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PI3K inhibitor, preparation method and application thereof in pharmacy
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A technology of inhibitors and drugs, applied in the field of medicine
Inactive Publication Date: 2016-11-16
FUDAN UNIV
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However, due to reasons such as toxicity, solubility and stability, it failed to enter clinical trials (Kong D et al., J.Curr.Med.Chem., 2009,16(22)2839-2854)
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[0095] 1: Preparation of N-(2-chloro-5-bromopyridin-3-yl)benzenesulfonamide (1-J)
[0096]
[0097] In a 100mL round bottom flask, add dichloromethane (DCM) (50mL), 3-amino-2-chloro-5-bromopyridine (B1) (5.0g, 24.0mmol), pyridine (3.8g, 48mmol), ice Under cooling in a water bath, benzenesulfonyl chloride (D1) (5.3 g, 31 mmol) was added dropwise. The reaction solution was slowly raised to room temperature, stirred for 24 h, followed by HPLC. After the reaction, pour it into water (30mL), separate the layers, wash the organic phase with saturated aqueous citric acid solution (50ml), saturated sodiumbicarbonate (50ml), and saturated brine, dry over anhydroussodiumsulfate, filter, and concentrate to remove DCM, a solid precipitated out. Recrystallization with petroleumether (PE) / DCM gave light whitesolid product N-(2-chloro-5-bromopyridin-3-yl)benzenesulfonamide (1-J), MS (ESI...
[0107] Preparation of N-[2-chloro-5-(quinolin-6-yl)pyridin-3-yl]benzenesulfonamide (compound 2)
[0108]
[0109] The experimental procedure is the same as the synthesis of compound 1 in Example 1, except that 3-bromoquinoline (Q3) is replaced by 6-bromoquinoline (Q6) to obtain compound 2. MS(ESI positive ion)m / z:396.86(M+1),1HNMR(400MHz,CDCl 3): δppm3.857(s, 1H), 7.504(t, J=7.6Hz, 2H), 7.597-7.616(m, 1H), 7.831-7.851(m, 2H), 7.903(d, J=8.0Hz, 1H), 8.010(d, J=8.0Hz, 1H), 8.236-8.284(m, 2H), 8.343(d, 2.8Hz, 2H), 8.477(d, J=2.0Hz, 1H), 8.991(d, J=4.0Hz, 1H).
[0113] Preparation of N-{2-chloro-5-[1H-pyrrole(2,3-b)pyridin-5-yl]pyridin-3-yl}benzenesulfonamide (Compound 3)
[0114]
[0115] The experimental procedure is the same as the synthesis of compound 1 in Example 1, except that 3-bromoquinoline (Q3) is replaced by 5-bromo-1H-pyrrole [2,3-b] pyridine (B3) to obtain the product N-{ 2-Chloro-5-[1H-pyrrole(2,3-b)pyridin-5-yl]pyridin-3-yl}benzenesulfonamide (3). MS(ESI positive ion)m / z:385.84(M+1),1HNMR(400MHz,DMSO-d6):δppm6.551(s,1H),7.595(t,J=8.0Hz,3H),7.695(d ,J=6.8Hz,1H),7.783(d,J=7.2Hz,2H),7.954(d,J=2.4Hz,1H),8.224(d,J=2.0Hz,1H),8.451(d,J =2.0Hz, 1H), 8.613(d, J=2.0Hz, 1H), 10.440(s, 1H), 11.866(s, 1H).
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Abstract
The invention belongs to the technical field of pharmaceuticals and particularly relates to a PI3K inhibitor, a preparation method and application thereof in the pharmacy. The PI3K inhibitor is a compound of the structure shown by the general formula I or medically acceptable salt of the inhibitor. After the PI3K inhibitor is tested with a PI3K biochemical activity test method, the compound has excellent inhibitory activity to PI3K alpha and PI3K gamma, wherein the IC50 values of a plurality of compounds to the PI3K alpha and PI3K gamma reach nanomole grades (smaller than 100 nM). The result shows that the compounds can provide the inhibitor with better effectiveness and selectivity for curing PI3K-acted proliferative disease, and further a targeted drug for curing No. I type diabetes mellitus, lungdisease, breast cancer, prostatic cancer, solid tumor, lymphoma, cardiovascular disease, rheumatoid arthritis, leukemia and the like can be hopefully developed. (Please see the general formula I in the description.).
Description
technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a PI3K inhibitor, a preparation method thereof and an application in pharmacy. Background technique [0002] Cancer is one of the major diseases that threaten human health. According to the third national cause of death survey released by the Ministry of Health in 2008, cancer has become the first cause of death in my country's urban population. Molecularly targeted anticancer drugs, as new anticancer drugs, act on specific molecular targets of tumor cells, and selectively inhibit the proliferation of tumor cells by taking advantage of the differences between tumor cells and normal cells in many aspects such as genes, enzymes, and signal transduction. , invasion, metastasis and other malignant biological behaviors, thereby producing anti-tumor effects, while having less toxic side effects on normal cells. Therefore, molecularly targeted anticancer drugs rarely produ...
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