Biphenyl compounds, intermediates, preparation methods, pharmaceutical compositions and applications thereof

A compound, biphenyl technology, applied in the field of biphenyl compounds, can solve the problems of β-cell function damage in patients

Active Publication Date: 2017-06-06
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, the treatment of type 2 diabetes is mainly based on small molecule oral drugs. Sulfonylureas, glinides, biguanides and thiazolidinediones are commonly used drugs for the treatment of type 2 diabetes, but long-term use of these hypoglycemic drugs can lead to Adverse reactions such as hypoglycemia, weight gain, and β-cell function damage occurred in patients

Method used

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  • Biphenyl compounds, intermediates, preparation methods, pharmaceutical compositions and applications thereof
  • Biphenyl compounds, intermediates, preparation methods, pharmaceutical compositions and applications thereof
  • Biphenyl compounds, intermediates, preparation methods, pharmaceutical compositions and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0358] 2',4'-Dichloro-2-aminomethyl-3-(3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3- a] preparation of pyrazin-7-yl) methyl biphenyl (I-1)

[0359] 2',4'-Dichloro-2-cyano-3-(3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a ]pyrazin-7-yl)methylbiphenyl (0.50g, 1.1mmol), Raney Ni (0.10g) and 2mL NH 3 / EtOH (3mol / L) and 8ml EtOH were placed in a hydrogenation reaction kettle, hydrogen was passed through, the pressure was 0.4MPa, and the reaction was carried out at room temperature for 6h, the TLC raw material disappeared completely, the reaction was stopped, the mother liquor was concentrated by suction filtration, and an off-white solid was obtained by column chromatography 0.12g, yield 24.2%.

[0360] The synthesis method of I-2, I-3 and I-4 is the same as that of I-1, and the physical and chemical properties of I-1~I-4 are shown in Table 2.

Embodiment 2

[0362] Preparation of 2',4'-dichloro-2-aminomethyl-3-imidazolylmethylbiphenyl hydrochloride (I-6 hydrochloride)

[0363] 2',4'-dichloro-2-cyano-3-bromomethylbiphenyl (0.50g, 1.5mmol), imidazole (0.11g, 1.5mmol), dissolved in 5mL of acetonitrile, then added anhydrous potassium carbonate (0.61g, 4.4mmol), stirred at 25°C for 2h, the TLC raw material disappeared completely, stopped stirring, evaporated the solvent, and column chromatography (dichloromethane:methanol=60:1) gave the oily intermediate 2', 4' - 0.35 g of dichloro-2-cyano-3-imidazolylmethyl, yield 72.0%.

[0364] The above oil (0.35g, 1.1mmol), Raney Ni (0.07g) and 3mL NH 3 / EtOH (3mol / L) and 7mlEtOH were placed in a hydrogenation reaction kettle, hydrogen was passed through, the pressure was 0.4MPa, and the reaction was carried out at room temperature for 6h. The TLC raw material disappeared completely, and the reaction was stopped. Suction filtration, the mother liquor was concentrated to obtain 0.32g oil, and colu...

Embodiment 3

[0367] Preparation of 2',4'-dichloro-2-aminomethyl-4-(1,2,4-triazol-1-yl)methylbiphenyl hydrochloride (I-24 hydrochloride)

[0368] 2',4'-dichloro-2-cyano-4-bromomethylbiphenyl (0.50g, 1.5mmol), 1,2,4-triazole (0.11g, 1.6mmol), dissolved in 5mL acetonitrile , then added anhydrous potassium carbonate (0.61g, 4.4mmol), stirred at room temperature for 9h, the TLC raw material disappeared completely, stopped stirring, evaporated the solvent, and column chromatography (petroleum ether: ethyl acetate=1:1) gave an oily substance Intermediate 2',4'-dichloro-2-cyano-4-(1,2,4-triazol-1-yl)methylbiphenyl 0.45g, yield 93.4%, 1 H-NMR (CDCl 3 ), δ(ppm): 8.21(s,1H), 8.04(s,1H), 7.67(s,1H), 7.57-7.54(m,2H), 7.47-7.45(d,1H,J=7.6Hz) ,7.40-7.37(m,1H),7.29-7.26(d,1H,J=8.4Hz),5.46(s,2H)

[0369] 2',4'-Dichloro-2-cyano-4-(1,2,4-triazol-1-yl)methylbiphenyl (0.45g, 1.4mmol), Raney Ni (0.09g) and 3mL NH 3 / EtOH (3mol / L) and 7ml EtOH were placed in a hydrogenation reaction kettle, hydrogen was pas...

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Abstract

The invention discloses a biphenyl compound, an intermediate, a preparation method, a pharmaceutical composition, and applications of the biphenyl compound and the pharmaceutical composition. The biphenyl compound and a pharmaceutically acceptable salt of the biphenyl compound are represented by formula 1. The invention also provides the preparation method of the biphenyl compound and the pharmaceutically acceptable salt of the biphenyl compound. According to the preparation method, in a solvent, with the presence of a reduction system, a compound II is subjected to cyano group reduction so as to obtain a compound I. The invention also provides applications of the biphenyl compound or the pharmaceutically acceptable salt in preparation of medicines used for treating and / or preventing non-insulin-dependent diabetes, hyperglycemia, or insulin resistance. The biphenyl compound and the pharmaceutically acceptable salt of the biphenyl compound possess excellent inhibiting effects on DPP-4, so that a novel direction is provided for research and development of DPP-4 inhibitors, and market development prospect is promising.

Description

technical field [0001] The invention relates to biphenyl compounds, intermediates, preparation methods, pharmaceutical compositions and applications thereof. Background technique [0002] Diabetes is a disease that seriously threatens human health. According to the report of the World Health Organization, there are about 180 million diabetic patients in the world, 90% of which are type 2 diabetes, and this number is expected to double by 2030. At present, the treatment of type 2 diabetes is mainly based on small molecule oral drugs. Sulfonylureas, glinides, biguanides and thiazolidinediones are commonly used drugs for the treatment of type 2 diabetes, but long-term use of these hypoglycemic drugs can lead to Adverse reactions such as hypoglycemia, weight gain, and β-cell function damage occurred in patients. The discovery of DPP-4 inhibitors can effectively avoid the deficiency of traditional oral hypoglycemic drugs, and DPP-4 is generally considered to be the most promisi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04C07D233/61C07D249/08C07C211/29C07C209/00C07C209/48C07C255/50C07C253/30C07D241/06C07D231/12C07C211/40C07D295/135C07D235/08C07C211/53A61K31/495A61K31/4174A61K31/4196A61K31/415A61K31/4453A61K31/40A61K31/5375A61K31/4184A61K31/137A61P3/10A61P5/50
CPCC07C209/48C07C211/29C07C211/40C07C211/52C07C211/53C07C253/30C07C255/50C07C2601/14C07D231/12C07D233/61C07D235/08C07D241/06C07D249/08C07D295/135C07D487/04
Inventor 孟祥国蔡正艳周伟澄郝群张文强陈小明黄火明
Owner SHANGHAI INST OF PHARMA IND CO LTD
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