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Alanine class compound, its preparing method and use

A technology of alanine and compounds, which is applied in the fields of medicinal chemistry and endocrine therapy, and can solve problems such as high liver toxicity

Inactive Publication Date: 2003-07-23
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In 1997, troglitazone, the first thiazolidinedione insulin sensitizer, was launched on the market. This drug and its similar drugs, pioglitazone and rosiglitazone, which were later marketed, can control blood sugar well in clinical practice. , but thiazolidinediones have shown varying degrees of liver toxicity after their marketing [Henry, R.R.Endocrinol.Metab.Clin.North Am.1997, 26, 553], among which troglitazone withdrawn from the market

Method used

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  • Alanine class compound, its preparing method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0105] Example 1: (2S)-2-[N-(trans-4-isopropylcyclohexanecarbonyl)amino]-3-[4-[2-(5-methyl-2-phenyl- 4-oxazole)ethoxy]phenyl]propanoic acid (1)

[0106] (1) Condensation: 2-(5-methyl-2-phenyl-4-oxazole) ethanol 0.313g (1.54mmol) and (S)-B(2S)-2-[N-(trans-4 -Isopropylcyclohexanecarbonyl)amino]-3-(4-hydroxyphenyl)propionic acid methyl ester 0.535g (1.54mmol) in 30mL of anhydrous tetrahydrofuran, add triphenylphosphine 0.605g (2.31mmol) , 370 μL (2.31 mmol) of diethyl azodicarboxylate was slowly added dropwise at 0°C. Stir at room temperature for 24 hours. The solvent was distilled off under reduced pressure, the residue was precipitated into a solid in ether, and a white solid was obtained by suction filtration. The solid was recrystallized from methanol to give (2S)-2-[N-(trans-4-isopropylcyclohexanecarbonyl)amino]-3-[4-[2-(5-methyl- 0.44 g of methyl 2-phenyl-4-oxazole)ethoxy]phenyl]propionate, yield 53.8%.

[0107] (2) Hydrolysis: Dissolve 0.26 g (0.5 mmol) of the product...

Embodiment 2

[0113] Example 2: (2R)-2-[N-(trans-4-isopropylcyclohexanecarbonyl)amino]-3-[4-[2-(5-methyl-2-phenyl- 4-oxazole)ethoxy]phenyl]propanoic acid (2)

[0114] Take (2R)-2-[N-(trans-4-isopropylcyclohexanecarbonyl)amino]-3-(4-hydroxyphenyl)propionic acid methyl ester) ((R)-B) as Starting materials, the title compound was obtained by the same preparation method as in Example 1. m.p.151-153°C (decomposition). [α] D 25 -82.5(c, 0.217, CHCl 3 ); 1 H NMR is the same as the title compound of Example 1.

[0115] Elemental Analysis, C 31 h 38 N 2 o 5 (518):

[0116] Calculated C, 71.81; H, 7.34; N, 5.41;

[0117] Found C, 71.40; H, 8.16; N, 5.33.

[0118] IR(KBr): 3282.3, 2933.2, 2854.2, 1712.5, 1633.4, 1554.4, 1513.9, 1249.7, 1176.4, 715.5, 686.5cm -1 .

Embodiment 3

[0119] Example 3: (2S)-2-[N-(trans-4-isopropylcyclohexanecarbonyl)amino]-3-[4-[2-[N-methyl-N-(2- Benzoxazole) amino] ethoxy] phenyl] propanoic acid (3)

[0120] 0.11 g (0.21 mmol) of compound D was dissolved in 2 ml of tetrahydrofuran, 240 μl (0.51 mmol) of triethylamine and 40 mg (0.26 mmol) of 2-chlorobenzoxazole were added. Stir at room temperature for 24 hours. Tetrahydrofuran was distilled off under reduced pressure, the residue was mixed with 4 ml of ethyl acetate, and the suspension was stirred evenly with 4 ml of saturated aqueous sodium bicarbonate solution. Stand to separate the ethyl acetate layer, and dry over anhydrous sodium sulfate. The residue was dissolved in a mixed solvent of petroleum ether: ethyl acetate = 1:1 to precipitate a white solid. The solid was hydrolyzed with potassium hydroxide to obtain 0.042 g of the target product, with a yield of 39.6%. m.p.179-180°C (decomposition). [α] D 25 81.1(c, 0.535, CHCl 3 );

[0121] 1H NMR (DMSO): δ=0.81...

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Abstract

A lactamic acid compound or its salt, its two preparing processes, and its application in preparing medicine to treat diabetes B are disclosed.

Description

technical field [0001] The invention relates to the fields of medicinal chemistry and endocrine therapy, in particular to the synthesis of alanine compounds and their use in the preparation of anti-II diabetes medicines. Background of the invention [0002] Type II diabetes mellitus is a metabolic disorder, and the patients mainly manifest as elevated blood glucose concentration (fasting blood glucose concentration greater than 130 mg / dL) and diabetes. Sustained hyperglycemia can lead to many complications, such as retinal, renal, and nervous system lesions, especially cardiovascular complications are the main cause of death and disability in diabetic patients [Shinkai, H.Exp.Opin.Ther.Patents.2000, 10:596]. Therefore, it is extremely important to control the patient's blood sugar level to delay or block the occurrence of complications. At present, sulfonylureas, drugs that promote insulin secretion, and biguanides are mainly used clinically to control blood sugar in patie...

Claims

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Application Information

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IPC IPC(8): A61K31/195A61K31/198A61K31/221A61K31/223A61K31/404A61K31/4402C07C227/14C07C229/36C07D209/08C07D209/12C07D213/30C07D213/72C07D235/30C07D263/58
Inventor 杨玉社汤磊嵇汝运陈凯先
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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