- Synthesis of main impurity of vildagliptin
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A four-step synthesis of the main impurity of vildagliptin has been easily accomplished with high-yielding starting from L-proline. This compound can be used as a reference marker in an analytical method to determine the chemical purity of the vildagliptin.
- Tao, Zhu,Deng, Yu,Chen, Yingjie,Wang, Anmin,Hu, Xiangnan
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Read Online
- Design, synthesis, biological screening, and molecular docking studies of piperazine-derived constrained inhibitors of DPP-IV for the treatment of type 2 diabetes
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Novel piperazine-derived conformationally constrained compounds were designed, synthesized, and evaluated for in vitro Dipeptidyl peptidase-IV (DPP-IV) inhibitory activities. From a library of compounds synthesized, 1-(2-(4-(7-Chloro-4-quinolyl)piperazin-1-yl)acetyl)pyrrolidine (2g) was identified as a potential DPP-IV inhibitor exhibiting better inhibitory activity than P32/98, reference inhibitor. The in vivo studies carried out in STZ and db/db mice models indicated that the compound 2g showed moderate antihyperglycemic activity as compared to the marketed drug Sitagliptin. A two-week repeated dose study in db/db mice revealed that compound 2g significantly declined blood glucose levels with no evidence of hypoglycemia risk. Furthermore, it showed improvement in insulin resistance reversal and antidyslipidemic properties. Molecular docking studies established good binding affinity of compound 2g at the DPP-IV active site and are in favor of the observed biological data. These data collectively suggest that compound 2g is a good lead molecule for further optimization studies.
- Kushwaha, Ram N.,Srivastava, Rohit,Mishra, Akansha,Rawat, Arun K.,Srivastava, Arvind K.,Haq, Wahajul,Katti, Seturam B.
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Read Online
- Bis-morpholinophosphorylchloride, a novel reagent for the conversion of primary amides into nitriles
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Bis-morpholinophosphorylchloride (Bmpc), in the presence of a base, is an efficient dehydrating agent for both aromatic and aliphatic primary amides, and gives corresponding nitriles under mild conditions in god yields and purity. During the reaction the enantiomeric integrity remains intact.
- Rao, P. Purnachandra,Nowshuddin, Shaik,Jha, Anjali,Rao, B. Leela Maheswara,Divi, Murali K.,Rao
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supporting information
(2021/01/21)
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- Production method of vildagliptin
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and Alkali metal bromides are in vildagliptin or a salt thereof. Use of a crystal form, a deuterated substance, a tritium substitute, and a solvate as a catalyst. The vildagliptin product produced by the method is high in purity and low in impurity content, particularly the product quality control of the vildagliptin bulk drug and/or the pharmaceutical preparation is facilitated. Moreover, the reaction condition is mild, operation and control are convenient, the yield is high, the energy consumption is low, the cost is low, and the method is suitable for industrial production and popularization and application.
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Paragraph 0079-0081; 0085-0087; 0096-0103
(2021/10/27)
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- Preparation method of high chiral purity (S)-1-(2-chloracetyl) pyrrolidine-2-formonitrile
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The invention discloses a preparation method of high chiral purity (S)-1-(2-chloracetyl) pyrrolidine-2-formonitrile, the preparation method comprises: S1, in the presence of a solvent and an acid-binding agent, carrying out a coupling reaction on L-proline and chloracetyl chloride to obtain an intermediate I; s2, in the presence of a solvent and sodium iodide, carrying out cyclization reaction on the intermediate I in an alkaline environment to obtain an intermediate II; s3, in the presence of a solvent and an ammonolysis agent, carrying out ammonolysis ring-opening reaction on the intermediate II to obtain an intermediate III; and S4, in the presence of a solvent and phosphorus oxychloride, carrying out chlorination and dehydration reaction on the intermediate III to obtain (S)-1-(2-chloracetyl) pyrrolidine-2-formonitrile. The method has the advantages of high chiral purity, simple steps, easily available and cheap raw materials, convenient post-treatment and high yield, and is suitable for industrial production.
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Paragraph 0037; 0042-0049; 0054-0056; 0061-0063; 0068; ...
(2021/08/19)
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- PYRROLIDINE AND PIPERIDINE COMPOUNDS
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The present technology provides pyrrolidine and piperidine compounds or pharmaceutically acceptable salts thereof, preparation processes thereof, pharmaceutical compositions comprising the same, and uses thereof. In particular, said compounds may be usefully applied in the treatment and prevention of FAP-mediated diseases.
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Paragraph 0250-0251
(2021/05/15)
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- PROCESS FOR THE PREPARATION OF VILDAGLIPTIN
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The present invention relates to process for the preparation of Vildagliptin. The present invention involves an ecologically friendly process by avoiding the dehydrating agent and use of reagents that are less expensive, easier to handle and its cost effective industrial applicable process.
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Page/Page column 7; 8
(2021/06/22)
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- A facile method to synthesize vildagliptin
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An efficient and high-yielding synthetic method for the preparation of vildagliptin via four steps is reported. The process starts from L-proline and involves a successful reaction with chloroacetyl chloride in tetrahydrofuran to afford (S)-1-(2-chloroacetyl)pyrrolidine-2-carboxylic acid, followed by a reaction with acetonitrile in the presence of sulfuric acid to give (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile. This is then reacted with 3-aminoadamantanol to give vildagliptin. 3-Aminoadamantanol is prepared from 1-aminoadamantane hydrochloride via oxidation with sulfuric acid/nitric acid and boric acid as the catalyst followed by ethanol extraction. The overall yield is 95%.
- Zhang, Li,Jiang, Lan,Guan, Xiaoshu,Cai, Linhong,Wang, Jingyu,Xiang, Peng,Pan, Junyi,Hu, Xiangnan
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p. 305 - 309
(2020/12/01)
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- Synthesis method of vildagliptin intermediate
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The invention discloses a synthesis method of a vildagliptin intermediate, and belongs to the technical field of organic synthesis. The method comprises the steps: reacting L-prolinamide serving as aninitial raw material with di-tert-butyl dicarbonate in the presence of a quaternary ammonium salt catalyst and potassium carbonate to obtain N-Boc-L-prolinamide, dehydrating and cyaniding the N-Boc-L-prolinamide and cyanuric chloride in a pure DMF system, adding acid carbonate and anhydrous sulfate, removing a solvent thoroughly, washing, adding p-toluenesulfonic acid, deprotecting, salifying, crystallizing, and obtaining (S)-pyrrolidine-2-carbonitrile p-toluenesulfonate; and finally, carrying out chloroacetylation reaction on the (S)-pyrrolidine-2-carbonitrile p-toluenesulfonate, and crystallizing by using a weak polar solvent to obtain (s)-1-(2-chloracetyl)pyrrolidine-2-carbonitrile. According to the method disclosed by the invention, the generation of impurities is reduced, the productyield loss caused by impurity treatment in the subsequent crystallization process is avoided, and the yield is as high as 80.6%; the purity reaches up to 99.7%; and the whole process is mild in reaction condition, stable in process material and suitable for industrial amplification.
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Paragraph 0031-0042
(2020/12/15)
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- Design and synthesis of tetrahydropyridopyrimidine derivatives as dual GPR119 and DPP-4 modulators
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Based on the approach of merged pharmacophores of GPR119 agonists and DPP-4 inhibitors, a series of tetrahydropyridopyrimidine compounds were designed as dual GPR119 and DPP-4 modulators with hypoglycemic activity. Seven fragments extracted from DPP-4 inhibitors were hybridized with the scaffold of tetrahydropyridopyrimidine. Among them, compound 51 displayed most potent GPR119 agonistic activity (EC50 = 8.7 nM) and good inhibition rate of 74.5% against DPP-4 at 10 μM. Furthermore, the blood glucose AUC0-2h of 51 was reduced to 19.5% in the oral glucose tolerance test (oGTT) at the dose of 30 mg/kg in C57BL/6N mice, which was more potent than that of vildagliptin (16.4%) at the same dose. The docking study of compound 51 with DPP-4 indicated GPR119 agonists could inhibit DPP-4 to serve as dual GPR119 and DPP-4 modulators.
- Fang, Yuanying,Zhang, Shaokun,Wu, Wenting,Liu, Yanhua,Yang, Juan,Li, Yuyuan,Li, Min,Dong, Huanhuan,Jin, Yi,Liu, Ronghua,Yang, Zunhua
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- Synthesis method of vildagliptin
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The invention discloses a synthesis method of vildagliptin. The method comprises the following steps: performing esterification reaction on L-glutamic acid and ethanol to obtain L-glutamic acid-gamma-ethyl ester; reducing the L-glutamic acid-gamma-ethyl ester under the action of potassium borohydride to obtain L-proline; mixing L-proline with ethyl chloroformate for reaction to obtain acid anhydride; further reacting the acid anhydride with amine to obtain amide; dehydrating the amide under the action of phosphorus pentoxide to obtain an intermediate 1; performing substitution reaction on theintermediate 1 and chloroacetyl chloride to obtain an intermediate 2; and further reacting the intermediate 2 with 3-amino-1-adamantanol to obtain vildagliptin. The method has the advantages that fewimpurities are generated in the vildagliptin preparation process, the yield of the prepared vildagliptin is high, and compared with the prior art, the process is simpler, and the vildagliptin preparation cost is greatly reduced.
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- Synthetic method of vildagliptin
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The invention discloses a synthetic method of vildagliptin. Glycolic acid and (S)-pyrrolidine-2-carbonitrile are used as raw materials; a condensation reaction is carried out under the action of a condensing agent, so that (S)-1-(2-hydroxyacetyl) pyrrolidine-2-formonitrile is prepared; and then the (S)-1-(2-hydroxyacetyl) pyrrolidine-2-carbonitrile and thionyl chloride are subjected to a substitution reaction, wherein only reduced pressure distillation is needed to remove small molecular compounds to obtain a relatively pure carbon tetrachloride solution containing (S)-1-(2-chloracetyl) pyrrolidine-2-carbonitrile; finally, 3-amino-1-adamantanol hydrate and cesium carbonate are added into the solution, and a substitution reaction is carried out just in 4-5 h, finally, the purity of a crudeproduct reaches up to 99.85% after ethyl alcohol recrystallization. According to the present invention, a high-efficiency synthesis route is provided for synthesis of high-purity vildagliptin, and good practicability is achieved.
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- Design, synthesis and exploration of in silico α-amylase and α-glucosidase binding studies of pyrrolidine-appended quinoline-constrained compounds
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A series of new pyrrolidine-appended phenoxy-substituted quinoline derivatives were synthesized using 2-chloro-3-formyl quinoline. Initially, the second position of 2-chloro-3-formyl quinoline was successfully converted into various substituted phenoxy-substituted quinolines using various substituted phenols; then, its aldehyde function was reduced to its corresponding alcohols which is in turn converted into its corresponding pyrrolidine-appended phenoxy-substituted quinolines by treating it with 1-(2-chloroacetyl)pyrrolidine-2-carbonitrile. All these newly synthesized compounds were subjected to the in silico studies with the α-amylase and α-glucosidase enzymes to predict the binding affinity.
- Hemanth Kumar,Jyothish Kumar,Pavithrra,Rajasekaran,Vijayakumar,Karan, Rohith,Sarveswari
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p. 1869 - 1880
(2020/01/21)
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- Acceptor-Controlled Transfer Dehydration of Amides to Nitriles
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Palladium-catalyzed dehydration of primary amides to nitriles efficiently proceeds under mild, aqueous conditions via the use of dichloroacetonitrile as a water acceptor. A key to the design of this transfer dehydration catalysis is the identification of an efficient water acceptor, dichloroacetonitrile, that preferentially reacts with amides over other polar functional groups with the aid of the Pd catalyst and makes the desired scheme exergonic, thereby driving the dehydration.
- Okabe, Hiroyuki,Naraoka, Asuka,Isogawa, Takahiro,Oishi, Shunsuke,Naka, Hiroshi
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supporting information
p. 4767 - 4770
(2019/06/17)
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- Preparation method of (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile
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The invention relates to the technical field of medicines, and especially relates to a preparation method of (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile. The preparation method least comprises the following steps: L-prolinamide, an acid-binding agent and chloroacetyl chloride are respectively dissolved in a solvent to prepare a material A, a material B and a material C, the material A, the material B and the material C are respectively introduced into a micro-channel reactor and are reacted, a first reaction solution is collected, and undergoes liquid separation, and the obtained upper organic phase is collected; and the upper organic phase and thionyl chloride are respectively introduced into the micro-channel reactor, and are reacted, and a second reaction solution is collected, andis post-treated to obtain the (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile. The micro-channel reactor is used as a reaction container in the invention, so rapid proceeding of the reactions of ispromoted, side reactions are inhibited, the reaction efficiency is improved, and the production cost is greatly reduced.
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Paragraph 0050; 0053-0061; 0064-0071; 0074-0080
(2019/12/25)
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- Preparation method for vildagliptin
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The invention provides a preparation method for vildagliptin. Through the presence of imidazo thiazole as a chiral ligand and a palladium catalyst, a vildagliptin product with high yield and high purity can be obtained by taking diethyl fumarate and amino protected (S)-3-amino-cyano-ethyl propanoate as initial raw materials through steps such as cyclization, deprotection and coupling; and the preparation method is short in reaction route, high in yield and less in by-product, so that production costs can be reduced, and industrial production can be realized.
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- Vildagliptin impurity compound and preparation method thereof, detection method and application
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The invention relates to a Vildagliptin impurity compound and a preparation method thereof, a detection method and application. The Vildagliptin impurity compound has a structure as shown in the formula (I), wherein R1 is polyhalogenated C1-C4 lower alkyl or CH2R3, and R3 is five-membered/six-membered heterocyclic radical containing an N atom. The heterocyclic radical can be optionally replaced with CN or CONH2. The compound, as a reference substance or standard substance of related substances, can be used in quality control of a Vildagliptin preparation.
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Paragraph 0091-0092; 0094
(2018/11/04)
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- A process for preparing (S)-1 - (2 - chloracetyl) pyrrolidine -2 - carbonitrile method
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The invention discloses a preparation method of (S)-1-(2-chloracetyl)pyrrolidine-2-carbonitrile, which is applied to the field of chemical synthesis. The preparation method comprises the following steps of (1) dropwise adding chloracetyl chloride into a mixed solution composed of L-prolinamide, organic alkali and dichloromethane, and reacting after finishing the dropwise adding operation to obtain a reaction solution I containing 1-chloroacetylpyrrolidine-2-carboxamide; and (2) enabling the reaction solution I to react with phosphorus oxychloride serving as a dehydrating agent to obtain (S)-1-(2-chloracetyl)pyrrolidine-2-carbonitrile. In the step (1), the temperature of the mixed solution I composed of L-prolinamide, organic alkali and dichloromethane ranges from 10 DEG C below zero to 60 DEG C, the temperature of reaction carried out after the dropwise adding operation is finished ranges from 50 DEG C below zero to 10 DEG C below zero, the reaction carried out after the dropwise adding operation is finished lasts for 0.5-4h, and the molar ratio of L-prolinamide to chloracetyl chloride is 1:(1.05-1.31). The preparation method is short in reaction step and simple in operation and has the advantages that the raw material cost is low, the yield is high, the product quality is good, little environment pollution can be caused, green resources can be favorably protected, the required equipment is simple, and the dosage of the used organic solvent is low.
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Paragraph 0015-0030
(2018/10/19)
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- Synthesis and evaluation of camphor and cytisine-based cyanopyrrolidines as DPP-IV inhibitors for the treatment of type 2 diabetes mellitus
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In this study, bornyl- and cytisine-based cyanopyrrolidines as potent dipeptidyl peptidase-IV (DPP-IV) inhibitors were synthesised. The in vitro inhibiting activities of bornyl- and cytisine derivatives towards DPP-IV were evaluated. Bornyl-based cyanopyrrolidines were shown to have moderate inhibitory activity with regard to DPP-IV (1.27–15.78 μM). A docking study was performed to elucidate the structure-activity relationship of the obtained compounds. The in vivo hypoglycemic activities of the same compounds were evaluated with the oral glucose tolerance test (OGTT) in mice. Bornyl-based cyanopyrrolidines were shown to have good hypoglycemic activity.
- Kuranov,Tsypysheva,Khvostov,Zainullina, Liana F.,Borisevich,Vakhitova, Yu.V.,Luzina,Salakhutdinov
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p. 4402 - 4409
(2018/07/30)
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- Preparation method of intermediate of medicine vildagliptin for treating type 2 diabetes
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The invention discloses a preparation method of an intermediate of a medicine vildagliptin for treating type 2 diabetes. The preparation method comprises the steps that 1, 2-carboxyl pyrrolidine and N-phthalimide are subjected to condensation to obtain a compound shown as the formula I which is shown in the description; 2, in the presence of tris(2-phenylpyridine)iridium, silver bromide and a compound shown as the formula II, the compound shown as the formula I and trimethylsilyl cyanide are subjected to heating reaction to obtain (S)-2-cyanopyrrolidine; 3, the (S)-2-cyanopyrrolidine is reacted with chloroacetyl chloride to obtain the vildagliptin intermediate (S)-1-(2-chloracetyl)-2-cyanopyrrolidine. According to the preparation method, the adopted raw materials are wider in resource, thereaction is high in selectivity and yield, the chiral target compound is obtained, the conditions are mild, and the method is easy to implement.
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- A high efficient synthesis method of vergeliptin
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The present invention relates to an efficient synthesis method of vildagliptin. According to the method, L-prolinamide is adopted as a raw material, N-chloro acetylation and amide dehydration are performed to generate an intermediate (S)-1-(2-chloroacetyl chloride)pyrrolidine-2-carbonitrile, and the (S)-1-(2-chloroacetyl chloride)pyrrolidine-2-carbonitrile and 3-amino adamantanol are subjected to condensation in acetonitrile in the presence of an organic base to obtain the target product vildagliptin. According to the present invention, the synthesis method operation only requires the separation of the one key intermediate, and the method has characteristics of simple and feasible operation, high efficiency, environmental protection, and easy industrial production achieving.
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Paragraph 0038; 0039; 0041; 0044-0045; 0047; 0050-0051; 0053
(2017/08/25)
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- Method for preparing 1-(2-chloracetyl)-2-(S)-cyano pyrrolidine through multiphase compound non-continuous production process
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The invention belongs to the technical field of medicines, and specifically relates to a method for preparing a vildagliptin intermediate 1-(2-chloracetyl)-2-(S)-cyano pyrrolidine (II) through a multiphase compound non-continuous production process. The method comprises the following steps: taking L-prolinamide as an initial raw material to perform acylation reaction with chloroacetyl chloride, then adding a dehydrating agents in batches, and performing the dehydrating treatment to obtain 1-(2-chloracetyl)-2-(S)-cyano pyrrolidine. The method for preparing the vildagliptin intermediate 1-(2-chloracetyl)-2-(S)-cyano pyrrolidine (II) through the multiphase compound non-continuous production process has the advantages of being high in yield, low in energy consumption, simple and fast in operation, and suitable for industrial large-scale production.
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Paragraph 0041; 0042; 0044
(2017/08/29)
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- 2 - substituted pyrrolidines compound, preparation method and its application in the preparation of the peculiar smell (by machine translation)
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The invention discloses a 2 - substituted pyrrolidines compound, preparation method and its application in the preparation of the peculiar smell, the tetrahydro-pyrrole derivatives of formula (I) has the structure as illustrated, using the intermediate synthesis when the peculiar smell, the preparation method of the original source of auxiliary materials are cheap and easily obtained, the process route is short, low cost, mild conditions in the reaction process of the security, without the special requirements of the device, can be suitable for industrial production. (by machine translation)
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Paragraph 0005; 0062; 0067; 0068
(2017/08/25)
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- Preparation method for Vildagliptin
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The invention relates to a preparation method for Vildagliptin. The preparation method comprises the following steps: using L-prolinamide as a raw material, performing the dehydration reaction with cyanuric chloride, and generating (S)-2-cyanopyrrolidine; performing the salt forming reaction to the (S)-2-cyanopyrrolidine and hydrogen chloride, to obtain intermediate-1; enabling the intermediate-1 to react with chloroacetic acid under the conditions of using EDCI as a condensing agent, using HOBt as a catalyst, and using DIEA as an acid-binding agent, to obtain intermediate-2; enabling the intermediate-2 to react with 3-amino-1-adamantanol, to obtain the Vildagliptin, filtering, concentrating, crystallizing, and re-filtering to obtain a Vildagliptin crude product; and preparing the Vildagliptin finished product by the acetone refining. The preparation method is capable of providing a new method, and reducing the generation of by-products in each step. The content of the disubstitution product of the Vildagliptin by-product and the 3-amino-1-adamantanol are reduced to less than 0.1%, the yield and purity of the Vildagliptin are effectively improved, the raw materials are easily obtained, the conditions are moderate, and the preparation method is suitable for the industrial large-scale production.
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Paragraph 0027; 0035; 0039; 0042; 0048; 0052
(2017/08/29)
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- Synthesis of Enantiomerically Pure N-Acyl Amino Nitriles via Catalytic Dehydration of Oximes and Application in a de Novo Synthesis of Vildagliptin
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An alternative route toward enantiomerically highly enriched N-acyl amino nitriles based on the Cu(OAc)2-catalyzed dehydration of aldoximes, which are readily available from N-acyl l- or d-α-amino aldehydes through condensation with hydroxylamine, has been developed. The desired products were obtained with high conversion and in enantiomeric excesses of 97-99% ee. Furthermore, this method has been applied in the synthesis of an N-chloroacetylated 2-cyanopyrrolidine, which represents a building block for the synthesis of Vildagliptin.
- Rommelmann, Philipp,Betke, Tobias,Gr?ger, Harald
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supporting information
p. 1521 - 1527
(2017/10/25)
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- Synthesis method of (S)-1-(2-chloracetyl)pyrrolidine-2-formonitrile
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The invention relates to a synthesis method of (S)-1-(2-chloracetyl)pyrrolidine-2-formonitrile. The method comprises the following steps: mixing (S)-N-chloracetyl-2-carbamoylpyrrolidine and chloroacetyl chloride in a reactor, carrying out dehydration reaction to obtain a target product which is (S)-1-(2-chloracetyl)pyrrolidine-2-formonitrile. The invention also relates to a method for synthesizing the target product which is (S)-1-(2-chloracetyl)pyrrolidine-2-formonitrile by taking L-prolinamide as raw material. The synthesis method has the advantages of simple operation, high efficiency, high yield, high purity and low cost, and is safe and environmentally friendly.
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Paragraph 0068-0108
(2018/01/17)
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- Direct Synthesis of Cyanopyrrolidinyl β-Amino Alcohols for the Development of Diabetes Therapeutics
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Cyanopyrrolidinyl β-amino alcohols are novel scaffolds with potential for a wide array of pharmacological properties. We have discovered that we can selectively access these scaffolds from simple and inexpensive commercially available chemicals in few synthetic steps with minimal purification. We have produced a 36-compound library of these scaffolds and tested them as dipeptidyl peptidase IV (DPP4) inhibitors. These novel inhibitors are useful in the treatment of diabetes and inflammatory disorders.
- Lizza, Joseph R.,Patel, Savan V.,Yang, Catherine F.,Moura-Letts, Gustavo
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supporting information
p. 5160 - 5168
(2016/10/26)
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- Method for preparing substituted (S)-pyrrolidine-2-formonitrile and vildagliptin
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The invention provides a method for preparing (S)-1-(2-halogenated acetyl)pyrrolidine-2-formonitrile as shown in the formula (I). Optionally in the presence of a diluent, (S)-1-(2-halogenated acetyl)pyrrolidine-2-formamide and a dehydrating agent propanephosphonic acid cyclic anhydride (T3P) react with each other. The invention also provides a method for preparing vildagliptin by using S-prolinamide involving the above reaction. The method for preparing the compound as shown in the formula (I) has the following advantages: use of expensive trifluoroacetic anhydride is not required, yield is increased, and cost is reduced; use of cyanuric chloride prepared from highly toxic raw materials is not required, and the reaction is more environmentally friendly; and an improved method for preparing vildagliptin is then obtained. In the formula (I) and formula (II), X1 is halogen.
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Paragraph 0074-0076; 0080; 0083
(2018/02/04)
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- A (S) - 1 - (2-acetyl) pyrrolidine-2-carbonitrile method for the synthesis of
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The invention discloses a synthesis method of (S)-1-(2-chloracetyl) pyrrolidine-2-formonitrile. (S)-2-nitrilepyrrolidinetosylate is taken as a raw material and reacts with chloroacetyl chloride in the presence of an aprotic organic solvent and an organic alkali to synthesize the (S)-1-(2-chloracetyl) pyrrolidine-2-formonitrile, wherein the aprotic organic solvent is dichloromethane or chloroform, and the organic alkali is triethylamine or diisopropylethylamine. The synthesis method has the advantages of low cost, high yield, high purity, simple and convenient operation and time saving, and is advantageous for industrial production.
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Paragraph 0047-0048
(2017/03/14)
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- Process for preparing (S)-1-(2-chloroacetyl chloride)-2-nitrile pyrrolidine
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The invention discloses a process for preparing (S)-1-(2-chloroacetyl chloride)-2-nitrile pyrrolidine. Acetonitrile is used as a main solvent system, or solvent systems comprise acetonitrile and toluene combinations and acetonitrile and DMF (dimethyl formamide) combinations or acetonitrile and THF (tetrahydrofuran) combinations; carbonate is used as an acid binding agent; trifluoro acetic anhydride (TFAA) or phosphorus oxychloride is used as a dehydrating agent. The process includes preparing (S)-1-(2-chloroacetyl chloride)-2-nitrile pyrrolidine intermediates from L-prolinamide via two-step reaction by the aid of a one-pot method. The process has the advantages of convenience, speediness and high yield.
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Paragraph 0046; 0047-0049
(2016/12/16)
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- Preparation method of vildagliptin
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The invention discloses a preparation method of vildagliptin; a non-homogeneous system with acetonitrile as a main solvent and potassium carbonate and iodine salt as main components is used, two key fragments of (S)-1-(2-chloroacetyl chloride)-2-nitrile pyrrolidine and 3-amino-1-adamantanol are coupled to prepare vildagliptin, and the intermediate conversion rate and the yield are both superior to those of the prior art; the preparation method adopts iodine ion salt for activating chlorine in a reactant structure, and a phase transfer catalyst is selected to be added for promoting the effect of a non-homogeneous reaction.
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Paragraph 0054; 0055
(2017/02/09)
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- HEXAHYDROPENTALENO DERIVATIVES, PREPARATION METHOD AND USE IN MEDICINE THEREOF
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The invention relates to hexahydropentaleno derivatives, the preparation method and use in medicine thereof, and in particular to hexahydropentaleno derivatives or stereo-isomers or pharmaceutically acceptable salts thereof as shown in general formula (I), and to the preparation method therefor and pharmaceutical compositions comprising the derivatives, and to the use thereof as a therapeutical agent, especially as a DPP-IV inhibitor. The definition of each substituent in formula (I) is the same as the definition in the description.
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Paragraph 0157; 0166
(2015/05/06)
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- Synthesis of vildagliptin utilizing continuous flow and batch technologies
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The preparation and utilization of the Vilsmeier reagent (VR) is well-known in the literature with its usefulness and scope being frequently demonstrated in organic synthesis. However, it is an irritant and has a high thermal energy of decomposition; consequently, these factors lead to operational issues on larger scale which suggests approaches whereby the reagent is not isolated. Herein, we report the in-line formation and instantaneous consumption of VR utilizing both conventional batch and flow technologies. The approach is demonstrated by way of the synthesis of Vildagliptin, thereby mitigating potential safety and hygiene hazards.
- Pellegatti, Laurent,Sedelmeier, Jorg
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supporting information
p. 551 - 554
(2015/04/27)
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- AN IMPROVED PROCESS FOR PREPARING VILDAGLIPTIN
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The present invention relates to efficient, environment friendly and economical processes for the preparation of vildagliptin without isolating the intermediate compounds. Also provided is a process for the recovery of expensive 1-aminoadamantane-3-ol and use thereof in the preparation of vildagliptin.
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Page/Page column 21-22
(2015/12/08)
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- A facile and economical method to synthesize vildagliptin
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A mild and economical method to prepare vildagliptin had been reported with a good yield. In this paper, vildagliptin was synthesized from L-proline and 3-amino-1-adamantanol through chloride acetylation, amination, dehydration and substitution. The total yield of the target compound was 59%.
- Deng, Yu,Wang, Anmin,Tao, Zhu,Chen, Yingjie,Pan, Xinmei,Hu, Xiangnan
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p. 780 - 784
(2015/04/14)
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- IMPROVED PROCESS FOR PREPARATION OF VILDAGLIPTIN
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The present invention relates to process for the preparation of vildagliptin.
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Page/Page column 16
(2014/07/21)
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- IMPROVED PROCESS FOR PREPARATION OF VILDAGLIPTIN INTERMEDIATE
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Provided is an improved process for preparation of Vildagliptin intermediate, 1-chloro acetyl (S)-2-cyano pyrrolidine.
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- An economical and facile method to synthesize vildagliptin
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A facile and economical synthefic method to prepare vildagliption with-reported.It was started from L proline via succsessful reaction with chloried in tetrahydrofuran to-afford 1(2-chloroacetyl) pyrrolidine-2-carboxylic-acid, followed by reacting with 2-chloro-46-dimethoxy-1,3,5-triazine,N-methylmorpholine and 2,4,6-triazine,N-methlmorpholine-2,4,6-trichloro-1,3,5-triazine-to-give 1-(2-chloroacetyl)-pynolidine 2-carbonitrile which was-reacfed-with 3-aminoadmantanol to get the-forget-compound-of-vildagliption.
- Deng, Yu,Wang, Anmin,Tao, Zhu,Chen, Yingjie,Pan, Xinmei,Hu, Xiangnan
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p. 6275 - 6278
(2015/02/19)
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- A cost-effective method to prepare pure vildagliptin
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A cost-effective synthetic approach to prepare vildagliptin under gentle experimental conditions has been reported with good yield and high purity. It was initiated with L-proline via successful reaction with chloroacetyl chloride in THF (Tetrahydrofuran) to give the 1-(2-chloroacetyl)-pyrrolidine-2-carboxylic acid, which was then treated by TCT (2, 4, 6-trichloro-1, 3, 5-triazine) in DCM (dichloromethane), and converted into 1-(2-chloroacetyl)-pyrrolidine-2- carboxamide, then further converted into 1-(2-chloroacetyl)-pyrrolidine-2- carbonitrile after dehydrated by TCT in DMF (N, N- dimethylformamide), the latter product was reacted with 3-Aminoadamantanol to get vildagliptin. The total yield of vildagliptin was about 48%, the purity was about 99%.
- Peng, Jun,Feng, Yue,Tao, Zhu,Chen, Yingjie,Hu, Xiangnan
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p. 159 - 163
(2013/07/26)
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- A PROCESS FOR THE PREPARATION OF VILDAGLIPTIN AND ITS INTERMEDIATE THEREOF
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A process for preparation of vildagliptin is discussed wherein 3-amino-1- adamantanol is reacted with 1-chloroacetyl(S)-2-cyanopyrrolidine in solvent and base to obtain vildagliptin. This invention also relates to a process for preparation of 1-chloroacetyl(S)-2-cyanopyrrolidine, a vildagliptin intermediate is provided. Further, the present invention also provides a co- precipitate of amorphous form of vildagliptin along with pharmaceutically acceptable excipients.
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Page/Page column 27; 28
(2014/01/07)
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- SYNTHESIS AND USE OF VILDAGLIPTIN FOR THE PREPARATION OF PHARMACEUTICAL DOSAGE FORMS
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The present invention relates the synthesis of vildagliptin in the presence of phase transfer catalysts; as well as the use of vildagliptin or its pharmaceutically acceptable salts for the preparation of solid oral dosage forms.
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Page/Page column 42-43
(2011/02/24)
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- PROCESS FOR PREPARATION OF DPP-IV INHIBITORS
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Process for the preparation of DPP-IV inhibitors, such as 1-[[(3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine are disclosed.
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Page/Page column 21-22
(2011/09/19)
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- ORGANIC COMPOUNDS
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The present invention relates to a compound The instant invention relates to a compound of formulae (I A), (I B), (X A), (X B), (Y A) or (Y B), wherein R′ represents and R″ represents hydrogen, hydroxy, C1-C7alkoxy, C1-C8-alkanoyloxy, or R5R4N—CO—O—, where R4 and R5 independently are C1-C7alkyl or phenyl which is unsubstituted or substituted by a substitutent selected from C1-C7alkyl, C1-C7alkoxy, halogen and trifluoromethyl and where R4 additionally is hydrogen; or R4 and R5 together represent C3-C6alkylene; in free form or in form of a pharmaceutically acceptable acid addition salt. Compounds of formulae (I A), (I B), (X A), (X B), (Y A) or (Y B) inhibit DPP-IV (dipeptidyl-peptidase-IV) activity. They are therefore indicated for use as pharmaceuticals in inhibiting DPP-IV and in the treatment of conditions mediated by DPP-IV, such as non-insulin-dependent diabetes mellitus, arthritis, obesity, osteoporosis and further conditions of impaired glucose tolerance.
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Page/Page column 6
(2010/10/19)
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- DIPEPTIDYL PEPTIDASE IV INHIBITORS
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Described are novel compounds of the Formula (I), their derivatives, analogs, tautomeric forms, regioisomers, stereoisomers, polymorphs, solvates, intermediates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs thereof. These compounds are effective in lowering blood glucose, serum insulin, free fatty acids, cholesterol, triglyceride levels; treatment of obesity, inflammation, autoimmune diseases such as multiple sclerosis, rheumatoid arthritis; treatment and/or prophylaxis of type II diabetes. These compounds are more particularly dipeptidyl peptidase (DPP IV) inhibitors.
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Page/Page column 42-43
(2010/08/04)
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- PROCESS FOR PREPARING VILDAGLIPTIN
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The present invention relates to a process for preparing vildagliptin of formula (I) with high chemical and enantiomeric purity and compositions comprising vildagliptin. In addition, the present invention relates to (2S,2′S)-1,1′-[[(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)imino]bis(1-oxo-2,1-ethanediyl)]di(2-pyrrolidinecarbonitrile) of formula (II), processes for preparing, and compositions comprising a compound for formula (II). Furthermore, the invention relates to processes for determining the purity of vildagliptin using a compound of formula (II).
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Page/Page column 5
(2008/12/06)
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- DIPEPTIDYL PEPTIDASE IV INHIBITOR COMPOUNDS AND COMPOSITIONS
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The present invention relates to dipeptidyl peptidase IV (DPP-IV) inhibitors of formula (1), pharmaceutical compositions containing them, processes for their preparation, and methods for treating disorders mediated by DPP-IV inhibition, such as diabetes, especially Type II diabetes, with them, wherein Rj is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl; R2 is hydrogen or Q-β alkyl; Y is -S(O)m, -CH2-, -CHF or CF2; R3 is hydrogen, nitrile (-CN), COOH, or an isostere of a carboxylic acid.
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Page/Page column 26
(2010/11/28)
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- NEW ADAMANTANE DERIVATIVES AS DIPEPTIDYL, PEPTIDASE IV INHIBITORS, PROCESSES FOR THEIR PREPARATION, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
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The present invention relates to dipeptidyl peptidase IV (DPP-IV) inhibitors of the formula (A): wherein R1, R2, Y, and n are as defined herein, pharmaceutical compositions containing the same, processes for their preparation, and methods for treating disorders mediated by DPP-IV inhibition, such as diabetes, especially Type II diabetes, with them.
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Page/Page column 28
(2008/06/13)
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- NOVEL DIPEPTIDYL PEPTIDASE IV INHIBITORS; PROCESS FOR THEIR PREPARATION AND COMPOSITIONS CONTAINING THEM
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The present invention relates to novel organic compounds, more particularly, novel Dipeptidyl peptidase IV (DPP-IV) inhibitors of general formula (I) wherein: Y is -S(O)m-, -CH2-, -CHF-, or -CF2; X and Z are independently -C(=O)-, -NR3-, - O- or -S(O)m-; each occurrence of m is independently 0, 1 or 2; a is 0, 1 or 2; b is 0, 1 or 2; the dotted line [----] in the carbocyclic ring represents an optional double bond; R1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heteroarylalkyl; R2 is hydrogene, nitrile (-CN), COOH, or an isostere of carboxylic; or analogs, tautomers, enantiomers, diastereomers, regioisomers, stereoisomers, polymorphs, pharmaceutically acceptable salts, N-oxides, pharmaceutically acceptable solvates and pharmaceutical compositions containing them.
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Page/Page column 30
(2010/02/15)
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- NOVEL DIPEPTIDYL PEPTIDASE IV INHIBITORS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, AND PROCESS FOR THEIR PREPARATION
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The present invention relates to novel compounds useful as dipeptidyl peptidase IV (DPP-IV) inhibitors of the formula: (I) wherein Y is -S(O)m, -CH2-, CHF, or -CF2; m is 0, 1, or 2; X is a bond, C1-C5 alkyl (e.g., -CH2-), or -C(=0)-; the dotted line [----] in the carbocyclic ring represents an optional double bond; R1 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, CN, -COOR3, CONR3R4, -OR3, -NR3R4, or NR3COR3; R2 is hydrogen, cyano, COOH, or an isostere of a carboxylic acid (such as SO3H, CONOH, B(OH)2, PO3R3R4, SO2NR3R4, tetrazole, -COOR3, -CONR3R4, NR3COR4, or -COOCOR3).
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Page/Page column 43-44
(2008/06/13)
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