CN1055919C - 芳基苯甲酰胍 - Google Patents
芳基苯甲酰胍 Download PDFInfo
- Publication number
- CN1055919C CN1055919C CN95116621A CN95116621A CN1055919C CN 1055919 C CN1055919 C CN 1055919C CN 95116621 A CN95116621 A CN 95116621A CN 95116621 A CN95116621 A CN 95116621A CN 1055919 C CN1055919 C CN 1055919C
- Authority
- CN
- China
- Prior art keywords
- methylsulfonyl
- acid
- reaction
- diamino methylene
- aminomethyl phenyl
- 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 - Fee Related
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Classifications
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- 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
- C07C317/48—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C317/50—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
-
- 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
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P9/06—Antiarrhythmics
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- 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
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Abstract
分子式Ⅰ的芳基苯甲酰胍(其中R1、R2、R3和Ph具有给定的定义)以及它的对生理无害的盐显示抗心律失常的性能并且能起到细胞Na+/H+反向转移剂的抑制剂的作用。
Description
其中R1是A,CF3,CH2F,CHF2,C2F5,CN,NO2,Hal,C≡CH或-X-R4,R2和R3分别为H,Hal,A,-X-R4,CN,NO2,CF3,CH2F,CHF2,C2F5,CH2CF3,-SOn-R6,-SO2NR4R5,Ph或OPh,R4是H,A,有5至7个碳原子的环烷基,有6至8个C原子的环烷甲基,CF3,CH2F,CHF2,CH2CF3,Ph或-CH2-Ph,R5是H或A,或其它,R4和R5在一起也是有4至5个C原子的亚烷基,此处一个CH2基也可由O、S、NH,N-A或N-CH2-Ph取代,R6是A或Ph,A是有1至6个C原子的烷基,X是O,S或NR5,Ph是苯基,萘基或联苯基,它是未被取代的或是被A,OA,NR4R5,F,Cl,Br,I或CF3取代一次,两次或三次的,n是1或2,及Hal是F,Cl,Br或I。
本发明的目的是揭示一种具有重要性能的新化合物,尤其是那些可用于制药的化合物。
已发现分子式I的化合物以及它的对生理无害的盐具有重要的药理学性质并且受到普遍接纳。
此新化合物是细胞Na+/h+反向转移剂的抑制剂,即抑制细胞的Na+/H+交换机理的活性化合物(Duesing等人,Med.Klin,87,378-384(1992)),因此此化合物相当于良好的抗心律失常剂,该制剂特别适于治疗由于缺氧的结果而产生的心律不齐。
最为熟知的酰胍基活性化合物是氨氯吡脒。然而此化合物首先和最先呈现低血压和排盐利尿效应,在治疗心脏节奏紊乱时,尤其是仅仅很微弱地表现抗心律不齐特性时,这些效应都是不希望有的。
除此之外,例如Ep 0416499,揭示了与其结构相似的化合物。
本发明涉及分子式I的化合物及其药理学可接受的盐。
本申请的新物质呈现良好的护理心脏效应,因此特别适于治疗梗塞,预防梗塞和治疗心绞痛。此外,该物质消解所有类型的病理缺氧和局部缺血损伤,因此可以治疗首次或第二次由这种损伤造成的失调。此活性化合物也非常适于防治应用。
由于这些物质在病理缺氧或局部缺血处境中的防护效应,因此有可能进一步使用这些化合物与外科手术相联系来保护器官(手术用器官往往不能正常提供),可与器官移植相联系保护已被取出的器官。可与血管成形术或心脏外科相联系,或与神经系统的局部缺血相联系,可与中风的治疗方法相联系,以及用于原发高血压的预防措施。
另外,该化合物也可以用作因细胞扩散而呈现的疾病的治疗剂,这些疾病是例如动脉硬化、糖尿病的晚期并发病,肿瘤病,纤维化病,尤其是肺,肝和肾的纤维化病,还有器官肥大症和增生症。除此之外,这些物质也适用于诊断与Na+/H+反向转移剂增长的活性相联系的疾病例如红细胞,血小板或白细胞的疾病。
此化合物的效应可用本来已知的方法来确定,所说的方法例如是由N.Escobales和J.Figueroa在J.Membrane Biol 120,41-49(1991)中所叙述的,或是由L.Counillon.W Scholz,H.J.Lang和J.Pouyssegur在Mol.Pharmaeol 44 1041-1045(1993)中所叙述的。
适宜的试验动物的例子是小鼠,鼠,荷兰猪,狗,猫,猴子或猪。
因此,该化合物可以用作人类和兽医的药物中的药物活性化合物。另外,它们可被用作媒介物用于进一步制备药物活性化合物。
在给定的分子式中,A优选是有1-6,最好1-4,特别是1,2或3个碳原子的分枝或未分枝的烷基,特别优选甲基,而乙基,丙基,异丙基,丁基或异丁基也是优选的,此外仲丁基,叔丁基,戊基,异戊基(3-甲基丁基),己基或异己基(4-甲基戊基)是优选的。
R1优选是A,OA或Hal,特别是Br或Cl,另外也优选CH2F,CHF2,CF3或C2F5。
R2和R3优选,各自独立地,是H,A-SO2,A,CF3,Cl,Br,CN或OA。特别优选两个基之一是H3C-SO2-,而另一个最好是氢。如果一个基是A-SO2-,则后者最好在间位取代胍基羰基。在5位上有一甲磺酰基而在2位有一烷基,优选甲基或乙基的苯甲酰基也是特别优选的。
R4优选是H或A,R5也是如此。
如果R4和R5共同是亚烷基,则该亚烷基优选是未分枝的,特别优选-(CH2)K-,此处K是4或5;然而-(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也是优选的。
Ph优选是苯基,它是未被取代的或是被Cl,Br,A,OA,NH2,NHA,NA2或CF3取代一次的。
R6优选是A,特别是甲基,未被取代的苯基也属优选的。
X基优选是O或NH。
对于一般应用,所有的基,例如出现几次的R4,R5或Ph,可以相同或不同,即它们彼此独立。
因此,本发明特别涉及分子式I的那些化合物,其中至少所说的一个基有一个上述的优选含义。化合物的一些优选基可用以下的分子式Ia至Ih表示,它们都与分子式I相符并且其中的未特别确切地叙述的基团具有与分子式I相同的定义,然而其中,在Ia中,R1是A而R2是-SO2-CH3或-SO2-NH2;在Ib中,R1是A而Ph是苯基,些苯基是未被取代的或是被A或
Hal取代过一次的;在Ic中,R1是A而R2是SO2-CH3;在Id中,Ph处于胍基羰基对位,并且是未取代的或仅被A取代一
次的苯基;在Ie中,Ph优选具有Id中所说的定义,R2是SO2-A并且处于胍
基羰基的间位;在If中,R1是甲基,乙基或是丙基或异丙基,R3是H;在Ig中,Ph基处于胍基羰基的对位,R2是SO2-CH3,R3是H;在Ih中,R1是Hal,R2是SO2-A。
本发明也涉及一种制备上述分子式I化合物及其盐的方法,其特征在于分子式II的化合物与胍反应,其中R1,R2,R3和Ph具有前述定义,而Q是Cl,Br,OA,O-CO-A,O-CO-Ph或OH,或另一个易反应的、己酯化的OH基或易于被亲核取代的离去基团,或者其特征在于分子式III的苯甲酰基胍与分子式IV的化合物反应,其中R1,R1和R3具有前述的定义,而R7是Cl,Br,I或O-SO2-R8以及R8是A,Ph或CF3
Ph-B(OR9)2 IV其中R9在所有情况下都是H,A,或合起来是有2至4个碳原子的亚烷基,
或者其特征在于用一还原剂处理一种化合物,该化合物含有一或多个还原基和/或一或多个附加的C-C和/或C-N键代替一或多个氢原子,但该化合物在其它方面仍与分子式I相符。
或者其特征在于用一溶剂分解剂处理一种化合物,该化合物含有一或多个可溶剂分解的基代替一或多个氢原子,但该化合物在其它方面仍与分子式I相符。
以及/或者其特征在于将已得到的分子式I的一个碱通过用一种酸处理转变成它的一种盐。
分子式I的化合物仍然可用本来已知的方法来制备,如在文献中叙述的(例如,在标准著作中,如Honben-Weyl,Methoden derorganischen Chemie(有机化学的方法),Georg-Thieme-verlag,Stuttgart;Organic Reactions,John Wiley & Sone,Inc,New York;并且也在上述的专利申请中),这些化合物特别要在对所说反应是已知的并且对这些反应是适宜的反应条件下来制备。在这种情况下,也可采用本来已知但在这里尚未提到细节的各种变形。
如果希望的话,超始化合物也可在现场形成,这样就不用将它们从反应混合物中离析而是使它们当即经受进一步反应形成分子式I的化合物。
优选的是,通过一种活化的分子式II的羧酸衍生物(其中Q特别优选是Cl或-O-CH3)与胍的反应来制备分子式I的化合物。各种反应变形都是特别合适的,其中游离的羧酸II(Q=OH)按本来已知的方式,转变为特别激活的衍生物,而后者然后直接与胍反应不必经过中间离析。可以免除中间离析的方法的例子是与羰酰二咪唑或二环己基碳化二亚胺的活化作用或Mukayama变形(Angew,Chem,91,788-812(1979))。
通常,分子式II的羧酸是已知的。它们特别是用钯-催化的交联偶合剂,例如Suzuki偶合剂(Synlett,207,1992)来制备的。优选的催化剂例子是Pd(PPh3)4或(Ph3P)2PdCl2。
分子式II的羧酸也可由亲核的芳族取代来制备,由适宜的苯甲酸衍生物出发,通过与相应的分子式IV的芳基硼酸或酯反应而制备。该反应的完成与化合物III和IV的反应相类似。在以下加以叙述。
特别适合的分子式IV的化合物例子是苯基硼酸和2-,3-或4-烷基苯基硼酸或其烷基酯,它们在合适的位置可以拥有另外的取代基。
分子式II的活性羧酸衍生物与胍的反应按本来已知的方式进行,优选在质子性或对质子有惰性的,极性或非极性的,惰性有机溶剂中进行。
以下叙述对分子式III和IV的化合物的反应适宜的溶剂。但是特别优选的溶剂是甲醇,THF,二甲氧基乙烷,二恶烷或由其制备的混合物,还有水。合适的反应温度例如是20℃和溶剂沸点之间的温度。反应时间是5分钟至12小时。在该反应中包括一种酸俘获剂是有利的。为此目的任何类型的碱是要它不影响该反应本身都是合适的。然而使用无机碱,例如碳酸钾,或有机碱,例如三乙胺或吡啶,要么就使用过量的胍,这些手段的任意一种都是特别合适的。
分子式I化合物也可通过分子式III的苯甲酰胍与分子式IV的化合物进行反应而制备。分子式III的起始化合物可以按简单的方式来制备,即将适当取代的苯甲酸,或易反应的酸性衍生物,例如酰基卤、酯或酐(它们均可由其衍生出来)与胍进行反应,反应条件为用于制备酰胺的已知常规条件。特别合适的反应变体还是前面所述的那些用于化合物II与胍的反应。
分子式IV的化合物就像制备它们的方法一样是本来已知的。如果化合物是未知的,则可通过本来已知的方法来制备。
化合物II的制备,还有化合物III与分子式IV化合物的反应,均按本来已知的方式进行,优选是在一种质子性或对质子有惰性的、极性的,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,在碱或过量碱性组分存在下进行反应也是有利的。适宜的碱的优选例子是碱金属或碱土金属氢氧化物,碳酸盐或醇化物,或有机碱例如三乙胺或吡啶,它们也可过量使用,再者它们可同时被用作溶剂。
适宜的惰性溶剂是,尤其是醇,如甲醇,乙醇,异丙醇,正丁醇或叔丁醇;醚,如乙醚,异丙醚,四氢呋喃(THF)或二噁烷,乙二醇醚,如乙二醇-甲基醚或乙二醇-乙基醚,(甲基乙二醇或乙基乙二醇)或乙二醇二甲基醚(二甘醇二甲醚);酮,如丙酮或丁酮;腈,如乙腈;硝基化合物,如硝基甲烷或硝基苯;酯,如乙酸乙酯或六甲基磷三酰胺;硫氧化物,如二甲基亚砜(DMSO);氯化烃,如二氯甲烷,氯仿,三氯乙烷,1,2-二氯乙烷或四氯化碳;烃,如苯,甲苯或二甲苯。除此之外,这些溶剂彼此的混合物也是适用的。
在III与IV反应时特别优选的手段包括将合适的苯甲酰胍悬浮在一种惰性溶剂(如甲苯)中,然后用四(三苯基磷)钯(O)处理它,接着滴加所希望的硼酸,或一合适的硼酸酯,(Suzuki偶合剂)。
分子式I的化合物也可从其官能衍生物通过加溶剂分解,尤其是水解,或通过氢解将其放出而得到。
优选用作加溶剂分解或氢解的起始化合物是这样的化合物,它们在符合分子式I的情况下,还含有相应的受保护氨基和/或羟基代替一或多个游离的氨基和/或羟基,更优选这样的化合物,它们携带一个氨保护基代替键合到N原子上的氢原子,尤其是这样的化合物,它们携带一个R1-N基(其中R1是一个氨保护基),代替一个HN基,和/或这样的化合物,它们携带一个羟基保护基代替羟基的H原子,例如这样的化合物,它们在符合分子式I的同时,还携带一个OR″基(其中R″是一个羟基保护基)代替一个OH基。
在起始化合物的分子中也可以存在几个相同或不同的受保护的氨基和/或羟基。如果所存在的保护基彼此不同,那么在许多情况下,就可以有选择地将它们消除。
词句“氨保护基”是熟知的,并且指的是这样的基,它们适于保护氨基(封端)阻止化学反应发生,而且一旦所希望的化学反应在该分子的另一位置进行时即可容易地除去该基团。这些基团的典型例子是,尤其是未取代的或已取代的酰基,芳基(例如,2,4-二硝基苯基(DNP)),芳烷氧甲基(例如,苄氧甲基(BOM))或芳烷基(例如,苄基,4-硝基苄基或三苯甲基)。因为氨保护基在所希望的反应(或反应序列)之后被消去,因此它们的性质和尺寸在不同情况下不是关键性的;所以,有1-20,尤其1-8个C原子的那些基是优选的。与本方法有关,词句“酰基”可在其最宽的意义被解释。它包括从脂族的,芳基脂族的,芳族的或杂环的羧酸或磺酸衍生的酰基,以及,尤其是烷氧羰基、芳氧羰基和,特别是芳烷氧羰基。此特征的酰基的例子是烷酰基,如乙酰基,丙酰基或丁酰基;芳烷酰基,例如苯基乙酰基;芳酰基,例如苯甲酰基、或甲苯酰基;芳氧基烷酰基,例如苯氧基乙酰基;烷氧羰基,例如甲氧羰基,乙氧羰基,2,2,2-三氯乙氧羰基,异丙氧羰基,叔-丁氧羰基(BOC)或2-碘乙氧羰基;芳烷氧羰基,例如苄氧羰基(CBZ),4-甲氧苄氧羰基或9-芴基甲氧羰基(FMOC)。优选的氨保护基是BOC、DNP和BOM以及另外还有CBZ,苄基和乙酰基。
词“羟基保护基”同样是熟知的并且指的是这样的基,它们适于保护羟基阻止化学反应发生,而且一旦所希望的化学反应在该分子的另一位置进行时即可容易地除去这些基团。上述未取代的或取代的芳基、芳烷基或酰基,还有烷基都是此类基团的典型例子。羟基保护基的性质和尺寸不是关键性的,因为在所希望的化学反应或反应序列之后这些基团被除去;优选的基有1 20,尤其是1 10个C原子。某些羟基保护基的例子是叔丁基,苄基,对-硝基苄基,对-甲苯磺酰和乙酰基,特别优选的是苄基和乙酰基。
分子式I的化合物的官能衍生物被用作起始化合物,可用通常的方法来制备这些衍生物,这些方法,例如在专门的标准著作和专利申请中叙述,例如将符合分子式II和III的化合物与至少一种含有保护基代替H原子的这些化合物进行反应。
根据所用的保护基,使用,例如强酸,较为有利的是使用三氟乙酸或高氯酸,或者使用其它强无机酸,例如盐酸或硫酸,或强有机羧酸,例如三氯乙酸,或磺酸,例如苯磺酸或对-甲苯磺酸,将分子式I的化合物从其官能衍生物中释放出来。同时可以在有附加的惰性溶剂存在下进行此反应,但这不总是必要的。
那些优选用作惰性溶剂的溶剂是有机的,例如羧酸,如乙酸,醚,如四氢呋喃(THF)或二恶烷,酰胺,如二甲基甲酰胺(DMF),卤代烃,如二氯甲烷,另外还有,醇,如甲醇,乙醇或异丙醇,还有水。上述溶剂的混合物也是合适的。三氟乙酸最好过量使用而不加入任何另外的溶剂,高氯酸以其混合物的形式使用,该混合物含有乙酸和70%的高氯酸,它们的比值为9∶1。裂解的反应温度在0和约50°之间有利,优选在15和30°(室温)之间进行反应。
BOC基最好使用二氯甲烷中40%三氟乙酸或在二恶烷中的约3至5N HCl在15-60°除去;FMOC基可以通过使用DMF中大约5-20%二甲胺,二乙胺或哌啶溶液在15-50℃除去。DNP基也可使用例如DMF/水中大约3-10%2-巯基乙醇溶液在15-30℃成功地除去。
可被氢解除去的保护基(例如,BOM,CBZ或苄基)举例来说,可在有催化剂存在下(例如,一种贵金属催化剂如钯,有利地位于载体,例如碳,上)通过用氢处理而除去。以上所说的溶剂,尤其是例如醇,如甲醇或乙醇,或酰胺,如DMF都适用于此范围。通常,氢解在0-100℃的温度和1-200巴的压力下进行。优选20-30℃及1-10巴下进行。CBZ基可以例如在甲醇中的5-10%Pd-C上在20-30℃成功地被氢解。
分子式I的碱也可用一种酸转变为相应的酸加成盐。适用于此反应的酸是产生生理学无害盐的那些酸。因此可以使用无机酸,如硫酸,硝酸,氢卤酸,如盐酸或氢溴酸,磷酸,如正磷酸,或氨基磺酸,也可使用有机酸,尤其是脂族的,脂环的,芳基脂族的,芳族的或杂环的一元或多元的羧酸,磺酸或硫酸,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,甲磺酸,乙磺酸,乙烷二磺酸,2-羟基乙磺酸,苯磺酸,对-甲苯磺酸,萘磺酸和萘二磺酸或月桂基硫酸。
分子式I的化合物及其生理无害的盐可以尤其是通过非化学路线生产药品制剂。当用于此目的时,将它们与至少一种固体,液体和/或半液体载体物质或辅助物质汇集在一起,并且在适宜情况下结合一或多种附加的活性化合物,成为合适的剂量形式。
本发明进一步涉及组合物,尤其是药品制剂,它们含有至少一种分子式I的化合物和/或一种它的生理无害的盐。
这些制剂可以用作人药或兽药。适宜的载体物质是有机或无机物质,它们适于肠内(例如口),非肠道或表面局部用药并且不与新化合物反应,它们是,例如水、植物油、苄醇、聚乙二醇,甘油三乙酸酯,明胶,糖类,例如乳糖或淀粉,硬脂酸镁,滑石,羊毛脂或凡士林。对于口服,尤其采用片剂,涂层的片剂,胶囊,糖浆,汁液或滴剂,对于栓剂的直肠应用,对于溶液的非肠道应用,优选采用含油的或水性的溶液,还有悬浮液,乳剂或移植片,对于表面应用,采用软膏,乳油,糊剂,洗液,凝胶,喷雾剂,泡沫,气溶胶,溶液(如醇类溶液,例如乙醇或异丙醇,乙腈,DMF,二甲基乙酰胺或1,2丙二醇,或它们相互之间的和/或与水的混合物)或粉末。此新的化合物也可被冻干,而所得的冻干体可用于例如,生产注射制剂。
脂质体制剂同样特别适于表面应用。所给出的制剂可被杀菌和/或含有助剂如助流剂(glidants),防腐剂,稳定剂和/或湿润剂,乳化剂,用于影响渗透压的盐,缓冲剂,染色剂,调味剂和/或芳香剂。如果需要,它们还可含有一或多种附加的活性化合物,例如一或多种维生素。
分子式I的化合物及其生理无害的盐可对人或动物给药,尤其是对哺乳动物如猴子、狗、猫、鼠或小鼠,它们可用于人或动物躯体的治疗也可用于控制疾病,尤其是结合治疗和/或预防心血管系统的失调。因此,它们适于治疗心律失常(尤其是因缺氧引起的心律失常)、心绞痛、梗塞、神经系统的局部缺血,例如,中风或脑水肿,休克的疾病,以及还适于防治。
该物质还可用于治疗细胞增生发挥作用的疾病,这些疾病是例如动脉硬化、糖尿病晚期并发症,肿瘤疾病,纤维性和器官肥大及增生。
在此范围内,本发明的物质通常用药方式类似于已知的抗心律失常药,如茚满丙二胺,优选剂量为每剂量单位约0.01至5mg,特别是0.02至0.5mg。每日用药剂量优选为每公斤体重大约0.0001至0.1mg,特别是0.0003至0.01mg。然而,对每位特殊患者的特殊剂量取决于广泛的变化因素,例如取决于所用特殊化合物的活性,患者年龄体重,综合健康状况,性别,饮食,用药时间及方法,排泄速度,所用药物的组合方式,以及所要治疗的疾病的严重程度。优选口服。
在以下的例子中,“通常的混合聚集”是指:
如果需要,加入水,使用有机溶剂例如乙酸乙酯进行萃取,分离有机相并在硫酸钠上干燥。之后进行过滤和蒸发;将残渣用色谱法和/或结晶作用提纯。
例1
将1.8克2-甲基-4-(4-甲苯基)-5-甲磺酰苯甲酸甲酯(可通过3-甲磺酰-4-溴-6-甲基苯甲酸甲酯与甲苯基硼酸反应而得到)和1.5克在50ml甲醇中的胍的溶液煮沸5小时,然后除去溶剂。用水处理残余物,将所留下的结晶真空过滤并用稀释的氢氧化钠溶液处理。滤掉固体残渣并从乙醇中再结晶。得到N-二氨基亚甲基-2-甲基-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺,mp.222-224℃。
以相类似的方式使胍与2-乙基-4-(4-甲基苯基)-5-甲磺酰苯甲酸甲酯反应,得到N-二氨基亚甲基-2-乙基-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺;
使胍与2-丙基-4-(4-甲基苯基)-5-甲磺酰苯甲酸甲酯反应,得到N-二氨基亚甲基-2-丙基-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺;
使胍与2-异丙基-4-(4-甲基苯基)-5-甲磺酰苯甲酸甲酯反应,得到N-二氨基亚甲基-2-异丙基-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺;
使胍与2-丁基-4-(4-甲基苯基)-5-甲磺酰苯甲酸甲酯反应,得到N-二氨基亚甲基-2-丁基-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺;
使胍与2-(2-丁基)-4-(4-甲基苯基)-5-甲磺酰苯甲酸甲酯反应,得到N-二氨基亚甲基-2-(2-丁基)-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺;
使胍与2-甲基-4-苯基-5-甲磺酰苯甲酸甲酯反应,得到N-二氨基亚甲基-2-甲基-4-苯基-5-甲磺酰苯甲酰胺;
使胍与2-乙基-4-苯基-5-甲磺酰苯甲酸甲酯反应,得到N-二氨基亚甲基-2-乙基-4-苯基-5-甲磺酰苯甲酰胺;
使胍与2-丙基-4-苯基-5-甲磺酰苯甲酸甲酯反应,得到N-二氨基亚甲基-2-丙基-4-苯基-5-甲磺酰苯甲酰胺;
使胍与2-异丙基-4-苯基-5-甲磺酰苯甲酸甲酯反应,得到N-二氨基亚甲基-2-异丙基-4-苯基-5-甲磺酰苯甲酰胺;
使胍与2-丁基-4-苯基-5-甲磺酰苯甲酸甲酯反应,得到N-二氨基亚甲基-2-丁基-4-苯基-5-甲磺酰苯甲酰胺;
使胍与2-(2-丁基)-4-苯基-5-甲磺酰苯甲酸甲酯反应,得到N-二氨基亚甲基-2-(2-丁基)-4-苯基-5-甲磺酰苯甲酰胺;
使胍与2-乙基-4-(3-甲基苯基)-5-甲磺酰苯甲酸甲酯反应,得到N-二氨基亚甲基-2-乙基-4-(3-甲基苯基)-5-甲磺酰苯甲酰胺;
使胍与2-氯-4-(4-甲基苯基)-5-甲磺酰苯甲酸甲酯反应,得到N-二氨基亚甲基-2-氯-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺;
使胍与2-溴-4-(4-甲基苯基)-5-甲磺酰苯甲酸甲酯反应,得到N-二氨基亚甲基-2-溴-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺;
使胍与2-氟甲基-4-(4-甲基苯基)-5-甲磺酰苯甲酸甲酯反应,得到N-二氨基亚甲基-2-氟甲基-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺;
使胍与2-三氟甲基-4-(4-甲基苯基)-5-甲磺酰苯甲酸甲酯反应,得到N-二氨基亚甲基-2-三氟甲基-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺;
使胍与2-五氟乙基-4-(4-甲基苯基)-5-甲磺酰苯甲酸甲酯反应,得到N-二氨基亚甲基-2-五氟乙基-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺;
使胍与2-甲氧基-4-(4-甲基苯基)-5-甲磺酰苯甲酸甲酯反应,得到N-二氨基亚甲基-2-甲氧基-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺;
使胍与2-氰基-4-(4-甲基苯基)-5-甲磺酰苯甲酸甲酯反应,得到N-二氨基亚甲基-2-氰基-4-(4-甲基苯基)-5甲磺酰苯甲酰胺;
使胍与2-硝基-4-(4-甲基苯基)-5-甲磺酰苯甲酸甲酯反应,得到N-二氨基亚甲基-2-硝基-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺;
使胍与2-乙炔基-4-(4-甲基苯基)-5-甲磺酰苯甲酸甲酯反应,得到N-二氨基亚甲基-2-乙炔基-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺;
例2
将700mg N-二氨基亚甲基-2-甲基-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺(可根据例1获得)悬浮于50ml水中,在搅拌的同时向此悬浮液中加入1.8ml的1N HCl。随后过滤并冻干,得到N-二氨基亚甲基-2-甲基-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺,氢氯化物m.p.205℃。
以相类似的方式从游离碱得到以下的氢氯化物:
N-二氨基亚甲基-2-乙基-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺,氢氯化物;
N-二氨基亚甲基-2-丙基-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺,氢氯化物;
N-二氨基亚甲基-2-异丙基-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺,氢氯化物;
N-二氨基亚甲基-2-丁基-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺,氢氯化物;
N-二氨基亚甲基-2-(2-丁基)-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺,氢氯化物;
N-二氨基亚甲基-2-乙基-4-苯基-5-甲磺酰苯甲酰胺,氢氯化物;
N-二氨基亚甲基-2-丙基-4-苯基-5-甲磺酰苯甲酰胺,氢氯化物;
N-二氨基亚甲基-2-异丙基-4-苯基-5-甲磺酰苯甲酰胺,氢氯化物;
N-二氨基亚甲基-2-丁基-4-苯基-5-甲磺酰苯甲酰胺,氢氯化物;
N-二氨基亚甲基-2-(2-丁基)-4-苯基-5-甲磺酰苯甲酰胺,氢氯化物;
N-二氨基亚甲基-2-甲基-4-苯基-5-甲磺酰苯甲酰胺,氢氯化物;
N-二氨基亚甲基-2-氯-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺,氢氯化物;
N-二氨基亚甲基-2-溴-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺,氢氯化物;
N-二氨基亚甲基-2-氟甲基-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺,氢氯化物;
N-二氨基亚甲基-2-三氟甲基-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺,氢氯化物;
N-二氨基亚甲基-2-五氟乙基-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺,氢氯化物;
N-二氨基亚甲基-2-甲氧基-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺,氢氯化物;
N-二氨基亚甲基-2-氰基-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺,氢氯化物;
N-二氨基亚甲基-2-硝基-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺,氢氯化物;
N-二氨基亚甲基-2-乙炔基-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺,氢氯化物。
例3
将溶于15ml水中的10mg四(三苯膦)-钯(O)和1.8克Na2CO3连续地加到100ml甲苯中的6.02克N-二氨基亚甲基-2-甲基-4-溴-5-甲磺酰苯甲酰胺(在有三乙胺存在下通过2-甲基-4-溴-5-甲磺酰苯甲酰氯与胍的反应而得到)悬浮液中,把反应混合物加热至50-60℃,然后滴加溶于20ml乙醇中的3克3-甲基苯基硼酸,把该混合物在90°搅拌2小时。过滤后,除去溶剂和通常的混合聚集物,得到N-二氨基亚甲基-2-甲基-4-(3-甲基苯基)-5-甲磺酰苯甲酰胺,用稀释的HCl甲磺酸水溶液处理并冷冻干燥后从其得到对应的氢氯化物或甲磺酸盐。
按类似的方式通过N-二氨基亚甲基-2-甲基-4-溴-5-甲磺酰苯甲酰胺与下列物质反应,得到相应的产物:
与2,4-二氯苯基硼酸反应,得到N-二氨基亚甲基-2-甲基-4-(2,4-二甲基苯基)-5-甲磺酰苯甲酰胺,氢氯化物;
与2,4-二氯苯基硼酸反应,得到N-二氨基亚甲基-2-甲基-4-(2,4-二氯苯基)-5-甲磺酰苯甲酰胺,氢氯化物,m.p.209-211℃;
与4-甲氧基苯基硼酸反应,得到N-二氨基亚甲基-2-甲基-4-(4-甲氧苯基)-5-甲磺酰苯甲酰胺,氢氯化物;
与4-氟苯基硼酸反应,得到N-二氨基亚甲基-2-甲基-4-(4-氟苯基)-5-甲磺酰苯甲酰胺,m.p.235-237℃,甲磺酸盐m.p.191-194℃;
与3,5-双-(三氟甲基苯基)硼酸反应,得到N-二氨基亚甲基-2-甲基-4-〔3,5-双-(三氟甲基苯基)〕-5-甲磺酰苯甲酰胺,m.p.190-194℃,甲磺酸盐m.p150℃;
与3-溴苯基硼酸反应,得到N-二氨基亚甲基-2-甲基4-(3-溴苯基)-5-甲磺酰苯甲酰胺,氢氯化物;
与2,4-二甲氧基苯基硼酸反应,得到N-二氨基亚甲基2-甲基-4-(2,4-二甲氧基苯基)-5-甲磺酰苯甲酰胺,氢氯化物;
与3,5-二氯苯基硼酸反应,得到N-二氨基亚甲基-2-甲基-4-(3,5-二氯苯基)-5-甲磺酰苯甲酰胺,m.p.215-218℃,甲磺酸盐231-233℃。
例4
将1.0克2-乙基-3-甲磺酰基-4-苯基苯甲酸〔通过2-乙基-3-甲磺酰基-4-溴苯甲酸甲酯与苯基硼酸在有四(三苯膦)-钯(O)存在下反应,然后水解而得到〕溶于15ml 1-甲基吡咯烷酮中,将0.67克1-甲基-2-氯吡啶鎓氯化物加入此溶液中,然后将其搅拌15分钟。再加入0.9克氯化胍和2.6ml二异丙基乙胺,将该混合物在室温下搅拌1小时。经通常的混合聚集之后得到N-二氨基亚甲基-2-乙基-3-甲磺酰-4-苯基苯甲酰胺。
按相类似的方式得到以下物质:
从2-甲基-3-甲磺酰-4-(3-氯苯基)-苯甲酸,得到N-二氨基亚甲基-2-甲基-3-甲磺酰-4-(3-氯苯基)苯甲酰胺;
从2-硝基-3-甲磺酰-4-(4-甲氧苯基)-苯甲酸酯,得到N-二氨基亚甲基-2-硝基-3-甲磺酰-4-(4-甲氧苯基)苯甲酰胺;
从2-氰基-3-甲磺酰-4-苯基苯甲酸,得到N-二氨基亚甲基-2-氰基-3-甲磺酰-4-苯基苯甲酰胺;
从2-乙炔基-3-甲磺酰-4-(4-氯苯基)苯甲酸,得到N-二氨基亚甲基-2-乙炔基-3-甲磺酰-4-(4-氯苯基)苯甲酰胺;
从2-氟-3-甲磺酰-4-苯基苯甲酸,得到N-二氨基亚甲基-2-氟-3-甲磺酰-4-苯基苯甲酰胺;
从2-二氟甲基-3-甲磺酰-4-苯基苯甲酸,得到N-二氨基亚甲基-2-二氟甲基-3-甲磺酰-4-苯基苯甲酰胺;
从2-氟甲基-3-甲磺酰-4-(4-甲基苯基)苯甲酸,得到N-二氨基亚甲基-2-氟甲基-3-甲磺酰-4-(4-甲基苯基)苯甲酰胺。
例5
按与例4相类似的方式,使1.0克2-乙基-3-氨基磺酰基-4-苯基苯甲酸(通过使2-乙基-3-氨基磺酰基-4-溴苯甲酸甲酯在有四(三苯基膦)-钯(O)存在下与苯基硼酸反应然后水解而得到)与0.9克氯化胍反应而得到N-二氨基亚甲基-2-乙基-3-氨基磺酰基-4-苯基苯甲酰胺。
按相类似的方式得到以下物质:
从2-甲基-3-氨基磺酰基-4-(3-氯苯基)苯甲酸甲酯,得到N-二氨基亚甲基-2-甲基-3-氨基磺酰基-4-(3-氯苯基)苯甲酰胺;
从2-硝基-3-氨基磺酰基-4-(4-甲氧基苯基)苯甲酸,得到N-二氨基亚甲基-2-硝基-3-氨基磺酰基-4-(4-甲氧基苯基)苯甲酰胺;
从2-氰基-3-氨基磺酰基-4-苯基苯甲酸,得到N-二氨基亚甲基-2-氰基-3-氨基磺酰基-4-苯基苯甲酰胺;
从2-乙炔基-3-氨基磺酰基-4-(4-氯苯基)苯甲酸,得到N-二氨基亚甲基-2-乙炔基-3-氨基磺酰基-4-(4-氯苯基)苯甲酰胺;
从2-氟-3-氨基磺酰基-4-苯基苯甲酸,得到N-二氨基亚甲基-2-氟-3-氨基磺酰基-4-苯基苯甲酰胺;
从2-二氟甲基-3-氨基磺酰基-4-苯基苯甲酸,得到N-二氨基亚甲基-2-二氟甲基-3-氨基磺酰基-4-苯基苯甲酰胺;
从2-氟甲基-3-氨基磺酰基-4-(4-甲基苯基)苯甲酸,得到N-二氨基亚甲基-2-氟甲基-3-氨基磺酰基-4-(4-甲基苯基)苯甲酰胺。
例6
按与例1相类似的方式,使1.8克2-甲基-4-(4-甲基苯基)-5-氨基磺酰基苯甲酸甲酯(通过3-氨基磺酰基-4-溴-6-苯甲酸甲酯与甲苯基硼酸反应而得到)与甲醇中的1.5克胍反应而得到N-二氨基亚甲基-2-甲基-4-(4-甲基苯基)-5-氨基磺酰基苯甲酰胺。
以相类似的方式使胍与以下物质反应而得到各产物:
与2-乙基-4-(4-甲基苯基)-5-氨基磺酰基苯甲酸甲酯反应,得到N-二氨基亚甲基-2-乙基-4-(4-甲基苯基)-5-氨基磺酰基苯甲酰胺;
与2-丙基-4-(4-甲基苯基)-5-氨基磺酰基苯甲酸甲酯反应,得到N-二氨基亚甲基-2-丙基-4-(4-甲基苯基)-5-氨基磺酰基苯甲酰胺;
与2-异丙基-4-(4-甲基苯基)-5-氨基磺酰基苯甲酸甲酯反应,得到N-二氨基亚甲基-2-异丙基-4-(4-甲基苯基)-5-氨基磺酰基苯甲酰胺;
与2-丁基-4-(4-甲基苯基)-5-氨基磺酰基苯甲酸甲酯反应,得到N-二氨基亚甲基-2-丁基-4-(4-甲基苯基)-5-氨基磺酰基苯甲酰胺;
与2-(2-丁基)-4-(4-甲基苯基)-5-氨基磺酰基苯甲酸甲酯反应,得到N-二氨基亚甲基-2-(2-丁基)-4-(4-甲基苯基)-5-氨基磺酰基苯甲酰胺;
与2-乙基-4-苯基-5-氨基磺酰基苯甲酸甲酯反应,得到N-二氨基亚甲基-2-乙基-4-苯基-5-氨基磺酰基苯甲酰胺;
与2-丙基-4-苯基-5-氨基磺酰基苯甲酸甲酯反应,得到N-二氨基亚甲基-2-丙基-4-苯基-5-氨基磺酰基苯甲酰胺;
与2-异丙基-4-苯基-5-氨基磺酰基苯甲酸甲酯反应,得到N-二氨基亚甲基-2-异丙基-4-苯基-5-氨基磺酰基苯甲酰胺;
与2-丁基-4-苯基-5-氨基磺酰基苯甲酸甲酯反应,得到N-二氨基亚甲基-2-丁基-4-苯基-5-氨基磺酰基苯甲酰胺;
与2-(2-丁基)-4-苯基-5-氨基磺酰基苯甲酸甲酯反应,得到N-二氨基亚甲基-2-(2-丁基)-4-苯基-5-氨基磺酰基苯甲酰胺;
与2-乙基-4-(4-甲基苯基)-5-氨基磺酰基苯甲酸甲酯反应,得到N-二氨基亚甲基-2-乙基-4-(4-甲基苯基)-5-氨基磺酰基苯甲酰胺;
与2-氯-4-(4-甲基苯基)-5-氨基磺酰基苯甲酸甲酯反应,得到N-二氨基亚甲基-2-氯-4-(4-甲基苯基)-5-氨基磺酰基苯甲酰胺;
与2-溴-4-(4-甲基苯基)-5-氨基磺酰基苯甲酸甲酯反应,得到N-二氨基亚甲基-2-溴-4-(4-甲基苯基)-5-氨基磺酰基苯甲酰胺;
与2-氟甲基-4-(4-甲基苯基)-5-氨基磺酰基苯甲酸甲酯反应,得到N-二氨基亚甲基-2-氟甲基-4-(4-甲基苯基)-5-氨基磺酰基苯甲酰胺;
与2-三氟甲基-4-(4-甲基苯基)-5-氨基磺酰基苯甲酸甲酯反应,得到N-二氨基亚甲基-2-三氟甲基-4-(4-甲基苯基)-5-氨基磺酰基苯甲酰胺;
与2-五氟乙基-4-(4-甲基苯基)-5-氨基磺酰基苯甲酸甲酯反应,得到N-二氨基亚甲基-2-五氟乙基-4-(4-甲基苯基)-5-氨基磺酰基苯甲酰胺;
与2-甲氧基-4-(4-甲基苯基)-5-氨基磺酰基苯甲酸甲酯反应,得到N-二氨基亚甲基-2-甲氧基-4-(4-甲基苯基)-5-氨基磺酰基苯甲酰胺;
与2-氰基-4-(4-甲基苯基)-5-氨基磺酰基苯甲酸甲酯反应,得到N-二氨基亚甲基-2-氰基-4-(4-甲基苯基)-5氨基磺酰基苯甲酰胺;
与2-硝基-4-(4-甲基苯基)-5-氨基磺酰基苯甲酸甲酯反应,得到N-二氨基亚甲基-2-硝基-4-(4-甲基苯基)-5氨基磺酰基苯甲酰胺;
与2-乙炔基-4-(4-甲基苯基)-5-氨基磺酰基苯甲酸甲酯反应,得到N-二氨基亚甲基-2-乙炔基-4-(4-甲基苯基)-5-氨基磺酰基苯甲酰胺。
例7
按与例1相类似的方式,通过使胍与下列物质反应,得到各产物:
与2-三氟-5-苯基苯甲酸甲酯反应,得到N-二氨基亚甲基-2-三氟-5-苯基苯甲酰胺;
与2-溴-5-苯基苯甲酸甲酯反应,得到N-二氨基亚甲基-2-溴-5-苯基苯甲酰胺;
与2-甲基-5-苯基苯甲酸甲酯反应,得到N-二氨基亚甲基-2-甲基-5-苯基苯甲酰胺;
与2-甲基-5-(4-甲基苯基)苯甲酸甲酯反应,得到N-二氨基亚甲基-2-甲基-5-(4-甲基苯基)苯甲酰胺。
以下的例子涉及药品制备:
例A:注射小瓶
将100克分子式I的活性化合物和5克磷酸氢二钠在3l二次蒸馏水中的溶液用2N盐酸调节其PH至6.5,通过过滤消毒并且用于充入注射小瓶;在无菌条件下将小瓶中的溶液冻干然后以无菌方式将小瓶密封。每个注射小瓶含有5mg活性化合物。
例B:栓剂
将20克分子式I的活性化合物与100克大豆卵磷脂和1400克可可乳脂的混合物一起熔融,把此混合物倒入模具中并使其冷却。每一栓剂含有20mg活性化合物。
例C:溶液
制备一种溶液,它由1克分子式I的活性化合物,9.38克NaH2PO4·2H2O,28.48克Na2HPO4·12H2O和0.1克氯苄烷铵(于940ml的二次蒸馏水中)组成。将该溶液调至PH为6.8并补足至1升,通过辐射消毒。此溶液可以用作例如滴眼剂。
例D:软膏
将500mg分子式I的活性化合物与99.5克凡士林在无菌条件下混合。
例E:片剂
将1公斤分子式I的活性化合物,4公斤乳糖,1.2公斤马铃薯淀粉,0.2公斤滑石和0.1公斤硬脂酸镁的混合物按通常方式压制为药片,使每一药片含有10mg活性化合物。
例F:包衣的片剂
按与例E相类似的方式压制片剂,接着将该片剂按通常方式用一包衣包被,该包衣由蔗糖,马铃薯淀粉,滑石,黄蓍胶和染包物质组成。
例G:胶囊
将2公斤分子式I的活性化合物按通常方式充入硬明胶胶囊使每个胶囊含有20mg该活性化合物。
例H:安瓿
将60l二次蒸馏水中的1公斤分子式I活性化合物的溶液通过过滤消毒并用其填充安瓿,将安瓿中的该溶液在消毒条件下冻干并以无菌的方式将安瓿密封。每一安瓿含有10mg活性化合物。
Claims (5)
2.(a)N-二氨基亚甲基-2-甲基-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺;
(b)N-二氨基亚甲基-2-乙基-4-(4-甲基苯基)-5-甲磺酰苯甲酰胺;
(c)N-二氨基亚甲基-2-乙基-3-甲磺酰-4-苯基苯甲酰胺。
4.药品制剂,其特征在于含有至少一种权利要求1的通式I化合物和/或一种其生理无害盐。
5.权利要求1的式I化合物及其生理无害盐在制备用来治疗与预防心律失常,心绞痛和梗塞的药物方面的用途。
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DE4430213A DE4430213A1 (de) | 1994-08-28 | 1994-08-28 | Arylbenzoylguanidine |
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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 |
NZ314105A (en) | 1996-02-02 | 1997-12-19 | Sumitomo Pharma | Guanidine derivative substituted with a substituted indole which is peri condensed with a heterocyclic ring |
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 |
DE19624178A1 (de) * | 1996-06-18 | 1998-01-08 | Hoechst Ag | Ortho-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
DE19833118C2 (de) * | 1998-07-23 | 2000-07-27 | Merck Patent Gmbh | Verfahren zur Herstellung von orthoalkylierten Benzoesäurederivaten |
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ATE440827T1 (de) * | 2002-12-04 | 2009-09-15 | Ore Pharmaceuticals Inc | Melanocortin-rezeptormodulatoren |
GB0323584D0 (en) * | 2003-10-08 | 2003-11-12 | Glaxo Group Ltd | Compounds |
GB0323585D0 (en) * | 2003-10-08 | 2003-11-12 | Glaxo Group Ltd | Compounds |
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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 |
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ZA957163B (en) | 1996-04-17 |
PL310193A1 (en) | 1996-03-04 |
ATE172716T1 (de) | 1998-11-15 |
JPH0859598A (ja) | 1996-03-05 |
EP0699660A3 (zh) | 1996-03-20 |
BR9503810A (pt) | 1996-04-16 |
HU216833B (hu) | 1999-09-28 |
EP0699660B1 (de) | 1998-10-28 |
NO953351L (no) | 1996-02-29 |
HU9502516D0 (en) | 1995-10-30 |
TW386988B (en) | 2000-04-11 |
NO305242B1 (no) | 1999-04-26 |
SK105395A3 (en) | 1996-03-06 |
HUT72303A (en) | 1996-04-29 |
DE4430213A1 (de) | 1996-02-29 |
CZ218295A3 (en) | 1996-03-13 |
ES2125537T3 (es) | 1999-03-01 |
AU704630B2 (en) | 1999-04-29 |
US5807896A (en) | 1998-09-15 |
NO953351D0 (no) | 1995-08-25 |
CN1117962A (zh) | 1996-03-06 |
EP0699660A2 (de) | 1996-03-06 |
CZ289058B6 (cs) | 2001-10-17 |
SK281135B6 (sk) | 2000-12-11 |
UA44237C2 (uk) | 2002-02-15 |
RU2153490C2 (ru) | 2000-07-27 |
AU3014495A (en) | 1996-03-14 |
KR960007540A (ko) | 1996-03-22 |
PL180872B1 (pl) | 2001-04-30 |
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CA2156960A1 (en) | 1996-03-01 |
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