Process for producing a carbamodithiopercapto)thiolate compound having a nitrogen-containing aliphatic heterocyclic ring and its application to the treatment of cachexia

Abstract

This invention relates to medicinal chemistry, the development of carbamo(di)- The present invention provides a method for preparing a thioperoxothiolate compound and its application. The compound is represented by general formula I: JPEG2023507444000039.jpg13161 In the formula, m is in the range of 1 to 11, and may be in the range of 1 to 9; X is a nitrogen-containing fat. The nitrogen atom in the ring is adjacent to the carbon atom of the thiocarbonyl group. In vivo and in vivo experiments have shown that the substance alleviates sarcopenia and lipolysis caused by cancer cachexia. Furthermore, in animal experiments, the compound was found to be effective in preventing weight loss due to cancer cachexia. It was found that carbamo(dithioperoxy) S) Thiolate chemical species have effects on cancer cachexia and related diseases, and It is an ideal compound that can be applied to the treatment of cerebrospinal fluid and related diseases.

Description

Technical Field

[0001] The present invention relates to a carbamodithioperoxo thioate compound in pharmaceutical chemistry, its production method and application, especially to the production method of a carbamodithioperoxo thioate compound having a nitrogen-containing aliphatic heterocyclic ring and its application in the treatment of cachexia.

Background Art

[0002] Cachexia is a progressive wasting syndrome characterized by weight loss, anemia, depression and other systemic disorders. It often occurs in cancer or severe chronic diseases (such as chronic obstructive pulmonary disease, chronic heart failure, AIDS, etc.). Cachexia caused by malignant tumors is called cancer cachexia. Cancer cachexia is regarded as one of the main complications in various malignant tumors and one of the factors leading to cancer death. The prevention and treatment of cancer cachexia are attracting daily attention in the multidisciplinary treatment of malignant tumors. Cancer cachexia is a progressive wasting syndrome characterized by systemic metabolic disorders, progressive muscle and fat wasting, weight loss and progressive multiple organ failure, caused by tumor cell products or cytokines derived from the body. Among them, the most prominent feature of cancer cachexia is significant weight loss caused by skeletal muscle atrophy. Cancer cachexia has an incidence rate of 50 - 80% in advanced cancer patients. Among them, 40% of breast cancer and leukemia patients, 50% of lung cancer, colon cancer and prostate cancer patients, 80% of gastric cancer and pancreatic cancer patients and 20% of cancer patients die of cardiopulmonary dysfunction caused by cachexia. Therefore, cancer cachexia is the leading cause of death in cancer patients. Cancer cachexia not only reduces the effectiveness of chemotherapy and radiotherapy and shortens the survival time, but also has a profound adverse impact on the quality of life of patients.

[0003] The essence of cancer cachexia involves multiple factors intricately intertwined, so there is still no effective treatment method. Currently, there are no commercially available anti-cancer cachexia drugs, and increasing the patient's nutrient intake is the only way to prevent the deterioration of cancer cachexia in clinical practice. To increase weight, stimulate appetite, and overcome cancer cachexia, current clinical treatments include nutritional administration, appetite stimulation, and suppression of inflammatory factors and cytokines. For example, omega-3 fatty acids have been administered as nutrients to head and neck cancer patients with cancer cachexia to maintain weight in clinical trials, but no significant improvement in the patients' weight and survival time has been found. Progestins such as megestrol and medroxyprogesterone are commonly used in general appetite-stimulating hormone therapy, and at the same time, ghrelin and omega-3 fatty acids are also used in combination. Such palliative care can relieve the symptoms of cancer cachexia patients, but it is difficult to achieve an effective therapeutic effect. Regarding inflammatory cytokines such as IL-1α, IL-6, TNF-α, and myostatin, research has also been conducted, but simply inhibiting one type of cytokine does not completely stop the onset of cachexia. When infliximab (anti-human TNF-α monoclonal antibody) and clazakizumab (anti-human IL-6 monoclonal antibody) were respectively applied to pancreatic cancer cachexia and non-small cell lung cancer cachexia, no significant improvement in weight loss, skeletal muscle atrophy, and quality of life was found. In addition, ghrelin receptor agonists, selective androgen receptor (AR) agonists, adrenergic β-blockers, and anti-myostatin peptides have also attracted attention. Recently, the most promising new drugs, anamorelin (a ghrelin receptor agonist) and enobosarm (a selective androgen receptor agonist), When a receptor agonist was subjected to a clinical phase III trial, ideal results were not obtained.

[0004] In conclusion, cancer cachexia is a complication commonly seen in patients with various malignant tumors, which not only reduces the effectiveness of chemotherapy and radiotherapy and shortens the survival time of patients, but also has a profound adverse impact on the quality of life of patients. The importance of treating cancer cachexia has been recognized, but since the pathological state of cancer cachexia still has many unclear parts, breakthroughs in treatment methods and new drugs have not been discovered, the treatment effect is limited, and there is no approved specific drug for cancer cachexia. Therefore, the development of an anti-cancer cachexia drug with intellectual property rights is an urgent issue in the field of science and technology, and great benefits are expected socially and economically.

Summary of the Invention

Problems to be Solved by the Invention

[0005] Breakthroughs in treatment methods and new drugs for cancer cachexia have not been discovered yet, the treatment effect is limited, and there is no approved commercially available specific drug. The present invention designs, synthesizes and studies a novel anti-cancer cachexia compound, develops a novel anti-cancer cachexia drug with independent intellectual property rights, and solves urgent issues in the field of science and technology in cancer treatment.

[0006] Therefore, the present invention aims to provide a carbamodithiopropionate compound, which is a novel oral preparation for anti-cancer cachexia. The compound affects various signal transduction pathways, alleviates skeletal muscle atrophy and fat breakdown, and exhibits excellent anti-cachexia effects in various tissues. Based on experimental results, the compound has good anti-cachexia activity by oral administration and is expected to become a novel anti-cachexia drug.

Means for Solving the Problems

[0007] In order to improve the above-mentioned shortcomings and deficiencies of the existing technology, the present invention provides a series of nitrogen-containing aliphatic heterocycles. The present invention provides carbamo(dithioperoxo)thiolate compounds which are effective in preventing toxic reactions. It can be used to treat cachexia, especially cancer cachexia.

[0008] The present invention provides the following solutions to the deficiencies of the existing technology:

[0009] A carbamo(dithioperoxo)thiolate compound, or a pharma- ceutical acceptable salt thereof, is The general formula I below:

[0010] [ka]

[0011] During the ceremony, m is in the range of 1 to 11, and may be in the range of 1 to 9; X is a nitrogen-containing aliphatic complex. It is a ring, and the nitrogen present in the ring is adjacent to the carbon of the thiocarbonyl group.

[0012] The carbamo(dithioperoxo)thiolate compound, or a pharma- ceutical acceptable salt thereof, In the salt, m is in the range of 3 to 5 and may be 5.

[0013] The carbamo(dithioperoxo)thiolate compound, or a pharma- ceutical acceptable salt thereof, In the salt, the aliphatic heterocycle may contain oxygen.

[0014] The carbamo(dithioperoxo)thiolate compound, or a pharma- ceutical acceptable salt thereof, The number of nitrogen atoms in the salt should be 1 to 2.

[0015] The carbamo(dithioperoxo)thiolate compound, or a pharma- ceutical acceptable salt thereof, Among the salts, the nitrogen-containing aliphatic heterocyclic ring is preferably selected from a saturated monocyclic aliphatic heterocyclic ring, or its fused ring or spiro derivative.

[0016] Among the carbamo(dithioperoxo)thiolate compounds, or pharmaceutically acceptable salts thereof, the nitrogen-containing saturated aliphatic heterocyclic ring has an atomic number in the range of 4 to 7, and is a saturated monocyclic aliphatic heterocyclic ring with an atomic number in the range of 4 to 6 is sufficient.

[0017] Among the carbamo(dithioperoxo)thiolate compounds, or pharmaceutically acceptable salts thereof, the nitrogen-containing saturated monocyclic aliphatic heterocyclic ring may have an atomic number in the range of 5 to 6. Furthermore , the nitrogen-containing saturated monocyclic aliphatic heterocyclic ring may have an atomic number of 5.

[0018] Among the carbamo(dithioperoxo)thiolate compounds, or pharmaceutically acceptable salts thereof, the nitrogen-containing saturated monocyclic aliphatic heterocyclic ring is preferably selected from pyrrolidine, substituted pyrrolidine, piperidine, morpholine, azetidine, piperazine. And the nitrogen-containing saturated fat aliphatic heterocyclic ring may be pyrrolidine.

[0019] Among the carbamo(dithioperoxo)thiolate compounds, or pharmaceutically acceptable salts thereof, the ring that combines with the nitrogen-containing saturated monocyclic aliphatic heterocyclic ring to form a fused heterocyclic ring or a spiro ring may have an atomic number in the range of 4 to 6.

[0020] Among the carbamo(dithioperoxo)thiolate compounds, or pharmaceutically acceptable salts thereof, the ring that combines with the nitrogen-containing saturated monocyclic aliphatic heterocyclic ring to form a fused heterocyclic ring or a spiro ring is preferably selected from the following.

[0021] [Chemical formula]

[0022] Among the above-mentioned carbamoyl(dithioperoxo)thiolate compounds or pharmaceutically acceptable salts, the nitrogen-containing aliphatic heterocyclic ring has a substituent and may be a hydroxy group or a C1-C4 alkyl group.

[0023] Among the above-mentioned carbamoyl(dithioperoxo)thiolate compounds or pharmaceutically acceptable salts, the nitrogen-containing aliphatic heterocyclic ring is preferably selected from pyrrolidine, substituted pyrrolidine, piperidine, morpholine , azetidine, piperazine, indoline, isoindoline, octahydro-1H-indole , octahydro-1H-isoindole, 2-oxa-6-azaspiro[3.4]octane .

[0024] The substituent of the above-mentioned pyrrolidine is preferably selected from a hydroxy group or a C1-C4 alkyl group.

[0025] The above-mentioned nitrogen-containing aliphatic heterocyclic ring is preferably selected from pyrrolidine, octahydro-1H-isoindole, azetidine , 2-oxa-6-azaspiro[3.4]octane. Furthermore, the nitrogen-containing aliphatic heterocyclic ring may be pyrrolidine.

[0026] The above-mentioned carbamoyl(dithioperoxo)thiolate compound or pharmaceutically acceptable salt is preferably selected from the following compounds or derivatives in which the nitrogen-containing aliphatic heterocyclic ring has a substituent .

[0027] [Chemical formula]

[0028]

Chem.

[0029] Preferably, the aforementioned substituent is selected from a hydroxy group or a C1-C8 alkyl group. More preferably, it is selected from a hydroxy group or a C1-C4 alkyl group.

[0030] The present invention also provides a method for producing a carbamodithiopercapto thioate compound or a pharmaceutically acceptable salt thereof. The production method is as follows: (1) Add the compound of formula II to a nitrogen-containing aliphatic heterocyclic compound, and then add carbon disulfide and triethylamine while stirring; (2) Add carbon tetrabromide while stirring; (3) After the reaction is completed, a carbamodithiopercapto thioate compound or a pharmaceutically acceptable salt thereof can be obtained.

[0031]

Chem.

[0032] (2) Add carbon tetrabromide while stirring; (3) After the reaction is completed, a carbamodithiopercapto thioate compound or a pharmaceutically acceptable salt thereof can be obtained. (3) After the reaction is completed, a carbamodithiopercapto thioate compound or a pharmaceutically acceptable salt thereof can be obtained.

[0033] In the aforementioned production method, the molar ratio of the compound having an aliphatic heterocyclic ring to the compound of formula II may be 1: (0.5-1.5); (0.5-1.5); The molar ratio of the compound having an aliphatic heterocyclic ring to carbon disulfide may be 1: (0.5-1.5); (0.5-1.5); The molar ratio of the compound having an aliphatic heterocyclic ring to triethylamine may be 1: (0.5-1.5) ; The molar ratio of the compound having an aliphatic heterocyclic ring to carbon tetrabromide may be 1: (1.5-2.5); (1.5-2.5).

[0034] In the above manufacturing method, steps (1) and (2) are carried out under ice bath conditions, and step (3) may be at room temperature.

[0035] In the above manufacturing method, step (1) may proceed in an organic solvent. The solvent may be dichloro methane or tetrahydrofuran.

[0036] In the above manufacturing method, the compound obtained in step (3) needs to be washed with water and saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate.

[0037] In the above manufacturing method, the reaction time of step (3) may be 1 to 3 hours; it is preferably carried out with stirring, and the stirring speed may be 800 - 1200 rpm.

[0038] In the above manufacturing method, after step (3) is completed, column chromatography is required, and the mobile phase used is composed of petroleum ether and dichloromethane, and the volume ratio may be (1 - 1 0):1; or the mobile phase is petroleum ether and ethyl acetate, and the volume ratio may be (3 - 25):1.

[0039] The present invention also provides a formulation of the above compound. The formulation is composed of a carbamodithiopero xothiolate compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, and the additive may be a pharmaceutically acceptable carrier, diluent or excipient.

[0040] The present invention also provides the application of the above carbamodithioxothiolate compound, or a pharmaceutically acceptable salt thereof, or the above formulation as an anti-cachexia drug, particularly an anti-cancer cachexia drug.

[0041] ​​​​ The term "thiocarbonyl group" in the present invention represents -CS-, and its structure is represented as follows :

[0042]

Chemical formula

[0043] The term "carbamodithio peroxo thioate" represents a compound having three sulfur atoms and its structure is represented as follows:

[0044]

Chemical formula

[0045] The term "cyclic compound" in the present invention represents a carbocyclic compound or a heterocyclic compound. The carbocyclic compound represents an aliphatic cyclic compound or an aromatic cyclic compound. The heterocyclic compound represents a heteroaliphatic cyclic compound or a heteroaromatic cyclic compound. The heteroaliphatic cyclic compound represents a heteroaliphatic cyclic compound or a heteroaromatic cyclic compound. The term "heterocycle" in the present invention represents an organic compound having a heterocycle. The atoms constituting the ring have at least one heteroatom in addition to carbon atoms, such as nitrogen atoms, sulfur atoms, and oxygen atoms. The heterocycle may include one ring, two rings, or a plurality of rings.

[0046] The term "aliphatic cyclic compound" in the present invention represents a cyclic hydrocarbon formed by intramolecular condensation of a chain hydrocarbon and its derivatives, and its derivatives, such as a saturated cyclic hydrocarbon (also called a saturated aliphatic ring) or an unsaturated cyclic hydrocarbon (also called an unsaturated aliphatic ring). Saturated cyclic hydrocarbons such as cycloalkane or cycloalkene have from three to seven carbons and heteroatoms and heteroatoms For example, saturated cyclic hydrocarbons such as cycloalkane or cycloalkene have from three to seven carbons and heteroatoms

[0047] The term "aliphatic cyclic compound" in the present invention represents a cyclic hydrocarbon formed by intramolecular condensation of a chain hydrocarbon and its derivatives, and its derivatives, such as a saturated cyclic hydrocarbon (also called a saturated aliphatic ring) or an unsaturated cyclic hydrocarbon (also called an unsaturated aliphatic ring). Saturated cyclic hydrocarbons such as cycloalkane or cycloalkene have from three to seven carbons and heteroatoms and heteroatoms For example, saturated cyclic hydrocarbons such as cycloalkane or cycloalkene have from three to seven carbons and heteroatoms and heteroatoms It may be a saturated cyclic hydrocarbon or an unsaturated cyclic hydrocarbon that does not contain a child, for example, cyclo Saturated cyclic hydrocarbons such as propane, cyclobutane, cyclopentane, and cyclohexane; cyclo Unsaturated cyclic hydrocarbons such as propene, cyclobutene, cyclopentene, cyclohexene, cyclobutadiene, and cyclo Pentadiene. The aliphatic ring may contain one ring, two rings, or Multiple rings.

[0048] The term "aromatic cyclic compound" in the present invention represents an aromatic molecule having a conjugated planar ring system and delocalized π electrons, for example, benzene, homologs of benzene, substituted benzene rings, condensed ring aromatic hydrocarbons, etc. Hydrocarbons.

[0049] The term "aliphatic heterocycle" in the present invention, also called an alicyclic heterocycle, represents a type of non-aromatic heterocyclic compound. The heterocyclic compound may contain one ring, two rings, or multiple rings. When the bond between atoms is a single bond, it is a saturated aliphatic heterocycle, or when it is a double bond, it is an unsaturated aliphatic heterocycle.

[0050] For the "aliphatic heterocycle", the term "aromatic heterocycle" in the present invention represents a heterocycle having aromaticity, specifically, a monocyclic molecule having delocalized π electrons by a completely conjugated planar multi-double bond.

[0051] The term "heterocyclic substituent" in the present invention represents a substituent formed by a heteroatom in a heterocycle losing hydrogen. For example, X bonded to the thiocarbonyl group in Claim 1 is also called a heterocyclic substituent.

[0052] The term "heteroatom" in the present invention represents nitrogen, oxygen, and sulfur.

[0053] ​​​​​​​​ The term "spiro ring" in the present invention refers to a polycyclic organic compound formed by two or more carbon rings or heterocyclic rings sharing one carbon atom. The rings sharing the carbon atom include a benzene ring and a benzene ring, a benzene ring and a heterocyclic ring, a benzene ring and an aliphatic ring, a heterocyclic ring and a heterocyclic ring, a heterocyclic ring and an aliphatic ring, and an aliphatic ring and an aliphatic ring. The rings sharing the carbon atom include a benzene ring and a benzene ring, a benzene ring and a heterocyclic ring, a benzene ring and an aliphatic ring, a heterocyclic ring and a heterocyclic ring, a heterocyclic ring and an aliphatic ring, and an aliphatic ring and an aliphatic ring. The rings sharing the carbon atom include a benzene ring and a benzene ring, a benzene ring and a heterocyclic ring, a benzene ring and an aliphatic ring, a heterocyclic ring and a heterocyclic ring, a heterocyclic ring and an aliphatic ring, and an aliphatic ring and an aliphatic ring. The rings sharing the carbon atom include a benzene ring and a benzene ring, a benzene ring and a heterocyclic ring, a benzene ring and an aliphatic ring, a heterocyclic ring and a heterocyclic ring, a heterocyclic ring and an aliphatic ring, and an aliphatic ring and an aliphatic ring.

[0054] The term "fused ring" in the present invention refers to a polycyclic organic compound formed by two or more carbon rings or heterocyclic rings sharing one ring edge. The rings sharing the ring edge include a benzene ring and a benzene ring, a benzene ring and a heterocyclic ring, a benzene ring and an aliphatic ring, a heterocyclic ring and a heterocyclic ring, a heterocyclic ring and an aliphatic ring, and an aliphatic ring and an aliphatic ring. The rings sharing the ring edge include a benzene ring and a benzene ring, a benzene ring and a heterocyclic ring, a benzene ring and an aliphatic ring, a heterocyclic ring and a heterocyclic ring, a heterocyclic ring and an aliphatic ring, and an aliphatic ring and an aliphatic ring. The rings sharing the ring edge include a benzene ring and a benzene ring, a benzene ring and a heterocyclic ring, a benzene ring and an aliphatic ring, a heterocyclic ring and a heterocyclic ring, a heterocyclic ring and an aliphatic ring, and an aliphatic ring and an aliphatic ring. The rings sharing the ring edge include a benzene ring and a benzene ring, a benzene ring and a heterocyclic ring, a benzene ring and an aliphatic ring, a heterocyclic ring and a heterocyclic ring, a heterocyclic ring and an aliphatic ring, and an aliphatic ring and an aliphatic ring.

[0055] The term "substituent" in the present invention includes a hydroxy group, a carboxyl group, a halo group, a cyano group, an alkyl group (C alkyl), an alkoxy group, an alkenyl group, an allyl group, a haloalkyl group, a haloalkoxy group, a heterocyclic alkyl group, a heterocyclic carbonyl group, a hydroxyalkyl group, a nitro group, and the like. 1-4 alkyl), an alkoxy group, an alkenyl group, an allyl group, a haloalkyl group, a haloalkoxy group, a heterocyclic alkyl group, a heterocyclic carbonyl group, a hydroxyalkyl group, a nitro group, and the like. alkyl), an alkoxy group, an alkenyl group, an allyl group, a haloalkyl group, a haloalkoxy group, a heterocyclic alkyl group, a heterocyclic carbonyl group, a hydroxyalkyl group, a nitro group, and the like. alkyl), an alkoxy group, an alkenyl group, an allyl group, a haloalkyl group, a haloalkoxy group, a heterocyclic alkyl group, a heterocyclic carbonyl group, a hydroxyalkyl group, a nitro group, and the like.

[0056] The term "compound of the present invention" in the present invention refers to the compound of formula I and its pharmaceutically acceptable enantiomers, diastereomers, and salts. The term "compound of the present invention" in the present invention refers to the compound of formula I and its pharmaceutically acceptable enantiomers, diastereomers, and salts.

[0057] The compound of the present invention may exist as a pharmaceutically acceptable salt, in the form of a water-soluble, oil-soluble or dispersible salt and zwitterions. "Pharmaceutically acceptable" means that there is no excessive toxicity, irritation or complication when contacted or used with a patient, and the expected effect is achieved. The compound of the present invention may exist as a pharmaceutically acceptable salt, in the form of a water-soluble, oil-soluble or dispersible salt and zwitterions. "Pharmaceutically acceptable" means that there is no excessive toxicity, irritation or complication when contacted or used with a patient, and the expected effect is achieved. The compound of the present invention may exist as a pharmaceutically acceptable salt, in the form of a water-soluble, oil-soluble or dispersible salt and zwitterions. "Pharmaceutically acceptable" means that there is no excessive toxicity, irritation or complication when contacted or used with a patient, and the expected effect is achieved.

[0058] The compound of the present invention, in addition to the compound of formula I and its pharmaceutically acceptable salts, may contain one or two pharmaceutically acceptable carriers, It can also be formulated into a preparation containing a pharmaceutically acceptable carrier, diluent or excipient. The aforementioned "pharmaceutically acceptable ability" means that there is no therapeutic toxicity, irritation reaction or complication to the patient, and it produces the expected effect .

[0059] The compound preparation of the present invention exists in the form of tablets, capsules, liquids, powders or aerosols, etc., and may also contain pharmaceutically inert carriers such as ethanol, glycerol, water, etc. If necessary, appropriate binders, neutralizing agents, flavors, preservatives, dispersants or coloring agents, etc. are also included.

[0060] The use of the present invention includes administering the compound preparation orally, rectally, nasally, locally (intraoral, sublingual or transdermal), etc., and it can be administered by a suitable administration route.

[0061] The term "room temperature" in the present invention represents 15 - 30 °C. Unless otherwise specified, all percentages used in the present invention are mass percentages.

[0062] The following abbreviations are used throughout the present invention: TLC: Thin layer chromatography, PE: Petroleum ether, EA: Ethyl acetate, Et3N : Triethylamine, DCM: Dichloromethane, Chloroform - d: Deuterated chloroform, 1 1H NMR: Proton nuclear magnetic resonance spectrum, 13 13C NMR: Carbon nuclear magnetic resonance spectrum, FBS: Fetal bovine serum, HS: Horse serum, DMEM: Dulbecco's modified Eagle's minimum essential medium, PBS: Phosphate - buffered saline, DMSO: Dimethyl sulfoxide, HE staining: Hematoxylin and eosin staining.

[0063] The advantages of the present invention are as follows: The compounds of the present invention have been found to reduce muscle atrophy and lipolysis caused by cancer cachexia in in vivo and in vitro experiments. Also, animal experiments have shown that they can significantly reduce the weight loss and decreased food intake caused by cancer cachexia. Thus, it is shown that the carbamodithio peroxo thioate compounds have an anti-cancer cachexia effect and can be used for the treatment of cancer cachexia and related diseases, and are ideal drugs for treating cancer cachexia.

Brief Description of the Drawings

[0064]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Mode for Carrying Out the Invention

[0065] In order to improve the drawbacks and deficiencies of the existing technology, the present invention provides a series of carbamoyl(dithioperoxo )thiolate compounds, a method for producing the same, and applications for the treatment of cachexia, particularly cancer cachexia and related diseases.

[0066] The present invention provides a new carbamoyl(dithioperoxo)thiolate compound having good anti-cachexia activity, particularly a carbamoyl(dithioperoxo) thiolate compound having a nitrogen-containing aliphatic heterocyclic ring as represented by Formula I.

[0067]

Chemical Formula

[0068] In the formula, m is in the range of 1 to 11 and may be in the range of 1 to 9.

[0069] X is a nitrogen-containing aliphatic heterocyclic ring, and the nitrogen present in the ring is adjacent to the carbon of the thiocarbonyl group.

[0070] Preferably, X is selected from a nitrogen-containing aliphatic 4-membered heterocyclic ring and its fused ring or spiro ring derivative, a nitrogen-containing aliphatic 5-membered heterocyclic ring and its fused ring or spiro ring derivative, and a nitrogen-containing aliphatic 6-membered heterocyclic ring and its fused ring or spiro ring derivative.

[0071] Most preferably, X is pyrrolidine, substituted pyrrolidine, piperidine, morpholine, azetidine, piperazine, indoline, isoindoline, octahydro-1H-indole, o​​​​ Kutahydro-1H-isoindole, 2-oxa-6-azaspiro[3.4]octane or selected.

[0072] The present invention provides the following compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15, 16, 17.

[0073]

Chemical formula

[0074]

Chemical formula

[0075] The present invention also provides the treatment of cachexia using carbamoyl(dithioperoxo)thiolate compounds, especially the treatment of cancer cachexia and related diseases.

[0076] The present invention also aims at a method for producing carbamoyl(dithioperoxo)thiolate compounds, especially carbamoyl(dithioperoxo)thiolate compounds having a nitrogen-containing aliphatic heterocyclic ring .

[0077] Taking Compound 1 as an example, the production method of the compounds of the present invention is shown below:

[0078]

Chemical formula

[0079] The pharmacological experimental methods used in the present invention are well known to those skilled in the art of this research field.

[0080] The C2C12 cells (mouse myoblasts), 3T3-L1 cells (mouse adipose cells) and C26 cells (mouse colon cancer cells) used in the present invention were purchased from the Cell Bank of Type Culture Collections, Chinese Academy of Sciences . They were introduced. BALB / c mice were purchased from Shanghai Lingchang Biotechnology Co., Ltd.

[0081] The petroleum ether (boiling point 60 - 90 °C) used in the present invention was purchased from Sinopharm Chemical Reagent Co., Ltd. Ltd.

[0082] FBS (fetal bovine serum) was purchased from Biological Industries Ltd. Ltd.

[0083] Horse serum was purchased from Gibco Ltd.

[0084] High - glucose DMEM medium was purchased from Hyclone Ltd.

[0085] RPMI - 1640 medium was purchased from Hyclone Ltd.

[0086] High - glucose DMEM medium without phenol red was purchased from Hyclone Ltd. Ltd.

[0087] P / S antibiotic (penicillin - streptomycin) was purchased from Hyclone Ltd. Ltd.

[0088] Dexamethasone was purchased from Sigma - Aldrich Co., Ltd.

[0089] IBMX (3 - isobutyl - 1 - methylxanthine), a broad - spectrum phosphodiesterase inhibitor was purchased from Sigma - Aldrich Co., Ltd.

[0090] Human recombinant insulin was purchased from Shanghai Jinmai Biotechnology Co., Ltd.

[0091] Glycerol detection kit was purchased from Beijing Prilai Genetic Engineering Co., Ltd.

[0092] The high-glucose DMEM medium containing 10% FBS was made of 10% FBS + 1% P / S + 89% high-glucose DMEM medium.

[0093] The RPMI 1640 medium containing 10% FBS was made of 10% FBS + 1% P / S + 89% RPMI-1640 medium.

[0094] The 2% HS differentiation induction medium was made of 2% HS + 1% P / S + 89% high-glucose D MEM medium.

[0095] The equipment used in the actual examples is shown below: Equipment used during synthesis: Rotary evaporator: Buchi, Rotavapor R-200; Column chromatography: silica gel (200 - 300 mesh) and thin-layer chromatography The TLC plates were purchased from Sinopharm Chemical Reagent Co., Ltd.

[0096] Equipment used for structural analysis and analysis: Fluorescence microscope: Olympus, IX-73. 1 H NMR, 13 C NMR: Varian Model Mercury 400 MHz.

[0097] The manufacturing method and application of the carbamoyl(dithioperoxo)thiolate compound of the present invention are exemplified as in the following actual examples.

[0098] [Example 1] Synthesis of Compound 1

[0099]

Chemical formula

[0100] Under ice bath conditions, pyrrolidine (58 μL, 0.70 mmol) and octan-1-thiol (122 μL, 0.70 mmol) were added to anhydrous dichloromethane (10 mL). Next, carbon disulfide (43 μL, 0.70 mmol) was added dropwise, and then triethylamine (108 μL, 0.77 mmol) was added slowly. After 5 minutes, a dichloromethane solution of CBr4 (466 mg, 1.41 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solution was washed with water (3 × 10 mL) and saturated NaCl solution (2 × 10 mL), and dried over sodium sulfate. The crude product was further purified by column chromatography (DCM: PE = 1:1). 121 mg of white solid was obtained in a yield of 59 .3%.

[0101] 1 H NMR (400 MHz, Chloroform-d): δ 3.97 (t, J = 7.0 Hz, 2H), 3.75 (t, J = 6.9 Hz , 2H), 2.86 (t, J = 7.4 Hz, 2H), 2.12 (p , J = 6.9 Hz, 2H), 2.00 (p, J = 6.9 Hz, 2H), 1.67 (p, J = 7.4 Hz, 2H), 1.39 (p, J = 6.9 Hz, 2H), 1.27 (q, J = 5.9, 5.3 H z, 8H), 0.88 (t, J = 6.6 Hz, 3H). [Example 2] Synthesis of Compound 2

[0102]

Chemical formula

[0103] Under ice bath conditions, pyrrolidine (58 μL, 0.70 mmol) and decane-1-thiol (146 μL, 0.70 mmol) were added to anhydrous dichloromethane (10 mL). Next, carbon disulfide (43 μL, 0.70 mmol) was added dropwise, and then triethylamine (108 μL, 0.77 mmol) was added slowly. After 5 minutes, a dichloromethane solution of CBr4 (466 mg, 1.41 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solution was washed with water (3 × 10 mL) and saturated NaCl solution (2 × 10 mL), and dried over sodium sulfate. The crude product was further purified by column chromatography (D CM: PE = 1:1). 139 mg of white solid was obtained in a yield of 62. 1%.

[0104] 1 H NMR (400 MHz, Chloroform-d): δ 3.97 (t, J = 7.0 Hz, 2H), 3.75 (t, J = 6.9 Hz , 2H), 2.86 (t, J = 7.4 Hz, 2H), 2.12 (p , J = 6.8 Hz, 2H), 2.00 (p, J = 6.9 Hz, 2H), 1.68 (q, J = 7.3 Hz, 2H), 1.39 (p, J = 6.9 Hz, 2H), 1.27 (d, J = 5.8 Hz, 12 H), 0.88 (t, J = 6.7 Hz, 3H). 13 C NMR (1 50 MHz, Chloroform-d): δ 193.02, 56.64, 50.53, 38.69, 31.89, 29.54, 29.49, 29.31 , 29.21, 28.63, 28.58, 26.51, 24.20, 22. 68, 14.12. [Example 3] Synthesis of Compound 3

[0105] [Chemical formula]

[0106] Under ice bath conditions, pyrrolidine (83 mg, 1.17 mmol) and undecane-1- thiol (219 mg, 1.17 mmol) were added to anhydrous dichloromethane (10 mL) . Next, carbon disulfide (71 μL, 1.17 mmol) was added dropwise, and then triethylamine (178 μL, 1.29 mmol) was slowly added. After 5 minutes, a dichloromethane solution of CBr4 (776 mg, 2.34 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solution was washed with water (3 × 10 mL) and saturated NaCl solution (2 × 10 mL), and dried over sodium sulfate. The crude product was further purified by column chromatography ( EA: PE = 1:25). 230 mg of white solid was obtained in a yield of 59 %.

[0107] 1 1H NMR (400 MHz, Chloroform-d) δ 3.68 ( t, J = 6.1 Hz, 2H), 3.39 (t, J = 6.0 Hz, 2H), 3.03 (t, J = 7.2 Hz, 2H), 1.90 - 1 .77 (m, 2H), 1.77 - 1.65 (m, 2H), 1.51 - 1.37 (m, 2H), 1.16 (s, 2H), 1.00 (s, 14H ), 0.62 (t, J = 5.5 Hz, 3H).13 C NMR (15 1 MHz, Chloroform-d) δ 192.86, 54.20, 49 .92, 35.98, 31.28, 28.97, 28.88, 28.70, 28.59, 28.36, 28.23, 25.40, 23.66, 22.05 , 13.48. [Example 4] Synthesis of Compound 4

[0108]

Chemical Structure

[0109] Under ice bath conditions, pyrrolidine (58 μL, 0.70 mmol) and dodecane-1-thiol (168 μL, 0.70 mmol) were added to anhydrous dichloromethane (10 mL). Next, carbon disulfide (43 μL, 0.70 mmol) was added dropwise, and then triethylamine (108 μL, 0.77 mmol) was added slowly. After 5 minutes, a dichloromethane solution of CBr4 (466 mg, 1.41 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solution was washed with water (3 × 10 mL) and saturated NaCl solution (2 × 10 mL), and dried over sodium sulfate. The crude product was further purified by column chromatography (DCM: PE = 1:1). 141 mg of a white solid was obtained in a yield of 58%. obtained.

[0110] 1 H NMR (400 MHz, Chloroform-d): δ 3.97 (t, J = 7.0 Hz, 2H), 3.75 (t, J = 6.8 Hz , 2H), 2.86 (t, J = 7.4 Hz, 2H), 2.12 (p ​​, J = 6.8 Hz, 2H), 2.00 (p, J = 6.6 Hz, 2H), 1.66 (p, J = 7.2 Hz, 2H), 1.38 (d, J = 7.8 Hz, 2H), 1.25 (s, 16H), 0.88 (t, J = 6.6 Hz, 3H). 13 C NMR (150 MHz, Chlo roform-d): δ 193.07, 56.63, 50.52, 38.73 , 31.92, 29.64, 29.59, 29.50, 29.35, 29. 22, 28.65, 28.59, 26.51, 24.20, 22.69, 1 4.12. [Example 5] Synthesis of Compound 5

[0111]

Chemical Structure

[0112] Under ice bath conditions, pyrrolidine (83 mg, 1.17 mmol) and tridecane-1- thiol (250 mg, 1.16 mmol) were added to anhydrous dichloromethane (10 mL) . Next, carbon disulfide (71 μL, 1.17 mmol) was added dropwise, and then triethylamine (178 μL, 1.29 mmol) was added slowly. After 5 minutes, a dichloromethane solution of CBr4 (776 mg, 2.34 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solution was washed with water (3 × 10 mL) and saturated NaCl solution (2 × 10 mL), and dried over sodium sulfate. The crude product was further purified by column chromatography( EA: PE = 1:25). 100 mg of a white solid was obtained in a yield of 27 %.

[0113] 1 1H NMR (400 MHz, Chloroform-d) δ 3.91 ( t, J = 6.8 Hz, 2H), 3.62 (t, J = 6.8 Hz, 2H), 3.26 (t, J = 7.4 Hz, 2H), 2.11 - 2 .00 (m, 2H), 1.96 (dd, J = 13.5, 6.7 Hz, 2H), 1.66 (dd, J = 14.7, 7.2 Hz, 2H), 1 .40 (dd, J = 14.8, 8.5 Hz, 2H), 1.24 (s, 18H), 0.85 (t, J = 6.3 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 192.71, 54.35 , 49.92, 36.15, 31.29, 29.04, 29.02, 28. 97, 28.88, 28.72, 28.59, 28.37, 28.23, 2 5.40, 23.67, 22.06, 13.48. [Example 6] Synthesis of Compound 6

[0114] [Chemical formula]

[0115] Under ice bath conditions, pyrrolidine (58 μL, 0.70 mmol) and tetradecane-1 -thiol (191 μL, 0.70 mmol) were added to anhydrous dichloromethane (10 mL ). Next, carbon disulfide (43 μL, 0.70 mmol) was added dropwise, and then , triethylamine (108 μL, 0.77 mmol) was slowly added. After 5 minutes , a dichloromethane solution of CBr4 (466 mg, 1.41 mmol) was added, and the mixture was stirred at room temperature. It was stirred at room temperature for 2 hours. The solution was washed with water (3 × 10 mL) and saturated NaCl solution (2 × 1 0 mL), and dried over sodium sulfate. The crude product was further purified by column chromatography (EA: PE = 1:1). 140 mg of white solid was obtained in a yield of 53 .1%.

[0116] 1 H NMR (400 MHz, Chloroform-d): δ 3.97 (t, J = 7.0 Hz, 2H), 3.75 (t, J = 6.9 Hz , 2H), 2.86 (t, J = 7.4 Hz, 2H), 2.12 (p , J = 6.9 Hz, 2H), 2.00 (p, J = 6.9 Hz, 2H), 1.68 (q, J = 7.4 Hz, 2H), 1.46 - 1. 34 (m, 2H), 1.26 (s, 20H), 0.93 - 0.83 ( m, 3H). 13 C NMR (150 MHz, Chloroform-d): δ 192.99, 56.63, 50.53, 38.69, 31.93, 2 9.69, 29.65, 29.58, 29.49, 29.36, 29.21, 28.64, 28.57, 26.51, 24.20, 22.69, 14.1 3. [Example 7] Synthesis of Compound 7

[0117] [Chemical formula]

[0118] Under ice bath conditions, pyrrolidine (58 μL, 0.70 mmol) and hexadecane-1 -Thiol (216 μL, 0.70 mmol) was added to anhydrous dichloromethane (10 mL ). Next, carbon disulfide (43 μL, 0.70 mmol) was added dropwise, and then , triethylamine (108 μL, 0.77 mmol) was added slowly. After 5 minutes , a dichloromethane solution of CBr4 (466 mg, 1.41 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solution was washed with water (3 × 10 mL), saturated NaCl solution (2 × 1 0 mL), and dried over sodium sulfate. The crude product was further purified by column chromatography (DCM: PE = 1:1). 161 mg of white solid was obtained in a yield of 5 6.8%.

[0119] 1 1H NMR (400 MHz, Chloroform-d): δ 3.97 (t, J = 7.0 Hz, 2H), 3.75 (t, J = 6.9 Hz , 2H), 2.86 (t, J = 7.4 Hz, 2H), 2.12 (p , J = 6.9 Hz, 2H), 2.00 (p, J = 6.9 Hz, 2H), 1.66 (p, J = 7.5 Hz, 2H), 1.40 (d, J = 7.4 Hz, 2H), 1.25 (s, 26H), 0.88 (t, J = 6.5 Hz, 3H). 13 13C NMR (150 MHz, Chlo roform-d): δ 193.06, 56.63, 50.52, 38.73 , 31.94, 29.70, 29.66, 29.59, 29.50, 29. 37, 29.22, 28.65, 28.59, 26.51, 24.20, 2 2.70, 14.12. [Example 8] Synthesis of Compound 8

[0120] [Chemical Formula]

[0121] Under ice bath conditions, pyrrolidine (58 μL, 0.70 mmol) and octadecane-1 -thiol (238 μL, 0.70 mmol) were added to anhydrous dichloromethane (10 mL ). Next, carbon disulfide (43 μL, 0.70 mmol) was added dropwise, and then , triethylamine (108 μL, 0.77 mmol) was added slowly. After 5 minutes , a dichloromethane solution of CBr4 (466 mg, 1.41 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solution was washed with water (3 × 10 mL), saturated NaCl solution (2 × 1 0 mL), and dried over sodium sulfate. The crude product was further purified by column chromatography (DCM: PE = 1:1). 154 mg of a white solid was obtained in a yield of 5 0.9%.

[0122] 1 H NMR (400 MHz, Chloroform-d): δ 3.97 (t, J = 7.0 Hz, 2H), 3.75 (t, J = 6.9 Hz , 2H), 2.86 (t, J = 7.4 Hz, 2H), 2.12 (p , J = 6.8 Hz, 2H), 2.00 (p, J = 6.9 Hz, 2H), 1.66 (p, J = 7.4 Hz, 2H), 1.38 (q, J = 7.1 Hz, 2H), 1.25 (s, 28H), 0.88 (t, J = 6.6 Hz, 3H). 13 C NMR (150 MHz, Chlo roform-d): δ 193.06, 56.63, 50.52, 38.73 , 31.94, 29.71, 29.67, 29.59, 29.50, 29. 37, 29.33, 29.22, 28.65, 28.59, 26.51, 2 4.20, 22.70, 14.12. [Example 9] Synthesis of Compound 9

[0123]

Chemical Structure

[0124] Under ice bath conditions, isoinoline (132 μL, 1.17 mmol) and dodecane- 1-thiol (237 mg, 1.17 mmol) were added to anhydrous dichloromethane (10 m L). Next, carbon disulfide (71 μL, 1.17 mmol) was added dropwise, and then triethylamine (178 μL, 1.29 mmol) was slowly added. After 5 minutes , a dichloromethane solution of CBr4 (776 mg, 2.34 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solution was washed with water (3 × 10 mL) and saturated NaCl solution (2 × 10 mL), and dried over sodium sulfate. The crude product was further purified by column chromatography -(EA: PE = 1:25). 270 mg of white solid was obtained in a yield of 58%.

[0125] 1 1H NMR (400 MHz, Chloroform-d) δ 7.38 - 7.26 (m, 4H), 5.24 (s, 2H), 5.07 (s, 2H ), 2.89 (t, J = 7.1 Hz, 2H), 1.79 - 1.63 (m, 2H), 1.40 (s, 2H), 1.25 (s, 16H), 0 .88 (t, J = 6.2 Hz, 3H). 13 C NMR (151 MH z, Chloroform-d) δ 193.52, 134.19, 127.3 8, 122.11, 61.32, 54.98, 38.05, 31.29, 2 9.02, 29.01, 28.96, 28.87, 28.72, 28.58, 28.05, 27.95, 22.07, 13.50. [Example 10] Synthesis of Compound 10

[0126] [Chemical Formula]

[0127] Under ice bath conditions, indoline (130 μL, 1.17 mmol) and dodecane-1- thiol (237 mg, 1.17 mmol) were added to anhydrous dichloromethane (10 mL). Next, carbon disulfide (71 μL, 1.17 mmol) was added dropwise, and then triethylamine (178 μL, 1.29 mmol) was added slowly. After 5 minutes, a dichloromethane solution of CBr4 (776 mg, 2.34 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solution was washed with water (3 × 20 mL) and saturated NaCl solution (2 × 10 mL), and dried over sodium sulfate. The crude product was further purified by column chromatography ( EA: PE = 1:25). 125 mg of a yellow oil was obtained in a yield of 27%.

[0128] 1 H NMR (400 MHz, Chloroform-d) δ 7.12 ( t, J = 7.4 Hz, 1H), 7.06 (d, J = 6.7 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.73 (t, J = 7.0 Hz, 1H), 3.70 (t, J = 8.4 Hz, 2 H), 3.01 (t, J = 8.2 Hz, 2H), 2.69 (t, J = 7.3 Hz, 2H), 1.62 - 1.54 (m, 2H), 1.3 8 (s, 2H), 1.25 (s, 16H), 0.88 (s, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 151.76 , 128.69, 126.84, 123.85, 118.35, 108.67 , 56.19, 34.68, 31.32, 29.04, 28.99, 28. 92, 28.75, 28.69, 28.33, 28.19, 27.78, 2 2.09, 13.53. [Example 11] Synthesis of Compound 11

[0129] [Chemical formula]

[0130] Under ice bath conditions, 2-oxa-6-azaspiro[3.4]octane (132 mg, 1 .17 mmol) and dodecane-1-thiol (237 mg, 1.17 mmol) were added to anhydrous dichloromethane (10 mL). Next, carbon disulfide (71 μL, 1. 17 mmol) was added dropwise, and then triethylamine (178 μL, 1.29 m mol) was slowly added. After 5 minutes, CBr4 (776 mg, 2.34 mmol ) The dichloromethane solution was added, and the mixture was stirred at room temperature for 2 hours. The solution was washed with water (3 × 20 mL ), saturated NaCl solution (2 × 10 mL), and dried over sodium sulfate. The crude product was further purified by column chromatography (EA: PE = 1:3) . 180 mg of white solid was obtained in 40% yield.

[0131] 1 H NMR (400 MHz, Chloroform-d) δ 4.43 ( ddd, J = 19.4, 17.9, 6.1 Hz, 4H), 3.96 ( s, 1H), 3.75 (s, 2H), 3.55 (t, J = 6.7 H z, 1H), 2.61 (t, J = 6.9 Hz, 2H), 2.19 ( t, J = 6.8 Hz, 1H), 2.06 (t, J = 7.0 Hz, 1H), 1.42 (s, 2H), 1.15 (s, 2H), 1.01 ( s, 16H), 0.64 (t, J = 6.3 Hz, 3H). 13 C N MR (151 MHz, Chloroform-d) δ 193.52, 79. 55, 63.48, 57.81, 54.22, 48.50, 45.78, 4 3.13, 38.04, 35.42, 33.17, 31.17, 29.00, 28.94, 28.85, 28.71, 28.57, 28.03, 27.9 2, 22.05, 13.49. [Example 12] Synthesis of Compound 12

[0132] [Chemical formula]

[0133] Under ice bath conditions, octahydro-1H-isoindole (147 mg, 1.17 m mol) and dodecane-1-thiol (237 mg, 1.17 mmol) were added to anhydrous dich loromethane (10 mL). Next, carbon disulfide (71 μL, 1.17 mm ol) was added dropwise, and then triethylamine (178 μL, 1.29 mmol) was added slowly. After 5 minutes, a dichlor loromethane solution of CBr4 (776 mg, 2.34 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solution was washed with water (3 × 20 mL) and saturated N aCl solution (2 × 10 mL), and dried over sodium sulfate. The crude product was further purified by column chromatography (EA: PE = 1:25). 360 mg of a yellow oil was obtained in a yield of 76%.

[0134] 1 H NMR (400 MHz, Chloroform-d) δ 3.66 ( dd, J = 12.9, 7.4 Hz, 1H), 3.56 (dd, J = 13.2, 6.3 Hz, 1H), 3.50 - 3.39 (m, 1H), 3.32 (dd, J = 11.1, 5.7 Hz, 1H), 2.56 ( t, J = 7.3 Hz, 2H), 2.08 (ddd, J = 33.1, 11.8, 5.9 Hz, 2H), 1.36 (dd, J = 14.4, 7.5 Hz, 4H), 1.27 - 1.06 (m, 8H), 0.95 ( s, 16H), 0.58 (t, J = 6.4 Hz, 3H). 13 C N MR (151 MHz, Chloroform-d) δ 193.54, 59. ​76, 53.96, 38.06, 37.53, 35.14, 31.30, 2 9.03, 29.01, 28.96, 28.88, 28.73, 28.59, 28.03, 27.95, 25.07, 24.92, 22.07, 21.9 8, 21.70, 13.51. [Example 13] Synthesis of Compound 13

[0135] [Chemical formula]

[0136] Under ice bath conditions, 3-hydroxypyrrolidine (174 mg, 2 mmol) and dodecane-1-thiol (404 mg, 2 mmol) were added to anhydrous dichloromethane (10 mL). Next, carbon disulfide (152 mg, 2 mmol) was added dropwise, and then triethylamine (204 mg, 2.2 mmol) was added slowly. After 5 minutes, a dichloromethane solution of CBr4 (1326 mg, 4 mmol) was added, and the mixture was stirred at room temperature for 2 hours. ( The solution was washed with water (3 × 10 mL) and saturated NaCl solution (2 × 10 mL), and dried over sodium sulfate. The crude product was further purified by column chromatography (DCM: PE = 1:6). 150 mg of white solid was obtained in a yield of 22%. ( ( ( (

[0137] 1 1H NMR (400 MHz, Chloroform-d) δ 4.60 ( s, 1H), 4.25 - 3.77 (overlap, 4H), 2.85 (t, J = 7.1 Hz, 2H), 2.30 - 1.79 (overla p, 3H), 1.72 - 1.61 (m, 2H), 1.44 - 1.35 (m, 2H), 1.25 (s, 16H), 0.88 (t, J = 6.3 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d ) δ 194.12, 71.41, 68.99, 64.58, 54.18, 48.39, 38.73, 31.92, 29.64, 29.59, 29.50 , 29.35, 29.22, 28.67, 28.58, 22.69, 14. 12. [Example 14] Synthesis of Compound 14

[0138] [Chemical formula]

[0139] Under ice bath conditions, piperidine (100 mg, 1.17 mmol) and dodecane-1- thiol (237 mg, 1.17 mmol) were added to anhydrous dichloromethane (10 mL) . Next, carbon disulfide (71 μL, 1.17 mmol) was added dropwise, and then triethylamine (178 μL, 1.29 mmol) was slowly added. After 5 minutes, a dichloromethane solution of CBr4 (776 mg, 2.34 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solution was washed with water (3 × 20 mL) and saturated NaCl solution (2 × 10 mL), and dried over sodium sulfate. The crude product was further purified by column chromatography ( EA: PE = 1:25). 210 mg of a white solid was obtained in a yield of 50 %.

[0140] 11H NMR (400 MHz, Chloroform-d) δ 4.33 ( s, 2H), 3.99 (s, 2H), 2.86 (t, J = 6.1 H z, 2H), 1.89 - 1.58 (m, 8H), 1.40 (s, 2H ), 1.27 (s, 16H), 0.89 (s, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 195.98, 54.55, 51.21, 38.16, 31.27, 29.00, 28.98, 28.9 4, 28.85, 28.70, 28.56, 27.94, 25.62, 24 .86, 23.55, 22.04, 13.48. [Example 15] Synthesis of Compound 15

[0141] [Chemical formula]

[0142] Under ice bath conditions, morpholine (100 mg, 1.17 mmol) and dodecan-1-thiol (237 mg, 1.17 mmol) were added to anhydrous dichloromethane (10 mL). Next, carbon disulfide (71 μL, 1.17 mmol) was added dropwise, and then triethylamine (178 μL, 1.29 mmol) was added slowly. After 5 minutes, a dichloromethane solution of CBr4 (776 mg, 2.34 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solution was washed with water (3 × 20 mL) and saturated NaCl solution (2 × 10 mL), and dried over sodium sulfate. The crude product was further purified by column chromatography (E A: PE = 1:25). 210 mg of a white solid was obtained in a 50% yield . ​

[0143] 1 H NMR (400 MHz, Chloroform-d) δ 4.36 ( s, 2H), 4.07 (s, 2H), 3.79 (s, 4H), 2.86 (t, J = 7.2 Hz, 2H), 1.73 - 1.58 (m, 2H ), 1.40 (s, 2H), 1.26 (s, 16H), 0.89 (t, J = 6.4 Hz, 3H). 13 C NMR (151 MHz, Chlo roform-d) δ 197.65, 65.65, 52.62, 50.54, 38.11, 31.27, 29.00, 28.98, 28.93, 28.8 4, 28.70, 28.55, 27.99, 27.92, 22.04, 13 .49. [Example 16] Synthesis of Compound 16

[0144]

Chemical Structure

[0145] Under ice bath conditions, 4-methylpiperazine (180 mg, 1.8 mmol) and dodecane-1-thiol (363 mg, 1.8 mmol) were added to anhydrous dichloromethane (10 mL). Next, carbon disulfide (139 mg, 1.8 mmol) was added dropwise, and then triethylamine (200 mg, 1.98 mmol) was added slowly. After 5 minutes, a dichloromethane solution of CBr4 (1200 mg, 3.6 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solution was washed with water (3 × 10 mL) and saturated NaCl solution (2 × 10 mL), and dried over sodium sulfate. The crude product was purified by column chromatography ​​​ It was further purified by EtOAc (DCM:PE = 1:3). 270 mg of a white solid was obtained in a yield of 40%.

[0146] 1 H NMR (400 MHz, Chloroform-d) δ 4.21 ( brs, 4H), 2.85 (t, J = 7.2 Hz, 2H), 2.53 (s, 4H), 2.34 (s, 3H), 1.76 - 1.55 (m, 2H), 1.39 (s, 2H), 1.25 (s, 16H), 0.87 ( d, J = 6.8 Hz, 3H). 13 C NMR (151 MHz, Ch loroform-d) δ 197.65, 54.45, 45.62, 38.7 5, 31.92, 29.65, 29.63, 29.58, 29.49, 29 .35, 29.21, 28.60, 28.57, 22.69, 14.13. [Example 17] Synthesis of Compound 17

[0147]

Chemical formula

[0148] Azetidine hydrochloride (187 mg, 2 mmol) and potassium hydroxide (112 mg , 2 mmol) were mixed in THF (10 mL) and stirred for 2 hours. The resulting azetidine was added to dodecane-1-thiol (0.48 mL, 2 mmol) and anhydrous dichloromethane (10 mL) under ice bath conditions. Next, carbon disulfide (0.12 mL, 2 mmol) was added dropwise, and then triethylamine (0.31 mL, 2.2 mmol was added slowly. After 5 minutes, a dichloromethane solution of CBr4 (1300 mg, 4 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solution was washed with water (3 × 10 mL) and saturated NaCl solution (2 × 10 mL), and dried over sodium sulfate. The crude product was further purified by column chromatography (DCM: PE = 1:8). 270 mg of pale yellow solid was obtained in 40% yield. The solution was washed with water (3 × 10 mL) and saturated NaCl solution (2 × 10 mL), and dried over sodium sulfate. The crude product was further purified by column chromatography (DCM: PE = 1:8). 270 mg of pale yellow solid was obtained in 40% yield. The solution was washed with water (3 × 10 mL) and saturated NaCl solution (2 × 10 mL), and dried over sodium sulfate. The crude product was further purified by column chromatography (DCM: PE = 1:8). 270 mg of pale yellow solid was obtained in 40% yield. The solution was washed with water (3 × 10 mL) and saturated NaCl solution (2 × 10 mL), and dried over sodium sulfate. The crude product was further purified by column chromatography (DCM: PE = 1:8). 270 mg of pale yellow solid was obtained in 40% yield.

[0149] 1 1H NMR (400 MHz, Chloroform-d) δ 4.35 (t, J = 7.6 Hz, 4H), 2.83 (t, J = 7.5 Hz, 2H), 2.49 - 2.39 (m, 2H), 1.72 - 1.62 (m, 2H), 1.38 (brs, 2H), 1.25 (s, 16H), 0.88 (s, 3H). 1H NMR (400 MHz, Chloroform-d) δ 4.35 (t, J = 7.6 Hz, 4H), 2.83 (t, J = 7.5 Hz, 2H), 2.49 - 2.39 (m, 2H), 1.72 - 1.62 (m, 2H), 1.38 (brs, 2H), 1.25 (s, 16H), 0.88 (s, 3H). 1H NMR (400 MHz, Chloroform-d) δ 4.35 (t, J = 7.6 Hz, 4H), 2.83 (t, J = 7.5 Hz, 2H), 2.49 - 2.39 (m, 2H), 1.72 - 1.62 (m, 2H), 1.38 (brs, 2H), 1.25 (s, 16H), 0.88 (s, 3H). 1H NMR (400 MHz, Chloroform-d) δ 4.35 (t, J = 7.6 Hz, 4H), 2.83 (t, J = 7.5 Hz, 2H), 2.49 - 2.39 (m, 2H), 1.72 - 1.62 (m, 2H), 1.38 (brs, 2H), 1.25 (s, 16H), 0.88 (s, 3H). 1H NMR (400 MHz, Chloroform-d) δ 4.35 (t, J = 7.6 Hz, 4H), 2.83 (t, J = 7.5 Hz, 2H), 2.49 - 2.39 (m, 2H), 1.72 - 1.62 (m, 2H), 1.38 (brs, 2H), 1.25 (s, 16H), 0.88 (s, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 193.88, 56.11, 53.94, 39.10, 31.92, 29.65, 29.58, 29.50, 29.35, 29.20, 28.68, 28.54, 22.69, 15.77, 14.12. 13C NMR (151 MHz, Chloroform-d) δ 193.88, 56.11, 53.94, 39.10, 31.92, 29.65, 29.58, 29.50, 29.35, 29.20, 28.68, 28.54, 22.69, 15.77, 14.12. 13C NMR (151 MHz, Chloroform-d) δ 193.88, 56.11, 53.94, 39.10, 31.92, 29.65, 29.58, 29.50, 29.35, 29.20, 28.68, 28.54, 22.69, 15.77, 14.12. 13C NMR (151 MHz, Chloroform-d) δ 193.88, 56.11, 53.94, 39.10, 31.92, 29.65, 29.58, 29.50, 29.35, 29.20, 28.68, 28.54, 22.69, 15.77, 14.12. [Example 18] The carbamodithio peroxo thioate analogues were evaluated for their ability to alleviate atrophy of mouse myoblasts (C2C12) induced by mouse colon cancer cells (C26) using a diameter measurement method. The staining method used in the experiment was hematoxylin and eosin staining, also known as HE staining. Hematoxylin staining is basic and positively charged, and binds to acidic deoxyribonucleic acid (DNA) with a negative charge in the cell nucleus. The carbamodithio peroxo thioate analogues were evaluated for their ability to alleviate atrophy of mouse myoblasts (C2C12) induced by mouse colon cancer cells (C26) using a diameter measurement method. The staining method used in the experiment was hematoxylin and eosin staining, also known as HE staining. Hematoxylin staining is basic and positively charged, and binds to acidic deoxyribonucleic acid (DNA) with a negative charge in the cell nucleus. The carbamodithio peroxo thioate analogues were evaluated for their ability to alleviate atrophy of mouse myoblasts (C2C12) induced by mouse colon cancer cells (C26) using a diameter measurement method. The staining method used in the experiment was hematoxylin and eosin staining, also known as HE staining. Hematoxylin staining is basic and positively charged, and binds to acidic deoxyribonucleic acid (DNA) with a negative charge in the cell nucleus. The carbamodithio peroxo thioate analogues were evaluated for their ability to alleviate atrophy of mouse myoblasts (C2C12) induced by mouse colon cancer cells (C26) using a diameter measurement method. The staining method used in the experiment was hematoxylin and eosin staining, also known as HE staining. Hematoxylin staining is basic and positively charged, and binds to acidic deoxyribonucleic acid (DNA) with a negative charge in the cell nucleus. The carbamodithio peroxo thioate analogues were evaluated for their ability to alleviate atrophy of mouse myoblasts (C2C12) induced by mouse colon cancer cells (C26) using a diameter measurement method. The staining method used in the experiment was hematoxylin and eosin staining, also known as HE staining. Hematoxylin staining is basic and positively charged, and binds to acidic deoxyribonucleic acid (DNA) with a negative charge in the cell nucleus. Eosin, on the other hand, is an acid dye that binds easily to negatively charged ions in water and gives a blue color; It dissociates into red and easily binds to the amino groups of positively charged proteins in the cytoplasm, producing a red stain. The stained cells were placed under a high-power microscope (magnification: 400) and photographed. The diameter of myotubes was counted using software.

[0150] By the above method, the therapeutic effect of a drug on a muscle atrophy cell model can be evaluated. The method is shown below.

[0151] C2C12 cells were cultured in 24-well plates in a high glucose culture medium containing 10% FBS and 1% P / S. The cells were inoculated into DMEM medium and placed in a 5% CO2, 37°C environment. When the cell culture reached 60%, the medium was changed to high glucose DMEM medium containing 2% HS and 1% P / S. The differentiation medium was changed every 48 hours until maturation on the 5th or 6th day. , C26 cells were cultured in a T75 flask in high glucose DMEM containing 10% FBS and 1% P / S. C26 cells (6 × 10 6 cell While subculturing the cells (1 flask / cell), 20 mL of medium was added and the cells were subcultured for 48 hours. The supernatant was separated by centrifuging the C26 medium at 1000 rpm for 3 min and then at 4000 rpm for 10 min. The C26 supernatant and 2% HS differentiation medium were mixed at a 1:1 (volume ratio) to form a muscle atrophy induction medium. The control group was added with 2% HS differentiation medium, and the other groups were added with an equal amount of muscle atrophy-inducing medium. One of them was the model group, and the other was the experimental group, which was administered the drug. Carbamo(dithioperoxo)thioate compounds were added to the cells in the following concentration gradients:

[0152]

Table 1-1

[0153]

Table 1-2

[0154]

Table 1-3

[0155] Here, the Cyrillic numbers correspond to the drawing numbers, that is, Figure 1-46 corresponds to the Cyrillic numbers 1- 46 in Table 1. μM means μmol / L.

[0156] Wherein, the serial numbers correspond to the numbers of the accompanying figures es, that is, Figure 1-46 corresponds to the samples of serial numbers 1-46 in Table 1. μM refers to μmol / L. The method for measuring the diameter of the muscle tube is as follows: After reacting for 48 hours, the muscle tube was fixed with a fixing solution (volume ratio of absolute ethanol: formaldehyde: glacial acetic acid = 20:2:1) for 1 hour or more, stained with hematoxylin-eosin staining method, and placed under a high magnification microscope to obtain an image, and the diameter of the muscle tube was counted using image J. The reversal rate of muscle atrophy was calculated by the following formula.

[0157] Reversal rate of muscle atrophy = (average value of muscle tubes in the drug administration group - average value of muscle tubes in the model group) / (average value of muscle tubes in the control group - average value of muscle tubes in the model group) × 100% Results and conclusions: Figures 1-46 show the reduction of C2C12 mature myotube atrophy induced by C26 cell culture medium It is a representative image of HE staining of carbamoyl(dithiopero)thioate analogs that reduce myotube atrophy. Table 2 shows the myotube statistical results. From Figures 1-46 and Table 2, carbamoyl(dithiopero)thioate analogs showed a significant reversal effect on muscle atrophy in a concentration-dependent manner. Based on the following results, it was found that long-chain substituted carbamoyl(dithiopero)thioate basically showed a good reversal effect on muscle atrophy. However, its effect is closely correlated with the chain length. Among them, compound 4 showed the most significant effect with a 92.83% muscle atrophy reversal rate under a cell-free cytotoxic concentration of 12.5 μM. This compound is expected as a candidate for further research and development. However, when the chain length was 18 carbon atoms (compound 8), the activity decreased.

[0158]

Table 2

[0159] [Example 19] Experimental results of compound 4 relaxing lipolysis in 3T3-L1 adipocytes The intracellular lipid content was evaluated by glycerol assay. Glycerol is phosphorylated by glycerol kinase to become glycerol 3-phosphate. Glycerol 3-phosphate is oxidized by glycerol phosphate oxidase to produce hydrogen peroxide. In the presence of peroxidase, the chromogenic substrate is converted to benzoquinone imine, and its optical density is directly proportional to the glycerol concentration.

[0160] The effect of drugs on the lipolysis cell model can be evaluated by the above method. The method is as follows: as follows: ​​​​​3T3-L1 cells were seeded in high-glucose DMEM medium containing 10% FBS and 1% P / S in a 6-well plate and placed in an environment of 5% CO2 at 37°C. After the cells reached confluence, they were allowed to fuse for another 3 days to initiate differentiation induction. For the first differentiation, 3T3-L1 cells were differentiated in high-glucose DMEM medium containing 0.5 mM IBMX, 5 mg / mL insulin, 1 μM dexamethasone, 10% FBS and 1% P / S for 72 hours; for the second differentiation, 3T3-L1 cells were differentiated in high-glucose DMEM medium containing 5 mg / mL insulin, 10% FBS and 1% P / S for 72 hours; for the third differentiation, 3T3-L1 cells were differentiated in high-glucose DMEM medium containing 10% FBS and 1% P / S for 72 hours. After the differentiation was completed, a large number of oil droplets were found in the cells. Also, C26 cells were seeded in high-glucose DMEM medium containing 10% FBS and 1% P / S in a T75 flask and placed in an environment of 5% CO2 at 37°C. While subculturing C26 cells (6×10 cells / flask), 15 mL of high-glucose DMEM medium without phenol red was added to the T75 flask with confluent cells and subcultured for 48 hours. The C26 supernatant was obtained by centrifuging the C26 medium at 1000 rpm for 3 minutes and then at 4000 rpm for 10 minutes. The C26 supernatant and high-glucose DMEM medium without phenol red were mixed at a ratio of 1:1 (volume ratio) as a lipolysis induction medium. High-glucose DMEM medium without phenol red was added to the control group, and an equal amount of lipolysis induction medium was added to each of the other groups. Among them, one was used as a model group, and the rest were used as experimental groups to administer drugs. At the same time, the stock solution of compound 4 was added to the cells at a concentration gradient of 12.5 μM, 25 μM, 50 μM, and 100 μM. After the cells reached confluence, they were allowed to fuse for another 3 days to initiate differentiation induction. For the first differentiation, 3T3-L1 cells were differentiated in high-glucose DMEM medium containing 0.5 mM IBMX, 5 mg / mL insulin, 1 μM dexamethasone, 10% FBS and 1% P / S for 72 hours; for the second differentiation, 3T3-L1 cells were differentiated in high-glucose DMEM medium containing 5 mg / mL insulin, 10% FBS and 1% P / S for 72 hours; for the third differentiation, 3T3-L1 cells were differentiated in high-glucose DMEM medium containing 10% FBS and 1% P / S for 72 hours. After the differentiation was completed, a large number of oil droplets were found in the cells. Also, C26 cells were seeded in high-glucose DMEM medium containing 10% FBS and 1% P / S in a T75 flask and placed in an environment of 5% CO2 at 37°C. While subculturing C26 cells (6×10 cells / flask), 15 mL of high-glucose DMEM medium without phenol red was added to the T75 flask with confluent cells and subcultured for 48 hours. The C26 supernatant was obtained by centrifuging the C26 medium at 1000 rpm for 3 minutes and then at 4000 rpm for 10 minutes. The C26 supernatant and high-glucose DMEM medium without phenol red were mixed at a ratio of 1:1 (volume ratio) as a lipolysis induction medium. High-glucose DMEM medium without phenol red was added to the control group, and an equal amount of lipolysis induction medium was added to each of the other groups. 6 Among them, one was used as a model group, and the rest were used as experimental groups to administer drugs. At the same time, the stock solution of compound 4 was added to the cells at a concentration gradient of 12.5 μM, 25 μM, 50 μM, and 100 μM. ​​​​​​​

[0161]

Table 3

[0162] The method for detecting glycerol is as follows: After reacting for 48 hours, the glycerol content in the supernatant was detected using a glycerol detection kit purchased from Beijing Applygen Technologies Co., Ltd.

[0163] Results and conclusions: Refer to Drawing 47.

[0164] Drawing 47 shows the glycerol detection results of Compound 4. As shown in Drawing 47, Compound 4 was found to dose-dependently decrease the glycerol released from 3T3-L1 mature adipocytes induced by C26 cell culture medium. The cellular glycerol contents of the control group, model group, experimental group 1, experimental group 2, experimental group 3, and experimental group 4 were 287.44 μM, 441.95 μM, 379.44 μM, 347.14 μM, 313.67 μM, and 310.95 μM, respectively.

[0165] [Example 20] The experimental results and method of the cancer cachexia animal model administered with Compound 4 are as follows: C26 cells were inoculated into RPMI-1640 medium containing 10% FBS and 1% P / S in a T75 flask and placed in an environment of 5% CO2 at 37°C. The C26 medium was centrifuged at 1000 rpm for 3 minutes, and the remaining medium was washed with ice-cold PBS buffer. The obtained C26 cells were prepared into a cell suspension at 1×10 cells / mL. For subsequent inoculation, the cell suspension was adjusted to 1×10 7 ​​​​​​​​​​​​​6 In cells / mice, it was inoculated under the left and right armpits of BALB / c mice. When the tumor reached approximately 800 c m 3 , the tumor was removed and homogenized in 3.5 mL of ice-cold physiological saline to obtain a tumor tissue suspension. The mice to be inoculated were grouped based on body weight, and the cell suspension was inoculated under the left armpit of BALB / c mice at 100 μL / mouse. Drug administration started on the day after inoculation. After dissolving compound 4 in DMSO, it was mixed with preheated PBS solution (37 °C) to form a homogeneous and stable solution at a final concentration of 1 mg / mL (3% DMSO + 2% absolute ethanol + 1% polyoxyethylene hydrogenated castor oil). The dosage was 5 mg / kg, and the administration route was intragastric administration (i.g). The body weight, body temperature, tumor size, and food intake of the mice were monitored daily. The mice in the model group were judged to have terminal cachexia due to a weight loss of approximately 10% after 16 days. After measuring the grip strength of the limb muscles of the mice, the mice were sacrificed by cervical dislocation, and samples of gastrocnemius muscle, epididymal fat, and tumor were taken out and weighed. The method for measuring muscle grip strength was as follows: The researcher firmly grasped the mouse with the right hand, placed the mouse on the "YLS-13A rat and mouse grip strength measuring instrument", and while stabilizing the gripping plate with the left hand, the mouse's forelimbs grasped the gripping plate firmly. Then, the researcher slowly released the left hand from the gripping plate and immediately pulled the mouse's tail slowly backward with the right hand. Finally, the mouse's forelimbs left the gripping plate and the grip strength was measured. Each mouse was repeated 8 times, and the average value of the 8 times was the skeletal muscle strength index of each mouse. Results and conclusions: The three curves in Figures 48 - 58 are the healthy group, C26 tumor model group, and In cells / mice, it was inoculated under the left and right armpits of BALB / c mice. When the tumor reached approximately 800 c m , the tumor was removed and homogenized in 3.5 mL of ice-cold physiological saline to obtain a tumor tissue suspension. The mice to be inoculated were grouped based on body weight, and the cell suspension was inoculated under the left armpit of BALB / c mice at 100 μL / mouse. Drug administration started on the day after inoculation. After dissolving compound 4 in DMSO, it was mixed with preheated PBS solution (37 °C) to form a homogeneous and stable solution at a final concentration of 1 mg / mL (3% DMSO + 2% absolute ethanol + 1% polyoxyethylene hydrogenated castor oil). The dosage was 5 mg / kg, and the administration route was intragastric administration (i.g). The body weight, body temperature, tumor size, and food intake of the mice were monitored daily. The mice in the model group were judged to have terminal cachexia due to a weight loss of approximately 10% after 16 days. After measuring the grip strength of the limb muscles of the mice, the mice were sacrificed by cervical dislocation, and samples of gastrocnemius muscle, epididymal fat, and tumor were taken out and weighed. The method for measuring muscle grip strength was as follows: The researcher firmly grasped the mouse with the right hand, placed the mouse on the "YLS-13A rat and mouse grip strength measuring instrument", and while stabilizing the gripping plate with the left hand, the mouse's forelimbs grasped the gripping plate firmly. Then, the researcher slowly released the left hand from the gripping plate and immediately pulled the mouse's tail slowly backward with the right hand. Finally, the mouse's forelimbs left the gripping plate and the grip strength was measured. Each mouse was repeated 8 times, and the average value of the 8 times was the skeletal muscle strength index of each mouse. Results and conclusions: The three curves in Figures 48 - 58 are the healthy group, C26 tumor model group, and In cells / mice, it was inoculated under the left and right armpits of BALB / c mice. When the tumor reached approximately 800 c m

[0166] In cells / mice, it was inoculated under the left and right armpits of BALB / c mice. When the tumor reached approximately 800 c m , the tumor was removed and homogenized in 3.5 mL of ice-cold physiological saline to obtain a tumor tissue suspension. The mice to be inoculated were grouped based on body weight, and the cell suspension was inoculated under the left armpit of BALB / c mice at 100 μL / mouse. Drug administration started on the day after inoculation. After dissolving compound 4 in DMSO, it was mixed with preheated PBS solution (37 °C) to form a homogeneous and stable solution at a final concentration of 1 mg / mL (3% DMSO + 2% absolute ethanol + 1% polyoxyethylene hydrogenated castor oil). The dosage was 5 mg / kg, and the administration route was intragastric administration (i.g). The body weight, body temperature, tumor size, and food intake of the mice were monitored daily. The mice in the model group were judged to have terminal cachexia due to a weight loss of approximately 10% after 16 days. After measuring the grip strength of the limb muscles of the mice, the mice were sacrificed by cervical dislocation, and samples of gastrocnemius muscle, epididymal fat, and tumor were taken out and weighed. The method for measuring muscle grip strength was as follows: The researcher firmly grasped the mouse with the right hand, placed the mouse on the "YLS-13A rat and mouse grip strength measuring instrument", and while stabilizing the gripping plate with the left hand, the mouse's forelimbs grasped the gripping plate firmly. Then, the researcher slowly released the left hand from the gripping plate and immediately pulled the mouse's tail slowly backward with the right hand. Finally, the mouse's forelimbs left the gripping plate and the grip strength was measured. Each mouse was repeated 8 times, and the average value of the 8 times was the skeletal muscle strength index of each mouse. Results and conclusions: The three curves in Figures 48 - 58 are the healthy group, C26 tumor model group, and In cells / mice, it was inoculated under the left and right armpits of BALB / c mice. When the tumor reached approximately 800 c

[0167] In cells / mice, it was inoculated under the left and right armpits of BALB / c mice. When the tumor reached approximately 800 c and the dosing group (the group administered with Compound 4, among which Compound 4 was administered at 5 mg / kg) are shown.

[0168] Figures 48 - 58 show the body weight with tumor (Body weight wi th tumor) (Figure 48), the body weight without tumor (Tumor-free body weight) (Figure 49), the tumor volume (Figure 50) and the actual photograph of the tumor (Figure 51) during the survival period of the mice. Among them, the body weight with tumor and the body weight without tumor are the average body weights of 8 mice, the tumor volume is the average tumor volume of 8 mice, and the photograph of the actual tumor is the photograph of the tumors of 8 mice. As shown in Figure 48, the body weight of the healthy group mice continued to increase, but the body weight of the tumor-bearing mice in the C26 tumor model group decreased from the 11th day and continued to decrease until the end. As shown in Figure 49, the body weight without tumor also decreased in the same way. On the other hand, the group administered with Compound 4 significantly alleviated the weight loss of the mice, and by the end of the experiment, both the body weight with tumor and the body weight without tumor were higher than those in the C26 tumor model group. The difference was statistically significant (p < 0.01). However, as shown in Figures 50 and 51, the tumor volume of the group administered with Compound 4 decreased slightly compared to the C26 tumor model group, but the difference was not significant. Therefore, it was suggested that Compound 4 had no significant inhibitory effect on the growth of C26 tumors.

[0169] The average daily food intake and accumulative food intake during the survival period of the mice were the average values of 8 mice and were shown as in Figures 52 and 53. The mice in the C26 tumor model group were the healthy group showed a significant decrease in food intake. The group administered with Compound 4 showed a higher food intake than the C26 tumor model group, suggesting that the appetite was improved.

[0170] Figures 54 and 55 show the mass of the gastrocnemius muscle (Gastrocnemius weight ) and the actual photographs of the gastrocnemius muscle. The gastrocnemius muscle mass is the average value of 8 mice, and the actual photographs are the results of 8 mice / group. As shown in Figures 54 and 55, the gastrocnemius muscle mass of the mice in the C26 tumor model group was significantly lighter than that of the healthy group, and the difference was statistically significant (p <0.001). Compound 4 significantly alleviated the atrophy of the gastrocnemius muscle (p <0.05). Figure 56 shows the grasp strength of the limb muscles of the mice. The muscle grip strength of the mice in the C26 tumor model group was significantly lower than that of the healthy group and the group administered with Compound 4, and the difference was statistically significant (p<0.001). Compound 4 had a significant effect of increasing the muscle grip strength. (p < 0.05).

[0171] Figures 57 and 58 show the epididymal white adipose tissue weight (eWAT weight) and the actual photographs of the epididymal white adipose tissue of the mice. As shown in the photographs, the epididymal white adipose tissue weight of the mice in the C26 tumor model group was significantly lighter than that of the healthy group and the group administered with Compound 4, and the difference was statistically significant (p <0.01). Compound 4 had a significant effect of increasing the epididymal white adipose tissue weight (p<0.05 ).

[0172] Based on the above results, it is suggested that Compound 4 has no effect on tumor volume and alleviates weight loss, muscle atrophy, lipolysis and hypothermia caused by cancer cachexia, and improves appetite.

[0173] The above is a preferred embodiment of the present invention. For those of ordinary skill in the technical field of the present invention, it is possible to make some supplements and improvements without departing from the method of the present invention. These supplements and improvements should also be within the protection scope of the present invention.

Claims

1. A carbamoyl(dithioperoxo)thiolate compound or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following general formula I: 【Chemical 1】 In the formula, m is in the range of 1 to 11; X is a nitrogen-containing aliphatic heterocyclic ring, the nitrogen present in the aliphatic heterocyclic ring is adjacent to the carbon of the thiocarbonyl group, and the nitrogen-containing aliphatic heterocyclic ring is selected from pyrrolidine, morpholine, azetidine, piperazine, indoline, isoindoline, octahydro-1H-indole, octahydro-1H-isoindole or 2-oxa-6-azaspiro[3.4]octane.

2. The carbamoyl(dithioperoxo)thiolate compound or a pharmaceutically acceptable salt thereof according to Claim 1, wherein the nitrogen-containing aliphatic heterocyclic ring is pyrrolidine.

3. The carbamoyl(dithioperoxo)thiolate compound or a pharmaceutically acceptable salt thereof according to Claim 1, wherein in the formula, m is in the range of 1 to 9.

4. The carbamoyl(dithioperoxo)thiolate compound or a pharmaceutically acceptable salt thereof according to Claim 1, wherein in the formula, m is in the range of 3 to 5.

5. The carbamoyl(dithioperoxo)thiolate compound or a pharmaceutically acceptable salt thereof according to Claim 1, wherein in the formula, m is 5.

6. A carbamoyl(dithioperoxo)thiolate compound or a pharmaceutically acceptable salt thereof, selected from the following compounds. 【Chemical Formula 3-1】 【Chemical Figure 3-2】

7. A pharmaceutical composition comprising a pharmaceutically acceptable additive and the carbamoyl(dithioperoxo)thiolate compound or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 6.

8. Use of the carbamoyl(dithioperoxo)thiolate compound or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 6, or the pharmaceutical composition according to Claim 7, in the manufacture of an anti-cachexia drug.

9. The use according to Claim 8, wherein the anti-cachexia is anti-cancer cachexia.

Images