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Cyclohexane amine D3/D2 receptor partial agonist

A cyclohexane amine and agonist technology, applied in the field of biomedicine, can solve problems such as increased risk of death and slurred speech, and achieve the effects of low clinical dose, enhanced mutual binding ability, and excellent PK properties

Active Publication Date: 2019-10-25
SHANGHAI XUNHE PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Although RGH-188 has certain advantages as a new schizophrenia drug, it still has certain defects: In two late-stage clinical trials, the most common side effects in the schizophrenia treatment group were tremor, slurred speech, and involuntary muscles Tremors, while patients with manic depression most often experience adverse events such as hyperactivity, dyspepsia, vomiting, lethargy, and restlessness
RGH-188, like other FDA-approved drugs for schizophrenia and manic depression, has a black box warning, suggesting that medical staff and dementia-related elderly patients have an increased risk of death when using RGH-188, so RGH-188 has not been approved treat these patients

Method used

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  • Cyclohexane amine D3/D2 receptor partial agonist
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  • Cyclohexane amine D3/D2 receptor partial agonist

Examples

Experimental program
Comparison scheme
Effect test

reference example 1

[0059] Reference example 1: Synthetic route of general intermediate 5.

[0060]

[0061] Steps:

[0062] Step 1: Synthesis of Intermediate 2.

[0063] Add compound 1 (2.43g, 10mmol) and triethylamine (2g, 20mmol) into dichloromethane (30mL), cool down to an internal temperature of 0-5°C, and add methanesulfonyl chloride (1.1g, 10mmol) dropwise under stirring. Chloromethane (10 mL) solution, after the dropwise addition, was raised to room temperature and reacted for 3 hours; after the reaction was completed, the solvent was concentrated to dryness to obtain the crude intermediate 2.

[0064] Step 2: Synthesis of Intermediate 4

[0065] In step 1, the crude intermediate 2 (10 mmol) was concentrated and added to acetonitrile (20 mL), then potassium carbonate (2.76 g, 20 mmol) and compound 3 (2.54 g, 11 mmol) were added, the temperature was raised to reflux and the reaction was stirred for 8 h. After the reaction was completed, the temperature was lowered to room temperature...

Embodiment 1

[0068] Embodiment 1: the synthesis of I-1

[0069] synthetic route:

[0070]

[0071] Steps:

[0072] Add compound 5 (500mg, 1.27mmol), IA-1 (142mg, 1.27mmol), triethylamine (643mg, 6.36mmol) into dichloromethane (5mL), cool the system to an internal temperature of 0-5°C, and add triphosgene (453 mg, 1.53 mmol). After the addition was completed, the reaction was stirred at room temperature for 4 h, and the reaction was monitored by TLC to complete. Dichloromethane (10mL) and water (10mL) were added to the reaction solution for extraction, the organic layer was washed with saturated brine (10mL), the organic layer was concentrated to dryness, and the residue was purified by silica gel column chromatography (the mobile phase was dichloromethane / methanol: 30 / 1), the product I-1 (250 mg, yield 43%) was obtained as a pale white solid. MS Calcd.: 457.4, MS Found: 458.1 [M+H] + . 1 H NMR (400MHz, CD 3 OD): δ=7.23(m,2H),6.81(m,1H),4.13-3.89(m,5H),3.67(m,1H),3.47(m,8H),2.49(...

Embodiment 2

[0073] The synthesis of embodiment 2:1-2

[0074] synthetic route:

[0075]

[0076] Steps:

[0077] Refer to Example 1 for the operation steps and purification method, and the yield is 50%. MS Calcd.: 475.4, MS Found: 476.1 [M+H] + . 1 H NMR (400MHz, CD 3 OD): δ=7.25(m,2H),6.83(m,1H),4.16(t,J=15.6Hz,4H),3.65(m,1H),3.47(m,8H),2.48(t,J =5.6Hz, 2H), 1.77(m, 2H), 1.55-1.37(m, 9H).

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Abstract

The invention belongs to the technical field of biomedicine, and particularly relates to a cyclohexane amine D3 / D2 receptor partial agonist, and a pharmaceutically acceptable salt, a synthesis methodand use of the cyclohexane amine D3 / D2 receptor partial agonist. According to the cyclohexane amine D3 / D2 receptor partial agonist, compared with the prior art, N-fluorocycloaminoformoxyl linked by cyclopentamine in a molecular structure has stronger metabolic stability than that of original N,N-dimethyl carbamoyl group, and time of action in drug bodies is prolonged. The introduction of fluorocycloamino changes the physical and chemical properties of original molecules, thus changing pharmacokinetic properties, the distribution of drugs in target tissues is enhanced, and the bioavailability of the drugs is improved. The inventors further surprisingly find that the introduction of the fluorocycloamino affects the local conformation of compounds, enhances mutually binding ability between ligands and target protein, and improves the selectivity of target spots.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, in particular to a class of cyclohexaneamines D 3 / D 2 Receptor partial agonist. Background technique [0002] Schizophrenia is a kind of mental illness characterized by the division of thinking, emotion and behavior, and the incoordination of mental activities and the environment. The worldwide prevalence of schizophrenia is nearly 1%. Male patients are about 1.4 times that of female patients. The onset is more common in young adults, and it is more common in men between 20 and 28 years old, and in women between 26 and 32 years old. The clinical symptoms of schizophrenia can be divided into three types: positive symptoms, negative symptoms and cognitive symptoms. [0003] Although the specific pathogenesis of schizophrenia is still unclear, pharmacological studies have shown that patients with schizophrenia exhibit abnormal functions of various transmitter neurons. It is now believed t...

Claims

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Application Information

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IPC IPC(8): C07D205/04C07D295/135C07D211/38A61P25/18A61P25/22A61P25/24A61P25/28A61P25/14A61P25/16A61P25/04A61P25/30A61K31/496A61K31/495
CPCA61P25/04A61P25/14A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P25/30C07D205/04C07D211/38C07D295/135
Inventor 郑永勇魏农农金华周峰黄美花
Owner SHANGHAI XUNHE PHARMA TECH CO LTD
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