- Production method of vildagliptin
-
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.
- -
-
Paragraph 0079-0084; 0096-0099
(2021/10/27)
-
- Design and synthesis of tetrahydropyridopyrimidine derivatives as dual GPR119 and DPP-4 modulators
-
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
-
-
- A new uygur geleg [...] ammonium salt impurity and its preparation method
-
The invention relates to a new uygur geleg [...] ammonium salt impurity, the glimepiride states uygur [...] ammonium salt the chemical name of the impurity (S)- 2 - (2 - carbamino pyrrolidine - 1 - yl) - N, N, N - triethyl - 2 - oxo ethyl ammonium chloride. The present invention provides a kind of new uygur geleg [...] ammonium salt impurity, the impurity in the existing literature has not been reported in, for vigelegting research further provides reference and conditions; the invention new uygur geleg [...] ammonium salt impurities of the preparation method is convenient, and the resulting high yield and purity, purity can be up to 98.7%, yield can reach 81.6%.
- -
-
Paragraph 0039; 0041; 0043
(2019/05/28)
-
- Vildagliptin related substance and preparation method thereof
-
The invention provides a preparation method of a vildagliptin related substance. The preparation method comprises the following steps: (1) performing hydrolysis reaction on a compound I under a basiccondition to form a compound II; (2) enabling the compound II to react with chloroacetyl chloride to form a compound III as shown in the specification; (3) dehydrating the compound III and trifluoroacetic anhydride (TFAA) to form a compound IV as shown in the specification; (4) enabling the compound IV to react with 3-amino-1-adamantanol to form a compound V as shown in the specification. The synthesis method of the vildagliptin related substance, provided by the invention, is simple in steps, mild in reaction conditions and high in operability, and the related substance meeting the quality requirements can be obtained by simple purification; the preparation method is of great significance for drug development.
- -
-
Paragraph 0064; 0065; 0066; 0067; 0068; 0085-0089
(2019/06/12)
-
- Preparation method of vildagliptin intermediate
-
Belonging to the technical field of heterocyclic compounds, the invention provides a preparation method of a vildagliptin intermediate. The preparation method includes: adding prolinamide into a solvent, performing stirring and heating to dissolve prolinamide; performing cooling, adding propylene oxide as an acid-binding agent, and adding chloroacetyl chloride dropwise under stirring; carrying outcondensation reaction at the end of adding; lowering the temperature and performing heat preservation; conducting filtering, washing the filter residue, and performing drying to obtain (S)-1-(2-chloracetyl)pyrrolidine-2-amide. The method has the advantages of simple process, mild reaction conditions, high product purity and the like.
- -
-
Paragraph 0019; 0025-0036
(2020/01/08)
-
- Acceptor-Controlled Transfer Dehydration of Amides to Nitriles
-
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
-
supporting information
p. 4767 - 4770
(2019/06/17)
-
- Preparation method of (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile
-
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.
- -
-
Paragraph 0050-0052; 0061-0063; 0071-0073
(2019/12/25)
-
- Preparation method of vildagliptin intermediate
-
The invention relates to a preparation method of a vildagliptin intermediate. The preparation method comprises the following steps: step 1, dissolving L-prolinamide in a heated organic solvent; step 2, adding chloroacetyl chloride for reaction; and step 3, after the reaction is finished, carrying out filtering, carrying out drip washing on the obtained solid by using the organic solvent in the step 1, and carrying out drying to obtain (S)-1-(2-chloroacetyl)-2-pyrrolidine carboxamide hydrochloride.
- -
-
Paragraph 0049-0064
(2018/03/25)
-
- Vildagliptin impurity compound and preparation method thereof, detection method and application
-
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.
- -
-
Paragraph 0091-0093; 0130; 0133
(2018/11/04)
-
- Synthesis and evaluation of camphor and cytisine-based cyanopyrrolidines as DPP-IV inhibitors for the treatment of type 2 diabetes mellitus
-
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
-
p. 4402 - 4409
(2018/07/30)
-
- A process for preparing (S)-1 - (2 - chloracetyl) pyrrolidine -2 - carbonitrile method
-
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.
- -
-
Paragraph 0015-0030
(2018/10/19)
-
- Method for preparing 1-(2-chloracetyl)-2-(S)-cyano pyrrolidine through multiphase compound non-continuous production process
-
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.
- -
-
Paragraph 0041-0043
(2017/08/29)
-
- A preparation method of the peculiar smell amide impurity
-
The invention discloses a method for preparing the peculiar smell amide impurity, relates to the technical field of chemical industry, steps are as follows: S1, to L - prolinamides (I) as raw materials, chlorine acetyl chloride reaction, obtaining the intermediate (II); S2, the intermediate product (II) and 3 - amino - adamantane aminol reaction, to generate the target product. The process of the invention is simple, is short, the peculiar smell preparation of high purity of the impurities, the purity of 98.5%, through the further study of the impurity of the peculiar smell, can better control the quality of the peculiar smell, improve the drug safety.
- -
-
Paragraph 0037; 0041; 0045; 0047; 0048; 0049
(2017/11/16)
-
- A high efficient synthesis method of vergeliptin
-
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.
- -
-
Paragraph 0038; 0039; 0040; 0044; 0045; 0046; 0050-0052
(2017/08/25)
-
- 2 - substituted pyrrolidines compound, preparation method and its application in the preparation of the peculiar smell (by machine translation)
-
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)
- -
-
Paragraph 0005; 0062; 0065; 0066
(2017/08/25)
-
- A (S) - 1-acetyl-pyrrolidin-2-carboxamide method for the preparation of
-
The invention relates to a preparation method of (S)-1-chloracetylpyrrolidine-2-formamide. According to the preparation method, a water-based post-treatment process is introduced; in the treatment process, by reacting with potassium carbonate, a salt produced from an acid-binding agent is freed out, enters an organic layer and is removed in a subsequent concentration process of the organic layer, a target product is always retained in the organic layer and exists in the form of relatively pure solid after being concentrated, and the purity of the target product is more than 96%; meanwhile, the preparation method is easy to operate and suitable for industriald production, and the yield is high and is more than 95%.
- -
-
Paragraph 0017; 0018; 0019
(2016/10/07)
-
- A method for synthesizing allah Geleg sandbank (by machine translation)
-
The invention relates to a method for preparing anti-II type diabetes drug allah Geleg sandbank method for the synthesis of bulk drug (Anagliptin). The lack of commercial synthetic allah Geleg sandbank solve the technical problems of the method. Synthetic method comprises the following steps : (1) with vinyl ether and trichloro acetyl chloride as the raw material, passes through the three-step reaction to obtain the aldehyde protected intermediates 4 ; The 3-amino-5-methyl pyrazole condensation for dehydrating and gets pyrazolo pyrimidine mother nucleus; Carboxy b ester hydrolysis to obtain 2-methyl-pyrazolo [1,5-a] pyrimidin 6-carboxylic acid 6 ; (2) to L-proline as a raw material, passes through the methyl esterification, ammoniation, acetylation, Carbonitride reaction to obtain the chiral cyano pyrrolizinone intermediate 11 ; Chiral cyano pyrrolizinone intermediate 11 And diamine fragment 12 In alkaline conditions to obtain intermediate affinity substituted 13 ; Finally, intermediate 13 Under the conditions of the hydrochloric acid removal protection Boc base namely obtain cyanopentanoyl Azolylamine intermediate 14 ; (3) 2-methyl-pyrazolo [1,5-a] pyrimidine-6-carboxylic acid 6 The cyano Azolylamine intermediate 14 The condensation conditions to obtain the bulk drug allah Geleg sandbank coupled. (by machine translation)
- -
-
Paragraph 0017
(2016/10/10)
-
- Method for preparing substituted (S)-pyrrolidine-2-formonitrile and vildagliptin
-
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.
- -
-
Paragraph 0059-0063
(2018/02/04)
-
- Direct Synthesis of Cyanopyrrolidinyl β-Amino Alcohols for the Development of Diabetes Therapeutics
-
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
-
supporting information
p. 5160 - 5168
(2016/10/26)
-
- AN ADVANCED AND COST-EFFECTIVE PROCESS FOR PREPARING HIGHLY PURE VILDAGLIPTIN
-
The present invention describes an improved process for preparing highly pure (S)-1-[N- (3-hydroxy-l-adamantyl) glycyl] pyrrolidine-2-carbonitrile known as Vildagliptin. Also the present invention discloses a novel insitu process for preparing an intermediate (2S)- l-(chloroacetyl)pyrrolidine-2-carbonitrile. Further, the present invention discloses a method of preparing undesired dimer impurity.
- -
-
-
- HEXAHYDROPENTALENO DERIVATIVES, PREPARATION METHOD AND USE IN MEDICINE THEREOF
-
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.
- -
-
Paragraph 0157; 0165
(2015/05/06)
-
- Synthesis of vildagliptin utilizing continuous flow and batch technologies
-
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
-
supporting information
p. 551 - 554
(2015/04/27)
-
- AN IMPROVED PROCESS FOR PREPARING VILDAGLIPTIN
-
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.
- -
-
Page/Page column 21-22
(2015/12/08)
-
- IMPROVED PROCESS FOR PREPARATION OF VILDAGLIPTIN
-
The present invention relates to process for the preparation of vildagliptin.
- -
-
Page/Page column 15
(2014/07/21)
-
- Synthesis of main impurity of vildagliptin
-
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
-
p. 3489 - 3492
(2014/08/05)
-
- A facile and economical method to synthesize vildagliptin
-
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
-
p. 780 - 784
(2015/04/14)
-
- A cost-effective method to prepare pure vildagliptin
-
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
-
p. 159 - 163
(2013/07/26)
-
- A PROCESS FOR THE PREPARATION OF VILDAGLIPTIN AND ITS INTERMEDIATE THEREOF
-
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.
- -
-
Page/Page column 27
(2014/01/07)
-
- Novel synthesis of heterocycle-containing adamantane derivatives
-
A novel approach to synthesize the of heterocycle-containing adamantane derivatives 1-{[(3-hydroxy-1-adamantyl)amino]acetyl}-2- cyano-(S)-pyrrolidine and N-{2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl}adamantane-1-carboxamide, which were effective in treatment of diabetes and depression respectively, have been described. The target compounds were synthesized by raw materials of inexpensive L-proline and available 1-(2-pyrimidinyl) piperazine respectively. Compared with traditional synthetic routes, the method provides several advantages such as inexpensive and readily available raw materials, convenient manipulation and high yield.
- Xu, Xiaojian,Guo, Jianwei,Su, Qiang,Zhong, Xing
-
p. 7557 - 7560
(2013/08/23)
-
- SYNTHESIS AND USE OF VILDAGLIPTIN FOR THE PREPARATION OF PHARMACEUTICAL DOSAGE FORMS
-
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.
- -
-
Page/Page column 41
(2011/02/24)
-
- PROCESS FOR PREPARATION OF DPP-IV INHIBITORS
-
Process for the preparation of DPP-IV inhibitors, such as 1-[[(3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine are disclosed.
- -
-
Page/Page column 20
(2011/09/19)
-
- PRODRUGS OF FUSED HETEROCYCLIC INHIBITORS OF D-AMINO ACID OXIDASE
-
The invention relates to prodrugs of fused heterocyclic inhibitors of D-amino oxidase (DAAO) and methods of treating diseases and conditions, wherein modulation of D-amino acid oxidase activity, D-serine levels, D-serine oxidative products and NMDA receptor activity in the nervous system of a mammalian subject is effective.
- -
-
Page/Page column 89; 90
(2011/02/26)
-
- PRODRUGS OF FUSED HETEROCYCLIC INHIBITORS OF D-AMINO ACID OXIDASE
-
The invention relates to prodrugs of fused heterocyclic inhibitors of D-amino oxidase (DAAO) and methods of treating diseases and conditions, wherein modulation of D- amino acid oxidase activity, D-serine levels, D-serine oxidative products and NMDA receptor activity in the nervous system of a mammalian subject is effective.
- -
-
Page/Page column 111
(2010/04/03)
-
- ORGANIC COMPOUNDS
-
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.
- -
-
Page/Page column 6
(2010/10/19)
-
- PROCESS FOR THE PREPARATION OF N-SUBSTITUTED 2-CYANOPYRROLIDINES
-
The present invention relates to a process for the preparation of a N-(N'-substituted glycyl)-2-cyanopyrrolidine comprising at least (a) reacting, in the presence of dimethylformamide, a compound of formula (V) wherein, independently of each other, X1 and X3 are halogen; X2 is halogen, OH, O-C(=O)-CH2X3, -O-SO2-(C1-8)alkyl or -O-SO2-(aryl), with L-prolinamide, followed by (b) reacting the resultant compound without isolation with a dehydration agent, optionally followed by (c) reacting, in the presence of a base, the resultant compound without isolation with an appropriate amine and (d) recovering the resultant cornpound in free form or in acid addition salt form.
- -
-
-
- 1-[[(3-Hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine: A potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties
-
Dipeptidyl peptidase IV (DPP-IV) inhibition has the potential to become a valuable therapy for type 2 diabetes. The synthesis and structure - activity relationship of a new DPP-IV inhibitor class, N-substituted-glycyl-2-cyanopyrrolidines, are described as well as the path that led from clinical development compound 1-[2-[5-cyanopyridin-2-yl)amino]ethylamino]acetyl-2-cyano-(S)pyrrolidine (NVP-DPP728, 8c) to its follow-up, 1-[[(3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)pyrrolidine (NVP-LAF237, 12j). The pharmacological profile of 12j in obese Zucker fa/fa rats along with pharmacokinetic profile comparison of 8c and 12j in normal cynomolgus monkeys is discussed. The results suggest that 12j is a potent, stable, selective DPP-IV inhibitor possessing excellent oral bioavailability and potent antihyperglycemic activity with potential for once-a-day administration.
- Villhauer, Edwin B.,Brinkman, John A.,Naderi, Goli B.,Burkey, Bryan F.,Dunning, Beth E.,Prasad, Kapa,Mangold, Bonnie L.,Russell, Mary E.,Hughes, Thomas E.
-
p. 2774 - 2789
(2007/10/03)
-
- 1-[2-[(5-Cyanopyridin-2-yl)amino]-ethylamino]acetyl-2-(S)-pyrrolidine -carbonitrile: A potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties
-
Dipeptidyl peptidase IV (DPP-IV) inhibition has the potential to become a valuable therapy for type 2 diabetes We report the first use of solid-phase synthesis in the discovery of a new DPP-IV inhibitor class and a solution-phase synthesis that is practical up to the multikilogram scale. One compound NVP-DPP728 (2), is profiled as a potent, selective, and short-acting DPP-IV inhibitor that has excellent oral bioavailability and potent antihyperglycemic activity.
- Villhauer, Edwin B.,Brinkman, John A.,Naderi, Goli B.,Dunning, Beth E.,Mangold, Bonnie L.,Mone, Manisha D.,Russell, Mary E.,Weldon, Stephen C.,Hughes, Thomas E.
-
p. 2362 - 2365
(2007/10/03)
-
- Sodium 2-ethylhexanoate: A mild acid scavenger useful in acylation of amines
-
A highly useful method for the acylation of amines with acid chlorides utilizing sodium 2-ethylhexanoate as the base is described. This procedure is superior to the Schotten-Baumann conditions whenever the product is water soluble.
- Fitt, John,Prasad, Kapa,Repic, Oljan,Blacklock, Thomas J.
-
p. 6991 - 6992
(2007/10/03)
-
