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Imidazo quinoline PI3K and mTOR (mammalian target of rapamycin) dual inhibitor

A technology of CH2 and compounds, applied in the field of medicine

Active Publication Date: 2012-03-14
SHANDONG XUANZHU PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no PI3K / mTOR dual inhibitor drug on the market. Therefore, it is necessary to develop more structural types of PI3K / mTOR dual inhibitors, and select compounds with better efficacy and safety for the treatment of cancer.

Method used

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  • Imidazo quinoline PI3K and mTOR (mammalian target of rapamycin) dual inhibitor
  • Imidazo quinoline PI3K and mTOR (mammalian target of rapamycin) dual inhibitor
  • Imidazo quinoline PI3K and mTOR (mammalian target of rapamycin) dual inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 18

[0172] Example 18-(2-methoxypyridin-5-yl)-3-methyl-2-oxo-1-(piperidin-4-yl)-2,3-dihydroimidazo[4,5 -c] quinoline (Compound 1) Preparation

[0173] Preparation of step 1-a 2-nitro-1-hydroxyaminoethylene

[0174]

[0175] Add 6.4g (105mmol) of nitromethane into a mixture of 28g of ice and 12.4g (310mmol) of NaOH cooled in an ice bath, stir at 0°C for 1 hour, then stir at room temperature for 1 hour, add 22.4g of the solution at 0°C Ice and 32.8mL concentrated hydrochloric acid (37%) (solution A), ready to put into the next reaction immediately.

[0176] Preparation of step 1-b 5-bromo-2-(2-nitro-vinylamino)benzoic acid

[0177]

[0178] 10g (46.3mmol) of 2-amino-5-bromo-benzoic acid in H 2 Stir in a solution of O-HCl (37%) (10:1) for 2 hours, then filter to make solution B, combine solution A and solution B at room temperature, stir for 18 hours, filter out the yellow precipitate, wash with water, and dry 10.2 g of the product was obtained with a yield of 76.8%.

...

Embodiment 28

[0205] Example 28-(2-methoxypyridin-5-yl)-3-methyl-2-oxo-1-[N-[(R)-2-hydroxypropionyl]piperidin-4-yl] -2,3- Preparation of dihydroimidazo[4,5-c]quinoline (compound 2)

[0206]

[0207] Compound 1 (160mg, 0.41mmol), 1-hydroxybenzotriazole (100mg, 1.1mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (150mg, 0.8mmol), triethylamine (360mg) and D-lactic acid (72mg, 0.8mmol), the reaction solution was stirred at room temperature for 17h, the reaction solution was evaporated to dryness, and 18mg of the product was obtained through the preparative liquid phase, with a yield of 9.5%.

[0208] Molecular formula: C 25 h 27 N 5 o 4 Molecular weight: 461.51MS: 462 (M+H + )

[0209] 1 H NMR (d 6 -DMSO) δ1.19 (2H, m), 1.21 (3H, s), 2.02-2.07 (2H, m), 2.56 (1H, m), 2.87 (1H, m), 3.50 (3H, s), 3.92 (3H,s), 4.16-4.20(1H,m), 4.49-4.57(2H,m), 5.13(1H,m), 7.01(1H,d), 8.24(1H,dd), 8.72(1H,d ), 8.79(1H,d), 9.00(1H,s), 9.26(1H,d).

Embodiment 38

[0210] Example 38-(2-methoxypyridin-5-yl)-3-methyl-2-oxo-1-(N-hydroxyacetylpiperidin-4-yl)-2,3-dihydroimidium Preparation of Azolo[4,5-c]quinoline (Compound 3)

[0211]

[0212] Compound 1 (130mg 0.33mmol), 1-hydroxybenzotriazole (100mg, 1.1mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (120mg, 0.63 mmol), triethylamine (350mg) and glycolic acid (50mg, 0.66mmol), the reaction solution was stirred at room temperature for 48h, the reaction solution was evaporated to dryness, and 18mg of the product was obtained through the preparative liquid phase, with a yield of 12.3%.

[0213] Molecular formula: C 24 h 25 N 5 o 4 Molecular weight: 447.49MS: 448 (M+H + )

[0214] 1 H NMR (CDC1 3 )δ8.73(s, 1H), 8.46(d, 1H), 8.25(s, 1H), 8.24(s, 1H), 7.86(dd, 1H), 7.79-7.82(m, 1H), 6.92(d , 1H), 5.10(s, 1H), 4.93-4.95(m, 1H), 4.22-4.30(m, 2H), 4.02(s, 3H), 3.79-3.83(m, 1H), 3.60(s, 3H ), 3.20-3.26(m, 1H), 2.76-2.92(m, 3H), 2.10(d, 2H)

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to an imidazo quinoline PI3K and mTOR (mammalian target of rapamycin) dual inhibitor disclosed in a general formula (I) and clinically-acceptable salt or stereoisomer thereof, wherein R1, R2, R3, R3', R4, R4', R5 and X are defined as in a specification. The invention also relates to a preparation method of the compounds, a medicine preparation containing the compounds and the application of the compounds in preparing medicines capable of treating and / or preventing proliferative diseases.

Description

1. Technical field [0001] The invention belongs to the field of medical technology, and in particular relates to imidazoquinoline PI3K and mTOR dual inhibitors, pharmaceutically acceptable salts or stereoisomers thereof, preparation methods of these compounds, pharmaceutical preparations containing these compounds, and these Application of the compound in the preparation of medicines for treating and / or preventing proliferative diseases. 2. Background technology [0002] Tumor is a new organism formed by the body under the action of various tumorigenic factors, causing changes in the genetic material of cells, resulting in abnormal gene expression and abnormal proliferation of cells. Tumor cells lose their normal growth regulation function and have the ability to grow independently or relatively independently. When the tumorigenic factors are stopped, they can continue to grow and consume a large amount of nutrients in the human body. If not found and treated in time, cance...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D519/00A61K31/4745A61P35/00A61P17/00A61P13/08
Inventor 黄振华
Owner SHANDONG XUANZHU PHARMA TECH CO LTD
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