Dual activator for mincle receptor and dectin-2 receptor

Abstract

The present application discloses, as one embodiment of the invention, for example, a dual activator for a Mincle receptor and a Dectin-2 receptor, the dual activator comprising a glycolipid derivative (I) represented by formula (I) (each symbol in the formula is as described in the present specification) or a salt thereof as an active ingredient.

Description

Dual activator of Mincle receptor and Dectin-2 receptor

[0001] As one embodiment of the invention, the present application discloses a dual activator that can activate both the Mincle receptor and the Dectin-2 receptor, and that contains as an active ingredient a glycolipid derivative with a specific structure, and that is useful as a vaccine adjuvant or the like, and is useful, for example, in the field of medicine.

[0002] It is known that not only antigens but also compounds called "adjuvants," which activate innate immunity, play an important role in activating immune responses. In particular, it has been reported that activation of Mincle (Macrophage-inducible C-type lectin) enhances Th1-type immune responses through increased expression of costimulatory molecules (see, for example, Non-Patent Document 1). Those skilled in the art recognize that Mincle ligands have immunostimulatory effects and are useful as vaccine adjuvants. To date, attempts have been made to develop ligands that efficiently activate Mincle and to apply them to novel adjuvants (see, for example, Non-Patent Document 2). However, most adjuvants developed to date have targeted receptors involved in a single immune response. Receptor recognition of a ligand is the starting point of an immune response, but each receptor is known to form a different immune response (see, for example, Non-Patent Document 3). Therefore, a compound that is recognized by multiple receptors is expected to function as a ligand for multiple receptors and induce a broader immune response than a compound that targets a single receptor. As described above, the technical field has been awaited to provide an immune response activator that uses a compound that is recognized by multiple receptors and can induce an immune response by simultaneously targeting multiple receptors.

[0003] J. Immunol. , 2010, 184:2756Front. Immunol. , 2018, 8: 1940 Sci. Signal. , 2023 “Synthesis of mycobacterial phenolic glycolipids”, Scholarly Publications, Leiden University, 2022-10-13

[0004] In view of the above problems, the present application aims to disclose, as one embodiment of the invention, a dual activator that contains as an active ingredient a glycolipid derivative with a specific structure that can activate both the Mincle receptor and the Dectin-2 (dendritic cell-associated C-type lectin) receptor, and that is useful as a vaccine adjuvant, etc. Note that, although a compound corresponding to the glycolipid derivative is described in Non-Patent Document 4, there is no description that the compound has ligand activity for the Mincle receptor and / or the Dectin-2 receptor.

[0005] The present inventors used intermediate metabolites present, or assumed to be present, in the synthetic pathway of the glycolipid PhenGL-K-I possessed by Mycobacterium kansasii to screen for receptors for which they have ligand activity using NFAT-GFP reporter cells. As a result, they obtained the novel finding that one of the putative intermediates has ligand activity for Dectin-2 in addition to Mincle. Based on this finding, and as a result of further intensive studies, they found that glycolipid derivatives having a specific structure can activate both the Mincle receptor and the Dectin-2 receptor (i.e., dual activation), thereby completing the present invention. Specific embodiments of the present invention include the following, but the present invention is not limited thereto.

[0006] [1] Formula (I):

[0007]

[0008] (In the formula, R １ represents a hydroxyl group, R ２ represents a hydroxyl group, R ３ represents a hydrogen atom, a hydroxyl group, or C １－６ alkyl group, or C １－６ represents an alkoxy group, R ４ represents a hydrogen atom, a hydroxyl group, or C １－６ alkyl group, or C １－６ represents an alkoxy group,

[0009]

[0010] represents a single bond (without specifying the configuration); ring S2, ring S3, and ring S4 each independently represent an optionally substituted pyranose or an optionally substituted deoxypyranose; L represents C ６－１４ represents an arylene group, and R ａ is an optionally substituted C ３－４０ [3] The activator according to [1] above, which is a TNF production enhancer, INF-γ production enhancer, cytokine secretion promoter, or immunostimulant. [4] The activator according to [1] above, which is an immunostimulant. [5] The activator according to [1] above, which is a vaccine adjuvant. [6] The activator according to [5] above, which further contains an antigen. [7] The activator according to any of [1] to [6] above, wherein in the glycolipid derivative (I), the terminal sugar represented by ring S1 and the sugar represented by ring S2 are linked via a 1,3 glycosidic bond, as viewed from ring S1. [8] The activator according to any one of the above [1] to [7], wherein in the glycolipid derivative (I), the sugar represented by ring S2 and the sugar represented by ring S3 are linked by a 1,3 glycosidic bond when viewed from ring S2. [9] The activator according to any one of the above [1] to [8], wherein in the glycolipid derivative (I), the sugar represented by ring S3 and the sugar represented by ring S4 are linked by a 1,3 glycosidic bond when viewed from ring S3.

[10] A compound represented by the following formula (Ia):

[0011]

[0012] (In the formula, R １ represents a hydroxyl group, R ２ represents a hydroxyl group, R ３ represents a hydrogen atom, a hydroxyl group, or C １－６ alkyl group, or C １－６ represents an alkoxy group, R４ represents a hydrogen atom, a hydroxyl group, or C １－６ alkyl group, or C １－６ represents an alkoxy group, R ５ ~R １３ are each independently a hydroxyl group, C １－６ Alkyl group, C １－６ L and R represent an alkoxy group or an acyloxy group. ａ , and

[0013]

[0014] and each have the same meaning as defined above.

[11] The activator according to any one of the above items [1] to [9], comprising, as an active ingredient, a glycolipid derivative (I) represented by the formula (I) or a salt thereof.

[12] In the glycolipid derivative (I), R １ is a hydroxyl group, and R ２ is a hydroxyl group, and R ３ is a hydroxyl group, and R ４ But C １－６

[12] The activator according to any one of the above [1] to

[11] , wherein in the glycolipid derivative (I), R is an alkoxy group (preferably a methoxy group).

[13] The activator according to any one of the above [1] to

[11] , wherein in the glycolipid derivative (I), R is a phenylene group.

[14] The activator according to any one of the above [1] to

[13] , wherein in the glycolipid derivative (I), R is an alkoxy group (preferably a methoxy group). ａ "Optionally substituted C ３－４０ The hydrocarbon group in the "hydrocarbon group" is C ６－４０

[14] The activator according to any one of the above [1] to

[12] , wherein R is a hydrocarbon group. ａ "Optionally substituted C ３－４０ The substituents in the "hydrocarbon group" are 1) a hydroxyl group, 2) an oxo group, 3) an optionally substituted C ３-４０ hydrocarbon group, 4) C １－６ 5) an optionally substituted C ３－４０ 5) a hydrocarbon-carbonyloxy group, 6) a group containing an epitope sequence, 7) an amino group or an acylamino group, 8) a thiol group, and 9) a halogen atom. Preferably, the substituents are 1 to 5 of the following: 1) a hydroxyl group, 2) a C １－６alkoxy group, and 3) hydroxyl group, oxo group, and C １－６ C optionally substituted with 1 to 5 identical or different substituents selected from alkoxy groups 3－４０

[15] The activator according to any one of the above [1] to

[13] , wherein R is the same or different from 1 to 5 substituents selected from the group consisting of a hydrocarbon-carbonyloxy group, and a hydroxyl group. ａ is represented by the following formula (III):

[0015]

[0016] (In the formula, R １４ is C １－６ represents an alkyl group, m represents an integer of 13 to 21, n represents an integer of 15 to 20 (preferably 15 to 17), o represents an integer of 3 to 5, p represents an integer of 3 to 5, q represents an integer of 15 to 20 (preferably 15 to 17), and * represents the bonding position to L.

[16] The activating agent according to any one of the above-mentioned [1] to

[14] , wherein in the glycolipid derivative (I), the formula (Ia) is a group represented by the following formula (Iaa):

[0017]

[0018]

[17] The activator according to any one of the above [1] to

[16] , which contains the glycolipid derivative (I) or a salt thereof as the sole active ingredient.

[0019]

[18] A method for preventing and / or treating cancer, bacterial infection, fungal infection, viral infection, and / or allergic disease, comprising administering an effective amount of the glycolipid derivative (I) defined in [1] above or a salt thereof to a mammal in need thereof.

[19] A method for immunostimulation, comprising administering an effective amount of the glycolipid derivative (I) defined in [1] above or a salt thereof to a mammal in need thereof.

[20] The method according to

[18] or

[19] above, wherein the glycolipid derivative (I) or a salt thereof is administered as the sole active ingredient.

[21] The glycolipid derivative (I) defined in [1] above or a salt thereof, used for the prevention and / or treatment of cancer, bacterial infection, fungal infection, viral infection, and / or allergic disease.

[22] The glycolipid derivative (I) defined in [1] above or a salt thereof, used for immunostimulation.

[23] The glycolipid derivative (I) or a salt thereof according to

[21] or

[22] above, used as the sole active ingredient.

[24] Use of the glycolipid derivative (I) or a salt thereof defined in [1] above for the manufacture of a medicament for the prevention and / or treatment of cancer, bacterial infections, fungal infections, viral infections, and / or allergic diseases.

[25] Use of the glycolipid derivative (I) or a salt thereof defined in [1] above for the manufacture of a medicament for immunostimulation.

[26] Use according to

[24] or

[25] above for the manufacture of a medicament containing the glycolipid derivative (I) or a salt thereof as the sole active ingredient.

[0020] As one embodiment of the present invention, a dual activator capable of activating both the Mincle receptor and the Dectin-2 receptor, which contains as an active ingredient a glycolipid derivative with a specific structure, is disclosed, and is useful as a vaccine adjuvant or the like.

[0021] Figure 1 shows the results of evaluating the ligand activity of test compounds for various C-type lectin receptors in Example 1, which will be described later. Figure 2 shows the results of evaluating gene expression when human peripheral blood mononuclear dendritic cells (hMo-DCs) were stimulated with test compounds, which will be described later in Example 2.

[0022] The present invention will be described in detail below based on the following embodiments, but the present invention is not limited thereto. Those skilled in the art may modify the embodiments of the present invention in various aspects without departing from the spirit of the present invention, and such modifications are also included within the scope of the present invention.

[0023] One embodiment of the present invention is as follows: "[A] A compound of the following formula (I):

[0024]

[0025] (In the formula, R １ represents a hydroxyl group, R ２ represents a hydroxyl group, R ３ represents a hydrogen atom, a hydroxyl group, or C １－６ alkyl group, or C １－６ represents an alkoxy group, R ４ represents a hydrogen atom, a hydroxyl group, or C １－６ alkyl group, or C １－６ represents an alkoxy group,

[0026]

[0027] represents a single bond (without specifying the configuration); ring S2, ring S3, and ring S4 each independently represent an optionally substituted pyranose or an optionally substituted deoxypyranose; L represents C ６－１４ represents an arylene group, and R ａ is an optionally substituted C ３－４０ A dual activator of the Mincle receptor and the Dectin-2 receptor ("activator (A)"), which contains, as an active ingredient, a glycolipid derivative (I) represented by the formula:

[0028] [Regarding the receptor] The activator (A) is a dual activator that can activate both the Mincle receptor and the Dectin-2 receptor. Here, "dual activation" refers to the activation of both the Mincle receptor and the Dectin-2 receptor being achieved in research or medical settings by a single glycolipid derivative (I) or a salt thereof. Depending on the type of glycolipid derivative (I) or a salt thereof ("active ingredient") used as the active ingredient of the activator (A), the strength of the two activations achieved by the active ingredient and the relationship between the degrees of the two activations achieved by the active ingredient may vary depending on the specific active ingredient used. For example, variations such as a situation where the degree of activation of the Mincle receptor is stronger with one active ingredient than the degree of activation of the Dectin-2 receptor with another active ingredient, and the degrees of both are equal with another active ingredient, or vice versa, are included within the scope of "dual activation." The Mincle receptor is a type of pattern-recognition receptor (PRR) that controls innate immunity. As described above, those skilled in the art recognize that activation of the Mincle receptor has an immunostimulatory effect, and compounds that serve as ligands for the receptor are useful as vaccine adjuvants. The Dectin-2 receptor, like the Mincle receptor, is a type of C-type lectin receptor. When activated by ligand binding, the Dectin-2 receptor promotes the differentiation of T cells into Th17 cells through cytokine production, and the produced IL-17 is known to play an important role in defense against fungal infections (Saijo et al. Immunity 2010; Kingston. Nat. Rev. Immunol. 2022). As demonstrated by tests using a representative glycolipid derivative (I), which is the active ingredient of activator (A), in the Examples section below, activator (A) can activate both the Mincle receptor and the Dectin-2 receptor simultaneously (including the case where there is a time lag). Thus, activator (A) can activate immune cells via both the Mincle receptor and the Dectin-2 receptor, and by expressing genes specific to each of them, can induce a broader immune response than single stimulation.As a result, in addition to the induction of the Th1 / Th17 immune response via the Mincle receptor as described above, it is believed that the immune response can be additively enhanced by raising the level of the Th17 immune response via the Dectin-2 receptor, and the activator (A) is useful as a drug and / or vaccine adjuvant based on the effects exerted by the Th1 and / or Th17 immune response. The finding that a derivative having a structure in which four sugars are linked, such as the glycolipid derivative (I), can activate both the Mincle receptor and the Dectin-2 receptor was not previously known and could not have been predicted by those skilled in the art. Note that, in order to achieve this dual activation, in the glycolipid derivative (I), R. １ and R ２ It is considered that an important structural feature is that both of the sugars in S1 are hydroxyl groups. In addition, it is also considered that an important structural feature is that the sugar in S1 is a mannose type.

[0029] [Regarding Glycolipid Derivative (I)] (Structure of Glycolipid Derivative (I)) Each symbol of the glycolipid derivative (I) will be explained. ａ－ｂ ” (e.g., C １－６ ) indicates that the number of carbon atoms constituting the group is a to b (for example, 1 to 6). In this specification, the expression "optionally substituted" indicates that the group may be substituted at any substitutable position in the group to be substituted. In this specification, examples of "halogen atom" include fluorine, chlorine, bromine, and iodine. In this specification, "C １－６ Examples of the alkyl (group) include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. １－６ Examples of the alkoxy (group) include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0030] In this specification, "pyranose" refers to an aldohexose (six-carbon sugar) carbohydrate that forms a six-membered ring with five carbons and one oxygen at the vertices, and examples thereof include allopyranose, altropyranose, glucopyranose, mannopyranose, gulopyranose, idopyranose, galactopyranose, and talopyranose. In carrying out the present invention, either the D-form or the L-form of the "pyranose" can be used. Furthermore, the "pyranose" used may be either natural or non-natural. The hydrogen atom of the hydroxyl group of the "pyranose" may be substituted, and suitable substituents include C １－６ alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, etc.), acyl groups (preferably C １－６ alkanoyl groups (for example, acetyl, etc.) The number of substituted hydroxyl groups is preferably 1 to 3.

[0031] As used herein, the term "deoxypyranose" refers to a pyranose having a structure in which one or more of the hydroxyl groups of the above-described "pyranose (aldohexose)" have been substituted with a hydrogen atom, and examples thereof include 2- (or 3- or 4- or 5- or 6-) deoxyallopyranose, 2- (or 3- or 4- or 5- or 6-) deoxyaltropyranose, 2- (or 3- or 4- or 5- or 6-) deoxyglucopyranose, 2- (or 3- or 4- or 5- or 6-) deoxymannopyranose, 2- (or 3- or 4- or 5- or 6-) deoxygulopyranose, 2- (or 3- or 4- or 5- or 6-) deoxyidopyranose, 2- (or 3- or 4- or 5- or 6-) deoxygalactopyranose, and 2- (or 3- or 4- or 5- or 6-) deoxytalopyranose. Although not limited thereto, preferred examples include 2- (or 3- or 4- or 5- or 6-) deoxyglucopyranose and 2- (or 3- or 4- or 5- or 6-) deoxymannopyranose, more preferred examples include 6-deoxypyranose, and even more preferred examples include 6-deoxyglucopyranose and 6-deoxymannopyranose (rhamnopyranose). The "deoxypyranose" may have a hydrogen atom of a hydroxyl group substituted, and preferred substituents include C １－６ alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, etc.), acyl groups (preferably C １－６ alkanoyl groups (for example, acetyl, etc.) The number of substituted hydroxyl groups is preferably 1 to 3.

[0032] In this specification, "C ６－１４ The "arylene group" is C ６－１４It refers to a divalent group derived from arene (such as benzene or naphthalene), and examples thereof include 1,2-, 1,3-, or 1,4-phenylene, 1,2-, 1,3-, 2,3-, 1,4-, 1,5-, 1,6-, 1,7-, or 1,8-naphthylene, and the like.

[0033] In this specification, "C ３－４０The term "hydrocarbon group" refers to a saturated or unsaturated, linear or branched hydrocarbon group having 3 to 40 carbon atoms, and specific examples include propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, 2-hexenyl, 1-hexynyl, heptyl, 1-methylhexyl, 6-heptynyl, octyl, 2-methylheptyl, 2-octyl, and the like. 7-thenyl, nonyl, 3-methyloctyl, decyl, 4-methylnonyl, undecyl, 5-methyldecyl, dodecyl, 6-methylundecyl, tridecyl, 7-methylundecyl, tetradecyl, 8-methyltridecyl, pentadecyl, 9-methyltetradecyl, hexadecyl, 10-methylpentadecyl, 12-hexadecenyl, 1-hexadecynyl, heptadecyl, 11-methylhexadecyl, 16-heptadecynyl, octadecyl, 12-methylhexadecyl, 12-octadecen-17-ynyl, nonadecyl 13-methyloctadecyl, icosyl, 14-methylnonadecyl, henicosyl, 15-methylicosyl, docosyl, 16-ethylicosyl, tricosyl, 10,17-dimethylhenicosyl, tetracosyl, 10,18-dimethylhenicosyl, pentacosyl, 19-ethyltricosyl, hexacosyl, 22-hexacosenyl, 1-hexacosinyl, 10,20-dimethyltetracosyl, heptacosyl, 21-methylhexacosyl, 26-heptacosinyl, octacosyl, 10,21-dimethylhexacosyl, 22-hexacosinyl Xacosene-27-ynyl, nonacosyl, 10-methyl-15-ethyl-22-propyltriacosyl, triacontyl, 24-methylnonacosyl, hentriacontyl, 25-methyltriacontyl, 1,3,5,7-tetramethylheptacosyl, dotriacontyl, 26-ethyltriacontyl, tritriacontyl, 20,27-dimethylhentriacontyl, tetratriacontyl, 20,28-dimethyldotriacontyl, pentatriacontyl, 29-methyltetracontyl, hexatriacontyl, 20,Examples of the "C, ３－４０ The term "hydrocarbon group" refers to a group having a ring structure (e.g., C ３－６ The cycloalkane may have 1 to 5 cycloalkane moieties (e.g., cyclopropane, cyclobutane, cyclopentane, cyclohexane, etc.). Examples include groups represented by the following formulas:

[0034]

[0035] (In the formula, m and n each independently represent an integer, and the sum of m and n is 33 or less.)

[0036] The "C ３－４０ The "hydrocarbon group" is preferably a hydrocarbon group having 6 or more carbon atoms, more preferably a hydrocarbon group having 6 to 35 carbon atoms. More specific examples include saturated or unsaturated hydrocarbon groups having 6 to 10, 11 to 15, 16 to 20, 21 to 25, 26 to 30, or 30 to 35 carbon atoms. Furthermore, a hydrocarbon group having 1 to 5 unsaturated bonds in the molecule, which may have 1 to 5 ring structure moieties in the molecule, or a saturated hydrocarbon group (alkyl group) is preferred.

[0037] The "C ３－４０ Examples of the substituents that may be substituted on the "hydrocarbon group" include: 1) a hydroxyl group, 2) an oxo group, 3) an optionally substituted C ３-４０ hydrocarbon group, 4) C １－６ 5) an optionally substituted C ３－４０ a hydrocarbon-carbonyloxy group, 6) a group containing an epitope sequence, 7) an amino group or an acylamino group (preferably an amino group or an optionally substituted C ３－４０8) a hydrocarbon-carbonylamino group), thiol group, and 9) a halogen atom.

[0038] Among the above, more preferred substituents are: 1) a hydroxyl group, 2) C １－６ an alkoxy group, and 3) an optionally substituted C ３－４０ hydrocarbon-carbonyloxy group.

[0039] The above-mentioned "optionally substituted C ３-４０ "hydrocarbon group," "optionally substituted C ３－４０ "hydrocarbon-carbonyloxy group" and "optionally substituted C ３－４０ "C" in "hydrocarbon-carbonylamino group" ３－４０ The "hydrocarbon" portion is the "C ３－４０ The substituents thereof include a hydroxyl group, an oxo group, a C １－６ Examples thereof include an alkoxy group.

[0040] The "group containing an epitope sequence" includes a group containing an epitope sequence determined depending on the target antigen (for example, a peptide group containing an epitope sequence), but may also be the epitope sequence itself. The epitope sequence includes a T cell epitope or a B cell epitope. Those skilled in the art will be able to select the "group containing an epitope sequence" according to the purpose and appropriately determine the "C ３－４０ The hydroxyl group can be linked to a "hydrocarbon group."

[0041] Preferred embodiments of the groups represented by each symbol in the glycolipid derivative (I) are explained below.

[0042] Rings S2, S3, and S4 are as defined above, but rings S2, S3, and S4 may each be any sugar independently selected from an optionally substituted pyranose and an optionally substituted deoxypyranose. For example, rings S2, S3, and S4 may each be an optionally substituted pyranose, or an optionally substituted deoxypyranose, or a pyranose in which one or two of rings S2, S3, and S4 are optionally substituted, and the remaining ring is an optionally substituted deoxypyranose. Furthermore, the sugar represented by ring S2 (hereinafter also referred to as "ring S2"), the sugar represented by ring S3 (hereinafter also referred to as "ring S3"), and the sugar represented by ring S4 (hereinafter also referred to as "ring S3") may each independently be a D-form or an L-form. Those skilled in the art can carry out the present invention by appropriately selecting rings S2, S3, and S4, but preferred specific examples include the following combinations (but are not limited to these): (1) Ring S2 is an optionally substituted pyranose or an optionally substituted deoxypyranose, preferably containing a hydroxyl group, C １－６ Alkyl group, C １－６ and pyranose or deoxypyranose (preferably deoxypyranose) optionally substituted with 1 to 3 substituents selected from an alkoxy group and an acyl group, and more preferably, each of the hydroxyl groups is C １－６ (2) Rings S3 and S4 each independently represent an optionally substituted pyranose or an optionally substituted deoxypyranose, preferably a hydroxyl group, C １－６ Alkyl group, C １－６and pyranose or deoxypyranose (preferably deoxypyranose) optionally substituted with 1 to 3 substituents selected from an alkoxy group and an acyl group, and more preferably, each of the hydroxyl groups is substituted with 1 to 2 C １－６ Examples include rhamnose (6-deoxymannose) or fucose (6-deoxy-galactose) (preferably rhamnose (6-deoxymannose)), which may be substituted with an alkyl group.

[0043] Preferred combinations of rings S2 to S4 are, for example, as follows: Ring S2, ring S3 and ring S4 each independently represent a hydroxyl group, C １－６ Alkyl group, C １－６ It is a deoxypyranose optionally substituted with 1 to 3 substituents selected from an alkoxy group and an acyl group, and more preferably, the hydroxyl groups in rings S2, S3 and S4 are each independently selected from C １－６ Fucose (6-deoxy-galactose) optionally substituted with 1 to 2 substituents selected from an alkyl group and an acyl group, or a hydroxyl group selected from C １－６ Rhamnose (6-deoxymannose) optionally substituted with 1 to 2 substituents selected from an alkyl group and an acyl group, and more preferably, the ring S2 is a hydroxyl group represented by C １－６ fucose (6-deoxy-galactose) optionally substituted by 1 to 2 substituents selected from an alkyl group and an acyl group, wherein ring S3 and ring S4 each independently have 1 to 2 hydroxyl groups each independently selected from C １－６ Rhamnose (6-deoxymannose) optionally substituted with an alkyl group.

[0044] Between ring S1 and ring S2, between ring S2 and ring S3, and between ring S3 and ring S4

[0045]

[0046] indicates the glycosidic bond connecting the two sugars.

[0047] The type of glycosidic bond is not particularly limited and is determined appropriately depending on the types of sugars constituting ring S1, ring S2, ring S3, and ring S4, for example. For example, (1) a case where the terminal sugar represented by ring S1 and the sugar represented by ring S2 are linked by a 1,3 glycosidic bond when viewed from ring S1 is exemplified as a preferred bonding type; (2) a case where the sugar represented by ring S2 and the sugar represented by ring S3 are linked by a 1,3 glycosidic bond when viewed from ring S2 is exemplified as a preferred bonding type; and (3) a case where the sugar represented by ring S3 and the sugar represented by ring S4 are linked by a 1,3 glycosidic bond when viewed from ring S3 is exemplified as a preferred bonding type.

[0048] A preferred embodiment of the above-mentioned rings S1, S2, S3 and S4, and one of the bonding modes between the rings, includes a structure represented by the following formula (Ia).

[0049] (In the formula, R １ represents a hydroxyl group, R ２ represents a hydroxyl group, R ３ represents a hydrogen atom, a hydroxyl group, or C １－６ alkyl group, or C １－６ represents an alkoxy group, R ４ represents a hydrogen atom, a hydroxyl group, or C １－６ alkyl group, or C １－６ represents an alkoxy group, R ５ ~R １３ are each independently a hydroxyl group, C １－６ Alkyl group, C １－６ It represents an alkoxy group or an acyloxy group, and the other symbols are as defined above.

[0050] Here, preferably, R １ represents a hydroxyl group, R ２ represents a hydroxyl group, R ３ represents a hydroxyl group, R ４ is C １－６ represents an alkoxy group, R ５ is C １－６ represents an alkyl group, R ６ is an acyloxy group (preferably C １－６alkanoyloxy group), R ７ is C １－６ represents an alkoxy group, R ８ is C １－６ represents an alkyl group, R ９ represents a hydroxyl group, R １０ is C １－６ represents an alkoxy group, R １１ is C １－６ represents an alkyl group, R １２ is C １－６ represents an alkoxy group, and R １３ is C １－６ represents an alkoxy group.

[0051] In the structure represented by formula (Ia), a more preferred structure is the following formula (Iaa):

[0052]

[0053] In the formula, each symbol has the same meaning as defined above for the structure represented by formula (Ia).

[0054] L is as defined above, but is preferably a phenylene group, more preferably a 1,4-phenylene group.

[0055] R ａ is as defined above, but is preferably optionally substituted; C ６－４０ A hydrocarbon group (preferably C ６－４０ alkyl group), and more preferably 1) a hydroxyl group, 2) an oxo group, 3) an optionally substituted C ３-４０ hydrocarbon group, 4) C １－６ 5) an optionally substituted C ３－４０ 6) a group containing an epitope sequence; 7) an amino group or an optionally substituted C ３－４０ C may be substituted with 1 to 5 identical or different substituents selected from a hydrocarbon-carbonylamino group, 8) a thiol group, and 9) a halogen atom; ６－４０ A hydrocarbon group (preferably C ６－４０alkyl group), and more preferably 1) a hydroxyl group, 2) an oxo group, 3) a hydroxyl group, an oxo group, and C １－６ C optionally substituted with 1 to 5 identical or different substituents selected from alkoxy groups ３－４０ Hydrocarbon group, 4) C １－６ alkoxy group, 5) hydroxyl group, oxo group, and C １－６ C optionally substituted with 1 to 5 identical or different substituents selected from alkoxy groups ３－４０ hydrocarbon-carbonyloxy group, 6) a group containing an epitope sequence, 7) an amino group, or a hydroxyl group, an oxo group, and C １－６ C optionally substituted with 1 to 5 identical or different substituents selected from alkoxy groups ３－４０ C may be substituted with 1 to 5 identical or different substituents selected from a hydrocarbon-carbonylamino group, 8) a thiol group, and 9) a halogen atom; ６－４０ A hydrocarbon group (preferably C ６－４０ alkyl group), and particularly preferably: 1) a hydroxyl group, 2) a C １－６ 3) an alkoxy group, a hydroxyl group, an oxo group, and C １－６ C optionally substituted with 1 to 5 identical or different substituents selected from alkoxy groups 3－４０ Hydrocarbons (preferably C 3－４０ C is a substituted or unsubstituted alkyl group, optionally substituted by 1 to 5 identical or different substituents selected from ６－４０ It is an alkyl group. ６－４０ Hydrocarbon groups and C ６－４０ The alkyl group is C ６－３５ Hydrocarbon groups and C ６－３５ It is more preferable that the alkyl group is C. ６－４０ Hydrocarbon groups and C ６－４０ Each alkyl group may have 1 to 5 ring structure moieties in the molecule.

[0056] The above R ａ One preferred specific embodiment of the above is a group represented by the following formula (III):

[0057]

[0058] (In the formula, R １４ is C １－６ represents an alkyl group, m represents an integer of 13 to 21, n represents an integer of 15 to 20 (preferably 15 to 17), o represents an integer of 3 to 5, p represents an integer of 3 to 5, q represents an integer of 15 to 20 (preferably 15 to 17), and * represents the bonding position to L.

[0059] In carrying out the present invention, glycolipid derivative (I) can be used in either its free form or its salt form (preferably, its pharmaceutically acceptable salt). Those skilled in the art can carry out the present invention by appropriately selecting either form based on the properties of the individual glycolipid derivative (I) used. Examples of pharmaceutically acceptable salts include salts with acids such as salts with inorganic acids (e.g., hydrochloride, hydrobromide, sulfate, phosphate), salts with organic acids (e.g., acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate, maleate), salts with bases (e.g., alkali metal salts (e.g., sodium salt, potassium salt), alkaline earth metal salts (e.g., calcium salt), and salts with amino acids (e.g., glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, aspartate).

[0060] (Method for Obtaining Glycolipid Derivative (I)) As the glycolipid derivative (I) or a salt thereof, a known compound or a compound that can be easily synthesized from a known compound by a person skilled in the art can be used. For example, reference can be made to the glycolipid derivatives described in detail in "Synthesis of mycobacterial phenolic glycolipids" (Chapter 6; pp. 197-260) (Scholarly Publications, Leiden University, 2022-10-13, https: / / hdl.handle.net / 1887 / 3480227; Non-Patent Document 4). Although general production methods are also described, for example, a person skilled in the art can obtain glycolipid derivative (I) or a salt thereof according to the following synthesis scheme in accordance with General procedure C: Sonogashira cross coupling.

[0061]

[0062] (In the above formula, R ａ ' is an optionally substituted C ３－３８ represents a hydrocarbon group, X represents a halogen atom, and the other symbols are as defined above.

[0063] [Usefulness of Activator (A)] (1) Use for Prevention / Treatment of Diseases The glycolipid derivative (I) or its salt, which is the active ingredient of activator (A), is useful as a pharmaceutical for the prevention and / or treatment of diseases, containing itself as an active ingredient. As demonstrated by the representative compound in the test examples described below, glycolipid derivative (I) or its salt is a ligand that can activate both the Mincle receptor and the Dectin-2 receptor, and can activate the actions of both receptors. Through this activation of the Micle receptor, activity of the innate immune system is evoked, resulting in, for example, a protective effect against infections against intracellular parasitic pathogens. Furthermore, glycolipid derivative (I) or its salt activates bone marrow-derived macrophages through activation of the Mincle receptor, and exhibits the effect of enhancing TNF (tumor necrosis factor) production, and is therefore useful as an anticancer agent (a preventive and / or therapeutic agent for cancer). The target cancer is not particularly limited, and examples thereof include cancers [e.g., colon cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer, duodenal cancer, small intestine cancer, breast cancer, ovarian cancer, testicular tumor, prostate cancer, thyroid cancer, kidney cancer, uterine cancer, etc.]. Furthermore, glycolipid derivative (I) or a salt thereof also exhibits the effect of enhancing the production of IFN-γ through activation of the Mincle receptor, and is therefore useful as a preventive and / or therapeutic agent for bacterial infections, viral infections, and / or allergic diseases. Furthermore, through activation of the Dectin-2 receptor, cytokine production promotes the differentiation of T cells into Th17 cells, and the produced IL-17 induces activity of the adaptive immune system, thereby exerting an infection-protecting effect against, for example, fungi.

[0064] Hereinafter, an embodiment in which an activator (A) containing a glycolipid derivative (I) or a salt thereof as an active ingredient is used as the above-mentioned medicine will be described in detail. "Prevention" includes preventing the onset of a disease (all pathologies or symptoms, or one or more pathologies or symptoms) and delaying the onset of the disease. "Prophylactically effective amount" refers to a dose of glycolipid derivative (I) or a salt thereof sufficient to achieve this purpose. "Treatment" includes curing a disease (all pathologies or symptoms, or one or more pathologies or symptoms), ameliorating the disease, and suppressing the progression of the severity of the disease. "Therapeutically effective amount" refers to a dose of glycolipid derivative (I) or a salt thereof sufficient to achieve this purpose.

[0065] The glycolipid derivative (I) or a salt thereof can be used as the activator (A) either alone or in the form of a pharmaceutical containing the glycolipid derivative (I) or a salt thereof as an active ingredient together with a pharmaceutically acceptable carrier. More specifically, the glycolipid derivative (I) or a salt thereof can be used as the activator (A) in either the form of a pharmaceutical consisting of the glycolipid derivative (I) or a salt thereof itself as the sole active ingredient, or the form of a pharmaceutical containing the glycolipid derivative (I) or a salt thereof as the sole active ingredient together with a pharmaceutically acceptable carrier (which has substantially no pharmacological activity) (the latter is also referred to as a "pharmaceutical composition"). Examples of such pharmaceutical compositions include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (including soft capsules and microcapsules), troches, syrups, liquids, emulsions, suspensions, controlled-release preparations (e.g., immediate-release preparations, sustained-release preparations, sustained-release microcapsules), aerosols, films (e.g., orally disintegrating films, oral mucosal patch films), injections (e.g., subcutaneous injections, intravenous injections (e.g., bolus), intramuscular injections, intraperitoneal injections), drip infusions, transdermal preparations, ointments, lotions, patches, suppositories (e.g., rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, etc. As the above-mentioned "pharmaceutically acceptable carrier," various carriers commonly used in the field of formulation technology can be used. Specific examples of "pharmaceutically acceptable carriers" that can be used in solid preparations include excipients (e.g., lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, etc.), lubricants (e.g., magnesium stearate, talc, colloidal silica, etc.), binders (e.g., crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, etc.), and disintegrants (e.g., starch, carboxymethylcellulose, carboxymethylcellulose calcium, sodium carboxymethylstarch, L-hydroxypropylcellulose, etc.).Liquid preparations may contain solvents (e.g., water for injection, isotonic saline, alcohol, propylene glycol, macrogol, sesame oil, etc.), solubilizing agents (e.g., polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, etc.), suspending agents (e.g., surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, glycerin monostearate, etc.; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, etc.), isotonic agents (e.g., glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, etc.), buffers (e.g., buffer solutions such as phosphates and citrates, etc.), and soothing agents (e.g., benzyl alcohol, etc.). If necessary, formulation additives such as preservatives (e.g., parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, sorbic acid, etc.), antioxidants (e.g., sulfites, ascorbic acid, α-tocopherol, etc.), colorants, sweeteners, etc. may be further added. The above-mentioned pharmaceutical compositions can be prepared by adding glycolipid derivative (I) or a salt thereof in a proportion of usually 0.01 to 99% (w / w), preferably 0.1 to 85% (w / w), based on the total amount of the formulation, although this varies depending on the dosage form, administration method, carrier, etc. The pharmaceutical compositions can be prepared by conventional methods in the field of formulation technology, depending on their form. The pharmaceutical compositions of the present invention may be formulated into controlled-release formulations, such as immediate-release or sustained-release formulations containing the active ingredient.

[0066] The glycolipid derivative (I) or its salt is expected to have low toxicity and few side effects, and also has excellent properties as a pharmaceutical. Therefore, the activator (A) can be safely administered to any animal having an immune system, including mammals (e.g., humans, monkeys, dogs, cattle, horses, etc.), particularly humans. The glycolipid derivative (I) or its salt, either alone or as a pharmaceutical composition, can be administered orally or parenterally (e.g., intravenously, by infusion, intramuscularly, subcutaneously, intraviscerally, intranasally, intradermally, transdermally, by ophthalmic administration, intracerebrally, rectally, intravaginally, intraperitoneally, and into a lesion). The dosage of the glycolipid derivative (I) or its salt varies depending on the subject, route of administration, and the age and symptoms of the subject, but is not particularly limited. For example, the dosage of the glycolipid derivative (I) or its salt, as the active ingredient, per oral administration is 0.1 to 1000 mg, preferably 0.1 to 500 mg, more preferably 1 to 300 mg. The dose can be administered in 1 to 3 divided doses per day. When administered in the form of a sustained-release preparation, it can also be administered every other day or at intervals longer than that, so as to correspond to the dose.

[0067] (2) Use as an Adjuvant As demonstrated by the representative compounds in the test examples described below, the glycolipid derivative (I) or its salt exhibits immunostimulatory activity and can therefore be used as an adjuvant. In the present invention, "adjuvant" is a general term for a substance that can increase antibody production and enhance immune responses when combined with an antigen. For embodiments in which an activator (A) containing the glycolipid derivative (I) or its salt as an active ingredient is used as an adjuvant, the above-mentioned embodiments for the "pharmaceutical composition" can be referenced, but more specific embodiments are described below. However, the present invention is not limited to these.

[0068] (Antigen) When the active agent (A) is used as an adjuvant, the antigen to be used in combination is not particularly limited as long as it is a substance capable of inducing an immune response, and examples thereof include (1) allergens (e.g., pollen allergens, food allergens, house dust allergens, etc.), (2) pathogen antigens (e.g., (i) pathogenic virus antigens (e.g., virus antigens such as human immunodeficiency virus, hepatitis virus, influenza virus, etc.), (ii) pathogenic microbial antigens (e.g., pathogenic bacteria (e.g., Streptococcus pneumoniae, Clostridium tetani, Corynebacterium diphtheriae, Bordetella pertussis, Vibrio cholerae, Salmonella enterica, Salmonella typhi, Clarias spp., etc.), and (iii) pathogenic bacteria (e.g., Streptococcus pneumoniae, Clostridium tetani, Corynebacterium diphtheriae, Bordetella pertussis, Vibrio cholerae, Salmonella enterica, Salmonella typhi, etc.). Mydia, Mycobacteria, Legionella, etc.), pathogenic yeast (e.g., Aspergillus, Candida, etc.), etc.), (iii) pathogenic protozoan antigens (e.g., antigens expressed in malaria, schistosomes, etc.), etc.), (3) in vivo self-antigens (e.g., amyloid beta and prions in neurological diseases such as Alzheimer's disease and Creutzfeldt-Jakob disease; ApoB100 in cardiovascular diseases such as arteriosclerosis and hypertension), (4) tumor antigens (e.g., antigens of solid tumors including epithelial and non-epithelial tumors, antigens of tumors in hematopoietic tissues, etc.), etc.

[0069] (Dosage Form) When the active agent (A) is used as an adjuvant, its dosage form can refer to the dosage forms described above for the "pharmaceutical composition." More specifically, it may be, for example, an aqueous or non-aqueous (e.g., oily, etc.) solution, suspension, emulsion, etc. These can be prepared by mixing the glycolipid derivative (I) or a salt thereof with a pharmaceutically acceptable carrier (e.g., solvent, suspending agent, etc.) and using methods such as manual shaking, mechanical shaking, ultrasonic dispersion, dispersion using a homomixer, self-emulsification, membrane emulsification, D-phase emulsification, vacuum emulsification, ultra-high pressure emulsification, etc. (hereinafter also referred to as "the present adjuvant"). The present adjuvant may also contain a target antigen in its formulation.

[0070] (Route of Administration) The adjuvant may be administered by a route selected from the group consisting of oral administration, intramuscular administration, transdermal administration, intradermal administration, subcutaneous administration, intraperitoneal administration, intratracheal administration, nasal administration (intranasal administration), intraocular administration, intravaginal administration, rectal administration, intravenous administration, intraintestinal administration, and inhalation administration.

[0071] (Dosage) The content of glycolipid derivative (I) or its salt in the present adjuvant is not particularly limited and may be adjusted appropriately depending on, for example, the type of antigen, the dose of the antigen, the subject of administration, the administration form, and the administration route, but is, for example, 2 μg to 1000 mg, usually 2 μg to 500 mg, preferably 2 μg to 20 mg, and more preferably 20 μg to 200 μg, for oral, intramuscular, transdermal, intradermal, subcutaneous, or intraperitoneal administration. For intratracheal, nasal (transnasal), intraocular, intravaginal, rectal, intravenous, small intestinal, or inhalation administration, it is usually 0.01 μg to 1 mg, preferably 0.1 μg to 100 μg. The dose of the present adjuvant can be appropriately determined by one skilled in the art depending on the characteristics of the target antigen, etc.

[0072] (Subject to be administered) The subject to which the present adjuvant is administered is not particularly limited as long as it is an animal having an immune system, and it can be safely administered to, for example, mammals (e.g., humans, monkeys, dogs, cows, horses, etc.) (particularly humans).

[0073] (Administration Timing) The adjuvant may be administered as a single dose or multiple consecutive doses. When the adjuvant is administered consecutively, the administration period is not particularly limited and may be appropriately determined depending on, for example, the type of antigen, the subject of administration, the administration form, and the administration route. However, it is usually in the range of 1 to 150 days, and can also be administered for an appropriate period of 1 to 120 days, 1 to 60 days, or 1 to 30 days, as necessary. The administration period of the adjuvant is not particularly limited and may be administered before, simultaneously with, or after the administration of the antigen. Those skilled in the art can appropriately determine this period depending on the characteristics of the target antigen, etc.

[0074] (Combination Use) The present adjuvant may be used in combination with other adjuvants. Examples of other adjuvants include adjuvants used in the art, such as Freund's incomplete adjuvant, Freund's complete adjuvant, fine particles (e.g., uric acid crystals, silica, aluminum hydroxide gel, polystyrene, asbestos, titanium dioxide, black nickel oxide, etc.), lipopolysaccharides (LPS), etc. If necessary, the present adjuvant may contain other adjuvants in its formulation.

[0075] The active agent (A) can also be provided as a vaccine using the glycolipid derivative (I) or a salt thereof as an antigen (hereinafter, also referred to as "the present vaccine"). This vaccine may be used in combination with other antigens, if necessary. The antigens can refer to those described above for the present adjuvant. The present vaccine can be administered by a route selected from the group consisting of oral, intramuscular, transdermal, intradermal, subcutaneous, intraperitoneal, intratracheal, nasal (intranasal), intraocular, intravaginal, rectal, intravenous, small intestinal, and inhalation administration, with subcutaneous or nasal (intranasal) administration being particularly preferred. The content of the antigen, such as the glycolipid derivative (I) or a salt thereof, in the present vaccine may be an effective amount to function as a vaccine, and this amount can be determined by one of ordinary skill in the art without undue experimentation, for example, based on tests using laboratory animals. Specifically, the content of the antigen in the present vaccine is typically 1 μg to 100 μg. The content of glycolipid derivative (I) or a salt thereof in the present vaccine may be adjusted appropriately depending on, for example, the subject of administration, the dosage form, and the administration route, and is not particularly limited. For oral, intramuscular, transdermal, intradermal, subcutaneous, or intraperitoneal administration, the content is, for example, 2 μg to 1000 mg, usually 2 μg to 500 mg, preferably 2 μg to 20 mg, and more preferably 20 μg to 200 μg. For intratracheal, nasal (transnasal), intraocular, intravaginal, rectal, intravenous, intraintestinal, or inhalation administration, the content is usually 0.01 μg to 1 mg, preferably 0.1 μg to 100 μg. The present vaccine may contain a pharmaceutically acceptable carrier in addition to an antigen such as glycolipid derivative (I) or a salt thereof. Examples of pharmaceutically acceptable carriers that may be contained in the present vaccine include the same pharmaceutically acceptable carriers as those exemplified as the pharmaceutically acceptable carriers that may be contained in the "pharmaceutical composition" described above for the present adjuvant. The present vaccine may further contain other adjuvants. Examples of such other adjuvants include those exemplified as adjuvants that can be used in combination with the present adjuvant.

[0076] Examples of dosage forms of the present vaccine include those exemplified as dosage forms of the "pharmaceutical composition" described above for the present adjuvant. The present vaccine can be produced by a method commonly used in the pharmaceutical technology field, such as the method described in the 16th Edition of the Japanese Pharmacopoeia. For example, it can be prepared by emulsifying or dispersing an antigen such as glycolipid derivative (I) or a salt thereof, as necessary.

[0077] The recipient of the present vaccine is not particularly limited as long as it is an animal with an immune system, and examples include the same animals as those exemplified as recipients of the present adjuvant. The present vaccine may be administered as a single dose or multiple consecutive doses. When the present vaccine is administered consecutively, the administration period is not particularly limited and may be appropriately determined depending on, for example, the type of antigen, the recipient, the administration form, and the administration route. However, the administration period is usually in the range of 1 to 150 days, and can also be appropriately set for a range of 1 to 120 days, 1 to 60 days, 1 to 30 days, etc., as needed. By administering the present vaccine to a subject, allergies, infectious diseases, cancer, etc. can be prevented and / or treated.

[0078] The present invention will be described in detail below with reference to examples, but the present invention is not limited thereto. Those skilled in the art may modify the embodiments of the present invention in various aspects without departing from the spirit of the present invention, and such modifications are also within the scope of the present invention.

[0079] Example 1: Evaluation of the ligand activity of glycolipid derivative (I) for various C-type lectin receptors (1) Test compound In this example, a glycolipid derivative having the following structure (hereinafter also referred to as HD-252) was used as a representative of glycolipid derivative (I) or its salt, which is the active ingredient of activator (A). HD-252 is a compound described as Compound 71 on page 250 of Non-Patent Document 4.

[0080]

[0081] (2) Test Method: NFAT-GFP reporter cells expressing various C-type lectin receptors were prepared according to a method described in a literature review (Yamasaki S et al. Nat. Immunol. (2008) 9:1179-88). HD-252 (0.3 nmol / well, n=3) was immobilized on a 96-well plate, and the reporter cells were added. After 20 hours of stimulation, reporter activity was analyzed by flow cytometry to evaluate the ligand activity of HD-252. Isopropanol, the solvent used for immobilization, was used as a negative control. The evaluation results are shown in Figure 1. The horizontal axis indicates the type of C-type lectin receptor expressed on the reporter cells, and the vertical axis indicates the quantified ligand activity. On the horizontal axis, "h" stands for "human," and "m" stands for "murine." This evaluation revealed that HD-252 has ligand activity for multiple receptors, including the human and mouse Mincle receptor and Dectin-2 receptor.

[0082] Example 2: Evaluation of changes in gene expression when human Mo-DCs are stimulated with HD-252 Dendritic cells (hMo-DCs) were induced from human peripheral blood monocytes according to the method described in the literature (Kiyotake et al. J. Biol. Chem. (2015) 290 (42): 25322-32). HD-252, trehalose dimycolic acid (TDM), or mannose-added lipoarabinomannan (Man-LAM) were immobilized on a 24-well plate at 1 nmol / well, 0.3 nmol / well, and 0.3 μg / well, respectively (n = 3). hMo-DCs were added and stimulated for 4 hours. The results of principal component analysis (A) and k-means clustering (B) of gene expression are shown in Figure 2. In Figure B, each column represents wells (n=3) stimulated with the test compounds HD-252, TDM, and Man-LAM, and a control group stimulated with isopropanol, and each row represents a gene. Brighter colors indicate higher gene expression. TDM and Man-LAM were used as specific ligands for Mincle (macrophage-inducible C-type lectin) and Dectin-2 (dendritic cell-associated lectin-2), respectively. TDM was purchased from Sigma (T3034). Man-LAM was purified from BCG. Isopropanol, the solvent used during immobilization, was used as a negative control. This evaluation revealed that TDM and Man-LAM each induce gene changes partially independently, while HD-252 induces gene changes that combine the characteristics of both. It was suggested that HD-252 activated cells via both Mincle and Dectin-2. First, we will discuss Figure A in more detail. Focusing on the direction of movement from 2-propanol, it can be seen from Figure A that the gene expression induced by HD-252 is located (angularly) between TDM and Man-LAM. Therefore, it was suggested that HD-252 possesses the characteristics of gene expression induced by both TDM and Man-LAM.As described above, Figure A shows that glycolipid derivative (I) activates immune cells via both Mincle and Dectin-2. Next, Figure B will be described in more detail. Genes whose expression was enhanced by HD-252 stimulation included il12b, malt1, nlrp3, ccl2, ccl5, cd58, cd80, tnfsf9, ccl3, ccl4, icam1, il6, and tnf. Of these, il12b, malt1, and nlrp3 are recognized by those skilled in the art as important genes for exerting adjuvant effects. However, enhanced expression was not observed with stimulation alone with TDM or Man-LAM (stimulation via either Mincle or Dectin-2), and enhanced expression of these genes was confirmed only after simultaneous stimulation with HD-252 (stimulation via both Mincle and Dectin-2). As described above, glycolipid derivative (I) was shown at the gene level to exert excellent effects that cannot be achieved by stimulation alone by simultaneously stimulating both Mincle and Dectin-2. TDM is a compound widely known to function as an adjuvant through binding to the Mincle receptor. The above experiments demonstrated that HD-252 not only enhances gene expression similar to TDM, but also enhances the expression of three other genes that are important for exerting adjuvant effects. Based on these results, those skilled in the art can understand the excellent properties of HD-252 as an adjuvant.

[0083] This application discloses, as one embodiment of the invention, a dual activator that can activate both the Mincle receptor and the Dectin-2 receptor, and that contains as an active ingredient a glycolipid derivative with a specific structure, is useful as a vaccine adjuvant, etc., and is useful, for example, in the field of medicine. This application is based on Japanese Patent Application No. 2024-153274 (filing date: September 5, 2024), the contents of which are incorporated in full herein.

Claims

1. A compound of the following formula (I): (In the formula, R １ represents a hydroxyl group, R ２ represents a hydroxyl group, R ３ represents a hydrogen atom, a hydroxyl group, C １－６ alkyl group, or C １－６ represents an alkoxy group, R ４ represents a hydrogen atom, a hydroxyl group, C １－６ alkyl group, or C １－６ represents an alkoxy group, represents a single bond (without specifying the configuration); ring S2, ring S3, and ring S4 each independently represent an optionally substituted pyranose or an optionally substituted deoxypyranose; L represents C ６－１４ represents an arylene group, and R ａ is an optionally substituted C ３－４０ A dual activator of the Mincle receptor and the Dectin-2 receptor, comprising, as an active ingredient, a glycolipid derivative (I) represented by the formula:

2. The activator according to claim 1, which is a TNF production enhancer, an INF-γ production enhancer, a cytokine secretion promoter, or an immunostimulator.

3. The activator according to claim 1 or 2, which is an agent for preventing and / or treating cancer; or bacterial infections, fungal infections, viral infections, or allergic diseases.

4. The activator according to claim 1 or 2, which is an immunostimulant.

5. The activator according to claim 4, which is a vaccine adjuvant.

6. The activator according to claim 5, further comprising an antigen.

7. The activator according to claim 1 or 2, wherein in glycolipid derivative (I), the terminal sugar represented by ring S1 and the sugar represented by ring S2 are linked by a 1,3 glycosidic bond as viewed from ring S1.

8. The activator according to claim 1 or 2, wherein in glycolipid derivative (I), the sugar represented by ring S2 and the sugar represented by ring S3 are linked via a 1,3 glycosidic bond as viewed from ring S2.

9. The activator according to claim 1 or 2, wherein in glycolipid derivative (I), the sugar represented by ring S3 and the sugar represented by ring S4 are linked via a 1,3 glycosidic bond as viewed from ring S3.

10. The following formula (Ia): (In the formula, R １ represents a hydroxyl group, R ２ represents a hydroxyl group, R ３ represents a hydrogen atom, a hydroxyl group, C １－６ alkyl group, or C １－６ represents an alkoxy group, R ４ represents a hydrogen atom, a hydroxyl group, C １－６ alkyl group, or C １－６ represents an alkoxy group, R ５ ~R １３ are each independently a hydroxyl group, C １－６ Alkyl group, C １－６ L and R represent an alkoxy group or an acyloxy group; ａ , and and (c) each have the same meaning as defined above.

3. The activator according to claim 1, comprising, as an active ingredient, a glycolipid derivative (I) represented by the following formula:

11. In the glycolipid derivative (I), R １ is a hydroxyl group, and R ２ is a hydroxyl group, and R ３ is a hydroxyl group, and R ４ But C １－６ The activator according to claim 1 or 2, which is an alkoxy group.

12. The activator according to claim 1 or 2, wherein in the glycolipid derivative (I), L is a phenylene group.

13. In the glycolipid derivative (I), R ａ "Optionally substituted C ３－４０ The hydrocarbon group in the "hydrocarbon group" is C ６－４０ The activator according to claim 1 or 2, which is a hydrocarbon group.

14. In the glycolipid derivative (I), R ａ "Optionally substituted C ３－４０ The substituents in the "hydrocarbon group" are 1) a hydroxyl group, 2) an oxo group, 3) an optionally substituted C ３-４０ hydrocarbon group, 4) C １－６ 5) an optionally substituted C ３－４０ 5) a hydrocarbon-carbonyloxy group; 6) a group containing an epitope sequence; 7) an amino group or an acylamino group; 8) a thiol group; and 9) a halogen atom.

15. In the glycolipid derivative (I), R ａ is represented by the following formula (III): (In the formula, R １４ is C １－６ represents an alkyl group, m represents an integer of 13 to 21, n represents an integer of 15 to 20, o represents an integer of 3 to 5, p represents an integer of 3 to 5, q represents an integer of 15 to 20, and * represents the bonding position to L.

16. In the glycolipid derivative (I), the formula (Ia) is the following formula (Iaa): The activator according to claim 10, wherein 17. A method for preventing and / or treating cancer, bacterial infections, fungal infections, viral infections, and / or allergic diseases, which comprises administering an effective amount of the glycolipid derivative (I) defined in claim 1 or its salt to a mammal in need thereof.

18. A method for immunostimulation, which comprises administering an effective amount of the glycolipid derivative (I) defined in claim 1 or its salt to a mammal in need thereof.

19. The glycolipid derivative (I) or a salt thereof defined in claim 1, which is used for the prevention and / or treatment of cancer, bacterial infections, fungal infections, viral infections, and / or allergic diseases.

20. The glycolipid derivative (I) or a salt thereof defined in claim 1, which is used for immunostimulation.

21. Use of the glycolipid derivative (I) or a salt thereof as defined in claim 1 for the manufacture of a medicament for the prevention and / or treatment of cancer, bacterial infections, fungal infections, viral infections, and / or allergic diseases.

22. Use of the glycolipid derivative (I) or a salt thereof as defined in claim 1 for the manufacture of an immunostimulant.

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