CN1064955C - 含氟的苯甲酰胍 - Google Patents
含氟的苯甲酰胍 Download PDFInfo
- Publication number
- CN1064955C CN1064955C CN961058854A CN96105885A CN1064955C CN 1064955 C CN1064955 C CN 1064955C CN 961058854 A CN961058854 A CN 961058854A CN 96105885 A CN96105885 A CN 96105885A CN 1064955 C CN1064955 C CN 1064955C
- Authority
- CN
- China
- Prior art keywords
- methyl
- trifluoromethyl
- reaction
- hydrochloride
- benzamide
- 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.)
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- 229910052731 fluorine Inorganic materials 0.000 title claims abstract description 18
- 239000011737 fluorine Substances 0.000 title claims abstract description 9
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- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 title claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims description 49
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
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- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
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- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
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- XQPDEGJIEUSTFZ-UHFFFAOYSA-N methyl 2,4-di(propan-2-yl)-5-(trifluoromethyl)benzoate Chemical compound COC(=O)C1=CC(C(F)(F)F)=C(C(C)C)C=C1C(C)C XQPDEGJIEUSTFZ-UHFFFAOYSA-N 0.000 description 1
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- FANGIKAQRGMYHS-UHFFFAOYSA-N methyl 2-butyl-4-tert-butyl-5-(trifluoromethyl)benzoate Chemical compound CCCCC1=CC(C(C)(C)C)=C(C(F)(F)F)C=C1C(=O)OC FANGIKAQRGMYHS-UHFFFAOYSA-N 0.000 description 1
- FJMPENKJHSJLDA-UHFFFAOYSA-N methyl 2-butyl-5-(trifluoromethyl)benzoate Chemical compound CCCCC1=CC=C(C(F)(F)F)C=C1C(=O)OC FJMPENKJHSJLDA-UHFFFAOYSA-N 0.000 description 1
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- GPYKFFMDSWSGAG-UHFFFAOYSA-N methyl 2-ethyl-4-methyl-5-(trifluoromethyl)benzoate Chemical compound CCC1=CC(C)=C(C(F)(F)F)C=C1C(=O)OC GPYKFFMDSWSGAG-UHFFFAOYSA-N 0.000 description 1
- PTUFQIQUXAKHOW-UHFFFAOYSA-N methyl 2-ethyl-5-(trifluoromethyl)benzoate Chemical compound CCC1=CC=C(C(F)(F)F)C=C1C(=O)OC PTUFQIQUXAKHOW-UHFFFAOYSA-N 0.000 description 1
- XOUMAABXMXACFQ-UHFFFAOYSA-N methyl 2-fluoro-3-(trifluoromethyl)benzoate Chemical compound COC(=O)C1=CC=CC(C(F)(F)F)=C1F XOUMAABXMXACFQ-UHFFFAOYSA-N 0.000 description 1
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- UAEUYKATVUSDCK-UHFFFAOYSA-N methyl 2-fluoro-5-(trifluoromethyl)benzoate Chemical compound COC(=O)C1=CC(C(F)(F)F)=CC=C1F UAEUYKATVUSDCK-UHFFFAOYSA-N 0.000 description 1
- FXRXVKXAJXZKKB-UHFFFAOYSA-N methyl 2-methyl-5-(trifluoromethyl)benzoate Chemical compound COC(=O)C1=CC(C(F)(F)F)=CC=C1C FXRXVKXAJXZKKB-UHFFFAOYSA-N 0.000 description 1
- NPNQVXRWDIMHDX-UHFFFAOYSA-N methyl 2-nitro-5-(trifluoromethyl)benzoate Chemical compound COC(=O)C1=CC(C(F)(F)F)=CC=C1[N+]([O-])=O NPNQVXRWDIMHDX-UHFFFAOYSA-N 0.000 description 1
- ZTSPSXHPFZALDU-UHFFFAOYSA-N methyl 2-tert-butyl-5-(trifluoromethyl)benzoate Chemical compound COC(=O)C1=CC(C(F)(F)F)=CC=C1C(C)(C)C ZTSPSXHPFZALDU-UHFFFAOYSA-N 0.000 description 1
- LQODVVRNKLSHHZ-UHFFFAOYSA-N methyl 3-methylsulfonyl-4-(trifluoromethyl)benzoate Chemical compound COC(=O)C1=CC=C(C(F)(F)F)C(S(C)(=O)=O)=C1 LQODVVRNKLSHHZ-UHFFFAOYSA-N 0.000 description 1
- TVWFEYRWSTXGQL-UHFFFAOYSA-N methyl 4-bromo-2-ethyl-5-(trifluoromethyl)benzoate Chemical compound CCC1=CC(Br)=C(C(F)(F)F)C=C1C(=O)OC TVWFEYRWSTXGQL-UHFFFAOYSA-N 0.000 description 1
- IFCDUZRSIQZRLO-UHFFFAOYSA-N methyl 4-bromo-2-methyl-5-(trifluoromethyl)benzoate Chemical compound COC(=O)C1=CC(C(F)(F)F)=C(Br)C=C1C IFCDUZRSIQZRLO-UHFFFAOYSA-N 0.000 description 1
- DHLYOOKOBOPBPK-UHFFFAOYSA-N methyl 4-bromo-2-nitro-5-(trifluoromethyl)benzoate Chemical compound COC(=O)C1=CC(C(F)(F)F)=C(Br)C=C1[N+]([O-])=O DHLYOOKOBOPBPK-UHFFFAOYSA-N 0.000 description 1
- GGUJFOGBSLBJED-UHFFFAOYSA-N methyl 4-chloro-2-methyl-5-(trifluoromethyl)benzoate Chemical compound COC(=O)C1=CC(C(F)(F)F)=C(Cl)C=C1C GGUJFOGBSLBJED-UHFFFAOYSA-N 0.000 description 1
- GHRBWSASQPRFJG-UHFFFAOYSA-N methyl 4-chloro-2-nitro-5-(trifluoromethyl)benzoate Chemical compound COC(=O)C1=CC(C(F)(F)F)=C(Cl)C=C1[N+]([O-])=O GHRBWSASQPRFJG-UHFFFAOYSA-N 0.000 description 1
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 1
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- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 description 1
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- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
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- 239000011664 nicotinic acid Substances 0.000 description 1
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- ILUJQPXNXACGAN-UHFFFAOYSA-N ortho-methoxybenzoic acid Natural products COC1=CC=CC=C1C(O)=O ILUJQPXNXACGAN-UHFFFAOYSA-N 0.000 description 1
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- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
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- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
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- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- SIMZKPFFQPBRPY-UHFFFAOYSA-N potassium;2,2,2-trifluoroacetic acid Chemical compound [K].OC(=O)C(F)(F)F SIMZKPFFQPBRPY-UHFFFAOYSA-N 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
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- 239000011541 reaction mixture Substances 0.000 description 1
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- 230000009257 reactivity Effects 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 239000007787 solid Substances 0.000 description 1
- 238000010129 solution processing Methods 0.000 description 1
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- 239000005720 sucrose Substances 0.000 description 1
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- 150000003462 sulfoxides Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 1
- 125000003652 trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
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- 235000013311 vegetables Nutrition 0.000 description 1
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Classifications
-
- 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
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
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- A—HUMAN NECESSITIES
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Abstract
通式Ⅰ的杂环基氧基苯甲酰胍
其中R1，R2和R3具有所指定的意义，和其生理上可接受的盐，它们具有抗心律失常性能并用作细胞Na+/H+抗输运剂的抑制剂。
Description
本发明涉及通式Ⅰ的含氟的苯甲酰胍：其中R1是H，F，Cl，Br，I，A，CN，NO2，CnFmH2n+1-mOp，具有2-4个碳原子的炔基或-X-R4，R2是CnFmH2n+1-mOp，R3是H，A，F，Cl，Br，I，CnFmH2n+1-mOp，SOq-R6，SO2NR4R5，Het，OR6，SR6，S-Het或NR7-Het，R4和R5相互独立地各自是H或A或者一起是另一个具有4-5个碳原子的亚烷基，其中CH2基团还能被O、S、NH或NA替代，R6是Ph或A，R7是H或A，A是具有1-6个碳原子的烷基，X是O、S或NR7，Ph是苯基，未取代的或被A，OA，NR4R5，F，Cl，Br，I或CnFmH2n+1-mOp单取代、二取代或三取代，Het是具有1-4个N、O和／或S原子的单核或双核饱和的、不饱和的或芳香族的杂环基，它是未取代的或被F、Cl、Br、CnFmH2n+1-mOp、A、X-R4、NO2、CN和／或羰基氧单取代、二取代或三取代，并经N或C连接于苯甲酰基体系，m是1，2，3，4，5，6或7，但至多2n+1，n是1，2或3，p是0或1，且q是1或2，
前提是，如果R3是SOp-R6或SO2NR4R5，R1只能是H，
以及它们的生理上可接受的盐类。
本发明的目的是发现具有有用性能的新型化合物，尤其能用来制药的那些化合物。
已知发现，通式Ⅰ的化合物和它们的生理上可接受的盐类具有有用的药理性能和良好的耐受性。
该新型化合物是细胞Na+／H+抗输运剂(antiporter)的抑制剂，即能抑制细胞的Na+／H+交换机理的活性化合物(Dusing等人，Med．Klin．87，378-384(1992))，因而是良好的抗心律失常药物，它尤其适合于治疗因缺氧引起的心律不齐。
酰基胍类中最佳的已知活性化合物是氨氯吡脒。但是，这一物质最初显示高血压和排盐利尿作用，它尤其在治疗心律失常方面是不需要的，尽管只是极其微弱地显示抗心律失常性能。
此外，结构上相似的化合物例如从EP 0416499是已知的。
根据本申请的发明的物质显示良好的心脏保护作用，因而特别适合于梗塞治疗、梗塞预防和心绞痛治疗。该物质进一步抵抗所有的病理性氧不足和局部缺血性损害，这样能治疗由此引起的原发性或继发性疾病。该活性物质还高度适合于预防应用。
由于这些物质在病理性氧不足或局部缺血情形中的预防作用，由其导致在保护暂时供应不足的器官的外科干预方面，在保护切除器官的器官移植方面，在原生质(angioplastic)血管或心脏干预方面，在神经系统的局部缺血方面，在休克症状的治疗和防止原发性高血压方面应用的其它可能性。
该化合物还能进一步用作由细胞增生引起的疾病的治疗剂，如动脉硬化，糖尿病后并发病，癌，纤维变性疾病(尤其肺、肝和肾的)以及器官肥大和增生。此外，这些物质还适合于诊断使用，用来诊断例如在红细胞、血小板或白细胞中Na+／H+抗输运剂的增高了的活性所伴随的疾病。
借助于本身已知的方法确定化合物的作用，例如由N．Es-cobales和J．Figueroa在J．Membrane Biol．120，41-49(1991)中或由L．Counillon，W．Scholz，H．J．Lang和J．Pouysségur在Mol．Pharmacol．44，1041-1045(1993)中所指出的方法。
合适的实验动物例如是鼠、家鼠、天竺鼠、狗、猫、猴或猪。
因而，这些化合物能用作人的药物活性化合物和兽药。它们还能用作制备其它药物活性化合物的中间体。
在所指出的结构式中，A是具有1-6个，优选1-4个，尤其1、2或3个碳原子的支化或未支化烷基；特别优选甲基，另外优选乙基，丙基，异丙基，丁基，异丁基，还优选仲丁基，叔丁基，戊基，异戊基(3-甲基丁基)，己基或异己基(4-甲基戊基)。
R1优选是H，特别优选A，Cl，Br或CnFmH2n+1-mOp，其中CnFmH2n+1-mOp，优选是CF3，C2F5或具有1-4个碳原子的部分氟化的烷基。如CH2F，CHF2，C2HF4，C2H2F3，C2H3F2或C2H4F。
R2优选是F，Cl，Br或CnFmH2n+1-mOp，其中CnFmH2n+1-mOp优选是OCF3，OCH2F，OCHF2，CF3，C2F5，或具有1-4个碳原子的部分氟化的烷基，
R3优选是H3C-SO2-或H2N-SO2-，但还优选是氢。两基团R2和R3中的一个优选处在苯甲酰基的4-位，而另一个处在3-或5-位。然而，一种分布方式是特别优选的，其中基团R2处在酰胺基的对位。如果基团R3是A-SO2-，它优选位于间位。在3-位上有一个甲基磺酰基和在6-位有一个烷基(优选甲基或乙基)的苯甲酰基是特别优选的。
R4和R5优选是H或A。
如果R4和R5一起是亚烷基，该亚烷基优选是未支化的，具体地说，优选是-(CH2)k-，其中k是4或5；但也优选是-(CH2)2-O-(CH2)2-，-(CH2)2-NH-(CH2)2-，-(CH2)2-NA-(CH2)2-，-CH2-O-(CH2)2-，-CH2-NH-(CH2)2-或-CH2-NA-(CH2)2-或-CO-(CH2)3-，-CO-(CH2)4-或-CH2-CO-(CH2)2-。
Ph优选是苯基，它是未取代的或被Cl，Br，A，OA，NH2，NHA，NA2或CF3单取代。
R6优选是A，尤其甲基或还优选是未取代的苯基。
基团X优选是O或NH。
Het优选是2-或3-呋喃基，2-或3-噻吩基，1-，2-或3-吡咯基，1-，2-，4-或5-咪唑基，1-，3-，4-或5-吡唑基，2-，4-或5-噁唑基，3-，4-或5-异噁唑基，2-，4-或5-噻唑基，3-，4-或5-异噻唑基，2-，3-或4-吡啶基，2-，4-，5-或6-嘧啶基，另外优选是1，2，3-三唑-1-基，-4-基或-5-基，1，2，4-三唑-1-基，-3-基或-5-基，1-或5-四唑基，1，2，3-噁二唑-4-基或-5-基，1，2，4-噁二唑-3-基或-5-基，1，3，4-噻二唑-2-基或-5-基，1，2，4-噻二唑-3-基或-5-基，1，2，3-噻二唑-4-基或-5-基，2-，3-，4-，5-或6-2H-噻喃基，2-，3-或4-4H-噻喃基，3-或4-哒嗪基，吡嗪基，2-，3-，4-，5-，6-或7-苯并呋喃基，2-，3-，4-，5-，6-或7-苯并噻吩基，1-，2-，3-，4-，5-，6-或7-吲哚基，1-，2-，4-或5-苯并咪唑基，1-，3-，4-，5-，6-或7-苯并吡唑基，2-，4-，5-，6-或7-苯并噁唑基，3-，4-，5-，6-或7-苯并异噁唑基，2-，4-，5-，6-或7-苯并噻唑基，2-，4-，5-，6-或7-苯并异噻唑基，4-，5-，6-或7-苯并-2，1，3-噁二唑基，2-，3-，4-，5-，6-，7-或8-喹啉基，1-，3-，4-，5-，6-，7-或8-异喹啉基，1-，2-，3-，4-或9-咔唑基，1-，2-，3-，4-，5-，6-，7-，8-或9-吖啶基，3-，4-，5-，6-，7-或8-喹啉基，2-，4-，5-，6-，7-或8-喹唑啉基。该杂环基团还可以是部分或完全氢化的。因而，Het例如还可以是2，3-二氢-2-，-3-，-4-或-5-呋喃基，2，5-二氢-2-，-3-，-4-，或-5-呋喃基，四氢-2-或-3-呋喃基，1，3-二氧戊环-4-基，四氢-2-或-3-噻吩基，2，3-二氢-1-，-2-，-3-，-4-或-5-吡咯基，2，5-二氢-1-，-2-，-3-，-4-或-5-吡咯基，1-，2-或3-吡咯烷基，四氢-1-，-2-或-4-咪唑基，2，3-二氢-1-，-2-，-3-，-4-或-5-吡唑基，四氢-1-，-3-或-4-吡唑基，1，4-二氢-1-，-2-，-3-或-4-吡啶基，1，2，3，4-四氢-1-，-2-，-3-，-4-，-5-或-6-吡啶基，1，2，3，6-四氢-1-，-2-，-3-，-4-，-5-或-6-吡啶基，1-，2-，3-或4-哌啶基，2-，3-或4-吗啉基，四氢-2-，-3-或-4-吡喃基，1，4-二噁烷基，1，3-二噁-2-，-4-或-5-基，六氢-1-，-3-或-4-哒嗪基，六氢-1-，-2-，-4-或-5-嘧啶基，1-，2-或3-哌嗪基，1，2，3，4-四氢-1-，-2-，-3-，-4-，-5-，-6-，-7-或-8-喹啉基，1，2，3，4-四氢-1-，-2-，-3-，-4-，-5-，-6-，-7-或-8-异喹啉基。
对于整个发明来说适用的是，反复出现的所有基团如Het，Ph或CnFmH2n+1-mOp，相互独立地是相同或不同的。
所以，本发明尤其涉及其中至少一个提到的基团具有一种上述优选的定义的那些通式Ⅰ化合物。化合物的一些优选的基团能由以下通式Ⅰa-Ⅰh表示，它们对应于通式Ⅰ，其中没有详细指明的基团具有通式Ⅰ中指定的定义，但是，其中
在Ⅰa中R1是H且R3是-SO2-CH2，-SO2-NH2或氢；
在Ⅰb中R1是H，甲基或乙基且R2是CF3，OCF3，OCH2F，OCHFF2，CF3，C2F5或具有1-4个碳原子的部分氟化的烷基，如CH2F，CHF2，C2HF4，C2H2F3，C2H3F2，C2H4F；
在Ⅰc中基团R2或R3中的一个是CnFmH2n+1-mOp而另一个基团是氢，CF3，Cl或Br；
在Ⅰd中R1是甲基，乙基，F，Cl或Br且R2和／或R3是CnFmH2n+1-mOp；
在Ⅰe中R2和R3两基团相互独立地是CnFmH2n+1-mOp；
在Ⅰf中R1是甲基，乙基，F，Cl或Br，R2是CnFmH2n+1-mOp而R3是氢；
在Ⅰg中基团CnFmH2n+1-mOp处在胍基羰基的对位且R1是甲基，乙基，F，Cl或Br；
在Ⅰh中R1是NO2或CN且R3是CnFmH2n+1-mOp。
本发明还涉及制备权利要求1的通式Ⅰ的化合物和它们的盐的方法，其特征在于通式Ⅱ的化合物
其中R1，R2和R3具有以上指定的定义，且Q是Cl，Br，OA，O-CO-A，O-CO-Ph，OH或另一个反应活性酯化了的OH基或易亲核取代的离去基团，
与胍反应，
或者在于通式Ⅲ的苯甲酰胍其中R1和R3具有以上所指定的定义，且R6是Br，Cl，F，I或另一个可亲核取代的基团，
与通式Ⅳ的化合物反应
CnFmH2n+1-mOp-L Ⅳ其中n，m和p具有所指定的定义且L是H，(CH3)3-Si，CO2K或CO2Na，碱金属阳离子，NH4 +，Ag+或Cu+。
或者在于一种通式Ⅰ的化合物，但它代替一个或多个氢原子的是含有一个或多个可还原的基团和／或一个或多个附加的C-C和／或C-N键，用还原剂进行处理，
或在于一种通式Ⅰ的化合物，但它代替一个或多个氢原子的是含有一个或多个溶剂可分解的基团，用溶剂分解进行处理，
和／或在于所获得的通式Ⅰ的碱用酸处理转变成它的一种盐。
另外还可由本身已知的方法，如在文献(例如在标准著作如Houben-Weyl，Methoden der organischen Chemie(有机化学方法)，Georg-Thieme-Verlag，Stuttgart；Organic Reaction，JohnWiley & Sons，Inc．，New York；和在上面指出的专利申请中)中描述的方法，即在已知的且适合于所述反应的反应条件下，制备通式Ⅰ的化合物。在这种情况下，还可以使用已知的派生方法，但这里不再详细叙述。
如果需要，该起始物质还能以这样一种方法就地制成：它们不从反应混合物中分离出来但立即再参与反应得到通式Ⅰ的化合物。
优选的是，通过让通式Ⅱ的活化羧酸衍生物，其中Q特别优选Cl或-O-CH3，与胍反应制备通式Ⅰ的化合物。反应派生形式是特别合适的。其中游离羧酸Ⅱ(Q=OH)按本身已知的方法参与反应得到各自的活化衍生物，它然后直接与胍反应而无需分离出中间体。其中不需要分离中间体的方法例如是用羰基二咪唑，二环己基碳化二亚胺或Mukaiyama变体(Angew．Chem．91，788-812(1979))活化。
从合适的苯甲酸开始，通过与合适的通式Ⅳ的化合物反应进行亲核芳族取代来制备通式Ⅱ的羧酸。该反应所进行的方式类似于化合物Ⅲ和Ⅳ的反应。下面进行描述。
特别合适的通式Ⅳ化合物例如是部分或完全氟化的链烷羧酸的碱金属盐。
通式Ⅱ的活性羧酸衍生物与胍的反应按本身已知的方法进行，优选在质子或非质子极性或非极性惰性有机溶剂中进行。
下面提到了用于化合物Ⅲ和Ⅳ的反应的合适溶剂。然而，特别优选的溶剂是甲醇，THF，二甲氧基乙烷，二噁烷或从它们制得的混合物以及水。合适的反应温度例如是20°-溶剂沸点之间的温度。反应时间是在5分钟和12小时之间。有利的是在反应中使用酸清除剂。合适的那些酸清除剂是在反应中无干扰作用的任何类型的碱。然而，无机碱如碳酸钾的使用或有机碱如三乙胺或吡啶的使用或者过量胍的使用是特别合适的。
权利要求1的通式Ⅰ化合物还可通过通式Ⅲ的苯甲酰胍与通式Ⅳ的化合物反应来制备。通过让合适取代的苯甲酸或能从它获得的反应活性衍生物如酰基卤、酯或酸酐与胍在本身已知的且一般常用于酰胺制备的反应条件下按简单方式能够制备通式Ⅲ的起始物质。其次，特别合适的是如以上关于化合物Ⅱ与胍的反应所指定的那些反应派生形式。
与制备它们的方法一样，通式Ⅳ的化合物本身也是已知的。如果它们不是已知的，则可以由本身已知的方法制备它们。
化合物Ⅱ的制备和化合物Ⅲ与通式Ⅳ的化合物的反应按本身已知的方式进行，优选在质子或非质子惰性有机溶剂中进行。
在Ⅱ的制备中，在Ⅱ与胍的反应中或在Ⅲ与Ⅳ的反应中，同样有利的是在碱存在下进行或用过量的碱性组分进行。合适的碱例如优选是碱金属或碱土金属氢氧化物，碳酸盐，醇盐或者有机碱类如三乙胺或吡啶，它们也可以过量使用并能同时用作溶剂。
合适的惰性溶剂尤其是醇类，如甲醇、乙醇、异丙醇、正丁醇或叔丁醇；醚类，如乙醚，二异丙基醚，四氢呋喃(THF)或二噁烷；乙二醇醚类，如乙二醇单甲醚或单乙醚(甲基乙二醇或乙基乙二醇)，乙二醇二甲醚(二甘醇二甲醚)；酮类，如丙酮或丁酮；腈类如乙腈；硝基化合物类如硝基甲烷或硝基苯；酯类，如乙酸乙酯；酰胺类，如六甲基磷酰胺；亚砜类，如二甲亚砜(DMSO)；氯代烃类，如二氯甲烷，氯仿，三氯乙烯，1，2-二氯乙烷或四氯化碳；烃类，如苯，甲苯或二甲苯。这些溶剂相互组成的混合物也是合适的。
特别合适的操作程序在于让过量的化合物Ⅳ以三甲基硅氧基衍生物的形式在没有添加溶剂的情况下直接与通式Ⅲ的苯甲酰胍在100°～400°之间的温度下，尤其在100°～200°之间的温度下进行反应。通式Ⅳ的化合物，优选钾盐或钠盐或相应的羧酸盐，能够在CuI存在下与通式Ⅲ的苯甲酰胍或合适的前体如酯进行反应。
此外，在通式Ⅰ的化合物中，一种或多种基团R1，R2和／或Het能被转化成其它的基团R1，R2和／或Het。
例如，有可能借助卤化以卤素原子替代H原子或借助硝化以硝基替代H原子和／或将硝基还原成氨基和／或氨基或羟基烷基化或酰化和／或通过氢解(例如用在催化剂如Pd上用H2或在甲醇中用甲酸铵)除去苄基。
硝化在常规条件下进行，例如，使用浓HNO3和浓H2SO4的混合物在0～30°之间的温度下。
同样适用于卤化，例如通过使用元素氯或溴在一种常规惰性溶剂中在约0～30°之间的温度下来进行。
通过用烷基化剂处理，伯或仲氨基和／或OH基能被转化成相应的仲或叔氨基和／或烷氧基。合适的烷基化剂例如是结构式A-Cl，A-Br或A-I的化合物或相应的硫酸或磺酸酯类如氯代、溴代或碘代甲基，硫酸二甲酯和对甲苯磺酸甲酯。还可能的是，例如在甲酸存在下使用甲醛引入一个或两个甲基。在一种上述惰性溶剂(例如DMF)存在或不存在下，在约0～约120°之间的温度下可方便地进行烷基化，还可能存在催化剂，优选碱如叔丁氧基钾或NaH。
用酸能将通式Ⅰ的碱转化成相应的酸加合盐。对于这一反应，合适的酸是产生生理上可接受的盐的那些酸。因而可使用无机酸，例如硫酸，硝酸，氢卤酸类如氢氯酸或氢溴酸，磷酸类如正磷酸，氨基磺酸，还有有机酸，尤其脂族、脂环族、芳脂族、芳族或杂环族的单或多元羧酸、磺酸或硫酸、例如甲酸、乙酸，丙酸，新戊酸，二乙基乙酸，丙二酸，琥珀酸，庚二酸，富马酸，马来酸，乳酸，酒石酸，苹果酸，苯甲酸，水杨酸，2-或3-苯基丙酸，柠檬酸，葡糖酸，抗坏血酸，烟酸，异烟酸，甲烷或乙烷磺酸，乙烷二磺酸，2-羟基乙烷磺酸，苯磺酸，对甲苯磺酸，萘单磺酸和萘二磺酸和月桂基硫酸。
通式Ⅰ的化合物和它们的生理上可接受的盐能用来制造药物制剂，尤其通过非化学途径。在本文中，它们能与至少一种固体、液体和／或半液体赋形剂或辅助剂以及如果合适的话与一种或多种其它活性化合物一起制成合适的剂量形式。
本发明进一步涉及包含至少一种通式Ⅰ的化合物和／或一种它的生理上可接受的盐的组合物，尤其是药物制剂。
这些制剂能够在人药或兽药中用作药剂。合适的赋形剂是适合于肠内(例如口服)或胃肠外给药或局部应用的且不与本新型化合物反应的有机或无机物质，例如是水，植物油，苄醇，聚乙二醇，三乙酸甘油酯，明胶，碳水化合物类如乳糖或淀粉，硬脂酸镁，滑石，羊毛脂或矿脂。片剂，包覆的片剂，胶囊剂，糖浆，液汁剂或滴剂尤其用于口服，栓剂用于直肠给药，溶液剂，优选油状溶液或水溶液，和悬浮剂，乳液剂或植入药剂用于胃肠外给药，膏剂，乳剂，糊剂，洗剂，凝胶剂，喷雾剂，泡沫剂，气溶胶，溶液剂(例如在醇类如乙醇或异丙醇，乙腈，DMF，二甲基乙酰胺，1，2-丙二醇或它们中的一种与另一种和／或与水的混合物中的溶液)或粉剂供局部应用。该新型化合物还能被冻干，所获得的冻干物例如用来生产注射制剂。
尤其，脂质制剂也适合于局部应用。所指出的这些制剂能够被消毒和／或含有辅助剂如润滑剂，防腐剂，稳定剂和／或润湿剂，乳化剂，影响渗透压的盐，缓冲物质，色料，调味剂或芳香物质。如果需要，它们还可合有一种或多种活性化合物，例如一种或多种维生素。
通式Ⅰ的化合物和它们的生理上可接受的盐类能施给人或动物，尤其哺乳动物如猴、狗、猫、鼠或小鼠以及用于人体或动物体的治疗，还用于控制疾病，尤其用于心血管系统的疾病的治疗和／或预防。所以，它们适合于治疗心律失常，尤其由缺氧引起的，治疗心绞痛，梗塞，神经系统的局部缺血如中风或大脑水肿，治疗休克以及适合于预防性治疗。
该物质也能用作细胞增生所引起的病症的治疗剂，如动脉硬化，糖尿病后并发病，癌，纤维变性，以及器官肥大和增生。
在本文中，本发明的物质一般按已知的抗心律失常药(例如茚满丙二胺)的方式施用，优选的剂量是在约0．01～5mg，尤其0．02～0．5mg／单位剂量之间。每天的剂量优选是约0．0001～0．1、尤其0．0003～0．01mg／kg体重之间。然而，对于每一位具体的病人来说特定的剂量取决于各种类型的因素，例如取决于所用特定化合物的活性，取决于年龄，体重，一般健康状态，性别，饭量，时间和给药途径，以及取决于排泄速度、药物的结合使用和治疗剂所针对的具体病症的严重性。口服是优选的。
在下面的实施例中，“常规处理”指：添加水，如果必要，用有机溶剂如乙酸乙酯萃取，分离出有机相，用硫酸钠干燥，过滤，蒸发和用色谱法和／或结晶法提纯。
实施例1
0．5g的2-甲基-4-苯氧基-5-三氟甲基苯甲酸(由2-甲基-4-苯氧基-5-溴苯甲酸甲酯与三氟乙酸钾在CuI和碘化四甲铵存在下进行反应，然后水解可得到)和300mg羰基二咪唑在15mg THF中的溶液在室温下搅拌2小时，然后添加到剂383mg胍中。混合物再搅拌两小时。在常规处理之后，获得N-二氨基亚甲基-2-甲基-4-苯氧基-5-三氟甲基苯甲酰胺。
下面各种物质是类似地由胍与下列各种相应的苯甲酸反应得到的：与2-甲基-5-二氟甲氧基苯甲酸反应
N-二氨基亚甲基-2-甲基-5-二氟甲氧基苯甲酰胺；与2-甲基-5-(2，2，2-三氟乙氧基)苯甲酸反应
N-二氨基亚甲基-2-甲基-5-(2，2，2-三氟乙氧基)苯甲酰胺；与3-甲基磺酰基-4-(五氟乙基)苯甲酸反应
N-二氨基亚甲基-3-甲基磺酰基-4-(五氟乙基)苯甲酰胺；与3-甲基磺酰基-4-三氟甲氧基苯甲酸反应
N-二氨基亚甲基-3-甲基磺酰基-4-三氟甲氧基苯甲酰胺；与3-甲基磺酰基-4-二氟甲氧基苯甲酸反应
N-二氨基亚甲基-3-甲基磺酰基-4-二氟甲氧基苯甲酰胺；与3-甲基磺酰基-4-氟甲氧基苯甲酸反应
N-二氨基亚甲基-3-甲基磺酰基-4-氟甲氧基苯甲酰胺；与2-甲基-4-五氟乙基-5-甲基磺酰基苯甲酸反应
N-二氨基亚甲基-2-甲基-4-五氟乙基-5-甲基磺酰基苯甲酰胺；与2-甲基-4-三氟甲氧基-5-甲基磺酰基苯甲酸反应
N-二氨基亚甲基-2-甲基-4-三氟甲氧基-5-甲基磺酰基苯甲酰胺；与2-甲基-4-二氟甲氧基-5-甲基磺酰基苯甲酸反应
N-二氨基亚甲基-2-甲基-4-二氟甲氧基-5-甲基磺酰基苯甲酰胺；与2-甲基-4-氟甲氧基-5-甲基磺酰基苯甲酸反应
N-二氨基亚甲基-2-甲基-4-氟甲氧基-5-甲基磺酰基苯甲酰胺；与3-甲基磺酰基-4-(1，6-二氢-6-氧代-3-哒嗪氧基)-6-三氟甲基苯甲酸反应
N-二氨基亚甲基-3-甲基磺酰基-4-(1，6-二氢-6-氧代-3-哒嗪氧基)-6-三氟甲基苯甲酰胺。
实施例2
1．1g的3-甲基磺酰基-4-三氟甲基苯甲酸甲酯[m．p．146-147°；由3-甲基磺酰基-4-溴苯甲酸甲酯与三氟乙酸钾在CuI和碘化四甲铵存在下在甲苯中进行反应获得]被加入到928mg胍在15ml甲醇中的溶液中。混合物在50°下搅拌45分钟，在除去溶剂和常规处理之后，获得N-二氨基亚甲基-3-甲基磺酰基-4-三氟甲基苯甲酰胺，m．p．233-234°。
在用稀HCl水溶液处理和冻干之后，从其获得相应的盐酸化物。
下面各种物质是类似地由胍与下列各种相应的苯甲酸酯反应得到的：与2-甲基-4-三氟甲基-5-甲基磺酰基苯甲酸甲酯(m．p．135-136°)反应
N-二氨基亚甲基-2-甲基-4-三氟甲基-5-甲基磺酰基苯甲酰胺，m．p．212-213°(碱)，盐酸化物；与2，5-双(2，2，2-三氟乙氧基)苯甲酸甲酯反应
N-二氨基亚甲基-2，5-双(2，2，2-三氟乙氧基)-苯甲酰胺，盐酸化物；与2-甲基-4-溴-5-三氟甲氧基苯甲酸甲酯反应
N-二氨基亚甲基-2-甲基-4-溴-5-三氟甲氧基苯甲酰胺，盐酸化物；与2-乙基-4-溴-5-三氟甲氧基苯甲酸甲酯反应
N-二氨基亚甲基-2-乙基-4-溴-5-三氟甲氧基苯甲酰胺，盐酸化物；与2，4-二溴-5-三氟甲氧基苯甲酸甲酯反应
N-二氨基亚甲基-2，4-二溴-5-三氟甲氧基苯甲酰胺，盐酸化物；与2-异丙基-4-溴-5-三氟甲氧基苯甲酸甲酯反应
N-二氨基亚甲基-2-异丙基-4-溴-5-三氟甲氧基苯甲酰胺，盐酸化物；与2-异丙基-4-氯-5-三氟甲氧基苯甲酸甲酯反应
N-二氨基亚甲基-2-异丙基-4-氯-5-三氟甲氧基苯甲酰胺，盐酸化物；与2-甲基-4-氯-5-三氟甲氧基苯甲酸甲酯反应
N-二氨基亚甲基-2-甲基-4-氯-5-三氟甲氧基苯甲酰胺，盐酸化物；与2-甲基-4-氰基-5-三氟甲氧基苯甲酸甲酯反应
N-二氨基亚甲基-2-甲基-4-氰基-5-三氟甲氧基苯甲酰胺，盐酸化物；与2-硝基-4-氯-5-三氟甲氧基苯甲酸甲酯反应
N-二氨基亚甲基-2-硝基-4-氯-5-三氟甲氧基苯甲酰胺，盐酸化物；与2-硝基-4-溴-5-三氟甲氧基苯甲酸甲酯反应
N-二氨基亚甲基-2-硝基-4-溴-5-三氟甲氧基苯甲酰胺，盐酸化物；与2，5-双(三氟甲氧基)-4-溴苯甲酸甲酯反应
N-二氨基亚甲基-2，5-双(三氟甲氧基)-4-溴苯甲酰胺，盐酸化物；与2，5-双(三氟甲氧基)-4-氯苯甲酸甲酯反应
N-二氨基亚甲基-2，5-双(三氟甲氧基)-4-氯苯甲酰胺，盐酸化物；与2，5-双(三氟甲氧基)-4-氰基苯甲酸甲酯反应
N-二氨基亚甲基-2，5-双(三氟甲氧基)-4-氰基苯甲酰胺，盐酸化物；与2-氯-5-三氟甲基苯甲酸甲酯反应
N-二氨基亚甲基-2-氯-5-三氟甲基苯甲酰胺，盐酸化物，m．p．205°；与2，5-双(三氟甲基)苯甲酸甲酯反应
N-二氨基亚甲基-2，5-双(三氟甲基)苯甲酰胺，盐酸化物，m．p．232°；与2，4-双(三氟甲基)苯甲酸甲酯反应
N-二氨基亚甲基-2，4-双(三氟甲基)苯甲酰胺，盐酸化物，m．p．179°；与2，3-双(三氟甲基)苯甲酸甲酯反应
N-二氨基亚甲基-2，3-双(三氟甲基)苯甲酰胺，盐酸化物；与2-甲基-4-溴-5-三氟甲基苯甲酸甲酯反应
N-二氨基亚甲基-2-甲基-4-溴-5-三氟甲基苯甲酰胺，盐酸化物；与2-乙基-4-溴-5-三氟甲基苯甲酸甲酯反应
N-二氨基亚甲基-2-乙基-4-溴-5-三氟甲基苯甲酰胺，盐酸化物；与2，4-二溴-5-三氟甲基苯甲酸甲酯反应
N-二氨基亚甲基-2，4-二溴-5-三氟甲基苯甲酰胺，盐酸化物；与2-异丙基-4-溴-5-三氟甲基苯甲酸甲酯反应
N-二氨基亚甲基-2-异丙基-4-溴-5-三氟甲基苯甲酰胺，盐酸化物；与2-异丙基-4-氯-5-三氟甲基苯甲酸甲酯反应
N-二氨基亚甲基-2-异丙基-4-氯-5-三氟甲基苯甲酰胺，盐酸化物；与2-甲基-4-氯-5-三氟甲基苯甲酸甲酯反应
N-二氨基亚甲基-2-甲基-4-氯-5-三氟甲基苯甲酰胺，盐酸化物；与2-甲基-4-氰基-5-三氟甲基苯甲酸甲酯反应
N-二氨基亚甲基-2-甲基-4-氰基-5-三氟甲基苯甲酰胺，盐酸化物；与2-硝基-4-氯-5-三氟甲基苯甲酸甲酯反应
N-二氨基亚甲基-2-硝基-4-氯-5-三氟甲基苯甲酰胺，盐酸化物；与2-硝基-4-溴-5-三氟甲基苯甲酸甲酯反应
N-二氨基亚甲基-2-硝基-4-溴-5-三氟甲基苯甲酰胺，盐酸化物；与2，5-双(三氟甲基)-4-溴苯甲酸甲酯反应
N-二氨基亚甲基-2，5-双(三氟甲基)-4-溴苯甲酰胺，盐酸化物；与2，5-双(三氟甲基)-4-氯苯甲酸甲酯反应
N-二氨基亚甲基-2，5-双(三氟甲基)-4-氯苯甲酰胺，盐酸化物；与2，5-双(三氟甲基)-4-氰基苯甲酸甲酯反应
N-二氨基亚甲基-2，5-双(三氟甲基)-4-氰基苯甲酰胺，盐酸化物。
实施例3
下面的物质是按类似实施例2的方式由胍与下列各种苯甲酸酯反应获得的：与2-硝基-5-三氟甲基苯甲酸甲酯反应
N-二氨基亚甲基-2-硝基-5-三氟甲基苯甲酰胺，盐酸化物；与2-甲基-5-三氟甲基苯甲酸甲酯反应
N-二氨基亚甲基-2-甲基-5-三氟甲基苯甲酰胺，盐酸化物；与2-乙基-5-三氟甲基苯甲酸甲酯反应
N-二氨基亚甲基-2-乙基-5-三氟甲基苯甲酰胺，盐酸化物；与2-丁基-5-三氟甲基苯甲酸甲酯反应
N-二氨基亚甲基-2-丁基-5-三氟甲基苯甲酰胺，盐酸化物；与2-叔丁基-5-三氟甲基苯甲酸甲酯反应
N-二氨基亚甲基-2-叔丁基-5-三氟甲基苯甲酰胺，盐酸化物；与2-丙基-5-三氟甲基苯甲酸甲酯反应
N-二氨基亚甲基-2-丙基-5-三氟甲基苯甲酰胺，盐酸化物；与2-异丙基-5-三氟甲基苯甲酸甲酯反应
N-二氨基亚甲基-2-异丙基-5-三氟甲基苯甲酰胺，盐酸化物；与2-氟-5-三氟甲基苯甲酸甲酯反应
N-二氨基亚甲基-2-氟-5-三氟甲基苯甲酰胺，盐酸化物；与2-氟-3-三氟甲基苯甲酸甲酯反应
N-二氨基亚甲基-2-氟-3-三氟甲基苯甲酰胺，盐酸化物；与2-氟-4-三氟甲基苯甲酸甲酯反应
N-二氨基亚甲基-2-氟-4-三氟甲基苯甲酰胺，盐酸化物。
实施例4
下面的物质是按类似实施例2的方式由胍与下列各种苯甲酸酯反应获得的：与2-硝基-5-三氟甲氧基苯甲酸甲酯反应
N-二氨基亚甲基-2-硝基-5-三氟甲氧基苯甲酰胺，盐酸化物；与2-甲基-5-三氟甲氧基苯甲酸甲酯反应
N-二氨基亚甲基-2-甲基-5-三氟甲氧基苯甲酰胺，盐酸化物；与2-乙基-5-三氟甲氧基苯甲酸甲酯反应
N-二氨基亚甲基-2-乙基-5-三氟甲氧基苯甲酰胺，盐酸化物；与2-丁基-5-三氟甲氧基苯甲酸甲酯反应
N-二氨基亚甲基-2-丁基-5-三氟甲氧基苯甲酰胺，盐酸化物；与2-叔丁基-5-三氟甲氧基苯甲酸甲酯反应
N-二氨基亚甲基-2-叔丁基-5-三氟甲氧基苯甲酰胺，盐酸化物；与2-丙基-5-三氟甲氧基苯甲酸甲酯反应
N-二氨基亚甲基-2-丙基-5-三氟甲氧基苯甲酰胺，盐酸化物；与2-异丙基-5-三氟甲氧基苯甲酸甲酯反应
N-二氨基亚甲基-2-异丙基-5-三氟甲氧基苯甲酰胺，盐酸化物；与2-氟-5-三氟甲氧基苯甲酸甲酯反应
N-二氨基亚甲基-2-氟-5-三氟甲氧基苯甲酰胺，盐酸化物；与2-氟-3-三氟甲氧基苯甲酸甲酯反应
N-二氨基亚甲基-2-氟-3-三氟甲氧基苯甲酰胺，盐酸化物；与2-氟-4-三氟甲氧基苯甲酸甲酯反应
N-二氨基亚甲基-2-氟-4-三氟甲氧基苯甲酰胺，盐酸化物。
实施例5
下面的物质是按类似实施例2的方式由胍与下列各种苯甲酸酯反应获得的：与2，4-二甲基-5-三氟甲基苯甲酸甲酯反应
N-二氨基亚甲基-2，4-二甲基-5-三氟甲基苯甲酰胺，盐酸化物；与2-甲基-4-异丙基-5-三氟甲基苯甲酸甲酯反应
N-二氨基亚甲基-2-甲基-4-异丙基-5-三氟甲基苯甲酰胺，盐酸化物；与2-乙基-4-甲基-5-三氟甲基苯甲酸甲酯反应
N-二氨基亚甲基-2-乙基-4-甲基-5-三氟甲基苯甲酰胺，盐酸化物；与2-丁基-4-叔丁基-5-三氟甲基苯甲酸甲酯反应
N-二氨基亚甲基-2-丁基-4-叔丁基-5-三氟甲基苯甲酰胺，盐酸化物；与2，4-双(叔丁基)-5-三氟甲基苯甲酸甲酯反应
N-二氨基亚甲基-2，4-双(叔丁基)-5-三氟甲基苯甲酰胺，盐酸化物；与2-丙基-4-乙基-5-三氟甲基苯甲酸甲酯反应
N-二氨基亚甲基-2-丙基-4-乙基-5-三氟甲基苯甲酰胺，盐酸化物；与2，4-二异丙基-5-三氟甲基苯甲酸甲酯反应
N-二氨基亚甲基-2，4-二异丙基-5-三氟甲基苯甲酰胺，盐酸化物；与2-氟-3-三氟甲基-4-甲基苯甲酸甲酯反应
N-二氨基亚甲基-2-氟-3-三氟甲基-4-甲基苯甲酰胺，盐酸化物。
下面的实施例有关药物制剂：
实施例A：注射小瓶
100g的通式Ⅰ的活性化合物和5g的磷酸氢二钠在3升的两次蒸馏过的水中的溶液用2N盐酸调节至pH6．5，无菌过滤，装入注射小瓶中，在无菌条件下冻干和无菌密封。每一注射小瓶含有5mg活性化合物。
实施例B：栓剂
20g通式Ⅰ的活性化合物的混合物与100g大豆磷脂和1400g可可油熔混在一起，倾入到模具中并让其冷却。每一栓剂含20mg活性化合物。
实施例C：溶液剂
将1g通式Ⅰ的化合物，9．38g NaH2PO4·2H2O，28．48gNa2HPO4·12H2O和0．1g氯苄烷铵(洁尔灭)溶于940ml的两次蒸馏过的水中制得溶液。该溶液被调节至pH6．8，补充至1升和辐射消毒。这一溶液例如以滴眼液的形式使用。
实施例D：膏剂
500mg通式Ⅰ的活性化合物与99．5g矿脂在无菌条件下混合。
实施例E：片剂
1kg的通式Ⅰ的活性化合物，4kg的乳糖，1．2kg马铃薯淀粉，0．2kg滑石和0．1kg硬脂酸镁的混合物按常规方式压制，得到片剂，要求每片含有10mg活性化合物。
实施例F：包覆片剂
类似于实施例E，压制片剂，然后按常规方式涂上蔗糖、马铃薯淀粉、滑石、黄蓍胶和色料的涂层。
实施例G：胶囊剂
将2kg的通式Ⅰ的活性化合物按常规方式装入硬明胶胶囊中，要求每只胶囊含有20mg的活性化合物。
实施例H：安瓿
1kg的通式Ⅰ的活性化合物在60升的两次蒸馏过的水中的溶液经无菌过滤，装入安瓿，在无菌条件下冻干并无菌密封。每一安瓿含有10mg的活性化合物。
Claims (4)
1．通式Ⅰ的含氟的苯甲酰胍：
其中R1是CH3，R2是CF3或OCF3，R3是SO2CH3，
以及它们的生理上可接受的盐类。
2．根据权利要求1的
N-二氨基亚甲基-2-甲基-4-三氟甲基-5-甲基磺酰基苯甲酰胺
及其生理上可接受的盐。
3．一种用来治疗心律失常、心绞痛、梗塞和用于上述疾病的预防性治疗的药物制剂，其特征在于它含有至少一种权利要求1的通式Ⅰ的化合物和／或其一种生理上可接受的盐。
4．权利要求1的通式Ⅰ的化合物在生产用来治疗心律失常、心绞痛、梗塞和用于上述疾病的预防性治疗的药剂方面的用途。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19517848.3 | 1995-05-16 | ||
| DE19517848A DE19517848A1 (de) | 1995-05-16 | 1995-05-16 | Fluorhaltige Benzoylguanidine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1143632A CN1143632A (zh) | 1997-02-26 |
| CN1064955C true CN1064955C (zh) | 2001-04-25 |
Family
ID=7761987
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN961058854A Expired - Fee Related CN1064955C (zh) | 1995-05-16 | 1996-05-13 | 含氟的苯甲酰胍 |
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| Country | Link |
|---|---|
| US (1) | US5747539A (zh) |
| EP (1) | EP0743301B1 (zh) |
| JP (1) | JPH08311011A (zh) |
| KR (1) | KR960041154A (zh) |
| CN (1) | CN1064955C (zh) |
| AT (1) | ATE204856T1 (zh) |
| AU (1) | AU713743B2 (zh) |
| CA (1) | CA2176553A1 (zh) |
| CZ (1) | CZ287750B6 (zh) |
| DE (2) | DE19517848A1 (zh) |
| DK (1) | DK0743301T3 (zh) |
| ES (1) | ES2161936T3 (zh) |
| GR (1) | GR3037033T3 (zh) |
| HU (1) | HU223046B1 (zh) |
| NO (1) | NO306157B1 (zh) |
| PL (1) | PL184192B1 (zh) |
| PT (1) | PT743301E (zh) |
| RU (1) | RU2159230C2 (zh) |
| SI (1) | SI0743301T1 (zh) |
| SK (1) | SK282052B6 (zh) |
| TW (1) | TW363052B (zh) |
| UA (1) | UA44260C2 (zh) |
| ZA (1) | ZA963870B (zh) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4328352A1 (de) * | 1993-08-24 | 1995-03-02 | Hoechst Ag | Substituierte N,N'-Di-benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
| DE19606509A1 (de) * | 1996-02-22 | 1997-08-28 | Hoechst Ag | Ortho-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
| DE19608161A1 (de) * | 1996-03-04 | 1997-09-11 | Hoechst Ag | Ortho-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
| US5747639A (en) * | 1996-03-06 | 1998-05-05 | Amgen Boulder Inc. | Use of hydrophobic interaction chromatography to purify polyethylene glycols |
| DE19713427A1 (de) * | 1997-04-01 | 1998-10-08 | Hoechst Ag | Ortho-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
| ID29523A (id) * | 1998-11-26 | 2001-09-06 | Marck Patent Gmbh | Penggunaan benzoilgunidin-benzoilguanidin untuk pengobatan diabetes melitus yang tidak bergantung pada insulin |
| DE10222192A1 (de) * | 2002-05-18 | 2003-11-27 | Aventis Pharma Gmbh | Pentafluorsulfuranyl-benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
| US7375138B2 (en) * | 2002-05-18 | 2008-05-20 | Sanofi-Aventis Deutschland Gmbh | Pentafluorosulfanylbenzoylguanidines, processes for their preparation, their use as medicaments or diagnostic aids, and medicaments comprising them |
| DE10226462A1 (de) * | 2002-06-13 | 2003-12-24 | Aventis Pharma Gmbh | Fluorierte Cycloalkyl-derivatisierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament, sowie sie enthaltendes Medikament |
| DE10353204A1 (de) * | 2003-11-13 | 2005-06-16 | Aventis Pharma Deutschland Gmbh | Verfahren zur Herstellung von 4-Pentafluorsulfanyl-benzoylguanidinen |
| OA13285A (en) * | 2003-11-13 | 2007-01-31 | Sanofi Aventis Deutschland | Pentafluorosulfanyl benzoylguanidines, method for their production, their use as medicaments or diagnostic agents and medicament containing the same. |
| US20050124666A1 (en) * | 2003-11-13 | 2005-06-09 | Aventis Pharma Deutschland Gmbh | Pentafluorosulfanylbenzoylguanidines, process for their preparation, use as a medicament or diagnostic aid, and medicament comprising same |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1050018A (zh) * | 1989-09-06 | 1991-03-20 | 赫彻斯特股份公司 | 苯甲酰基胍、它们的制备方法、它们作为药剂的应用以及含有它们的药剂 |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2108144T3 (es) * | 1992-02-15 | 1997-12-16 | Hoechst Ag | Benzoilguanidinas sustituidas en orto, procedimiento para su preparacion, su utilizacion como medicamento o agente de diagnostico, asi como medicamento que las contiene. |
| ATE139526T1 (de) * | 1992-02-15 | 1996-07-15 | Hoechst Ag | 3,5-substituierte benzoylguanidine, mit antiarrythmischer wirkung und inhibierender wirkung auf die proliferationen von zellen |
| CZ284456B6 (cs) * | 1992-02-15 | 1998-12-16 | Hoechst Aktiengesellschaft | Aminosubstituované benzoylguanidiny, způsob jejich přípravy, jejich použití jako léčiv a léčivo, které je obsahuje |
| EP0589336B1 (de) * | 1992-09-22 | 1997-01-08 | Hoechst Aktiengesellschaft | Benzoylguanidine, Verfahren zu ihrer Herstellung, sowie ihre Verwendung als Antiarrhythmika |
| TW250477B (zh) * | 1992-12-15 | 1995-07-01 | Hoechst Ag | |
| TW250479B (zh) * | 1992-12-15 | 1995-07-01 | Hoechst Ag | |
| 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 |
| DE4318756A1 (de) * | 1993-06-05 | 1994-12-08 | Hoechst Ag | Substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
| DE4328869A1 (de) * | 1993-08-27 | 1995-03-02 | Hoechst Ag | Ortho-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
| DE4417004A1 (de) * | 1994-05-13 | 1995-11-16 | Hoechst Ag | Perfluoralkyl-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
| DE4430916A1 (de) * | 1994-08-31 | 1996-03-07 | Merck Patent Gmbh | Alkyl-benzoylguanidin-Derivate |
-
1995
- 1995-05-16 DE DE19517848A patent/DE19517848A1/de not_active Withdrawn
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1996
- 1996-03-25 TW TW085103561A patent/TW363052B/zh active
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- 1996-05-02 AT AT96106881T patent/ATE204856T1/de not_active IP Right Cessation
- 1996-05-02 ES ES96106881T patent/ES2161936T3/es not_active Expired - Lifetime
- 1996-05-02 DE DE59607559T patent/DE59607559D1/de not_active Expired - Fee Related
- 1996-05-02 SI SI9630361T patent/SI0743301T1/xx unknown
- 1996-05-09 SK SK590-96A patent/SK282052B6/sk unknown
- 1996-05-13 UA UA96051860A patent/UA44260C2/uk unknown
- 1996-05-13 AU AU52252/96A patent/AU713743B2/en not_active Ceased
- 1996-05-13 CN CN961058854A patent/CN1064955C/zh not_active Expired - Fee Related
- 1996-05-14 CA CA002176553A patent/CA2176553A1/en not_active Abandoned
- 1996-05-15 ZA ZA963870A patent/ZA963870B/xx unknown
- 1996-05-15 CZ CZ19961408A patent/CZ287750B6/cs not_active IP Right Cessation
- 1996-05-15 PL PL96314259A patent/PL184192B1/pl unknown
- 1996-05-15 KR KR1019960016096A patent/KR960041154A/ko not_active Abandoned
- 1996-05-15 NO NO961997A patent/NO306157B1/no not_active IP Right Cessation
- 1996-05-15 US US08/647,789 patent/US5747539A/en not_active Expired - Fee Related
- 1996-05-15 HU HU9601305A patent/HU223046B1/hu not_active IP Right Cessation
- 1996-05-15 RU RU96109204/04A patent/RU2159230C2/ru not_active IP Right Cessation
- 1996-05-16 JP JP8144881A patent/JPH08311011A/ja active Pending
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1050018A (zh) * | 1989-09-06 | 1991-03-20 | 赫彻斯特股份公司 | 苯甲酰基胍、它们的制备方法、它们作为药剂的应用以及含有它们的药剂 |
Also Published As
| Publication number | Publication date |
|---|---|
| TW363052B (en) | 1999-07-01 |
| SK59096A3 (en) | 1996-12-04 |
| GR3037033T3 (en) | 2002-01-31 |
| PT743301E (pt) | 2002-01-30 |
| SI0743301T1 (en) | 2002-02-28 |
| NO306157B1 (no) | 1999-09-27 |
| CZ140896A3 (en) | 1997-02-12 |
| HU223046B1 (hu) | 2004-03-01 |
| HUP9601305A3 (en) | 1997-11-28 |
| CZ287750B6 (en) | 2001-01-17 |
| ZA963870B (en) | 1996-11-21 |
| DE19517848A1 (de) | 1996-11-21 |
| EP0743301A3 (de) | 1997-06-11 |
| NO961997L (no) | 1996-11-18 |
| HU9601305D0 (en) | 1996-07-29 |
| HUP9601305A2 (en) | 1997-05-28 |
| DE59607559D1 (de) | 2001-10-04 |
| ATE204856T1 (de) | 2001-09-15 |
| KR960041154A (ko) | 1996-12-19 |
| JPH08311011A (ja) | 1996-11-26 |
| EP0743301A2 (de) | 1996-11-20 |
| ES2161936T3 (es) | 2001-12-16 |
| UA44260C2 (uk) | 2002-02-15 |
| PL314259A1 (en) | 1996-11-25 |
| RU2159230C2 (ru) | 2000-11-20 |
| AU5225296A (en) | 1996-11-28 |
| CA2176553A1 (en) | 1996-11-17 |
| AU713743B2 (en) | 1999-12-09 |
| DK0743301T3 (da) | 2001-11-26 |
| CN1143632A (zh) | 1997-02-26 |
| SK282052B6 (sk) | 2001-10-08 |
| PL184192B1 (pl) | 2002-09-30 |
| US5747539A (en) | 1998-05-05 |
| EP0743301B1 (de) | 2001-08-29 |
| NO961997D0 (no) | 1996-05-15 |
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