Pyrimidine derivatives and methods of treatment related to the use thereof

A technology of compounds and hydrates, applied in organic chemistry, drug combinations, pharmaceutical formulations, etc., can solve problems such as energy intake and consumption imbalance, without considering muscle proportions, etc.

Inactive Publication Date: 2007-06-06
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 etiological mechanisms of obesity need further elucidation, the ultimate effect of this mechanism is to cause an imbalance between energy intake and expenditure

Method used

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  • Pyrimidine derivatives and methods of treatment related to the use thereof
  • Pyrimidine derivatives and methods of treatment related to the use thereof
  • Pyrimidine derivatives and methods of treatment related to the use thereof

Examples

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preparation example Construction

[1429] Preparation of compound of formula (I)-general synthetic method

[1430] The novel substituted pyrimidines of the present invention can be easily prepared according to various synthetic methods, all of which are familiar to those skilled in the art. Preferred methods for preparing the compounds of the present invention include, but are not limited to those described in Schemes 1-8.

[1431] Pyrimidine (C) can be prepared as shown in Scheme 1. With or without alkali, 4,6-dihydroxypyrimidine (A), which is commercially available or obtained by condensation of malonic acid derivatives and amidine derivatives, can be obtained by halogenating agents, wherein Z 1 And Z 2 As defined above, it is converted to 4,6-dihalo-pyrimidine (B) (where X is halogen, such as chlorine, bromine or iodine). The halogenating agent includes phosphoryl chloride (POCl 3 ), phosphoryl bromide (POBr 3 ) Or phosphorus pentachloride (PCl 5 ). The base includes tertiary amines (preferably N,N-diisopropylet...

Embodiment 1

[1540] N'-(cis-4-{[4-bromo-2-trifluoromethoxy)benzyl]amino}cyclohexyl)-N,N-dimethylpyrimidine-4,6-diamine dihydrochloride

[1541] Step A: (6-Chloro-pyrimidin-4-yl)-dimethyl-amine synthesis

[1542] Add iPr to a solution of 4,6-dichloro-pyrimidine (10.0g) in THF (10mL) 2 NEt (10.4g) and 50% Me 2 NH aqueous solution (6.05 g). After stirring the resulting mixture at room temperature for 28 hours, pour into saturated NaHCO 3 In aqueous solution. CHCl for water layer 3 Extraction (three times). MgSO for combined organic layer 4 Dry, filter, and concentrate under reduced pressure. Suspend the residue in Et 2 O in. Filter to collect the precipitate, Et 2 Wash with O and dry under reduced pressure to obtain (6-chloro-pyrimidin-4-yl)-dimethyl-amine (6.37 g).

[1543] ESI MS m / e 157, M + ; 1 H NMR(300MHz, CDCl 3 )δ3.12(s, 6H), 6.41(s, 1H), 8.37(s, 1H).

[1544] Step B: Synthesis of N-(cis-4-bromo-2-trifluoromethoxy-benzyl)-cyclohexane-1,4-diamine

[1545] To (4-amino-cyclohexyl)-carbamic a...

Embodiment 2

[1551] N-(cis-4-{[6-(dimethylamino)pyrimidin-4-yl]amino}cyclohexyl)-3,4-difluorobenzamide hydrochloride

[1552] Step A: Synthesis of (cis-4-{[1-(3,4-difluoro-phenyl)-formyloxy]-amino}-cyclohexyl)-carbamic acid tert-butyl ester

[1553] To the DMF solution (50 mL) of 3,4-difluoro-benzoic acid (4.10g) and (cis-4-amino-cyclohexyl)-carbamic acid tert-butyl ester (5.05g) was added Et 3 N(90mL), HOBt-H 2 O (5.41g) and EDC-HCl (4.97g). The resulting mixture was stirred at room temperature for 17 hours. Water (200 mL) was added to the reaction mixture, and the resulting suspension was stirred at room temperature for 10 minutes. Filter to collect the precipitate, use H 2 O and EtOH washed, dried under reduced pressure at 80 ℃ to obtain (cis-4-{[1-(3,4-difluoro-phenyl)-formyloxy]-amino}-cyclohexyl)-carbamic acid tert-butyl Esters (5.20 g).

[1554] ESI MS m / e 377, M+Na + ; 1 H NMR(300MHz, CDCl 3 )δ1.45 (s, 9H), 1.53-1.95 (m, 8H), 3.60-3.74 (m, 1H), 4.00-4.16 (m, 1H), 4.50-4.68 (m, 1H), 5.95-...

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Abstract

The present invention encompasses novel substituted pyrimidine compounds of Formula (I): which act as MCH receptor antagonists. These compounds 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 the use of these compounds in pharmaceutical compositions. Background of the invention [0002] Melanin concentrating hormone (MCH) is a cyclic peptide, which has been determined to be 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). Various studies have shown that the role of MCH is as a neurotransmitter / neuromodulator to change many behavioral responses, such as eating habits. For example, it has been reported that injection of MCH into rats increases food intake. Reports indicate that genetically engineered mice lacking MCH have reduced body weight and increased metabolism. See Saito et al., TEM, vol. 11, 299 (2000). Therefore, the literature indicates that the discovery of MCH antagonists that interact with SCL-1 expressing cells can be used to develop obesity treatmen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/48C07D473/34C07D403/04A61K31/505C07D405/12A61P3/04C07D487/04A61P3/10C07D239/00C07D239/42C07D239/54C07D239/545C07D401/12C07D403/12C07D409/12C07D409/14C07D413/12C07D413/14C07D417/12
CPCC07D239/545C07D413/14C07D239/42C07D403/04C07D403/12C07D405/12C07D409/12C07D409/14C07D413/12C07D401/12C07D239/48C07D417/12C07D473/34C07D487/04A61P25/08A61P25/14A61P25/16A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P25/30A61P3/04A61P43/00A61P9/00A61P9/10A61P9/12A61P3/10A61K31/505
Inventor 关口喜功鹿沼幸祐表寺克纪T·A·特兰G·森普尔B·A·克雷默
Owner TAISHO PHARMACEUTICAL CO LTD
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