阅读说明：本技术 一种二苯酮类化合物及其制备方法和应用 (Benzophenone compound and preparation method and application thereof ) 是由 刘冰 陈宁 陈刚 刘颖杰 赵丹 于 2019-06-26 设计创作，主要内容包括：本发明属于医药技术领域,具体为一种新化合物及其应用,该化合物为新二苯酮类化合物,所涉及的应用是关于上述化合物用于制备抗氧化药物；该化合物具有明显的抗氧化的作用；且制备该化合物的原料资源丰富,提取分离技术难度小,溶剂可回收使用,生产成本低。(The invention belongs to the technical field of medicines, and particularly relates to a novel compound and application thereof, wherein the compound is a novel benzophenone compound, and the related application relates to the application of the compound in preparing an antioxidant drug; the compound has obvious antioxidant effect; and the raw material resources for preparing the compound are rich, the difficulty of the extraction and separation technology is small, the solvent can be recycled, and the production cost is low.)

1. A benzophenone compound is characterized in that the structural formula of the compound is as follows:

wherein R1 is selected from hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C4) alkyl which is halogenated or (C1-C4) alkoxy, (C1-C6) alkylthio, amino substituted by mono or di (C1-C6 alkyl), (C1-C6) alkylamido, (C1-C6) alkylsulfinyl, (C1-C6) alkylacyl and halogen.

2. The benzophenone-based compound according to claim 1, wherein: the difference between the numbers of carbon atoms of R1 and R2 is within 3.

3. The benzophenone-based compound according to claim 1, wherein: the difference between the numbers of carbon atoms of R3 and R4 is within 3.

4. Benzophenone-type compound according to claim 1, wherein R1 is hydrogen and/or R2 is hydrogen.

5. A benzophenone-type compound according to claim 1, characterized in that R3 is methyl and/or R4 is methyl.

6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 and pharmaceutically acceptable salts thereof as an active ingredient together with pharmaceutically acceptable excipients.

7. Use of the pharmaceutical composition according to claim 6 or the compound according to any one of claims 1 to 5 for the preparation of an antioxidant health food and/or an antioxidant medicament.

8. A process for the preparation of a compound according to any one of claims 1 to 5, characterized in that (1) after oral administration of butyrrolactone I to animals, urine and/or feces thereof are collected and extracted with an organic solvent; (2) adopting a chromatography mode, eluting and separating to obtain the butyrolactone metabolic ketone I.

9. The method of claim 8, wherein: the animal is a mouse; and/or the organic solvent is ethyl acetate.

10. The method of claim 8, wherein: the chromatography is (1) silica gel column chromatography and elution, and/or (2) C18 reversed-phase column chromatography and elution.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a novel ketone compound separated from a rat fecal metabolite of a secondary metabolite of aspergillus terreus butylrolactone I and application thereof.

Background

Butyrolactone-i (butyrolactone i) is the major active secondary metabolite of Aspergillus terreus, a fungus of the genus Aspergillus, Kiriyama was first isolated in 1977 from Aspergillus terreus var. africanus ifo 8835, and was named butyrolactone i because it has a five-membered unsaturated lactone ring in its structure.

The butyrrolactone I has a clear selective cell Cycle Dependent Kinase (CDK) inhibitory activity, the mechanism of the in vitro inhibitory action of the butyrolactone I on cdc2 and CDK2 is also clarified, and the butyrrolactone I is a potential anti-tumor candidate drug. The butyrrolactone I and the derivatives thereof are proved to be a multi-effect natural active substance and have wide pharmacological activity.

After the butyrolactone I is orally taken by rats, urine and feces are collected, various chemical and chromatographic means are utilized to separate and identify the metabolites of the butyrolactone I in vivo, the transformation process of the butyrolactone I in vivo is presumed, and the pharmacological activity of the metabolites is simultaneously measured, so that the structural change after the drug metabolic transformation and the relationship between the change and the curative effect and toxicity are known.

Disclosure of Invention

The invention aims to provide a benzophenone compound and a preparation method and application thereof.

The invention relates to a novel benzophenone compound separated from a rat fecal metabolite of a secondary metabolite of aspergillus terreus, namely butyrrolactone I and application thereof, wherein the benzophenone compound has a chemical structural formula (I):

wherein R1 is selected from hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C4) alkyl which is halogenated or (C1-C4) alkoxy, (C1-C6) alkylthio, amino substituted by mono or di (C1-C6 alkyl), (C1-C6) alkylamido, (C1-C6) alkylsulfinyl, (C1-C6) alkylacyl and halogen.

Further, the number of carbon atoms of R1 and R2 is within 3.

Further, the number of carbon atoms of R3 and R4 is within 3.

Further, R1 is hydrogen and/or R2 is hydrogen.

Further, R3 is methyl and/or R4 is methyl.

Furthermore, the chemical structural formula (II),

named butyrolactone metabolizing ketone I.

A pharmaceutical composition, said compounds and pharmaceutically acceptable salts thereof as active ingredients together with pharmaceutically acceptable excipients.

The pharmaceutical composition or the application of the compound in preparing antioxidant health food and/or antioxidant drugs.

A preparation method for preparing the compound, (1) after the butyl rolactone I is orally taken by animals, urine and/or feces are collected and extracted by adopting an organic solvent; (2) adopting a chromatography mode, eluting and separating to obtain the butyrolactone metabolic ketone I.

The preparation method is characterized in that the animal is a mouse; and/or the organic solvent is ethyl acetate.

The preparation method comprises (1) silica gel column chromatography and elution, and/or (2) C18 reversed-phase column chromatography and elution.

The compound of the invention has rich raw material resources, small difficulty of extraction and separation technology, recyclable solvent and low production cost.

The preparation method of the compound comprises the following steps:

(1) extraction: wistar rats with 40 animals, each half of male and female, 200 +/-20 g, after the animals are adaptively raised for 1 week, 40 mg.kg < -1 > is administrated by gastric gavage, the rats are respectively placed in a metabolism cage with 1 rat per cage, and 24h of excrement is collected. During the experiment, the rats are fed with the starch steamed buns, and the drinking water is fed with 4 per mill of physiological saline and 1 per mill of glucose solution. Feces were collected every morning for 24 hours and stored in a refrigerator at-80 ℃. Cumulative gavage was administered for 4 weeks, once daily. The total amount of extract obtained was 8g from ethyl acetate extract of feces.

(2) Separation: subjecting the extract to silica gel column chromatography, performing gradient elution with dichloromethane-methanol system at volume ratio of 100:0-100:50, detecting by thin layer chromatography, collecting fraction containing new compound, performing gradient elution with petroleum ether-ethyl acetate system at volume ratio of 100:0-0:100, performing C18 reversed phase column chromatography to obtain liquid phase, and eluting with methanol-water at volume ratio of 68:32 to obtain new compound butyrolactone metabolic ketone I.

The novel compounds of the invention, butyrolactone metabolizing ketone I, colorless oil (methanol), UV (MeOH) lambda_maxAt 209 nm. HR-ESI-MS gives [ M + Na ] at M/z 333.1447]⁺Peak, presumed to be of formula C₂₀H₂₂O₃。¹H-NMR and¹³the C-NMR data are shown in Table 1.

Experimental research shows that the compound has obvious antioxidation effect. Therefore, the compound can be used for preparing antioxidant drugs.

TABLE 1 butyrolactone metabolizing Ketone I¹H and¹³c nuclear magnetic resonance data

The new compound butyrolactone metabolic ketone I is structurally resolved.

As shown in FIG. 1, the novel compounds of the present invention¹H NMR、¹³The structure of the compound is known from C NMR, 2D-NMR (HSQC, HMBC) spectra and HR-ESI-MS spectra. Specifically, the method comprises the following steps:

colorless oil (methanol), UV (MeOH) lambda_max209 nm. Infrared Spectroscopy (IR) suggests the presence of hydroxyl groups (3431 cm) in the structure^-1) Double bond (1638 cm)^-1) And the like. HR-ESI-MS gives [ M + Na ] at M/z 333.1447]⁺Peak (calcd.333.1467), and molecular formula C₂₀H₂₂O₃。

¹H-NMR(400MHz,DMSO-d₆) The aromatic region of the spectrum gives the proton signal delta for a set of AA 'BB' coupled systems_H6.91(2H, d, J ═ 8.4Hz, H-2 ', 6'), 6.68(2H, d, J ═ 8.4Hz, H-3 ', 5'), structures presumed to exist for para-substituted benzenes; delta_H6.76(1H, dd, J ═ 8.0,2.0Hz, H-6 "), 6.75(1H, d, J ═ 2.0Hz, H-2"), 6.70(1H, d, J ═ 8.0Hz, H-5 "), suggesting the presence of a 1,3, 4-trisubstituted benzene ring structure. From two methyl groups_H1.65(3H, s, H-10') and 1.67 (3H)S, H-11'), a double bond hydrogen signal delta_H5.23(1H, t, J ═ 7.2Hz, H-8') and hydrogen signals coupled thereto delta_H3.16(2H, d, J ═ 7.2Hz, H-7 "), a prenyl fragment is presumed to be present.

¹³C-NMR (100MHz, DMSO-d6) spectrum gives 14 aromatic or double bond carbon signals, the number of carbons of two benzene ring segments and isopentenyl segment is consistent with the above conjecture, compared with butyrolactone I, the compound butyrolactone metabolizes ketone I to reduce carbon signals of-COOCH 3 and lactone structure segment, and ketone carbonyl carbon signal delta appears_C206.9(C-2) and two methylene carbon signals δ C47.8 (C-1), 48.0 (C-3). The above information suggests that the lactone ring is opened and decarboxylation rearrangement occurs.

The HSQC spectra give information on the direct attachment of all hydrogens to carbons in the structure, as shown in Table 1.

Proton signal δ in HMBC spectra_H3.61(2H, s, H-1) vs. carbon Signal δ_C206.9(C-2), 125.2(C-1'), 130.9(C-2'), delta_H3.59(2H, s, H-3) vs. carbon signals δ_C206.9(C-2), 128.2(C-6 ') and C-2' (δ C130.9) relative H-7 ' (δ_H3.16) associated with the carbon signals C-4 '(δ C154.0), C-3' (δ C127.8) and C-8 '(δ C123.3), H-10' (δ C123.3)_H1.67) related to C-9 ' (δ C131.5) and C-8 ' (δ C123.3), H-11 ' (δ C123.3)_H1.65) relative to C-9 ' (Δ C131.5) and C-8 ' (Δ C123.3), active hydrogen signal 4 ' -OH (Δ C123.3)_H9.21) associated with C-4 '(δ C156.5) and C-5' (δ C115.6), 4 "-OH (δ C115.6)_H9.19) are associated with C-4 '(Δ C154.0) and C-5' (Δ C115.1). The structure of the compound is determined to be 1- (4-hydroxy-3- (3-methylene-2-enyl) phenyl) -3- (4-hydroxyphenyl) propan-2-one.

The compound is a novel diphenyl acetone compound which is not reported in the literature, and the attribution of related NMR data is shown in a table 1.

Drawings

Process for the preparation of the novel compounds of FIG. 1¹H NMR spectrum;

FIG. 2 Process for the preparation of novel compounds¹³C NMR spectrum;

FIG. 3 HSQC spectra of the novel compounds;

FIG. 4 HMBC spectra of the novel compounds;

FIG. 5 HR-ESI-MS spectra of the novel compounds.

Detailed Description

The invention is further described below by way of examples to provide the skilled person with a more complete understanding of the invention, without restricting it in any way.