Substituted heterocyclic compound as well as derivative, medicinal composition, preparation method and application thereof

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

Active Publication Date: 2018-06-12
SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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 as well as derivative, medicinal composition, preparation method and application thereof
  • Substituted heterocyclic compound as well as derivative, medicinal composition, preparation method and application thereof
  • Substituted heterocyclic compound as well as derivative, medicinal composition, preparation method and application thereof

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preparation example Construction

[0154] The preparation of solvates is generally known. A typical non-limiting method involves dissolving the compound in the required amount of solvent (organic or water or a mixture thereof) at a temperature 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 the crystal as a solvate (or hydrate).

[0155] The term "prodrug" as used herein refers to a substance that is transformed in vivo to produce a compound having the structure of formula (A) or formula (A) or a pharmaceutically acceptable salt of the compound. Conversion can be accomplished by various mechanisms (e.g., through metabolism or chemical treatment), e.g., through hydrolysis in the blood.

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

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] Add compound A1 (1.0g, 2.0mmol) to 20mL of CD at room temperature 3 To OD, add 100mg of 10% Pd / C, shake well, and after deuterium replacement, stir at room temperature until the reaction is complete. After filtering, after the filtrate is concentrated, the residue is 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. Preparation of (S)-2-(((benzyloxy)carbonyl)amino)-2-(4-fluorophenyl)acetic acid (1a)

[0250] At room temperature, dissolve sodium hydroxide (38g, 0.95mol) in 500mL of H 2 In O, compound SM-1 (70g, 0.42mol) was added. Under ice-cooling, 98% Cbz-Cl (68 mL, 0.50 mol) was added to the reaction solution and stirred at room temperature until the reaction was complete. Then, 6N HCl was added to the reaction solution to adjust to pH=1-2, filtered, the filter cake was washed with water until the filtrate was neutral, and vacuum dried at 55° C. for 20 hours 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 temperature, compound 1a (72g, 0.24mol), 1L a...

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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] This 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, include 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). It is known that there are at least three types of neurokinin receptors. According to the relative selectivity of neurokinin receptors to substance P, neurokinin A and neurokinin B, neurokinin receptors are divided into NKl (neural kinin receptors). Peptide 1), NK2 (Neurokinin 2) and NK3 (Neurokinin 3) receptors. [0003] Neurokinin receptors can be found in the nervous system, circulatory system, and peripheral tissues of mammals. Therefore, modulation of such receptors can be used...

Claims

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Application Information

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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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