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Cyclohexaneamines d 3 /d 2 partial receptor agonist
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A cyclohexylamine and agonist technology, applied in the field of biomedicine, can solve problems such as slurred speech and increased risk of death
Active Publication Date: 2021-05-18
SHANGHAI XUNHE PHARMA TECH CO LTD
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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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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 complete as monitored by TLC. 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, ...
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 (400 MHz, 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, in particular to a cyclohexane amine D 3 / D 2 Receptor partial agonist and its pharmaceutically acceptable salt, its synthesis method and application. Compared with the prior art, the N-fluorocyclic carbamoyl group connected by cyclopentylamine in the molecular structure provided by the present invention has stronger metabolic stability than the original N,N-dimethylcarbamoyl group, prolonging the drug In vivo action time. The introduction of the fluorinated cyclic amino group changes the physical and chemical properties of the original molecule, thereby changing the pharmacokinetic properties, enhancing the distribution of the drug in the target tissue, and improving the bioavailability of the drug. The inventors also surprisingly found that the introduction of the fluorinated cyclic amino group affects the local conformation of the compound, enhances the mutual binding ability between the ligand and the target protein, and improves the selectivity of the target.
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 agonists. 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 ...
Claims
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Application Information
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