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Tanshinone IIA phosphoric acid derivative and synthesis and use thereof as medicine

A technology of tanshinone and prodrug, applied in the field of medicine, can solve the problems of high irritation of products, pain of patients, low pH value of injections, etc.

Active Publication Date: 2017-03-08
北京益佰医药研究有限公司
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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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  • Tanshinone IIA phosphoric acid derivative and synthesis and use thereof as medicine
  • Tanshinone IIA phosphoric acid derivative and synthesis and use thereof as medicine
  • Tanshinone IIA phosphoric acid derivative and synthesis and use thereof as medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] 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)phosphoric acid (DP-1)

[0036]

[0037] step 1 : Tanshinone IIA Sulfonyl chloride ( intermediate IN-A) preparation of

[0038] 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.

[0039] step 2 ： DP-1 preparation of

[0040] Dissolve the intermediate IN-A (1g, about 2.55mmol) obtained in step 1 in 25mL of toluene, place the reaction bottle in an ice-water bath, and when the internal temperature drops to 5°...

Embodiment 2

[0042] Example 2: (2-((1,6,6-trimethyl-10,11-dioxo-6,7,8,9,10,11-hexahydrophenanthrene[1,2-b] Preparation of furan)-2-sulfonamido)ethyl)trisodium phosphate (DP-1-S)

[0043]

[0044] DP-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 DP-1-S, 110 mg, with a quantitative yield.

[0045] 1 H NMR (400MHz, D 2 O) δ8.10-7.99(m, 2H), 3.35(m, 2H), 3.25(m, 2H), 2.59(s, 3H), 1.91(m, 2H), 1.60(m, 2H), 1.51( m, 2H), 1.39 (s, 6H), LCMS (ESI) m / z, 482.1 (M+1) + .

Embodiment 3

[0046] 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) phosphoric acid (DP-2)

[0047]

[0048]

[0049] step 1 : Formyltanshinone IIA( intermediate IN-B) preparation of

[0050] 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.

[0051] 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...

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PUM

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Abstract

The invention discloses a tanshinone IIA phosphoric acid derivative and synthesis and use thereof as a medicine for treatment. In particular, the present invention provides a novel derivative shown as a general formula (I) and a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the novel derivative shown as the general formula (I), and a method for preparing the novel derivative shown as the general formula (I). The invention also discloses use of the novel derivative, the pharmaceutically acceptable salt thereof or the pharmaceutical composition containing the novel derivative in preparation of medicines for treatment of coronary heart disease, angina, myocardial infarction, viral myocarditis, arrhythmia, cerebrovascular disease, hepatitis, pulmonary heart disease, bronchial asthma, cancer, kidney disease, eye disease, thromboangiitis obliterans, hypertension, fractures, burns, surgical operations or behcet ' s syndrome. On the basis of ensurance of the activity of tanshinone IIA, the novel derivative, the water solubility of the pharmaceutically acceptable salt thereof or the pharmaceutical composition containing the novel derivative can be improved. Compared with tanshinone IIA sodium sulfonate, the stability is improved, and because the acidity of the pharmaceutically acceptable salt thereof or the pharmaceutical composition containing the novel derivative is reduced obviously, injection stimulation can be avoided. All substituents of the general formula (I) are as defined in the specification.

Description

[0001] 【Technical field】 [0002] The invention belongs to the technical field of medicine, and relates to tanshinone IIA phosphoric 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 use of these compounds in the preparation of cardiovascular and cerebrovascular system disease treatment and prevention drugs Applications. [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 promotes blood circulation and removes blood stasis, and is often use...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J73/00A61K31/665A61K45/06A61P9/10A61P9/06A61P9/00A61P1/16A61P11/06A61P13/12A61P27/02A61P35/00A61P9/12A61P19/08A61P9/14A61P37/02
Inventor 陈剑
Owner 北京益佰医药研究有限公司
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