- Synthesis and Microbial Evaluation of Some New 1-(3-Methyl-1-phenyl-1Hpyrazol- 5-yl) Piperazine Sulfonamide/Amides
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A series of new 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazines bearing sulfonamide and amide derivatives was synthesized starting from 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one through sequential chlorination, SNAr, deprotection followed by coupling with acid chloride/sulfonyl chloride. The structures of the newly synthesized inhibitors 3-19, were confirmed by using spectral analysis. All the synthesized compounds were evaluated against the selected bacterial (Staphylococcus aureus ATCC 6538 and Escherichia coli ATCC 8739) and fungal stains (Candida albicans ATCC 10231 and Aspergillus niger ATCC 6275). The sulfonamide derivatives 4-12 were found inactive toward the tested bacterial/fungal stains, while the amide derivative 14, 16, 17, 18 and 19 showed moderate activity against S. aureus ATCC 6538 bacterial stain.
- Chavan, Kamlesh H.,Jadhav, Rahul I.,Kedar, Nathrao A.
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p. 111 - 117
(2022/03/27)
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- The optimization of xanthine derivatives leading to HBK001 hydrochloride as a potent dual ligand targeting DPP-IV and GPR119
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A series of xanthine compounds derived from the previous hit 20i with modification on the terminal side chain was discovered through ring formation strategy. Systematic optimization of the compounds with rigid heterocycles in the hydrophobic side chain led to the new lead compound HBK001 (21h) with the improved DPP-IV inhibition and moderate GPR119 agonism activity in vitro. As a continuing work to further study the PK and PD profiles, 21h and its hydrochloride (22) were synthesized on grams scale and evaluated on the ADME/T and oral glucose tolerance test (OGTT) in ICR mice. Compound 22 showed the improved bioavailability and blood glucose-lowering effect in vivo compared to its free base 21h probably attributed to its improved solubility and permeability. The preliminary toxicity studies on compound 22 exhibited that the result of mini-Ames was negative and the preliminary acute toxicity LD50 in mice was above 1.5 g/kg, while it showed moderate inhibition on hERG channel with IC50 4.9 μM maybe due to its high lipophilicity. These findings will be useful for the future drug design for more potent and safer dual ligand targeting DPP-IV and GPR119 for the treatment of diabetes.
- Li, Gang,Meng, Bingxu,Yuan, Baokun,Huan, Yi,Zhou, Tian,Jiang, Qian,Lei, Lei,Sheng, Li,Wang, Weiping,Gong, Ningbo,Lu, Yang,Ma, Chen,Li, Yan,Shen, Zhufang,Huang, Haihong
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- Preparation method of 5-piperazinyl-3-methyl-1-phenylpyrazole
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The invention discloses a preparation method of a Teneligliptin key intermediate 5-piperazinyl-3-methyl-1-phenylpyrazole, and belongs to the technical field of pharmaceutical manufacturing. Accordingto the preparation method disclosed by the invention, 3-
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Paragraph 0037; 0038; 0039; 0040; 0041
(2018/06/15)
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- Method for preparing hydrobromic acid teneligliptin
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The invention provides a method for preparing hydrobromic acid teneligliptin. The method includes steps of preparing L-hydroxyproline; mixing the L-hydroxyproline and sodium bicarbonate with each other to obtain mixtures, dissolving the mixtures in water, adding acetone into the water, dropping di-tert-butyl dicarbonate into the water, carrying out room-temperature reaction overnight and then treating reaction products to obtain t-butyloxycarboryl-N-hydroxyproline; preparing t-butyloxycarboryl-N-4-oxo-proline from the t-butyloxycarboryl-N-hydroxyproline; preparing (2S)-4-oxo-2-(3-thiazolidine carbonyl)-1-pyrrolidine carboxylic acid tert-butyl ester from the t-butyloxycarboryl-N-4-oxo-proline; preparing compounds III from compounds IV; preparing compounds II from the compounds III; preparing compounds 1-(3-methyl-1-phenyl-1H-pyrazole-5-base) piperazine from the compounds II; preparing intermediates I; preparing the hydrobromic acid teneligliptin from the intermediates I. The method has the advantages that the method is low in cost, and the cost of the method is only two-thirds of the cost of an existing method in the prior art; the yield of the hydrobromic acid teneligliptin is higher than 95%, and the purity of the hydrobromic acid teneligliptin is higher than 98%.
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- Key intermediate for geleg sandbank 1 - (3-methyl-1-phenyl-5-pyrazolyl) method for the preparation of piperazine
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The invention provides a teneligliptin key intermediate 1-(3-methyl-1-phenyl-5-pyrazolyl) piperazine preparation method which is as follows: reacting N-Boc-N-acetyl acetyl piperazine with phenylhydrazine in an organic solvent with Lawesson reagent, and then removing the protection base in the presence of concentrated hydrochloric acid to obtain an teneligliptin key intermediate. The preparation method has the advantages of being high in yield, low in cost, friendly to the environment and the human body, and more suitable for industrial production.
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Paragraph 0031; 0032; 0033; 0034
(2016/12/01)
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- Teneligliptin key intermediate preparation method
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The present invention discloses a preparation method of a teneligliptin key intermediate 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (compound I), and belongs to the technical field of medicine preparation. According to the method of the present inven
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Paragraph 0025; 0026; 0027
(2016/10/07)
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- For the preparation of pyrazole derivatives
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The present invention provides a prolinamide compound useful as a drug or the like and an industrially advantageous method for producing a piperazinyl pyrazole compound that is a production intermediate of the prolinamide compound. Specifically, the invention is a method for producing a compound represented by general formula (1) as represented by the following formula (where the symbols in the formula are the same as defined in the specification) or a salt thereof, wherein a compound represented by general formula (2) is produced, a pyrazole ring being formed via a reaction between a compound represented by general formula (3) and phosphorus pentasulfide; and, once the compound represented by general formula (2) is deprotected, a carboxylate of a compound represented by general formula (6) is produced, the compound obtained by forming a carboxylic acid and a salt.
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Paragraph 0129; 0130
(2017/02/24)
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- Process for the preparation of teneligliptin
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A process for the preparation of teneligliptin.
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Page/Page column 30
(2017/01/02)
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- Preparation method for 1-(3-methyl-1-phenyl-1H-pyrazole-5-yl)piperazine
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The invention discloses a preparation method for 1-(3-methyl-1-phenyl-1H-pyrazole-5-yl)piperazine. The method uses phenylhydrazine and ethyl acetoacetate as starting materials, and obtains a compound I through cyclization, chloride acetylation, substituti
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Paragraph 0032; 0033; 0034
(2016/10/08)
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- PROCESS FOR THE PREPARATION OF TENELIGLIPTIN AND ITS NOVEL INTERMEDIATES
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The present invention relates to a novel process for the preparation of Teneligliptin or its pharmaceutically acceptable salts and its hydrates thereof. The invention also relates to novel intermediates used in the synthesis of Teneligliptin and their preparation.
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Page/Page column 25-26
(2016/01/26)
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- Discovery and preclinical profile of teneligliptin (3-[(2S,4S)-4-[4-(3- methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl] thiazolidine): A highly potent, selective, long-lasting and orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes
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Dipeptidyl peptidase IV (DPP-4) inhibition is suitable mechanism for once daily oral dosing regimen because of its low risk of hypoglycemia. We explored linked bicyclic heteroarylpiperazines substituted at the γ-position of the proline structure in the course of the investigation of l-prolylthiazolidines. The efforts led to the discovery of a highly potent, selective, long-lasting and orally active DPP-4 inhibitor, 3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5- yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine (8g), which has a unique structure characterized by five consecutive rings. An X-ray co-crystal structure of 8g in DPP-4 demonstrated that the key interaction between the phenyl ring on the pyrazole and the S2 extensive subsite of DPP-4 not only boosted potency, but also increased selectivity. Compound 8g, at 0.03 mg/kg or higher doses, significantly inhibited the increase of plasma glucose levels after an oral glucose load in Zucker fatty rats. Compound 8g (teneligliptin) has been approved for the treatment of type 2 diabetes in Japan.
- Yoshida, Tomohiro,Akahoshi, Fumihiko,Sakashita, Hiroshi,Kitajima, Hiroshi,Nakamura, Mitsuharu,Sonda, Shuji,Takeuchi, Masahiro,Tanaka, Yoshihito,Ueda, Naoko,Sekiguchi, Sumie,Ishige, Takayuki,Shima, Kyoko,Nabeno, Mika,Abe, Yuji,Anabuki, Jun,Soejima, Aki,Yoshida, Kumiko,Takashina, Yoko,Ishii, Shinichi,Kiuchi, Satoko,Fukuda, Sayaka,Tsutsumiuchi, Reiko,Kosaka, Keigo,Murozono, Takahiro,Nakamaru, Yoshinobu,Utsumi, Hiroyuki,Masutomi, Naoya,Kishida, Hiroyuki,Miyaguchi, Ikuko,Hayashi, Yoshiharu
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p. 5705 - 5719
(2012/10/30)
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