Substituted heterocyclic compound and derivative thereof, pharmaceutical composition, preparation method and use thereof

A compound and derivative technology, applied in the field of medicine, can solve problems such as insufficient activity and safety

Active Publication Date: 2020-06-19
SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Patent application document WO2003051840A provides a neurokinin receptor (NK1) antagonist, however, the activity and safety of the neurokinin receptor (NK1) antagonist are insufficient

Method used

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  • Substituted heterocyclic compound and derivative thereof, pharmaceutical composition, preparation method and use thereof
  • Substituted heterocyclic compound and derivative thereof, pharmaceutical composition, preparation method and use thereof
  • Substituted heterocyclic compound and derivative thereof, pharmaceutical composition, preparation method and use thereof

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preparation example Construction

[0154] The preparation of solvates is generally known. Typical, non-limiting procedures include dissolving the compound in the required amount of the desired solvent (organic or water or mixtures thereof) at above ambient temperature, cooling the solution at a rate sufficient to form crystals, and then isolating the crystals by standard methods. Analytical techniques such as infrared spectroscopy can confirm the presence of solvent (or water) in crystals as solvates (or hydrates).

[0155] The term "prodrug" as used herein means a substance that is transformed in vivo into a compound having formula (A) or the structure of formula (A) or a pharmaceutically acceptable salt of the compound. Transformation can be accomplished by various mechanisms (eg, by metabolic or chemical processing), eg, by hydrolysis in blood.

[0156] The compounds described herein can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0157] As used herein isomer...

Embodiment 1

[0241] (5S,8S,9R,10s)-8-(((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)methyl)-9,10-dideuterium- Preparation of 8-phenyl-1,7-diazaspiro[4.5]-2-decanone (I-1)

[0242] Compound A1 (1.0 g, 2.0 mmol) was added to 20 mL of CD at room temperature 3 In OD, add 100 mg of 10% Pd / C, shake well, replace with deuterium and stir at room temperature until the reaction is complete. After filtration, the filtrate was concentrated and the residue was separated and purified by column chromatography to obtain compound I-1 (about 970 mg, yield 96.2%).

[0243] 1 HNMR (400MHz, CDCl 3 )δ:7.88(br,1H),7.61(s,1H),7.41-7.29(m,5H),7.19(s,2H),4.37(q,1H,J=6.4Hz),3.80-3.78(m ,1H),3.20-3.18(m,2H),2.79-2.76(m,1H),2.35-2.30(m,2H),2.05-2.03(m,1H),1.80-1.61(m,3H),1.33 (d,3H,J=6.4Hz).

[0244] MS m / z(ESI):503.1[M+H] +

[0245] The reaction route is:

[0246]

Embodiment 2

[0248] (5R,8S)-8-(((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)methyl)-8-(4-fluorophenyl)-1 , Preparation of 7-diazaspiro[4.5]-9-double bond-2-decanone (II-1)

[0249] Step 1, the preparation of (S)-2-((((benzyloxy)carbonyl)amino)-2-(4-fluorophenyl)acetic acid (1a)

[0250] Sodium hydroxide (38 g, 0.95 mol) was dissolved in 500 mL of H at room temperature 2 In O, compound SM-1 (70 g, 0.42 mol) was added. Under cooling in an ice bath, 98% Cbz-Cl (68 mL, 0.50 mol) was added to the reaction liquid, and stirred at room temperature until the reaction was complete. Then 6N HCl was added to the reaction solution to adjust the pH to 1-2, filtered, the filter cake was washed with water until the filtrate was neutral, and vacuum-dried at 55° C. for 20 h to obtain the target product 1a (96 g, yield 75.4%).

[0251] MS m / z(ESI):302.2[M+H] +

[0252] Step 2, Preparation of (2R,4S)-benzyl 4-(4-fluorophenyl)-5-carbonyl-2-phenyloxazolidine-3-carboxylate (1b)

[0253] At room temperatur...

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PUM

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Abstract

The invention provides a substituted heterocyclic compound as well as a preparation method and application thereof, particularly a substituted heterocyclic compound as well as a derivative, a medicinal composition, a preparation method and application thereof to preparation of a medicine for treating neurogenic diseases. Furthermore, the invention provides a compound or a derivative thereof of a structure of formula A shown in the specification. The derivative is a pharmaceutically acceptable salt, a solvent compound, a nitric oxide, a prodrug, an isomer or a mixture of the substances.

Description

technical field [0001] The present application relates to the field of medicine, in particular to a neurokinin receptor (NK1) antagonist compound and its derivatives, its pharmaceutical composition, preparation method and application. Background technique [0002] Neurokinins, also known as tackykinins, comprise a class of peptide neurotransmitters found in the peripheral and central nervous systems. The three main neurokinins are substance P (SP), neurokinin A (neurokinin A) and neurokinin B (neurokinin B). At least three types of neurokinin receptors are known, which are classified into NK1 (neurokinin receptors) based on their relative selectivity for substance P, neurokinin A, and neurokinin B. Peptide 1), NK2 (neurokinin 2) and NK3 (neurokinin 3) receptors. [0003] Neurokinin receptors can be found in the mammalian nervous system, circulatory system, and in peripheral tissues. Thus, modulation of such receptors can be used to potentially treat or prevent a variety o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/10C07D491/113C07D498/10A61K31/438A61K31/537A61P1/00A61P1/08A61P11/00A61P25/00A61P29/00
CPCC07D471/10C07D491/113C07D498/10Y02P20/55
Inventor 刘钢于华任云董振文曾宏宋宏梅苏东海刘薇王利春王晶翼
Owner SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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