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Tetrahydro indazolone or tetrahydro indolone substituted indazole derivative and salt thereof

A technology of tetrahydroindolinone and tetrahydroindazole, which is applied in the field of tetrahydroindazolone or tetrahydroindolinone-substituted indazole derivatives and salts thereof, and can solve the problems of patient toxicity, side effects and the like

Active Publication Date: 2009-07-15
广州少伯控股集团有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As a result, these drugs often also cause irreversible toxicity and side effects to patients

Method used

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  • Tetrahydro indazolone or tetrahydro indolone substituted indazole derivative and salt thereof
  • Tetrahydro indazolone or tetrahydro indolone substituted indazole derivative and salt thereof
  • Tetrahydro indazolone or tetrahydro indolone substituted indazole derivative and salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Example 1.1-(6-(3-amino-1-methyl)indazole)-3,6,6-trimethyl-1,5,6,7-tetrahydroindazol-4-one

[0075] (Compound I-01)

[0076] Add 3,6,6-trimethyl-1,5,6,7-tetrahydroindazol-4-one (0.20 g, 1.1 mmol), dry DMF (15 ml), sodium hydride ( 33 mg, 1.3 mmol), A3 (0.3 g, 1.1 mmol) was added with stirring, and the reaction was heated to 150°C and stirred for 2 hours. After cooling, it was extracted with ethyl acetate, washed with saturated NaCl aqueous solution, and dried over anhydrous magnesium sulfate. Filtration, removal of solvent, separation and purification of the product by silica gel column chromatography, eluting with ethyl acetate / cyclohexane (60:40) to obtain 0.34 g of intermediate, which was dissolved in trifluoroacetic acid (15 ml) at room temperature After stirring for 2 hours, the solvent was removed under reduced pressure, extracted with ethyl acetate, washed with saturated NaCl aqueous solution, and dried over anhydrous magnesium sulfate. Filtration, removal o...

Embodiment 2

[0077] Example 2.1-(6-(3-amino-1-propenyl)indazole)-3,6,6-trimethyl-1,5,6,7-tetrahydroindazol-4-one

[0078] (Compound I-02)

[0079] Taking intermediate A4 as starting material, synthesize 1-(6-(3-amino-1-propenyl) indazole)-3,6,6-trimethyl-1,5 with the method in Example 1, 6,7-tetrahydroindazol-4-one, yield 54% (two steps); mp (°C) 173-175; 1 HNMR (500MHz, DMSO-D 6 )δ (ppm): 7.71-7.73 (d, 1H), 7.39-7.41 (b, 1H), 7.11-7.13 (d, 1H), 5.75 (m, 1H), 4.95-4.98 (m, 2H), 3.97 (m, 2H), 3.72(s, 2H), 2.64(s, 3H), 2.42(s, 2H), 2.37(s, 2H), 1.07-1.10(s, 6H); MS 350.2(M + +1).

Embodiment 3

[0080] Example 3.1-(6-(3-amino-1-(3-(1-methylcyclohexyl-4-amino)-4-carbamoylphenyl))indazole)-3,6,6-tri Methyl-1,5,6,7-tetrahydroindazol-4-one

[0081] (Compound I-03)

[0082]According to the method of Example 1, the corresponding 1-(6-(1-tert-butoxy Formyl-3-tert-butoxycarboxamido)indazole)-3,6,6-trimethyl-1,5,6,7-tetrahydroindazol-4-one, yield 78%; mp( ° C) 157-159; 1 HNMR (500MHz, DMSO-D 6 )δ (ppm): 7.92-7.94 (b, 1H), 7.69-7.71 (d, 1H), 7.51-7.53 (d, 1H), 6.78-6.80 (m, 1H), 2.66 (s, 3H), 2.44 (s, 2H), 2.35 (s, 2H), 1.08-1.11 (s, 6H); MS 510.3 (M + +1).

[0083] The above product (0.25 g, 0.4 mmol) was dissolved in trifluoroacetic acid (15 mL) to remove tert-butoxyformyl to give the corresponding 1-(6-(1H-3-amino)indazole)-3,6,6 - Trimethyl-1,5,6,7-tetrahydroindazol-4-one 0.1 g, yield 80%. 1-(6-(1H-3-amino)indazole)-3,6,6-trimethyl-1,5,6,7-tetrahydroindazol-4-one (0.1 g, 0.3 mmol ) was dissolved in dry DMF (15 ml), sodium hydride (10 mg, 0.4 mmol) was added, and ...

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Abstract

The invention relates to tetrahydroindazolone or tetrahydroindazolone-substituted indazole derivatives with right general formula (I) or (II) and pharmaceutically acceptable salt thereof. The compounds and the pharmaceutically acceptable salt thereof are characterized by inhibiting growth of tumor cells and malignant cells. The tumor cells comprise cancer cells such as breast cancer, lung cancer, cervical carcinoma, rectum cancer, prostatic cancer, liver cancer, blood cancer and the like, thus the tetrahydroindazolone or tetrahydroindazolone-substituted indazole derivatives and the salt thereof can be used for preparing drugs for preventing and treating the breast cancer, the lung cancer, the cervical carcinoma, the rectum cancer, the prostatic cancer, the liver cancer and the blood cancer.

Description

technical field [0001] The present invention relates to tetrahydroindazolone or tetrahydroindolinone substituted indazole derivatives and their salts, their preparation methods and their application in anti-tumor drugs. Background technique [0002] In the past ten years, great progress has been made in tumor treatment, and new anticancer drugs enter the market every year, which improves the survival and quality of life of cancer patients. However, cancer is still the number one killer that endangers people's health. Anticancer drugs currently used clinically have defects such as high toxicity and poor drug resistance. Many of these drugs stop cancer cell growth by inhibiting DNA synthesis. However, these drugs not only kill cancer cells, but also have the same killing effect on normal cells. As a result, these drugs often also cause irreversible toxicity and side effects to patients. People are eager to get new and effective anti-tumor drugs. Contents of the invention...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/56C07D403/12C07D403/14C07D401/14C07D403/04A61K31/416A61K31/454A61K31/5377A61P35/00
Inventor 王一飞邢国文夏敏钱垂文熊盛张美英刘秋英杨柯
Owner 广州少伯控股集团有限公司
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