Quinazolinone derivatives inhibiting pi3k and pharmaceutical compositions containing them

A composition and drug technology, applied in the field of novel quinazolinone derivatives, can solve the problems of development termination and poor selectivity, and achieve the effects of solving side effects and reducing immunotoxicity

Inactive Publication Date: 2020-06-23
BIOWAY INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, during the clinical trial, the development of Duvelisib was terminated due to issues similar to Adeleris
The inhibitory potency of this substance is known to be less selective for PI3Kδ and PI3Kγ than for PI3Kβ

Method used

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  • Quinazolinone derivatives inhibiting pi3k and pharmaceutical compositions containing them
  • Quinazolinone derivatives inhibiting pi3k and pharmaceutical compositions containing them
  • Quinazolinone derivatives inhibiting pi3k and pharmaceutical compositions containing them

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0183] Example 1: (S)-2-(((7H-purin-6-yl)amino)(cyclopropyl)methyl)-5-fluoro-3-phenylquinazolin-4(3H)-one Preparation of (Formula 7)

[0184] [Reaction 1]

[0185]

[0186] Step 1: Preparation of (S)-tert-butylcyclopropyl(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)methylcarbamate

[0187] To a solution in which 2-amino-6-fluorobenzoic acid (1.0 equiv) and (S)-2-(tert-butoxycarbonylamino)-2-cyclopropylacetic acid (1.0 equiv) were mixed in pyridine solvent Triphenyl phosphite (1.4 equiv) was added while stirring the solution at room temperature. The resulting mixture was stirred at 55°C to 60°C for 12 hours. Aniline (1.4 equivalents) was added thereto, followed by reaction at about 110°C for 7 hours. Thereafter, the mixed reaction solution was cooled to room temperature and extracted with ethyl acetate and water. The obtained organic layer was washed with anhydrous magnesium sulfate (MgSO 4 ) was dehydrated and concentrated under reduced pressure. n-heptane was...

Embodiment 2

[0197] Example 2: (S)-2-(((7H-purin-6-yl)amino)(cyclopropyl)methyl)-5-methyl-3-phenylquinazoline-4(3H)- Preparation of ketone (Formula 8)

[0198] [Reaction 2]

[0199]

[0200] Step 1: Preparation of (S)-tert-butylcyclopropyl(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)methylcarbamate

[0201] (S)-tert-butylcyclopropyl (5-methyl-4- Oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)methylcarbamate.

[0202] 1 H NMR (400MHz, CDCl 3 ):δ8.33(br.s.,3H),7.50(d,4H,J=7.9Hz), 7.28(t,11H,J=7.7Hz),7.07(t,2H,J=7.3Hz), 5.35(br.s.,1H),3.61(br.s.,3H),1.32-1.51(m,12H),1.17-1.30(m,1H),0.51-0.73(m,4H),0.47(td , 3H, J=4.7, 9.6Hz).

[0203] Step 2: Preparation of (S)-2-(amino(cyclopropyl)methyl)-5-methyl-3-phenylquinazolin-4(3H)-one

[0204] (S)-2-(Amino(cyclopropyl)methyl)-5-methyl-3-phenylquinazolin-4(3H)-one was prepared in the same manner as in Example 1.

[0205] 1 H NMR (400MHz, DMSO-d 6):δ8.41(br.s.,2H),7.79(t,1H,J=7.7 Hz),7.54-7.73(m,2H),7.31-7.46(m,1H),2.74(s,3H) , 1.23 (br....

Embodiment 3

[0210] Example 3: (S)-2-(((7H-purin-6-yl)amino)(cyclopropyl)methyl)-5-amino-3-phenylquinazolin-4(3H)-one Preparation of (Formula 9)

[0211] [reaction formula 3]

[0212]

[0213] Step 1: (S)-2-(((7H-purin-6-yl)amino)(cyclopropyl)methyl)-5-((4-methoxybenzyl)amino)-3-phenyl Preparation of quinazolin-4(3H)-one

[0214] Accommodate (S)-2-(((7H-purin-6-yl) amino) (cyclopropyl )methyl)-5-fluoro-3-phenylquinazoline-4(3H) (1.0 equiv) and triethylamine (5.0 equiv), and 4-methoxybenzylamine was added.

[0215] Subsequently, the tube was replaced with nitrogen and sealed, and then the reaction mixture was heated to 180° C. and reacted for one day. After cooling to room temperature, the ethanol solvent was removed under reduced pressure. After this time, the crude mixture was subjected to silica gel column chromatography (dichloromethane / methanol 20:1) to afford (S)-2-(((7H-purin-6-yl)amino)(cyclopropyl )methyl)-5-((4-methoxybenzyl)amino)-3-phenylquinazolin-4(3H)-one (yield: 38%...

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Abstract

The present invention relates to novel quinazolinone derivatives that inhibit PI3K; methods for preparing the derivatives; and pharmaceutical compositions containing quinazolinone derivatives for treating hematological malignancies or liver diseases, wherein, according to the present invention The invented novel quinazolinone derivatives have beneficial effects in treating hematological malignancies or liver diseases. In particular, compared with traditional PI3Kδ inhibitor anticancer drugs, quinazolinone derivatives inhibit PI3Kδ with high selectivity, thereby significantly reducing immunotoxicity, or simultaneously inhibit PI3Kδ and PI3Kγ, thereby making autoimmune The treatment of diseases and the anti-cancer treatment of hematological malignancies are possible. These targeted drugs have the advantage of being able to address the side effects of traditional highly toxic anticancer therapies.

Description

technical field [0001] The present invention relates to novel quinazolinone derivatives that inhibit PI3K and methods of preparing these derivatives. [0002] In addition, the present invention provides a pharmaceutical composition for treating hematological malignancy, liver disease or autoimmune disease, said pharmaceutical composition comprising the quinazolinone derivative. Background technique [0003] Cancer is the second leading cause of death in the United States after heart disease (Cancer Facts and Figures 2005, American Cancer Society, Inc.). In the early stages of cancer development, chemotherapy, radiation therapy, etc. to remove tumors or kill cancer cells can be chosen, but in the case of advanced cancer patients, the side effects due to aggressive treatment are relatively large and the response rate after treatment Low, and thus can choose therapies that reduce side effects by delaying cancer progression and improving quality of life. In these respects, ant...

Claims

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Application Information

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Patent Type & AuthorityPatents(China)
IPC IPC(8): A61K31/52A61K31/517C07D473/34C07D239/88
CPCA61K31/52A61P1/16A61P35/00A61P35/02A61P37/00C07D239/91C07D473/34Y02P20/55A61K31/517C07D239/88
Inventor金钟宇李致雨洪琇智
OwnerBIOWAY INC