Aminoquinazolinone and aminoisoquinolinone derivatives and application thereof

A technology of aminoisoquinolinone and aminoquinazolinone, which is applied in the fields of aminoquinazolinone and aminoisoquinazolinone derivatives, anti-tumor and anti-inflammatory diseases, and can solve the problem of poor selectivity. , liver toxicity and side effects, poor pharmacokinetic properties and other problems, to achieve the effect of structural optimization, improved pharmacokinetic properties, and good clinical application prospects

Active Publication Date: 2019-03-26
ZHEJIANG UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although many PI3K inhibitors have been developed by people, there are still some defects in the two drugs that have been marketed. For example, Idelalisib can cause elevated transaminases in CLL patients and has certain toxic side effects on the liver; while Copanlisib has multiple subtypes of PI3K. The activity of Copanlisib is very high, but the selectivity is p

Method used

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  • Aminoquinazolinone and aminoisoquinolinone derivatives and application thereof
  • Aminoquinazolinone and aminoisoquinolinone derivatives and application thereof
  • Aminoquinazolinone and aminoisoquinolinone derivatives and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] Example 1: 2-amino-N-(8-methoxy-3-methyl-7-(3-morpholinopropyl)-4-oxo-3,4-dihydroquinazolone-2 -yl) Preparation of pyrimidine-5-carboxamide (compound 8a-1)

[0090]

[0091] Step 1 Preparation of 2-amino-3-methoxy-4-benzyloxy-N-methylbenzamide (compound 5a-1)

[0092] Dissolve 2-amino-3-methoxy-4-benzyloxybenzoic acid (4,546mg, 2mmol) in 20mL DCM, add methylamine hydrochloride (102mg, 2.4mmol), HOBT (405mg, 3mmol) successively , DIC (378mg, 3mmol), triethylamine (0.83mL, 6mmol), stirred at room temperature for 2h, added water, extracted with dichloromethane, combined organic layers, washed with saturated NaCl, anhydrous Na 2 SO 4 Dry, recover the solvent to get white powder 0.48g, Yield: 80%; ESI-MS: 287.1[M+H] + .

[0093] Step 2. 2-Amino-N-(8-methoxy-3-methyl-7-benzyloxy-4-oxo-3,4-dihydroquinazolinone-2-yl)pyrimidine-5- Preparation of formamide (compound 6a-1)

[0094] 2-Amino-3-methoxy-4-benzyloxy-N-methylbenzamide (5a-1, 0.2mmol), 2-aminopyrimidine-5-acyl i...

Embodiment 2

[0102] Embodiment 2: the synthesis of compound 8a-2~8a-9

[0103] Using compound 7a-1 as raw material, chloroacetamide, chloropropionamide, N-methylchloroacetamide, N,N-dimethylchloroacetamide, 2-(2-chloroethyl)-4-methyl Morpholine, 1-(3-chloro-propionyl)-4-methylpiperazine, chloroacetylmorpholine, 4-chlorobutanamide, difluorochloromethane, chloroethylsulfonamide, TMSCF 3 , Chloropropyl sulfonamide instead of N-(3-chloropropyl) morpholine to prepare compounds 8a-2 to 8a-14. The series of target molecules are shown in Table 1 below.

[0104] Table 1

[0105]

Embodiment 3

[0106] Example 3: Synthesis of compounds 8a-14 to 8a-26 The synthetic route is shown in the following formula

[0107]

[0108] Using compound 5a-1 as a raw material, it was mixed with pyrimidine-5-formyl isothiocyanate, pyridazine-4-formyl isothiocyanate, 2-amino-pyridine-5-formyl isothiocyanate, respectively , 6-amino-pyridazine-3-formyl isothiocyanate, 2-amino-pyrazine-5-formyl isothiocyanate, 5-aminopyridine-2-formyl isothiocyanate, 3-cyano-benzoyl isothiocyanate, pyrazine-2-formyl isothiocyanate, pyrazole-4-formyl isothiocyanate, thiazole-4-formyl isothiocyanate Ester, purine-6-formyl isothiocyanate, benzimidazole-5-formyl isothiocyanate, benzothiophene-5-formyl isothiocyanate, etc. react first, and then under the action of EDC Ring closure to obtain intermediates 6a-2~6a-14, and then catalytic hydrogenation debenzylation with Pd / C to obtain 7a-2~7a-14, and finally they reacted with N-(3-chloropropyl)morpholine to finally obtain Target molecules 8a-14 to 8a-26. Its ...

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PUM

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Abstract

The invention provides aminoquinazolinone and aminoisoquinolinone derivatives. Through multiple experiments, it is validated that the synthesized compounds have excellent PI3Kalpha and PI3Kgamma inhibition effects, and most of the compounds have a significant inhibition effect on PI3Kalpha, and show a potent growth inhibition effect on tumor cell lines such as a PIK3CA-mutated human breast cancercell line (MCF7). Therefore, the aminoquinazolinone and aminoisoquinolinone derivatives can be applied to preparing antitumor and anti-inflammatory drugs, and can be applied to drugs for the treatmentof human or animal cell proliferation-related tumors as a PI3Kalpha inhibitor. The drugs are prepared from any one or more of the derivatives, and pharmaceutically acceptable salt and solvate of thederivatives, and a pharmaceutically acceptable carrier. The general formulas a and b of the compounds are shown in the description.

Description

technical field [0001] The invention relates to the field of medicines, in particular to an aminoquinazolinone and aminoisoquinolinone derivatives, a pharmaceutical composition containing them and their applications in the fields of anti-tumor and anti-inflammatory diseases. Background technique [0002] Although great progress has been made in early diagnosis and treatment of tumors in recent years, and anticancer drugs have been able to control or delay the development of some tumors, such as leukemia, the treatment of solid tumors, which account for more than 90% of malignant tumors, is far from satisfactory. The PI3K / Akt / mTOR signaling pathway regulates various cellular processes such as cell division and growth. Studies have found that this signaling pathway is often overactivated in tumor cells, and the key kinase PI3K, that is, phosphatidylinositol 3-kinase, is often found in tumor cells. In the state of overexpression, PI3K has many subtypes, including the inhibition...

Claims

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Application Information

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IPC IPC(8): C07D239/95C07D401/12C07D403/12C07D417/12C07D413/14C07D473/00C07D491/056A61K31/517A61K31/5377A61K31/519A61K31/506A61P35/00A61P35/02A61P29/00A61P37/08A61P11/06A61P19/02A61P19/08A61P11/00A61P17/06A61P13/12
CPCA61P11/00A61P11/06A61P13/12A61P17/06A61P19/02A61P19/08A61P29/00A61P35/00A61P35/02A61P37/08C07D239/95C07D401/12C07D403/12C07D413/14C07D417/12C07D473/00C07D491/056C07D405/04C07D471/04C07D401/14C07D403/14C07D491/107
Inventor 盛荣李佳顾东炎周宇波危俊张梦梦胡永洲张凯祥刘婕妤
Owner ZHEJIANG UNIV
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