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Heptazine type compound and application thereof in preparing anti-schizophrenia medicine

A compound and heptazine technology, applied in the application field of anti-schizophrenia drugs, can solve the problems of interfering with the objective evaluation of animal cognitive function behavioral results, difficult for patients to return to society, and reduced medication compliance.

Inactive Publication Date: 2019-11-26
SHANGHAI ZHONGZE THERAPEUTICS CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Anti-schizophrenia drugs are used for a long time, and the long-term sedation of patients will seriously affect their normal work, study, interpersonal communication and other social activities, making it difficult for patients to return to society; in the stage of preclinical drug effectiveness evaluation, strong sedation will interfere Objective Evaluation of Behavioral Results of Animal Cognitive Function
Antischizophrenia drugs due to strong alpha 1 Receptor effect (risperidone, 0.7nM, Ki; quetiapine, 7nM, Ki; asenapine, 1.2nM, Ki), causing side effects of orthostatic hypotension, reducing the patient's medication compliance, and the recurrence rate is significant Increase

Method used

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  • Heptazine type compound and application thereof in preparing anti-schizophrenia medicine
  • Heptazine type compound and application thereof in preparing anti-schizophrenia medicine
  • Heptazine type compound and application thereof in preparing anti-schizophrenia medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0121] N-(trans-4-(2-((R)-8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-yl ) ethyl) cyclohexyl) acetamide (I-1) and the preparation of salts thereof

[0122] Trans-4-(2-((R)-8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-yl)ethyl Base) cyclohexyl-1-amine (6-1, prepared according to general method 1) (1.0g, 3.1mmol), triethylamine (4.7mmol) were added to CH 2 Cl 2 (20mL), stirred, 0 ~ 5 ℃ dropwise added acetyl chloride (0.3g, 3.4mmol) CH 2 Cl 2 (5mL) solution, dropwise, stirred at room temperature for 2-4h, the system was washed successively with water and saturated brine, the organic layer was concentrated to dryness, and recrystallized with absolute ethanol to obtain 0.9g of white solid, with a yield of 78%.

[0123] 1 H NMR (Chloroform-d, δ:ppm) δ7.15(d, J=2.3Hz, 1H), 7.09(dd, J=8.0, 2.2Hz, 1H), 6.98(d, J=7.9Hz, 1H) ,6.31(d,J=8.5Hz,1H),3.80–3.71(m,1H),2.92–2.76(m,3H),2.71(t,J=7.6Hz,2H),2.52–2.41(m,2H ),2.35–2.21(m,2H),2.00(s,3H),1.43-1.40(m,2H),...

Embodiment 2

[0132] N-(trans-4-(2-((R)-8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-yl ) ethyl) cyclohexyl) butanamide (I-2) and the preparation of salts thereof

[0133] Using intermediate 6-1 (5.0 mmol) (prepared according to General Method 8) and butyryl chloride (5.5 mmol) as raw materials, according to the preparation method of compound I-1, 1.7 g of white solid I-2 was obtained, with a yield of 89%.

[0134] 1 H NMR (Chloroform-d, δ:ppm) δ7.14(d, J=2.2Hz, 1H), 7.09(dd, J=8.0, 2.2Hz, 1H), 6.98(d, J=8.0Hz, 1H) ,6.30(d,J=8.5Hz,1H),3.80–3.71(m,1H),2.92–2.76(m,3H),2.71(t,J=7.6Hz,2H),2.52–2.41(m,2H ),2.36–2.20(m,4H),1.43-1.40(m,2H), 1.33-1.30(m,5H),1.24–1.21(m,5H),1.14–1.02(m,4H),0.61(t ,J=7.6Hz,3H).

[0135] ESI-MS:391[M+H + ]

[0136] Preparation of Compound I-2 Mesylate

[0137] Using compound I-2 (1.0 mmol) and methanesulfonic acid (1.0 mmol) as starting materials, the synthesis method of compound I-1 hydrochloride was used to obtain 0.42 g of a white solid with a y...

Embodiment 3

[0140] (trans-4-(2-((R)-8-chloro-1-methyl-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-yl)ethyl Base) cyclohexyl) ethyl carbamate (I-3) and the preparation of salt thereof

[0141] Using intermediate 6-1 (5.0 mmol) (prepared according to General Method 8) and ethyl chloroformate (5.5 mmol) as raw materials, according to the preparation method of compound I-1, 1.8 g of white solid I-3 was obtained, with a yield of 93% .

[0142] 1 H NMR (Chloroform-d, δ: ppm) δ7.13 (d, J = 2.3Hz, 1H), 7.08 (dd, J = 8.0, 2.2Hz, 1H), 7.00 (d, J = 7.9Hz, 1H) ,6.33(d,J=8.5Hz,1H),3.81–3.70(m,1H),2.93–2.78(m,3H),2.73(t,J=7.6Hz,2H),2.54–2.43(m,2H ),2.37–2.22(m,2H),2.01(s,3H),1.44-1.41(m,2H),1.35-1.33(m,3H),1.28–1.25(m,5H),1.17–1.05(m ,4H).

[0143] ESI-MS:393[M+H + ]

[0144] Preparation of compound 1-3 hydrobromide

[0145] Using compound I-3 (1 mmol) and 5% hydrobromic acid (1 mmol) as starting materials, the synthesis method of compound I-1 hydrochloride was used to obtain 0.3 g of white solid w...

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Abstract

The invention discloses a heptazine type compound and application thereof in preparing an anti-schizophrenia medicine. Pharmacology experiment results show that the benzisothiazole compound disclosedby the invention has high affinity for acceptors of dopamine D2, dopamine D3, serotonin 5-HT1A and serotonin 5-HT2A, has good selectivity for a D3 / D2 acceptor, and has weak or no affinity for histamine H1 and alpha 1. In-vivo experiment results show that the optional compound has a good anti-schizophrenia function, is low in toxic and side effect and high in security and has development value of novel anti-schizophrenia medicines with high efficiency and low toxicity. The heptazine type compound is a compound of a structural formula (I) shown in the description, or an optical isomer, a salt ora hydrate of the compound.

Description

technical field [0001] The invention relates to a heptazine compound with antipsychotic activity and its application as an antipsychotic drug. Background technique [0002] Schizophrenia is the most serious, the most harmful, and the highest disability rate among mental diseases. Its clinical manifestations include thinking disorders (loose thinking, lack of thinking, delusions, etc.), hallucinations, affective disorders (apathy, emotional perversion), behavioral disorders (social withdrawal, strange behavior, nervous excitement, etc.) and loss of learning and working memory. . With the deterioration of social environment and the increase of life pressure, the incidence of schizophrenia is increasing year by year. [0003] Modern medicine believes that schizophrenia is a collection of symptoms and signs of unknown etiology. In recent years, the research on neurotransmitters and receptors has been more active, and it has been found that in some patients with schizophrenia,...

Claims

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Application Information

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IPC IPC(8): C07D223/16C07D405/12C07D401/12C07D409/12C07D403/12C07D403/08C07D401/08C07D413/08A61K31/55A61P25/18
CPCC07D223/16C07D405/12C07D401/12C07D409/12C07D403/12C07D403/08C07D401/08C07D413/08A61P25/18
Inventor 李建其李林陈晓文齐阳历马志龙浦强
Owner SHANGHAI ZHONGZE THERAPEUTICS CO LTD
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