Use of a benzamide compound for preventing and treating cancer cachexia

Abstract

The application relates to application of a compound in the biological medical field, in particular to application of a benzamide compound in preparation of a drug for preventing and / or treating cancer cachexia. The application of the compound shown in formula I or a pharmaceutically acceptable salt thereof in preparation of a drug for preventing and / or treating cancer cachexia. The compound involved in the application has the effect of significantly improving, reducing and alleviating cancer cachexia, improving the weight of animal body, bone muscle and fat, and has a good application and development prospect.

Description

Technical Field

[0001] This invention relates to a method for adjuvant treatment of malignant tumors, used to prevent and / or treat malignant tumor cachexia, and belongs to the field of biomedicine. The method involves using the compound to prevent and / or treat cachexia in patients with malignant tumors, as an adjuvant to the treatment of the malignant tumor. Background Technology

[0002] Cancer is one of the leading causes of death worldwide. A 2020 report by the World Health Organization stated that nearly ten million people die from cancer each year, accounting for almost one-sixth of all deaths globally. Cancer is characterized by the rapid growth of abnormal cells that can invade nearby sites and spread to other organs.

[0003] Malignant tumor cachexia is a wasting syndrome characterized by muscle and fat loss and progressive malnutrition, manifesting as progressive weight loss, fatigue, loss of appetite, and varying degrees of damage to organs throughout the body, leading to a decline in quality of life and an increased mortality rate. The most prominent feature of cachexia is muscle loss with or without fat loss. Cachexia differs from starvation and age-related muscle loss. Although cachexia typically occurs in the late stages of malignant tumors, 60%-80% of malignant tumor patients may experience cachexia at any stage of the disease, severely affecting the body's sensitivity and tolerance to treatment. Approximately 20% of malignant tumor patients die from cachexia. Patients in a cachectic state who receive various anti-tumor treatments will not benefit from these treatments, but will instead experience increased complications and toxic side effects. Malignant tumor cachexia is a clinical syndrome that can be prevented and treated early.

[0004] The mechanism of cachexia in malignant tumors remains unclear, but it is currently believed to be primarily caused by accelerated skeletal muscle loss under inflammatory conditions. Cytokine activation and several tumor-derived factors that potentially induce cachexia may play important roles. Various inflammatory factors can lead to hypermetabolism, such as TNF-α, IL-1β, and IL-6. Increased levels of inflammatory factors and skeletal muscle atrophy are also observed in cancer patients experiencing weight loss. Skeletal muscle atrophy manifests as a decrease in skeletal muscle mass and strength. It not only increases mortality in patients with malignant tumors but also affects their quality of life. However, effective treatments for malignant tumor cachexia, especially skeletal muscle atrophy, are currently lacking. Existing methods include increasing the intake of various nutrients, especially protein rich in essential amino acids, to counteract high catabolism and promote appetite. For cases where nutritional therapy is ineffective, drug therapy can be used, including appetite stimulants, prokinetic agents, steroid hormones, and nonsteroidal anti-inflammatory drugs (NSAIDs). However, the treatment outcomes of these drugs remain unsatisfactory.

[0005] The compound Tak-715 described in this invention is a p38 MAPK inhibitor. MAPK family proteins are evolutionarily conserved serine / threonine protein kinases that play a central role in signal transduction pathways. p38MAPK can be activated by many extracellular and intracellular stimuli, including pro-inflammatory factors, reactive oxygen species, and stressors. Based on bioinformatics and in vivo / in vitro screening and validation, we found that the small-molecule p38 MAPK inhibitor TAK-715 has a good effect on improving skeletal muscle atrophy caused by cachexia in malignant tumors. Our study found that Tak-715 improves both inflammation and cachexia induced by Lewis lung cancer in C57BL / 6J mice. The use of Tak-715 in the treatment or prevention of cachexia in malignant tumors is disclosed for the first time in this invention. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide an application of a compound in the treatment and prevention of cachexia in malignant tumors.

[0007] To solve the technical problem of this invention, the present invention provides the following technical solution:

[0008] The first aspect of the present invention is to provide the use of compounds as shown in formula (I) and pharmaceutically acceptable salts thereof in the preparation of drugs for the prevention or treatment of cachexia in malignant tumors.

[0009]

[0010] CAS No.: 303162-79-0(Ⅰ).

[0011] The malignant tumor cachexia mentioned above is selected from malignant epithelial tumors, malignant mesenchymal tumors, leukemia, lymphoma, and myeloma.

[0012] A mouse cachexia model induced by inflammatory factors and malignant tumor cells was used. The effects of this compound on animal body weight, skeletal muscle, and adipose tissue were examined. The application of this compound in the prevention and / or treatment of malignant tumor cachexia was determined.

[0013] The purpose of this invention is to provide the use of a compound as shown in general formula (I) and its pharmaceutically acceptable salt in the preparation of a drug for the prevention or treatment of cachexia in malignant tumors.

[0014] The compound represented by general formula (I) has the molecular formula C. 24 H 21N3OS, chemically named N-[4-[2-ethyl-4-(3-methylphenyl)-5-thiazolyl]-2-pyridyl]benzamide, CAS number 303162-79-0, is a p38MAPK inhibitor. Currently, there are no international reports or patents regarding Tak-715's ability to improve cachexia in malignant tumors.

[0015] The second aspect of the present invention is to provide a pharmaceutical composition for the preparation of a treatment and / or prevention of malignant tumor cachexia, characterized in that the pharmaceutical composition contains an effective dose of the compound shown in (I) and its pharmaceutically acceptable salt.

[0016]

[0017] CAS No.: 303162-79-0(Ⅰ).

[0018] The pharmaceutical compositions include the following dosage forms: solutions, suspensions, lyophilized powder for injection, emulsions, pills, capsules, powders, controlled-release, sustained-release formulations, and microparticle delivery systems.

[0019] The pharmaceutically acceptable carriers include starch, dextrin, sodium polymethyl cellulose, magnesium stearate, and talc.

[0020] This invention relates to pharmaceutical compositions of general formula (I), comprising an effective amount of a compound of general formula (I) and a pharmaceutically acceptable salt. The pharmaceutical composition can be prepared according to methods known in the art. It can be formulated into any dosage form suitable for human or animal use by combining the compound of the invention with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants. The content of the compound of the invention in its pharmaceutical composition is typically 0.1-99.9% by weight.

[0021] The dosage of the pharmaceutical compositions of this invention can vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration, and the dosage form. Generally, the appropriate daily dose range of the compounds of this invention is 0.01-1000 mg / kg body weight, preferably 0.1-100 mg / kg body weight. The above dose can be administered as a single dose unit or divided into several dose units, depending on the physician's clinical experience and the dosing regimen, including the use of other treatment methods. The compounds or compositions of this invention can be used alone or in combination with other therapeutic or symptomatic drugs. When the compounds of this invention have a synergistic effect with other therapeutic drugs, their dosage should be adjusted according to the actual situation.

[0022] The compounds of this invention, or pharmaceutical compositions containing them, can be administered in unit doses via non-enteric routes, such as intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lungs and respiratory tract, skin, rectum, etc. The dosage form is a liquid dosage form. Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o / w, w / o, and double emulsions), suspensions, injections (including aqueous injections, powder injections, and infusions), eye drops, nasal drops, lotions, and liniments, etc. The compounds of this invention can be formulated into conventional formulations, sustained-release formulations, controlled-release formulations, targeted formulations, and various microparticle delivery systems.

[0023] Beneficial technical effects

[0024] 1. The compounds of this invention can prevent / or treat cachexia caused by malignant tumors. This is the first public disclosure of the use of the compounds of this invention in the prevention / treatment of cachexia caused by malignant tumors. In particular, there are currently no clinically effective drugs for this type of disease. These compounds broaden the range of drugs available for treating nutritional deficiencies and wasting syndromes.

[0025] 2. Currently, there are no patents or literature reports internationally regarding the effects of TAK-715 on cachexia in malignant tumors. This patent is the first report of the compound's effects on nutritional deficiencies and wasting syndrome.

[0026] 3. The application of the compounds in this invention has demonstrated significant improvement in weight loss, skeletal muscle atrophy, and fat reduction in animals caused by malignant tumor cachexia. As a drug, it offers clear advantages. Detailed Implementation

[0027] The role of the compound represented by general formula (I) in the preparation of drugs for the prevention, relief and / or treatment of malignant tumor cachexia is further explained below in conjunction with the present invention.

[0028] The following embodiments illustrate the present invention in more detail, but are not intended to limit the invention in any way. Therefore, non-essential improvements and adjustments made to the embodiments by those skilled in the art based on the above description are still within the scope of protection of the present invention.

[0029] Example 1. Preparation of the compound

[0030] Compound TAK-715 was purchased from Selleck (catalog number S2928) with a purity >99.97%. The compound powder was dissolved in DMSO to prepare a 100 mg / mL solution, which was then aliquoted and stored at -80°C for later use. Before use, it was diluted with physiological saline to the appropriate concentration.

[0031] Example 2. Effect of the compound on LPS-induced body weight in C57BL / 6J mice

[0032] Significance: Malignant tumor cachexia is closely related to systemic inflammation levels. This experiment observed the effect of lipopolysaccharide (LPS) on animal body weight to reflect the effect of drugs on systemic consumption induced by inflammatory factors.

[0033] Experimental Methods: SPF-grade male C57BL / 6 mice were acclimatized for one week and then randomly divided into three groups of 10 mice each: normal control group (NC group), LPS group (1 mg / kg), and LPS (1 mg / kg) + TAK-715 (10 mg / kg) group. TAK-715 was administered orally at 10 mg / kg daily for 3 days. After that, LPS was administered intraperitoneally at a dose of 0.1 mL / 10 g, followed by continued TAK-715 administration for 3 weeks.

[0034] Experimental Results: In this experiment, the model group animals experienced a decrease in body weight, and TAK-715 administration had no significant effect on body weight (Table 1). In mice, LPS administration caused a sharp drop in body weight during running, while TAK-715 significantly improved this phenomenon (Table 2).

[0035] Table 1. Effects of compounds on LPS-induced changes in body weight in C57BL / 6J mice.

[0036]

[0037] Table 2. Effects of compounds on LPS-induced weight changes in C57BL / 6J mice after exercise.

[0038]

[0039] Example 3. Effect of the compound on LPS-induced pulling force in mice

[0040] Significance: Skeletal muscle strength is a primary indicator of skeletal muscle contractile function and is closely related to the degree of skeletal muscle atrophy. Skeletal muscle tensile strength tests reflect the maximum strength of an animal's skeletal muscles.

[0041] Experimental Methods: SPF-grade male C57BL / 6 mice were acclimatized for one week and then randomly divided into three groups of 10 mice each: normal control group (NC group), LPS group (1 mg / kg), and LPS (1 mg / kg) + TAK-715 (10 mg / kg) group. TAK-715 was administered orally at 10 mg / kg daily for 3 days. Afterward, LPS was injected intraperitoneally at a dose of 0.1 mL / 10 g, followed by continued TAK-715 administration for 3 weeks. Two weeks after administration, forelimb pulling force was measured using a mouse muscle grip strength meter. Forelimb pulling force was measured 10 times per animal, and the maximum value was selected as the animal's value.

[0042] Experimental Results: In this experiment, the forelimb pulling force in the model group was significantly lower than that in the control group, while TAK-715 significantly increased the muscle pulling force of the forelimb induced by LPS in mice, indicating that TAK-715 has the effect of improving muscle strength. The results are shown in Table 3.

[0043] Table 3 Effects of compounds on LPS-induced forelimb pulling force in mice

[0044]

[0045]

[0046] Example 4. Effect of the compound on body weight of Lewis lung adenocarcinoma-induced C57BL / 6J mice

[0047] Significance: Cachexia has the highest incidence in lung cancer, pancreatic cancer, esophageal cancer, gastrointestinal cancer, and head and neck cancer. Lewis lung adenocarcinoma (LLC) cells are commonly used to induce cachexia models in mice. This tumor induces rapid and progressive body and tissue wastage. This experiment observes the effect of drugs on body weight in a Lewis lung adenocarcinoma-induced cachexia model to reflect the effect of drugs on tumor-induced systemic wastage.

[0048] Experimental methods: 4-6 week old male mice (C57BL / 6) were divided into two groups: a control group and a model group. For the LLC-induced cancer cachexia model, 100 μL of LLC cells (5 × 10⁻⁶) were subcutaneously injected into the right side of the mice. 6 Or an equal volume of physiological saline (normal control). On day 5 after LLC implantation, mice were weighed and the subcutaneous tumor volume was measured. Mice were grouped according to body weight and tumor volume: model group (LLC group) and model + drug group (LLC + 3 mg / kg TAK-715 group). Drugs were administered intraperitoneally at a dose of 0.1 mL / 10 g, with the following specific dosing regimens: 1) NC group: intraperitoneal injection of physiological saline; 2) LLC group: intraperitoneal injection of physiological saline; 3) LLC + 3 mg / kg TAK-715 group: intraperitoneal injection of 3 mg / kg TAK-715 for 18 days. Mice were administered the drug daily, and cachexia development was monitored by tumor size, body weight, and tension.

[0049] Experimental Results: In this experiment, the body weight of the animals in the model group decreased; after administration of TAK-715, the body weight level increased, indicating that TAK-715 can improve LLC-induced body weight loss in animals. The results are shown in Table 4.

[0050] Table 4. Effects of compounds on body weight in Lewis lung adenocarcinoma-induced C57BL / 6J mice.

[0051]

[0052] Example 5. Effect of the compound on skeletal muscle weight in Lewis lung adenocarcinoma-induced C57BL / 6J mice

[0053] Significance: Lung cancer, pancreatic cancer, esophageal cancer, gastrointestinal cancer, and head and neck cancer have the highest incidence of cachexia. Among these, Lewis lung adenocarcinoma (LLC) cells are commonly used to induce cachexia models in mice. This tumor induces rapid and progressive body and tissue wastage. This experiment observed the effect of drugs on skeletal muscle weight in a Lewis lung adenocarcinoma-induced cachexia model to reflect the effect of drugs on tumor-induced skeletal muscle wastage.

[0054] Experimental methods: 4-6 week old male mice (C57BL / 6) were divided into two groups: a control group and a model group. For the LLC-induced cancer cachexia model, 100 μL of LLC cells (5 × 10⁻⁶) were subcutaneously injected into the right side of the mice. 6 Mice were given either a normal volume of saline or an equal volume of normal saline (normal control). On day 5 after LLC implantation, mice were weighed and the subcutaneous tumor volume was measured. They were then grouped according to body weight and tumor volume: a model group (LLC group) and a model + drug group (LLC + 3 mg / kg TAK-715 group). The drugs were administered intraperitoneally at a dose of 0.1 mL / 10 g, with the following specific dosing regimens: 1) NC group: intraperitoneal injection of normal saline; 2) LLC group: intraperitoneal injection of normal saline; 3) LLC + 3 mg / kg TAK-715 group: intraperitoneal injection of 3 mg / kg TAK-715 for 18 days. Mice were given the drug daily, and the development of cachexia was monitored by tumor size, body weight, and tension. Skeletal muscle weight was measured after the last administration.

[0055] Experimental Results: In this experiment, the skeletal muscle weight of the model group animals decreased; after administration of TAK-715, the gastrocnemius muscle weight level increased, indicating that TAK-715 can improve LLC-induced skeletal muscle weight loss in animals. The results are shown in Table 5.

[0056] Table 5. Effects of compounds on skeletal muscle weight in Lewis lung adenocarcinoma-induced C57BL / 6J mice.

[0057]

[0058] Example 6. Effect of the compound on skeletal muscle tension induced by Lewis lung adenocarcinoma cells in C57BL / 6J mice

[0059] Significance: Lung cancer, pancreatic cancer, esophageal cancer, gastrointestinal cancer, and head and neck cancer have the highest incidence of cachexia. Among these, Lewis lung adenocarcinoma (LLC) cells are commonly used to induce cachexia models in mice. This tumor induces rapid and progressive body and tissue wastage. This experiment observed the effect of drugs on skeletal muscle tension in a Lewis lung adenocarcinoma-induced cachexia model to reflect the effect of drugs on tumor-induced skeletal muscle wastage. Skeletal muscle strength is a major indicator reflecting skeletal muscle contractile function and is closely related to the degree of skeletal muscle atrophy. Skeletal muscle tension tests reflect the maximum strength of animal skeletal muscles.

[0060] Experimental methods: 4-6 week old male mice (C57BL / 6) were divided into two groups: a control group and a model group. For the LLC-induced cancer cachexia model, 100 μL of LLC cells (5 × 10⁻⁶) were subcutaneously injected into the right side of the mice. 6 Or an equal volume of physiological saline (normal control). On day 5 after LLC implantation, mice were weighed and the subcutaneous tumor volume was measured. They were then grouped according to body weight and tumor volume: model group (LLC group) and model + drug group (LLC + 3 mg / kg TAK-715 group). The drugs were administered intraperitoneally at a dose of 0.1 mL / 10 g, with the following specific dosing regimens: 1) NC group: intraperitoneal injection of physiological saline; 2) LLC group: intraperitoneal injection of physiological saline; 3) LLC + 3 mg / kg TAK-715 group: intraperitoneal injection of 3 mg / kg TAK-715 for 18 days. Mice were given the drug daily, and the development of cachexia was monitored by tumor size, body weight, and traction force. Forelimb traction force was measured using a mouse muscle grip strength meter. Forelimb traction force was measured 10 times for each animal, and the maximum value was selected as the animal's value.

[0061] Experimental Results: In this experiment, the explosive force of the pulling force in the model group animals decreased; after 2 weeks of TAK-715 administration, the explosive force level of the forelimbs increased, indicating that TAK-715 can improve the LLC-induced decrease in the pulling force of animal skeletal muscles. The results are shown in Table 6.

[0062] Table 6. Effects of compounds on tensile strength induced by Lewis lung adenocarcinoma cells in C57BL / 6J mice.

[0063]

[0064] Example 7. Effect of the compound on fat weight in Lewis lung adenocarcinoma-induced C57BL / 6J mice

[0065] Significance: Lung cancer, pancreatic cancer, esophageal cancer, gastrointestinal cancer, and head and neck cancer have the highest incidence of cachexia. Among these, Lewis lung adenocarcinoma (LLC) cells are commonly used to induce cachexia models in mice. This tumor induces rapid and progressive body and tissue wastage. This experiment observes the effect of drugs on fat weight in a Lewis lung adenocarcinoma-induced cachexia model to reflect the drug's effect on tumor-induced energy and fat consumption.

[0066] Experimental methods: 4-6 week old male mice (C57BL / 6) were divided into two groups: a control group and a model group. For the LLC-induced cancer cachexia model, 100 μL of LLC cells (5 × 10⁻⁶) were subcutaneously injected into the right side of the mice. 6 Mice were given either a normal volume of saline or an equal volume of normal saline (normal control). On day 5 after LLC implantation, mice were weighed and the subcutaneous tumor volume was measured. They were then grouped according to body weight and tumor volume into two groups: a model group (LLC group) and a model + drug group (LLC + 3 mg / kg TAK-715 group). The drugs were administered intraperitoneally at a dose of 0.1 mL / 10 g, with the following specific dosing regimens: 1) NC group: intraperitoneal injection of normal saline; 2) LLC group: intraperitoneal injection of normal saline; 3) LLC + 3 mg / kg TAK-715 group: intraperitoneal injection of 3 mg / kg TAK-715 for 18 days. Mice were given the drug daily, and the development of cachexia was monitored by tumor size, body weight, and tension. Fat weight was measured after the last administration.

[0067] Experimental Results: In this experiment, the adipose tissue weight of the model group animals decreased; after administration of TAK-715, the decrease in adipose tissue weight in mice was improved, indicating that TAK-715 can improve LLC-induced adipose tissue weight loss in animals. The results are shown in Table 7.

[0068] Table 7 Effects of compounds on fat weight in Lewis lung adenocarcinoma-induced C57BL / 6J mice

[0069]

Claims

1. The use of compounds of formula (I) and pharmaceutically acceptable salts thereof in the preparation of drugs for the prevention or treatment of malignant tumor cachexia, characterized in that, The drug specifically improves tumor-free weight and skeletal muscle function in patients with malignant tumors without altering the weight loss induced by acute inflammation at rest. Equation (Ⅰ).

2. The application according to claim 1, characterized in that, The malignant tumors mentioned are selected from malignant epithelial tumors, malignant mesenchymal tumors, leukemia, lymphoma, and myeloma.

3. The use of a pharmaceutical composition in the preparation of a drug for the prevention, relief, and / or treatment of cachexia in malignant tumors, characterized in that, The pharmaceutical composition contains an effective dose of the compound of formula (1) and a pharmaceutically acceptable salt; The pharmaceutical composition specifically improves tumor-free weight and skeletal muscle function in patients with malignant tumors without altering the weight loss caused by acute inflammation at rest. Equation (Ⅰ).

4. The application according to claim 3, characterized in that, The pharmaceutical composition is selected from the following dosage forms: suspension, lyophilized powder for injection, emulsion, pills, and capsules.

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