- Preparation method of anticoagulant drug dabigatran etexilate and analogues thereof
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The invention discloses a preparation method of an anticoagulant drug dabigatran etexilate and analogues thereof. The preparation method comprises the following steps: 3-[(3-amino-4-methylaminobenzoyl)pyridin-2-ylamino]propionic acid ethyl ester (DGM1) and isopropyl 2-(4-cyanophenylamino)acetate (DGM2) which are taken as reaction initial raw materials undergo a docking reaction under the action ofan alkali reagent and a condensing agent to prepare an intermediate DG1; the intermediate DG1 reacts in an alcohol solvent to produce imino ester, and acid catalysis and ammonia reaction are carriedout to prepare a formamidine compound; an intermediate DG2 reacts with n-hexyl chloroformate under the action of the alkali reagent to remove one molecule of water and form an amido bond in order to obtain dabigatran etexilate; and the dabigatran etexilate analogues DG-D1 to DG-D4 are prepared from the dabigatran etexilate and its intermediate DG2. The preparation method of the dabigatran etexilate and analogues thereof has the advantages of short and feasible synthesis route, simplicity in operation, high product yield is high, and suitableness for large-scale industrial production.
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Paragraph 0039; 0041-0043
(2020/05/01)
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- Method for purifying dabigatran etexilate intermediate
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The invention relates to a purification method. of a dabigatran etexilate intermediate, and discloses a purification method 3 - [[[2 - [[(4 - for preparing the intermediate formula I compound) cyanophenyl] amino] - 1 - methyl]-yl](amino)-ethyl propionate of dabigatran etexilate, firstly, recrystallization] with acetone-water and recrystallization, with ethyl acetate enables high-yield .efficiency purification of I compound.
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Paragraph 0022-0026
(2020/03/23)
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- Preparation method of dabigatran intermediate
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The invention discloses a dabigatran intermediate preparation method which is as follows: a formula V compound as a raw material reacts with a formula VI compound to prepare a formula III compound, the formula III compound reacts with 4-amino cyanobenzene under the effect of an alkali to obtain a formula II compound, and then a target product formula I compound is obtained by transfer hydrogenation. The dabigatran intermediate preparation method is short and simple in steps, mild in conditions, high in total reaction yield, and suitable for industrial production.
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Paragraph 0036; 0037
(2019/12/25)
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- Dabigatran etexilate key intermediate preparation method
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The invention relates to the field of pharmaceutical intermediates, particularly to an industrial preparation method of a dabigatran etexilate key intermediate. According to the preparation method, astarting raw material is subjected to nitro reduction, amide condensation and cyclization reaction to obtain a key intermediate 3-{2-[(4-cyanophenylamino)methyl]-1-methyl-N-(pyridine-2-yl)-1H-benzo[d]imidazole-5-amido}ethyl propionate. According to the present invention, the preparation method can reduce the production cost, make the production process safe, and improve the yield, and is suitablefor industrial large-scale production.
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- Synthetic method for pradaxa key intermediate
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The invention relates to a synthetic method for ethyl [2-[[(4-cyanophenyl)amino]-methyl] -1-methyl-1H-benzimidazol-5-yl]carbonyl] (pyridin-2-yl)amino]propanoate. According to the synthetic method, thereaction formula is as shown in the description. The synthetic method comprises the following steps that 1) a compound SM01 reacts with a coupling reagent CDI in a toluene solution; 2) after the reaction in the step 1) is finished, an obtained reaction solution is cooled, and an SM02 toluene solution is added for reaction; and 3) after the reaction is finished, acetic acid is added, and then thereaction is continued to the end. Compared with the prior art, the synthetic method has the advantages that a solvent is single and does not need to be replaced in the reaction process, the operationis simple and convenient, by-products are few, the yield is high and is 93-96%, a high-purity product of DB02 is easily obtained, the HPLC content is 99% or above, and the method is suitable for industrial production.
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Paragraph 0012; 0035-0050
(2018/11/03)
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- Production process of pradaxa mesylate
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The invention discloses a production process of pradaxa mesylate. The production process comprises the following steps: (1) preparing an intermediate PR-I; (2) preparing an intermediate PR-II; (3) preparing pradaxa PR-III; (4) refining the pradaxa PR-III; and (5) preparing pradaxa mesylate. The production process is mild in reaction condition, simple in reaction route, convenient in operation, high in selectivity, and capable of shortening the production period; and the obtained pradaxa intermediate is low in water content, the prepared pradaxa mesylate is high in yield and purity, and the maximum impurity is low in impurity content; and the production process is less in emission of three wastes, environmentally friendly, free from requiring the columnar chromatography purification, suitable for the industrialized production, capable of avoiding the requirement of palladium-on-carbon high-pressure hydrogenation on equipment and capable of reducing the risk.
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Paragraph 0073; 0075; 0098; 0100-0104; 0128; 0130 ; 0154
(2018/11/22)
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- Preparation method for dabigatran etexilate
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The invention provides a method for preparing dabigatran etexilate. The method comprises the following steps: A) subjecting a compound as shown in a formula I and a compound as shown in a formula II to a reaction in an inert solvent so as to obtain a compound as shown in a formula III, wherein the compound as shown in the formula II comprises an R which is one selected from the group consisting of methyl, ethyl, propyl or isopropyl; B) subjecting the compound as shown in the formula III to activation through a hydrogen chloride solution in an inert solvent, and carrying out a reaction of the activated material and an ammonium salt so as to obtain a product IV; and C) subjecting a compound as shown in a formula IV and a compound as shown in a formula V to a reaction under the action of an acid-binding agent so as to obtain dabigatran etexilate VI. The method provided by the invention has the advantages of low cost, high yield, mild reaction conditions, avoidance of using unstable reagents, etc.
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- Industrial preparation method of dabigatran
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The invention discloses an industrial preparation method of dabigatran, and belongs to the field of medicinal chemistry, wherein the preparation method sequentially comprises a condensation reaction, a closed cyclization reaction, a Pinner reaction, and other steps. According to the present invention, the hydrogen chloride/alcohol/ester solution is prepared by using acyl chloride and alcohol as raw materials, such that the problems of corrosion on equipment, high hidden safety danger, environmental pollution and the like caused by the use of hydrogen chloride gas in the prior art are solved; and the reactions in various steps are subjected to the industrial-scale-based optimization, the unnecessary distillation, extraction and re-crystallization process is reduced, the process is simplified, the purification method of the final product dabigatran is improved, the purification efficiency is increased in the case of the ensuring of the process yield and the product quality, the process reproducibility is good, the preparation cost is low, and the method is the ideal industrial preparation method of the dabigatran.
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- A darbey adds the group ester preparation method
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The invention relates to a preparation method of Dabigatran etexilate. In a preparation process, acyl chloride or anhydride is used for replacing N, N minute-Carbonyldiimidazole (CDI ) or palladium on activated carbon, which must be used and is expensive in the prior art, the cost is greatly lowered, and used materials are cheap and are easily available, the process is simple and feasible, aftertreatment steps are simplified, column chromatography purification is not needed in whole operation steps, so that the process of the whole preparation method is simplified, and industrialization is convenient to realize; when a compound with a formula 2 is compounded, a sodium amide and ammonium salt system is adopted, and generation of a mass of acid pickle is avoided, so the production is safe, the environment is not polluted, and the preparation process is convenient and easy; when a compound with a formula 1 is compounded, a stable-property compound with a formula 7 is adopted, great convenience is brought for production, and the yield of the Dabigatran etexilate is effectively improved; the total yield of the Dabigatran etexilate prepared by the method reaches 60 to 70 percent.
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Paragraph 0044; 0045; 0046; 0054; 0062
(2017/09/01)
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- Multi-substituted 4-methyl ester derivative of amino benzonitrile trunk and its preparation and use
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The invention provides new ester derivatives with a general formula (I) shown in the specification of multi-substituted 4-methylamino-benzamidine or pharmaceutically acceptable salts, wherein A1, A2, A3 and A4 in the formula are as defined in the specification. The compounds have an anticoagulant effect and can be used for preparing medicaments for preventing and treating thromboembolic diseases.
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- New method for preparing dabigatran etexilate intermediate
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The invention discloses a new method for preparing a dabigatran etexilate intermediate. The new method includes the steps that 3-methoxy-4-aminobenzoate serves as a starting raw material firstly, and then the dabigatran etexilate key intermediate 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazole-5-yl]carbonyl]-pyridine-2-yl amino]ethyl propionate is prepared through the steps of substitution, condensation, cyclization and the like. Reaction conditions in all the steps of the synthetic process are mild, the reaction yield is high, the purity of the end product is higher than 99.0%, and the new method is suitable for industrialized production.
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- PROCESSES FOR THE PREPARATION OF DABIGATRAN ETEXILATE AND INTERMEDIATES THEREOF
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The present invention relates to a process for the preparation of dabigatran etexilate of Formula (I), or a pharmaceutically acceptable salt thereof, to processes for the preparation of intermediates of dabigatran etexilate, and to dabigatran etexilate in substantially pure form.
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- Preparation method of dabigatran etexilate mesylate
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The invention discloses a preparation method of dabigatran etexilate mesylate, and belongs to the technical field of medicine. The preparation method comprises the following steps: taking 3-[(3-amino-4-methylaminobenzoyl)pyridine-2-ylamino]ethyl propanoate and N-(4-cyanphenyl)amino acetic acid as the raw materials to synthesize an intermediate (S3); making the intermediate (S3) carry out ring-closure reactions to generate an intermediate (S4); subjecting the intermediate (S4) to acid splitting in the presence of a hydrogen chloride-ethanol solution at first, then carrying out ammonification in the presence of ammonia water to generate an intermediate (S5); carrying out reactions between the intermediate (S5) and n-hexyl chloroformate under an alkaline condition to generate an intermediate (S6); dissolving the intermediate (S6), and finally carrying out reactions between the intermediate (S6) and methylsulfonic acid to obtain dabigatran etexilate mesylate. The preparation method has the advantages of simpleness, controllable and mild conditions, high yield, high product purity, stable product property, and suitability for industrial production.
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- Dabigatran etexilate synthesis method
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The invention belongs to the field of pharmaceutical chemical engineering and relates to a dabigatran etexilate synthesis method. The invention provides the preparation method of dabigatran etexilate with a high yield and good quality and stability. The method has simple processes, is convenient for operation, simplifies post-treatment processes, is free of column chromatography purification in the whole processes and is suitable for industrial production.
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Paragraph 0011; 0039; 0040
(2017/02/02)
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- Preparation method of dabigatran etexilate intermediate
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The invention discloses a preparation method of a dabigatran etexilate intermediate. The preparation method specifically comprises the following steps of firstly, dissolving a compound III and a condensing agent into mixed solvent, stirring and heating to reflux, and carrying out heat-insulation reaction, wherein the mixed solvent comprises dichloromethane and petroleum ether or dichloromethane and diethyl ether; secondly, adding a compound II, and continuously refluxing for performing condensation reaction to obtain a reaction system containing a compound IV; thirdly, adding acetic acid into the reaction system, first carrying out concentration under reduced pressure to remove the mixed solvent by steaming, and then performing cyclization reaction at the temperature of 30 to 100 DEG C; fourthly, after the reaction is ended, pouring the reaction system into water, cooling, crystallizing, and performing suction filtration; after a filter cake is recrystallized, performing secondary suction filtration on the recrystallized filter cake, and drying the filter cake to obtain a compound I. According to the condensation reaction disclosed by the invention, the dichloromethane and the petroleum ether or the diethyl ether are adopted as the mixed solvent and the consumption is less; compared with the prior art, the preparation method disclosed by the invention has the advantages that the production cost of the condensation reaction can be greatly reduced, and higher reaction yield and production purity can be kept.
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Paragraph 0016; 0017; 0018; 0019; 0020
(2016/10/08)
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- PROCESS FOR THE PREPARATION OF DABIGATRAN ETEXILATE MESYLATE AND POLYMORPHS OF INTERMEDIATES THEREOF
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The present invention provides crystalline form of intermediates of Formula 2A, The present invention also provides process for the preparation of dabigatran etexilate mesylate; polymorph of intermediates thereof; particularly processes for the preparation of crystalline form of intermediates. The present invention also relates to the use of crystalline intermediates for the preparation of dabigatran etexilate mesylate.
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- IMPROVED PROCESSES FOR THE PREPARATION OF DABIGATRAN ETEXILATE USING NOVEL INTERMEDIATES
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Disclosed herein are novel, commercially viable and industrially advantageous processes for the preparation of Dabigatran or a salt thereof, in high yield and purity, using novel intermediate compounds. The novel process solves the drawbacks associated with the prior processes and is commercially viable for preparing Dabigatran and its salts or derivatives thereof.
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- A PROCESS FOR PREPARATION OF DABIGATRAN ETEXILATE MESYLATE AND INTERMEDIATES THEREOF
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The present invention relates to an improved process for the preparation of Dabigatran etexilate and its acid addition salts thereof, wherein the said process substantially eliminates the potential impurities. The present invention also relates to an intermediate of Dabigatran etexilate and process for preparation thereof.
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- PROCESS FOR THE PREPARATION OF BENZIMIDAZOLE DERIVATIVES AND ITS SALTS
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An dabigatran etexilate intermediate of Formula-6a, and the use in the preparation of dabigatran etexilate thereof.
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- PROCESS FOR THE PREPARATION OF INTERMEDIATES FOR THE SYNTHESIS OF DABIGATRAN ETEXILATE, AND CRYSTALLINE FORMS OF SAID INTERMEDIATES
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The present invention relates to new processes for the preparation of synthesis intermediate products useful in the preparation of Dabigatran Etexilate on an industrial scale. The invention also relates to new crystalline forms of intermediate products thus obtained.
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Page/Page column 16; 17
(2014/02/15)
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- AN IMPROVED PROCESS FOR PREPARATION OF DABIGATRAN ETEXILATE AND PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF
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The present invention provides an improved process for preparation of dabigatran etexilate and pharmaceutically acceptable acid addition salts thereof, particularly mesylate salt. The present invention also provides novel salts of intermediates of Dabigatran etexilate and their polymorphs.
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Page/Page column 21; 22
(2014/12/12)
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- PROCESS FOR THE PREPARATION OF DABIGATRAN ETEXILATE MESYLATE AND POLYMORPHS OF INTERMEDIATES THEREOF
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The present invention provides crystalline form of intermediates of Formula 2A, Formula 2B and Formula E. The present invention also provides process for the preparation of dabigatran etexilate mesylate; polymorph of intermediates thereof; particularly processes for the preparation of crystalline form of intermediates. The present invention also relates to the use of crystalline intermediates for the preparation of dabigatran etexilate mesylate.
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- IMPROVED PROCESS FOR PREPARATION OF DABIGATRAN ETEXILATE AND ITS NOVEL INTERMEDIATE
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Provided are intermediates for preparing dabigatran etexilate i.e. isopropanol solvate of l-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide hydrochloride of formula (Vila) and crystalline form II of l-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide hydrochloride of formula (VII).
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- Synthesis, characterization and suppression of impurities during optimization of dabigatran etexilate
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The synthetic methods for two impurities of dabigatran etexilate are firstly described, and both of two impurities are characterized by NMR and MS spectral data. The suppression of impurities as well as the optimization process of dabigatran etexilate is also disclosed.
- Chen, Yu,Liang, Jun,Chen, Huansheng,Yuan, Li
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p. 1699 - 1710
(2013/09/12)
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- PROCESS FOR THE PREPARATION OF BENZIMIDAZOLE DERIVATIVES AND ITS SALTS
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The Present Invention Provides An Improved Process For The Preparation Of 1-methyl-2-[n-[4-(n-n-hexyloxycarbonylamidino) Phenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-n-(2-pyridyl)-n-(2-ethoxycarbonylethyl)amide Compound Of Formula-1 And Its Methanesulfonate Salt Compound Of Formula-1a.
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- PROCESS OF PREPARING A THROMBIN SPECIFIC INHIBITOR
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A process of preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 and R2 represent H; or either R1 represents ethyl and R2 represents n-hexyloxycarbonyl that applies to industrial scale, novel intermediates useful for the preparation thereof, and processes of preparing said intermediates.
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Page/Page column 21-22
(2012/02/01)
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- PROCESS FOR THE PREPARATION OF A BENZIMIDAZOLE DERIVATIVE
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The invention relates to a process for preparing the compound of formula 1, a valuable intermediate product in the synthesis of the pharmaceutical active substance dabigatran etexilate.
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Page/Page column 10-11
(2008/12/08)
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- Structure-based design of novel potent nonpeptide thrombin inhibitors
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The clinical syndromes of thromboembolism are evoked by an excessive stimulation of the coagulation cascade. In this context, the serine protease thrombin plays a key role. Considerable efforts have therefore been devoted to the discovery of safe, orally active inhibitors of this enzyme. On the basis of the X-ray crystal structure of the peptidelike thrombin inhibitor NAPAP complexed with bovine thrombin, we have designed a new structural class of nonpeptidic inhibitors employing a 1,2,5-trisubstituted benzimidazole as the central scaffold. Supported by a series of X-ray structure analyses, we optimized the activity of these compounds. Thrombin inhibition in the lower nanomolar range could be achieved although the binding energy mainly results from nonpolar, hydrophobic interactions. To improve in vivo potency, we increased the overall hydrophilicity of the molecules by introducing carboxylate groups. The very polar compound 24 (BIBR 953) exhibited the most favorable activity profile in vivo. This zwitterionic molecule was converted into the double-prodrug 31 (BIBR 1048), which showed strong oral activity in different animal species. On the basis of these results, 31 was chosen for clinical development.
- Hauel, Norbert H.,Nar, Herbert,Priepke, Henning,Ries, Uwe,Stassen, Jean-Marie,Wienen, Wolfgang
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p. 1757 - 1766
(2007/10/03)
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- Disubstituted bicyclic heterocycles, the preparations and the use thereof as pharmaceutical compositions
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New disubstituted bicyclic heterocycles of general formula Ra-A-Het-B-Ar-E (I)Compounds of the above general formula I, wherein E denotes an RbNH-C(=NH)- group, have valuable pharmacological properties, particularly a thrombin-inhibiting effect and the effect of prolonging thrombin time, and those wherein E denotes a cyano group, are valuable intermediates for preparing the other compounds of general formula I. Exemplary compounds of formula I are: (a) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)-amide, (b) 1-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)-amide, (c) 1-Methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)-amide, and (d) 1-Methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) amide.
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