Novel quinazoline derivatives and methods of treatment related to the use thereof

A compound and hydrate technology, applied in the field of MCH receptor antagonist compounds, can solve problems such as energy absorption and consumption imbalance

Inactive Publication Date: 2006-06-28
TAISHO PHARMACEUTICAL CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Although the etiological mechanisms of obesity need further elucidation, the actual impact of such mechanisms leads to an imbalance between energy intake and expenditure

Method used

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  • Novel quinazoline derivatives and methods of treatment related to the use thereof
  • Novel quinazoline derivatives and methods of treatment related to the use thereof
  • Novel quinazoline derivatives and methods of treatment related to the use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1669] 1-(3,4-Dimethoxy-phenyl)-3-[cis-4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-urea hydrochloride

[1670] Step A: Synthesis of 2,4-dichloro-quinazoline.

[1671] 1H-quinazoline-2,4-dione (150 g, 925 mmol) in POCl 3 (549 mL, 5.89 mol) suspension was added dimethyl-phenyl-amine (123 mL, 962 mmol). The mixture was stirred at reflux for 7 h and then concentrated. The solution was poured into ice water, and the aqueous layer was washed with CHCl 3 Extraction (three times). The combined organic layers were washed with MgSO 4 dried, filtered, concentrated, and purified by flash chromatography (silica gel, 50% CHCl 3 / Hexane to 10% EtOAc / CHCl 3 ) afforded 2,4-dichloro-quinazoline (159 g, 86%) as a pale yellow solid.

[1672] CI MS m / e 199, M + ; 1 H NMR (300MHz, CDCl 3 ), δ7.71-7.81 (m, 1H), 7.95-8.04 (m, 2H), 8.27 (dt, J=8.3, 1.1 Hz, 1H).

[1673] Step B: Synthesis of (2-chloro-quinazolin-4-yl)-dimethyl-amine.

[1674] A solution of 2,4-dichloro-quinazoline ...

Embodiment 2

[1689] 1-(2,3-Dichloro-phenyl)-3-[cis-4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-urea hydrochloride

[1690] Step A: Synthesis of (cis-4-hydroxymethyl-cyclohexyl)-carbamic acid tert-butyl ester.

[1691] A suspension of cis-4-amino-cyclohexanecarboxylic acid (244 g, 1.71 mol) in MeOH (2.45 L) was cooled to -8°C. Thionyl chloride (440 mL, 6.03 mol) was added dropwise. The resulting solution was stirred at room temperature for 4.5 h and then concentrated to give a white solid. CHCl of the above solid 3 (3.00L) suspension was added successively triethylamine (261mL, 1.88mol) and (Boc) 2 O (409 g, 1.88 mol). The reaction mixture was stirred at room temperature for 5 h and poured into water. CHCl for aqueous layer 3 Extraction (three times). The combined organic layers were washed with MgSO 4 Dry, filter, concentrate, and flash chromatography (silica gel, 11% EtOAc / hexane to 10% MeOH / CHCl 3 ) and flash chromatography (NH-silica, 33% EtOAc / hexane to 9% MeOH / ...

Embodiment 3

[1709] 1-(2,6-Dichloro-phenyl)-3-[cis-4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-urea hydrochloride

[1710] Step A: Synthesis of 1-(2,6-dichloro-phenyl)-3-[cis-4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-urea Hydrochloride.

[1711] Following the method of step F of Example 1, the title compound was obtained.

[1712] ESI MS m / e 509, M(free)+Na + ; 1 H NMR (300MHz, CDCl 3 ), δ1.51-2.06(m, 9H), 3.37-3.42(m, 2H), 3.52(s, 6H), 4.37-4.47(m, 1H), 6.35-6.45(m, 1H), 6.96-7.06 (m, 1H), 7.23-7.31(m, 3H), 7.43-7.49(m, 1H), 7.61-7.68(m, 1H), 7.91(d, J=7.9Hz, 2H), 8.72(d, J =8.7Hz, 1H), 12.64(s, 1H).

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PUM

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Abstract

The present invention relates to novel compounds of formula (I) useful as MCH receptor antagonists. These compounds are useful in pharmaceutical compositions for the prevention or therapeutic improvement of memory dysfunction, sleep and wakefulness disorders, anxiety, depression, mood disorders, seizures, obesity, diabetes, appetite and food intake Abnormalities, cardiovascular disease, hypertension, dyslipidemia, myocardial infarction, binge eating disorder (including bulimia), anorexia, psychosis (including manic depression), schizophrenia, delirium, dementia, catatonia, cognitive impairment , attention deficit disorder, substance use disorder, movement disorders (including Parkinson's disease), epilepsy, and addiction.

Description

field of invention [0001] The present invention relates to compounds useful as MCH receptor antagonists and to the use of these compounds in pharmaceutical compositions. Background of the invention [0002] Melanin-concentrating hormone (MCH) is a cyclic peptide identified as the endogenous ligand of the orphan G-protein-coupled receptor SLC-1. See eg Shimomura et al., Biochem. Biophys. Res. Commun. 261, 622-26 (1999). Studies have shown that MCH acts as a neurotransmitter / neuromodulator to alter many behavioral responses, such as eating habits. For example, increased food intake has been reported in MCH-injected rats. Reports indicate that genetically engineered mice lacking MCH lose weight and have increased metabolism. See Saito et al., TEM, vol. 11, 299 (2000). Thus, the literature suggests that MCH antagonists affecting SCL-1 expressing cells could be used to develop therapies for obesity. See Shimomura et al., Biochem. Biophys. Res. Commun. 261, 622-26 (1999). ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/84A61K31/517A61P3/00A61P3/04A61P9/00A61P9/12A61P25/08A61P25/16A61P25/20A61P25/22A61P25/24A61P25/28C07D239/95C07D405/12C07D409/12C07D413/12
CPCC07D239/95C07D405/12C07D409/12C07D413/12A61P25/00A61P25/08A61P25/16A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P25/30A61P3/00A61P3/04A61P3/06A61P9/00A61P9/10A61P9/12A61P3/10
Inventor 关口喜功鹿沼幸祐表寺克纪毒岛刚T·-A·特兰S·韩M·卡斯佩B·A·克拉梅
Owner TAISHO PHARMACEUTICAL CO LTD
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