- Microwave assisted synthesis of novel six-membered 4-C, 4-O and 4-S lactams derivatives: Characterization and in vitro biological evaluation of cytotoxicity and anticoagulant activity
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A series of six-membered lactam derivatives containing C, O and S atoms in position 4 were synthesized using microwave methodology through coupling reactions. The novel compounds were synthesized following two step reaction to yield fifteen derivatives. The final derivative N-(4-(3-oxotiomorpholin)phenyl) hexanamide was selectively toxic to the HCT-116 cell line over the HeLa cancerous and HEK-293 human non-malignant control cells with low inhibition Factor Xa (FXa) activity. The new products were characterized by spectral data including 1H and 13C nuclear magnetic resonance (NMR), infrared (IR) and high-resolution mass spectrometry (HRMS). Cytotoxicity of products on HCT-116, HeLa, HEK-293 cell lines and FXa activity assays are also reported.
- Nú?ez-Navarro, Nicolás E.,Segovia, Gerardine F.,Burgos, Renato A.,Lagos, Carlos F.,Fuentes-Ibacache, Nataly,Faúndez, Mario A.,Zacconi, Flavia C.
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Read Online
- Synthesis method of 4-(4-aminophenyl)-3-morpholone
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The invention provides a synthesis method of 4-(4-aminophenyl)-3-morpholone. The method comprises the following steps: condensing p-halonitrobenzene and morpholine which are used as starting materials to generate 4-(4-nitrophenyl) morpholine, oxidizing 4-(4-nitrophenyl) morpholine by taking a halite or chlorine dioxide as an oxidizing agent and controlling the pH value of a reaction system to be less than 7 to generate 4-(4-nitrophenyl)-3-morpholone, and finally reducing to generate the target product 4-(4-aminophenyl)-3-morpholone. The synthesis method of 4-(4-aminophenyl)-3-morpholinone provided by the invention has the advantages of greenness, high efficiency, easiness in industrial application and the like.
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Paragraph 0053-0055
(2021/06/12)
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- Catalytic production of anilines by nitro-compounds hydrogenation over highly recyclable platinum nanoparticles supported on halloysite nanotubes
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Pt-nanoparticles supported on halloysite-nanotubes (HNTs) were selectively deposited onto the inner (Pt(IN)/HNT) or outer (Pt(OUT)/HNT) surface of the support to evaluate their operational stability on the cleaner and efficient hydrogenation of nitro compounds to produce their corresponding anilines. The formation of Pt0-aggregates on the inner or outer surfaces was observed, with mean particles sizes of 2.4–2.9 nm. The catalysts were evaluated using ethanol as solvent and nitrobenzene as a model substrate at a temperature of 298 K, under 1 bar of H2 pressure. The Pt(IN)/HNT catalyst showed better catalytic performance than Pt(OUT)/HNT, which was mainly attributed to the confinement effect of the Pt-nanoparticles inside the HNTs. However, the operational stability showed that Pt(OUT)/HNT retained its catalytic performance after 15 cycles, while the Pt(IN)/HNT catalyst suffered deactivation after the 5th cycle. The best catalytic system showed a moderate-to-high efficiency in the efficient hydrogenation of 7 nitro compounds used to produce their corresponding anilines, which are important pharmaceutical building blocks.
- Aepuru, Radhamanohar,Bustamante, Tatiana M.,Campos, Cristian H.,Leal-Villarroel, Edgardo,Mangalaraja, Ramalinga Viswanathan,Shanmugaraj, Krishnamoorthy,Torres, Cecilia C.,Vinoth, Victor
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- Gold nanoparticles supported on mesostructured oxides for the enhanced catalytic reduction of 4-nitrophenol in water
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In this work, Au nanoparticles supported on aluminum oxide (Au/ANT) and titanate (Au/TNT) nanotubes were synthesized for their use as catalysts in the reduction of 4-nitrophenol to produce 4-aminophenol with NaBH4 as the reducing agent. The catalysts were prepared with a 0.5 % metal loading employing the nanotube supports modified with 3-aminopropyl-trimethoxysilane (APTMS) to provide plentiful anchoring sites to trap the Au nanoparticles and prevent their agglomeration. All materials were characterized using a range of analytical techniques, and it was found that Au zero-valent nanoparticles were homogenously supported on the inner/outer surfaces of the nanotubular-structured carriers. Both catalytic systems were highly active and selective in the reduction of 4-nitrophenol, giving TOF values of 20,561 and 19,560 h?1 for Au/TNT and Au/ANT, respectively. The excellent catalytic activity was attributed to the highly dispersed Au clusters on the support surfaces through enhanced functionalization with APTMS, and the confinement effect of the nanotubular carriers. Furthermore, Au/TNT exhibited a high operational stability for the reduction of 4-nitrophenol reaching 10 catalytic cycles with only a moderate decrease in the conversion level after the seventh cycle, which was attributed to a degree of metal leaching. Finally, the catalytic reduction performance of the Au/TNT catalyst was tested in different nitroarene-substituted pharmaceuticals, and revealed a high activity (>99 % after 60 min of reaction) and selectivity toward production of the desired substituted anilines, thereby highlighting the potential of this catalyst for application in these processes.
- Bustamante, Tatiana M.,Campos, Cristian H.,Shanmugaraj, Krishnamoorthy,Torres, Cecilia C.
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- Facile preparation of 4-(4-nitrophenyl)morpholin-3-one via the acid-catalyzed selective oxidation of 4-(4-nitrophenyl)morpholine by sodium chlorite as the sole oxidant
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4-(4-Nitrophenyl)morpholin-3-one and 4-(4-aminophenyl) morpholin-3-one are the key intermediates for rivaroxaban synthesis. A facile and economically efficient process has been developed for the preparation of these intermediates. Excellent yield of 4-(4-nitrophenyl)morpholine is obtained by condensing 4-chloro nitrobenzene and morpholine, and 4-(4- nitrophenyl)morpholine is oxidized using inexpensive sodium chlorite to achieve a good yield of the corresponding 4-(4- nitrophenyl)morpholin-3-one. Finally, the key intermediate of rivaroxaban, 4-(4-aminophenyl) morpholin-3-one, is achieved by the iron(III)-catalyzed reduction of the nitro group with aqueous hydrazine. No high-cost materials were used, and the process did not require column purification.
- Chu, Changhu,Jia, Qiang,Liu, Chaoyang,Qin, Cheng,Sun, Haozhou,Yang, Tiannuo,Yu, Tao
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p. 2633 - 2638
(2020/12/29)
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- A high-purity 4 - (4 - aminophenyl) morpholine -3 - ketone (by machine translation)
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The invention relates to a low-cost, high-purity of 4 - (4 - aminophenyl) morpholine - 3 - one (II) of the preparation method. The use of hydroxy acetonitrile and 1, 2 - dihalo substituted ethane in the reaction process for preparing halogenated ethyl oxygen radical second grade nitrile IV, then with the para-nitroaniline III substituted reaction, acid lower ring becomes a 4 - (4 - nitrophenyl) morpholine - 3 - ketone V, 4 - (4 - nitrophenyl) morpholine - 3 - ketone V obtained by hydrogenating and reducing 4 - (4 - aminophenyl) morpholine - 3 - one II. The present invention the used raw materials are cheap and easily obtained, and the cost is low; the process route is simple, safety and environmental protection; the design of each step the reaction selectivity is high, high yield, high purity for the 4 - (4 - aminophenyl) morpholine - 3 - ketone preparation provides a guarantee, to industrial production of high-purity [...]. (by machine translation)
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Paragraph 0079; 0080; 0081; 0083
(2019/03/15)
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- PROCESS FOR THE PREPARATION OF 4-(4-AMINOPHENYL)MORPHOLIN-3-ONE
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The field of this invention relates to a novel process, suitable for industrial scale manufacture, for the preparation of 4-(4-aminophenyl)morpholin-3-one of Formula (I), the key intermediate of rivaroxaban according to the scheme. In the process 2-(2-chloroethoxy)ethanol of Formula (XI) is oxidized to 2-(2-chloroethoxy)- acetic acid with aqueous sodium- or calcium-hypochlorite and a catalyst. The 2-(2~ chloroethoxy)acetic acid of Formula (X) is reacted with 4-nitro-aniline of Formula (VII) with phenylboronic acid catalyst. Then the 2-(2-chloroetoxy)-N-(4-nitrophenyl)acetamide of Formula (IX) is transformed to 4-(4-nitrophenyl)morpholin-3-one of Formula (IV) in a ?one- pot" procedure. The 4-(4-nitrophenyl)morpholin-3-one of Formula (IV) is hydrogenated to get 4-(4-aminophenyl)morpholin-3-one of Formula (I).
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Page/Page column 11
(2019/08/20)
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- Synthesis of substituted 4-(4-((3-Nitro-2-oxo-2H-chromene-4-yl)amino)phenyl)morpholine-3-one coumarin derivatives
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A series of novel 4-(4-amino phenyl) morpholine-3-one substituted coumarin derivatives have been prepared by chloramine coupling reaction and were identified. The novel synthetic route involves nucleophilic substitution reaction of 4-chloro-3-nitro-2H-chromene-2- one with 4-(4-amino phenyl)morpholine-3-one. Due to the presence of nitro group in coumarin derivatives make substitution reaction easy and convenient at low temperature. Using DMF as solvent and K2CO3 as base various substituted 4-(4-((3-nitro-2-oxo-2H-chromen- 4-yl)amino)phenyl)morpholine-3-one derivatives (YS-1 to YS-10) can be obtain in good yield and high purity. Structural characterization of all synthesized compound was done by NMR, Mass and IR spectra.
- Sanghani, Yogesh J.,Koradiya, Suresh B.,Patel, Anilkumar S.
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p. 1461 - 1464
(2019/06/11)
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- METHOD FOR PRODUCTION OF 4-(4-AMINOPHENYL)-3-MORPHOLINON
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PROBLEM TO BE SOLVED: To provide a method for producing 4-(4-aminophenyl)-3-morpholinon in an industrially advantageous manner. SOLUTION: By using a heterogeneous metal catalyst comprising nickel and/or cobalt, 4-(4-nitrophenyl)-3-morpholinon is allowed to react with hydrogen. SELECTED DRAWING: None COPYRIGHT: (C)2019,JPOandINPIT
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Paragraph 0071; 0072-0086
(2019/08/16)
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- Preparation method of rivaroxaban intermediate
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The invention discloses a preparation method of a Rivaroxaban intermediate. The preparation method includes the following steps that (1) in existence of an organic lithium salt or the organic lithiumsalt and an inorganic lithium salt, a compound in a following formula I is reacted with a compound in a following formula II to obtain a compound in a following formula III; and (2) the compound in the formula III is subjected to an acidification reaction in existence of inorganic acid HX, the Rivaroxaban intermediate shown in a following formula IV is obtained, wherein R in the compound in the formula I is selected from methyl, isopropyl, normal-butyl and phenyl or benzyl, and the inorganic acid HX is selected from hydrochloric acid or sulfuric acid. The preparation method is easy to operateand high in yield, and industrial production and patent medicine quality control are convenient.
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Paragraph 0040; 0041; 0042; 0043; 0044; 0045; 0046
(2019/12/25)
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- Synthetic method of high-selectivity 4-(4-aminophenyl) morpholine-3-one
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The invention relates to a synthetic method of high-selectivity 4-(4-aminophenyl) morpholine-3-one; according to the method, by condensation of p-nitrohalobenzene and 2-aminoethoxy acetate in the presence of an alkali, 2-(4-nitrophenyl) aminoethoxy acetate is obtained, by hydrogenation reduction under the action of a solvent and a hydrogenation catalyst, 2-(4-aminophenyl) aminoethoxy acetate is obtained, and the 4-(4-aminophenyl) morpholine-3-one is obtained by intramolecular dealcoholization cyclization. The reaction route disclosed by the invention is high in reaction selectivity, the reaction selectivity of each step reaches more than 99.0%, and the total yield is up to 96.0%. The raw materials are cheap and easy to obtain, the separation process is few, the process route is concise, and the method is low in wastewater quantity, high in reaction atom economy, green and environment-friendly in process.
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Paragraph 0073-0074
(2019/04/30)
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- The preparation method of the [...] (by machine translation)
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The invention provides a method for preparing [...], using 4 - (4 - aminophenyl) - 3 - morpholone and 5 - chloro - N - (2 - ethylene oxide-based methyl) - 2 - thiophene carboxamide reaction to obtain 5 - [...] - 2 - {(R)- 2 - hydroxy - 3 - [4 - (3 - oxo - 4 - morpholinyl) phenyl amino] - propyl} amide, then adding N, N' - carbonyl di-imidazole, 4 - dimethylamino pyridine, begins to stir, heating reaction to obtain the - 5 - chloro - N - (( (5 S) - 2 - oxo - 3 - (4 - (3 - oxo-morpholine - 4 - yl) phenyl) - 1, 3 - Oxacillin - 5 - yl) methyl) thiophene - 2 - carboxamide. The technique of the invention route after the condition is optimized, mild reaction, high yield. (by machine translation)
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Paragraph 0041; 0042; 0043; 0044
(2018/11/22)
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- A micro-channel reactor synthesis [...] intermediates
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A micro-channel reactor synthesis [...] intermediates, which belongs to the organic synthesis in the field of anti-thrombus drug synthesis. In order to solve the traditional high-pressure catalytic hydrogenation reaction kettle in the course of synthesizing potential safety hazards, the invention will be raw materials 4 - (4 - nitrophenyl) - 3 - morpholone, organic solvent and activated carbon to load the noble metal of the catalyst after mixing as the material I, with hydrogen gas in the microchannel reactor to carry out the reaction, after-treatment has been [...] intermediate 4 - (4 - aminophenyl) - 3 - colectomy. The invention can safe production [...] intermediate.
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Paragraph 0046-0093
(2018/10/11)
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- Preparation method of 4-(4-aminophenyl)-3-molindone
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The invention provides a preparation method of 4-(4-aminophenyl)-3-molindone. The preparation method has the advantages that reaction steps with high risk and high environmental pressure are omitted,especially the use of mixed acid and chloroacetyl chloride is avoid, so that the pressure of environmental protection is reduced; in addition, the use of strong oxidants such as potassium permanganateis avoided, so that the production of by-products is reduced, the synthesis yield is high, the product quality is good and the purification of reaction post treatment is facilitated; besides, all thesteps related in the reaction process are easy to carry out, so that the reaction in which passivation effect of functional groups and the like are difficult to generate in an existing method is avoided, for example, the route which takes p-nitroaniline as a raw material to carry out substitution reaction is almost impossible to perform; besides, the selected raw materials such as p-fluoronitrobenzene and bromoethylamine hydrobromide, disclosed by the invention are easy to obtain; compared with the molindone and other raw materials involved in the existing method, the preparation method is low in price and is suitable for industrialized production.
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Paragraph 0073; 0076; 0082; 0091; 0100
(2018/11/03)
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- Preparation method of Rivaroxaban intermediates
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The invention discloses a preparation method of Rivaroxaban intermediates. The invention relates to a green and efficient preparation method of 4-(4-aminophenyl)morpholinyl-3-one and an amino protected derivative thereof. A structure of a formula II is obtained through an oxidation reaction of a structure of a formula II, and a structure of a formula I can be obtained through a deprotection reaction of the structure of the formula II, wherein the compound I and the compound II are both important intermediates for synthesizing the anticoagulation drug Rivaroxaban. Potassium permanganate is usedas an oxidizing agent in the oxidation reaction, tetraethyl benzyl ammonium chloride (TEBAC) is used as a phase transfer catalyst, dichloromethane is used as a solvent, and the reaction temperature in the oxidation reaction is 15-55 DEG C. The invention provides the preparation method of the Rivaroxaban intermediates, and the preparation method has the advantages that the raw materials are cheapand easily available, the reactions are mild in condition and are easy to operate, the preparation method is green and is friendly to the environment, the intermediate products and the final product are easy to purify, the total yield is high, industrial production is easy to realize, and the preparation method is effective and practical.
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Paragraph 0076-0080
(2019/01/08)
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- A method for preparing [...]
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The invention discloses a preparation method of rivaroxaban, which includes the steps of 1) performing a one-step cyclization reaction to an intermediate, N-(4-aminophenyl)-2-(2-haloethyoxyl)acetamide, to prepare a key intermediate, 4-(4-aminophenyl)-3-morpholinone, of the rivaroxaban; 2) performing a series reactions comprising ring opening with an epoxide, a substitution reaction, a ring formation reaction and the like to the 4-(4-aminophenyl)-3-morpholinone to obtain an intermediate, 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholine-3-one; and 3) performing a substitution reaction to the 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholine-3-one with 2-chloroformyl-5-chlorothiophene to obtain the rivaroxaban. The whole preparation process is short in route, is high in yield, is less in pollution, can avoid usage of expensive metal palladium for nitroreduction and is suitable for industrial production.
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Paragraph 0067; 0068; 0069; 0071; 0072
(2018/05/16)
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- A the advantage cuts down Sha Ban preparation method of the midbody and intermediate
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The invention discloses a preparation method of a rivaroxaban intermediate and an intermediate. The invention discloses a preparation method of a compound represented by the formula 4. The preparation method comprises a step of making a compound 3 carry out a ring closing reaction, which is represented in the description, so as to obtain the compound 4. The invention also discloses a preparation method of a compound represented by the formula 3 and a preparation method of a compound represented by the formula 1. The invention also discloses a compound represented by the formula 3 and a compound represented by the formula 5. The preparation method has the advantages of easily-available and cheap raw materials, simple technology and post-treatment, easy purification of intermediate and end products, high total yield, and high purity, and is easy for being applied to industrial production.
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Paragraph 0238; 0239; 0245; 0246; 0247
(2017/08/25)
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- A process for preparing 4 - (4 - aminophenyl) - 3 - morpholinon method (by machine translation)
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The invention discloses a process for preparing 4 - (4 - aminophenyl) - 3 - morpholone (type IV) method, which belongs to the field of chemical synthesis. The specific method comprises: intermediate N - (4 - aminophenyl) - 2 - (2 - halo ethoxy) acetamide (type III) by the one-step cyclization reaction systems benefit cuts down Sha Ban key intermediate 4 - (4 - aminophenyl) - 3 - morpholone (type IV), wherein X represents halogen. The prepared 4 - (4 - aminophenyl) - 3 - morpholinon purity is good, the reaction yield is high, can be as high as 87% of the left and right, and the preparation process avoids the use of expensive metal palladium on nitro reduction, the operation is simple, and is suitable for industrial production. (by machine translation)
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Paragraph 0061-0063
(2017/08/24)
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- Synthesis of 4 - {4 - [(5 S) - 5 - (aminomethyl) - 2 - oxo - 1, 3 - oxazolidine - 3 - yl] phenyl} morpholine - 3 - one method
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The invention provides a method of synthesizing 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholine-3-one, wherein the method includes the steps of (1) performing a one-step cyclization reaction to an intermediate N-(4-aminophenyl)-2-(2-haloethyoxyl)acetamide to prepare 4-(4-aminophenyl)-3-morpholinone; and (2) carrying out a ring-opening reaction with an epoxy compound, a substitution reaction, a cyclization reaction and like to the 4-(4-aminophenyl)-3-morpholinone to obtain the key intermediate, 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholine-3-one, of rivaroxaban. The method is high in yield, is less in pollution, is free of an expensive metal palladium for performing nitro-reduction during the process and is suitable for industrial production.
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Paragraph 0066-0068; 0071
(2018/03/13)
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- Design, synthesis and biological evaluation of novel 2,3-dihydroquinazolin- 4(1H)-one derivatives as potential fXa inhibitors
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Coagulation factor Xa (fXa) is a particularly attractive target for the development of effective and safe anticoagulants. In this study, novel 2,3-dihydroquinazolin-4(1H)-one derivatives were designed as potential fXa inhibitors based on anthranilamide structure which has been reported in our previous research. The experimental data showed that most of the designed compounds exhibited significant in?vitro potency against fXa. Among them, compound 8e displayed the strongest potency against fXa with the IC50value of 21?nM and highly selectivity versus thrombin (IC50?=?67?μM) and excellent in?vitro antithrombotic activity with its 2?×?PT value of 1.2?μM and 2?×?aPTT value of 0.6?μM. In addition, 8e also displayed excellent in?vivo antithrombotic activity in the rat arteriovenous shunt (AV-SHUNT) model. The bleeding risk evaluation showed that 8e had a similar safety profile as that of betrixaban. All results demonstrated that compound 8e could be considered as a potential fXa inhibitor for the prevention and treatment of thromboembolic diseases.
- Xing, Junhao,Yang, Lingyun,Yang, Yifei,Zhao, Leilei,Wei, Qiangqiang,Zhang, Jian,Zhou, Jinpei,Zhang, Huibin
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p. 411 - 422
(2016/10/03)
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- Pyrazolo [3, 4 - c] pyridine - 7 - ketone compound and use thereof
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Belonging to the technical field of medicine, the invention relates to a 4, 5-dihydro-1H-pyrazolo[3, 4-c]pyridine-7-one containing derivative shown as general formula I, and pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein the substituents A, R1 and R2 have meanings given in the specification. The preparation also relates to a preparation method of the general formula I compound and its pharmaceutically acceptable salt or prodrug, medicinal compositions containing the compound and application of the compound as an Xa factor inhibitor, especially application in preparation of drugs for treatment and/or prevention of thromboembolic diseases. (formula I).
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Paragraph 0197; 0238; 0251; 0252
(2017/09/01)
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- A 4 - (4-amino-phenyl) - 3-morpholinon process and intermediates for the preparation of
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The invention belongs to the technical field of preparing 4-(4-amino phenyl)-3-morpholone, especially relates to a preparation method of 4-(4-amino phenyl)-3-morpholone and intermediate of the 4-(4-amino phenyl)-3-morpholone. The method comprises the following steps: amide intermediate cyclization, nitration, and reduction. The raw material aniline is a low-cost chemical, and the acylation raw material is easy to synthetize and low in cost. Compared with documents in which acylation is directly carried out after nitration, in the method disclosed by the invention, nitration is carried out after acylation, so that the method disclosed by the invention has the advantages no substituted group protection, high selectivity, less steps, high yield and the like. The preparation process does not need harsh reaction conditions such as high pressure, high temperature and deep cooling and also does not need an expensive palladium-carbon catalyst, and meets the requirements of industrial production.
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Paragraph 0047; 0048
(2017/04/08)
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- PROCESS FOR THE PREPARATION OF RIVAROXABAN
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The present invention relates to an environmentally friendly process for preparing rivaroxaban. The present invention provides a process for preparing rivaroxaban of formula I, the process comprising: reacting a compound of formula VI with a base in the presence of a solvent to form a compound of formula VII; and condensing the compound of formula VII with a compound of formula VIII or a compound of formula IX in the presence of a solvent to prepare rivaroxaban of formula I, wherein the solvent used in both steps comprises water.
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Page/Page column 28
(2016/03/22)
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- 4 - (nitro-phenyl) - 3-preparation of morpholinones the advantage cuts down Sha Ban method and using the same method of preparation
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The invention relates to the technical field of preparation of rivaroxaban and an intermediate thereof and particularly relates to a preparation method of 4-(nitrobenzophenone)-3-morpholone which is prepared from halogenated nitrobenzene, ethanolamine and chloroacetyl chloride through a one-pot method. The method for preparing rivaroxaban comprises the steps of reducing 4-(nitrobenzophenone)-3-morpholone into 4-(aminophenyl)-3-morpholone; enabling 4-(aminophenyl)-3-morpholone to react with R-epichlorohydrin to obtain a product; enabling the product to react with N, N-carbonyldiimidazole to obtain a product; enabling the product to react with tert-butyl iminodicarboxylate; preparing hydrochloride; enabling hydrochloride to react with 5-penphene-2-carbonyl chloride. The preparation method of 4-(nitrobenzophenone)-3-morpholone is capable of realizing one-pot production and free of purifying intermediate products in the process, so that the operation process is simplified, the time is saved, and the labor cost is reduced; the preparation method of 4-(nitrobenzophenone)-3-morpholone is low in raw material price, high in obtained product yield and easy to realize large-scale industrial production; in addition, the method for preparing rivaroxaban is cheap, nontoxic and harmless in raw material, simple in process and high in product yield.
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- A process for the preparation of intermediates the advantage cuts down Sha Ban
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The invention discloses a synthetic method of rivaroxabanintermediate4-(4-nitrosobenzene)-3-morpholine. The method comprises steps as follows: (1), halogenated benzene (I) and ethanolamine react under the condition of a catalyst and alkali to generate N-ethoxylaniline (II), N-ethoxylaniline (II) and nitrous acid or nitrite react to generate 4-nitroso-N-ethoxylaniline (III), and 4-nitroso-N-ethoxylaniline (III) and chloroacetyl chloride react to generate 4-(4-nitrosobenzene)-3-morpholine (IV). According to the synthetic method of 4-(4-nitrosobenzene)-3-morpholine, required raw materials and reagents are cheap and are easy to obtain, the yield is high, and the cost is low; the reaction condition is mild; fewer three wastes are produced; and the product quality is reliable and stable, and the whole process is very suitable for industrial production.
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- Identification of anthranilamide derivatives as potential factor Xa inhibitors: Drug design, synthesis and biological evaluation
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The coagulation enzyme factor Xa (fXa) plays a crucial role in the blood coagulation cascade. In this study, three-dimensional fragment based drug design (FBDD) combined with structure-based pharmacophore (SBP) model and structural consensus docking were employed to identify novel fXa inhibitors. After a multi-stage virtual screening (VS) workflow, two hit compounds 3780 and 319 having persistent high performance were identified. Then, these two hit compounds and several analogs were synthesized and screened for in-vitro inhibition of fXa. The experimental data showed that most of the designed compounds displayed significant in vitro potency against fXa. Among them, compound 9b displayed the greatest in vitro potency against fXa with the IC50 value of 23 nM and excellent selectivity versus thrombin (IC50 Combining double low line 40 μM). Moreover, the prolongation of the prothrombin time (PT) was measured for compound 9b to evaluate its in vitro anticoagulant activity. As a result, compound 9b exhibited pronounced anticoagulant activity with the 2 × PT value of 8.7 μM.
- Xing, Junhao,Yang, Lingyun,Li, Hui,Li, Qing,Zhao, Leilei,Wang, Xinning,Zhang, Yuan,Zhou, Muxing,Zhou, Jinpei,Zhang, Huibin
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supporting information
p. 388 - 399
(2015/04/14)
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- NOVEL METHOD OF PREPARING 4-(4-AMINOPHENYL)-3-MORPHOLINONE
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The present invention provides a method of preparing 4-(4-aminophenyl)-3-morpholinone, including the step of reducing 4-(4-nitrophenyl)-3-morpholinone by reacting sodium hydrosulfite (Na2S2O4) with 4-(4-nitrophenyl)-3-morpholinone. This method is safe and economical because high-temperature and high-pressure hydrogen gas is not used, can easily produce 4-(4-aminophenyl)-3-morpholinone in large amounts because an expensive hydrogenation catalyst is not used, and is environmentally friendly because 4-(4-aminophenyl)-3-morpholinone can be crystallized in water after the reaction.
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Paragraph 79; 80; 81
(2014/11/13)
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- PROCESSES AND INTERMEDIATES FOR PREPARING RIVAROXABAN
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The invention discloses processes for the preparation of rivaroxaban and its pharmaceutically acceptable salts, solvates, and hydrates thereof. The invention also relates to novel intermediates for the preparation of rivaroxaban.
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Paragraph 0190; 0191
(2015/01/07)
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- PROCESSES AND INTERMEDIATES FOR PREPARING RIVAROXABAN
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The invention discloses processes for the preparation of rivaroxaban and its pharmaceutically acceptable salts, solvates, and hydrates thereof. The invention also relates to novel intermediates for the preparation of rivaroxaban.
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Page/Page column 36-37
(2013/07/19)
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- Potent direct inhibitors of factor Xa based on the tetrahydroisoquinoline scaffold
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Direct inhibition of coagulation factor Xa (FXa) carries significant promise for developing effective and safe anticoagulants. Although a large number of FXa inhibitors have been studied, each can be classified as either possessing a highly flexible or a rigid core scaffold. We reasoned that an intermediate level of flexibility will provide high selectivity for FXa considering that its active site is less constrained in comparison to thrombin and more constrained as compared to trypsin. We studied several core scaffolds including 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid for direct FXa inhibition. Using a genetic algorithm-based docking and scoring approach, a promising candidate 23 was identified, synthesized, and found to inhibit FXa with a Ki of 28 μM. Optimization of derivative 23 resulted in the design of a potent dicarboxamide 47, which displayed a Ki of 135 nM. Dicarboxamide 47 displayed at least 1852-fold selectivity for FXa inhibition over other coagulation enzymes and doubled PT and aPTT of human plasma at 17.1 μM and 20.2 μM, respectively, which are comparable to those of clinically relevant agents. Dicarboxamide 47 is expected to serve as an excellent lead for further anticoagulant discovery.
- Al-Horani, Rami A.,Mehta, Akul Y.,Desai, Umesh R.
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supporting information; experimental part
p. 771 - 783
(2012/09/08)
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- PROCESS FOR THE PREPARATION OF RIVAROXABAN AND INTERMEDIATES THEREOF
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A process for the preparation of rivaroxaban, or a pharmaceutically acceptable salt thereof, or a solvate thereof, including a hydrate, comprising submitting an amine compound of formula (III) wherein R1 is a (C4-C10)-alkyl radical which is attached to the N atom by a tertiary C atom, first to an acylation reaction and then to a dealkylation reaction.
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Page/Page column 15; 16
(2011/07/30)
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- PROCESSES FOR CRYSTALLIZATION OF RIVAROXABAN
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The invention relates to rivaroxaban, more particularly to a process for preparation of rivaroxaban or a pharmaceutically acceptable salt or solvate thereof and its crystallization in order to obtain product having desired quality properties.
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Page/Page column 31
(2011/02/24)
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- An approach to the anticoagulant agent rivaroxaban via an isocyanate-oxirane cycloaddition promoted by MgI2.etherate
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A convergent and efficient synthesis of anticoagulant rivaroxaban was developed using the cycloaddition of commercially available (R)-epichlorohydrin with 4-(morpholin-3-one)phenyl isocyanate catalysed by MgI2 etherate as the key step, in 22% overall yield.
- Li, Chao,Liu, Yingshuai,Zhang, Yongjun,Zhang, Xingxian
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scheme or table
p. 400 - 401
(2011/10/08)
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- 4,6-DIAMINONICOTINAMIDE COMPOUND
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[Problem] The present invention provides a 4,6-diaminonicotinamide compound which is useful as an active ingredient of a pharmaceutical composition, in particular, a pharmaceutical composition for treating diseases caused by undesirable and/or abnormal cytokine signal transduction. [Means for Solution] The present inventors have extensively studied compounds having a JAK3 inhibitory action, and as a result, they have found that a 4,6-diaminonicotinamide compound which is the compound of the present invention has an excellent JAK3 inhibitory action and is useful as an agent for preventing or treating diseases caused by undesirable and/or abnormal cytokine signal transduction, thereby completing the present invention.
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Page/Page column 42
(2011/09/20)
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- COMBINATION THERAPY OF SUBSTITUTED OXAZOLIDINONES
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The present invention relates to combinations of A) oxazolidinones of the formula (I) with B) acetylsalicylic acid (aspirin) and C) an ADP receptor antagonist, in particular P2Y12 purinoreceptor blocker, to a process for producing these combinations and to the use thereof as medicaments, in particular for the prophylaxis and/or treatment of thromboembolic disorders.
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- MICROANGIOPATHY TREATMENT AND PREVENTION
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The present invention relates to the use of selective factor Xa inhibitors, in particular of oxazolidinones of the formula (I) for the treatment and/or prophylaxis of microangiopathies and also their use for the production of medicaments for the treatment and/or prophylaxis of microangiopathies.
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- Combination Therapy Comprising Substituted Oxazolidinones for the Prevention and Treatment of Cerebral Circulatory Disorders
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The present invention relates to combinations of A) oxazolidinones of the formula (I), with B) antiarrhythmics, processes for the production of these combinations, their use for the prophylaxis and/or treatment of diseases, and their use for the manufacture of medicaments for the prophylaxis and/or treatment of diseases, especially of thromboembolic disorders and/or complications.
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- Practical and efficient processes for the preparation of 4-(4-aminophenyl)morpholin-3-ones on a larger scale: Precursor of factor Xa inhibitors
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Factor Xa inhibitors are interesting targets for the development of antithrombotic agents. Our personal efforts in the discovery of small molecule inhibitors led to the compounds EMD 495235 and EMD 503982, which entered preclinical and clinical studies, respectively. Therefore, kilograms of both drugs in particular 4-(4-aminophenyl)morpholin-3-one moieties have to be provided. The scale-up results of these special P-4 ligands will be described herein.
- Mederski, Werner W.K.R.,Wendel, Peter Ludwig,Woissyk, Markus
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p. 437 - 445
(2008/09/17)
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- Method for the production of 4-(4-aminophenyl)-3-morpholinone
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The present invention relates to a process for preparing 4-(4-aminophenyl)-3-morpholinone by reacting 4-(4-nitrophenyl)-3-morpholinone with hydrogen in the presence of a hydrogenation catalyst, characterized in that the reaction is effected in an aliphatic alcohol.
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- PROLINE DERIVATIVES
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The invention relates to novel compounds of formula (I), wherein X, Y, R1, R2, R3, R4 and n have the meaning cited in claim 1, are inhibitors of the coagulation factor Xa and can be used for the prophylaxis and/or therapy of thromboembolic diseases and for the treatment of tumours.
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Page/Page column 41
(2008/06/13)
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- PYRAZINE DICARBOXAMIDES AND THE USE THEREOF
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The invention relates to novel pyrazine dicarboxamides, methods for the use thereof, their use for treating and/or preventing diseases as well as to their use for producing medicaments for treating and/or preventing diseases, particularly thromboembolic disorders.
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Page/Page column 26
(2010/11/08)
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- TETRAHYDROISOQUINOLINES AS FACTOR XA INHIBITORS
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The present invention is directed to compounds represented by Formula I and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof which are inhibitors of Factor Xa. The present invention is also directed to and intermediates used in making such compounds, pharmaceutical compositions containing such compounds, methods to prevent or treat a number of conditions characterized by undesired thrombosis and methods of inhibiting the coagulation of a blood sample.
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Page/Page column 44
(2008/06/13)
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- UREAS AS FACTOR XA INHIBITORS
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The present invention is directed to compounds represented by Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof which are inhibitors of Factor Xa. The present invention is also directed to and intermediates used in making such compounds, pharmaceutical compositions containing such compounds, methods to prevent or treat a number of conditions characterized by undesired thrombosis and methods of inhibiting the coagulation of a blood sample.
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Page/Page column 99
(2010/11/08)
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- THIOUREAS AS FACTOR Xa INHIBITORS
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The present invention is directed to compounds represented by Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof which are inhibitors of Factor Xa. The present invention is also directed to and intermediates used in making such compounds, pharmaceutical compositions containing such compounds, methods to prevent or treat a number of conditions characterized by undesired thrombosis and methods of inhibiting the coagulation of a blood sample.
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Page/Page column 43
(2010/11/08)
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- METHOD FOR THE PRODUCTION OF 4-(4-AMINOPHENYL)-3-MORPHOLINON
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The invention relates to a method for the production of 4-(4-aminophenyl)-3-morpholinon by reacting 4-(4-nitrophenyl)-3-morpholinon with hydrogen in the presence of a hydrogenation catalyst. The invention is characterised in that the reaction is carried out in an aliphatic alcohol.
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Page/Page column 7
(2008/06/13)
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- Beta-aminoacid-derivatives as factor Xa inhibitors
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The present invention relates to compounds of the formula I, in which R0 ; R1 ; R2 ; R3 ; R4; R5, R6, Q; V, G and M have the meanings indicated in the claims. The compounds of the formula I are valuable pharmacologically active compounds. They exhibit a strong antithrombotic effect and are suitable, for example, for the therapy and prophylaxis of cardiovascular disorders like thromboembolic diseases or restenoses. They are reversible inhibitors of the blood clotting enzymes factor Xa (FXa) and/or factor VIIa (FVIIa), and can in general be applied in conditions in which an undesired activity of factor Xa and/or factor VIIa is present or for the cure or prevention of which an inhibition of factor Xa and/or factor VIIa is intended. The invention furthermore relates to processes for the preparation of compounds of the formula I, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.
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- Chlorothiophenecarboxamides as P1 surrogates of inhibitors of blood coagulation factor Xa
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Neutral chlorothiophenecarboxamides bearing an amino acid and a substituted aniline were synthesized and investigated for their factor Xa inhibitory activity in vitro. From selected 2-methylphenyl morpholinones the solution properties were determined. The most soluble and active compounds were then investigated in different animal species to compare the pharmacokinetic parameters. This led to a potent, water soluble and orally bioavailable candidate for further development: EMD 495235.
- Mederski, Werner W.K.R.,Cezanne, Bertram,Amsterdam, Christoph Van,Bühring, Karl-Ulrich,Dorsch, Dieter,Gleitz, Johannes,M?rz, Joachim,Tsaklakidis, Christos
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p. 5817 - 5822
(2007/10/03)
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- Indazole-derivatives as factor Xa inhibitors
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The present invention relates to compounds of the formulae I and Ib wherein R0 ; R1 ; R2 ;Q; V, G and M have the meanings indicated in the claims. The compounds of the formula I are valuable pharmacologically active compounds. They exhibit a strong antithrombotic effect and are suitable, for example, for the therapy and prophylaxis of cardiovascular disorders like thromboembolic diseases or restenoses. They are reversible inhibitors of the blood clotting enzymes factor Xa (FXa) and/or factor VIIa (FVIIa), and can in general be applied in conditions in which an undesired activity of factor Xa and/or factor VIIa is present or for the cure or prevention of which an inhibition of factor Xa and/or factor VIIa is intended. The invention furthermore relates to processes for the preparation of compounds of the formulae I and Ib, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.
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- CARBONYL COMPOUNDS
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The invention relates to the novel compounds of formula (I), wherein D, E, G, W, X, Y, T, R and R are defined as in claim 1. The inventive compounds inhibit coagulation factor Xa and can be used in the prophylaxis and/or therapy of thrombo-embolic diseases and for treating tumors.
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Page/Page column 112
(2008/06/13)
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- Benzimidazole-derivatives as factor xa inhibitors
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Benzimidazole-derivatives as factor Xa inhibitors The present invention relates to compounds of the formula I, wherein R0 ; R1 ; R2 ; R3 ; R4; Q; V, G and M have the meanings indicated in the claims. The compounds of the formula I are valuable pharmacologically active compounds. They exhibit a strong antithrombotic effect and are suitable, for example, for the therapy and prophylaxis of cardiovascular disorders like thromboembolic diseases or restenoses. They are reversible inhibitors of the blood clotting enzymes factor Xa (FXa) and/or factor VIIa (FVIIa), and can in general be applied in conditions in which an undesired activity of factor Xa and/or factor VIIa is present or for the cure or prevention of which an inhibition of factor Xa and/or factor VIIa is intended. The invention furthermore relates to processes for the preparation of compounds of the formula I, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.
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