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Fused ring compound and preparation method, pharmaceutical composition and application thereof

A technology of compounds and oxides, applied in drug combinations, antipyretics, organic chemistry, etc., can solve the problems of high toxicity and side effects, poor long-term safety, and low tolerance, and achieve high metabolic stability and excellent drug efficacy pharmacokinetic effect, excellent pharmacokinetic effect

Active Publication Date: 2021-11-30
GUANGZHOU FERMION TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although many patients benefit from existing pain medications, these drugs only provide adequate relief for a quarter of patients
Coupled with the problems of low tolerance, high toxicity, poor long-term safety, potential drug abuse and inconvenient use of existing drugs, patients urgently need safer and more effective analgesic drugs

Method used

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  • Fused ring compound and preparation method, pharmaceutical composition and application thereof
  • Fused ring compound and preparation method, pharmaceutical composition and application thereof
  • Fused ring compound and preparation method, pharmaceutical composition and application thereof

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Experimental program
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preparation example Construction

[0302] Embodiments of the present invention also provide a preparation method of the compound, comprising the steps of:

[0303]

[0304] Condensation reaction is carried out with compound 1 and compound 2, wherein Q represents a nitrogen protecting group;

[0305] The nitrogen protecting group Q is removed from the product of the condensation reaction.

[0306] Embodiments of the present invention also provide a pharmaceutical composition containing a therapeutically effective dose of the above-mentioned compound or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutical Pharmaceutically acceptable salts, polymorphs or prodrugs, and pharmaceutically acceptable carriers or excipients.

[0307] Embodiments of the present invention also provide a compound as described above or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug, or as described above The above pharmaceutical composition is used in t...

Embodiment 1

[0357] (1R,5S,6r)-N-(2-(8-(Methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1 .0] hexane-6-carboxamide hydrochloride (compound 1)

[0358]

[0359] The first step: 2-cyano-3-methylthiopyridine (1B)

[0360]

[0361] 2-cyano-3-fluoropyridine (2.0 g, 16.38 mol) and sodium methylthiolate (1.2 g, 18.02 mmol) were added to dimethyl sulfoxide (10 mL), and the mixture was stirred at room temperature for 5 hours. Add ethyl acetate (120mL), wash with water and saturated brine, spin the organic phase to dry the solvent in vacuo, and purify the residue on a silica gel column (petroleum ether / ethyl acetate=3 / 1) to obtain a white solid, which is 2-cyano - 3-Methylthiopyridine 1B (900 mg, yield: 36.6%).

[0362] The second step: (3-(methylthio)pyridin-2-yl)methanamine dihydrochloride (1C)

[0363]

[0364] Dissolve 2-cyano-3-methylthiopyridine 1B (800mg, 5.33mmol) in ethanol (20mL), add 10% palladium / carbon (520mg, 0.53mmol) and hydrochloric acid (6M, 5mL), and ...

Embodiment 2

[0385] (1R,5S,6r)-N-(2-Methyl-1-((2-(trifluoromethyl)phenyl)thio)prop-2-yl)-3-azabicyclo[3.1.0 ]Hexane-6-carboxamide formate (compound 2)

[0386]

[0387] The first step: 2-methyl-2-nitropropyl 4-methylbenzenesulfonate (2B)

[0388]

[0389] 2-Methyl-2-nitropropan-1-ol 2A (1.19g, 10.00mmol) and triethylamine (2.02g, 20.00mmol) were mixed and dissolved in dichloromethane (50mL), cooled to 0-5 ℃. Add 4-methylbenzenesulfonyl chloride (2.86 g, 15.00 mmol), and stir at room temperature for 18 hours. New spots were detected by TLC. Add dichloromethane (100 mL) to dilute, wash with 1M hydrochloric acid (100 mL) and saturated sodium bicarbonate solution (100 mL), and then wash with saturated brine. The organic phase was separated, dried with anhydrous sodium sulfate, filtered, and purified with a silica gel column (petroleum ether / ethyl acetate=10 / 1) to obtain 2-methyl-2-nitropropyl 4-methylbenzenesulfonate Ester 2B, off-white solid (2.46 g, yield: 90%).

[0390] 1 H NMR...

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PUM

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Abstract

The invention relates to a fused ring compound and a preparation method, a pharmaceutical composition and application thereof. The fused ring compound has the structural characteristics of a formula (I). The fused ring compound is a somatostatin receptor subtype 4 (SSTR4) agonist compound which is novel in structure, better in drug effect, high in bioavailability and better in solubility.

Description

technical field [0001] The present invention relates to organic compounds, in particular to an acrocyclic compound and its preparation method, pharmaceutical composition and application. Background technique [0002] The somatostatin receptor family (somatostatin receptors, SSTRs) is a family of G protein-coupled receptors that mediate somatostatin and its analogues and have a variety of biological effects. focus on. Studies have shown that there are specific membrane receptors on these cell membranes, including SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5, which can regulate growth hormone (GH) secretion, induce apoptosis, and inhibit tumor cells through cAMP, PTP, and MAPK signaling pathways. Biological processes such as proliferation, inhibition of insulin action, and inhibition of cell growth play important roles, while also displaying kinetic characteristics similar to those of other G protein-coupled receptors. [0003] Somatostatin (SST) is a cyclic polypeptide widely dist...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D403/12C07D209/52A61P25/28A61P25/08A61P25/24A61P29/00A61P25/00A61K31/437A61K31/416A61K31/403
CPCC07D471/04C07D403/12C07D209/52A61P25/28A61P25/08A61P25/24A61P29/00A61P25/00Y02A50/30A61K31/437A61K31/416A61P25/04
Inventor 邓代国邱关鹏王永钢雷曾荣
Owner GUANGZHOU FERMION TECH CO LTD
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