CN110746419B

CN110746419B - Compound, preparation method and application thereof, and medicine

Info

Publication number: CN110746419B
Application number: CN201911057447.1A
Authority: CN
Inventors: 黄勤; 王文学; 刘玮; 於俊; 覃坚和; 曾丽英; 姚小秋
Original assignee: Guilin Pharmaceutical Co ltd
Current assignee: Guilin Pharmaceutical Co ltd
Priority date: 2019-10-31
Filing date: 2019-10-31
Publication date: 2020-09-01
Anticipated expiration: 2039-10-31
Also published as: CN110746419A

Abstract

The invention relates to the field of artemisinin, and particularly provides a novel compound, a preparation method and application thereof, and a medicament. The novel compound has a structure shown in formula (I); in formula (I): r₁、R₂And R₃Each independently is a substituted or unsubstituted C1-C20 linear or branched alkyl group; r₄And R₅Each independently hydrogen, substituted or unsubstituted C1-C20 straight or branched alkyl. The new compound has novel structure, has good effects of resisting bacterial infection, malaria, tumor, cancer, hepatic fibrosis and lupus erythematosus, and provides a new possibility for selecting artemisinin compounds.

Description

Compound, preparation method and application thereof, and medicine

Technical Field

The invention relates to the field of artemisinin, and particularly relates to a compound, and a preparation method, application and a medicament thereof.

Background

Artemisinin is a hemiterpene lactone compound with peroxy group and separated from herba Artemisiae Annuae to obtain antimalarial effective monomer₁₅H₂₂O₅. Clinical application proves that the artemisinin has outstanding curative effects of high efficiency, quick effect and low toxicity on malaria. The artemisinin derivatives mainly include dihydroartemisinin, artesunate and artemether, and have antimalarial effectBesides, the artemisinin compound also has the effects of resisting tumors, cancers, hepatic fibrosis, lupus erythematosus and the like. Therefore, the development of novel artemisinin compounds is continuously carried out, and the artemisinin compounds have positive effects on expanding the application range of the artemisinin compounds.

In view of the above, the present invention is particularly proposed.

Disclosure of Invention

The first purpose of the invention is to provide a compound, which has a novel structure, has good effects of resisting bacterial infection, malaria, tumors, liver fibrosis and lupus erythematosus and provides a new possibility for selecting artemisinin compounds.

The second purpose of the invention is to provide a preparation method of the compound.

The third purpose of the invention is to provide the application of the compound.

The fourth object of the present invention is to provide a medicament.

In order to achieve the above purpose of the present invention, the following technical solutions are adopted:

in a first aspect, the present invention provides a compound having the formula:

in formula (I):

R₁、R₂and R₃Each independently is a substituted or unsubstituted C1-C20 linear or branched alkyl group;

R₄and R₅Each independently hydrogen, substituted or unsubstituted C1-C20 straight or branched alkyl.

As a further preferred embodiment, R₁、R₂、R₃、R₄Or R₅In (3), the linear or branched alkyl groups of C1-C20 include linear or branched alkyl groups of C1-C4.

As a further preferred embodiment, the C1-C4 linear or branched alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

As a further preferred embodiment, the compound comprises at least one of the following compounds:

in a second aspect, the present invention provides a process for the preparation of the above compound, comprising: reacting the artemisinin compound with a substance containing N element to obtain the compound.

As a further preferred technical scheme, the artemisinin compound comprises at least one of dihydroartemisinin, artemisinin, artesunate or artemether, preferably dihydroartemisinin;

the substance containing N element comprises at least one of ammonia water, ammonium salt or N-containing organic substance, preferably ammonia water.

As a further preferred embodiment, the reaction conditions include at least one of the following conditions:

(a)7＜pH＜14；

(b) the reaction temperature is 30-100 ℃;

(c) the reaction time is 1-72 h.

As a further preferred technical scheme, the reaction further comprises the steps of extraction, primary drying, purification and final drying in sequence to obtain a compound;

preferably, the solvent used for extraction comprises petroleum ether and/or ethyl acetate;

preferably, the solvent used for extraction includes petroleum ether and ethyl acetate;

preferably, the volume ratio of petroleum ether to ethyl acetate is 1: (0.5-1.5);

preferably, the purification comprises: sequentially carrying out at least one time of dissolution, at least one time of solid-liquid separation, at least one time of chromatographic separation and at least one time of intermediate drying on the primarily dried substance until oil drops disappear;

preferably, the solvent used for dissolution comprises a nitrile compound, preferably a nitrile compound of C2-C10, further preferably acetonitrile;

preferably, the chromatographic separation comprises: preparing liquid chromatography or supercritical chromatography;

preferably, the last drying comprises pre-freeze drying.

In a third aspect, the invention provides an application of the compound in preparing a medicament for treating bacterial infection, malaria, tumor, cancer, hepatic fibrosis or lupus erythematosus;

or the application of the compound obtained by the preparation method in preparing medicines for treating bacterial infection, malaria, tumor, cancer, hepatic fibrosis or lupus erythematosus.

In a fourth aspect, the present invention provides a medicament comprising a compound as defined above or a compound obtainable by a process as defined above;

preferably, the medicament comprises an anti-bacterial infection medicament, an anti-malaria medicament, an anti-tumor medicament, an anti-cancer medicament, an anti-hepatic fibrosis medicament or an anti-lupus erythematosus medicament.

Compared with the prior art, the invention has the beneficial effects that:

the compound provided by the invention has a novel structure, has good effects of resisting bacterial infection, malaria, tumors, cancers, hepatic fibrosis and lupus erythematosus, and provides a new possibility for selecting artemisinin compounds.

Drawings

FIG. 1 is a HRMS spectrum of the compound obtained in example 1;

FIG. 2 shows the preparation of the compound obtained in example 1¹H-NMR spectrum;

FIG. 3 shows the preparation of the compound obtained in example 1¹³A C-NMR spectrum;

FIG. 4 is a DEPT90 spectrum of the compound obtained in example 1;

FIG. 5 is a DEPT135 spectrum of the compound obtained in example 1;

FIG. 6 is a COSY spectrum of the compound obtained in example 1;

FIG. 7 is a HSQC-DEPT spectrum of the compound obtained in example 1;

FIG. 8 shows the HMBC spectrum of the compound obtained in example 1.

Detailed Description

Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer.

According to one aspect of the present invention, there is provided a compound having the formula:

in formula (I):

The compound has novel structure, has good effects of resisting bacterial infection, malaria, tumor, cancer and hepatic fibrosis and treating lupus erythematosus, and provides a new possibility for selecting artemisinin compounds.

The compound explains one of degradation mechanisms of artemisinin structural compounds, and is applied to qualitative and quantitative analysis of impurities in the quality standards of artemisinin, dihydroartemisinin, artesunate, artemether and other medicaments, so that the quality standards of artemisinin and derivatives thereof are improved. Meanwhile, the compound is researched on genotoxicity, and is found to have antibacterial infection, so that a new possibility is provided for the compound in the technical field of medicines.

The above-mentioned "C1-C20 linear alkyl group or branched alkyl group" means a linear alkyl group or branched alkyl group having 1 to 20 carbon atoms.

In a preferred embodiment, R₁、R₂、R₃、R₄Or R₅In (3), the linear or branched alkyl groups of C1-C20 include linear or branched alkyl groups of C1-C4. The above-mentioned "C1-C4 linear alkyl group or branched alkyl group" means a linear alkyl group or branched alkyl group having 1 to 4 carbon atoms.

In a preferred embodiment, the C1-C4 linear or branched alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

In a preferred embodiment, the compound comprises at least one of the following compounds:

the compound may be, for example, any one of the above compounds 1 to 15, a combination of the

compounds

1 and 2, a combination of the compounds 3 to 4, a combination of the compounds 5 to 8, a combination of the compounds 9 to 12, a combination of the compounds 13 to 15, or the like.

According to another aspect of the present invention, there is provided a process for preparing the above compound, comprising: reacting the artemisinin compound with a substance containing N element to obtain the compound. The method has simple and scientific process, and the obtained compound has stable structure and performance, and has good effects of resisting bacterial infection, malaria, tumor, cancer and hepatic fibrosis and treating lupus erythematosus.

In a preferred embodiment, the artemisinin compound comprises at least one of dihydroartemisinin, artemisinin, artesunate or artemether, preferably dihydroartemisinin. Artemisinin compounds include, but are not limited to, dihydroartemisinin, artemisinin, artesunate, artemether, a combination of dihydroartemisinin and artemisinin, a combination of artemisinin and artemether, a combination of dihydroartemisinin and artemether, or a combination of dihydroartemisinin, artemisinin and artemether, and the like.

Preferably, the substance containing the N element includes at least one of ammonia, ammonium salt or an N-containing organic substance, preferably ammonia. The ammonia water can be common strong ammonia water sold in the market, wherein the mass fraction of the ammonia is 25-28%. The ammonia water has wide source and low price, does not contain other metal ions, and is beneficial to improving the conversion efficiency and the purity of the compound. The above-mentioned mass fraction of ammonia (NH3) in aqueous ammonia is typically, but not limited to, 25%, 25.5%, 26%, 26.5%, 27%, 27.5% or 28%.

In a preferred embodiment, the reaction conditions include at least one of the following conditions:

(a)7＜pH＜14；

(b) the reaction temperature is 30-100 ℃;

(c) the reaction time is 1-72 h.

The above pH is typically, but not limited to, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5 or 14. The reaction temperature is typically, but not limited to, 30, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 ℃. Reaction times are typically, but not limited to, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6h, 10h, 12h, 18h, 24h, 36h, 48h, or 72 h. When the reaction conditions satisfy at least one of the above conditions, the reaction speed can be accelerated, the reaction efficiency is better, and the conversion rate is higher.

In a preferred embodiment, the reaction is followed by the steps of extraction, primary drying, purification and final drying to obtain the compound. The purity of the compound obtained after the reaction is relatively low, and can be further improved by the process in the preferred embodiment.

Preferably, the solvent used for extraction comprises petroleum ether and/or ethyl acetate. The extraction efficiency of the petroleum ether and/or the ethyl acetate is higher, and the required substances can be basically and completely extracted by few times of extraction.

Preferably, the solvent used for extraction includes petroleum ether and ethyl acetate.

Preferably, the volume ratio of petroleum ether to ethyl acetate is 1: (0.5-1.5). The above volume ratio is typically, but not limited to, 1: 0.5, 1: 0.6, 1: 0.8, 1: 1. 1: 1.2 or 1: 1.5, etc.

The extraction effect is relatively better when petroleum ether and ethyl acetate are jointly used as solvents for extraction, and the ratio of the petroleum ether to the ethyl acetate is 1: (0.5-1.5), the comprehensive advantages of the two can be fully exerted, the extraction rate is higher, and the extraction times are less, so that the yield is improved, and the production cost is reduced.

Preferably, the purification comprises: and (3) sequentially carrying out at least one time of dissolution, at least one time of solid-liquid separation, at least one time of chromatographic separation and at least one time of intermediate drying on the primarily dried substance until oil drops disappear. After primary drying, the solid matter containing the compound contains impurities, the purity of the compound is low, partial impurities are separated out through dissolution and solid-liquid separation, the compound is remained in a liquid phase, and then oil drops disappear through chromatographic separation and intermediate drying, so that the pure compound is obtained. If the oil drops do not disappear after the first dissolution, the first solid-liquid separation, the first chromatographic separation and the first intermediate drying, the steps of the dissolution, the solid-liquid separation, the chromatographic separation and the intermediate drying are repeated until the oil drops disappear.

It should be understood that: when the oil drops can disappear after the substances subjected to primary drying are subjected to multiple times of dissolution, multiple times of solid-liquid separation, multiple times of chromatographic separation and multiple times of intermediate drying, the dissolution, the solid-liquid separation, the chromatographic separation and the intermediate drying are sequentially and circularly carried out, namely the steps of dissolution, solid-liquid separation, the chromatographic separation, the intermediate drying, dissolution, solid-liquid separation, the chromatographic separation and the intermediate drying … are carried out. In multiple cycles, the parameters of dissolution, solid-liquid separation, chromatographic separation and intermediate drying can be the same or different, for example, different liquid chromatographic separations or supercritical chromatographic separations can be adopted for the chromatographic separation, and different filters can be adopted for the apparatuses for the solid-liquid separation, etc.

Preferably, the solvent used for dissolution comprises a nitrile compound, preferably a nitrile compound of C2-C10, more preferably acetonitrile. The "nitrile compound" refers to a compound having a-CN group. The "nitrile compound having C2-C10" refers to a nitrile compound having 2 to 10 carbon atoms. The acetonitrile is wide in source, colorless and volatile, has better solubility to the compound, can be dissolved out from a solid as much as possible, and improves the yield of the product.

Preferably, the chromatographic separation comprises: preparative liquid chromatography or supercritical chromatography.

Preferably, the last drying comprises pre-freeze drying. "Pre-freeze drying" refers to a drying mode in which a material is frozen and then sublimed.

It should be understood that the terms "primary drying", "intermediate drying" and "final drying" in the present invention are named according to the order of drying, and there is no other special meaning for "primary", "intermediate" and "final".

According to another aspect of the present invention there is provided the use of a compound as described above in the manufacture of a medicament for the treatment of bacterial infection, malaria, tumours, cancer, liver fibrosis or lupus erythematosus;

According to another aspect of the present invention, there is provided a medicament comprising a compound as described above;

The medicine comprises the compound, thus having good efficacies of resisting bacterial infection, malaria, tumors, cancers, hepatic fibrosis and lupus erythematosus and providing a new possibility for selecting medicines for treating the diseases.

The present invention will be described in further detail with reference to examples.

Example 1

A compound of the formula:

the preparation method comprises the following steps:

(1) putting 150g of dihydroartemisinin into a 3000mL reaction bottle, adding 20mL of ammonia water with the mass fraction of 26%, fully shaking up, sealing by using a buffer balloon, heating in a water bath at the temperature of 80 ℃ for 2 hours, taking out, standing at room temperature, and treating 1000g of dihydroartemisinin according to the reaction route.

(2) The product is extracted by 300mL of mixed solution of petroleum ether and ethyl acetate (1:1), repeated for 3 times, and the extracts are combined and spin-dried under the condition of 30 ℃ water bath.

(3) Dissolving the rotary-dried substance with acetonitrile, filtering the solution with 0.45 μm filter head, separating the filtrate with preparative liquid chromatography to obtain solution containing the target substance, adding saturated saline solution, standing for 5min to fully separate acetonitrile and water, removing water phase through a separating funnel, and performing rotary drying under the condition of 30 deg.C water bath of acetonitrile solution to obtain oily substance.

(4) The oily substance was dissolved in acetonitrile, the solution was filtered through a 0.45 μm filter, the filtrate was subjected to separation by supercritical chromatography to obtain a fraction containing the objective substance, and the solution of the fraction was spin-dried in a water bath at 30 ℃ to obtain 1.3g of an oily substance.

(5) Dissolving the oily matter with acetonitrile to 30mL, filtering with a 0.45-micrometer pinhole filter after completely dissolving a sample, separating the filtrate by using a preparative liquid chromatography to obtain a solution containing the target matter, wherein about 200mL of the solution is obtained by separation, carrying out rotary evaporation on the solution at 30 ℃ in a water bath condition until white milky solution can not generate oil drops, adding acetonitrile to dissolve and re-carry out rotary evaporation if the white milky solution generates, transferring the white milky solution to a 250-mL eggplant-shaped bottle (1/2 not exceeding the volume of the bottle), pre-freezing with dry ice acetone, and finally freeze-drying with a freeze dryer to obtain 220mg of light yellow powdery matter, wherein the content of the target product is 95.09% by quantitative nuclear magnetic assay.

The chromatographic conditions used in the preparation are as follows:

the parameters of the liquid phase preparative chromatography in the step (3) are as follows:

the instrument comprises the following steps: agela Prep-HPLC;

a chromatographic column: agela MP C18, 10 μ 250 × 80 mm;

mobile phase: a H₂O；B CH₃CN；

Gradient: b from 33% to 78% in 20 min;

flow rate: 150 mL/min;

detection wavelength: 220&254 nm;

sample introduction amount: 80 mL/injection.

The supercritical chromatography instrument parameters in the step (4) are as follows:

the instrument comprises the following steps: THar SFC80 preliminary SFC;

a chromatographic column: chiralpak AD-H, 10 μ 250 × 30 mm;

mobile phase: aCO₂；B MeOH；

Gradient: b% ═ 20%;

flow rate: 50 g/min;

wavelength: 220 nm;

column temperature: 100 bar.

The parameters of the liquid phase preparative chromatography in the step (5) are as follows:

the instrument comprises the following steps: shimadzu Prep-HPLC;

a chromatographic column: luna C18, 10 μ 250 × 50 mm;

mobile phase: a H₂O；B CH₃CN；

Gradient: b from 30% to 70% in 20 min;

flow rate: 80 mL/min;

detection wavelength: 220&254 nm;

sample introduction amount: 10 mL/injection.

Performing structural characterization on the prepared light yellow powdery substance by HRMS,¹H-NMR、¹³C-NMR、DEPT90、DEPT135、¹H¹H-COSY, HSQC-DEPT and HMBC were analyzed comprehensively.

(1) High resolution mass spectrometry: ESI-MS m/z: 218.15414[ M + H]⁺；

(2)¹H-NMR(400MHz,Acetonitrile-d₃)0.92(m,1H)，0.92(d,J＝6.60Hz,3H)，1.16(m,1H),1.46(m,1H)，1.68(dd,J＝1.47,1.59Hz,3H),1.80(m,1H)，1.95(overlap,1H)，2.20(m,3H)，2.23(m,1H),2.29(m,1H)，2.72(ddd,J＝1.83,4.65,14.18Hz,1H)，3.39(d,J＝11.00Hz,1H)，4.70(m,1H)；

(3)¹³C-NMR(100MHz，Acetonitrile-d₃)8.8,18.2,20.1,26.0,29.2,36.3,37.5,48.6,64.3,107.2,126.0,134.8,154.2,171.7。

According to the characterization result, the yellowish powdery substance can be determined to be 1,4, 7-trimethyl-31, 6,6a,7,8, 9-hexahydro-2H-pyrrolo [3,2,1-ij ] quinoline-2-ketone, and the chemical structural formula of the yellowish powdery substance is shown as the formula 1.

In the drawings, the figure 1-figure 8 are HRMS and the like of light yellow powdery substances,¹H-NMR、¹³C-NMR, DEPT90, DEPT135, COSY, HSQC-DEPT, HMBC spectra.

Example 2

Different from the example 1, in the example, the dihydroartemisia apiacea in the step (1) is replaced by the artemisinin, the reaction time is 24 hours, the reaction temperature is 60 ℃, and the rest is the same as the example 1. 180mg of a pale yellow powdery substance were obtained.

And (3) carrying out high-resolution mass spectrometry on the product obtained in the embodiment, and determining that the product obtained in the embodiment is the target product.

The content of the target product is 94.95 percent through quantitative nuclear magnetic determination.

Example 3

A compound, different from example 1, was obtained in this example in which the temperature of the water bath in step (1) was 48 ℃ and the reaction time was 8 hours. The rest is the same as in example 1. 232mg of a pale yellow powdery substance were obtained.

The content of the target product is 95.02 percent through quantitative nuclear magnetic determination.

Examples 4 to 8

A compound, different from the compound in the embodiment 1, the solvent used for the extraction in the step (2) of the embodiments 4 to 8 is petroleum ether, ethyl acetate, and a solvent with the volume ratio of 1: 2, petroleum ether and ethyl acetate in a volume ratio of 1: 0.5 of petroleum ether and ethyl acetate, and a volume ratio of 1: 1.5 of petroleum ether and ethyl acetate. The rest is the same as in example 1. 151mg-196mg of a pale yellow powdery substance are obtained.

The content of the target product is 94.86-95.05% by quantitative nuclear magnetic determination.

Example 9

A compound, different from example 1, in example 9 wherein dihydroartemisinin in step (1) is replaced by artesunate, ammonia water is replaced by triethylamine, the reaction time is 43h, and the rest is the same as example 1. 202mg of a pale yellow powdery substance was obtained.

The content of the target product is respectively 94.87 percent through quantitative nuclear magnetic assay.

Experimental example 1:

ames experiment of the compound of example 1:

1. cell strains and cell cultures

Histidine auxotrophic salmonella typhimurium strains TA98 and TA100, available from MolTox, usa, were selected for this experiment.

Test strains TA98 and TA100 were rapidly thawed in a 37. + -. 1 ℃ water bath from liquid nitrogen, inoculated into nutrient broth, and shake-cultured (120. + -. 25 times/min) in a 35. + -. 2 ℃ air bath constant temperature culture shaker for 16-18 hours (overnight culture).

2. Preparation of solutions

The compound used was the product obtained according to the method described in example 1 of the present invention, and was dissolved in DMSO to prepare a solution of 8 concentration groups.

The negative control solution is DMSO, the positive control product 2-nitrofluorene is dissolved in DMSO to prepare stock solution of 10 mu g/mL, sodium azide is dissolved in sterile water for injection to prepare stock solution of 22 mu g/mL, and 2-aminoanthracene is dissolved in DMSO to prepare stock solution of 30 mu g/mL.

The S9 mixture was freshly prepared just before use as a mixture of S9 and S9 cofactors S9 was purchased from MolTox, USA and prepared from the liver of male SD rats induced by Aroclor 1254 at 500mg/kg S9 cofactors comprising glucose-6-phosphate (G-6-P), β -oxidized Nicotinamide Adenine Dinucleotide Phosphate (NADP), KCl, MgCl₂、Na₂HPO₄、NaH₂PO₄And deionized water. The proportion of S9 in the S9 mixed liquid was 10%.

Ames experiment

The sample addition for each sample was not performed under dark conditions. During the test, 1000 mu L of top agar medium containing 0.5mmol/L histidine-biotin solution is loaded into test tubes, the test tubes are placed in a water bath at the temperature of 46 +/-2 ℃ for heat preservation, and then 50 mu L of test strain enrichment liquid, 50 mu L of dosing preparation (negative control dosing preparation, each test sample dosing preparation and positive control dosing preparation), 250 mu L S9 mixed liquid (+ S9) or 0.2M sodium phosphate buffer solution (-S9) are sequentially added into each tube. After mixing well, 540. mu.L of the mixture was quickly added to the 6-well plate V-B bottom agar plate by aspirating it from the tube, and the plate was rotated to distribute it evenly. Duplicate wells were performed for 2 per assay condition, and negative and positive controls were placed in parallel. Horizontally placing the mixture for condensation and solidification, and then inversely placing the mixture in an incubator at 37 +/-1 ℃ for incubation for 48-72 hours, and observing the result.

And after the culture is finished, observing whether the test article/reference article precipitates and the growth condition of background bacterial plaque exist in each hole under the naked eye/microscope, and meanwhile, counting the number of the revertant mutant bacterial colonies in each hole by adopting an artificial counting method.

Ames test results

As can be seen from tables 1 and 2, the number of revertant colonies in the positive control group was 3 times higher than that in the negative control group in the strains TA98 and TA100, indicating that the test system was effective. Under the condition of adding and not adding the S9 metabolic activation system, the number of reversion mutation colonies of the TA98 and TA100 strains induced by each concentration group of the compound is not more than 2 times of that of a negative control group, and no concentration-effect relation exists, which indicates that the compound has no potential mutagenicity to the TA98 and the TA100 strains under the test condition. The compound concentration group of more than or equal to 333 mu g/hole causes moderate reduction of background bacterial plaque of the TA100 bacterial strain and severe reduction or disappearance of the background bacterial plaque of the TA98 bacterial strain, which indicates that the compound has certain anti-infection performance to bacteria.

The experimental results show that the compound related to the invention is a common impurity, but not a genotoxic impurity; the anti-infection of bacteria shows that the compound has better potential medicinal value. The compound provides a new possibility in the technical field of medicines.

Table 1 Compound bacterial Remutation 6 well preliminary screening test results (TA98)

Remarking:

"-" indicates that there was no need to count the number of revertant clones when background plaque was severely reduced or disappeared.

T0 (normal); t1 (mild reduction); t2 (moderate reduction); t3 (severe reduction); t4 (disappeared).

The T98 strain negative control is DMSO, the positive control is 2-nitrofluorene (0.2 μ g/well) without S9, and the positive control is 2-aminoanthracene (0.6 μ g/well) with S9

Positive reaction indicates that the number of revertant colonies was more than 3 times the number of revertant colonies of the negative control.

TABLE 2 Compound bacterial Reversal mutagenesis 6 well plate preliminary screening test results (TA100)

Remarking:

The T100 strain negative control was DMSO, the positive control was sodium azide (0.4. mu.g/well) without S9 and 2-aminoanthracene (0.6. mu.g/well) with S9.

Positive reaction indicates that the number of revertant colonies was more than 3 times the number of revertant colonies of the negative control. While particular embodiments of the present invention have been illustrated and described, it would be obvious that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

Claims

1. A compound having the formula:

2. a process for preparing a compound of claim 1, comprising: reacting dihydroartemisinin with ammonia water to obtain the compound.

3. The method of claim 2, wherein the reaction conditions include at least one of:

(a)7＜pH＜14；

(b) the reaction temperature is 30-100 ℃;

(c) the reaction time is 1-72 h.

4. The method according to claim 2 or 3, wherein the reaction is further followed by the steps of extraction, primary drying, purification and final drying to obtain the compound.

5. The method according to claim 4, wherein the solvent used for extraction is petroleum ether and/or ethyl acetate.

6. The method according to claim 4, wherein the solvent used for extraction is petroleum ether or ethyl acetate.

7. The method according to claim 6, wherein the volume ratio of petroleum ether to ethyl acetate is 1: (0.5-1.5).

8. The method of claim 4, wherein the purifying comprises: and (3) sequentially carrying out at least one time of dissolution, at least one time of solid-liquid separation, at least one time of chromatographic separation and at least one time of intermediate drying on the primarily dried substance until oil drops disappear.

9. The production method according to claim 8, wherein the solvent used for dissolving is a nitrile compound.

10. The method according to claim 9, wherein the solvent used for dissolving is a nitrile compound of C2 to C10.

11. The method according to claim 9, wherein the solvent used for the dissolution is acetonitrile.

12. The method of claim 8, wherein the chromatographic separation is: preparative liquid chromatography or supercritical chromatography.

13. The method of claim 4, wherein the final drying is pre-lyophilization.

14. Use of a compound according to claim 1 in the manufacture of a medicament for the treatment of a bacterial infection.

15. A medicament comprising a compound of claim 1.