Application of compound containing dibenzofuran structure in preparation of medicine for preventing and / or treating nausea and vomiting

Abstract

The invention discloses application of a compound containing a dibenzofuran structure in preparation of a medicine for preventing and / or treating nausea and vomiting, and relates to the technical field of medicinal chemistry. The invention provides application of a compound containing a dibenzofuran structure in preparation of a medicine for preventing and / or treating nausea and vomiting, the molecular formula of the compound is C19H11ClN2O4, and the CAS number is 328255-08-9. The compound can effectively reduce the number of times of canine retching and vomiting caused by cis-platinum, has an effect superior to that of metoprazole, has the potential of preventing and / or vomiting caused by chemotherapy, and has an application prospect in development of drugs for treating vomiting caused by chemotherapy drugs.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and more specifically to the use of a compound containing a dibenzofuran structure in the preparation of medicaments for the prevention and / or treatment of nausea and vomiting. Background Technology

[0002] Chemotherapy and radiotherapy remain the main treatments for cancer, but chemotherapy drugs (cisplatin, doxorubicin, imatinib, gefitinib, etc.) can cause various adverse reactions, with nausea and vomiting being one of the most common. This is also a major factor affecting the efficacy of anti-tumor drugs. Chemotherapy-induced nausea and vomiting can cause nutritional and metabolic imbalances, and lead to depression and low spirits. Severe nausea and vomiting can directly prevent the effective implementation of treatment. The mechanism of chemotherapy-induced nausea and vomiting is complex. Studies have found that it is related to certain neurotransmitters, such as dopamine, histamine, serotonin, and substance P. Dopamine, serotonin, and substance P bind to dopamine receptor 2, serotonin 3, and NK1 receptors, respectively, stimulating the vomiting center and causing vomiting. When chemotherapy drugs act on the gastrointestinal mucosa, chromaffin cells in the gastrointestinal tract release dopamine and serotonin (5-HT). These neurotransmitters bind to 5-HT3 receptors and act on the vomiting center through a neural reflex, causing nausea and vomiting.

[0003] Currently, various drugs are used to control chemotherapy-induced nausea and vomiting, such as phenothiazines, dopamine antagonists, antihistamines, and serotonin antagonists. Ondansetron, a potent and highly selective 5-HT3 receptor antagonist marketed by GlaxoSmithKline in the 1990s, is clinically used to treat nausea and vomiting caused by chemotherapy drugs (such as cisplatin and doxorubicin). However, due to problems with tolerability and numerous side effects, its usage has remained limited, and patient acceptance and comfort after administration have been consistently criticized. Therefore, the development of new drugs with preventative and / or therapeutic effects against nausea and vomiting is still needed. Summary of the Invention

[0004] The purpose of this invention is to overcome the shortcomings of the prior art and provide the use of a compound containing a dibenzofuran structure in the preparation of a medicament for the prevention and / or treatment of nausea and vomiting.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is: the use of the compound shown in formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and / or treatment of nausea and vomiting. (I).

[0006] Chemotherapy-induced nausea and vomiting (CINV) is caused by stimulation of the vomiting center or chemoreceptor trigger zones by neurotransmitters (dopamine, serotonin, histamine, acetylcholine, and substance P) after chemotherapy. Without any preventative measures, the incidence of CINV is as high as 70-80%. CINV has a high incidence and significant impact; mild to moderate vomiting often leads to patient irritability, while moderate to severe vomiting can affect daily diet and nutrition, even causing electrolyte imbalances, and in severe cases, forcing the interruption of chemotherapy, impacting the patient's quality of life and overall treatment. Currently, CINV treatment often involves combination drug therapy, with clinically used antiemetics including dopamine receptor blockers, vomiting center depressants, antihistamines, corticosteroids, 5-HT3 receptor blockers, and NK-1 receptor antagonists. However, current CINV treatments are expensive, have significant side effects, and their long-term adverse reactions are still unclear. Through extensive experimental screening and verification, the inventors of this application discovered that the compound shown in formula (I) has an unexpected effect in preventing and treating nausea and vomiting. Animal experiments have verified that the compound shown in formula (I) can effectively reduce the frequency of vomiting and dry heaving in chemotherapy animals, and its effect is superior to that of metoclopramide, indicating that the compound has the potential to prevent or treat vomiting and can be used to develop drugs for treating vomiting caused by chemotherapy drugs.

[0007] In a preferred embodiment of the application described in this invention, the nausea and vomiting are vomiting and nausea induced by chemotherapy drugs.

[0008] In a preferred embodiment of the application described in this invention, the chemotherapy drug includes platinum-based chemotherapy drugs.

[0009] In a preferred embodiment of the application described in this invention, the chemotherapy drug is cisplatin.

[0010] The present invention also provides a kit product for treating nausea and vomiting after chemotherapy, the kit product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. (I).

[0011] As a preferred embodiment of the medicine box product for treating nausea and vomiting after chemotherapy according to the present invention, the medicine box product further includes a second drug; the second drug is suitable for treating the same or related conditions that are medically indicated to be treatable or preventable by the compound shown in formula (I).

[0012] In a preferred embodiment of the medicine box product for treating nausea and vomiting after chemotherapy as described in this invention, the second drug is metoclopramide.

[0013] Beneficial effects of the present invention: The present invention provides the use of a compound containing a dibenzofuran structure in the preparation of a medicament for the prevention and / or treatment of nausea and vomiting, wherein the molecular formula of the compound is C 19 H 11 ClN2O4, CAS No. 328255-08-9. This compound effectively reduces the frequency of vomiting and heaving in dogs induced by cisplatin, with better efficacy than metoclopramide, demonstrating potential for preventing and / or treating chemotherapy-induced vomiting, and showing promise for development into a drug for treating chemotherapy-induced vomiting. Attached Figure Description

[0014] Figure 1 This is a statistical chart showing the number of times beagle dogs in each group retched and vomited in Example 1. Detailed Implementation

[0015] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention.

[0016] Example 1: Construction of an animal model of vomiting and evaluation of its efficacy This embodiment evaluates the therapeutic effect of the compound of formula (I) of the present invention on cisplatin-induced nausea and vomiting by constructing an animal model of vomiting. The specific experimental method is as follows: 1. Experimental materials: Nine healthy beagle dogs aged 12-24 months, weighing 8-12 kg, were purchased from Hubei Yizhicheng; Compound 2154-0397, cisplatin, and sodium carboxymethyl cellulose (CMC-Na) were commercially available; Metoclopramide was purchased from McLean; The CAS numbers and structures of Compound 2154-0397 and Metoclopramide are shown in Table 1.

[0017] Table 1 2. Experimental steps: 1) Administration: Nine beagle dogs were randomly divided into three groups: cisplatin + vehicle group (n=3), cisplatin + 2154-0397 group (n=3, 4 mg / kg), and cisplatin + metoclopramide group (n=3, 2 mg / kg). Cisplatin was administered three times: 15 min before injection, 6 h after injection, and 12 h after injection. The cisplatin + vehicle group received vehicle (1% CMC-Na solution) orally each time, the cisplatin + 2154-0397 group received 2154-0397 orally each time, and the cisplatin + metoclopramide group received metoclopramide orally each time. 2) Scoring: Each dog was observed using a camera, and a comprehensive behavioral score was calculated. Nausea assessment indicators included: drooling, lip licking, lethargy, restlessness, circling behavior, gagging, vomiting behavior, and vomit volume. Scores were assigned based on the severity of each indicator: 0-10 points, where 0 indicates no symptom and 10 indicates the most severe symptom. Each animal was assessed twice individually. Two designated individuals were used for scoring, and the average score for each group was calculated.

[0018] Experimental results are as follows Figure 1 As shown. By Figure 1 The results showed that the cisplatin + vehicle group resulted in an increased frequency of vomiting and dry heaving in beagles, indicating the successful establishment of the vomiting animal model. Compared with the cisplatin + vehicle group, the number of vomiting and dry heaving in beagles in the treatment groups (cisplatin + 2154-0397 group and cisplatin + metoclopramide group) was significantly reduced, indicating that both compound 2154-0397 and metoclopramide can effectively reduce vomiting and dry heaving induced by cisplatin. Compared with the cisplatin + metoclopramide group, the number of vomiting and dry heaving in beagles in the cisplatin + 2154-0397 group was significantly reduced, indicating that compound 2154-0397 has a better relieving effect on cisplatin-induced vomiting and dry heaving than metoclopramide.

[0019] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of medicaments for the prevention and / or treatment of nausea and vomiting. （I）。 2. The application according to claim 1, characterized in that, The nausea and vomiting mentioned are caused by chemotherapy drugs.

3. The application according to claim 2, characterized in that, The chemotherapy drugs include platinum-based chemotherapy drugs.

4. The application according to claim 3, characterized in that, The chemotherapy drug is cisplatin.

5. A medicine box product for treating nausea and vomiting after chemotherapy, characterized in that, The kit product comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof. （I）。 6. The medicine box product according to claim 5, characterized in that, The medicine box product also includes a second medicine; the second medicine is suitable for treating the same or related conditions that are medically indicated to be treatable or preventable by the compound of formula (I).

7. The medicine box product according to claim 6, characterized in that, The second drug is metoclopramide.

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