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Chiral pyrazolone spiro[ethylenethiourea] spirooxindole compounds and their derivatives

A technology of pyrazolone spiro and ethylene thiourea, which can be used in organic chemistry, drug combination, metabolic diseases, etc., and can solve problems such as limitations

Inactive Publication Date: 2019-10-11
DALIAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although chiral 4-spirocyclic pyrazolone structures can be constructed asymmetrically through some series reactions, they are limited to the 4-position all-carbon chiral center, and there is no asymmetric catalytic construction of 4-position heteroatom-containing spirocyclic pyrazolones. Report on the structure of oxazolinone

Method used

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  • Chiral pyrazolone spiro[ethylenethiourea] spirooxindole compounds and their derivatives
  • Chiral pyrazolone spiro[ethylenethiourea] spirooxindole compounds and their derivatives
  • Chiral pyrazolone spiro[ethylenethiourea] spirooxindole compounds and their derivatives

Examples

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preparation example Construction

[0056] The technical purpose of the second aspect of the present invention is to provide the preparation method of above-mentioned chiral pyrazolone spiro[ethylenethiourea] spirooxindole compound, comprising the following steps:

[0057] (1) The compound of formula i is reacted with concentrated hydrochloric acid and sodium nitrite in ethanol at a molar ratio of 1:1:1 to 1:1.5:1.5 at 0°C to prepare the compound of formula ii;

[0058]

[0059] (2) The compound of formula ii and palladium carbon (Pd / C) are reacted overnight at room temperature under a hydrogen atmosphere in methanol at a mass ratio of 1:0.05 to 0.1 to prepare a compound of formula iii;

[0060]

[0061] (3) The compound of formula iii, in ethanol, reacts with carbon disulfide and triethylamine in a molar ratio of 1:5:2 to 1:10:4 at room temperature for 0.5-1h; then cools down to 0°C, and then press formula iii The compound: Boc anhydride: 4-dimethylaminopyridine molar ratio is 1:1:0.05~1:1.2:0.1 Add Boc a...

Embodiment 1

[0099] Preparation of Compound 22 of Formula II:

[0100] Prepare compound 2 first:

[0101]

[0102] Reagents and conditions: a) sodium nitrite, concentrated hydrochloric acid, ethanol, react at 0°C for 1 hour, and the yield is 95%; b) Pd / C, hydrogen, methanol, concentrated hydrochloric acid, react at room temperature for 4 hours; c) carbon disulfide, triethylamine , Boc anhydride, 4-dimethylaminopyridine, 10% hydrochloric acid, 0-25 ° C reaction, yield 70% (two-step yield).

[0103] (1) Synthesis of 4-oximino-1-phenyl-3-(4-methylphenyl)pyrazolone:

[0104] 1-Phenyl-3-(4-methylphenyl)pyrazolone (1.0 g, 4.0 mmol, 1.0 eq.) and absolute ethanol (15 mL) were sequentially added into a 250 mL reaction flask. The reaction solution was placed in an ice bath, concentrated hydrochloric acid (0.5mL, 6.0mmol, 1.5eq.) was added dropwise, and the solid dissolved after stirring for 10min. Under an ice bath, an aqueous solution (1.5 mL) of sodium nitrite (0.41 g, 6.0 mmol, 1.5 eq.) was...

Embodiment 2-20

[0112] Compounds 12-21 and 23-31 were prepared by using the same reaction conditions as in Example 1 and selecting raw materials corresponding to the structural formulas of compounds 12-21 and 23-31.

[0113] The properties and structural characterization results of compound 12-31 are shown in Table 2:

[0114] Table 2

[0115]

[0116]

[0117]

[0118]

[0119]

[0120] In the following examples, the specific preparation process for preparing the racemate and enantiomer of compound 22 is also given:

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Abstract

The invention relates to chiral pyrazolone spiro [ethylenethiourea] spirooxindole compounds and derivatives thereof. The chiral pyrazolone spiro [ethylenethiourea] spirooxindole compounds and the derivatives thereof have structures shown in general formulae II and III, wherein R<1> and R<2> are independently selected from C1-6 alkyl, phenyl, substituted phenyl, benzyl, phenethyl, phenylpropyl, thienyl and naphthyl respectively; R<3> is selected from hydrogen, C1-6 alkyl, C1-6 alkenyl and benzyl; R<4> is selected from hydrogen, C1-6 alkyl, phenyl, halogen, C1-6 alkoxy and C1-6 halogenated alkyl; R<5> is selected from hydrogen, carbalkoxy, acetyl and phenyl. The compounds are prepared from 4-position non-substituted pyrazolone through a synthetic reaction. A series of hCE1 (human carboxylesterase 1) inhibitors are developed on the basis of pyrazolone spiro [ethylenethiourea] spirooxindole skeletons, so that potential selections are provided for treatment of hCE1 related diseases such as hyperlipidemia and the like.

Description

technical field [0001] The invention relates to a chiral pyrazolone spiro[ethylenethiourea] spirooxindole compound and its derivatives, including its preparation method and application in inhibiting human carboxylesterase 1 (hCE1). It belongs to the field of fine organic chemistry and biomedicine technology. Background technique [0002] The pyrazolone skeleton has important physiological and pharmacological activities, such as aminopyrine, antipyrine, etc. are important antipyretic and analgesic drugs, and edaravone is a neuroprotective agent (Acute Pain, 1997, 1:33- 40; CNSDrug Rev., 2006:12,9-20); the structure of ethylene thiourea is an important part of active molecules such as vitamin H; at the same time, the structure of oxindole is widely found in many natural products and drugs (Eur. J.Med.Chem., 2016,123:858-894), such as the antipsychotic drug ziprasidone and ropinirole for the treatment of Parkinson's, etc. At present, the combination of different pharmacophore...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/20A61P3/06
Inventor 王保民鲍晓泽张文珠邹立伟黄跃曲景平
Owner DALIAN UNIV OF TECH
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