阅读说明：本技术 化合物在治疗溃疡性结肠炎药物制备中的应用 (Application of compound in preparation of medicine for treating ulcerative colitis ) 是由 曾克武 屠鹏飞 张晓雯 于 2020-07-29 设计创作，主要内容包括：本发明涉及式(I)所示化合物或其药学上可接受的盐在制备治疗肠炎的药物中的应用,<Image he="174" wi="700" file="DDA0002608192800000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>式(I)中,每个R各自独立地为H、C1～C6的烷基、C1～C8的酰基。(The invention relates to an application of a compound shown in a formula (I) or a pharmaceutically acceptable salt thereof in preparing a medicament for treating enteritis, in the formula (I), each R is H, C1-C6 alkyl and C1-C8 acyl respectively and independently.)

1. The application of the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof in preparing the medicines or health-care foods for treating enteritis,

in the formula (I), each R is H, C1-C6 alkyl and C1-C8 acyl respectively and independently.

2. The use according to claim 1, wherein the compound of formula (I) is a compound of formula (II),

3. the use according to claim 1 or 2, wherein the medicament for the treatment of enteritis further comprises one or more substances selected from sulfasalazine, norfloxacin, metronidazole, brazilein, protosappan a, protosappan B.

4. Use according to claim 1 or 2, wherein the medicament for the treatment of enteritis is for the treatment of ulcerative colitis.

5. The use according to claim 1 or 2, wherein the medicament for the treatment of enteritis is for the treatment or alleviation of abdominal pain, hematochezia, tenesmus, emesis caused by enteritis.

6. The use of claim 1 or 2, wherein the medicament is an oral formulation selected from the group consisting of tablets, capsules, pills, granules, powders, oral films and oral liquids; or a non-oral preparation selected from injection, ointment, cream and suppository.

7. The use according to claim 1 or 2, wherein each dose of the medicament comprises 120 to 700mg of the compound of formula (I).

8. A composition or health food for treating enteritis, which comprises a compound represented by the following formula (I) and a pharmaceutically acceptable carrier,

in the formula (I), each R is H, C1-C6 alkyl and C1-C8 acyl respectively and independently.

9. The composition according to claim 8, wherein the compound of formula (I) is a compound of formula (II),

10. the composition of claim 8, further comprising one or more substances selected from sulfasalazine, norfloxacin, metronidazole, brazilin, protosappanin A, protosappanin B.

Technical Field

The invention relates to a new medical application of a compound, in particular to an application of the compound in the preparation of a medicine for treating ulcerative colitis.

Background

Ulcerative Colitis (UC) is a chronic nonspecific inflammatory bowel disease that mainly affects the mucosa and submucosa of the rectum and colon, and is clinically manifested by abdominal pain, diarrhea, mucopurulent bloody stool, etc. Because UC is difficult to cure and easy to recur, the incidence rate is on the trend of increasing year by year and has the tendency of canceration, and the UC is listed as one of modern refractory diseases by the World Health Organization (WHO).

With regard to the pathogenesis of ulcerative colitis, the medical community has a plurality of debates and guesses of genetics, infection theory, immunity theory and the like, has no consensus or conclusion, and brings great difficulty for screening and developing drugs for treating the disease. For a long time, most of the clinical medicines for ulcerative colitis can only provide partial protection, have insignificant curative effect and are accompanied by side effects of different degrees. Therefore, the development of a novel medicament for treating ulcerative colitis is of great significance. However, there is no ideal drug for treating ulcerative colitis at present.

The structural compound shown as the formula (II) is commonly named as the hematoxylin A, and is originally a compound extracted from a traditional Chinese medicine of sappan wood, but the content of the structural compound in natural medicinal materials is very low, and the content of the structural compound in dried medicinal materials is only about 0.46ppm (see non-patent document 1), so that the structural compound is not a well-known active ingredient of the natural medicinal materials.

Because the natural content is too low, the compounds are not found to be obviously related to the traditional effects of activating blood circulation to dissipate blood stasis and relieving swelling and pain of the traditional Chinese medicinal material sappan wood, but the compounds are widely reported as neuroprotective agents, and the neuroprotective effect of the compounds is reported to be possibly related to the fact that the hematoxylin A can down-regulate miR-15a expression so as to activate Wnt/beta-catenin and PI3K/AKT signal pathways (see non-patent document 2). In addition, it has been reported that hematoxylin a has a protective effect on renal injury caused by cisplatin, and may be achieved by increasing Nrf2 expression, thereby regulating its downstream related gene to exert an antioxidant effect and an anti-apoptotic effect (see non-patent document 3). It has also been reported that hematoxylin a inhibits the AKT/GSK-3 β signaling pathway to inhibit osteoclastogenesis and has an inhibitory effect on LPS-induced inflammatory bone loss (see non-patent document 4).

Non-patent document 1:

Chemical constituents from Sappan Lignum，Y.P.Chen et al.Journal ofChinese Pharmaceutical Sciences.2008，17：82–86

non-patent document 2:

Sappanone A prevents hypoxia-induced injury in PC-12 cells by down-regulation of miR-15a.Int J Biol Macromol.2019，15：35-41.

non-patent document 3:

Sappanone A Protects Mice Against Cisplatin-Induced Kidney Injury.IntImmunopharmacol.2016，38：246-51.

non-patent document 4:

Sappanone A Inhibits RANKL-induced Osteoclastogenesis in BMMs andPrevents Inflammation-Mediated Bone Loss.Int Immunopharmacol.2017，52：230-237.

disclosure of Invention

The present inventors have been working on developing a therapeutic drug for ulcerative colitis. In screening for active compounds, it was unexpectedly found that a hematoxylin a compound significantly reduced the extent of enteritis in mice in a model of enteritis induced by DSS (dextran sulfate sodium).

Specifically, the DSS-induced enteritis model is a well-known model for research on enteritis therapeutic drugs using mice, and is an acute ulcerative enteritis model in which the mice are allowed to drink drinking water containing dextran sodium sulfate dissolved therein, and then are changed to normal drinking water, and the mice have ulcerative lesions in the intestinal tract, including edema, diarrhea, and hematochezia, and simulate ulcerative enteritis in humans.

Pharmacological tests carried out by the inventor show that the compound shown in the formula (II) can obviously inhibit DSS-induced intestinal inflammation of mice, and the activity and the action are in a dose-dependent relationship. The compound shown in the formula (II) can reduce the hematochezia condition of enteritis mice, reduce the damage of the colon of the mice, maintain the length of the colon and protect the colon tissue from inflammatory damage. The new medical application of the compound shown in the formula (II) is suggested, so that a new choice is provided for the clinical treatment of colonic inflammation.

The compound represented by the following formula (I) of the present invention is considered to be a prodrug of the compound represented by the formula (II), which can be converted into the compound represented by the formula (II) in vivo to exert physiological activity. Specifically, the invention provides the following technical scheme:

the invention provides an application of a compound shown in a formula (I) or a pharmaceutically acceptable salt thereof in preparing a medicament for treating enteritis,

in the formula (I), each R is H, C1-C6 alkyl and C1-C8 acyl respectively and independently.

The expression Ca to Cb means that the group has carbon atoms a to b, and the number of carbon atoms does not generally include the number of carbon atoms of the substituent unless otherwise specified. In the present invention, unless otherwise specified, the expressions of chemical elements generally include the concept of chemically identical isotopes, such as the expression "hydrogen", the concept of chemically identical "deuterium" and "tritium", and the concept of carbon (C) includes¹²C、¹³C, etc., will not be described in detail.

Specific examples of the alkyl group having 1 to 6 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, and cyclohexyl groups. Preferably, methyl, ethyl, etc. are used. Examples of the acyl group having C1 to C8 include a formyl group, an acetyl group, a propionyl group, and a benzoyl group.

In the present invention, R is preferably H. From the prodrug viewpoint, R is preferably methyl, ethyl, acetyl, benzoyl, or the like.

The inventor of the invention directly proves the effectiveness of the compound of the formula (II) in treating ulcerative enteritis through pharmacological experiments, and the effect can be expanded to have a treatment effect on general enteritis.

The compound of the formula (I) of the present invention can be used with other conventional compounds for treating enteritis, and examples of the conventional compounds include sulfasalazine, norfloxacin, metronidazole, brazilin, protosappanin a, and protosappanin B.

From the results of pharmacological experiments, it is presumed that the compound represented by the formula (I) of the present invention is useful for the treatment of abdominal pain, hematochezia, tenesmus, and vomiting due to enteritis, and can play a role in alleviation or treatment.

The compound of formula (I) of the present invention can be administered by conventional formulation methods, such as tablet, capsule, drop pill, granule, powder, oral film and oral liquid, or injection, ointment, cream, suppository, etc., but not limited thereto. The compound of the present invention is preferably formulated into an oral preparation for the purpose of treatment and convenience.

When the compound of the present invention is formulated into a preparation, it can be used together with pharmaceutically acceptable excipients, which include, for example, solvents (e.g., water, ethanol, propylene glycol, oil for injection, etc.), diluents (e.g., starch, sugar powder, dextrin, lactose, pregelatinized starch, microcrystalline fiber, inorganic calcium salts (e.g., calcium sulfate, calcium hydrogen phosphate, calcium carbonate for pharmaceutical use, etc.), mannitol, vegetable oils, polyethylene glycol, etc.), binders (e.g., water, ethanol, starch slurry, sodium carboxymethylcellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, etc.), disintegrants (e.g., dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, lubricants (e.g., magnesium stearate, aerosil, talc, hydrogenated vegetable oils, etc.), diluents, etc., which are conventional in the pharmaceutical field, Polyethylene glycols, magnesium lauryl sulfate, etc.), absorption promoters (e.g., surfactants, Azone, EDTA, salicylic acid, amino acid ethylamine derivatives, acetoacetates, β -dicarboxylates, aromatic acidic compounds, fatty acids, etc.), preservatives (e.g., benzoic acid, hydroxypropyl butyl ester, hydroxypropyl methyl ester, phenol, m-cresol, etc.), flavoring agents (e.g., sucrose, steviosin, etc.), and the like. But is not limited thereto.

When used for treating intestinal inflammation, the medicament of the invention is applied to a human or a mammal. For this purpose, the intake mass or the administration mass of the drug of the present invention is usually 120 to 700mg per day, and more preferably 300 to 400mg per day, calculated as the weight of an adult human being 60 to 70kg, in terms of the amount of the hematein a.

The present invention provides a composition for treating enteritis, which is characterized by comprising a compound represented by the formula (I) and a pharmaceutically acceptable carrier, and preferably, a compound represented by the formula (II) as an active ingredient. The descriptions of the composition for treating enteritis of the present invention can refer to the description of the compound represented by formula (I) of the present invention in the application of preparing medicine for treating enteritis.

Drawings

Figure 1 is a graph showing the change over time of mouse DAI scores in DSS-induced enteritis model.

Figure 2 is a statistical graph showing the total DAI score and colon length of mice administered the last day in a DSS-induced enteritis model.

Figure 3 is a photograph showing colon and HE staining of various groups of mice in a DSS-induced enteritis model.

Detailed Description

The following description shows specific examples of compounds of formula (I) of the present invention which demonstrate the promise of treating enteritis. The experimental procedures in the following examples are conventional unless otherwise specified. The raw materials and reagent materials used in the following examples are all commercially available products unless otherwise specified.

Synthesis example preparation of the Compound represented by the formula (II)

Synthesized in the laboratory, see high selective inhibition of IMPDH2 precursors of the basic therapy, PNAS.2017: E5986.

The structure is determined by methods such as UV, MS, NMR and the like, and the purity is over 95 percent. The spectral data for the compound of formula (II) are as follows:

¹H NMR(DMSO-d6,500MHz)_H10.58(brs,1H),9.57(brs,1H),9.21(brs,1H),8.24(s,1H),7.72(d,J＝8.7Hz,1H),7.52(s,1H),6.83(m,2H),6.76(dd,J＝8.3,1.7Hz,1H),6.54(dd,J＝8.7,2.2Hz,1H),6.31(d,J＝2.2Hz,1H),5.35(d,J＝1.6Hz,2H)；and(-)-ESIMSm/z 283.4[M-H]-.