Compound of new benzo heterocycle categories, preparation method and application

A technology of compounds and heterocycles is applied in the preparation of anti-type II diabetes drugs and the synthesis of benzoheterocycles, and can solve problems such as liver toxicity and weight gain.

CN101092415AInactive Publication Date: 2007-12-26SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +1
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Authority / Receiving Office
CN · China
Current Assignee / Owner
Publication Date
2007-12-26
Estimated Expiration
Not applicable · inactive patent

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Abstract

This invention provides benzothiazolyl compounds as shown in chemical formual (I), their pharmaceutically acceptable salts, and their application in preparing drugs for treating type II diabetes. In chemical formual (I), 2nd and 3rd sites are single bond or double bonds; when 2nd and 3rd sites are single bond, the configuration of the carbon atoms at 2nd site is R or S or racemate; R1 is H, or substituted or unsubstituted C1-6 alkyl; R2 is H, or substituted or unsubstituted C1-6 alkyl; R3 is H, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted aromatic cyclic or aromatic heterocyclic goup; X is CH2, C=O, O or S; n is 1-4 integer. Biological experiments show that the benzothiazolyl compounds have a strong insulin-sensitizing activity.
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Description

technical field

[0001] The invention relates to the fields of medicinal chemistry and endocrine therapy, in particular to the synthesis of benzoheterocyclic compounds and their use in the preparation of anti-II diabetes drugs. Background technique

[0002] Diabetes mellitus is a group of clinical syndromes characterized by chronic hyperglycemia (fasting blood glucose concentration greater than 130 mg / dL) and glucosuria due to abnormal carbohydrate, fat and protein metabolism caused by insufficient insulin secretion or insulin resistance. Sustained hyperglycemia can lead to many complications, such as retinal, renal, nervous system lesions and vascular complications, especially cardiovascular complications are the main threat to death and disability in diabetic patients, so controlling the patient's blood sugar level is very important for delaying or preventing diabetes. Interruption complications are extremely important. The traditional antidiabetic drugs mainly include big...

Examples

Embodiment 1

[0126] Example 1: 6-(2-(5-methyl-2-phenyl-4-oxazole)ethoxy)-4-oxo-4H-benzopyrone-2-carboxylic acid methyl ester Preparation (compound 1)

[0127]2-(5-methyl-2-phenyl-4-oxazole) ethanol 0.14g (0.69mmol), 6-hydroxy-4-oxo-4H-benzopyrone-2-carboxylic acid methyl ester 0.15 g (0.69 mmol) was dissolved in 20 ml of anhydrous tetrahydrofuran, 0.21 g (0.79 mmol) of triphenylphosphine was added, and 0.16 ml (0.79 mmol) of diisopropyl azodicarboxylate was added dropwise at 0°C. Stir at room temperature for 12 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in methanol to precipitate a white solid. The resulting solid was recrystallized from methanol to obtain 0.22 g of the target product, yield: 79.7%. M.P. 154-155°C. 1 HNMR (CDCl 3 ): δ=2.39(s, 3H), 3.02(t, J=6.59Hz, 2H), 4.00(s, 3H), 4.35(t, J=6.59Hz, 2H), 7.09(s, 1H), 7.32 (dd, J=9.20Hz, J=3.16Hz, 1H), 7.43(m, 3H), 7.53(d, J=9.02Hz, 1H), 7.56(d, J=3.02Hz, 1H), 7.98(dd , J=8.10Hz, J=2.0...

Embodiment 2

[0130] Embodiment 2: the preparation of 6-(2-(5-methyl-2-phenyl-4-oxazole) ethoxy)-4-oxo-4H-benzopyrone-2-carboxylic acid ( Compound 2)

[0131] Compound 1 0.12 (0.30 mmol) prepared in Example 1 was dissolved in 15 ml of methanol, 1.5 ml of 2N NaOH solution was added, and the reaction was stirred at 45° C. for 1.5 hours. Evaporate the methanol solvent under reduced pressure, add water, adjust the pH value to about 2 with 10% hydrochloric acid, extract with 2×10ml ethyl acetate, wash the organic phase with water, wash with saturated brine, dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure. The residue was recrystallized from methanol and ether to obtain 0.10 g of the product, yield: 86.3%. M.P.>200°C (oxidation). 1 H NMR (CDCl 3 ): δ=2.36(s, 3H), 2.98(t, J=6.58Hz, 2H), 4.35(t, J=6.58Hz, 2H), 7.03(s, 1H), 7.32(dd, J=9.20Hz , J=3.16Hz, 1H), 7.43(m, 3H), 7.53(d, J=9.02Hz, 1H), 7.56(d, J=3.02Hz, 1H), 7.98(dd, J=8.10Hz, J =2.06Hz, 2H). EI-MS (m...

Embodiment 3

[0134] Example 3: 6-(2-(5-methyl-2-(3-methyl)phenyl-4-oxazole)ethoxy)-4-oxo-4H-benzopyrone-2 - Preparation of methyl carboxylate (compound 3)

[0135] With 2-(5-methyl-2-(3-methyl)phenyl-4-oxazole)ethanol and 6-hydroxy-4-oxo-4H-benzopyrone-2-carboxylic acid methyl ester As the starting material, Compound 3 was prepared in the same manner as in Example 1, with a yield of 82.0%. M.P. 162-163°C. 1 H NMR (CDCl 3 ): δ=2.38(s, 3H), 2.40(s, 3H), 3.02(t, J=6.56Hz, 2H), 4.00(s, 3H), 4.34(t, J=6.56Hz, 2H), 7.09 (s, 1H), 7.22(d, J=7.63Hz, J=3.16Hz, 1H), 7.32(m, 2H), 7.53(d, J=9.15Hz, 1H), 7.56(d, J=3.05 Hz, 1H), 7.77 (d, J=7.76Hz, 1H), 7.82 (s, 1H). EI-MS (m / z): 4 1 9 (76, M + ), 200(100).

[0136] Elemental Analysis, C 24 h 21 NO 6 (419): Calculated C, 68.73; H, 5.05; N, 3.34.

[0137] Found values ​​C, 68.50; H, 4.90; N, 3.25.