Use of stilbene derivatives for preventing and / or treating ulcers - Patent Application 20070122997

Abstract

The present invention relates to the use of a stilbene derivative for preventing and / or treating ulcers. The compound of formula (I) or a pharmaceutically acceptable salt thereof can effectively prevent or treat ulcers, and has excellent therapeutic effects, particularly on oral ulcers. [Formula 1] JPEG2025532421000008.jpg32169

Description

Detailed Description of the Invention

[0001] This application claims patent application number 202211236827.3, filed with the State Intellectual Property Office of China on October 10, 2022, entitled "Use of stilbene derivatives for preventing and / or treating ulcers," the entire text of which is incorporated herein by reference.

[0002] [Technical Field] The present invention relates to the use of stilbene derivatives for preventing and / or treating ulcers and belongs to the pharmaceutical field.

[0003] [Background technology] Ulcers are lesions or defects of mucous membranes or skin in the human body, and clinically they frequently occur in the gastrointestinal tract, oral cavity, genitals, etc., and their etiology is complex.

[0004] Oral ulcers, commonly called "aphthous ulcers," are a common ulcerative lesion that occurs in the oral mucosa, commonly found on the inner lips, tongue, flank of the tongue, buccal mucosa, vestibular sulcus, and soft palate, and currently have a relatively high incidence. Oral ulcers include recurrent oral ulcers, traumatic oral ulcers, and disease-related oral ulcers. Recurrent oral ulcers are also called recurrent aphthous ulcers or frequent oral ulcers. According to the "Guidelines for the Treatment of Recurrent Aphthous Ulcers" published by China in 2012, 10% to 25% of the population suffers from recurrent oral ulcers, with the most common ages being between 10 and 30. Traumatic oral ulcers include those caused by mechanical injury (e.g., oral mucosal damage caused by fish bones in food, hard objects such as sand, toothbrushes, or tartar buildup on the teeth), chemical burns (e.g., local oral mucosal damage caused by irritating drugs such as aspirin or other analgesic buccal tablets, silver nitrate, or iodine tincture), and cold and heat stimuli (e.g., mucosal burns caused by excessively hot water or hot food, or mucosal frostbite caused by improper cryotherapy). Disease-related oral ulcers include those associated with Behçet's disease, Reiter's syndrome, and tumors.

[0005] At present, the etiology of oral ulcers is still unclear, and possible triggers include genetic factors, dietary factors, immunological factors, psychological factors, or traumatic factors. Drug treatment for oral ulcers primarily involves local treatment, including the use of analgesics (e.g., lidocaine, benzocaine, benzydamine), anti-inflammatory drugs (e.g., chlorhexidine, cediodine), healing promoters (e.g., icing powder, watermelon frost, recombinant human epidermal growth factor), and healing liquids. For patients with severe or frequently recurring oral ulcers, systemic administration can be used, including the use of immune preparations or vitamins.

[0006] Currently, there is still a need to develop new drugs that have good therapeutic effects on ulcers, especially oral ulcers.

[0007] Summary of the Invention In order to solve the above technical problems, the present invention provides use of at least one compound selected from the group consisting of compounds represented by the following formula (I) and pharmaceutically acceptable salts thereof, for use in the manufacture of a medicament for preventing and / or treating ulcers.

[0008] [ka]

[0009] According to an embodiment of the present invention, the drug is a pharmaceutical composition. Preferably, the pharmaceutical composition comprises at least one of the compounds represented by formula (I) and their pharmaceutically acceptable salts.

[0010] The present invention further provides a pharmaceutical composition, which comprises at least one of the compounds represented by formula (I) and pharmaceutically acceptable salts thereof, wherein the pharmaceutical composition is used for the prevention and / or treatment of ulcers.

[0011] According to an embodiment of the present invention, the pharmaceutical composition comprises a therapeutically effective amount of at least one of the compounds represented by formula (I) and pharmaceutically acceptable salts thereof.

[0012] The present invention further provides use of the compound represented by the above formula (I), a pharmaceutically acceptable salt of the compound represented by the formula (I), the above drug or the above pharmaceutical composition, which is used for the prevention and / or treatment of ulcers.

[0013] The present invention further provides a compound represented by formula (I) above, a pharmaceutically acceptable salt of the compound represented by formula (I), the drug or the pharmaceutical composition above for preventing and / or treating ulcers.

[0014] The present invention further provides a method for preventing and / or treating an ulcer, said method comprising administering to a patient an effective or therapeutically effective amount of at least one of the compounds represented by formula (I) above and pharmaceutically acceptable salts thereof.

[0015] According to an embodiment of the present invention, the ulcer may be one or more selected from pressure ulcers (also called bedsores), genital ulcers, ulcerative dermatitis, anal ulcers, rectal ulcers, foot ulcers, diabetic foot ulcers, corneal ulcers, oral ulcers, aphthous ulcers (also called aphthous stomatitis), peptic ulcers, venous ulcers, stress ulcers (ulcers in the stomach and proximal duodenum), ulcerative sarcoidosis, ulcerative lichen planus, ulcerative colitis, and ulcerative disposition.

[0016] According to an embodiment of the present invention, the oral ulcer is selected from recurrent oral ulcers, traumatic oral ulcers and oral ulcers associated with or caused by disease.

[0017] In the context of this specification, said recurrent oral ulcers are also called recurrent aphthous ulcers or frequent oral ulcers.

[0018] According to an embodiment of the present invention, the traumatic oral ulcer includes oral ulcers caused by mechanical injury (e.g., oral mucosal injury caused by fish bones in food, hard objects such as sand, toothbrushes, tartar accumulated on the tooth surface, etc.), chemical burns (e.g., local oral mucosal injury caused by irritants such as analgesic buccal tablets such as aspirin, silver nitrate, iodine tincture, etc.), and cold and heat stimuli (e.g., mucosal burns caused by too hot water or too hot food, or mucosal frostbite caused by inappropriate cryotherapy).

[0019] According to an embodiment of the present invention, oral ulcers associated with or caused by the above diseases include oral ulcers associated with or caused by diseases such as Behcet's disease, Reiter's syndrome, tumors, etc.

[0020] According to an exemplary embodiment of the present invention, the medicament is used for the prevention and / or treatment of at least one of recurrent oral ulcers and traumatic oral ulcers.

[0021] According to an embodiment of the present invention, the compound represented by the above formula (I) may be an E- or Z-isomer, and is preferably an E-isomer represented by the following formula (I-1):

[0022] [ka]

[0023] According to a preferred embodiment of the present invention, the compound of formula (I) is benvitimod.

[0024] According to an embodiment of the present invention, said pharmaceutically acceptable salt may be selected from addition salts of compounds of formula (I) with pharmaceutically acceptable bases.

[0025] Preferably, the drug or pharmaceutical composition contains only the compound represented by formula (I) as an active ingredient, more preferably only the E-isomer represented by formula (I-1) as an active ingredient.

[0026] According to an embodiment of the present invention, the daily dosage of the medicament or pharmaceutical composition is a therapeutically effective amount calculated based on the compound of formula (I), for example, 0.01-1 mg / kg / d, for example, 0.02-0.4 mg / kg / d, illustratively 0.05 mg / kg / d, 0.06 mg / kg / d, 0.07 mg / kg / d, 0.08 mg / kg / d, 0.09 mg / kg / d, 0.1 mg / kg / d, 0.12 mg / kg / d, 0.15 mg / kg / d, 0.2 mg / kg / d, 0.3 mg / kg / d, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg / d, 0.7 mg / kg / d, 0.8 mg / kg / d, 0.9 mg / kg / d, or 1 mg / kg / d.

[0027] According to an embodiment of the present invention, the drug or pharmaceutical composition is preferably a pharmaceutical preparation. More preferably, the pharmaceutical composition is a single-dose preparation, in which the content of the compound of formula (I) and its pharmaceutically acceptable salts in the single-dose preparation is a therapeutically effective amount, calculated based on the compound of formula (I), for example, 1-10 mg, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg.

[0028] According to an embodiment of the present invention, the single-dose formulation refers to a unit-dose formulation, in which the compound of formula (I) or a salt thereof is contained in one unit package.

[0029] According to an embodiment of the present invention, the drug or pharmaceutical composition may further comprise a pharmaceutically acceptable adjuvant, such as a carrier or excipient. The pharmaceutically acceptable adjuvant is preferably one that is chemically unreactive or inert to the active ingredient. For example, the pharmaceutically acceptable adjuvant may be at least one selected from the following adjuvants, including, but not limited to, fillers, disintegrants, adhesives, lubricants, surfactants, flavoring agents, wetting agents, matrices, etc.

[0030] According to an embodiment of the present invention, the administration route of the drug or pharmaceutical composition includes, but is not limited to, gastrointestinal administration or non-gastrointestinal administration, whereby the gastrointestinal administration may be oral administration, and the non-gastrointestinal administration may be topical administration, transdermal administration, injection administration, etc.

[0031] In one embodiment, the administration route of the drug or pharmaceutical composition may be a combination of topical and oral administration.

[0032] According to an embodiment of the present invention, the dosage form of the drug or pharmaceutical composition may be selected from capsules, tablets, patches, films, pills, powders, troches, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, suppositories, or injections.

[0033] <Definitions and explanations of terms> Unless otherwise specified, the definitions of terms used in the specification and claims of this application, including their illustrative definitions, exemplary definitions, preferred definitions, definitions set forth in tables, definitions of specific compounds in the examples, etc., may be combined or linked in any way, and such combinations or links are to be included within the scope described in the specification of this application.

[0034] The term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a compound described in the present invention to achieve the expected application (including, but not limited to, the treatment of diseases defined below). The therapeutically effective amount may vary depending on the expected application (in vitro or in vivo), or the subject and disease condition being treated, such as the subject's weight and age, the severity of the disease condition, and the method of administration, and this may be readily determined by one skilled in the art. The specific dosage will vary depending on the particular compound selected, the method of administration used, whether or not it is co-administered with other compounds, the time schedule of administration, the tissue to which it is administered, and the physical delivery system involved.

[0035] The term "patient" refers to a mammal suffering from or at risk of suffering from such an ulcer, such as selected from rodents, bovines, porcines, canines, felines and primates, and in particular humans.

[0036] <Beneficial Effects> The present inventors have unexpectedly found that the compound of formula (I) or a pharmaceutically acceptable salt thereof can effectively prevent or treat ulcers, and has particularly excellent therapeutic effects on oral ulcers.

[0037] [Mode for Carrying Out the Invention] The technical solutions of the present invention will be described in more detail below with reference to specific examples. It should be understood that the following examples are merely for illustrative purposes and should not be construed as limiting the scope of the claims of the present invention. Any technology realized based on the above content of the present invention is included within the scope of the claims of the present invention.

[0038] Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available or may be prepared by known methods.

[0039] <Example 1 Experiment on the therapeutic effect of oral ulcer> The drug selected for the following experiment was a cream containing 1% benvitimod, which contained 1% benvitimod by weight, as well as mometasone furoate, propylene glycol, white petrolatum, light liquid paraffin, hexadecanol, glycerin monostearate, purified water, ethylparaben, etc.

[0040] Administration method: Squeeze a small amount of the above cream onto a cotton swab, and after 3 meals and before going to bed, thoroughly clean the mouth, then apply it to the surface of the ulcer to cover it. This was administered 4 times a day until the ulcer healed. No other drugs were used during administration.

[0041] Subject 1: A patient with non-recurrent oral ulcers, multiple ulcers approximately 0.3 x 0.6 cm in size, had a disease course of approximately 10 days, and was not taking any other medication. On the first day of application of the medication, pain was significantly reduced, on the second day the ulcers were significantly improved, and on the fourth day the ulcers had all healed and disappeared.

[0042] Subject 2: A patient with recurrent oral ulcers, with multiple ulcers measuring approximately 0.3 x 0.7 cm, had a disease course of approximately 6 days, and was not taking any other medication. On the first day of application of the medication, the pain was significantly reduced, and on the third day, all the ulcers had healed and disappeared.

[0043] Example 2: Efficacy of 7-day treatment in an oral ulcer model in SD male rats Eighteen male SD rats were randomly divided into three groups: the model group (propylene glycol solvent group), the 2% indigo group (1 mg / rat), and the 2% benvitimod group (1 mg / rat). Oral ulcer model construction: A 1 cm x 0.6 cm filter paper (soaked in 60% glacial acetic acid solution) was placed on the labial mucosa of the alveolar bone of the rat's mandibular incisor and maintained for 1 minute. Administration: After anesthetizing the rats, 50 μL of each solution was pipetted and evenly applied to the ulcer site twice daily for 7 consecutive days. As shown in Table 1, after treatment with glacial acetic acid, all groups exhibited symptoms such as temporary membrane coverage, central depression, redness and swelling at the edges, and a pronounced pain response after stimulation. All symptoms were alleviated after administration. 2% benvitimod had a good therapeutic effect and its efficacy was superior to that of 2% indigo.

[0044] [Table 1]

[0045] Example 3: Efficacy of 10-day treatment of DB / DB male mouse diabetic foot ulcer model Eighteen DB / DB male mice were randomly divided into three groups: a model group (propylene glycol solvent group), a 2% indigo group (1 mg / mouse), and a 2% benvitimod group (1 mg / mouse).

[0046] Construction of foot ulcer model: After anesthetizing the mice, the foot was disinfected, a 4 mm x 5 mm rectangular area was marked on the dorsum of the foot, and the skin and fascia within the area were removed.

[0047] Administration: 50 μL of each solution was taken up with a pipette and evenly applied to the ulcer site on the dorsum of the mouse's foot. The administration was carried out twice a day for 10 consecutive days, and the length and width of the ulcer were recorded.

[0048] The experimental results are shown in Table 2. After treatment, the paws of each group were red and swollen, ulcers appeared around the wounds, pain responses were obvious, and the mice exhibited claw retraction behavior. After 10 days of administration, 2% benvitimod had a clear inhibitory effect, and the results were superior to those of the 2% indigo group.

[0049] [Table 2]

[0050] The above is an illustrative description of the embodiments of the technical solution of the present invention. It should be understood that the scope of the claims of the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made by those skilled in the art within the spirit and principle of the present invention should be included in the scope of the claims of the present application.

Claims

1. Use of at least one compound represented by the following formula (I) and a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing and / or treating ulcers. 【Chemical 1】

2. the drug is a pharmaceutical composition; Preferably, the pharmaceutical composition comprises at least one of the compounds of formula (I) and pharmaceutically acceptable salts thereof, More preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one of the compounds of formula (I) and pharmaceutically acceptable salts thereof.

2. The use according to claim 1.

3. The compound represented by formula (I) is an E- or Z-isomer, and is preferably an E-isomer represented by the following formula (I-1): 【Chemistry 2】 3. Use according to claim 1 or 2.

4. The ulcer is one or more selected from bedsores, genital ulcers, ulcerative dermatitis, anal ulcers, rectal ulcers, foot ulcers, diabetic foot ulcers, corneal ulcers, oral ulcers, aphthous ulcers, peptic ulcers, venous ulcers, stress ulcers, ulcerative sarcoidosis, ulcerative lichen planus, ulcerative colitis, and ulcer proneness; Use according to any one of claims 1 to 3.

5. The oral ulcer is selected from recurrent oral ulcers, traumatic oral ulcers, and oral ulcers associated with or caused by disease; 5. The use according to claim 4.

6. The recurrent oral ulcer is selected from recurrent aphthous ulcers or frequent oral ulcers.

6. The use according to claim 5.

7. The traumatic oral ulcer includes oral ulcers caused by mechanical injury, chemical burns, and cold and heat stimuli; 6. The use according to claim 5.

8. Oral ulcers associated with or caused by the above diseases include oral ulcers associated with or caused by diseases such as Behcet's disease, Reiter's syndrome, tumors, etc.

6. The use according to claim 5.

9. The oral ulcer is at least one selected from recurrent oral ulcers and traumatic oral ulcers.

6. The use according to claim 5. The drug is a single-dose formulation, and preferably, the content of the compound represented by formula (I) and its pharmaceutically acceptable salt in the single-dose formulation is a therapeutically effective amount, calculated based on the compound represented by formula (I), for example, 1 to 10 mg. Use according to any one of claims 1 to 9.

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