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Intermediates of DPP-IV inhibitor

A next-step, isomer technology, applied in the field of intermediates of DPP-IV inhibitors, can solve problems such as inactivation and limitation of clinical application

Active Publication Date: 2016-06-15
HITGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, GLP-1 is easily hydrolyzed by DPP-IV from the two N-terminal amino acid residues in vivo and then inactivated, and its plasma half-life is less than 2 minutes, which severely limits its clinical application.

Method used

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  • Intermediates of DPP-IV inhibitor
  • Intermediates of DPP-IV inhibitor
  • Intermediates of DPP-IV inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0185] Example 1 (R)-3-amino-1-((6R,9S)-3-trifluoromethyl-6,7,8,9-tetrahydro-5H-6,9-cycloimine [1, 2,4]triazolo[4,3-a]azepine-10-alkyl)-4-(2,4,5-trifluorophenyl)-1-butanone trifluoroacetate ( Compound 1) Preparation

[0186]

[0187] Step 1: Methyl L-pyroglutamate (compound 1b)

[0188] Thionyl chloride (65 mL, 900 mmol) was added dropwise to 100 mL of methanol in an ice bath, followed by L-pyroglutamic acid 1a (58 g, 449 mmol). The reaction mixture was stirred at room temperature for 16 h, and then the solvent was dried under reduced pressure. Ethyl acetate (200 mL), sodium carbonate (50 g) and water (100 mL) were added and stirred for 1 hour. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain compound 1b, 51 g of a colorless liquid, with a yield of 79%.

[0189] MS (ESI) m / z: 144 (M+1); 1 HNMR (400mHz, CDCl 3 ): δ2.20-...

Embodiment 2

[0223] Example 2: (3R)-3-amino-1-(3-trifluoromethyl-6,7,9,10-tetrahydro-5H-6,10-cycloimine[1,2,4]tri Azolo[3,4-d][1,5]oxazocin-11-alkyl)-4-(2,4,5-trifluorophenyl)-1-butanone trifluoroacetate (compound 2)

[0224]

[0225] Step 1: (2S)-3-(3-tert-butoxycarbonylamino-2-hydroxypropoxy)-2-p-nitrobenzyloxycarbonylamino-propionic acid methyl ester (compound 2b)

[0226] To a solution of compound 2l (6.82 g, 35.7 mmol) and compound 2a (5 g, 17.8 mmol) in toluene (80 mL) was added boron trifluoride diethyl ether (0.3 mL, 48%) dropwise at room temperature. After stirring at room temperature for 2 h, the solvent was removed by concentration and column chromatography (silica gel, petroleum ether: ethyl acetate = 2:1) to obtain product 2b, 4.8 g of yellow oil, with a yield of 57%.

[0227] MS(ESI) m / z:472(M+1),416(M-56+1); 1 HNMR (400mHz, CDCl 3 ):δ8.22(d,J=8.4Hz,2H),7.52(d,J=8.4Hz,2H),5.08–5.13(m,1H),5.19-5.26(m,2H),4.42–4.58( m,1H),3.91–3.94(m,1H),3.78(s,3H),3.73-3.83(m,2H),3.54–...

Embodiment 3

[0257] Example 3 (R)-3-amino-1-((6R,9S)-3-methyl-6,7,8,9-tetrahydro-5H-6,9-cycloimine[1,2, 4] Triazolo[4,3-a]azepine-10-alkyl)-4-(2,4,5-trifluorophenyl)-1-butanone trifluoroacetate (compound 3 ) preparation

[0258]

[0259] Step 1: ((R)-4-carbonyl-4-((1S,5R)-2-thiocarbonyl-3,8-diazabicyclo[3.2.1]-8-octyl)-1-( tert-butyl 2,4,5-trifluorophenyl)-2-butyl)carbamate (Compound 3a)

[0260] Diisopropylethylamine ( 593mg, 4.6mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (265mg, 1.38mmol), 1-hydroxybenzotriazole (186mg, 1.38mmol), Stir at room temperature for 1 hour. Then compound 1j (150 mg) was added to the reaction system and stirred overnight at room temperature. The reaction solution was washed with saturated brine, dried and concentrated. The crude product was purified by silica gel column (dichloromethane:methanol=80:1) to obtain compound 3a, white solid 170mg, yield 42%. MS (ESI) M / Z: 458 (M+H), 358 [(M+H)-Boc].

[0261] Step 2: ((R)-4-((6R,9S)-...

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Abstract

The invention provides intermediates IAA, IBA, IAB, IBB, IIIAA, IIIBA, IVA and IVB of a DPP-IV inhibitor as shown in formulas IA and IB. The compounds as shown in the formulas IA and IB can effectively inhibit activity of DPP-4 and has well selectivity, and these compounds can become potential diabetes new drugs or drugs for treatment of DPP-4 related diseases, and provide a new choice for clinical medication. The intermediates can effectively synthesize the DPP-4 inhibitors as shown in the formulas IA and IB.

Description

[0001] This application is a divisional application with the application number 201410061271.8, the application date of February 24, 2014, and the title of the invention "a compound and its intermediate for inhibiting DPP-IV". technical field [0002] The present invention relates to an intermediate of DPP-IV inhibitor. Background technique [0003] Diabetes is a metabolic disorder caused by genetic factors and environmental factors, which seriously threatens human health and life safety. In my country, with the improvement of quality of life and changes in lifestyle, the prevalence of diabetes has increased dramatically. According to the diabetes epidemiological data released by the International Diabetes Federation (IDF) in 2013, the number of adults with diabetes in China has reached 98.4 million, ranking first in the world, and the prevention and control situation is severe. In the face of huge market demand, the research and development of new diabetes treatment drugs ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/18C07D498/18C07D498/08C07D487/08A61P3/10A61P5/50
CPCC07D487/08C07D487/18C07D498/08C07D498/18A61P3/10A61P5/50
Inventor 李进斯托克斯·迈克尔窦登峰万金桥冯静超潘飞宋宏梅胡晓易磊
Owner HITGEN INC
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