Synthesis and pharmaceutical application of sulfamide derivative

A technology of pharmacy and prodrug, applied in the field of medicine, can solve the problems of patient suffering, poor stability, easy desulfonation, etc.

Active Publication Date: 2015-02-11
北京桦冠医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the strong acidity of the sulfonic acid group, the pH of the injection is low, and the product is very irritating, which brings pain to the patient.
And because of its poor stability, it is easy to remove sulfonate groups during the drug placement process to form tanshinone IIA, which is precipitated in the injection

Method used

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  • Synthesis and pharmaceutical application of sulfamide derivative
  • Synthesis and pharmaceutical application of sulfamide derivative
  • Synthesis and pharmaceutical application of sulfamide derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] [Example 1] 2-(1-(1,6,6-trimethyl-10,11-dioxo-6,7,8,9,10,11-hexahydrophenanthrene[1,2- b] furan-2-yl)methyl-3-phosphonoguanidino)acetic acid Preparation of trisodium

[0072] Step 1: Preparation of Tanshinone IIA-2-carbaldehyde

[0073] Tanshinone IIA (30 g, 0.01 mol) was dissolved in 300 mL of DMF, 30 mL of phosphorus oxychloride was added dropwise at room temperature, and stirred at room temperature for 2 hours. After the reaction, the reaction solution was poured into 1000 mL of ice-water mixture, stirred slowly, and a pale yellow solid was precipitated, filtered with suction, and the filter cake was washed with cold water three times, 100 mL each time. The filter cake was collected and vacuum-dried to obtain 32 g of tanshinone IIA-2-carbaldehyde (light yellow solid), and the yield was quantitative. 1 H NMR (400MHz, CDC13), 9.85(s, 1H), 7.78-7.69(d and d, 2H), 3.19(m, 2H), 1.80(m, 2H), 1.67(m, 2H), 2.65(s , 3H), 1.31 (s, 6H). LCMS (ESI) m / z, 323 (M+1) +

...

Embodiment 2

[0082] [Example 2]: (2S)-2-(1-(1,6,6-trimethyl-10,11-dioxo-6,7,8,9,10,11-hexahydrophenanthrene [1,2-b]furan-2-yl)methyl-3-phosphonoguanidine) Preparation of trisodium propionate

[0083] According to the preparation method in Example 1, using L-alanine methyl ester instead of glycine methyl ester as raw material, (2S)-2-(1-(1,6,6-trimethyl-10,11-di Trisodium oxo-6,7,8,9,10,11-hexahydrophenanthrene[1,2-b]furan-2-yl)methyl-3-phosphonoguanidino)propionate. 1 H NMR (400MHz, D 2 O) δ7.75-7.73(m, 2H), 4.32(m, 1H), 3.48(s, 2H), 3.05(m, 2H), 2.04(s, 3H), 1.70(m, 2H), 1.61( m, 2H), 1.35(d, 3H) 1.21(s, 6H), LCMS m / z=518.14(M+1) +

Embodiment 3

[0084] [Example 3]: (2S)-2-(1-(1,6,6-trimethyl-10,11-dioxo-6,7,8,9,10,11-hexaoxophenanthrene [1,2-b]furan-2-yl)methyl-3-phosphonoguanidine base)-3-methyl-trisodium butyrate

[0085] According to the preparation method in Example 1, using L-valine methyl ester instead of glycine methyl ester as raw material, (2S)-2-(1-(1,6,6-trimethyl-10,11-di Oxo-6,7,8,9,10,11-hexahydrophenanthrene[1,2-b]furan-2-yl)methyl-3-phosphonoguanidino)-3-methyl-butanoic acid Trisodium. 1 H NMR (400MHz, D 2 O) δ7.73-7.69 (m, 2H), 4.23 (m, 1H), 3.44 (s, 2H), 3.02 (m, 2H), 2.01 (s, 3H), 1.71 (m, 2H), 1.60 ( m, 2H), 1.77(m, 1H), 1.33(d, 3H), 1.20(s, 6H), 1.01(d, 6H).LCMS m / z=546.14(M+1) +

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PUM

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Abstract

The invention discloses a tanshinone IIA derivative. A connecting arm, phosphocreatine and an analogue of the phosphocreatine form a conjugate of which the structure is as shown in formula (I) in the specification, wherein n is equal to 1-3, m is equal to 0-3, R1 and R2 respectively independently represent hydrogen atoms, C1-C5 alkyl, cycloalkyl, vinyl and alkynyl, the R1 and the R2 also can form ternary to hexatomic rings, and M represents metal ions, like sodium ions. The compound can be used for improving the water solubility of the whole molecule through sodium phosphate in the phosphocreatine on the premise of maintaining the activity of the tanshinone IIA; moreover, a phosphocreatine fragment in the molecule can play a dual protection effect on myocardial muscles.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a tanshinone IIA phosphate sodium conjugate, a pharmaceutically acceptable salt and a hydrate thereof. The present invention also relates to a preparation method of these compounds, a pharmaceutical composition containing these compounds, a compound drug containing these compounds and one or more other pharmaceutically active substances, and the use of these compounds in the preparation of cardiovascular and cerebrovascular system disease treatment and prevention drugs Applications. Background technique [0002] Salvia miltiorrhiza is the dry root and rhizome of Salvia miltiorrhiza Bge., a plant of the Labiatae family, which was included in "Shen Nong's Herbal Classic" and successive dynasties of herbal medicines. Danshen is a traditional Chinese medicine that promotes blood circulation and removes blood stasis, and is often used to treat cardiovascular and cerebrovascular diseas...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/655A61K31/665A61P9/10A61P9/06A61P9/00A61P1/16A61P11/00A61P11/06A61P35/00A61P13/12A61P27/02A61P9/12A61P19/08A61P17/02A61P9/14
Inventor 付翌秋陈剑
Owner 北京桦冠医药科技有限公司
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