阅读说明：本技术 一种咔唑类化合物及其制备方法与在抗hiv药物中的应用 (Carbazole compound, preparation method thereof and application thereof in anti-HIV (human immunodeficiency virus) medicines ) 是由 汪云松 汪欣怡 扬靖华 卢溶 白逸欣 于 2019-10-15 设计创作，主要内容包括：本发明公开了一种咔唑类化合物及其制备方法与在抗HIV药物中的应用,属于药物技术领域。本发明咔唑类化合物的化学结构式为<Image he="302" wi="460" file="DDA0002233548590000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>命名为咔唑类化合物Clauolenzoles B。本发明咔唑类化合物Clauolenzoles B对HIV具有抑制活性,EC<Sub>50</Sub>值为3.7μg/mL；咔唑类化合物Clauolenzoles B与药用载体和/或赋形剂可制成抗HIV药物组合物,抗HIV药物组合物的剂型为注射剂、片剂、丸剂、胶囊剂、溶液、悬浮剂或乳剂。(The invention discloses a carbazole compound, a preparation method thereof and application thereof in anti-HIV drugs, belonging to the technical field of drugs. The carbazole compound has the chemical structural formula Named as carbazole compound Clauolenzoles B. The carbazole compound Clauolenzoles B has the inhibitory activity on HIV, EC 50 The value was 3.7. mu.g/mL; the carbazole compound Clauolenzoles B and a medicinal carrier and/or an excipient can be prepared into an anti-HIV medicinal composition, and the anti-HIV medicinal composition is in the dosage form of injection, tablets, pills, capsules, solution, suspending agent or emulsion.)

1. A carbazole-based compound characterized in that: has the following chemical structural formula

2. An anti-HIV pharmaceutical composition characterized by: comprising a pharmaceutically acceptable carrier and/or excipient, and the carbazole-based compound according to claim 1.

3. The anti-HIV pharmaceutical composition of claim 2, in the form of injection, tablet, pill, capsule, solution, suspension or emulsion.

4. The extraction method of the carbazole-based compound according to claim 1, comprising the following steps:

(1) percolating and extracting Clausena ansum-olens Merr dry powder of the flaccid Clausena by adopting ethanol to obtain an extracting solution, and concentrating under reduced pressure to obtain a crude extract;

(2) suspending the crude extract obtained in the step (1) in water to obtain a suspension, extracting the suspension with petroleum ether to obtain a petroleum ether extract and a petroleum ether extraction aqueous phase, concentrating the petroleum ether extract to obtain a petroleum ether extraction extract, extracting the petroleum ether extraction aqueous phase with ethyl acetate to obtain an ethyl acetate extract, and concentrating the ethyl acetate extract to obtain an ethyl acetate extraction extract;

(3) performing silica gel column chromatography on the ethyl acetate extract obtained in the step (2), performing gradient elution by sequentially adopting a petroleum ether/ethyl acetate mixed solution system and a dichloromethane/methanol mixed solution system, and checking and merging similar fractions according to thin-layer chromatography to obtain 8 components, namely A, B, C, D, E, F, G and H;

(4) performing gel column chromatography on the component C in the step (3), eluting by adopting dichloromethane, and merging similar fractions according to thin-layer chromatography inspection to obtain 5 components, namely a, b, C, d and e;

(5) and (4) performing silica gel column chromatography on the component B, and performing gradient elution by adopting a petroleum ether/ethyl acetate mixed solution system to obtain the carbazole compound Clauolenzoles B.

5. The method for extracting carbazole-based compounds according to claim 4, wherein: and (3) carrying out gradient elution by using petroleum ether/ethyl acetate mixed liquor, wherein the volume ratio of the petroleum ether to the ethyl acetate is 8:2, 2:1, 5:5, 4:6 and 0:1 in sequence, and the component B is an elution part with the volume ratio of the petroleum ether to the ethyl acetate being 5: 5.

6. The method for extracting carbazole-based compounds according to claim 4, wherein: and (3) carrying out gradient elution by sequentially using dichloromethane/methanol mixed solution to obtain dichloromethane/methanol mixed solution with the volume ratio of 8:2, 7:3, 6:4, 1:1 and 0: 1.

7. The method for extracting carbazole-based compounds according to claim 4, wherein: the volume ratio of petroleum ether to ethyl acetate in the petroleum ether/ethyl acetate mixed solution for gradient elution in the step (5) is 7:3, 6:4 and 5:5 in sequence.

Technical Field

The invention relates to a carbazole compound, a preparation method thereof and application thereof in anti-HIV drugs, belonging to the technical field of drugs.

Background

Current aids treatment regimens rely on a series of drugs, known as combined antiretroviral therapy (cART), which can improve the quality of life of HIV positive patients (Trends in pharmaceutical Sciences2011,32(12), 715.); another is the development of molecules capable of interacting with multiple targets simultaneously (drug discov. today, 2004, 9, 641.; med. chem., 2014, 22, 4658.); however, due to increasing drug resistance and side effects of current drugs, new anti-HIV drug molecules are constantly being discovered (clin. trials, 2005, 6, 5.; bmbrep.2015,48,121.); therefore, the search and development of highly effective and low-toxic anti-HIV drugs have become one of the most important research subjects in the world medical field.

Disclosure of Invention

Aiming at the problem of toxic and side effects of anti-HIV drugs in the prior art, provides a carbazole compound, a preparation method thereof and application thereof in anti-HIV drugs, wherein the carbazole compound Clauolenzoles B is extracted and separated from Clausena anium-olens Merr, has an inhibitory activity on HIV, and has EC ₅₀The value is 3.7 mu g/mL, and can be used for preparing anti-HIV pharmaceutical compositions.

A carbazole compound with the following chemical structural formula

Named as carbazole compound Clauolenzoles B.

An anti-HIV pharmaceutical composition comprises a medicinal carrier and/or an excipient, and the carbazole compound Clauolenzoles B.

The anti-HIV pharmaceutical composition is in the dosage form of injection, tablet, pill, capsule, solution, suspension or emulsion.

The extraction method of the carbazole compound comprises the following specific steps:

(1) percolating and extracting Clausena ansum-olens Merr dry powder of the flaccid Clausena by adopting ethanol to obtain an extracting solution, and concentrating under reduced pressure to obtain a crude extract;

(2) suspending the crude extract obtained in the step (1) in water to obtain a suspension, extracting the suspension with petroleum ether to obtain a petroleum ether extract and a petroleum ether extraction aqueous phase, concentrating the petroleum ether extract to obtain a petroleum ether extraction extract, extracting the petroleum ether extraction aqueous phase with ethyl acetate to obtain an ethyl acetate extract, and concentrating the ethyl acetate extract to obtain an ethyl acetate extraction extract;

(3) performing silica gel column chromatography on the ethyl acetate extract obtained in the step (2), performing gradient elution by sequentially adopting a petroleum ether/ethyl acetate mixed solution system and a dichloromethane/methanol mixed solution system, and checking and merging similar fractions according to thin-layer chromatography to obtain 8 components, namely A, B, C, D, E, F, G and H;

(4) performing gel column chromatography on the component C in the step (3), eluting by adopting dichloromethane, and merging similar fractions according to thin-layer chromatography inspection to obtain 5 components, namely a, b, C, d and e;

(5) and (4) performing silica gel column chromatography on the component B, and performing gradient elution by adopting a petroleum ether/ethyl acetate mixed solution system to obtain the carbazole compound Clauolenzoles B.

The volume ratio of petroleum ether to ethyl acetate in the petroleum ether/ethyl acetate mixed solution for gradient elution in the step (3) is 8:2, 2:1, 5:5, 4:6 and 0:1 in sequence, and the component B is an elution part with the volume ratio of petroleum ether to ethyl acetate of 5: 5.

The volume ratio of dichloromethane to methanol in the dichloromethane/methanol mixed solution for gradient elution in the step (3) is 8:2, 7:3, 6:4, 1:1 and 0:1 in sequence.

The volume ratio of petroleum ether to ethyl acetate in the petroleum ether/ethyl acetate mixed solution for gradient elution in the step (5) is 7:3, 6:4 and 5:5 in sequence.

Further, the mass percentage content of the carbazole compound Clauolenzoles B in the clausena lansium extract is 0.03%; the pharmaceutically acceptable carrier and/or excipient is non-toxic to both humans and animals and is inert;

the medicinal carrier is one or more of solid diluent, semisolid diluent, liquid diluent, filler and pharmaceutical product adjuvant;

the pharmaceutical composition is administered in the form of an amount administered per unit body weight;

the medicine can be administered by injection (intravenous injection, intramuscular injection), oral administration or skin administration.

The invention has the beneficial effects that:

(1) the carbazole compound Clauolenzoles B has the inhibitory activity on HIV, EC ₅₀The value was 3.7. mu.g/mL; the carbazole compound Clauolenzoles B and a medicinal carrier and/or an excipient can be prepared into an anti-HIV medicinal composition;

(2) the carbazole compound Clauolenzoles B is from edible natural plant components, and the anti-HIV medicinal composition prepared from the carbazole compound Clauolenzoles B is non-toxic or low-toxic.

Detailed Description

The present invention will be described in further detail with reference to specific embodiments, but the scope of the present invention is not limited to the description.