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Novel quinoline,Tetrahydroquinazoline,And pyrimidine derivatives and methods of treatment related to the use thereof

A technology of compounds and hydrates, applied in the fields of active ingredients of heterocyclic compounds, medical preparations containing active ingredients, organic chemistry, etc., which can solve problems such as muscle ratio, energy intake and consumption imbalance, etc.

Inactive Publication Date: 2006-07-05
TAISHO PHARMACEUTICAL CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The problem with this definition is that it doesn't take into account the ratio of muscle to fat (adipose tissue) in body weight
[0017] Although the underlying etiology of obesity needs to be further elucidated, this mechanism alone contributes to an imbalance between energy intake and expenditure

Method used

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  • Novel quinoline,Tetrahydroquinazoline,And pyrimidine derivatives and methods of treatment related to the use thereof
  • Novel quinoline,Tetrahydroquinazoline,And pyrimidine derivatives and methods of treatment related to the use thereof
  • Novel quinoline,Tetrahydroquinazoline,And pyrimidine derivatives and methods of treatment related to the use thereof

Examples

Experimental program
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preparation example Construction

[5798] The activity level 125 I. The synthetic methods for binding to target molecules include: A. Sandenzyme and other reactions-this method converts aryl or heteroaryl amines into diazonium salts, such as tetrafluoroborate, followed by Na 125 I is converted to 125 I labeled compound. A representative method was reported by Zhu, D.-G and colleagues in J. Org. Chem. 2002, 67, 943-948. B. Ortho position of phenol 125 Iodination-This method makes 125 I binds to the ortho position of phenol, as reported by Collier, T.L and colleagues in J. Labelled Compd Radiopharm. 1999, 42, S264-S266. C. Aryl and heteroaryl bromide and 125 I Exchange-This method is usually a two-step method. The first step is in the tri-alkyl tin halide or hexaalkyl ditin [for example, (CH 3 ) 3 SnSn(CH 3 ) 3 ] In the presence of, for example, Pd catalyzed the reaction [ie Pd(Ph 3 P) 4 ] Or through aryl or heteroaryl lithium, the aryl or heteroaryl bromide is converted into the corresponding tri-alkyltin intermedia...

Embodiment 1

[5988] N 2 -[Cis-4-(4-bromo-2-trifluoromethoxy-benzyl)-amino-cyclohexyl]-N 4 -Methyl-quinoline-2,4-diamine dihydrochloride

[5989] Step A: Synthesis of 2,4-dichloro-quinoline.

[5990] Combine quinoline-2,4-diol (150g, 931mmol) in POCl 3 The suspension in (975 mL, 10.4 mol) was stirred under reflux for 6 hours, and the reaction mixture was concentrated. Use CHCl 3 (500 mL) was diluted and the solution was poured into ice water. CHCl 3 Extract (3 times). The combined organic layer was dried over magnesium sulfate, filtered, concentrated, and purified by flash chromatography (silica gel, 20% EtOAc in hexane) to give 2,4-dichloro-quinoline (177g, 96%) as light brown solid.

[5991] EI MS m / e 197, M + ; 1 H NMR(300MHz, CDCl 3 )δ7.50(s, 1H), 7.65(ddd, J=8.3, 7.0, 1.3Hz, 1H), 7.79(ddd, J=8.5, 7.0, 1.3Hz, 1H), 8.00-8.06(m, 1H) , 8.16-8.21 (m, 1H).

[5992] Step B: Synthesis of (2-chloro-quinolin-4-yl)-methyl-amine.

[5993] To a solution of 2,4-dichloro-quinoline (29.8g, 150mmol) in THF...

Embodiment 2

[6011] N 2 -{Cis-4-[2-(4-bromo-2-trifluoromethoxy-phenyl)-ethylamino]-cyclohexyl}-N 4 -Methyl-quinoline 2,4-diamine dihydrochloride

[6012] Step A: Synthesis of (4-bromo-2-trifluoromethoxy-phenyl)-acetaldehyde.

[6013] To (methoxymethyl)-triphenylphosphonium chloride (5.29g, 14.9mol) in Et 2 Add 1.8M phenyl lithium 30% Et to the suspension in O (50mL) 2 O in cyclohexane solution (8.58 mL, 15.5 mmol). The mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added 4-bromo-2-trifluoromethoxy-benzaldehyde (4.00 g, 14.9 mmol) obtained in step F of Example 1 in Et 2 O (18 mL) solution. The mixture was stirred at room temperature for 4 hours, filtered and concentrated. A solution of 10% sulfuric acid in AcOH (40 mL) was added to the above residue. The mixture was stirred at room temperature for 90 minutes. Pour the solution into water and use CHCl 3 Extract (3 times). The combined organic layer was washed with saturated aqueous sodium bicarbonate solution...

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Abstract

The present invention relates to novel compounds of the Formula (I): which act as MCH receptor antagonists. These compositions are useful in pharmaceutical compositions whose use includes prophylaxis or treatment of improving memory function, sleeping and arousal, anxiety, depression, mood disorders, seizure, obesity, diabetes, appetite and eating disorders, cardiovascular disease, hypertension, dyslipidemia, myocardial infarction, binge eating disorders including bulimia, anorexia, mental disorders including manic depression, schizophrenia, delirium, dementia, stress, cognitive disorders, attention deficit disorder, substance abuse disorders and dyskinesias including Parkinson's disease, epilepsy, and addiction.

Description

Invention field [0001] The present invention relates to compounds used as MCH receptor antagonists, and to the use of these compounds in pharmaceutical compositions. Background of the invention [0002] Melanin Concentrating Hormone (MCH), a cyclic peptide, has been identified as the endogenous ligand of the orphan G-protein coupled receptor SLC-1. See, for example, Shimomura et al., Biochem. Biophys. Res. Commun. 261, 622-26 (1999). Studies have shown that MCH is used as a neurotransmitter / neuromodulator to modify many behavioral responses, such as eating habits. For example, it has been reported that injection of MCH into rats can increase their food consumption. The report pointed out that genetically engineered mice lacking MCH showed weight gain and increased metabolism. See Saito et al., TEM, vol. 11, 299 (2000). Likewise, this document proposes that the discovery of MCH antagonists that interact with SCL-1 expressing cells will be useful in the development of therapeutics ...

Claims

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Application Information

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IPC IPC(8): C07D215/42C07D215/38C07D239/28C07D239/72A61K31/47A61K31/505A61P3/04A61P25/00A61P9/00A61P43/00
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G·塞普勒N·周
Owner TAISHO PHARMACEUTICAL CO LTD
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