CN1445220A - Lactone category compound of sweetsop as well as new usage in medicines and its preparing method - Google Patents

Abstract

The present invention relates to annona lactone compound and its new medicinal use and preparation method. It has promoting activity on the ability of differentiated C2C12 myoblasts to absorb glucose and produce lactic acid, suggesting that it has hypoglycemic effect, and can be used alone or in combination or with Appropriate excipients are combined to prepare anti-diabetic drugs in oral dosage form or non-oral dosage form, which are used for the treatment of type II or type I diabetes. Its preparation method includes separation from natural plant raw materials and chemical synthesis, etc., and is prepared through processes such as concentration, extraction, elution, and chromatographic separation. Its molecular structure contains at least one saturated or unsaturated five-membered lactone ring structure and a long multi-substituted aliphatic chain structure.

Description

Annona lactone compound and its new medicinal application and preparation method

Technical field:

The invention relates to the technical field of medicine, in particular to an annona lactone compound, a new medicine application and a preparation method.

Background technique:

Annona Linn. plants contain mainly actogenins, styrylactones, polyoxanes, alkaloids, flavonoids and terpenoids. The current research hotspot is the anticancer and insecticidal activities of the annonaceous lactone compounds contained in the plants of this family. Since the first annonaceolide was reported in 1982, more than 300 such compounds have been discovered so far, and it is considered to be another class of natural compounds with strong anticancer activity after paclitaxel. We used the glucose uptake function of differentiated C2C12 myoblasts and the ability to produce lactic acid as indicators to screen the extracts of more than a thousand kinds of natural medicinal plants for anti-diabetic activity, and found several extracts with strong activity, among which Contains extracts of various Annonaceae plants. And use the method of activity tracking to isolate several kinds of annona lactone compounds with strong activity from the extracts of soursop and Jinping Gornarica.

Invention content:

The purpose of the present invention is to provide annona lactone compound and its new medical application and preparation method. The compound is expected to be developed into a new type of natural hypoglycemic drug for the treatment of diabetes. It is characterized in that: the anemone lactone compound molecule contains at least one saturated or unsaturated five-membered lactone ring structure and a long multi-substituted aliphatic chain structure, which can be one of the following structures:

Structure I:

R ₁ can be one of CH ₃ , CH ₂ OH, CH ₂ COCH ₃ ; R2 or R3 can be one of H, O, OH, OCOCH3 (if it is O, it should form a carbonyl group with the connected carbon ); x, m or n can be 0-10.

Structure II:

R ₁ can be one of CH ₃ , CH ₂ OH and CH ₂ COCH ₃ ; m or n can be 0-10.

Structure III:

R ₁ can be one of CH ₃ , CH ₂ OH, CH ₂ COCH ₃ ; R ₂ ~ R ₇ can be one of O, OH, OCH ₃ , OCOCH3 (if it is O, it should be connected with carbon to form a carbonyl); m or n can be 0-10.

Structure IV:

R ₁ can be one of CH ₃ , CH ₂ OH, CH ₂ COCH ₃ ; R2 ~ R9 can be one of H, O, OH, OCH3, OCOCH3 (if it is O, it should be connected with the connected carbon form a carbonyl group); m, n, x, y, z can be 0-10.

Structure V:

R ₁ can be one of CH ₃ , CH ₂ OH, CH ₂ COCH ₃ ; R ₂ ~ R ₇ can be H, O, OH, OCH ₃ , OCOCH ₃

One of (when it is O, it forms a carbonyl group with the connected carbon); m, n, x, y can be 0-10.

Structure VI:

R ₁ can be one of CH ₃ , CH ₂ OH, CH ₂ COCH ₃ ; R ₂ or R ₃ can be one of H, O, OH, OCH ₃ , OCOCH ₃ (when it is O, the same The attached carbon forms a carbonyl); m or n can be 0-10.

Structure VII:

R ₁ can be one of CH ₃ , CH ₂ OH, CH ₂ COCH ₃ ; R ₂ ~ R ₄ can be H, O, OH, OCH ₃ , OCOCH ₃

One of them (when it is O, it forms a carbonyl group with the connected carbon); m or n can be 0-10.

Structure VIII:

R ₁ can be one of CH ₃ , CH ₂ OH, CH ₂ COCH ₃ ; R ₂ or R ₃ can be H, O, OH, OCH ₃ , OCOCH ₃

One of them (when it is O, it forms a carbonyl group with the connected carbon); m or n can be 0-10.

Structure IX:

R ₁ can be one of CH ₃ , CH ₂ OH, CH ₂ COCH ₃ ; R ₂ or R ₃ can be H, O, OH, OCH ₃ , OCOCH ₃

One of them (when it is O, it forms a carbonyl group with the connected carbon); m or n can be 0-10.

The present invention is not limited to the above nine structural types, but also includes other acetogenins.

The preparation method of the anemone lactone compound may be separation from natural products, chemical synthesis, or structural modification or biotransformation on the basis of a certain anemone lactone compound. The following is the procedure for isolating annonaceous lactones from natural plants:

Using the branches, leaves, trunks, roots, peels or seeds of Annonaceae plants as raw materials, one or two of the processes such as solvent extraction and resin adsorption are used to make concentrated extracts, and then organic solvents such as chloroform and ether are used to make concentrated extracts. extraction. The extract was separated by silica gel column chromatography. The particle size of the silica gel filled in the silica gel column can be 60-300 mesh (the optimal particle size is 100-200 mesh), and it is washed with an elution solvent composed of cyclohexane, chloroform, acetone, methanol, etc. from small polarity to large polarity. Take off, the obtained annona lactone-containing compound part utilizes high performance liquid chromatography (normal phase silica gel chromatographic column or reverse phase ODS chromatographic column) to separate and prepare annona lactone.

In the solvent extraction method adopted, organic solvents such as water or methanol, ethanol, propanol, butanol, amyl alcohol, acetone, ethyl acetate, ethyl formate, chloroform, methylene chloride, ether, or two or more A variety of miscible mixed solvents can be extracted by dipping at room temperature or by ultrasonic extraction or reflux extraction under heating. The number of extractions can be one time or multiple times.

In the solvent extraction method adopted, the extract obtained above can be suspended in water and extracted directly with a suitable solvent (butanol, pentanol, ethyl acetate, ethyl formate, chloroform, dichloromethane, ether, etc.). The number of times of extraction can be one time or multiple times.

The resin method used, macroporous adsorption resin, etc. For example, water, alcohol or alcohol-water extract can be treated with macroporous adsorption resin, the water eluted part is discarded, and the alcohol eluted part is collected.

The separation method of the anemone lactone compound of the present invention also includes supercritical extraction and separation of carbon dioxide.

The prepared anemone lactone compounds can be used as anti-diabetic active ingredients, which can be used alone or in combination, or combined with suitable excipients, etc., to make oral dosage forms or non-oral dosage forms (injections, sprays, patches, etc.) according to conventional methods. etc.) for the treatment of diabetes.

The advantage of the present invention is that: the present invention utilizes anemone lactone compound as the anti-diabetic active ingredient, has the characteristics of natural medicine, and is expected to be developed into a new type of natural hypoglycemic medicine for the treatment of type II type I diabetes. In addition, the process of the invention is simple, easy to scale up, and convenient for industrialized production.

Description of drawings:

Fig. 1 is the test result table of the promoting effect (n=4) of cis-Annonacin and arianacin of the present invention on the uptake of glucose by differentiated C2C12 cells

Fig. 2 is the test result table of Leiogenin and Gigantriocin of the present invention on glucose uptake and lactic acid production in differentiated C2C12 cells (n=4)

Detailed ways:

Example 1: 1 kg of soursop seeds, pulverized, extracted with 10 times the amount of 95% ethanol under reflux for 2 hours, filtered, and concentrated to a semi-solid extract. Suspended with water, extracted with chloroform. The obtained chloroform extract was mixed with three times the amount of silica gel (100-140 mesh), and 50 times the amount of silica gel (100-200 mesh) was used for column chromatography, and the part containing annona lactone compounds was subjected to high-performance liquid phase analysis. Chromatographic preparation (normal phase SiO2 packing chromatographic column: reverse phase ODS packing chromatographic column) obtained cis-annonacin (32mg), arianacin (14mg) annonacin-10-one (11mg), gigantetronein (6mg), gigantetrocinA (4mg), goniothalamicin ( 23mg). Some of the obtained compounds can promote the glucose uptake ability of differentiated C2C12 myoblasts, and the test results are shown in Table 1. The planar chemical structure of cis-Annonacin: Planar chemical structure of Arianacin:

Gigantriocin的化学结构： Example 2: 2 kg of dried root of Goniothalamus Leiocarpus was pulverized, extracted with 10 times the amount of chloroform under reflux for 2 hours, filtered, and concentrated to a semi-solid extract. The obtained extract was mixed with three times the amount of silica gel (100-140 mesh), and 50 times the amount of silica gel (100-200 mesh) was used for column chromatography, and the part containing anemone lactone compounds was subjected to high-performance liquid chromatography. Chromatographic preparation (normal phase SiO2 packed column or reversed phase ODS packed column) yielded Leiogenin and Gigantriocin. Table 2 shows their promoting effects on the ability of differentiated C2C12 myoblasts to uptake glucose and produce lactic acid. The chemical structure of Leiogenin:

Chemical structure of Gigantriocin:

Claims (8)

1, the new medicine use of Annonaceousacetogenicompounds compounds, it is characterized in that: with the effective ingredient of lipoid substance in the sweetsop as the preparation antidiabetic medicine, can use separately or share or combine, make the antidiabetic medicine of oral dosage form or non-oral dosage form according to ordinary method with suitable vehicle etc.

2, the new medicine use of Annonaceousacetogenicompounds compounds according to claim 1, it is characterized in that: Annonaceousacetogenicompounds compounds can be isolating from natural goods, also can be chemosynthesis, can also be on the basis of certain annonaceous acetogenins, carry out structural modification or bio-transformation etc.

3, a kind of Annonaceousacetogenicompounds compounds as claimed in claim 1 is characterized in that: containing at least one saturated or unsaturated five Yuans lactonic ring structures and a long polysubstituted fat chain structure in the molecule, can be following structure:

Structure I:

R ₁Can be CH ₃, CH ₂OH, CH ₂COCH ₃In a kind of; R2 or R3 can be a kind of (as when the O, should form carbonyl with the carbon that is connected) among H, O, OH, the OCOCH3; X, m or n can be 0～10.

Structure I I:

R ₁Can be CH ₃, CH ₂OH, CH ₂COCH ₃In a kind of; M or n can be 0～10.

Structure III:

R ₁Can be CH ₃, CH ₂OH, CH ₂COCH ₃In a kind of; R ₂～R ₇, can be O, OH, OCH ₃, a kind of (when being O, should form carbonyl) among the OCOCH3 with the carbon that is connected; M or n can be 0～10.

Structure I V:

R ₁Can be CH ₃, CH ₂OH, CH ₂COCH ₃In a kind of; R2～R9 can be a kind of (as when the O, should form carbonyl with the carbon that is connected) among H, O, OH, OCH3, the OCOCH3; M, n, x, y, z can be 0～10.

Structure V:

R ₁Can be CH ₃, CH ₂OH, CH ₂COCH ₃In a kind of; R ₂～R ₇, can be H, O, OH, OCH ₃, OCOCH ₃In a kind of (when being O, forming carbonyl) with the carbon that is connected; M, n, x, y can be 0～10.

Structure VI:

R ₁Can be CH ₃, CH ₂OH, CH ₂COCH ₃In a kind of; R ₂Or R ₃, can be H, O, OH, OCH ₃, OCOCH ₃In a kind of (when being O, forming carbonyl) with the carbon that is connected; M or n can be 0～10.

Structure VII:

R ₁Can be CH ₃, CH ₂OH, CH ₂COCH ₃In a kind of; R ₂～R ₄, can be H, O, OH, OCH ₃, OCOCH ₃In a kind of (when being O, forming carbonyl) with the carbon that is connected; M or n can be 0～10.

Structure VIII:

R ₁Can be CH ₃, CH ₂OH, CH ₂COCH ₃In a kind of; R ₂Or R ₃, can be H, O, OH, OCH ₃, OCOCH ₃In a kind of (when being O, forming carbonyl) with the carbon that is connected; M or n can be 0～10.

Structure I X:

R ₁Can be CH ₃, CH ₂OH, CH ₂COCH ₃In a kind of; R ₂Or R ₃, can be H, O, OH, OCH ₃, OCOCH ₃In a kind of (when being O, forming carbonyl) with the carbon that is connected; M or n can be 0～10.

4, a kind of preparation method of Annonaceousacetogenicompounds compounds as claimed in claim 3, it is characterized in that: with the branches and leaves of annonaceae plant, trunk, root, pericarp or seed are raw material, adopt solvent-extraction process, one or both technologies in the technologies such as resin adsorption method are made concentrated extract, use chloroform then, organic solvent extractions such as ether, extract separates through silica gel column chromatography, the silica gel granularity of filling in the silicagel column can be 60～300 orders, use hexanaphthene, chloroform, acetone, methyl alcohol etc. form by the eluting solvent wash-out of little polarity to high polarity, the annonaceous acetogenins that contains that obtains is partly utilized high performance liquid chromatography to separate to prepare Annona lactone.

5, the preparation method of Annonaceousacetogenicompounds compounds according to claim 4, it is characterized in that: in the solvent-extraction process that is adopted, organic solvents such as optional water or methyl alcohol, ethanol, propyl alcohol, butanols, amylalcohol, acetone, ethyl acetate, ethyl formate, chloroform, methylene dichloride, ether, or two or more mixed solvents that dissolve each other, at room temperature dipping extracts or with the refluxing extraction under supersound extraction or the heated condition, extraction time can be once, also can be repeatedly.

6, the preparation method of Annonaceousacetogenicompounds compounds according to claim 4, it is characterized in that: in the solvent extration that is adopted, the above-mentioned extract that obtains can be suspended in water directly extracts with suitable solvent, and extraction times can be once, also can be repeatedly.

7, the preparation method of Annonaceousacetogenicompounds compounds according to claim 4, it is characterized in that: the resin method that is adopted, macroporous adsorbent resins etc. can be handled with macroporous adsorbent resin as water, alcohol or pure water extract, discard the water elution part, collect pure wash-out part.

8, the preparation method of Annonaceousacetogenicompounds compounds according to claim 4 is characterized in that: the separation method of Annonaceousacetogenicompounds compounds comprises that also carbon dioxide upercritical fluid extraction separates.