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Triazolyl pyrimidinone compounds as PDE2 inhibitors

一种化合物、溶剂化物的技术，应用在抑制剂的化合物领域，能够解决缺乏功效、药物不依从、不耐受副作用等问题

Inactive Publication Date: 2018-01-02
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite improvements in antipsychotic treatment, available therapies, including typical (haloperidol) and atypical (clozapine or olanzapine) antipsychotics, fall short of acceptable levels and result in extremely high rates of medication nonadherence or drug discontinuation
Treatment dissatisfaction due to lack of efficacy, or intolerance and unacceptable side effects

Method used

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  • Triazolyl pyrimidinone compounds as PDE2 inhibitors
  • Triazolyl pyrimidinone compounds as PDE2 inhibitors
  • Triazolyl pyrimidinone compounds as PDE2 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0027]

[0028] where R 1 Choose from H, C 1-6 Alkyl, C 2-6 Alkenyl, (CH 2 ) n C 3-10 Cycloalkyl, and (CH 2 ) n C 6-10 Aryl, the alkyl and aryl are optionally replaced by 1 to 3 R a group substitution.

[0029] When Y is triazolyl, one of its nitrogen atoms is attached to R 2 And when one of its carbon atoms is attached to J, another embodiment of formula I of the present invention is realized. When Y is a triazolyl group wherein one of its nitrogen atoms is attached to J and one of its carbon atoms is attached to R 2 When, realize another embodiment of the formula I of the present invention.

[0030] When Y is a triazolyl group selected from the following groups,

[0031]

[0032] where R 2 and R b Another embodiment of formula I of the present invention is realized when as originally described, and the ~ line represents the point of attachment.

[0033]When Y is (a), (b), (c), (d), (e), (f) or (g) and R b When is hydrogen, one aspect of this sub-embodim...

preparation Embodiment 1 and 2

[0261]

[0262] 2-(Cyclopropylmethyl)-4-ethynyl-6-methoxy-pyrimidine and (E)-2-(but-1-enyl)-4-ethynyl-6- Methoxypyrimidine (Scheme 1).

[0263] Step 1. 2-(cyclopropylmethyl)pyrimidine-4,6-diol: To a mixture of NaOMe (4.95 g, 92.0 mmol) in methanol (80 mL) was added 2-cyclopropylacetamidine hydrochloride (6.00 g, 44.8 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 minutes, then dimethyl malonate (5.91 g, 44.8 mmol) was added. The reaction mixture was stirred at 65°C for 16 hours. The resulting mixture was cooled and filtered. The filter cake was washed with methanol (80 mL). The combined filtrates were diluted with water (320 mL). The pH of the mixture was adjusted to 2 with 5M aqueous HCl. The mixture was then filtered. The filter cake was washed with diethyl ether (20 mL) and dried to give the title compound as a solid, which was used in the next step without further purification. MS = 167.1 (M+1).

[0264] Step 2. 4,6-d...

preparation Embodiment 6

[0271]

[0272] 4-Methoxy-2-methyl-6-(2H-1,2,3-triazol-4-yl)pyrimidine (Scheme 1).

[0273] 4-methoxy-2-methyl-6-(2H-1,2,3-triazol-4-yl)pyrimidine: To azido-trimethylsilane (1.17g, 10.1mmol) and 4-ethynyl-6-methoxy-2-methylpyrimidine (1.00g, 6.75mmol) in DMF (13.5mL) and MeOH (1.5 mL) was added CuI (0.129 g, 0.7 mmol). The reaction mixture was purged 3 times with nitrogen, sealed and stirred at 100°C for 4 hours. The resulting mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel chromatography (50% ethyl acetate in petroleum ether) to afford the title compound. MS = 192.0 (M+1).

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Abstract

The present invention is directed to pyrimidine carboxamide compounds of formula I which are useful as therapeutic agents for the treatment of central nervous system disorders associated with phosphodiesterase 2 (PDE2). The present invention also relates to the use of such compounds for treating neurological and psychiatric disorders, such as schizophrenia, psychosis, Parkinson's disease, Parkinson's disease dementia (PDD), or Huntington's disease, and those associated with striatal hypofunction or basal ganglia dysfunction.

Description

technical field [0001] The present invention relates generally to compounds useful as inhibitors of phosphodiesterase (PDE) 2 enzymes, compositions thereof and therapeutic uses thereof. Background technique [0002] Schizophrenia is a degenerative disease that affects the mental and motor functions of the brain. It is usually diagnosed in individuals in their early to mid twenties, and symptoms include hallucinations and delusions, or at the other extreme: anhedonia or social withdrawal. Across the spectrum, the symptoms are indicative of cognitive impairment and functional impairment. Despite improvements in antipsychotic treatment, available therapies, including typical (haloperidol) and atypical (clozapine or olanzapine) antipsychotics, fall short of acceptable levels and result in extremely high rates of medication Non-adherence or drug discontinuation. Dissatisfaction with treatment is attributed to lack of efficacy, or intolerance and unacceptable side effects. Sid...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/513C07D401/04C07D401/14
CPCA61K31/4192A61K31/4196A61K31/506A61P25/00C07D403/04C07D471/04C07D487/04C07D498/04
Inventor D·沈C·J·辛兹A·克雷斯波J·E·威尔逊T·麦克拉肯S·徐H·李
Owner MERCK & CO INC
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