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Sulfotanshinone IIA derivatives, and synthesis and applications thereof as drug

A technology of tanshinone and prodrug, which is applied in the field of medicine, can solve the problems of easy removal of sulfonate groups, high product irritation, and poor stability, and achieve the effects of reducing irritation, improving water solubility, and improving stability

Active Publication Date: 2017-03-08
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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  • Sulfotanshinone IIA derivatives, and synthesis and applications thereof as drug
  • Sulfotanshinone IIA derivatives, and synthesis and applications thereof as drug
  • Sulfotanshinone IIA derivatives, and synthesis and applications thereof as drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1: (2-((1,6,6-trimethyl-10,11-dioxo-6,7,8,9,10,11-hexahydrophenanthrene[1,2-b] Preparation of furan)-2-sulfonamido)ethyl)sulfonic acid (DS-1)

[0047]

[0048] Step 1: Preparation of Tanshinone IIA Sulfonyl Chloride (Intermediate IN-A)

[0049] Tanshinone IIA (10 g, 33 mmol) was added dropwise into 150 mL of sulfuryl chloride, and refluxed for 1 hour. The temperature of the reaction system was lowered to room temperature, and the unconsumed sulfuryl chloride was distilled off under reduced pressure. The remaining black oily liquid was dried under reduced pressure with an oil pump for 2 hours under the condition of avoiding light, and the obtained black oily liquid was directly used in the next reaction.

[0050] Step 2: Preparation of DS-1

[0051] The intermediate IN-A (1 g, about 2.55 mmol) obtained in step 1 was dissolved in 25 mL of toluene, the reaction flask was placed in an ice-water bath, and the inner temperature dropped to 5° C., and aminoetha...

Embodiment 2

[0053] Example 2: (2-((1,6,6-trimethyl-10,11-dioxo-6,7,8,9,10,11-hexahydrophenanthrene[1,2-b] Preparation of trisodium furan)-2-sulfonamido)ethyl)sulfonate (DS-1-S)

[0054]

[0055] DS-1 (100 mg, 0.20 mmol) was placed in 5 mL of methanol, sodium bicarbonate (50 mg) was added thereto, stirred at room temperature for 30 minutes, filtered, and the filtrate was evaporated to dryness to obtain DS-1-S, 108 mg, with a quantitative yield.

[0056] 1 H NMR (400MHz, D 2 O) δ8.12-8.02(m, 2H), 4.21(m, 2H), 3.52(m, 2H), 3.31(m, 2H), 2.60(s, 3H), 1.60(m, 2H), 1.45( m, 2H), 1.29 (s, 6H), LCMS (ESI) m / z, 482.2 (M+1) + .

Embodiment 3

[0057] Example 3: (2-(1,6,6-trimethyl-10,11-dioxo-6,7,8,9,10,11-hexahydrophenanthrene[1,2-b]furan Preparation of -2-carbonylamide) ethyl) sulfonic acid (DS-2)

[0058]

[0059] Step 1: Preparation of formyltanshinone IIA (intermediate IN-B)

[0060] 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 was completed, the reaction solution was poured into 1000 mL of ice-water mixture, stirred slowly, and a light 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.

[0061] 1 H NMR (400MHz, CDCl3), 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). LC...

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Abstract

The invention discloses sulfotanshinone IIA derivatives, and synthesis and applications thereof as a drug. Specifically, the invention relates to novel derivatives represented by the formula (I) and pharmaceutically acceptable salts of the derivatives, a pharmaceutical composition comprising the same, and a preparation method thereof. The invention also discloses applications of the derivatives in the preparation of drugs for treating coronary heart disease, angina pectoris, myocardial infarction, viral myocarditis, arrhythmia, cerebrovascular disease, hepatitis, pulmonary heart disease, bronchial asthma, tumors, kidney diseases, eye diseases, vasculitis with artery occlusion, hypertension, bone fracture, burns, surgical operation, Bechcets syndrome, and the like. The derivatives have the advantages that the activity of tanshinone IIA is maintained, and the water solubility of tanshinone IIA is improved. Compared with sodium sulfotanshinone IIA, the stability is improved, the acidity of the derivatives is prominently reduced, and the irritancy in injection is avoided. The definitions of substituents of the formula (I) are the same as the definitions in the description.

Description

[0001] 【Technical field】 [0002] The invention belongs to the technical field of medicine, and specifically relates to tanshinone IIA sulfonic acid derivatives, pharmaceutically acceptable salts thereof, or prodrugs thereof, or salts of prodrugs 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 preparation of these compounds, pharmaceutical compositions and compound drugs for the treatment of and the application of drugs for the prevention of cardiovascular and cerebrovascular diseases [0003] 【Background technique】 [0004] Salvia miltiorrhiza is the dry root and rhizome of Salvia miltiorrhizaBge., a plant of the Labiatae family, which is included in "Shen Nong's Materia Medica" and successive dynasties of herbal medicines. Danshen is a traditional Chinese medicine that pro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J73/00A61K31/58A61P9/10A61P9/06A61P1/16A61P29/00A61P11/00A61P11/06A61P35/00A61P27/02A61P9/00A61P9/12A61P19/08A61P17/02
Inventor 陈剑
Owner 北京桦冠医药科技有限公司
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