Anti-inflammatory immune enhancers

Abstract

The present invention provides an anti-inflammatory immunoenhancer that simultaneously triggers an anti-inflammatory effect and an immunopotentiating effect. An anti-inflammatory immunoenhancer containing, as an active ingredient, at least one selected from heterocyclic compounds represented by formula (I) (the symbols in the formula are as described in the specification) or salts thereof, and isothiocyanate compounds represented by the formula S=C=N-R5 (II) (the symbols in the formula are as described in the specification).

Description

[Technical Field]

[0001] This invention relates to a technology for simultaneously inducing anti-inflammatory and immune-enhancing effects, based on a mechanism that activates latent innate life-protective capabilities through sensory stimulation. [Background technology]

[0002] Humans and animals have evolved life-protective abilities to adapt to diverse situations. It is believed that organisms facing a life-threatening situation maximize their survival chances by utilizing their latent life-protective capabilities. Therefore, theoretically, if new technologies that induce these latent life-protective mechanisms evolved by organisms can be utilized in human and animal medical settings, improvements in survival rates and prognoses can be expected. However, the biological theoretical basis for developing such new technologies had long been lacking.

[0003] Against this backdrop, the inventors discovered that a group of heterocyclic and linear odor molecules that induce innate fear emotions transmit danger information to the brain via the activation of the sensory receptor TRPA1 (transient receptor potential ankyrin 1), thereby inducing a potential life-protective effect. Furthermore, they developed a technology to obtain therapeutic effects against hypoxic injury and inflammation using the group of heterocyclic and linear odor molecules developed here (referred to as thiazoline-related fear odors) (Patent Document 1).

[0004] The immune system is essential for protecting the body from infection. However, an excessive immune response can cause inflammation that destroys the body's own cells and tissues. To treat inflammatory diseases, it is necessary to administer anti-inflammatory drugs to suppress the excessive immune response. However, suppressing the immune response means weakening the body's defense against infections, sepsis, cancer, and other diseases. Since both excessive strengthening and suppression of the immune response can be detrimental to life and health, it needs to be continuously regulated to an appropriate level.

[0005] Steroid anti-inflammatory drugs affect the expression of genes involved in various immune functions and other physiological functions through the activation of glucocorticoid receptors. Therefore, while steroid administration has excellent anti-inflammatory effects, it also strongly suppresses the immune system. Consequently, steroid administration has the side effect of weakening the body's ability to fight off bacteria infecting the body from the outside or cancers that develop within the body (Non-patent Literature 1-3).

[0006] Therefore, it would be ideal to have a drug that induces anti-inflammatory effects while simultaneously enhancing immune function, but such a drug has not yet been developed. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] WO2019 / 177142 [Non-patent literature]

[0008] [Non-Patent Document 1] Allergy 60(2), 193-198, 2011 [Non-Patent Document 2] Yutaka Mizushima (ed.), "Today's Therapeutic Drugs: Commentary and Handbook," Nankodo Publishing. [Non-Patent Document 3] Kazuhiko Yamamoto (ed.), "Handbook on Choosing and Using Steroid Medications," Yodosha Publishing Co., Ltd. [Non-Patent Document 4] Miller et al., Nat Immunol 20, 326-336 (2019) [Non-Patent Document 5] Tikhonova et al., Nature 569, p222-228 (2019) [Non-Patent Document 6] Matsuo et al., bioRxiv, doi: https: / / doi.org / 10.1101 / 2020.05.17.100933 (2020) [Non-Patent Document 7] Matsuo et al., Commun Biol 4, 101 (2021) [Overview of the project] [Problems that the invention aims to solve]

[0009] The present invention aims to provide a drug that induces both anti-inflammatory and immune-enhancing effects. [Means for solving the problem]

[0010] The inventors have proposed a model in which thiazoline-based phobias activate the brain's powerful crisis recognition system via sensory nerves, thereby maximizing the intrinsic life-protective functions acquired during evolution (Non-Patent Literature 6, 7). They believe that thiazoline-based phobias, by intervening in the brain's crisis response system that integrates and controls the state of the entire body, may be able to simultaneously induce the contradictory effects of anti-inflammatory and immune enhancement, which has been difficult with conventional technologies.

[0011] Following this unique hypothesis, we discovered that stimulating the body with thiazoline-based phobic odors induces a potent anti-inflammatory effect, while simultaneously increasing the blood concentrations of monocytes, dendritic cells, neutrophils, basophils (which perform innate immune functions), and lymphocytes (which also perform adaptive immune functions). Under normal conditions, an increase in these immune cells would exacerbate the inflammatory state. However, stimulating the body with thiazoline-based phobic odors increases the expression of genes that suppress inflammation and genes that enhance innate immune function within innate immune cells. This makes it possible for the first time to induce an anti-inflammatory type of immune enhancement, simultaneously inducing immune enhancement and anti-inflammatory effects, which has been difficult to achieve with conventional drugs.

[0012] Therefore, the present invention has developed a technology that uses thiazoline phobic odors to provide anti-inflammatory effects, which were difficult to achieve with existing anti-inflammatory drugs, while simultaneously enhancing immune function.

[0013] In other words, the present invention relates to the following. [1] Equation (I)

[0014]

Chem.

[0015] (wherein, ring A is a 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms selected from a nitrogen atom, an optionally oxidized sulfur atom, and an oxygen atom; R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a halogen atom, an amino group, -SH, a C 1-6 alkylthio group, a C 2-6 alkenylthio group, a C 1-6 alkyl-carbonyl group, a formyl group, a C 6-10 aryl group, a C 1-6 alkoxycarbonyl group, a 5- or 6-membered heteroaryl group, a 5- or 6-membered heteroaryl-C 1-6 alkyl group, a 5- or 6-membered heteroaryl-C 1-6 alkylthio group, or an oxo group; R 1 and R 2 may be bonded to each other to form an optionally substituted 5- to 10-membered ring; n is 0, 1, or 2) a heterocyclic compound represented by or a salt thereof, and Formula (II) S=C=N-R 5 (II) (wherein, R 5 is a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 2-6 alkenyl group, a C 1-6 alkylthio-C 1-6 alkyl group, a C 6-10 aryl group, a C 6-10 aryl-C 1-6 alkyl group, or a 5- or 6-membered heteroaryl group) An anti-inflammatory immune enhancer containing at least one selected from the isothiocyanate compounds shown as indicated by as an active ingredient. [2] The agent according to [1], wherein ring A is thiazoline, thiazole, thiazolidinedione, thiomorpholine, thiophene, pyrrole, morpholine, azepane, pyridine, pyrazine, furan, 2,3-dihydro-4H-1,4-thiazine, imidazole, or tetrahydrofuran. [3] The agent according to [1] or [2], wherein the active ingredient is a heterocyclic compound represented by formula (I) or a salt thereof. [4] The agent according to [1], wherein the active ingredient is an isothiocyanate compound represented by formula (II). [5] Use of at least one compound selected from a heterocyclic compound represented by formula (I) or a salt thereof, and an isothiocyanate compound represented by formula (II), for the production of an anti-inflammatory immunostimulator. [6] The use described in [5] wherein ring A is thiazoline, thiazole, thiazolidinedione, thiomorpholine, thiophene, pyrrole, morpholine, azepane, pyridine, pyrazine, furan, 2,3-dihydro-4H-1,4-thiazine, imidazole, or tetrahydrofuran. [7] The use according to [5] or [6], wherein the compound is a heterocyclic compound represented by formula (I) or a salt thereof. [8] The use according to [5], wherein the compound is an isothiocyanate compound represented by formula (II). [9] A method for enhancing immunity in a mammal, comprising administering to a mammal an effective amount of at least one compound selected from a heterocyclic compound represented by formula (I) or a salt thereof and an isothiocyanate compound represented by formula (II).

[10] The method according to [9], which is a method for enhancing immunity and suppressing inflammation in mammals.

[11] The method according to [9] or

[10] , wherein ring A is thiazoline, thiazole, thiazolidinedione, thiomorpholine, thiophene, pyrrole, morpholine, azepane, pyridine, pyrazine, furan, 2,3-dihydro-4H-1,4-thiazine, imidazole, or tetrahydrofuran.

[12] The method according to any one of [9] to

[11] , wherein the compound is a heterocyclic compound represented by formula (I) or a salt thereof.

[13] The method according to [9] or

[10] , wherein the compound is an isothiocyanate compound represented by formula (II).

[14] At least one compound selected from heterocyclic compounds represented by formula (I) or salts thereof, and isothiocyanate compounds represented by formula (II), for use in enhancing immunity.

[15] The compounds described in

[14] for use in enhancing immunity and suppressing inflammation.

[16] Compounds for use as described in

[14] or

[15] , wherein ring A is thiazoline, thiazole, thiazolidinedione, thiomorpholine, thiophene, pyrrole, morpholine, azepane, pyridine, pyrazine, furan, 2,3-dihydro-4H-1,4-thiazine, imidazole, or tetrahydrofuran.

[17] A compound for use as described in any one of

[14] to

[16] , which is a heterocyclic compound represented by formula (I) or a salt thereof.

[18] Compounds for use as described in

[14] or

[15] , which are isothiocyanate compounds represented by formula (II). [Effects of the Invention]

[0016] The present invention provides an anti-inflammatory immunostimulant that simultaneously induces anti-inflammatory and immune-enhancing effects. The anti-inflammatory immunostimulant of the present invention can be used to enhance immunity in the prevention or treatment of infectious diseases, sepsis, or cancer. [Brief explanation of the drawing]

[0017] [Figure 1]AC: This shows the results of classifying peripheral blood mononuclear cells (PBMCs) 16 hours after intraperitoneal injection of saline (control) or thiazoline-related phobic odor (2-methyl-2-thiazoline; 2MT) by single-cell RNA sequencing (scRNAseq). A shows the control condition, B shows the 2MT administration condition, and C shows the result of merging the control and 2MT conditions. D: This shows the ratio of cells annotated as monocytes and dendritic cells in conditions A and B. [Figure 2] Figure 1 shows the results of analyzing the changes in gene expression under control and 2MT administration conditions for each cell type annotated by scRNAseq analysis. [Figure 3] The results of flow cytometry analysis of the relative abundance of neutrophils and monocytes in peripheral blood under conditions of intraperitoneal administration or odor presentation of thiazoline-related phobic odor (2MT), and administration of corticosterone, are shown. [Figure 4] The results of measuring the number of neutrophils in peripheral blood 16 hours after intraperitoneal injection of saline (control) or each compound in Example 4 are shown. [Figure 5] The chemical structure of the compound used in Example 4 is shown. [Figure 6] The results of measuring the number of neutrophils in peripheral blood 16 hours after intraperitoneal injection of saline (control) or each compound in Example 5, as well as the chemical structures of the compounds used, are shown. [Figure 7] The results of measuring the number of monocytes in peripheral blood 16 hours after intraperitoneal injection of saline (control) or each compound in Example 6, as well as the chemical structures of the compounds used, are shown. [Figure 8] The results of measuring the number of monocytes in peripheral blood 16 hours after intraperitoneal injection of saline (control) or allyl isothiocyanate in Example 7, along with the chemical structures of the compounds used, are shown. [Figure 9] The results of measuring the number of basophils in peripheral blood 16 hours after intraperitoneal injection of saline (control) or each compound in Example 8, as well as the chemical structures of the compounds used, are shown. [Figure 10] The results of measuring the number of lymphocytes in peripheral blood 16 hours after intraperitoneal injection of saline (control) or each compound in Example 9, as well as the chemical structures of the compounds used, are shown. [Figure 11] The results of measuring the percentage of monocytes in whole blood cells 16 hours after intraperitoneal injection of saline (control) or each compound in Example 10 are shown. [Figure 12] The chemical structure of the compound used in Example 10 is shown. [Figure 13] The results of measuring the percentage of monocytes in whole blood cells 16 hours after intraperitoneal injection of saline (control) or allyl isothiocyanate in Example 11, along with the chemical structures of the compounds used, are shown. [Figure 14] The results of measuring the percentage of neutrophils in whole blood cells 16 hours after intraperitoneal injection of saline (control) or each compound in Example 12 are shown. [Figure 15] The chemical structure of the compound used in Example 12 is shown. [Figure 16] The results of measuring the percentage of neutrophils in whole blood cells 16 hours after intraperitoneal injection of saline (control) or each compound in Example 13, and the chemical structures of the compounds used are shown. [Figure 17] The results of measuring the percentage of basophils in whole blood cells 16 hours after intraperitoneal injection of saline (control) or each compound in Example 14 are shown. [Figure 18] The chemical structure of the compound used in Example 14 is shown. [Figure 19] The results of measuring the percentage of lymphocytes in whole blood cells 16 hours after intraperitoneal injection of saline (control) or each compound in Example 15, and the chemical structures of the compounds used are shown. [Modes for carrying out the invention]

[0018] Ring A in formula (I) represents a 5- to 7-membered heterocycle containing one or two heteroatoms selected from a nitrogen atom, an optionally oxidized sulfur atom, and an oxygen atom. A 5- to 7-membered heterocycle containing one or two heteroatoms selected from a nitrogen atom and an optionally oxidized sulfur atom is preferred for Ring A. A 5- to 7-membered heterocycle containing a nitrogen atom and an optionally oxidized sulfur atom is more preferred for Ring A. The number of members in Ring A is more preferably 5 or 6.

[0019] Examples of the aforementioned heterocycles include, but are not limited to, pyrrole, pyridine, pyridazine, pyrimidine, pyrazine, piperazine, pyrrolidine, hexahydropyridazine, imidazole, imidazolidine, piperidine, thiophene, thiolane, tetrahydro-2H-thiopyran, thiazoline (e.g., 2-thiazoline, 3-thiazoline, 4-thiazoline), thiazole, thiazolidin, isothiazoline, isothiazoline, thiomorpholine, thiadiazoline, thiadiazoline, thiadiazolidin, 1,3-thiadinane, 5,6-dihydro-4H-1,3-thiaidine, 2,3-dihydro-4H-1,4-thiaidine, furan, 2H-pyran, 4H-pyran, oxazole, isoxazole, morpholine, oxazoline, azepane, and tetrahydrofuran. Preferably, the compounds are thiazoline, thiazole, thiazolidinedione, thiomorpholine, thiophene, pyrrole, morpholine, azepane, pyridine, pyrazine, furan, 2,3-dihydro-4H-1,4-thiazine, imidazole, or tetrahydrofuran; more preferably, thiazoline (e.g., 2-thiazoline, 3-thiazoline, 4-thiazoline), thiazole, thiazolidinedione, thiomorpholine, thiophene, pyrrole, morpholine, azepane, pyridine, pyrazine, furan, 2,3-dihydro-4H-1,4-thiazine, or imidazole; and even more preferably, thiazoline (e.g., 2-thiazoline), thiazole, thiazolidinedione, thiomorpholine, thiophene, or 2,3-dihydro-4H-1,4-thiazine.

[0020] The "halogen atom" used here is preferably selected from fluorine, chlorine, bromine, and iodine atoms.

[0021] The "C" used here 1-6 An alkyl group (when used as a group or part of a group) refers to a linear or branched alkyl group having 1 to 6 carbon atoms. 1-6 Examples of alkyl groups include, but are not limited to, methyl group, ethyl group, propyl group, isopropyl group, butyl group, 1-methylpropyl group (sec-butyl group), 2-methylpropyl group (isobutyl group), tert-butyl group, pentyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 1,1-dimethylpropyl group, 2,2-dimethylpropyl group, 1,2-dimethylpropyl group, 1-ethylpropyl group, hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, and 1-ethyl-2-methylpropyl group. Preferred C 1-6 Examples of alkyl groups include C 1-4 Examples include alkyl groups (linear or branched alkyl groups having 1 to 4 carbon atoms), with methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and sec-butyl groups being more preferred, and methyl groups being particularly preferred.

[0022] The "C" used here 1-6 A "haloalkyl group" is a C molecule substituted with 1 to 5 halogen groups. 1-6 This refers to an alkyl group, and when there are two or more halogen groups, the types of halogen groups may be the same or different. Examples of halogen groups include fluoro groups, chloro groups, and bromo groups. 1-6Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, 1,1,2,2,2-pentafluoroethyl, 1-fluoropropyl, 1,1-difluoropropyl, 2,2-difluoropropyl, 3-fluoropropyl, 3,3,3-trifluoropropyl, 4-fluorobutyl, 4,4,4-trifluorobutyl, 5-fluoropentyl, 5,5,5-trifluoropentyl, 6-fluorohexyl, and 6,6,6-trifluorohexyl.

[0023] The "C" used here 2-6 An alkenyl group (when used as a group or part of a group) refers to a linear or branched alkenyl group having 2 to 6 carbon atoms. 2-6 Examples of alkenyl groups include, but are not limited to, vinyl groups, allyl groups, propa-1-enyl groups, buta-1-en-1-yl groups, buta-2-en-1-yl groups, penta-4-en-1-yl groups, and 2-methylallyl groups.

[0024] The "C" used here 1-6 An alkoxy group (when used as a group or part of a group) refers to a linear or branched alkoxy group having 1 to 6 carbon atoms. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 2,2-dimethylpropoxy, 1,2-dimethylpropoxy, 1-ethylpropoxy, and hexyloxy groups.

[0025] The "C" used here 1-6 The alkylthio group is C 1-6 This refers to an -SH group substituted with an alkyl group. 1-6 Examples of alkylthio groups include, but are not limited to, methylthio groups, ethylthio groups, propylthio groups, and butylthio groups.

[0026] The "C" used here 2-6 The "alkenylthio group" is C 2-6 This refers to an -SH group substituted with an alkenyl group. 2-6 Examples of alkenylthio groups include, but are not limited to, vinylthio groups, allylthio groups, propa-1-enylthio groups, buta-1-en-1-ylthio groups, buta-2-en-1-ylthio groups, penta-4-en-1-ylthio groups, and 2-methylallylthio groups.

[0027] The "C" used here 1-6 The alkyl-carbonyl group is C 1-6 This refers to a carbonyl group to which an alkyl group is attached. 1-6 Examples of alkyl-carbonyl groups include, but are not limited to, acetyl, propionyl, butyryl, isobutyryl, valeryl, and hexanoyl groups.

[0028] The "C" used here 1-6 The "alkoxycarbonyl group" is C 1-6 This refers to a carbonyl group to which an alkoxy group is attached. 1-6 Examples of alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl groups, ethoxycarbonyl groups, propoxycarbonyl groups, isopropoxycarbonyl groups, and butoxycarbonyl groups.

[0029] The "C" used here 6-10 An "aryl group" refers to an aromatic hydrocarbon group having 6 to 10 carbon atoms. 6-10 Examples of aryl groups include, but are not limited to, phenyl groups and naphthyl groups (1-naphthyl group, 2-naphthyl group).

[0030] The "C" used here 1-6 Alkylthio-C 1-6 "Alkyl alkyl group" is "C 1-6 A "C" that has an alkylthio group attached to it. 1-6 It means "alkyl group". 1-6 Alkylthio-C 1-6 Examples of alkyl groups include, but are not limited to, methylthiomethyl, 2-(methylthio)ethyl, 3-(methylthio)propyl, ethylthiomethyl, and 2-(ethylthio)ethyl groups.

[0031] The "C" used here 6-10 Aryl-C 1-6 "Alkyl alkyl group" is "C 6-10 A "C" bonded to an "aryl group" 1-6 It means "alkyl group". 6-10 Aryl-C 1-6 Examples of alkyl groups include, but are not limited to, the benzyl group and the 2-phenylethyl group.

[0032] The term "5- or 6-membered heteroaryl group" as used herein refers to a 5- or 6-membered heteroaryl group containing at least one (preferably 1 to 3, more preferably 1 or 2) heteroatoms selected from a nitrogen atom, an optionally oxidized sulfur atom, and an oxygen atom. A preferred 5- or 6-membered heteroaryl group is one containing one or two heteroatoms selected from a nitrogen atom and an optionally oxidized sulfur atom.

[0033] Examples of 5- or 6-membered heteroaryl groups include, but are not limited to, pyrrolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, imidazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, furyl, oxazolyl, and isoxazolyl groups. Preferably, they are pyridyl, thienyl, etc.

[0034] The term "5 or 6-membered heteroaryl-C" used here refers to the "5 or 6-membered heteroaryl-C" used here.1-6 An alkyl group is a group to which a 5 or 6-membered heteroaryl group is attached. 1-6 This means "alkyl group". 5 or 6-membered heteroaryl-C 1-6 Examples of alkyl groups include, but are not limited to, the furfuryl group.

[0035] The term "5 or 6-membered heteroaryl-C" used here refers to the "5 or 6-membered heteroaryl-C" used here. 1-6 The alkylthio group is a group to which a 5 or 6-membered heteroaryl group is attached. 1-6 This refers to an alkylthio group. It is a 5 or 6-membered heteroaryl-C group. 1-6 Examples of alkylthio groups include, but are not limited to, the furfurylthio group.

[0036] The term "oxo group" used here (when used as a group or part of a group) refers to an O group.

[0037] The term "sulfur atom that may be oxidized" used here refers to S, SO, or SO2.

[0038] R 1 and R 2 However, the "5 to 10 membered rings" that are bonded together and formed by these rings, which may be substituted, refer to 5 to 10 membered rings that may contain at least one (preferably 1 to 3, more preferably 1 or 2) heteroatoms selected from nitrogen atoms, optionally oxidized sulfur atoms, and oxygen atoms. Examples of the 5 to 10 membered rings include benzene rings, tetrahydropyrimidine rings, and decahydronaphthalene rings. The 5 to 10 membered rings may be substituted, and examples of substituents include C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogen atom, amino group, -SH, C 1-6 Alkylthio group, C 2-6 Alkenylthio group, C 1-6 Alkyl-carbonyl group, formyl group, C 1-6Examples of 1 to 4 substituents (preferably 1 or 2) selected from an alkoxycarbonyl group, an oxo group, etc. As the substituent, preferably, C 1-6 an alkyl group (e.g., methyl), C 1-6 an alkoxy group (e.g., methoxy), and 1 to 4 substituents selected from an oxo group.

[0039] R 1 and R 2 which are bonded to each other to form an "optionally substituted 5- to 10-membered ring" is preferably an "optionally substituted 5- or 6-membered ring". R 1 and R 2 which are bonded to each other to form the "5- or 6-membered ring" of the "optionally substituted 5- or 6-membered ring" means a 5- or 6-membered ring which may contain at least 1 (preferably 1 to 3, more preferably 1 or 2) heteroatom selected from a nitrogen atom, an optionally oxidized sulfur atom, and an oxygen atom. Examples of the 5- or 6-membered ring include a benzene ring, a tetrahydropyrimidine ring, etc. The 5- or 6-membered ring may be optionally substituted, and examples of the substituent include, for example, C 1-6 an alkyl group, a halogen atom, an amino group, -SH, C 1-6 an alkylthio group, C 2-6 an alkenylthio group, C 1-6 an alkyl-carbonyl group, a formyl group, C 1-6 an alkoxycarbonyl group, an oxo group, etc. Examples of 1 to 4 substituents (preferably 1 or 2) selected from an alkoxycarbonyl group, an oxo group, etc. As the substituent, preferably, C 1-6 an alkyl group (e.g., methyl) and 1 to 4 substituents selected from an oxo group.

[0040] In formula (I), preferably, R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, C 1-6 an alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, hexyl), C 1-6An alkoxy group (e.g., methoxy, ethoxy), a halogen atom (e.g., chlorine atom), an amino group, -SH, C 1-6 An alkylthio group (e.g., methylthio), C 2-6 An alkenylthio group (e.g., allylthio), C 1-6 An alkyl-carbonyl group (e.g., acetyl, propionyl), a formyl group, C 6-10 An aryl group (e.g., phenyl), a 5- or 6-membered heteroaryl group (e.g., thienyl), a 5- or 6-membered heteroaryl-C 1-6 An alkyl group (e.g., furfuryl), a 5- or 6-membered heteroaryl-C 1-6 An alkylthio group (e.g., furfurylthio), or an oxo group; R 1 And R 2 May be bonded to each other to form an optionally substituted 5- to 10-membered ring (e.g., benzene ring, tetrahydropyrimidine ring, decahydronaphthalene ring).

[0041] In formula (I), preferably, R 1 , R 2 , R 3 And R 4 Are each independently a hydrogen atom, a C 1-6 ​​​​​​​​​​​​​​​​​​​​​​​4 Preferably, at least one of them is not a hydrogen atom. In equation (I), when n=0, R 1 , R 2 and R 3 Preferably, at least one of them is not a hydrogen atom.

[0043] In formula (II), preferably, R 5 C 1-6 Alkyl group (e.g., isopropyl, hexyl), C 1-6 Haloalkyl group, C 2-6 Alkenyl group (e.g., allyl, methallyl, 4-pentenyl), C 1-6 Alkylthio-C 1-6 Alkyl group (e.g., 3-(methylthio)propyl), or C 6-10 Aryl-C 1-6 It is an alkyl group (e.g., benzyl).

[0044] In the present invention, suitable heterocyclic compounds of formula (I) used as active ingredients include, but are not limited to, the following compounds. 2-methyl-2-thiazoline (2MT) 4-Ethyl-2-methylthiazoline 2-Mercaptothiazolin 2-(methylthio)-2-thiazoline 4-(methylthio)-2-thiazoline 2-Isobutyl-4,5-dimethyl-3-thiazoline 2-Ethoxythiazole 5-acetyl-2,4-dimethylthiazole 4,5-dimethylthiazole 5-Methylthiazole 4-tert-butyl-2-methylthiazole 2-(methylthio)benzothiazole 2-methylthiomorpholine 2H-1,4-benzothiazine-3(4H)one Thiazolidine-2,4-Zion 3-acetyl-2,5-dimethylthiophene 2,5-dimethylthiophene 2-ethylthiophene 2-Hexylthiophene 3-Chlorothiophene Benzothiophene 2-Furfurylthio-3-methylpyrazine 2,3-Diethylpyrazine 2-acetylpyrrole 2-acetyl-1-methylpyrrole 3-acetylpyridine 4-acetylpyridine Azepan 6-Methoxyquinoline Morpholine 2-(allylthio)-2-thiazoline 4-Phenyl-thiomorpholine-1,1-dioxide 2-acetyl-3,5-dimethylpyrazine 2-methyl-3-tetrahydrofuranchiol 2,6-ru Chiji hmm 2-acetyl-5-methylfuran 2,5-dimethylfuran 2,5-dimethyltetrahydrofuran 2-methylfuran 2,3-dimethylbenzofuran 2-acetyl-6-methylpyridine 2,3-dimethylpyridine (-)-Ambroxide Thiomorpholine 2,3-dimethylthiomorpholine 2-acetyl-3-ethylpyrazine 2-methyl-3-methylthiopyrazine, 2-methyl-5-methylthiopyrazine, 2-methyl-6-methylthiopyrazine, or mixtures of these isomers 2-methylindole Thiazole 2-Methylthiazole 2-Isobutylthiazole 2,4,5-Trimethylthiazole 2-Chlorothiazole 2-acetylthiazole 2-Isopropyl-4-methylthiazole 2,2-dimethylthiazolidine 2-Propionylthiophene 2-methylthiophene 1-Furfrillpyrrole 2-ethylpyrrole 2,4-dimethylpyrrole 3-methylpyrrole 3-methylthiophene 3-acetyl-2,5-dimethylfuran 2-ethylfuran 5-Formylthiazole

[0045] In the present invention, suitable isothiocyanate compounds of formula (II) used as active ingredients include, but are not limited to, the following compounds. Allyl isothiocyanate Isopropyl isothiocyanate Metallyl isothiocyanate 4-Pentenyl isothiocyanate 3-(methylthio)propyl isothiocyanate Hexyl isothiocyanate Benzyl isothiocyanate

[0046] In the present invention, the heterocyclic compound of formula (I) and the isothiocyanate compound of formula (II) used as active ingredients include substances commonly known as reagents, which can be commercially available or obtained by methods known to the present day. The use of the heterocyclic compound of formula (I) and the isothiocyanate compound of formula (II) as anti-inflammatory immune enhancers has not been disclosed or suggested to date.

[0047] Preferred examples of heterocyclic compounds represented by formula (I) include the compounds represented by formulas (A) to (E) below, or salts thereof.

[0048] [ka]

[0049] (In the formula, X 1 is S, O, or N(R 16 ) and; X 2 is N or CR 12 and; X 3 is S, SO2, O, or -(CH2)2-; X 4 is N or CR 15 and;

[0050] [ka]

[0051] This indicates a single bond or a double bond; R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 These are, independently, hydrogen atoms and C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogen atom, amino group, -SH, C 1-6 Alkylthio group, C 2-6 Alkenylthio group, C 1-6 Alkyl-carbonyl group, formyl group, C 6-10 Aryl group, C 1-6 Alkoxycarbonyl group, 5 or 6-membered heteroaryl group, 5 or 6-membered heteroaryl-C 1-6 Alkyl, 5- or 6-membered heteroaryl-C 1-6 It is an alkylthio group or an oxo group; R 13 and R 14 These combine with one to four C atoms. 1-6 A benzene ring which may be substituted with an alkoxy group, C 1-6 A tetrahydropyrimidine ring which may be substituted with 1 to 4 substituents selected from alkyl groups and oxo groups, or 1 to 4 C1-6 A decahydronaphthalene ring may be formed, which may be substituted with an alkyl group; However, in equation (A), R 11 and R 12 It is not an oxo group; In equation (A),

[0052] [ka]

[0053] When R exhibits a double bond, 13 and R 14 It is not an oxo group; In equation (D), R 11 , R 12 , R 13 , R 14 and R 15 It is not an oxo group, but in formula (B), R 11 and R 12 (They may come together to form an oxo group.)

[0054] In formulas (A) to (E), preferably, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 These are, independently, hydrogen atoms and C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, hexyl), C 1-6 Alkoxy groups (e.g., methoxy, ethoxy), halogen atoms (e.g., chlorine atom), amino groups, -SH, C 1-6 Alkylthio group (e.g., methylthio), C 2-6 Alkenylthio group (e.g., allylthio), C 1-6 Alkyl-carbonyl group (e.g., acetyl, propionyl), formyl group, C 6-10 Aryl group (e.g., phenyl), 5 or 6-membered heteroaryl group (e.g., thienyl), 5 or 6-membered heteroaryl-C 1-6Alkyl (e.g., furfuryl), 5 or 6-membered heteroaryl-C 1-6 It is an alkylthio group (e.g., furfurylthio) or an oxo group; R 13 and R 14 These combine with one to four C atoms. 1-6 A benzene ring which may be substituted with an alkoxy group, C 1-6 A tetrahydropyrimidine ring which may be substituted with 1 to 4 substituents selected from alkyl groups and oxo groups, or 1 to 4 C 1-6 A decahydronaphthalene ring may be formed, which may be substituted with an alkyl group.

[0055] The salts of the compounds according to the present invention may be any pharmaceutically acceptable salts, such as alkali metal salts like sodium salts and potassium salts; alkaline earth metal salts like magnesium salts and calcium salts; ammonium salts like dimethylammonium salts and triethylammonium salts; inorganic acid salts like hydrochloride salts, perchlorate salts, sulfate salts and nitrate salts; and organic acid salts like acetate salts and methanesulfonate salts.

[0056] The anti-inflammatory immunostimulants disclosed in this invention can be used as preventive or therapeutic agents for infectious diseases, sepsis, or cancer. The anti-inflammatory immunostimulants of this invention can be used to enhance immunity in the prevention or treatment of infectious diseases, sepsis, or cancer. "Anti-inflammatory immunostimulant" means a drug that exhibits both anti-inflammatory and immunostimulatory effects.

[0057] Infectious diseases include those caused by bacteria, viruses, fungi, and other pathogens. Examples of cancers include solid cancers such as head and neck cancer, esophageal cancer, gastric cancer, colorectal cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer (small cell lung cancer, non-small cell lung cancer), breast cancer, uterine cancer, cervical cancer, ovarian cancer, prostate cancer, kidney cancer, bladder cancer, oral cancer, gallbladder cancer, bile duct cancer, malignant melanoma, and mesothelioma; and hematopoietic malignancies such as acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, malignant lymphoma, and multiple myeloma.

[0058] For the purpose of preventing the onset of injury or alleviating symptoms in animals, including humans, that have developed or are at risk of developing infectious diseases, sepsis, or cancer, a heterocyclic compound represented by formula (I) or a salt thereof, or an isothiocyanate compound represented by formula (II) (hereinafter also referred to as the "compound of the present invention") can be administered. A gaseous gas derived from the compound of the present invention, generated at a concentration of 0.1 to 100,000 ppm, can be inhaled through the nasal cavity or lungs using a gas mask or a device with a similar function. Alternatively, the compound of the present invention can be administered orally at a dose of 1 μg / kg to 5,000 mg / kg. Alternatively, the compound of the present invention can be injected into the body at a dose of 1 μg / kg to 5,000 mg / kg by methods such as intradermal injection, subcutaneous injection, intramuscular injection, intravenous injection, intra-arterial injection, intrathecal injection, or intraperitoneal injection. The frequency of administration can be a single dose, continuous administration at regular intervals, or continuous administration at different time intervals. The animals targeted for this treatment include mammals (humans, mice, rats, hamsters, rabbits, cats, dogs, cattle, sheep, pigs, horses, monkeys, etc.).

[0059] When the compound of the present invention is used as an anti-inflammatory immune enhancer (hereinafter also referred to as the agent of the present invention), pharmaceutically acceptable additives may be added as needed.

[0060] Specific examples of pharmaceutically acceptable additives include, but are not limited to, antioxidants, preservatives, colorants, flavorings, and diluents, emulsifiers, suspending agents, solvents, fillers, bulking agents, buffers, delivery vehicles, carriers, excipients, and / or pharmaceutically acceptable adjuvants.

[0061] The formulation of the agent of the present invention is not particularly limited, but examples include liquid formulations, injectable formulations, and sustained-release formulations. The solvent used to formulate the agent of the present invention as the above formulations may be either aqueous or non-aqueous.

[0062] Injectable preparations can be prepared by methods well known in the art. For example, an injectable preparation can be prepared by dissolving it in a suitable solvent (such as physiological saline, a buffer such as PBS, or sterile water), filtering and sterilizing it, and then filling it into a sterile container (such as an ampoule). This injectable preparation may include a conventional pharmaceutical carrier as needed. A non-invasive catheter-based administration method may also be used. Carriers that can be used in this invention include neutral buffered physiological saline or physiological saline containing serum albumin.

[0063] The present invention will be described in more detail and specifically below with reference to examples, but these examples are not intended to limit the present invention.

[0064] Example 1: Increase in innate immune cells in peripheral blood due to thiazoline-related phobic odors Experimental method Approximately 3-month-old C57 / BL6 mice were intraperitoneally administered 200 μl of saline (control) or 1% 2MT solution (dissolved in saline). Blood was collected 16 hours later, and peripheral blood mononuclear cells (PBMCs) were isolated using Ficoll Paque PREMIUM 1.084 (GE Healthcare). A single-cell RNA cDNA library was prepared from the isolated cells using the 10X Chromium preparation system and Chromium Single Cell 3' Library & Gel Bead Kit v3, and then sequenced using Illumina HiSeq. The obtained scRNAseq data were analyzed according to the methods described in Non-Patent Documents 4 and 5. The results of clustering based on gene expression in each cell and visualization by tSNE are shown in Figures 1A-C. A shows the cell types present in the PBMCs of control mice administered saline (gray), B shows the cell types present in the PBMCs of mice stimulated with 2MT (black), and C shows the result of overlaying A and B. D represents the cell ratio of monocytes (total of Mono1 and Mono2 clusters in AB) and dendritic cells in PBMCs under control and 2MT administration conditions.

[0065] result The results are shown in Figure 1. It was revealed that 2MT stimulation, which induces innate fear emotions, significantly increases the number of monocytes (Mono1, Mono2) and dendritic cells (DCs) involved in strengthening innate immunity (AC). Monocytes can be classified into two groups based on the specificity of gene expression, designated as Mono1 and Mono2. In addition to monocytes and dendritic cells, three types of B cells (B1, B2, B3) and four types of T cells (Naive CD4) were also stimulated. + T, Naive CD8 + T, Memory CD4 + T, IL2rb + Naive CD8 + T), megakaryocytes (MK) were detected.

[0066] In PBMCs, the proportion of monocytes was only 3.7% under control conditions, but increased to 23.7% under 2MT stimulation conditions. Similarly, the proportion of dendritic cells increased from 0.83% under control conditions to 2.2% with 2MT stimulation (Figure 1D). These results indicate that innate fear-induced odor stimulation increases the proportion of monocytes and dendritic cells in the serum, which are involved in innate immunity.

[0067] Example 2: Inflammation-suppressing and immune-enhancing genes whose expression is enhanced by innate fear stimuli. Experimental method Based on the scRNAseq data obtained in Example 1, Figure 2 shows a comparison of the expression changes of each gene in cells present in each cluster between the control condition and the 2MT administration condition. Genes whose expression changes were observed with 2MT stimulation are shown at the top of the table, and the functional category of the gene is shown above that. The numbers in the table indicate the gene expression level, and the intensity of the shadow indicates the degree of increase in gene expression. Darker shadows indicate a greater increase in gene expression.

[0068] result The results are shown in Figure 2. Compared to the control condition, 2MT stimulation increased the expression levels of Nfkbia, Nfkbiz, and Socs3, which are suppressors of the NF-κB and JAK-STAT pathways that promote inflammation through cytokine release. Therefore, 2MT stimulation is thought to suppress inflammation. 2MT stimulation also increased the expression levels of Ccr1, Ccr2, Ccrl2, and Cxcl2, genes that promote blood cell migration, and increased the expression levels of Lyz2, F13a1, Cd14, Chil3, and Hp, which are involved in strengthening the body's defense response. These changes in gene expression are presumed to increase the number of cells involved in innate immunity in the blood and strengthen immune capacity. These results indicate that innate fear stimulation by 2MT strengthens innate immunity by promoting the migration of monocytes and neutrophils into the bloodstream, while simultaneously suppressing the inflammatory response that would normally be induced simultaneously with this migration by increasing the expression of cytokine suppressor genes. In other words, it induces a state of crisis immunity that strengthens innate immunity while suppressing inflammation.

[0069] Example 3: Increase in innate immune cells in peripheral blood due to intraperitoneal injection of congenital phobia odor and olfactory stimulation. Experimental method Approximately 3-month-old C57 / BL6 mice were intraperitoneally administered 200 μl of saline (control) or 1% 2MT solution (dissolved in saline). Blood was collected 16 hours later, and the number of various leukocytes in the peripheral blood was measured by peroxidase staining flow cytometry and two-angle laser flow cytometry. The ratios of neutrophils and monocytes in the peripheral blood under each condition, as revealed by the measurements, are shown below.

[0070] result The results are shown in Figure 3. The vertical axis represents the relative cell number. Compared to the condition in which physiological saline was injected intraperitoneally (Saline ip), the number of neutrophils increased in the condition in which 2MT was injected intraperitoneally (black graph, 2MT ip). Similarly, compared to the condition without odor stimulation (no odor), the number of neutrophils also increased in the condition in which 2MT odor stimulation was applied (polka dot graph, 2MT odor). 2MT stimulation increases the stress hormone (corticosterone) in the blood. However, in the condition in which corticosterone was injected intraperitoneally to the same concentration as that increased by 2MT stimulation (Corticosterone ip), the number of neutrophils decreased. Compared to the condition in which physiological saline was injected intraperitoneally (Saline ip), the number of monocytes increased in the condition in which 2MT was injected intraperitoneally (black graph, 2MT ip). Similarly, compared to the condition without odor stimulation (no odor), the number of monocytes also increased in the condition with 2MT odor stimulation (polka dot graph, 2MT odor). 2MT stimulation increases the stress hormone (corticosterone) in the blood. However, in the condition in which corticosterone was injected intraperitoneally to the same concentration as that increased by 2MT stimulation (Corticosterone ip), the number of monocytes did not significantly increase. N=6, Student's t-test. * P<0.05,** P<0.01

[0071] Example 4 Experimental method Approximately 3-month-old C57 / BL6 mice were intraperitoneally injected with 200 μl of saline (control) or a 1% solution of each compound (dissolved in saline). Blood was collected 16 hours later, and the number of neutrophils in the peripheral blood was measured using a Siemens Advia 120.

[0072] result The results are shown in Figure 4. The chemical structures of the compounds used are shown in Figure 5. It was found that the following compounds increased neutrophils in peripheral blood. 4-Ethyl-2-methyl-thiazoline 2-Methyl-2-thiazoline 2-Mercaptothiazoline 2-(Methylthio)-2-thiazoline 4-(Methylthio)-2-thiazoline 2-Isobutyl-4,5-dimethyl-3-thiazoline 2-Ethoxythiazole 5-Acetyl-2,4-dimethylthiazole 4,5-Dimethylthiazole 5-Methylthiazole 4-tert-butyl-2-methylthiazole 2-(methylthio)benzothiazole 2-Methylthiomorpholine 2H-1,4-benzothiazin-3(4H)one Thiazolidine-2,4-dione 3-Acetyl-2,5-dimethylthiophene 2,5-Dimethylthiophene 2-Ethylthiophene 2-Hexylthiophene 3-Chlorothiophene Benzothiophene 2-Furfurylthio-3-methylpyrazine 2,3-Diethylpyrazine 2-Acetylpyrrole 2-Acetyl-1-methylpyrrole 3-Acetylpyridine 4-Acetylpyridine Azepane 6-Methoxyquinoline Morpholine n≧5, Student's t-test, * P<0.05, ** P<0.01, *** P<0.001

[0073] Example 5 Experimental method Approximately 3-month-old C57 / BL6 mice were intraperitoneally injected with 200 μl of saline (control) or a 1% solution of each compound (dissolved in saline). Blood was collected 16 hours later, and the number of neutrophils in the peripheral blood was measured using a Siemens Advia 120.

[0074] result The results and the chemical structures of the compounds used are shown in Figure 6. It was found that the following compounds increased neutrophils in peripheral blood. Allyl isothiocyanate Isopropyl isothiocyanate Metallyl isothiocyanate 4-Pentenyl Isothiocyanate 3-(Methylthio)propyl isothiocyanate Hexyl isothiocyanate Benzyl isothiocyanate N≧5, Student's t-test, * P<0.05, ** P<0.01, *** P<0.001

[0075] Example 6 Experimental method Approximately 3-month-old C57 / BL6 mice were intraperitoneally injected with 200 μl of saline (control) or a 1% solution of each compound (dissolved in saline). Blood was collected 16 hours later, and the number of monocytes in the peripheral blood was measured using Siemens Advia 120.

[0076] result The results and the chemical structures of the compounds used are shown in Figure 7. It was found that the following compounds increased the number of monocytes in peripheral blood. 2-Methyl-2-thiazoline 2-(Allylthio)-2-thiazoline 2-Mercaptothiazoline 4-Phenyl-thiomorpholine-1,1-dioxide 6-Methoxyquinoline 4-Acetylpyridine 2-Acetyl-3,5-Dimethylpyrazine 2-Furfurylthio-3-methylpyrazine Morpholine 2-Methyl-3-tetrahydrofuranthiol N≧5, Student's t-test, * P<0.05, ** P<0.01, *** P<0.001

[0077] Example 7 Experimental method Approximately 3-month-old C57 / BL6 mice were intraperitoneally injected with 200 μl of saline (control) or 1% allyl isothiocyanate solution (dissolved in saline). Blood was collected 16 hours later, and the number of monocytes in the peripheral blood was measured using Siemens Advia 120.

[0078] result The results are shown in Figure 8. Administration of allyl isothiocyanate increased the number of monocytes in peripheral blood. N=6, Student's t-test, * P<0.05

[0079] Example 8 Experimental method Approximately 3-month-old C57 / BL6 mice were intraperitoneally injected with 200 μl of saline (control) or a 1% solution of each compound (dissolved in saline). Blood was collected 16 hours later, and the basophil count in the peripheral blood was measured using a Siemens Advia 120.

[0080] result The results and the chemical structures of the compounds used are shown in Figure 9. It was found that administration of the following compounds increased the number of basophils in peripheral blood. 2,5-Dimethylthiophene 2,6-ru Chiji (2,6-Lutidine) 6-Methoxyquinoline 2-Acetyl-3,5-Dimethylpyrazine 2-Acetyl-5-methylfuran 2,5-Dimethylfuran 2,5-Dimethyltetrahydrofuran 2-Methyl-3-tetrahydrofuranthiol 2-Methylfuran 2,3-Dimethylbenzofuran N≧5, Student's t-test, * P<0.05, ** P<0.01, *** P<0.001

[0081] Example 9 Experimental method Approximately 3-month-old C57 / BL6 mice were intraperitoneally injected with 200 μl of saline (control) or a 1% solution of each compound (dissolved in saline). Blood was collected 16 hours later, and the lymphocyte count in the peripheral blood was measured using Siemens Advia 120.

[0082] result The results and the chemical structures of the compounds used are shown in Figure 10. It was found that administration of the following compounds increased the number of lymphocytes in the peripheral blood. 2,5-Dimethylthiophene 4-Phenyl-thiomorpholine-1,1-dioxide 2-Acetyl-6-methylpyridine 2,3-dimethylpyridine Morpholine (-)-Ambroxide N≧5, Student's t-test, * P<0.05

[0083] Example 10 Experimental method Approximately 3-month-old C57 / BL6 mice were intraperitoneally injected with 200 μl of saline (control) or a 1% solution of each compound (dissolved in saline). Blood was collected 16 hours later, and the percentage of monocytes in whole blood cells was measured using Siemens Advia 120.

[0084] result The results are shown in Figure 11, and the chemical structures of the compounds used are shown in Figure 12. It was found that administration of the following compounds increased the proportion of monocytes in whole blood cells. 2-(Allylthio)-2-thiazoline 2-Mercaptothiazoline 4,5-Dimethylthiazole 4-(Methylthio)-2-thiazoline 2-Methyl-2-thiazoline 4-Ethyl-2-methyl-thiazoline 5-Methylthiazole 2-Ethoxythiazole Thiomorpholine 2,3-Dimethylthiomorpholine 3-Acetyl-2,5-dimethylthiophene 3-Chlorothiophene 4-Acetylpyridine 6-Methoxyquinoline 2-Acetyl-3-ethylpyrazine 2-Methyl-(3 or 5 or 6)-methylthiopyrazine (a mixture of isomers) 2-Furfurylthio-3-methylpyrazine 2-Methylindole Azepane 2,5-Dimethyltetrahydrofuran 2-Methyl-3-tetrahydrofuranthiol N≧5, Student's t-test, * P<0.05, ** P<0.01, *** P<0.001

[0085] Example 11 Experimental method Approximately 3-month-old C57 / BL6 mice were intraperitoneally injected with 200 μl of saline (control) or 1% allyl isothiocyanate solution (dissolved in saline). Blood was collected 16 hours later, and the percentage of monocytes in whole blood cells was measured using Siemens Advia 120.

[0086] result The results and the chemical structures of the compounds used are shown in Figure 13. It was revealed that administration of allyl isothiocyanate increased the proportion of monocytes in whole blood cells. N=6, Student's t-test, *** P<0.001

[0087] Example 12 Experimental method Approximately 3-month-old C57 / BL6 mice were intraperitoneally injected with 200 μl of saline (control) or a 1% solution of each compound (dissolved in saline). Blood was collected 16 hours later, and the percentage of neutrophils in whole blood cells was measured using Siemens Advia 120.

[0088] result The results are shown in Figure 14, and the structures of the compounds used are shown in Figure 15. It was found that administration of the following compounds increased the percentage of neutrophils in whole blood cells. 4-Ethyl-2-methyl-thiazoline 2-Mercaptothiazoline 2-(Methylthio)-2-thiazoline 2-Methyl-2-thiazoline 4-(Methylthio)-2-thiazoline Thiazole 2-Methylthiazole 2-Isobutylthiazole 2,4,5-Trimethylthiazole 2-Chlorothiazole 2-Acetylthiazole 5-Acetyl-2,4-dimethylthiazole 4,5-Dimethylthiazole 2-Ethoxythiazole 2-Isopropyl-4-methylthiazole 5-Methylthiazole 2-(methylthio)benzothiazole 2,2-Dimethylthiazolidine 2-Methylthiomorpholine 2-Hexylthiophene 2-Propionylthiophene 3-Acetyl-2,5-dimethylthiophene 2-Methylthiophene 2-Acetyl-1-methylpyrrole 1-Furfurylpyrrole 2-Ethylpyrrole 3-Acetylpyridine 4-Acetylpyridine 2-Acetyl-3-ethylpyrazine 2,3-Diethylpyrazine 2-Methyl-(3 or 5 or 6)-methylthiopyrazine (a mixture of isomers) 2-Furfurylthio-3-methylpyrazine 6-Methoxyquinoline 2-Acetylpyrrole Benzothiophene 2,4-Dimethylpyrrole 3-Methylpyrrole 3-Chlorothiophene Azepane 2H-1,4-benzothiazin-3(4H)one 2-Acetyl-5-methylfuran 2,3-Dimethylbenzofuran N≧5, Student's t-test, * P<0.05, ** P<0.01, *** P<0.001

[0089] Example 13 Experimental method Approximately 3-month-old C57 / BL6 mice were intraperitoneally injected with 200 μl of saline (control) or a 1% solution of each compound (dissolved in saline). Blood was collected 16 hours later, and the percentage of neutrophils in whole blood cells was measured using Siemens Advia 120.

[0090] result The results and the chemical structures of the compounds used are shown in Figure 16. It was found that administration of the following compounds increased the proportion of neutrophils in whole blood cells. Allyl isothiocyanate Metallyl isothiocyanate 4-Pentenyl Isothiocyanate Hexyl isothiocyanate Benzyl isothiocyanate N≧5, Student's t-test, *** P<0.001

[0091] Example 14 Experimental method Approximately 3-month-old C57 / BL6 mice were intraperitoneally injected with 200 μl of saline (control) or a 1% solution of each compound (dissolved in saline). Blood was collected 16 hours later, and the percentage of basophils in whole blood cells was measured using Siemens Advia 120.

[0092] result The results are shown in Figure 17, and the chemical structures of the compounds used are shown in Figure 18. It was revealed that administration of the following compounds increased the proportion of basophils in whole blood cells. 2-Mercaptothiazoline 2-Chlorothiazole 2-Acetylthiazole 5-Acetyl-2,4-dimethylthiazole 2-Isopropyl-4-methylthiazole 2-Methylthiazole 2,2-Dimethylthiazolidine 3-Methylthiophene 3-Acetyl-2,5-dimethylthiophene 3-Chlorothiophene 2-Ethylpyrrole 2-Acetyl-3-ethylpyrazine 2,6-Lutidine 6-Methoxyquinoline 2-Methylfuran 2,3-Dimethylbenzofuran 3-Acetyl-2,5-dimethylfuran 2-Acetyl-5-methylfuran 2,5-Dimethyltetrahydrofuran 2-Ethylfuran N≧5, Student's t-test, * P<0.05, ** P<0.01, *** P<0.001

[0093] Example 15 Experimental method C57 / BL6 mice at about 3 months of age were intraperitoneally injected with 200 μl of saline (control) or a 1% solution of each compound (dissolved in saline). Blood was collected 16 hours later, and the proportion of lymphocytes in whole blood cells was measured using the Siemens Advia 120.

[0094] Results The results and the chemical structures of the compounds used are shown in Fig. 19. It was revealed that the administration of the following compounds increased the proportion of lymphocytes in whole blood cells. 4-Ethyl-2-methyl-thiazoline 5-Methylthiazole 5-Formylthiazole N≧5, Student’s t-test, * P<0.05, ** P<0.01, *** P<0.001

Industrial Applicability

[0095] The anti-inflammatory immune enhancer of the present invention can simultaneously induce an anti-inflammatory action and an immune enhancing action, and can be used to enhance immunity in the prevention or treatment of infectious diseases, sepsis or cancer.

[0096] This application is based on Japanese Patent Application No. 2020-054032 filed in Japan, the content of which is incorporated herein in its entirety.

Claims

1. 2-methyl-2-thiazoline, 4-Ethyl-2-methyl-2-thiazoline, 2-(methylthio)-2-thiazoline, 2,3-Diethylpyrazine, 2-(allylthio)-2-thiazoline, 2,6-Lutidine, Thiomorpholine, 2-Isobutylthiazole, 2,4,5-trimethylthiazole, 2-chlorothiazole, 2,2-dimethylthiazolidinedione, 2-ethylpyrrole, 2-ethylfuran, and 5-Formylthiazole An anti-inflammatory immunostimulant used to enhance immunity in the prevention or treatment of cancer, containing a heterocyclic compound selected from or 2H-1,4-benzothiazine-3(4H)-one, or a salt thereof, as an active ingredient.

2. An anti-inflammatory immunostimulant used to enhance immunity in the prevention or treatment of cancer, comprising 2-methyl-2-thiazoline or a salt thereof as an active ingredient.

Images