苯基硫基)-3-氨磺酰基苯甲酰基胍4-(4-甲氧苯基硫基)-3氨磺酰基苯甲酰基胍4-甲基-3-甲磺酰基苯甲酰基胍4-甲基-3-氨磺酰基苯甲酰基胍实验部分实施例14-氯-3-氨磺酰基苯甲酰基胍氢氯化物
1.9g钠放在90ml甲醇中，制成一个甲醇钠溶液，向该溶液中加入8.5g胍氢氯化物，随后再加5g4-氯-3-氨磺酰基苯甲酸甲酯。在惰性气体中(氮或氩)用30小时温热该混合物至50-60℃小时后，蒸去其中的溶剂。移出剩余物后，用2N乙酸调节PH＝6，并用乙酸乙酯萃取。在用乙醚中的盐酸(etherischerSalzsure)对干燥后的萃取物(在硫酸镁上干燥)进行酸化之后，过滤即得题称化合物。
无色晶体，熔点：305-308℃。实施例23-N，N-二乙基氨磺酰基-4-氯苯甲酰基胍氢氯化物
从10.7g胍氢氯化物和等摩尔量甲醇钠在70ml甲醇中制得0.112mol胍，再按类似于实施例I中所述过程，由此制得题称胍化合物。
无色晶体，熔点：202-205℃实施例34-氯-3-甲磺酰基苯甲酰基胍氢氯化物
由4.03g胍氢氯化物和7.7g钠-(双-三甲基甲硅烷基胺)通过在甲醇中用6小时温热至50℃，并进行类似的分离，可制得42.2mmol的胍，再按类似于实施例1所述步骤，由此制得题称胍化合物。
无色晶体，熔点：220℃(分解)实施例43-甲磺酰基-4-(1-哌啶基)-苯甲酰基胍a)5-羧-2-氯苯亚硫酸二钠盐
通过在70℃、PH为9-10的700ml水中用157g亚硫酸钠使261g5-羧-2-氯苯磺酰氯还原，随后用Hcl酸化，得到186g5-羧-2-氯苯亚硫酸再用在2l水中的67.6g苛性钠中和，蒸去水并在丙酮中对剩余物结晶，可制得题称化合物。
白色晶粉，熔点＞340℃。b)4-氯-3-甲磺酰基苯甲酸甲酯
把52.9g在4a)中制得的二钠盐加入具有99.3g碘甲烷的400ml无水二甲基甲酰胺中，并在50-60℃下搅拌5小时，蒸去溶剂，多次搅拌并用水洗涤剩余物后，过滤得到题称化合物。
白色晶体粉末，熔点：150-153℃c)4-氯-3-甲磺酰基苯甲酸
将14.3g在4b)中制得的苯甲酸甲酯衍生物置于120ml甲醇和50ml 2N苛性纳溶液中于室温下搅拌6小时。蒸去溶剂，将剩余物溶于水后，用2 N盐酸调节PH为0-1并过滤，得到题称化合物。
白色晶体粉末，熔点：220-224℃d)3-甲磺酰基-4-(1-哌啶子基)-苯甲酸
将92g4-氯-3-甲磺酰基苯甲酸放入460ml哌啶中，用一回流冷凝加热器沸腾11小时，之后，用800ml水稀释并用浓盐酸调节至PH为2。在冰浴中结晶之后，滤得固体物质。
从乙醇结晶出无色晶体，熔点：234-238℃e)3-甲磺酰基-4-(哌啶子基)-苯甲酰氯
通过在400ml亚硫酰氯中对50g3-甲磺酰基-4-(1-哌啶子基)-苯甲酸作4小时的回流沸腾，减压下仔细蒸去溶剂，并用二甲基醚结晶剩余物。f)3-甲磺酰基-4-(1-哌啶子基)苯甲酰基胍
在200ml 1，2-二甲氧乙烷中。在情性气体保护下，将21.8g 3-甲磺酰基-4-(1-哌啶子基)-苯甲酰氯与31.4g胍在5-10℃搅拌2小时，冷却下加入约200ml水，并用2N HCl调节PH为6-7。蒸至溶液体积的一半后，滤出晶体，并从甲醇中重结晶出产品。
无色晶体，熔点：210-213℃(分解)实施例53-甲磺酰基-4-(1-哌啶子基)-苯甲酰基胍二氢氯化物
在10倍(重量)的甲醇中含有3-甲磺酰基-4-(1-哌啶子基)-苯甲酰基胍，向其中加入过量的HCl乙醚溶液，并在冰浴中冷却的情况下，搅拌产生的盐沉淀物，由此得到题称化合物。
白色晶体粉末，熔点：210-214℃(分解)实施例63-甲磺酰基-4-(1-哌啶子基)-苯甲酰基胍氢氯化物
在1.3至1.4l水中，200g实施例5制得的二氢氯化物用-种等当量的单价碱(NaOH、NaHCO3、N(C2H5)3等)处理，或在1.3-1.4l水中使提到数量的物质重结晶，得到题称化合物。
无色晶体，熔点：235-237℃实施例74-氯-3-N，N-二甲基氨甲酰基苯甲酰基胍氢氯化物
按类似于实施例1中所述步骤，通过使2.77g(0.01mol)4-氯-3-二甲基氨磺酰基苯甲酸甲酯(熔点：95-96℃)与0.04mol胍在甲醇中反应，随后进行类似的分离，可得到题称化合物。
白色晶体粉末，熔点：224-226℃(分解)实施例84-氯-3-(1-哌啶基—磺酰基)—苯甲酰基胍氢氯化物
类似于实施例1中给定的步骤，由4-氯-3-(1-哌啶基-磺酰基)-苯甲酸甲酯(熔点：110-112℃)和胍在溶剂甲醇中反应，制得题称化合物。
白色晶体粉末，熔点：232-234℃实施例93-N-苯甲基氨磺酰基-4-氯苯甲酰基胍氢氯化物
类似于实施例1中所述步骤，由3-N-苯甲基氨磺酰基-4-氯苯甲酸甲酯(熔点：93-95℃)和胍在反应介质甲醇中的反应，制得题称化合物。
白色晶体粉末，熔点：224-225℃实施例104-氨磺酰基苯甲酰基胍
类似于实施例1中所述步骤，由4-氨磺酰基苯甲酸-五氟苯酯(它是在1mol吡啶存在下，由4-氨磺酰基苯甲酰氯和五氟苯酚制得的)与胍在反应介质甲醇中反应，制得题称化合物。
白色晶体粉末，熔点：200℃(分解)实施例114-氨磺酰基苯甲酰基胍氢氯化物
在乙酸乙酯中，用HCl的乙醚溶液处理在实施例10中制得的化合物，得到题称化合物。
无色晶体粉末，熔点：282℃实施例124-N，N-二乙基氨磺酰基苯甲酰基胍氢氯化物
按实施例1中所述步骤，由4-N.N-二乙基氨磺酰基苯甲酸五氟苯酯(由4-N，N-二乙基氨磺酰基苯甲酸、五氟苯酚、亚硫酰氯和吡啶(熔点：113-114℃)制得)和胍在溶剂甲醇中反应，并进行类似的分离，制得题称化合物。
白色晶体粉末，熔点：216-218℃实施例134-(1-哌啶基磺酰基)-苯甲酰基胍氢氯化物
按实施例1中所述步骤，由4-(1-哌啶基磺酰基)-苯甲酸甲酯和胍在反应介质甲醇中反应，制得题称化合物。
白色晶体，熔点：281℃实施例144-甲硫基苯甲酰基胍氢氯化物
按类似于实施例1中所述的步骤，由4-甲硫基苯甲酸甲酯和胍在溶剂甲醇中反应，制得题称化合物。
白色晶体粉末，熔点：255-259℃实施例154-苯硫基-3-氨磺酰基苯甲酰基胍氢氯化物a)按类似于实施例1所述的步骤，由4-苯硫基-3-氨磺酰基苯甲酸甲酯和胍在溶剂甲醇中反应，制得题称化合物。
白色晶体粉末，熔点：275-283℃b)通过使4.4g4-氟-3-氨磺酰基苯甲酸甲酯(熔点：127-129℃)(由4-氟-3-氨磺酰基苯甲酸和亚硫酰氯反应，随后用甲醇处理而制得)与2.2g苯硫酚和1.38g无水且磨碎的K2CO3在20ml无水二甲基甲酰胺中、80℃下反应两小时，然后添加约100ml水进行沉淀，得到a)中使用的4-苯硫基-3-氨磺酰基苯甲酸甲酯。
甲醇中结晶得到白色晶体，熔点：154～157℃实施例163-甲磺酰基-4-苯硫基苯甲酰基胍氢氯化物a)按实施例1中所述步骤，由3-甲磺酰基-4-苯硫基苯甲酸甲酯和胍在反应介质甲醇中反应，并进行类似的分离，制得产物。
无色晶体，熔点：279～281℃b)按15b)中给定的方法，由4-氯-3-甲磺酰基苯甲酸甲酯制得a)中使用的3-甲磺酰基-4-苯硫基苯甲酸甲酯。
白色晶体，熔点：155～156℃实施例174-苯氧基-3-氨磺酰基苯甲酰基胍a)按实施例1中所述步骤，(没有经过HCl处理)，由4-苯氧基-3-氨磺酰基苯甲酸甲酯和胍在甲醇中反应，制得题称化合物。
白色晶体粉末，熔点：178～181℃b)按类似于15b)中给出的步骤，由4-氟-3-氨磺酰基苯甲酸与苯酚在DMF中、在K2CO3存在下、80℃搅拌6小时，制得a)中所用的4-苯氧基-3-氨磺酰基苯甲酸甲酯。
白色晶状固体，熔点：148-151℃实施例183-甲磺酰基-4-N-吗啉代基苯甲酰基胍
类似于实施例4f)中给出的步骤，通过3-甲磺酰基-4-吗啉代基-苯甲酰氯与胍在无水四氢呋喃中反应，制得题称化合物。
白色晶体粉末，熔点：260℃(分解)
上面使用的3-甲磺酰基-4-吗啉代基-苯甲酰氯可经多个步骤制备a)把4-氯-3-甲磺酰基苯甲酸放在2倍(重量)的吗啉中，110℃下搅拌5小时，把该反应混合物倾入水中，用HCl酸化后，从中得到3-甲磺酰基-4-N-吗啉代子基苯甲酸(甲醇中得到的产物熔点：252-255℃)b)把5g a)中提到的4-氯-3-甲磺酰基苯甲酸放在50ml亚硫酰氯中，用一回流冷凝加热器使之沸腾2小时，蒸去液态成分后，使所需的苯甲酰氯衍生物在二异丙基醚/石油醚混合物中结晶出来。熔点：98-102℃实施例193-甲磺酰基-4-N-吡咯烷子基(Pyrrolidino)苯甲酰基胍
按类似于实施例4f)中给出的步骤，在室温下通过使5g3-甲磺酰基-4-N-吡咯烷子基苯甲酰基胍与3.4g胍在无水四氢呋喃中反应后，倒入200ml水中并用乙酸乙酯萃取。蒸去萃取剂后，使固体物质在甲醇中结晶，溶解该固体于乙酸乙酯中，并经硅胶层析柱提纯(洗脱剂：乙酸乙酯)。蒸去洗脱剂后，再在二异丙基醚中结晶出产品。
无色晶体，熔点：128-135℃(分解)
根据以下叙述，上述所用的3-甲磺酰基-4-N-吡咯烷子基苯甲酰氯可从多个步骤制得：a)按实施例18a)中给定的步骤，由4-氯-3-甲磺酰基-苯甲酸起始，把它放在吡咯烷中加热5小时至100℃，并进行类似的分离，产生的3-甲磺酰基-4-吡咯烷基苯甲酸；由乙醇中得出的产物为无色晶体，熔点：228-230℃b)按类似于实施例18b)中的步骤，a)中制得的苯甲酸转化成所需的3-甲磺酰基-4-吡咯烷子基苯甲酰氯(熔点：137-139℃)实施例204-N-吗啉代基-3-氨磺酰基苯甲酰基胍
按类似于实施例1中所述的步骤，由4-N-吗啉代基-3-氨磺酰基苯甲酸甲酯和胍在甲醇中沸腾4小时，在用乙酸乙酯萃取，并用乙酸乙酯作为洗脱剂进行硅胶柱层析提纯后，分离得到题称化合物(没有随后经HCl转化成其氢氯化物)。
白色晶体粉末，熔点：239-241℃
在8ml二甲基乙酰胺中，通过使2g4-氟-3-氨磺酰基苯甲酸甲酯与1.5g吗啉在100℃加热5小时，随后加入水使该物质沉淀，再在水中使非晶的酯沉淀物结晶出来，可制得用作起始物料的4-N-吗啉代基-3-氨磺酰基苯甲酸甲酯。熔点：61-64℃实施例213-甲磺酰基-4-(1-甲基-4-哌嗪子基(piperazino))苯甲酰基胍
按类似于实施例1中所述的步骤，由1g 3-甲磺酰基-4-(1-甲基-4-哌嗪子基)苯甲酸甲酯和1g胍在25ml反应介质甲醇中60℃下反应6小时。静置过夜，沉淀并滤出题称化合物。
淡黄色晶状固体，熔点：248-250℃
作为起始原料使用的3-甲磺酰基-4-(1-甲基-4-哌嗪子基)苯甲酸甲酯可经多个步骤得到：a)使4.7g 4-氯-3-甲磺酰基苯甲酸与5.2gN-甲基哌嗪在15ml二甲基乙酰胺中、120℃下反应5小时，蒸去溶剂，把剩余物倾入水中，用2N盐酸酸化并滤出结晶。它为晶状固体，熔点＞300℃b)在亚硫酰氯中回流a)中制得的苯甲酸衍生物，用甲醇和三乙胺对剩余物进行蒸馏和反应。在重新蒸去溶剂和用水处理其剩余物后，分离出所需的甲酯沉淀物，使它在二异丙基醚中结晶。
白色的晶状固体，熔点；138-145℃实施例224-N-苄基-N-甲基氨基-3-甲磺酰基苯甲酰基胍氢氯化物
类似于实施例4f)中所述步骤，由4.3g 4-N-苄基-N-甲基氨基-3-甲磺酰基苯甲酰氯与5.2g胍在30ml无水四氢呋喃中、5-10℃下反应。在用甲醇中的氯化氢转化之前，游离的题称苯甲酰胍经硅胶层析柱提纯，洗脱剂为乙酸乙酯(10Vol)+环己烷(5Vol)+氯仿(5Vol)+甲醇(5Vol)+氨水(1Vol)所构成的混合物。
无色晶体粉末，熔点：234-240
所述的4-N-苄基-N-甲基氨基-3-甲磺酰基苯甲酰氯(油状的无定形产物，它未经进一步的提纯步骤)可经多步骤制得：从4-氯-3-甲磺酰苯甲酸出发，按类似于实施例21，a)的步骤，与N-苄基-N-甲胺反应，得到4-N-苄基-N-甲基氨基-3-甲磺酰基苯甲酸(熔点：196-202℃)，随后与亚硫酰氯反应。实施例234-苄基氨基-3-甲磺酰基苯甲酰基胍-乙酸酯
类似于实施例4f)中所述方法，由4-苄基-3-甲磺酰基-苯甲酰氯与胍在无水四氢呋喃中反应。用乙酸进行酸化至PH为4，以实现分离；部分蒸去溶剂、尤其是THF成分后，分离出4-苄基氨基-3-甲磺酰基苯甲酰基胍-乙酸酯晶体。浅黄色晶状固体，具有2个熔点，熔点1：163-168℃；熔点2：230-232℃。
按类似于实施例21中描述的反应过程，从4-氯-3-甲磺酰基苯甲酸和苄胺反应，可制得用作反应起始物的4-苄基氨基-3-甲磺酰基苯甲酸(熔点：230-235℃)，并同样类似地用亚硫酰氯与该产物反应，即制得所需的4-苄基-3-甲磺酰基苯甲酰氯(熔点：100-104℃)。
按类似于实施例4f)中给出的步骤，由相应的式II苯甲酰氯和胍在无水四氢呋喃中反应，得到下列式I化合物或其盐：实施例24：3-(3-甲基-1-丁基磺酰基-4-N-哌啶子基-苯甲酰基胍-氢氯化物(熔点：155℃/分解)。
以2-氯-5-羧基苯亚磺酸二钠盐作为起始物料，经过4-氯-3-(3-甲基-1-丁磺酰基)苯甲酸3-甲基-1-丁基酯(非晶形化合物)、4-氯-3-(3-甲基-1-丁磺酰基)苯甲酸(熔点：140-144℃、3-(3-甲基-1-丁磺酰基)-4-N-哌好基苯甲酸(熔点：161-165℃)以及3-(3-甲基-1-丁磺酰基)-4-N-哌啶子基-苯甲酰氯(油)而制得产物。实施例253-(1-丁磺酰基)-4-N-哌啶子基苯甲酰基胍二氢氯化物(熔点：184℃/分解)
用2-氯-5-羧基苯亚磺酸二钠盐作为起始物料，经过3-(1-丁磺酰基)-4-氯苯甲酸1-丁酯(油)、3-(1-丁磺酰基)-4-氯苯甲酸(熔点：142-146℃)、3-(1-丁磺酰基-4-N-哌啶子基苯甲酸(熔点：156℃)和3-(1-丁磺酰基)-4-N-哌啶子基苯甲酰氯(油)而制得产物。实施例264-N-(1-己基氨基)-3-甲磺酰基苯甲酰基胍
向一个由2.99g 4-N-(1-己基氨基)-3-甲磺酰基苯甲酸在40ml无水四氢呋喃中形成的溶液中加入1.78g二咪唑羰(Carbonyldiimidazol)，室温下搅拌2小时，45℃下再搅拌1小时，随后使该混合物在20℃下与4.13g胍反应。室温下搅拌12小时，蒸去溶剂，用2N的HCl调节PH至6-7，在冰浴中搅拌1小时，滤出固体物质并在用水洗涤后再使之溶解，从乙醇中重结晶。
无色固体，熔点：135-145℃。
实施例26的起始物由4-氯-3-甲磺酰基苯甲酸起始，经过4-N-(1-己基氨基)-3-甲磺酰基苯甲酸(无色晶体，熔点：169℃)而制得。实施例273-N-乙基-N-异丙基氨磺酰基-4-(1-哌啶子基)苯甲酰基胍
按类似于实施例26中给定的过程，通过使3-N-乙基-N-异丙基氨磺酰基-4-(1-哌啶子基)苯甲酸、二咪唑羰和胍反应而制得。
无色晶体，熔点：212℃
实施例27的起始物由3-氯磺酰基-4-氟-苯甲酸经过3-N-乙基-N-异丙基氨磺酰基-4-氟苯甲酸(熔点：108-115℃)、3-N-乙基-N-异丙基氨磺酰基苯甲酸(熔点：138-140℃)而制得。实施例284-氨基-3-甲磺酰基苯甲酰基胍氢氯化物
按类似于实施例1所述过程，由4-氨基-3-甲磺酰基苯甲酸甲酯和胍在甲醇中制得。
白色晶体粉末，熔点：245-248℃
实施例28中的起始物是如下制得的：
以4-氯-3-甲磺酰基-苯甲酸为起始物，经过4-N-肼基-3-甲磺酰基苯甲酸(熔点：243-245℃)和它在甲醇/氨水中用Raney-镍催化剂进行的N-N键加氢分解(室温常压下)，分解成为4-氨-3-甲磺酰基苯甲酸(熔点：258-262℃)，并随后用亚硫酰氯和甲醇与之反应，成为4-氨基-3-甲磺酰基苯甲酸甲酯(熔点：146℃)。实施例291，1-二甲基-3-(3-甲磺酰基-4-N-哌啶子基苯甲酰基)胍
3.6g N-(3-甲磺酰基-4-(1-哌啶子基)-苯甲酰基-羧酸酰胺-3，5-二甲基吡唑-1-羧酸溶于30ml 40％二甲胺水溶液中，将它放入一高压釜中于80℃温热4小时，滤出结晶沉淀，并用乙醇重结晶。
无色晶体，熔点：207℃。
实施例29的起始反应物如下制备：由2.92g 3-甲磺酰基-4-N-哌啶子基-苯甲酰氯溶于10ml乙酸乙酯中制得一个溶液，并把它滴加到一个在12.8ml 10％NaOH中的3，5-二甲基吡唑-1-羧酸酰胺硝酸酯的溶液中(10-15℃)，室温下搅拌2小时，蒸去溶剂，并用乙酸乙酯对剩余物重结晶(无色晶状固体，熔点：201-202℃)。实施例301-甲基-3-(3-甲磺酰基-4-N-哌啶子基-苯甲酰基)-胍
按类似于实施例29中所述过程，通过在高压釜中与40％甲基胺水溶液反应而制得。
无色晶状固体，熔点：202-203℃(从乙醇中重结晶)。实施例314-氯-3-(3-苯基-1-丙磺酰基)苯甲酰基胍氢氯化物
按类似于实施例26中所述过程，通过4-氯-3-(3-苯基-1-丙磺酰基)苯甲酸与胍和二咪唑羰反应而制得。
无色晶体，熔点：178-182℃(分解)。
由2-氯-5-羧基苯-亚磺酸起始，经4-氯-3-(3-苯基-1-丙磺酰基)-苯甲酸(3-苯基-1-丙基)酯(粘性油)和4-氯-3-(3-苯基-1-丙磺酰基)苯甲酸(无色晶体，熔点：126-130℃)，可制得目的产物的起始物。实施例324-(2，3-二氢-1-吲哚基)-3-甲磺酰基苯甲酰基胍
按类似于实施例26中给出的过程，由4-(2，3-二氢-1-吲哚基)-3-甲磺酰基苯甲酸、二咪唑羰和胍可制得(熔点136℃/分解)。
由4-氯-3-甲磺酰基苯甲酸经过4-(2，3-二氢-1-吲哚基)-3-甲磺酰基苯甲酸可制得实施例32中所用的起始反应物(熔点158℃)。实施例33：3-(3-苯基-1-丙磺酰基)-4-(1-哌啶子基)-苯甲酰基胍二氢氯化物
按类似于实施例26中给出的过程，通过3-(3-苯基-1-丙磺酰基)-4-(1-哌啶子基)-苯甲酸、二咪唑羰和胍的反应而制得。
无色晶体，熔点：160℃(分解)。
起始物：由4-氯-3-(3-苯基-1-丙磺酰基)苯甲酸(参见实施例31)起始，经3-(3-苯基-1-丙磺酰基)-4-(1-哌啶子基)苯甲酸而制得(熔点：170℃)。实施例344-(N-2，4-二氯苄基-N-甲基氨基)-3-甲磺酰基苯甲酰基胍氢氯化物
按类似于实施例1中所述步骤，由4-(N-2，4-二氯苄基-N-甲基氨基)-3-甲磺酰基苯甲酸甲酯和胍在溶剂甲醇中反应而制得(熔点：180℃)。实施例354-(1-哌啶子基)-3-氨磺酰基苯甲酰基胍氢氯化物
按类似于实施例26中给出的过程，由4-(1-哌啶子基)-3-氨磺酰基苯甲酸、二咪唑羰和胍的反应而制得。
无色晶状固体，熔点：236℃(分解)。
由4-氟-3-氨磺酰基苯甲酸经过4-(1-哌啶子基)-3-氨磺酰基苯甲酸而制得上面的起始反应物(熔点：246-247℃)。
类似于实施例26中给出的过程，由一种式II苯甲酸衍生物(X＝OH)的反应，用二咪唑羰对它活化，随后用胍使之反应，制得下列式I化合物：实施例36：4-(3-甲氧基-1-丙基氨基)-3-甲磺酰基苯甲酰基胍氢氯化物，无色晶体，熔点：167-169℃
其起始物是由4-氯-3-甲磺酰基苯甲酸经4-(3-甲氧基-1-丙基氨基)-3-甲磺酰基苯甲酸而制得(熔点：190℃/由乙醇中结晶)。实施例374-(3-苯基-1-丙基氨基)-3-甲磺酰基苯甲酰基胍
白色晶体粉末，熔点：177-178℃
由4-氯-3-甲磺酰基苯甲酸经4-(3-苯基-1-丙基氨基)-3-甲磺酰基苯甲酸而制得起始物(熔点：172℃)。实施例384-异丁基氨基-3-甲磺酰基苯甲酰基胍氢氯化物
白色晶体粉末，熔点：163-166℃
由4-氯-3-甲磺酰基苯甲酸经4-异丙基氨基-3-甲磺酰基苯甲酸而制得起始物，熔点：180℃。实施例393-(3-甲氧基-1-丙基氨磺酰基)-4-(1-哌啶子基)苯甲酰基胍氢氯化物
白色晶体粉末，熔点：209-211℃
由4-氯-3-氯磺酰基苯甲酸经4-氯-3-(3-甲氧基-1-丙基氨磺酰基)苯甲酸(熔点：149-150℃)和3-(3-甲氧基-1-丙基氨磺酰基)-4-(1-哌啶子基)苯甲酸(熔点：138-140℃)而制得起始反应物。实施例403-异丙基氨磺酰基-4-(1-哌啶子基)苯甲酰基胍氢氯化物
白色晶体粉末，熔点：209-211℃。
起始物由4-氯-3-异丙基氨磺酰基苯甲酸经3-异丙基氨磺酰基-4-(1-哌啶子基)-苯甲酸而制得(熔点：186-188℃)。实施例413-(1-丙基氨磺酰基)-4-(1-哌啶子基)苯甲酰基胍氢氯化物
白色晶体粉末，熔点：176℃(分解)
起始物由4-氯-3-(1-丙基氨磺酰基)苯甲酸经3-(1-丙基氨磺酰基)-4-(1-哌啶子基)苯甲酸而制得(熔点：138-139℃)。实施例423-(3，5-二甲基-1-哌啶子基-磺酰基)-4-(1-哌啶子基)苯甲酰基胍
白色晶体粉末，熔点：202-204℃。
由3-氯磺酰基-4-氟苯甲酸经3-(3，5-二甲基-1-哌啶子基磺酰基)-4-氟苯甲酸(熔点：207℃)、3-(3，5-二甲基-1-哌啶子基磺酰基)-4-(1-哌啶子基)-苯甲酸(熔点：198℃)而制得起始物。实施例433-甲磺酰基-4-(N，N-双-1-丙基氨基)苯甲酰基胍氢氯化物
白色晶体粉末，熔点：157-159℃
由3-甲磺酰基-4-氯苯甲酸经3-甲磺酰基-4-(N，N-双-1-丙基氨基)苯甲酸(熔点：122-124℃)而制得起始物。实施例444-环戊基氨基-3-甲磺酰基苯甲酰基胍
白色晶体粉末，熔点：238-240℃
由4-氯-3-甲磺酰基苯甲酸经4-环戊基氨基-3-甲磺酰基苯甲酸(熔点：219-222℃)而制得起始物。实施例454-乙磺酰基-3-N-吡咯烷子基苯甲酰基胍氢氯化物
类似于实施例2，由4-乙磺酰基-3-N-吡咯烷子基苯甲酸甲酯和胍制得。
熔点：180-182℃。实施例464-苯磺酰基-3-N-吡咯烷子基苯甲酰基胍氢氯化物
类似于实施例2，由4-苯磺酰基-3-吡咯烷子基苯甲酸甲酯和胍制得。
熔点：226-228℃。实施例474-环己基磺酰基-3-N-吡咯烷子基苯甲酰基胍
类似于实施例2，由6-环己基磺酰基-3-N-吡咯烷子基苯甲酸甲酯和胍制得。将首先得到的题称化合物的氢氯化物溶于H2O中，并加入2N的苛性钠溶液，使题称化合物以游离碱形式沉淀下来，然后吸滤出来。
熔点：234-236℃。实施例484-甲磺酰基-3-N-吡咯烷子基苯甲酰基胍
类似于实施例2，由4-甲磺酰基-3-N-吡咯烷子基-苯甲酸甲酯和胍制得。
熔点：165-168℃。
实施例45-48中所用反应起始物的制备：
为了制备用于实施例45-48中相应的苯甲酸甲酯，用4-氯-3-硝基苯甲酸甲酯作为反应起始物。用乙硫醇(45)、苯硫酚(46)、环己基硫醚(Cyclohexylsulfid)(47)或甲硫醇(48)与之反应，该反应在标准条件下如K2CO3于DMF中进行，得到相应的4-硫代-3-硝基苯甲酸甲酯，它在冰乙酸中用H2O2氧化成相应的4-磺酰基-3-硝基苯甲酸酯。3-硝基还原后，用琥珀酸酐将吡咯烷基引入，并用NaBH4/BF3·Et2O使之还原：
10g3-氨基-4-甲磺酰基苯甲酸甲酯与8.7g琥珀酸酐在160℃下熔化搅拌5小时。把固体剩余物溶于甲醇中并导入水中，沉淀出的固体吸滤出来。
熔点：218-220℃
12.2g这样制得的4-甲磺酰基-3-N-(2，5-二氧代吡咯烷子基苯甲酸甲酯溶于100ml二甘醇二甲醚中，并在加入14.5ml BF3醚合物后使之冷却至2℃。随后加入4.4gNaBH4并在该温度下搅拌5小时。然后把该物料倾入冰/水中，并吸滤出沉淀的4-甲磺酰基-3-N-吡咯烷子基苯甲酸甲酯(熔点：96-98℃)。
类似于此，得到相应的用于实施例45、46和47中的苯甲酸酯。实施例494-环己硫基-3-甲磺酰基苯甲酰基胍
类似于实施例1，但用4-环己硫基-3-甲磺酰基苯甲酸甲酯作为反应起始物。
熔点：201-204℃药理学数据：毒毛旋花子甙K诱发狗的心动过速(VentricularTachykardia)方法：
静脉内输入3μg/Kg·min毒毛旋花甙G在40-60分钟内引起乙基戊基巴比通麻醉的比哥猎狗的心动过速(VT)，当VT-旦开始，中止毒毛旋花甙G的注入，但VT继续约2小时并经连续的ECG检测监视。在完成毒毛旋花甙注入后，供试物质在10分钟内由静脉内给药。结果：
5只狗中的4只，经10mg/kg实施例34制得的化合物处理，产生6-11分钟的ECG正常化值。
Claims (4)
1.式I苯甲酰基胍及其它们的药用盐的制备方法
其中，R(1)或R(2)代表R(6)-S(O)n-或
，同时，还代表其它取代基H、F、Cl、Br、I、1-4碳烷基、1-4碳烷氧基、苯氧基、该苯氧基是未取代的或具有1-3个选自氟、氯、甲基或甲氧基、以及R(6)-S(O)n-或
的取代基，且其中，R(6)代表1-6碳烷基、5-7碳环烷基、环戊基甲基、环己基甲基或苯基，它是未取代的或具有1-3个选自氟、氯、甲基或甲氧基的取代基，且其中，R(7)和R(8)相同或不同，且代表H、1-6碳烷基，或R(7)代表m＝1-4的苯基-(CH2)m-或是未取代的或具有1-2个选自氟、氯、甲基或甲氧基的取代基的苯基，且其中，R(7)和R(8)也可共同成为一个直链的或支化的4-7碳链，其中该链可另外被O、S或NR(9)间隔，且R(9)代表H或甲基，R(3)、R(4)和R(5)代表氢、1-2碳烷基，或要么R(3)和R(4)可共同形成一个2-4碳亚烷基链，要么R(4)和R(5)可共同形成一个4-7碳亚烷基链，n代表0、1或2，该方法包括，使式II化合物
与式III胍衍生物反应
其中R(1)至R(5)的意义同上述，X是一个易于被亲核试剂取代的离去基团。
2.权利要求1的方法，其中化合物II和III中的基团意义为：R(1)为氟、氯、NR(7)R(8)、R(6)-S(O)n-或苯氧基，1-4碳烷基，R(2)是R(6)-S(O)n-和R(7)R(8)N-SO2-，其中＝n为0、1或2，R(3)、R(4)和R(5)为氢，且R(6)、R(7)和R(8)如权利要求1所定义。
3.权利要求1所要求的方法，其中的化合物II和III中，R(1)为R(7)R(8)N-或R(6)-S(O)n-，其中R(6)是具有1-3个碳原子的烷基或苯基，n为0，R(7)和R(8)为氢或具有1-4个碳原子的烷基，或R(7)和R(8)共同形成一个(4-7)碳亚甲基链，且R(2)为CH3-SO2-或H2N-SO2-，和R(3)、R(4)和R(5)为氢。
4.权利要求1所要求的方法，按此方法制备了以下化合物或它们的药用盐：3-甲磺酰基-4-(1-哌啶基)苯甲酰基胍4-苯硫基-3-氨磺酰基苯甲酰基胍，或3-甲磺酰基-4-苯硫基苯甲酰基胍。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3929582.6 | 1989-09-06 | ||
| DE3929582A DE3929582A1 (de) | 1989-09-06 | 1989-09-06 | Benzoylguanidine, verfahren zu ihrer herstellung, ihre verwendung als medikament sowie sie enthaltendes medikament |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1050018A CN1050018A (zh) | 1991-03-20 |
| CN1049888C true CN1049888C (zh) | 2000-03-01 |
Family
ID=6388731
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN90107457A Expired - Lifetime CN1049888C (zh) | 1989-09-06 | 1990-09-05 | 苯甲酰基胍的制备方法 |
Country Status (32)
| Country | Link |
|---|---|
| US (2) | US5091394A (zh) |
| EP (1) | EP0416499B1 (zh) |
| JP (1) | JPH07592B2 (zh) |
| KR (1) | KR0159095B1 (zh) |
| CN (1) | CN1049888C (zh) |
| AT (1) | ATE121738T1 (zh) |
| AU (1) | AU631007B2 (zh) |
| CA (1) | CA2024700C (zh) |
| CY (1) | CY2030A (zh) |
| CZ (1) | CZ278318B6 (zh) |
| DE (2) | DE3929582A1 (zh) |
| DK (1) | DK0416499T3 (zh) |
| ES (1) | ES2073487T3 (zh) |
| FI (1) | FI105182B (zh) |
| HK (1) | HK1008843A1 (zh) |
| HR (1) | HRP940702B1 (zh) |
| HU (1) | HU210770B (zh) |
| IE (1) | IE67451B1 (zh) |
| IL (1) | IL95581A (zh) |
| LT (1) | LT3771B (zh) |
| LV (1) | LV10427B (zh) |
| MA (1) | MA21944A1 (zh) |
| MX (1) | MX22240A (zh) |
| NO (1) | NO179371C (zh) |
| NZ (1) | NZ235168A (zh) |
| PH (1) | PH30477A (zh) |
| PL (1) | PL164167B1 (zh) |
| PT (1) | PT95206B (zh) |
| RU (1) | RU1836338C (zh) |
| SK (1) | SK431890A3 (zh) |
| YU (1) | YU48468B (zh) |
| ZA (1) | ZA907062B (zh) |
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| DK0577024T3 (zh) * | 1992-07-01 | 1997-02-24 | Hoechst Ag | |
| EP0589336B1 (de) * | 1992-09-22 | 1997-01-08 | Hoechst Aktiengesellschaft | Benzoylguanidine, Verfahren zu ihrer Herstellung, sowie ihre Verwendung als Antiarrhythmika |
| DK0600371T3 (da) * | 1992-12-02 | 1999-09-20 | Hoechst Ag | Guanidinalkyl-1,1-bisphosphonsyrederivater, fremgangsmåde til deres fremstilling samt deres anvendelse |
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| TW250477B (zh) * | 1992-12-15 | 1995-07-01 | Hoechst Ag | |
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| EP0604852A1 (de) * | 1992-12-28 | 1994-07-06 | Hoechst Aktiengesellschaft | 2,4-Substituierte 5-(N-substituierte-Sulfamoyl)-Benzoylguanidine, als Antiarrythmika, Inhibitoren der Proliferationen von Zellen, und Inhibitoren des Natrium-Protonen-Antiporters |
| EP0612723B1 (de) * | 1993-02-20 | 1997-08-27 | Hoechst Aktiengesellschaft | Substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament, als Inhibitoren des zellulären Na+/H+-Austauschs oder als Diagnostikum sowie sie enthaltendes Medikament |
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- 1989-09-06 DE DE3929582A patent/DE3929582A1/de not_active Withdrawn
-
1990
- 1990-09-03 AT AT90116859T patent/ATE121738T1/de not_active IP Right Cessation
- 1990-09-03 EP EP90116859A patent/EP0416499B1/de not_active Expired - Lifetime
- 1990-09-03 DK DK90116859.1T patent/DK0416499T3/da active
- 1990-09-03 ES ES90116859T patent/ES2073487T3/es not_active Expired - Lifetime
- 1990-09-03 DE DE59008959T patent/DE59008959D1/de not_active Expired - Lifetime
- 1990-09-04 RU SU904831136A patent/RU1836338C/ru active
- 1990-09-04 US US07/576,937 patent/US5091394A/en not_active Expired - Lifetime
- 1990-09-04 NZ NZ235168A patent/NZ235168A/en unknown
- 1990-09-04 FI FI904362A patent/FI105182B/fi active IP Right Grant
- 1990-09-04 IL IL9558190A patent/IL95581A/en active IP Right Grant
- 1990-09-04 HU HU905773A patent/HU210770B/hu unknown
- 1990-09-05 ZA ZA907062A patent/ZA907062B/xx unknown
- 1990-09-05 CZ CS904318A patent/CZ278318B6/cs not_active IP Right Cessation
- 1990-09-05 SK SK4318-90A patent/SK431890A3/sk not_active IP Right Cessation
- 1990-09-05 AU AU62178/90A patent/AU631007B2/en not_active Expired
- 1990-09-05 PT PT95206A patent/PT95206B/pt not_active IP Right Cessation
- 1990-09-05 CA CA002024700A patent/CA2024700C/en not_active Expired - Lifetime
- 1990-09-05 IE IE322990A patent/IE67451B1/en not_active IP Right Cessation
- 1990-09-05 NO NO903872A patent/NO179371C/no not_active IP Right Cessation
- 1990-09-05 PL PL90286747A patent/PL164167B1/pl unknown
- 1990-09-05 JP JP2233444A patent/JPH07592B2/ja not_active Expired - Lifetime
- 1990-09-05 MA MA22216A patent/MA21944A1/fr unknown
- 1990-09-05 CN CN90107457A patent/CN1049888C/zh not_active Expired - Lifetime
- 1990-09-05 MX MX2224090A patent/MX22240A/es unknown
- 1990-09-05 YU YU169190A patent/YU48468B/sh unknown
- 1990-09-06 KR KR1019900014031A patent/KR0159095B1/ko not_active Expired - Lifetime
-
1992
- 1992-01-31 US US07/830,355 patent/US5292755A/en not_active Expired - Lifetime
-
1993
- 1993-05-05 LV LVP-93-287A patent/LV10427B/lv unknown
- 1993-11-12 LT LTIP1459A patent/LT3771B/lt not_active IP Right Cessation
-
1994
- 1994-06-24 PH PH48506A patent/PH30477A/en unknown
- 1994-10-19 HR HRP-1691/90A patent/HRP940702B1/xx not_active IP Right Cessation
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1998
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