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Matrine compound derivatives, and preparation method and application thereof

A compound and solvate technology, applied in the field of matrine compound derivatives and their preparation, can solve the problems of large dosage, narrow selective treatment window of sophocarpine, limited action intensity and the like

Active Publication Date: 2017-01-04
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the anti-CVB3 effect of sophocarpine is limited, the dosage is large, and it is an injection drug. It is reported that the current clinical dosage is 5-6mg / kg -1 , and the intravenous drip rate must be strictly controlled during the intravenous drip process, indicating that the selective therapeutic window of sophocarpine is narrow

Method used

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  • Matrine compound derivatives, and preparation method and application thereof
  • Matrine compound derivatives, and preparation method and application thereof
  • Matrine compound derivatives, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0171] Example 1 Preparation of 12-N-trifluoromethoxybenzenesulfonyl matrine butyric acid morpholine amide hydrochloride (KCA-1)

[0172]

[0173] Step 1: Preparation of matrine butyric acid (MT-1)

[0174]

[0175] Put matrine (1g, 4mmol) into 20mL 5N NaOH aqueous solution, heat to reflux for 9h, after the reaction, cool to room temperature, a large amount of white solid precipitates, filter, and slowly put the filter cake into 6N HCl, and keep the pH< 5. Evaporate the solvent water to dryness, add methanol to fully dissolve the residue, filter to remove inorganic salts, and obtain a methanol solution of matrine butyric acid, which is directly used in the next reaction.

[0176] Step 2: Preparation of methyl matrine butyrate (MT-2) hydrochloride

[0177]

[0178] Heat the MT-1 methanol solution obtained in step 1 to reflux for 2 hours, and detect it by TLC. After the reaction, evaporate the solvent methanol to dryness, heat 10 mL of absolute ethanol, a large amount ...

Embodiment 2

[0187] Example 2 Preparation of 12-N-trifluoromethoxybenzenesulfonyl matrine butyric acid azetidine amide hydrochloride (KCA-3)

[0188]

[0189] With reference to the operation steps described in Example 1, MT-11-1 and azetidine were reacted under the reaction conditions described in Step 5 and corresponding post-treatments were performed to obtain the target product, a white solid (96.8mg, 45 %); Melting point: 97-99°C. MS-ESI m / z: 530.2; 1 H NMR(400MHz,DMSO)δ10.67(s,1H),7.97(d,J=8.3Hz,2H),7.61(d,J=8.3Hz,2H),4.24-3.86(m,7H),3.91 -3.67(m,2H),3.68-3.53(m,1H),3.17(d,J=19.3Hz,2H),2.88(dd,J=16.5,7.5Hz,2H),2.30-2.20(m,2H ),2.18-2.05(m,1H),2.02-1.80(m,3H),1.77-1.50(m,8H),1.37-1.06(m,2H); 13 C NMR (101MHz, DMSO) δ172.13, 151.39, 140.73, 129.74(2), 121.92(2), 119.03, 63.44, 57.88, 55.06, 54.94, 49.99, 48.98, 47.66, 38.56, 35.27, 30.18, 24.27.62, ,20.87,18.75,18.51,14.98.HRMS: cacld for C26H37N3O5F3S·HCl[M-Cl+H] +:530.2295,found:530.2295.

Embodiment 3

[0190] Example 3 Preparation of 12-N-trifluoromethoxybenzenesulfonyl matrine butyric acid dimethylamine amide hydrochloride (KCA-2)

[0191]

[0192] Referring to the operation steps described in Example 1, MT-11-1 was reacted with dimethylamine under the reaction conditions described in Step 5 and corresponding post-treatment was performed to obtain the target product as a white solid (74 mg, 45%); Melting point: 175-177°C. MS-ESI m / z: 518.2; 1 H NMR(400MHz,DMSO)δ10.84(s,1H),7.97(d,J=8.3Hz,2H),7.55(d,J=8.3Hz,2H),4.23-4.07(m,1H),3.93 -3.78(m,1H),3.77-3.70(m,1H),3.60(d,J=10.1Hz,1H),3.27-3.09(m,2H),3.00-2.90(m,2H),2.83(s ,3H),2.72(s,3H),2.35-2.18(m,3H),2.14-1.99(m,1H),2.00-1.82(m,2H),1.82-1.50(m,8H),1.34-1.10 (m,2H); 13 C NMR (101MHz, DMSO) δ172.01,151.34,140.91,129.76(2),121.73(2),119.01,63.44,58.03,55.07,54.94,49.07,38.54,37.08,35.22,35.10,32.28,247.64,25.64, ,21.34,18.74,18.47.HRMS: calcd for C24H35F3N3O4S·HCl[M-HCl+H] + :518.2295,found:518.2291.

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Abstract

The invention provides a compound shown in Formula I, an isomer, pharmaceutically-acceptable salt or solvate thereof, a preparation method thereof and application thereof in preparation of drugs for preventing and / or treating diseases caused by a Coxsackie virus. According to the invention, the compound keeps the activity of inhibiting the Coxsackie virus group B; and meanwhile, the pharmacokinetic parameters and safety of the compound drug are improved, thus indicating that the compound provided by the invention has favorable druggability and application prospects. The Formula I is shown in the specification.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a matrine compound derivative and a preparation method and application thereof. Background technique [0002] Coxsackievirus is a member of the family Picornaviridae and the genus Enterovirus, and is divided into two groups, A and B, according to the clinical symptoms and histopathological characteristics of infected neonatal mice. Coxsackievirus Group B (Group B coxsackievirus, CVB) contains 6 serotypes, namely B1-B6, among which Coxsackievirus B3 (CVB3) is a subtype of enterovirus coxsackievirus, belonging to Picornavirus (Picornavirus) family is a positive-strand RNA virus with no envelope and a 20-hedron three-dimensional symmetry in the capsid; CVB3 is an important pathogenic agent that can cause systemic multiple organ and tissue infections in newborn mice. In addition to viral myocarditis, it can also cause pericarditis, aseptic meningitis, epidemic chest pain, pancreatitis, hand,...

Claims

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Application Information

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IPC IPC(8): C07D471/16A61K31/4375A61K31/444A61K31/5377A61P31/14A61P9/00A61P11/00A61P1/18A61P29/00A61P25/00
CPCC07D471/16
Inventor 宋丹青李玉环唐胜李迎红蒋建东孔兰英王圣刚
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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