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Pyridazine derivative and preparation method and application thereof

A kind of derivative, pyridazine technology, applied in the field of medicine, can solve the problems such as unsatisfactory drug effect

Inactive Publication Date: 2016-12-07
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 of2-[(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 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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  • Pyridazine derivative and preparation method and application thereof
  • Pyridazine derivative and preparation method and application thereof
  • Pyridazine derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0117] Embodiment 1: N-cyclohexyl-6-morpholine pyridazine-3-carboxamide (compound 1)

[0118] a) 1,4,5,6-tetrahydro-6-oxypyridazine-3-carboxylic acid (compound 1a)

[0119] Sodium hydroxide (0.69g, 17.25mmol) and hydrazine sulfate (1.02g, 7.85mmol) were placed in a 10mL double-necked flask, 4.5mL of hot water was added to dissolve it, and 1.8mL of hot α - Aqueous solution of ketoglutaric acid (1.14g, 7.81mmol), after the dropwise addition, the reaction solution was heated to slight boiling and reacted overnight. Stop the reaction, cool and stand in an ice bath to precipitate a white solid, which is suction filtered. The white solid obtained by suction filtration was recrystallized with 2N hydrochloric acid to obtain 691.1 mg of colorless needle crystals. Yield: 62%; Melting point: 197.6-200.3°C.

[0120] b) 1,6-dihydro-6-oxopyridazine-3-carboxylic acid (compound 1b)

[0121] Put compound 1a (568mg, 4.0mmol) in a 10mL double-necked flask, add 2mL of acetic acid, stir magnet...

Embodiment 2

[0130] Example 2: N-(adamantan-1-yl)-6-morpholine pyridazine-3-carboxamide (compound 2)

[0131] a) N-(adamantan-1-yl)-6-chloropyridazine-3-carboxamide (compound 2a)

[0132] The experimental method was the same as the preparation of compound 1d in Example 1, except that 1-adamantanamine was used instead of cyclohexylamine to obtain 103.6 mg of a yellow solid. Yield: 50%; Melting point: 200.8-202.1°C.

[0133] 1 H NMR (500MHz, CDCl 3 )δ8.25 (d, J=8.5Hz, 1H), 7.86 (s, 1H), 7.66 (d, J=8.5Hz, 1H), 2.16 (s, 9H), 1.78-1.72 (m, 6H).

[0134] b) N-(adamantan-1-yl)-6-morpholine pyridazine-3-carboxamide (compound 2)

[0135] The experimental method was the same as the preparation of compound 1 in Example 1 to obtain 19 mg of white solid. Yield: 93%; Melting point: 191.6-192°C.

[0136] 1 H NMR (500MHz, CDCl 3 )δ8.02(d, J=9.5Hz, 1H), 7.77(s, 1H), 6.96(d, J=9.5Hz, 1H), 3.86(t, J=4.5Hz, 4H), 3.72(t, J=5.0Hz, 4H), 2.14(s, 9H), 1.76-1.70(m, 6H).

Embodiment 3

[0137] Example 3: N-(adamantan-2-yl)-6-morpholine pyridazine-3-carboxamide (compound 3)

[0138] a) N-(adamantan-2-yl)-6-chloropyridazine-3-carboxamide (compound 3a)

[0139] The experimental method was the same as the preparation of compound 1d in Example 1, except that 2-adamantanamine was used instead of cyclohexylamine to obtain 105.7 mg of a yellow solid. Yield: 51%; Melting point: 171.2-172.5°C.

[0140] 1 H NMR (500MHz, CDCl 3 )δ8.46(d, J=5.0Hz, 1H), 8.29(d, J=8.5Hz, 1H), 7.69(d, J=8.5Hz, 1H), 4.30-4.28(m, 1H), 2.08( s, 2H), 1.97 (d, J = 13.5Hz, 2H), 1.92 (s, 6H), 1.80 (s, 2H), 1.72 (d, J = 13.0Hz, 2H).

[0141] b) N-(adamantan-2-yl)-6-morpholine pyridazine-3-carboxamide (compound 3)

[0142] The experimental method was the same as the preparation of compound 1 in Example 1 to obtain 19.4 mg of white solid. Yield: 85%; Melting point: 219.4-219.8°C.

[0143] 1 H NMR (500MHz, CDCl 3)δ8.34(d, J=8.0Hz, 1H), 8.05(d, J=9.5Hz, 1H), 6.97(d, J=9.5Hz, 1H), 4.27-4.25(m, J...

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Abstract

The invention provides a pyridazine derivative and a pharmaceutically acceptable salt or hydrate of the pyridazine derivative. The compound is an active ligand of a novel cannabinoid II type receptor CB2. The compound and the pharmaceutically acceptable salt or hydrate of the compound generally have high calcium current activity and quite good selectivity for anthropogenic marijuana receptors CB2. The compound is a specificity agonist of the cannabinoid receptor CB2, and can be used for treating, preventing and inhibiting diseases mediated by CB2 receptors. The compound I has the general formula shown in the description.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a compound with pyridazine as its core and its pharmaceutically acceptable salt or hydrate, its preparation method and the role of this type of compound in treating, preventing and inhibiting mediated by CB2 receptors. The application of drugs in the leading diseases. Background technique [0002] As early as several centuries ago, people have realized that plant cannabis has medicinal effects such as pain relief, anti-vomiting, anti-convulsion, and anti-inflammation. one. In 1964, Gaoni and Mechoulam reported that the main active substance of cannabis was Δ 9 - THC (Δ 9 -THC) and structural confirmation, 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, namely, cannabinoid type I receptor (CB1) and cannabinoi...

Claims

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Application Information

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IPC IPC(8): C07D237/24C07D401/12C07D405/12A61K31/5377A61K31/541A61K31/50A61K31/501A61P35/00A61P29/00A61P31/18A61P37/08A61P1/16A61P19/10A61P9/10A61P25/00A61P25/28A61P25/16A61P25/14A61P25/04
CPCC07D237/24C07D401/12C07D405/12
Inventor 陈建忠谢欣钱海燕陈炯炯王志龙
Owner ZHEJIANG UNIV
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