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Quinazoline dione derivatives and preparation method and application thereof

A kind of technology of quinazoline dione and derivatives, applied in the field of medicine, can solve problems such as unsatisfactory drug effect and the like

Inactive Publication Date: 2016-11-23
ZHEJIANG UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the CB2 agonist GW842166X reported by GSK has completed three clinical phase II studies as an analgesic drug, but the drug effect is not satisfactory (Giblin, G.M.P.; et al. Discovery of 2-[(2,4-Dichlorophenyl) amino]-N-[(tetrahydro-2H-pyran-4-yl)methyl]-4-(trifluoromethyl)-5-pyrimi dinecarboxamide, a Selective CB2 Receptor Agonist for the Treatment of Inflammatory Pain.J.Med.Chem.2007,50 , 2597-2600); CB2 agonist S-777469 as a candidate drug for the treatment of atopic dermatitis has also completed clinical phase II research (Odan, M., et al., Discovery of S-777469: an orally available CB2agonist as an antipruriticagent. Bioorg. Med. Chem. Lett., 2012, 22, 2803-2806)
At present, the research on CB2 selective ligands is mostly concentrated in the preclinical stage and clinical research stage, and there is no marketed drug yet

Method used

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  • Quinazoline dione derivatives and preparation method and application thereof
  • Quinazoline dione derivatives and preparation method and application thereof
  • Quinazoline dione derivatives and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101] Example 1: N-tert-butyl-2-(1-cyclopropylmethyl-5-methyl-2,4-dione-1,2-dihydroquinazolin-3(4H)-yl)ethyl Amide (compound 1)

[0102] a) 2-chloro-N-tert-butylacetamide (compound 1a)

[0103] Put tert-butylamine (438.8mg, 6.00mmol) and potassium carbonate (995.1mg, 7.20mmol) in 6mL of dichloromethane solution, and slowly add chloroacetyl chloride (677.6mg, 6.00mmol) dropwise to the above reaction flask under ice-cooling medium, room temperature overnight. After the reaction, an appropriate amount of water was added, extracted with dichloromethane, the combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to obtain a crude product as a white solid. Yield: 74.9%; Melting point: 81.0-82.1°C.

[0104] b) 2-amino-N-tert-butyl-6-methylbenzamide (compound 1b)

[0105] 2-amino-6-methylbenzoic acid (800.0mg, 5.29mmol) was placed in a 50mL single-necked round bottom flask, N 2 After replacement, add...

Embodiment 2

[0121] Example 2: 2-(1-(3-buten-1-yl)-5-methyl-2,4-dione-1,2-dihydroquinazolin-3(4H)-yl)- N-tert-butylacetamide (compound 2)

[0122] a) 1-(3-buten-1-yl)-3-tert-butyl-5-methylquinazoline-2,4(1H,3H)-dione (compound 2a)

[0123] The experimental method was the same as the preparation method of compound 1e in Example 1, except that bromomethylcyclopropane was replaced by 4-bromo-1-butene to obtain a yellow liquid, which was directly used in the next reaction.

[0124] b) 1-(3-buten-1-yl)-5-methylquinazoline-2,4(1H,3H)-dione (compound 2b)

[0125] The experimental method was the same as that of compound 1f in Example 1, except that compound 2a (42.6 mg, 0.15 mmol) was used instead of compound 1f to obtain a white solid. Yield: 42.9%; Melting point: 167.4-168.8°C.

[0126] 1 H NMR (500MHz, CDCl 3 )δ8.42(s, 1H), 7.54(t, J=8.0Hz, 1H), 7.08(d, J=8.5Hz, 1H), 7.05(d, J=7.5Hz, 1H), 5.92-5.84( m, 1H), 5.15-5.10(m, 2H), 4.20-4.16(m, 2H), 2.82(s, 3H), 2.52-2.47(m, 2H).

[0127] c) 2-...

Embodiment 3

[0130] Example 3: N-tert-butyl-2-(5-methyl-2,4-diketone-1-n-propyl-1,2-dihydroquinazolin-3(4H)-yl)acetamide (compound 3)

[0131] a) 3-tert-butyl-5-methyl-1-propylquinazoline-2,4(1H,3H)-dione (compound 3a)

[0132] The experimental method was the same as the preparation method of compound 1e in Example 1, except that bromomethylcyclopropane was replaced by bromo-n-propane to obtain a yellow liquid, which was directly used in the next reaction.

[0133] b) 5-methyl-1-propylquinazoline-2,4(1H,3H)-dione (compound 3b)

[0134] The experimental method was the same as that of compound 1f in Example 1, except that compound 3a (53.8 mg, 0.20 mmol) was used instead of compound 1f to obtain a white solid. Yield: 70.3%; Melting point: 183.8-184.8°C.

[0135] 1 H NMR (500MHz, CDCl 3 )δ8.46(s, 1H), 7.52(t, J=7.5Hz, 1H), 7.07(d, J=8.5Hz, 1H), 7.04(d, J=7.5Hz, 1H), 4.06(t, J=7.5Hz, 2H), 2.82(s, 3H), 1.79-1.75(m, 2H), 1.04(t, J=7.0Hz, 3H).

[0136] c) N-tert-butyl-2-(5-methyl-2,4-dione...

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Abstract

The invention provides novel quinazoline dione derivatives and a preparation method and application thereof. The compounds include compounds with the structure shown in the general formula V in the description and pharmaceutically acceptable salts or hydrates thereof. The compounds are active ligands of novel cannabinoid II receptors (CB2) and can be used for preparing medicine for treating, preventing and relieving CB2 receptor-mediated diseases, wherein the medicine is an agonist or partial agonist or inverse agonist or antagonist of CB2 receptors.

Description

technical field [0001] The invention belongs to the field of medical technology, and in particular relates to a compound with quinazolinedione as its core and its pharmaceutically acceptable salt or hydrate, its preparation method and the role of this type of compound in the treatment, prevention and inhibition of CB2 Drug applications for receptor-mediated diseases. Background technique [0002] The plant cannabis has been used as medicine for thousands of years, and its active components are collectively known as cannabinoids. In 1964, Gaoni and Mechoulam reported that the main active ingredient of cannabis is Δ 9 - THC (Δ 9 -THC), which was subsequently isolated and confirmed, marking the beginning of modern human research on cannabinoids. Cannabinoids mainly act on cannabinoid receptors in the human body. There are two main types of cannabinoid receptors that are widely known at present, namely, cannabinoid type I receptor (CB1) and cannabinoid type II receptor (CB2)...

Claims

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Application Information

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IPC IPC(8): C07D239/96A61K31/517A61P35/00A61P29/00A61P31/18A61P37/00A61P37/08A61P1/16A61P9/10A61P19/10A61P25/00A61P37/02A61P25/16A61P25/28A61P25/14
CPCC07D239/96
Inventor 陈建忠谢欣钱海燕韩爽王志龙
Owner ZHEJIANG UNIV
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