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Novel thiazole derivative compound as well as preparation method, pharmaceutical composition and pharmaceutical application of novel thiazole derivative compound

A compound, thiazole technology, applied in the field of thiazole derivatives, can solve the problems of limited tumor cell inhibitory ability, limited influence of downstream signals, and drug resistance, and achieve high tumor cell proliferation inhibitory ability, weak normal cell toxicity, and increased The effect of binding ability

Inactive Publication Date: 2018-01-09
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The classic representative drugs of mTOR single inhibitors are rapamycin and its derivatives. mTOR single inhibitors can easily lead to drug resistance. When rapamycin derivatives inhibit mTOR, there will be feedback activation of Akt, resulting in the reactivation of PI3K signaling pathway , so rapamycin has limited ability to inhibit tumor cells in in vitro tumor cell inhibition experiments
[0005] PI3K single inhibitors can avoid the feedback activation of Akt due to the inhibition of mTOR, but because PI3K is located upstream of mTOR, inhibiting PI3K alone has limited influence on downstream signaling
PI3K / mTOR dual inhibitors have stronger inhibitory ability, but may also bring more obvious side effects

Method used

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  • Novel thiazole derivative compound as well as preparation method, pharmaceutical composition and pharmaceutical application of novel thiazole derivative compound
  • Novel thiazole derivative compound as well as preparation method, pharmaceutical composition and pharmaceutical application of novel thiazole derivative compound
  • Novel thiazole derivative compound as well as preparation method, pharmaceutical composition and pharmaceutical application of novel thiazole derivative compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0131] Example 1: Preparation of 1-(4-(2,4-dimorpholinobenzothiazol-6-yl)phenyl)-3-ethylurea

[0132]

[0133] Step 1: Preparation of 2,4,6-tribromoisothiocyanate (Intermediate 1)

[0134] Add 2,4,6-tribromoaniline (20g, 60.6mmol) into dichloromethane (100ml) at room temperature, and add thiophosgene (20.9g, 181.8mmol) to dichloromethane once dissolved . DMAP (4-dimethylaminopyridine) (37.01 g, 303 mmol) was dissolved in dichloromethane (100 ml), and slowly added dropwise to the reaction solution within 1 h, and the reaction was stopped after stirring for 5 hours. Column chromatography gave 2,4,6-tribromoisothiocyanate (21.41 g, 57.6 mmol, yield 95%).

[0135] Step 2: Preparation of 2-morpholino-4,6-dibromo-benzothiazole (intermediate 2)

[0136] 2,4,6-Tribromoisothiocyanate (21.41g, 57.6mmol) was dissolved in dioxane (250ml) at room temperature, morpholine (5.27g, 60.48mmol) was added, and the reaction was stirred for 30min. After all the raw materials were reacted, ce...

Embodiment 2

[0140] Example 2: Preparation of 1-cyclopropyl-3-(4-(2,4-dimorpholinobenzothiazol-6-yl)phenyl)urea

[0141]

[0142] Carry out synthesis according to the synthesis method of the compound of Example 1, change the 6-position side chain into 4-isopropylurea-phenylboronic acid pinacol ester, obtain white powder 1-cyclopropyl-3-(4-(2,4 - pure dimorpholinobenzothiazol-6-yl)phenyl)urea (total yield: 27.2%). m.p.238-240℃; 1 H-NMR (400MHz, DMSO-d 6 δppm), 8.39(s, 1H), 7.64(s, 1H), 7.56(d, 2H, J=8.0Hz), 7.47(d, 2H, J=8.0Hz), 6.96(s, 1H), 6.41(s , 1H), 3.80(s, 4H), 3.75(s, 4H), 3.53(s, 4H), 3.38(s, 4H), 3.12(m, 2H), 1.99(s, 1H), 1.17(t, 1H, J=8.0Hz), 0.65(d, 2H, J=8.0Hz), 0.41(s, 2H); EI-MS: 480.1[M+1] + .

Embodiment 3

[0143] Example 3: Preparation of 1-benzyl-3-(4-(2,4-dimorpholinobenzothiazol-6-yl)phenyl)urea

[0144]

[0145]Carry out synthesis according to the synthesis method of the compound of Example 1, change the 6-position side chain into 4-benzyl urea-phenylboronic acid pinacol ester, obtain white powder 1-benzyl-3-(4-(2,4- Pure dimorpholinobenzothiazol-6-yl)phenyl)urea mTOR-20 (total yield: 24.5%). m.p.252-255℃; 1 H-NMR (400MHz, DMSO-d 6 δppm), 8.68(s, 1H), 7.64(s, 1H), 7.58(d, 2H, J=8.0Hz), 7.48(d, 2H, J=8.0Hz), 7.33(m, 4H), 7.25(m , 1H), 6.96(s, 1H), 6.66(t, 1H, J=4.0Hz), 4.32(s, 2H, J=4.0Hz), 3.80(s, 4H), 3.75(s, 4H), 3.54 (s, 8H); EI-MS: 530.2[M+1] + .

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Abstract

The invention belongs to the field of pharmaceutical and chemical industries and relates to a compound as shown in a general formula I, a pharmaceutical salt or a hydrate of the compound, a preparation method of the compound as shown in the general formula I, a pharmaceutical composition containing the compound as shown in the general formula I or the pharmaceutical salt or the hydrate of the compound and an application of the compound as shown in the general formula I or the pharmaceutical salt or the hydrate of the compound in production of drugs, wherein the compound as shown in the generalformula I has an effect on inhibiting a PI3K / Akt / mTOR signal pathway of a mammal, all substituent groups in the general formula I are defined as the specification, and the drugs are used for treatingdiseases caused by abnormal expression of the PI3K / Akt / mTOR signal pathway of the mammal.

Description

technical field [0001] The present invention relates to thiazole derivative compounds, which are used in the field of antitumor drugs and related diseases caused by PI3K / Akt / mTOR pathway signal disturbance. The present invention also relates to the preparation methods of these compounds, pharmaceutical compositions containing them and their use as medicines application. Background technique [0002] The PI3K / Akt / mTOR signaling pathway mainly includes three members: PI3K (phosphoinositide-3-kinase, PI3K), Akt and mTOR. PI3K is an esterase, which mainly exists in the cytoplasm in the resting state; when PI3K is fully activated, it catalyzes the transformation of the substrate PIP2 into PIP3, and PIP3 acts as a second messenger to activate the downstream Akt. Akt is a key protein downstream of PI3K, and it is a highly conserved serine / threonine protein kinase in evolution. It is mostly located in the cytoplasm in the resting state; activated Akt can phosphorylate and inhibit t...

Claims

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Application Information

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IPC IPC(8): C07D277/82C07D417/04C07D417/12C07D417/14A61K31/5377A61K31/541A61P35/00A61P35/02A61P37/06A61P31/04A61P31/12A61P39/06A61P25/28A61P29/00A61P9/10
Inventor 钟武李松曹爽曹瑞源杨晶晶
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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