Hydroxycitric acid derivative or salt thereof

Abstract

To provide a novel hydroxycitric acid derivative.SOLUTION: A hydroxycitric acid derivative having a predetermined structure, which is a lactone diester derivative, a triester derivative, a lactone diamide derivative, or a lactone acyl derivative of hydroxycitric acid, is effective as a novel compound having CYSLTR2 inhibitory activity.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to novel hydroxycitric acid derivatives or salts thereof. [Background technology]

[0002] Hydroxycitric acid, contained in the peel of Garcinia cambogia, is a physiologically active substance that is effective in burning fat and suppressing weight gain (Non-Patent Document 1), promoting glycogen accumulation (Non-Patent Document 2), and improving endurance (Non-Patent Document 3), and also exhibits an inhibitory effect on calcium oxalate-induced inflammatory cytokines (Non-Patent Document 4).

[0003] On the other hand, there have been case reports of patients with a history of allergic asthma who took Garcinia extract supplements containing hydroxycitric acid, which resulted in severe liver damage and death (Non-Patent Document 5). [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Journal of Nutrition & Food Sciences, 3(4). 23-30 (2000). [Non-patent document 2] British Journal of Nutrition, 107, 1048-1055 (2012) [Non-patent document 3] Journal of Nutritional Science and Vitaminology, 49, 163-167 (2003) [Non-patent document 4] Current Molecular Medicine, 20(7), 527-535 (2020) [Non-patent document 5] Digestive and Liver Disease 39(10), 953-5 (2007) Summary of the Invention [Problem to be solved by the invention]

[0005] Hydroxycitric acid is a compound that has an additional hydroxyl group attached to the 2-position of citric acid, which is widely used as a food additive. Hydroxycitric acid has unique physiological activities not found in citric acid. However, despite the fact that hydroxycitric acid has reactive functional groups, hydroxyl and carboxyl groups, its useful derivatives have not been sufficiently investigated.

[0006] Therefore, an object of the present disclosure is to provide novel hydroxycitric acid derivatives. [Means for solving the problem]

[0007] As a result of extensive research, the present inventors have discovered novel hydroxycitric acid derivatives that exhibit CYSLTR2 inhibitory activity, which has not been reported for hydroxycitric acid. The present disclosure was completed through further research based on this finding.

[0008] That is, the present disclosure provides the inventions of the following aspects. Item 1. A hydroxycitric acid derivative or a salt thereof represented by any one of the following formulas (I) to (IV): [ka] (In formula (I), R 1 and R 2 may be the same or different and may have a substituent, and are [A] a linear alkyl group, [B] a branched alkyl group, [C] a cycloalkyl group, [D] a cycloalkylalkyl group, [E] an aralkyl group, [F] a heterocycloalkylalkyl group, [G] an aryloxyalkyl group, and / or [H] an aralkylpolyoxyalkylene group). [ka] (In formula (II), R 3 , R 4 and R 5may be the same or different and may have a substituent, and are [A] a linear alkyl group, [B] a branched alkyl group, [C] a cycloalkyl group, [D] a cycloalkylalkyl group, [E] an aralkyl group, and / or [F] a heterocycloalkylalkyl group). [ka] (In formula (III), R 61 , R 62 and R 63 and R 71 , R 72 and R 73 may be the same or different from each other, R 61 and R 71 is [I] hydrogen, [A] a linear alkyl group and / or [B] a branched alkyl group, R 62 and R 72 is a [J] alkylene group and / or a [K] alkyleneimino group, and R 63 and R 73 is an optionally substituted [L]aryl group, or R 61 and R 62 and / or R 71 and R 72 are bonded to each other to form a nitrogen-containing aliphatic ring [AB / JK] together with the nitrogen atom to which they are attached, and / or R 61 and R 63 and / or R 71 and R 73 are bonded to each other, respectively, R 61 and / or R 71 The nitrogen atom to which R is bonded 63 and / or R 73 R to which 62 and / or R 72 together form a nitrogen-containing aliphatic ring [AB / L / JK]). [ka] (In formula (IV), R 8is [A] a linear alkyl group, [B] a branched alkyl group, [D] a cycloalkylalkyl group or [L] an aryl group which may have a substituent, [M] an acyloxyalkyl group, or [N] an alkoxycarbonylalkyl group). Item 2. The hydroxycitric acid derivative or salt thereof according to Item 1, wherein in formula (I), the substituent is [a] an alkyl group, [b] a halogen group, [c] a halogenated alkoxy group, and / or [d] an alkoxy group. Item 3. In the formula (I), R 1 and R 2 the substituent that the linear alkyl group [A] may have is an alkyl group, a halogen group, a halogenated alkoxy group, and / or an alkoxy group; and R 1 and R 2 Item 3. The hydroxycitric acid derivative or a salt thereof according to Item 1 or 2, wherein the optional substituent on the other of the linear alkyl groups [A] is an alkyl group [a], a halogen group [b], and / or a halogenated alkoxy group [c]. Item 4. In the formula (I), Item 4. The hydroxycitric acid derivative or a salt thereof according to any one of Items 1 to 3, wherein the linear alkyl group [A] has 2 or more carbon atoms. Item 5. The hydroxycitric acid derivative or salt thereof according to any one of Items 1 to 4, wherein in formula (I), the optional substituent on the cycloalkylalkyl group [D] is an alkyl group [a]. Item 6. The hydroxycitric acid derivative or salt thereof according to any one of Items 1 to 5, wherein, in formula (I), when the [E] aralkyl group has the [d] alkoxy group as a substituent, the number of the [d] group as a substituent is one. Item 7. The hydroxycitric acid derivative or salt thereof according to any one of Items 1 to 6, wherein, in formula (I), when the aralkyl group [E] has the halogen group [b] as a substituent, the group [b] is a chloro group. Item 8. In the formula (I), the R 1 and R 2are each the above-mentioned [E] aralkyl group, Any of the [E] groups is an aryl (C2 or higher) alkyl group, or Item 8. The hydroxycitric acid derivative or a salt thereof according to any one of Items 1, 2, 6, and 7, wherein at least one of the [E] groups is an aryl (C1 or higher) alkyl group and at least one of the [E] groups has the substituent. Item 9. The hydroxycitric acid derivative or salt thereof according to any one of Items 1 to 7, wherein in the formula (I), the heterocycloalkylalkyl group [F] is an oxetanylalkyl group. Item 10. The hydroxycitric acid derivative or salt thereof according to any one of Items 1 to 7 and 9, wherein, in the formula (I), the number of repeating oxyalkylene groups in the [H]aralkylpolyoxyalkylene group is 3 or more. Item 11. The hydroxycitric acid derivative or salt thereof according to Item 1, wherein in formula (II), the substituents are [b] a halogen group and / or [d] an alkoxy group. Item 12. The hydroxycitric acid derivative or salt thereof according to Item 1, wherein in formula (III), the substituents are [b] a halogen group and / or [d] an alkoxy group. Item 13. The hydroxycitric acid derivative or salt thereof according to Item 1 or 12, wherein in formula (III), the nitrogen-containing aliphatic ring [AB / JK] is a piperidine ring, a piperazine ring, a pyrrolidine ring, and / or an imidazolidine ring. Item 14. The hydroxycitric acid derivative or salt thereof according to Item 1, 12, or 13, wherein in formula (III), the [AB / L / JK] nitrogen-containing aliphatic ring is a piperidine ring and / or a piperazine ring. Item 15. The hydroxycitric acid derivative or salt thereof according to Item 1, wherein in formula (IV), the substituents are [d] an alkoxy group and / or [e] a hydroxyl group. Item 16. The hydroxycitric acid derivative or salt thereof according to Item 1 or 15, wherein in formula (IV), the branched alkyl group [B] is a 1,1-dimethylpropyl group or an isopentyl group. Item 17. The hydroxycitric acid derivative or salt thereof according to Item 1, 15, or 16, wherein in formula (IV), the [N]alkoxycarbonylalkyl group is an [N]alkoxycarbonyl(C3 or higher)alkyl group. Item 18. The hydroxycitric acid derivative or salt thereof according to any one of Items 1 and 15 to 17, wherein in formula (IV), the substitution position of the optional substituent on the [L]aryl group is the ortho position and / or the para position. Item 19. A cysteinyl leukotriene receptor 2 inhibitor comprising the hydroxycitric acid derivative or a salt thereof according to any one of items 1 to 18. Item 20. A method for inhibiting cysteinyl leukotriene receptor 2, comprising administering to a subject in need of cysteinyl leukotriene receptor 2 inhibition an effective amount of the hydroxycitric acid derivative or salt thereof according to any one of Items 1 to 18. Item 21. Use of the hydroxycitric acid derivative or a salt thereof according to any one of Items 1 to 18 for the manufacture of a cysteinyl leukotriene receptor 2 inhibitor. Item 22. The hydroxycitric acid derivative or a salt thereof according to any one of Items 1 to 18 for use in treating or preventing a cysteinyl leukotriene receptor 2-mediated disease. Item 23. Non-therapeutic use of the hydroxycitric acid derivative or a salt thereof according to any one of Items 1 to 18 for inhibiting cysteinyl leukotriene receptor 2. [Effects of the Invention]

[0009] According to the present disclosure, novel hydroxycitric acid derivatives and salts thereof are provided. [Brief explanation of the drawings]

[0010] [Figure 1] 1 is a 1H NMR spectrum of the compound of Example 1. [Figure 2] 1H NMR spectrum of the compound of Example 5. [Figure 3] 1H NMR spectrum of the compound of Example 6. [Figure 4]1H NMR spectrum of the compound of Example 8. [Figure 5] 1H NMR spectrum of the compound of Example 10. [Figure 6] 1H NMR spectrum of the compound of Example 13. [Figure 7] 1H NMR spectrum of the compound of Example 16. [Figure 8] 1H NMR spectrum of the compound of Example 28. [Figure 9] 1H NMR spectrum of the compound of Example 30. [Figure 10] 1H NMR spectrum of the compound of Example 31. [Figure 11] 1H NMR spectrum of the compound of Example 33. [Figure 12] 1H NMR spectrum of the compound of Example 36. [Figure 13] 1H NMR spectrum of the compound of Example 42. [Figure 14] 1H NMR spectrum of the compound of Example 43. [Figure 15] 1H NMR spectrum of the compound of Example 46. [Figure 16] 1H NMR spectrum of the compound of Example 47. [Figure 17] 1H NMR spectrum of the compound of Example 49. [Figure 18] 1H NMR spectrum of the compound of Example 51. [Figure 19] 1H NMR spectrum of the compound of Example 53. [Figure 20] 1H NMR spectrum of the compound of Example 54. DETAILED DESCRIPTION OF THE INVENTION

[0011] 1. Hydroxycitric acid derivatives or their salts The present disclosure relates to a hydroxycitric acid derivative represented by any one of the following formulas (I) to (IV) or a salt thereof. That is, the present disclosure relates to a hydroxycitric acid derivative represented by the following formula (I) (hereinafter also referred to as "compound (I)"), a hydroxycitric acid derivative represented by the following formula (II) (hereinafter also referred to as "compound (II)"), a hydroxycitric acid derivative represented by the following formula (III) (hereinafter also referred to as "compound (III)"), or a hydroxycitric acid derivative represented by the following formula (IV) or a derivative thereof (hereinafter also referred to as "compound (IV)"). The hydroxycitric acid derivatives and salts thereof of the present disclosure are described in detail below.

[0012] 1-1. Compound (I) 1-1-1. General formula Compound (I) is a hydroxycitric acid derivative represented by the following formula (I): Compound (I) is a lactone diester derivative of hydroxycitric acid. [ka]

[0013] In the above formula (I), R 1 and R 2 may be the same or different and may have a substituent, and are [A] a linear alkyl group, [B] a branched alkyl group, [C] a cycloalkyl group, [D] a cycloalkylalkyl group, [E] an aralkyl group, [F] a heterocycloalkylalkyl group, [G] an aryloxyalkyl group, and / or [H] an aralkylpolyoxyalkylene group.

[0014] 1-1-2.R 1 and R 2 [A]~[H] groups in The linear alkyl group [A] in Compound (I) may be a linear alkyl group having 2 or more carbon atoms (a (C2 or more) linear alkyl group). The upper limit of the carbon number of the linear alkyl group [A] may be, for example, 15 or less. Specific examples of the linear alkyl group [A] include an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an n-heptyl group, an n-octyl group, an n-nonyl group, an n-decyl group, an n-undecyl group, an n-dodecyl group, an n-tridecyl group, an n-tetradecyl group, and an n-pentadecyl group. Preferably, the linear alkyl group [A] is a linear alkyl group having 3 or more carbon atoms, more preferably 4 or more carbon atoms, and even more preferably 5 or more carbon atoms. The upper limit of the carbon number of the linear alkyl group [A] is preferably 10 or less, more preferably 8 or less, and even more preferably 7 or less.

[0015] The branched alkyl group [B] in compound (I) may be a branched alkyl group having 3 or more carbon atoms (a (C3 or more) branched alkyl group). The upper limit of the number of carbon atoms in the branched alkyl group [B] may be, for example, 15 or less. Specifically, examples of the branched alkyl group [B] include an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isopentyl group, a sec-pentyl group, a tert-pentyl group, a neopentyl group, an isohexyl group, a sec-hexyl group, a tert-hexyl group, a neohexyl group, a 3-methylpentyl group, a 2-methylpentyl group, a 1,2-dimethylbutyl group, a 1-ethylpropyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 1,2-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1-ethylbutyl group, a 2-ethylbutyl group, an isoheptyl group, a sec-heptyl group, a tert-heptyl group, a neoheptyl group, a 2-methylhexyl group, a 3-methylhexyl group, a 2,2-dimethylpentyl group, a 3-ethylpentyl group, a 2,4-dimethylpentyl group, a 1-ethyl- Examples of such groups include a 1-methylbutyl group, a 1,2,3-trimethylbutyl group, an isooctyl group, a sec-octyl group, a tert-octyl group, a neooctyl group, an isononyl group, a sec-nonyl group, a tert-nonyl group, a neononyl group, an isodecyl group, a sec-decyl group, a tert-decyl group, a neodecyl group, an isoundecyl group, a sec-undecyl group, a tert-undecyl group, a neoundecyl group, an isododecyl group, a sec-dodecyl group, a tert-dodecyl group, a neododecyl group, an isotridecyl group, a sec-tridecyl group, a tert-tridecyl group, a neotridecyl group, an isotetradecyl group, a sec-tetradecyl group, a tert-tetradecyl group, a neotetradecyl group, an isopentadecyl group, a sec-pentadecyl group, a tert-pentadecyl group, and a neopentadecyl group. The branched alkyl group [B] preferably includes a linear alkyl group having 4 or more carbon atoms, more preferably 5 or more carbon atoms, and even more preferably 6 or more carbon atoms. The upper limit of the number of carbon atoms in the branched alkyl group [B] is preferably 10 or less, more preferably 8 or less.

[0016] The [C]cycloalkyl group in Compound (I) refers to a monovalent saturated hydrocarbon ring, and includes a cycloalkyl group having 3 or more carbon atoms (a (C or more) cycloalkyl group). The upper limit of the carbon number of the [C]cycloalkyl group is, for example, 12 or less. The [C]cycloalkyl group includes a monocycloalkyl group and a polycycloalkyl group. Specific examples of the monocycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, a cyclodecyl group, a cycloundecyl group, and a cyclododecyl group. Preferably, the monocycloalkyl group has 4 or more carbon atoms, more preferably 5 or more carbon atoms. Furthermore, the upper limit of the monocycloalkyl group is preferably 10 or less, more preferably 8 or less, and even more preferably 7 or less. Specific examples of polycycloalkyl groups include bicycloalkyl groups and tricycloalkyl groups, and examples of bicycloalkyl groups include norbornyl groups (e.g., 1-norbornyl and 2-norbornyl groups), and examples of tricycloalkyl groups include adamantyl groups (e.g., 1-adamantyl and 2-adamantyl groups). Among these, the [C]cycloalkyl group is preferably a polycycloalkyl group, more preferably a bicycloalkyl group or a tricycloalkyl group, and even more preferably a 2-norbornyl group or a 2-adamantyl group.

[0017] The cycloalkylalkyl group [D] in compound (I) refers to an alkyl group substituted with a cycloalkyl group (i.e., a monovalent saturated hydrocarbon ring). Specific examples of the cycloalkyl group moiety constituting the cycloalkylalkyl group [D] are the same as those described above for the cycloalkyl group [C]. The alkyl group moiety (substituted with a cycloalkyl group) constituting the cycloalkylalkyl group [D] includes a linear or branched alkyl group having two or more carbon atoms. The upper limit of the carbon number is, for example, 15 or less. Specifically, specific examples of the alkyl group moiety constituting the cycloalkylalkyl group [D] are the same as those described above for the linear alkyl group [A] and the branched alkyl group [B]. The [D] cycloalkylalkyl group is preferably a (C3-10, preferably 4-8, more preferably 5-6) monocycloalkyl (C1-6, preferably 1-4, more preferably 1-2) alkyl group or a polycycloalkyl (C1-6, preferably 1-4, more preferably 1-2) alkyl group, more preferably a norbornyl or adamantyl (C1-6, preferably 1-4, more preferably 1-2) alkyl group, and even more preferably a 2-norbornyl or 2-adamantyl (C1-6, preferably 1-4, more preferably 1-2) alkyl group.

[0018] The aralkyl group [E] in Compound (I) refers to an arylalkyl group. The aryl group moiety constituting the aralkyl group [E] includes homoaryl groups derived from aromatic carbocyclic compounds and heteroaryl groups derived from aromatic heterocyclic compounds. The aryl group moiety includes an aryl group having 3 to 12 carbon atoms. Specific examples of the aryl group moiety include homoaryl groups such as phenyl and naphthyl, and specific examples of heteroaryl groups such as pyridyl, pyrrole, furyl, and thienyl. Specific examples of the alkyl group moiety (substituted with an aryl group) constituting the aralkyl group [E] include linear or branched alkyl groups having 2 or more carbon atoms. The upper limit of the carbon number is, for example, 15 or less. Specific examples of the alkyl group moiety constituting the aralkyl group [E] are the same as those described above for the linear alkyl group [A] and branched alkyl group [B]. Preferably, the [E]aralkyl group includes a phenyl (C1-6, preferably 1-4, more preferably 1-2) alkyl group or a pyridyl (C1-6, preferably 1-4, more preferably 1-2) alkyl group, more preferably a benzyl group or a phenethyl group.

[0019] The heterocycloalkyl group [F] in compound (I) refers to an alkyl group substituted with a heterocycloalkyl group. The heterocycloalkyl group constituting the heterocycloalkyl group [F] typically includes a monovalent alicyclic ether ring. Specific examples of the monovalent alicyclic ether ring include a glycidyl group, an oxetanyl group, and a tetrahydrofuranyl group. Specific examples of the alkyl group moiety (substituted with a heterocycloalkyl group) constituting the heterocycloalkyl group [F] may be a linear or branched alkyl group having one or more carbon atoms. The upper limit of the number of carbon atoms is, for example, 15 or less. Specific examples of the alkyl group moiety constituting the heterocycloalkyl group [F] are the same as those described above for the linear alkyl group [A] and the branched alkyl group [B]. Preferably, the heterocycloalkylalkyl group [F] includes a glycidyl (C1-6, preferably 1-4, more preferably 1-2) alkyl group, an oxetanyl (C1-6, preferably 1-4, more preferably 1-2) alkyl group, or a tetrahydrofuranyl (C1-6, preferably 1-4, more preferably 1-2) alkyl group, more preferably an oxetanyl (C1-6, preferably 1-4, more preferably 1-2) alkyl group.

[0020] The [G] aryloxyalkyl group in Compound (I) refers to an alkyl group substituted with an aryloxy group. The aryloxy group moiety constituting the [G] aryloxyalkyl group includes a homoaryloxy group derived from a carbocyclic compound and a heteroaryloxy group derived from a heterocyclic compound. The aryloxy group moiety can be an aryloxy group having 3 to 12 carbon atoms. Specific examples of the aryloxy group moiety include a phenyl group and a naphthyl group, and specific examples of the heteroaryloxy group moiety include a pyridyloxy group, a pyrroloxy group, a furyloxy group, and a thienyloxy group. Specific examples of the alkyl group moiety (substituted with an aryloxy group) constituting the [G] aryloxyalkyl group include a linear or branched alkyl group having 2 or more carbon atoms. The upper limit of the carbon number is, for example, 15 or less. Specifically, specific examples of the alkyl group moiety constituting the [G] aryloxyalkyl group are the same as those described above for the linear alkyl group [A] and the branched alkyl group [B]. Preferably, the aryloxyalkyl group [G] is a phenyloxy (C1 to 8, preferably 1 to 6, more preferably 2 to 4) alkyl group or a pyridyloxy (C1 to 8, preferably 1 to 6, more preferably 2 to 4) alkyl group.

[0021] The [H]aralkyl polyoxyalkylene group in Compound (I) refers to a polyoxyalkylene group substituted with an aralkyl group. Specific examples of the aralkyl group moiety constituting the [H]aralkyl polyoxyalkylene group are the same as those described above for the [E]aralkyl group. The polyoxyalkylene group moiety constituting the [H]aralkyl polyoxyalkylene group includes a polyoxy(C1-3, preferably C2-3, more preferably C2) alkylene group, and the number of repeating oxyalkylene groups is, for example, 2-6, preferably 3-4. Preferred examples of the [H]aralkyl polyoxyalkylene group include a benzyl dioxyethylene group, a benzyl trioxyethylene group, and a benzyl tetraoxyethylene group.

[0022] Unless otherwise specified, the specific examples and preferred examples of the groups [A] to [H] above also apply to the preferred examples of combinations of the groups [A] to [H] and substituents listed in the following item 1-1-3.

[0023] 1-1-3.R 1 and R 2 The substituents that the [A] to [H] groups in The substituents that the [A] linear alkyl group, [B] branched alkyl group, [C] cycloalkyl group, [D] cycloalkylalkyl group, [E] aralkyl group, [F] heterocycloalkylalkyl group, [G] aryloxyalkyl group, and [H] aralkylpolyoxyalkylene group in compound (I) may have are preferably [a] alkyl group, [b] halogen group, [c] halogenated alkoxy group, and / or [d] alkoxy group.

[0024] The alkyl group [a] in compound (I) includes a linear alkyl group and a branched alkyl group. When the alkyl group [a] is a linear alkyl group, the linear alkyl group may have one or more carbon atoms (a (C1 or more) linear alkyl group). The upper limit of the carbon number of the linear alkyl group may be, for example, six or less. Specific examples of the linear alkyl group include an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, and an n-hexyl group. When the alkyl group [a] is a branched alkyl group, the branched alkyl group may have three or more carbon atoms (a (C3 or more) branched alkyl group). The upper limit of the carbon number of the branched alkyl group may be, for example, eight or less. Specifically, the branched alkyl group includes an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isopentyl group, a sec-pentyl group, a tert-pentyl group, a neopentyl group, an isohexyl group, a sec-hexyl group, a tert-hexyl group, a neohexyl group, a 3-methylpentyl group, a 2-methylpentyl group, a 1,2-dimethylbutyl group, a 1-ethylpropyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 1,2-dimethylbutyl group, a Examples of the alkyl group include a 2,2-dimethylbutyl group, a 1-ethylbutyl group, a 2-ethylbutyl group, an isoheptyl group, a sec-heptyl group, a tert-heptyl group, a neoheptyl group, a 2-methylhexyl group, a 3-methylhexyl group, a 2,2-dimethylpentyl group, a 3-ethylpentyl group, a 2,4-dimethylpentyl group, a 1-ethyl-1-methylbutyl group, a 1,2,3-trimethylbutyl group, an isooctyl group, a sec-octyl group, a tert-octyl group, and a neooctyl group. Preferably, the alkyl group [a] is a linear alkyl group having 1 to 4 carbon atoms, more preferably 1 or 2 carbon atoms, or a branched alkyl group having 3 to 6 carbon atoms, more preferably 3 or 4 carbon atoms.

[0025] [b] The halogen group in Compound (I) includes, for example, a fluoro group, a chloro group, a bromo group, and an iodo group, and more preferably a fluoro group or a chloro group.

[0026] The halogenated alkoxy group [c] in compound (I) refers to an alkoxy group substituted with a halogen group. Specific examples of the halogen moiety of the halogenated alkoxy group [c] are the same as those described above for the halogen group [b]. Specific examples of the alkoxy moiety of the halogenated alkoxy group [c] include alkoxy groups having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and more preferably 1 to 2 carbon atoms.

[0027] The alkoxy group [d] in Compound (I) includes, for example, an alkoxy group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and more preferably 1 or 2 carbon atoms.

[0028] Unless otherwise specified, the specific examples and preferred examples of the substituents [a] to [d] above also apply to the preferred examples of combinations of the following groups [A] to [H] with the substituents.

[0029] (Preferable Examples of Combinations of Groups [A] to [H] and Substituents) In a preferred example of compound (I), when the [A] group to the [H] group have the above-mentioned substituent, preferred examples of the [A] group to the [H] group having the substituent include an [A] linear alkyl group substituted with a [b] halogen group, an [D] cycloalkylalkyl group substituted with an [a] alkyl group, an [E] aralkyl group substituted with a [a] alkyl group, an [b] aralkyl group substituted with a [E] halogen group, an [c] aralkyl group substituted with a halogenated alkoxy group, an [E] aralkyl group substituted with an alkoxy group, and an [F] heterocycloalkylalkyl group substituted with a [a] alkyl group.

[0030] In a preferred example of compound (I), the R 1 and R 2 The substituent that the linear alkyl group [A] may have is an alkyl group, a halogen group, a halogenated alkoxy group, and / or an alkoxy group, and 1 and R 2The substituent that the other of the straight-chain alkyl groups (A) may have is an alkyl group (a), a halogen group (b), and / or a halogenated alkoxy group (c).

[0031] In a preferred example of compound (I), when the aralkyl group (E) has the alkoxy group (d) as a substituent, the number of the alkoxy group (d) is one.

[0032] In a preferred example of compound (I), when the [E] aralkyl group has the [b] halogen group as a substituent, the [b] group is a chloro group.

[0033] In a preferred example of compound (I), the R 1 and R 2 are both the [E] aralkyl group, both of the [E] groups are aryl (C2 or higher) alkyl groups, or at least one of the [E] groups is an aryl (C1 or higher) alkyl group and at least one has the above-mentioned substituent.

[0034] In a preferred example of compound (I), the heterocycloalkylalkyl group [F] is an oxetanylalkyl group.

[0035] 1-2. Compound (II) 1-2-1. General formula Compound (II) is a hydroxycitric acid derivative represented by the following formula (II): Compound (II) is a triester derivative of hydroxycitric acid.

[0036] [ka]

[0037] In formula (II), R 3 , R 4 and R 5may be the same or different and are, optionally having a substituent, [A] a linear alkyl group, [B] a branched alkyl group, [C] a cycloalkyl group, [D] a cycloalkylalkyl group, [E] an aralkyl group, and / or [F] a heterocycloalkylalkyl group.

[0038] 1-2-2.R 3 、R 4 and R 5 [A]~[F] groups in The linear alkyl group [A] in Compound (II) may be a linear alkyl group having one or more carbon atoms (a (C2 or more) linear alkyl group). The upper limit of the carbon number of the linear alkyl group [A] may be, for example, 15 or less. Specific examples of the linear alkyl group [A] include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an n-heptyl group, an n-octyl group, an n-nonyl group, an n-decyl group, an n-undecyl group, an n-dodecyl group, an n-tridecyl group, an n-tetradecyl group, and an n-pentadecyl group. Preferably, the linear alkyl group [A] is a linear alkyl group having two or more carbon atoms, more preferably three or more, even more preferably four or more, and even more preferably five or six or more. The upper limit of the carbon number of the linear alkyl group [A] is preferably 10 or less, more preferably eight or less, and even more preferably seven or six or less.

[0039] Specific examples and preferred examples of the branched alkyl group [B] in compound (II) are the same as the specific examples and preferred examples of the branched alkyl group [B] in compound (I) above.

[0040] Specific examples and preferred examples of the [C]cycloalkyl group in compound (II) are the same as the specific examples and preferred examples of the [C]cycloalkyl group in compound (I) above.

[0041] Specific examples and preferred examples of the [D]cycloalkylalkyl group in compound (II) are the same as the specific examples and preferred examples of the [D]cycloalkylalkyl group in compound (I) above.

[0042] Specific examples and preferred examples of the [E]aralkyl group in compound (II) are the same as the specific examples and preferred examples of the [E]aralkyl group in compound (II) above.

[0043] The [F]heterocycloalkylalkyl group in compound (II) refers to an alkyl group substituted with a heterocycloalkyl group. The heterocycloalkyl group constituting the [F]heterocycloalkylalkyl group typically includes a monovalent alicyclic ether ring. Specific examples of the monovalent alicyclic ether ring include a glycidyl group, an oxetanyl group, a tetrahydrofuranyl group, and a tetrahydropyranyl group. Specific examples and preferred examples of the alkyl group moiety (substituted with a heterocycloalkyl group) constituting the [F]heterocycloalkylalkyl group are the same as the specific examples and preferred examples of the alkyl group moiety constituting the [F]heterocycloalkylalkyl group in compound (I). Preferably, the heterocycloalkylalkyl group [F] includes a glycidyl (C1-6, preferably 1-4, more preferably 1-2) alkyl group, an oxetanyl (C1-6, preferably 1-4, more preferably 1-2) alkyl group, a tetrahydrofuranyl (C1-6, preferably 1-4, more preferably 1-2) alkyl group, or a tetrahydropyranyl (C1-6, preferably 1-4, more preferably 1-2) alkyl group, more preferably a tetrahydropyranyl (C1-6, preferably 1-4, more preferably 1-2) alkyl group.

[0044] Unless otherwise specified, the specific examples and preferred examples of the groups [A] to [F] above also apply to the preferred examples of combinations of the groups [A] to [F] and substituents listed in the following item 1-2-3.

[0045] 1-2-3.R 3、R 4 and R 5 The substituents that the groups [A] to [F] in The substituents that the [A] linear alkyl group, [B] branched alkyl group, [C] cycloalkyl group, [D] cycloalkylalkyl group, [E] aralkyl group, and [F] heterocycloalkylalkyl group in compound (II) may have are preferably [b] halogen group and / or [d] alkoxy group.

[0046] Specific examples and preferred examples of the halogen group [b] in compound (II) are the same as the specific examples and preferred examples of the halogen group [b] in compound (I) above.

[0047] Specific examples and preferred examples of the [d]alkoxy group in compound (II) are the same as the specific examples and preferred examples of the [d]alkoxy group in compound (I) above.

[0048] Unless otherwise specified, the specific examples and preferred examples of the substituents [b] and [d] above also apply to the preferred examples of combinations of the following groups [A] to [F] with substituents.

[0049] (Preferable Examples of Combinations of Groups [A] to [F] and Substituents) In the preferred examples of compound (II), when the [A] group to the [F] group have the above-mentioned substituent, preferred examples of the [A] group to the [F] group having the substituent include the [A] linear alkyl group substituted with the [d] alkoxy group, and the [D] cycloalkylalkyl group substituted with the [b] halogen group.

[0050] 1-3. Compound (III) 1-3-1. General formula Compound (III) is a hydroxycitric acid derivative represented by the following formula (III): Compound (III) is a lactone diamide derivative of hydroxycitric acid.

[0051] [ka]

[0052] In formula (III), R 61 , R 62 and R 63 and R 71 , R 72 and R 73 may be the same or different from each other, R 61 and R 71 is [I] hydrogen, [A] a linear alkyl group and / or [B] a branched alkyl group, R 62 and R 72 is a [J] alkylene group and / or a [K] alkyleneimino group, and R 63 and R 73 is an optionally substituted [L]aryl group, or R 61 and R 62 and / or R 71 and R 72 are bonded to each other to form a nitrogen-containing aliphatic ring [AB / JK] together with the nitrogen atom to which they are attached, and / or R 61 and R 63 and / or R 71 and R 73 are bonded to each other, respectively, R 61 and / or R 71 The nitrogen atom to which R is bonded 63 and / or R 73 R to which 62 and / or R 72 Together they form a nitrogen-containing aliphatic ring [AB / L / JK].

[0053] 1-3-2.R 61 ~R 63 and R 71 ~R 73 [A], [B], [J]-[L] groups, [AB / JK], [AB / L / JK] rings in Specific examples and preferred examples of the straight-chain alkyl group [A] in compound (III) are the same as the specific examples and preferred examples of the straight-chain alkyl group [a] in compound (I) above.

[0054] Specific examples and preferred examples of the branched alkyl group [B] in compound (III) are the same as the specific examples and preferred examples of the branched alkyl group [a] in compound (I).

[0055] The alkylene group [J] in compound (III) may be an alkylene group (a (C1 or higher) alkyl group) having one or more carbon atoms. The upper limit of the number of carbon atoms in the alkylene group is, for example, five or less. Specific examples of the alkylene group [J] include a methylene group, an ethylene group, an n-propylene group, an isopropylene group, an n-butylene group, an isobutylene group, a sec-butylene group, a tert-butylene group, an n-pentylene group, an isopentylene group, a neopentylene group, a sec-pentylene group, a tert-pentylene group, and a 3-pentylene group. Preferably, the alkylene group [J] is an alkylene group having 1 to 4 carbon atoms, more preferably 1 to 2 carbon atoms.

[0056] The alkyleneimino group [K] in compound (III) refers to a divalent group formed by linking an alkylene group and an imino group (-NH-). Specific and preferred examples of the alkylene group moiety constituting the alkyleneimino group [K] are the same as those described above for the alkylene group [J]. Preferred examples of the alkyleneimino group [K] include a methyleneimino group (-CHNH-) and an ethyleneimino group (-CHCHNH-).

[0057] The [L]aryl group in compound (III) includes a homoaryl group derived from an aromatic carbocyclic compound and a heteroaryl group derived from an aromatic heterocyclic compound. The [L]aryl group includes an aryl group having 3 to 12 carbon atoms. Specific examples of the [L]aryl group include a phenyl group and a naphthyl group as specific examples of the homoaryl group, and a pyridyl group, a pyrrole group, a furyl group, and a thienyl group as specific examples of the heteroaryl group. The [L]aryl group is preferably a homoaryl group, more preferably a phenyl group.

[0058] The nitrogen-containing aliphatic ring [AB / JK] in compound (III) is R 61 and R 62 and / or R 71 and R 72 are further bonded to each other to form a ring together with the nitrogen atom to which they are bonded. [AB / JK] Nitrogen-containing aliphatic rings are generally represented by the following formula (where R 62 and R 72 R bonded to 63 and R 73 (also shown). [ka]

[0059] That is, when the above [AB / JK] nitrogen-containing aliphatic ring is formed, R 61 ,R 71 One hydrogen atom of the linear alkyl group [A] or branched alkyl group [B] represented by R 61 ,R 71 [J] a group obtained by removing one hydrogen atom from an alkylene group represented by the formula: 61 ,R 71

[0033] Specific examples of the nitrogen-containing aliphatic ring [AB / JK] include a piperidine ring, a piperazine ring, a pyrrolidine ring, an imidazolidine ring, etc., and preferably a piperazine ring or a pyrrolidine ring.

[0060] The nitrogen-containing aliphatic ring [AB / L / JK] in compound (III) is R 61 and R 63 and / or R 71 and R 73 are bonded to each other, respectively, R 61 and / or R 71 The nitrogen atom to which R is bonded 63 and / or R 73 R to which 62 and / or R 72 The nitrogen-containing aliphatic ring [AB / L / JK] is generally represented by the following formula: [ka]

[0061] That is, when the above [AB / L / JK] nitrogen-containing aliphatic ring is formed, R 61 ,R 71 One hydrogen atom of the linear alkyl group [A] or branched alkyl group [B] represented by R 63 ,R 73 [L] aryl group represented by the following formula: [L] is substituted with a group consisting of the remaining atomic group obtained by removing one hydrogen atom from the aryl group represented by the following formula: Preferably, the nitrogen-containing aliphatic ring [AB / L / JK] forms a fused ring with the aryl group [L]. Specific examples of the nitrogen-containing aliphatic ring [AB / L / JK] include a piperidine ring, a piperazine ring, a pyrrolidine ring, an imidazolidine ring, etc., and preferably a pyrrolidine ring or a piperidine ring.

[0062] Unless otherwise specified, the above specific examples and preferred examples of the [A], [B], [J] to [L] groups and the [AB / JK] and [AB / L / JK] rings also apply to the respective preferred examples of the combinations of the [L] group and the [AB / L / JK] rings with substituents listed in the following item 1-3-3.

[0063] 1-3-3.R 63 and 73 The substituents that the [L] group in The substituents that the [L] aryl group (and the [AB / L / JK] nitrogen-containing aliphatic ring containing the [L] group) in compound (III) may have are preferably a [b] halogen group and / or a [d] alkoxy group.

[0064] Examples of the halogen group [b] in compound (III) include a fluoro group, a chloro group, a bromo group, and an iodo group, more preferably a fluoro group or a chloro group, and even more preferably a chloro group.

[0065] The alkoxy group [d] in compound (III) includes, for example, an alkoxy group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and more preferably 1 or 2 carbon atoms.

[0066] Unless otherwise specified, the specific examples and preferred examples of the above substituents [b] and [d] also apply to the preferred examples of the combination of the below-described [L] group and the [AB / L / JK] ring with the substituent.

[0067] (Preferable examples of combinations of [L] group and [AB / L / JK] ring with substituents) In a preferred example of compound (III), when the [L] group has the above-mentioned substituent (including when the [AB / L / JK] ring has a substituent at the [L] group portion), preferred examples of the [L] group having the substituent include an [L] aryl group substituted with a [b] halogen group, and an [L] aryl group substituted with a [b] halogen group and a [d] alkoxy group.

[0068] 1-4. Compound (IV) 1-4-1. General formula Compound (IV) is a hydroxycitric acid derivative represented by the following formula (IV) or a salt thereof: Compound (IV) is a lactone acyl derivative of hydroxycitric acid.

[0069] [ka]

[0070] In formula (IV), R 8 is [A] a linear alkyl group, [B] a branched alkyl group, [D] a cycloalkylalkyl group or [L] an aryl group which may have a substituent, [M] an acyloxyalkyl group, or [N] an alkoxycarbonylalkyl group.

[0071] 1-4-2.R 8 [A], [B], [D], [L], [M], [N] groups in Specific examples of the linear alkyl group [A] in compound (IV) are the same as those in (II) above. Preferred examples of the linear alkyl group [A] include an ethyl group, an n-hexyl group, and an n-heptyl group.

[0072] Specific examples of the branched alkyl group [B] in compound (IV) are the same as those in compound (I). Preferably, the branched alkyl group [B] is a branched alkyl group having a branch at a terminal, more preferably an isopropyl group, an isobutyl group, an isopentyl group, an isohexyl group, an isoheptyl group, an isooctyl group, an isononyl group, an isodecyl group, an isoundecyl group, a sododecyl group, an isotridecyl group, an isotetradecyl group, an isopentadecyl group, and the like, and even more preferably an isobutyl group, an isopentyl group, an isohexyl group, or an isoheptyl group.

[0073] Specific examples and preferred examples of the [D]cycloalkylalkyl group in compound (IV) are the same as the specific examples and preferred examples of the [D]cycloalkylalkyl group in compound (I) above.

[0074] Specific examples and preferred examples of the [L]aryl group in compound (IV) are the same as the specific examples and preferred examples of the [L]aryl group in compound (III) above.

[0075] The [M] acyloxyalkyl group in compound (IV) refers to an alkyl group substituted with an acyloxy group. Specific examples of the acyloxy group moiety constituting the [M] acyloxyalkyl group include acyloxy groups having two or more carbon atoms ((C2 or higher) acyloxy groups). The upper limit of the carbon number of the acyloxy group is, for example, six or less. Specific examples of the acyloxy group include acetyloxy, propionyloxy, butanoyloxy, pentanoyloxy, and hexanoyloxy groups. The alkyl group moiety constituting the [M] acyloxyalkyl group includes linear alkyl groups and branched alkyl groups. Specific and preferred examples of the alkyl group are the same as the specific and preferred examples of the [a] alkyl group in compound (I). The [M] acyloxyalkyl group is preferably a (C2-4, preferably 2-3, more preferably 2) acyloxy(C2-4, preferably C2-3 or C3-4) alkyl group.

[0076] The [N]alkoxycarbonylalkyl group in Compound (IV) refers to an alkyl group substituted with an alkoxycarbonyl group. The alkoxycarbonyl group moiety constituting the [N]alkoxycarbonylalkyl group may be a carbonyl group having an alkoxy group, and examples of the alkoxy group include alkoxy groups having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. That is, examples of the alkoxycarbonyl group moiety constituting the [N]alkoxycarbonylalkyl group include alkoxycarbonyl groups having 2 to 7 carbon atoms, preferably 2 to 5 carbon atoms. The alkyl group moiety constituting the [N]alkoxycarbonylalkyl group includes linear alkyl groups and branched alkyl groups. Examples of the linear alkyl group include linear alkyl groups having 3 or more carbon atoms ((C3 or more) linear alkyl groups). The upper limit of the carbon number of the linear alkyl group is, for example, 6 or less. Specific examples of the linear alkyl group include n-propyl, n-butyl, n-pentyl, and n-hexyl groups. When the alkyl group [a] is a branched alkyl group, specific examples and preferred examples of the branched alkyl group are the same as the specific examples when the alkyl group [a] in compound (I) is a branched alkyl group. Preferably, the alkyl group [a] is a linear alkyl group having 3 to 5 carbon atoms. Preferably, the alkoxycarbonyl alkyl group [N] is a (C3 to 5, preferably 3 to 4, more preferably 3) alkoxycarbonyl (C3 to 5) alkyl group.

[0077] Unless otherwise specified, the specific examples and preferred examples of the [A], [B], [D], [L], [M], and [N] groups described above also apply to the preferred examples of combinations of the [D] and [L] groups and substituents listed in the following item 1-4-3.

[0078] 1-4-3.R 8 The substituents that the [D] and [L] groups in The substituents that the [D] cycloalkylalkyl group and the [L] aryl group in the compound (IV) may have are preferably [d] alkoxy group and / or [e] hydroxyl group.

[0079] Specific examples and preferred examples of the [d]alkoxy group in compound (IV) are the same as the specific examples and preferred examples of the [d]alkoxy group in compound (I) above.

[0080] The above specific examples and preferred examples of the substituent [d] group also apply to the preferred examples of compound (IV) listed in item 4-4 below, unless otherwise specified.

[0081] (Preferable examples of combinations of [D] and [L] groups with substituents) In the preferred examples of compound (IV), when the [D] and [L] groups have the above-mentioned substituents, preferred examples of the [D] and [L] groups having the substituents include an [L] aryl group substituted with an [d] alkoxy group, and an [L] aryl group substituted with a [e] hydroxyl group.

[0082] In a preferred example of compound (IV), the substitution position of the substituent that the [L]aryl group may have is the ortho position and / or the para position.

[0083] 1-4-4. Salt The salt of the hydroxycitric acid derivative, Compound (IV), is not particularly limited as long as it is pharmaceutically acceptable. The salt is represented by the following formula (IV'): [ka]

[0084] In the above formula (IV'), M 1 and M 2 each independently represents hydrogen, an alkali metal, an alkaline earth metal, or an organic base, provided that M 1 and M 2 and hydrogen at the same time. 1 and M 2 When M is an alkali metal, alkaline earth metal, or organic base, 1 and M 2 may be the same as or different from each other.

[0085] Alkali metals include potassium and sodium. Alkaline earth metals include calcium. Organic bases include monoethanolamine, diethanolamine, triethanolamine, aminomethylpropanol, and aminomethylpropanediol.

[0086] 2. Method for producing hydroxycitric acid derivatives or salts thereof The hydroxycitric acid derivative can be synthesized by using a hydroxycitric acid lactone as a raw material and derivatizing the carboxyl group or hydroxyl group of the hydroxycitric acid lactone.

[0087] 2-1. Method for producing homodiester of compound (I) In compound (I), R 1 and R 2 Compounds having the same structure (homodiesters) can be obtained by dehydration condensation of hydroxycitric acid lactone (compound 1) in the presence of an alcohol (ROH) or halide (RX) as an esterification reagent, as shown in the following formula.

[0088] [ka]

[0089] In the above formula, R constituting the alcohol or halide which is the esterification reagent is R 1 and R 2 (R 1 and R 2 are the same). R 1 and R 2 The details of are as described above in "1-1. Compound (I)." X represents a halogen, specifically Cl, Br, or I. The alcohol may be used in an amount of at least two equivalents of hydroxycitric acid, preferably at least three equivalents, and more preferably at least four equivalents.

[0090] In order to promote the above esterification reaction, a catalyst such as a strong acid such as sulfuric acid or p-toluenesulfonic acid, a tetravalent hafnium compound, diphenylammonium trifluoromethanesulfonate (DPAT), pentafluorobenzenesulfonic acid, or N-(2,6-diisopropylphenyl)mesitylammonium pentafluorobenzenesulfonate can be used in combination, and these can be used alone or in combination of two or more.

[0091] The reaction solvent that can be used in the above-mentioned esterification reaction is not particularly limited as long as it is a solvent inert to the esterification reaction, and may be either a non-polar solvent or a polar solvent. Examples of the reaction solvent include alkanes such as hexane, heptane, octane, etc.; haloalkanes such as methylene chloride, chloroform, carbon tetrachloride, ethylene chloride, etc.; benzenes such as benzene, toluene, xylene, mesitylene, pentamethylbenzene, etc.; halobenzenes such as chlorobenzene, bromobenzene, etc.; and ethers such as diethyl ether, anisole, etc., and these can be used alone or in combination of two or more.

[0092] The reaction temperature and reaction time in the above esterification reaction may be appropriately determined by those skilled in the art depending on the reaction system. The reaction temperature is, for example, 30°C or higher, preferably 50°C or higher, and more preferably 70°C or higher. The upper limit of the reaction temperature is the reflux temperature or lower, preferably 90°C or lower, and more preferably 85°C or lower. The reaction time is, for example, 0.5 to 72 hours.

[0093] In the above esterification reaction, ring-opening of the lactone ring may simultaneously occur, resulting in the formation of a triester corresponding to compound (II) as a co-product. A method for separating compound (I) from the co-product can be appropriately selected by those skilled in the art, and for example, column chromatography or the like can be used.

[0094] 2-2. Method for producing compound (I)-heterodiester In compound (I), R 1 and R 2The method for synthesizing a compound in which the groups are different from each other (heterodiester) is not particularly limited, and typically, the compound can be obtained by esterifying a monoester synthesized by any method.

[0095] 2-2-1. Method for producing heterodiesters - First example A first example of a method for synthesizing a heterodiester is to first protect both carboxyl groups of a hydroxycitric acid lactone (compound 1) with a protecting group (PG), deprotect one of the protected carboxyl groups and esterify it with an esterifying agent in the first step, and then deprotect the other protected carboxyl group and esterify it with an esterifying agent in the second step. An example of synthesizing a heterodiester based on this method is shown in the following formula.

[0096] [ka]

[0097] The above formula shows a process for protecting both carboxyl groups of a hydroxycitric acid lactone (compound 1) with a protecting group (PG) to obtain compound 10 in which both carboxyl groups are protected with PG. In the above formula, PG represents a protecting group. As the protecting group PG, any group generally used as a protecting group for a carboxyl group can be used without any particular limitation. Specific examples of the protecting group PG include a benzyl group, a methyl group, an ethyl group, and a tert-butyl group. In addition, the R 1 and R 2 In the present disclosure, a benzyl group is preferably used as the protecting group PG. A specific method for introducing the protecting group PG into the hydroxycitric acid lactone (compound 1) may be a general method for protecting a carboxyl group, and for example, the esterification reaction described above in the "Method for producing a homodiester of compound (I)" may be used.

[0098] [ka]

[0099] The above scheme shows the process of deprotecting one of the protecting groups PG from compound 10, both of which have carboxyl groups protected with the protecting group PG, to obtain compounds 5' and 6', which are then esterified with the first-step esterifying agent R-OH to obtain monoesters 10c and 11c.

[0100] As a deprotection method for synthesizing compounds 5' and 6' from compound 10, a conventional deprotection method for a carboxyl protecting group may be used, for example, a conventional reduction reaction of an ester may be used. When using this reduction reaction, any hydrogenation reagent may be used as a reducing reagent for synthesizing compounds 5' and 6', for example, a hydride reducing agent such as hydrogen (H) used together with a metal catalyst such as palladium on carbon, preferably hydrogen used together with a metal catalyst, more preferably hydrogen used together with palladium on carbon.

[0101] In the first step of esterification to obtain compounds 10c and 11c from compounds 5' and 6' obtained by the above deprotection, an esterification agent for the first step is an alcohol R-OH (wherein R is R 1 is the same as R 2 The method described above in "2-1. Method for producing homodiester of compound (I)" can be used to obtain compounds 10c and 11c in which the carboxyl groups of compounds 5' and 6' are esterified.

[0102] [ka]

[0103] The above scheme shows a process in which the remaining protecting group PG of compounds 10c and 11c is deprotected to obtain monoesters 5c and 6c, which are then esterified with an esterifying agent RX in the second step to obtain heterodiesters (I)-h1 and (I)-h2.

[0104] The deprotection method for synthesizing monoesters 5c and 6c from compounds 10c and 11c can also be a conventional deprotection method for a carboxyl protecting group, and a method similar to the deprotection method for synthesizing compounds 5' and 6' from compound 10 described above can be used.

[0105] The second-stage esterification method for obtaining heterodiesters (I)-h1 and (I)-h2 from the monoesters 5c and 6c obtained by the above deprotection can be carried out by using an esterifying agent RX (wherein R is R 1 is the same as R 2 and X represents a halogen, specifically Cl, Br, or I. The O-alkylation can be carried out in the presence of a base, and examples of the base include alkali metal or alkaline earth metal hydroxides such as sodium hydroxide; amines such as DIEA, DMAP, NMM, TMP, and TEA; and metal carbonates such as potassium carbonate and cesium carbonate, with metal carbonates being preferred.

[0106] The reaction solvent that can be used in the above-mentioned esterification reaction by O-alkylation is not particularly limited as long as it is a solvent inert to the O-alkylation reaction, whether it is a non-polar solvent or a polar solvent. Examples of the reaction solvent include alkanes such as hexane, heptane, octane, etc.; haloalkanes such as methylene chloride, chloroform, carbon tetrachloride, ethylene chloride, etc.; benzenes such as benzene, toluene, xylene, mesitylene, pentamethylbenzene, etc.; halobenzenes such as chlorobenzene, bromobenzene, etc.; ethers such as diethyl ether, anisole, tetrahydrofuran, etc.; and ketones such as acetone, methyl ethyl ketone, etc., and these can be used alone or in combination of two or more.

[0107] The reaction temperature and reaction time for the above-mentioned esterification reaction by O-alkylation may be appropriately determined by those skilled in the art depending on the reaction system. The reaction temperature may be, for example, 15 to 30°C. The reaction time may be, for example, 0.5 to 72 hours.

[0108] In the above example, compounds 5', 6', compounds 10c, 11c, monoesters 5c, 6c, and heterodiesters (I)-h1, (I)-h2 are obtained as a mixture, but this mixture can also be separated using a chiral column or supercritical column. Compounds 5', 6', compounds 10c, 11c, and monoesters 5c, 6c can be separated from the mixture at any stage, followed by subsequent reactions to synthesize heterodiesters (I)-h1 and heterodiesters (I)-h2 independently. Alternatively, a mixture of heterodiesters (I)-h1 and (I)-h2 can be separated into the individual heterodiesters to obtain heterodiesters (I)-h1 and heterodiesters (I)-h2 as single compounds.

[0109] 2-2-2. Method for producing heterodiesters - second example A second example of a method for synthesizing a heterodiester is a method in which a monoester synthesized using an esterifying agent in a first step is converted into a diester using an esterifying agent in a second step that is different from the esterifying agent in the first step. An example of synthesizing a heterodiester based on this method is shown in the following formula.

[0110] [ka]

[0111] In the above example, the first-step esterification (esterification by condensation) can be carried out in the same manner as in "2-1. Method for producing homodiester of compound (I)" except that the amount of alcohol (ROH) used as the esterification reagent is half the equivalent amount of that described in "2-1. Method for producing homodiester of compound (I)". The second-step esterification (esterification by O-alkylation) can be carried out in the same manner as in the first example of the method for synthesizing heterodiester.

[0112] The reaction route in the upper part of the above formula and the reaction route in the lower part of the formula may proceed in the same reaction system without being distinguished from each other. R 1 and R 2 and R are the same group, and the first-stage esterification reaction may produce a mixture of a monoester (compound 5') in which one carboxyl group of the hydroxycitric acid lactone is esterified and a monoester (compound 6') in which the other carboxyl group is esterified in the same reaction system. In this case, the second-stage esterification reaction can be carried out as the mixture. In other words, the non-underlined R in the above formula 1 and R 2 and (I)-h2 are the same group, and by using one kind of esterification reagent in the second-step esterification reaction, the other carboxyl group of compound 5′ and one carboxyl group of compound 6′ are simultaneously esterified, thereby obtaining a mixture of two kinds of compounds (I)-h1 and (I)-h2 in which one and the other carboxyl groups are derivatized to the opposite ester groups.

[0113] 2-3. Method for producing compound (II) Compound (II) can be synthesized by dehydrating and condensing a hydroxycitric acid lactone in the presence of an alcohol (ROH) or a halide (RX) as an esterifying agent, and then opening the lactone ring, as shown in the following formula.

[0114] [ka]

[0115] In the above formula, R constituting the alcohol or halide which is the esterification reagent is R 3 , R 4 and R 5 (R 3 , R 4 and R 5 are the same). R 3 , R 4 and R 5The details of the above are as described in "1-2. Compound (II)." The alcohol may be used in an amount of at least three times the equivalent of hydroxycitric acid, preferably at least four times the equivalent.

[0116] In order to promote the above esterification reaction, a catalyst such as a strong acid such as sulfuric acid or p-toluenesulfonic acid, a tetravalent hafnium compound, diphenylammonium trifluoromethanesulfonate (DPAT), pentafluorobenzenesulfonic acid, or N-(2,6-diisopropylphenyl)mesitylammonium pentafluorobenzenesulfonate can be used in combination, and these can be used alone or in combination of two or more.

[0117] The reaction solvent that can be used in the above-mentioned esterification reaction is not particularly limited as long as it is a solvent inert to the esterification reaction, and may be either a non-polar solvent or a polar solvent. Examples of the reaction solvent include alkanes such as hexane, heptane, octane, etc.; haloalkanes such as methylene chloride, chloroform, carbon tetrachloride, ethylene chloride, etc.; benzenes such as benzene, toluene, xylene, mesitylene, pentamethylbenzene, etc.; halobenzenes such as chlorobenzene, bromobenzene, etc.; and ethers such as diethyl ether, anisole, etc., and these can be used alone or in combination of two or more.

[0118] The reaction temperature and reaction time in the above esterification reaction may be appropriately determined by those skilled in the art depending on the reaction system. The reaction temperature is, for example, 30°C or higher, preferably 50°C or higher, and more preferably 70°C or higher. The upper limit of the reaction temperature is the reflux temperature or lower, preferably 90°C or lower, and more preferably 85°C or lower. The reaction time is, for example, 0.5 to 72 hours.

[0119] In the above esterification reaction, a diester corresponding to compound (I) may be produced as a co-product without ring-opening of the lactone ring. A method for separating compound (II) from the co-product can be appropriately selected by those skilled in the art, and for example, column chromatography or the like can be used.

[0120] 2-4. Method for producing compound (III) Compound (III) can be synthesized by reacting a hydroxycitric acid lactone with an amine (NH R R) can be obtained by condensation.

[0121] [ka]

[0122] In the above formula, the underlined compound constituting the amide, which is the amidating reagent, R is R 61 and R 71 and the ununderlined R represents R 62 -R 63 and R 72 -R 73 Represents R 61 , R 62 , R 63 , R 71 , R 72 , R 73 The details of the above are as described in "1-3. Compound (III)." The alcohol may be used in an amount of at least 2 times the equivalent of hydroxycitric acid, preferably at least 2.4 times the equivalent.

[0123] It is preferable to add a base such as DIEA, DMAP, NMM, TMP, or TEA to the amidation reaction system, and these may be used alone or in combination of two or more.

[0124] To promote the amidation reaction, a carboxylic acid activator can be used in combination. Examples of carboxylic acid activators include acid halide agents such as thionyl hydrochloride; acid azidation agents such as diphenylphosphoryl azide; activated esterification agents such as 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), ethyl (hydroxyimino)cyanoacetate (Oxyma), and water-soluble carbodiimide (WSCD); and phosphonium / uronium coupling agents such as TBTU, TATU, HATU, HBTU, COMU, and HOTU. These can be used alone or in combination.

[0125] The reaction solvent that can be used in the above-mentioned amidation reaction is not particularly limited as long as it is a solvent inert to the amidation reaction. Examples thereof include amide solvents such as dimethylformamide, dimethylacetamide, and N-methylpyrrolidone; sulfoxide solvents such as dimethyl sulfoxide; and the like. These can be used alone or in combination of two or more.

[0126] The reaction temperature and reaction time for the above amidation reaction may be appropriately determined by those skilled in the art depending on the reaction system. The reaction temperature may be, for example, 15 to 30° C. The reaction time may be, for example, 0.5 to 72 hours.

[0127] 2-5. Method for producing compound (IV) Compound (IV) can be prepared by adding an acylating agent (R 8 COX) to carry out acylation, and then reduce the ester group possessed by compound (I) to a carboxyl group.

[0128] [ka]

[0129] In the above formula, R constituting the acylating agent 8The details of are as described above in "1-4. Compound (IV)". X represents a halogen, specifically Cl, Br, or I, preferably Cl. Compound (I) as a raw material is a diester, preferably a homodiester, more preferably R 1 and R 2 and the like are homodiesters in which each of [E] is an aralkyl group (more preferably a benzyl group). The acylating agent may be used in an amount of 1 equivalent or more, preferably 5 equivalents or more, more preferably 9 equivalents or more, relative to the amount of the starting compound (I).

[0130] In the above reaction, compound (I) is formed by converting the carboxyl group of the lactone of hydroxycitric acid to R 1 and R 2 The hydroxyl group of compound (I) is protected by an acylating agent, and an acylated compound of compound (I) (compound 4) is obtained by the action of an acylating agent on the hydroxyl group of compound (I). Compound 4 is then subjected to an ester decomposition reaction to obtain R 1 and R 2 The reagent used in the ester decomposition reaction includes a hydrolysis reaction using hydrogen, an acid, or an alkali together with a metal catalyst, and any ester decomposition reagent can be used, for example, an acid (including PBr3, PCl3, LiCl, and LiI), a base, a fluoride source, a lipase enzyme, chlorotrimethylsilane, etc., preferably hydrogen together with a metal catalyst, more preferably hydrogen together with palladium on carbon.

[0131] 3. Cysteinyl leukotriene receptor 2 inhibitors The above-described hydroxycitric acid derivatives or salts thereof have inhibitory activity against cysteinyl leukotriene receptor 2 (human CYSLTR2). Therefore, the present disclosure also provides cysteinyl leukotriene receptor 2 inhibitors. Cysteinyl leukotriene receptor 2 inhibitory activity has not been reported for hydroxycitric acid, and has been discovered for the first time for the hydroxycitric acid derivatives of the present disclosure.

[0132] Specifically, the cysteinyl leukotriene receptor 2 inhibitors of the present disclosure can be used as therapeutic or preventive agents for cysteinyl leukotriene receptor 2-mediated diseases. Cysteinyl leukotriene receptor 2-mediated diseases include, but are not limited to, asthma, sinus disease, allergic fungal sinusitis, migraine, chronic urticaria, atopic dermatitis, chronic obstructive pulmonary disease, allergic conjunctivitis, mastocytosis, bronchiolitis, idiopathic pulmonary fibrosis, interstitial cystitis, irritable bowel syndrome, rheumatoid arthritis, perennial allergic rhinitis, cystic fibrosis, recurrent vulvovaginal candidiasis, psoriasis, capsular contracture, and other inflammatory diseases. From the viewpoint of expected effectiveness, asthma is a preferred example of a cysteinyl leukotriene receptor 2-mediated disease, and bronchial asthma is a more preferred example. Furthermore, since allergic bronchial asthma is a more specific example of bronchial asthma, which is a cysteinyl leukotriene receptor 2-mediated disease, the cysteinyl leukotriene receptor 2 inhibitor of the present disclosure has a therapeutic effect on allergic asthma, a pre-existing condition for which the use of Garcinia extract supplements containing hydroxycitric acid is avoided. Therefore, a particularly preferred example of a cysteinyl leukotriene receptor 2-mediated disease to which the cysteinyl leukotriene receptor 2 inhibitor of the present disclosure is applied is allergic bronchial asthma.

[0133] 3-1. Active ingredients The cysteinyl leukotriene receptor 2 inhibitor of the present disclosure contains a hydroxycitric acid derivative and / or a salt thereof as an active ingredient. The specific structures and production methods of the hydroxycitric acid derivative and its salt are as described above in "1. Hydroxycitric acid derivative or salt thereof" and "2. Production method of hydroxycitric acid derivative or salt thereof."

[0134] 3-2.Other ingredients In addition to the active ingredient, the cysteinyl leukotriene receptor 2 inhibitor of the present disclosure may contain other ingredients depending on the application form, as long as the effects of the present disclosure are not impaired. Such ingredients include, for example, physiologically active substances and additives.

[0135] Examples of physiologically active substances include collagen, type II collagen, non-denatured active type II collagen, and Gen, collagen peptides, methylsulfonylmethane (MSM), glucosamine, glucosamine hydrochloride, N-acetylglucosamine, N-acetylglucosamine sulfate, chondroitin, chondroitin sulfate, galactosamine, N-acetylgalactosamine, glucuronic acid, uronic acid, proteoglycan, non-denatured proteoglycan, heparin, heparan sulfate, iduronic acid, keratan sulfate, dermatan sulfate, S-adenosylmethionine, creatine, theanine, piperine, maslinic acid, 5-aminolevulinic acid phosphate, cat's claw, black ginger, boswellia serrata, artichoke, amino acids, vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D2, vitamin D3 These include vitamin E, vitamin K, folic acid, hyaluronic acid, bonito-derived elastin peptide, imidazole dipeptide, quercetin glycoside, krill oil-derived EPA and DHA, moringa seed-derived glucomoringin, Japanese knotweed, devil's claw, chicken foot-derived hyaluronic acid production promoter (HAS-II), soy isoflavones, beta-cryptoxanthin, bonepep, whey protein concentrate (CBP), 3-hydroxy-3-methylbutyrate (HMB), calcium bis-3-hydroxy-3-methylbutyrate monohydrate (HMB calcium), calcium maltobionate, calcium, magnesium, zinc, iron, selenium, potassium, estrogen, calcitonin, aspirin, steroidal anti-inflammatory agents, and non-steroidal anti-inflammatory agents. These physiologically active substances may be used singly or in combination.

[0136] Examples of additives include pharmaceutically or food-related acceptable excipients, disintegrants, diluents, lubricants, flavoring agents, colorants, sweeteners, flavoring agents, suspending agents, wetting agents, emulsifiers, dispersing agents, adjuvants, preservatives, buffers, binders, stabilizers, bulking agents, thickeners, pH adjusters, surfactants, coating agents, nutritional components, etc. These additives may be used singly or in combination of two or more.

[0137] 3-3. Formulation The form and properties of the cysteinyl leukotriene receptor 2 inhibitor of the present disclosure are not particularly limited, as long as it contains the above-mentioned active ingredient.

[0138] The cysteinyl leukotriene receptor 2 inhibitor of the present disclosure may be administered orally or parenterally, and may be administered orally, injectably, as an infusion, infusion, nasal drops, transdermal preparation (external preparation), or the like.

[0139] Furthermore, the cysteinyl leukotriene receptor 2 inhibitor of the present disclosure may be in liquid or solid form. Examples of liquid forms include solutions, drinks, emulsions, suspensions, spirits, syrups, elixirs, soft extracts, etc., and examples of solid forms include tablets, pills, powders, fine granules, granules, tablets, capsules (including hard capsules and soft capsules), troches, chewable tablets, etc.

[0140] The method for producing the cysteinyl leukotriene receptor 2 inhibitor of the present disclosure can be carried out using the above-mentioned active ingredient and other ingredients that are blended as necessary, according to various forms, properties, and intended uses, following conventional formulation procedures known in the art. [Example]

[0141] The present disclosure will be explained in more detail below by showing examples, but the present invention is not limited to these examples.

[0142] [Test Example 1] The hydroxycitric acid derivatives shown in Tables 1 to 5 below were synthesized. In the tables, the structure of each hydroxycitric acid derivative and the type of the derivatized functional group (R 1 , R 2 , R 3 , R 4 , R 5 , R61 , R 62 , R 63 , R 71 , R 72 , R 73 , R 8 and the substituents [a] to [e] that they may have), as well as the reagents used for derivatization (esterification reagent, amidation reagent, acylation reagent). [Table 1A] [Table 1B] [Table 1C]

[0143] [Table 2]

[0144] [Table 3A] [Table 3B]

[0145] [Table 4] [Table 5A] [Table 5B]

[0146] Synthesis Example 1: Synthesis of homodiesters and triesters by diesterification using a DPAT catalyst (Synthesis Example 1-1) The hydroxycitric acid derivatives (homodiesters) of Examples 9, 11, 12, 13, 14, 15, and 27 and the hydroxycitric acid derivatives (triesters) of Examples 44, 45, 46, and 48 were synthesized by the following procedure. A mixture of (2S,3S)-3-hydroxy-5-oxotetrahydrofuran-2,3-dicarboxylic acid (compound 1, 30 mg, 0.160 mmol), the esterification reagent alcohol (R-OH, 0.640 mmol) shown in the table above, and diphenylammonium trifluoromethanesulfonate (DPAT, 5.0 mg, 0.016 mmol) in toluene (1.5 mL) was stirred overnight at 80 °C. The mixture was evaporated at 60 °C. The residue was purified by preparative HPLC (MS Trigger) (CERI L-Column 2 ODS, eluted with HO in acetonitrile containing 10 mM ammonium bicarbonate). The desired fractions were lyophilized to obtain compound (I) (major product, homodiester) and compound (II) (minor product, triester). The resulting homodiester and triester were purified by MS-triggered preparative HPLC.

[0147] (Synthesis Example 1-2) The hydroxycitric acid derivatives (homodiesters) of Examples 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 28, and 29 and the hydroxycitric acid derivative (triester) of Example 47 were synthesized by the following procedure. A mixture of (2S,3S)-3-hydroxy-5-oxotetrahydrofuran-2,3-dicarboxylic acid (compound 1, 30 mg, 0.160 mmol), the esterification reagent alcohol (R-OH, 0.640 mmol) shown in the table above, and DPAT (5.0 mg, 0.016 mmol) in toluene (1.5 mL) was stirred at 80 °C overnight. The mixture was evaporated at 60 °C. The residue was purified by preparative HPLC (YMC Triart C18, eluted with 0.1% TFA in acetonitrile / 0.1% TFA in water). The desired fractions were evaporated to give compound (I) (major product, homodiester) and compound (II) (minor product, triester).

[0148] [ka]

[0149] Synthesis Example 2: Synthesis of homodiesters and triesters by diesterification using a sulfuric acid catalyst The hydroxycitric acid derivatives (homodiesters) of Examples 1, 2, 3, 4, 5, 6, 7, 8, and 10 and the hydroxycitric acid derivatives (triesters) of Examples 37, 38, 39, 40, 41, 42, and 43 were synthesized by the following procedure. A mixture of (2S,3S)-3-hydroxy-5-oxotetrahydrofuran-2,3-dicarboxylic acid (compound 1, 30 mg, 160 μmol), the esterification reagent alcohol (R-OH, 1 mL) shown in the table above, and sulfuric acid (0.0028 mL, 0.047 mmol) was stirred at 75 °C overnight. The mixture was evaporated at 60 °C. The residue was purified by preparative HPLC (MS Trigger) (CERI L Column 2 ODS, eluted with HO in acetonitrile containing 10 mM ammonium bicarbonate). The desired fractions were lyophilized to obtain compound (I) (major product, homodiester) and compound (II) (minor product, triester).

[0150] [ka]

[0151] Synthesis Example 3-1: Synthesis of heterodiester by esterification of monoester The hydroxycitric acid derivatives of Examples 30, 32, 34, and 35 were synthesized by the following procedure. First, compound 7' (a compound classified as compound (I)) was obtained by the same method as used to synthesize compound (I) (homodiester) in Synthesis Example 1-1 above, using the first-stage esterification agent (benzyl alcohol) shown in Table 2 as the esterification agent.

[0152] [ka]

[0153] Next, a mixture of compound 7' (11 g, 30 mmol) and Pd-C (16 g, 10% wt, 15 mmol) in THF (100 mL) was hydrogenated at room temperature for 3 hours. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the concentrate (8.48 g) was dissolved in ethyl acetate (100 mL) and washed with water (50 mL x 2). The organic solvent layer was washed with saturated aqueous sodium bicarbonate (50 mL x 2), and the aqueous sodium bicarbonate layer was adjusted to pH 4 with 10% aqueous citric acid and extracted with ethyl acetate (100 mL x 3). The resulting organic solvent layer was dried over sodium sulfate and concentrated under reduced pressure to give a mixture of compounds 5' and 6'.

[0154] [ka]

[0155] The identification data of compounds 5' and 6' are as follows: 1 H NMR (400 MHz, CDCl3, 300 K) δ 2.72-2.87 (1H, m), 3.07-3.20 (1H, m), 4.95 (1H, s), 5.11-5.27 (2H, m), 6.38-6.64 (1H, m), 7.12 (1H, br s), 7.30-7.39 (5H, m). MS m / z 279.0 (M−H) -

[0156] Next, potassium carbonate (44 mg, 0.32 mmol) was added to a solution of the mixture of 5' and 6' (30 mg, 0.11 mmol) and the esterification reagent halide (RX, 0.32 mmol) shown in the table above in N,N-dimethylformamide (DMF) (1 mL) at room temperature. This mixture was stirred overnight at room temperature. The reaction mixture was neutralized with 2 N aqueous HCl at room temperature. Insoluble material was removed by filtration. The resulting filtrate was purified by preparative HPLC (MS Trigger) (CERI L-Column 2 ODS, eluted with HO in acetonitrile containing 10 mM ammonium bicarbonate). The desired fraction was lyophilized to obtain a mixture of compound (I)-h1 and compound (I)-h2 (heterodiester).

[0157] [ka]

[0158] Synthesis Example 3-2. Synthesis of heterodiester The hydroxycitric acid derivatives of Examples 31, 33, and 36 were synthesized by the following procedure. To a DMF solution (1 ml) containing a mixture of compounds 5' and 6' (50 mg, 0.18 mmol), the intermediate compounds obtained in Synthesis Example 3-1, and (4-bromobutoxy)benzene (82 mg, 0.36 mmol) as the first-stage esterification agent, K2CO3 (49 mg, 0.36 mmol) was added at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was neutralized with 1N HCl at room temperature and purified by preparative HPLC (YMC-Triart C18, eluted with acetonitrile-water containing 0.1% trifluoroacetic acid). The desired fractions were lyophilized to obtain compounds 10c and 11c (39 mg, 91 μmol, 51%, 99% purity) as colorless oils. The molecular weights of compounds 10c and 11c were m / z 427.1 (MH). - It was.

[0159] Compounds 10c and 11c (39 mg, 91 μmol) and Pd / C (50 mg, 10% wt, 47 μmol) in THF (3 mL) were subjected to hydrogenation under balloon pressure at room temperature for 6 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give a mixture of compounds 5c and 6c (27 mg, 80 μmol, 88%, 86% purity) as a colorless oil. The molecular weight of this mixture was m / z 337.0 (MH). - This product was subjected to the next reaction (second-stage esterification reaction) without further purification.

[0160] (In the case of Example 31) To a DMF solution (1 ml) containing a mixture of compounds 5c and 6c (27 mg, 80 μmol) and iodopropane (41 mg, 0.24 mmol) as the second-stage esterification agent, K2CO3 (22 mg, 0.16 mmol) was added at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was neutralized with 1N HCl at room temperature and purified by preparative HPLC (YMC-Triart C18, eluted with acetonitrile-water containing 0.1% trifluoroacetic acid). The desired fraction was lyophilized to obtain compound (I)-h1 and compound (I)-h2 (19 mg, 50 μmol, 63%, 100% purity) as a colorless oil. The molecular weights of compound (I)-h1 and compound (I)-h2 were m / z 379.1 (MH). - It was.

[0161] (In the case of Example 33) To a DMF solution (1 ml) containing a mixture of compounds 5c and 6c (36 mg, 0.11 mmol) and 2-iodopropane (54 mg, 0.32 mmol) as the second-stage esterification agent, K2CO3 (29 mg, 0.21 mmol) was added at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was neutralized with 1N HCl at room temperature and purified by preparative HPLC (YMC-Triart C18, eluted with acetonitrile-water containing 0.1% trifluoroacetic acid). The desired fraction was lyophilized to obtain compound (I)-h1 and compound (I)-h2 (11 mg, 29 μmol, 27%, 100% purity) as a colorless oil. The molecular weights of compound (I)-h1 and compound (I)-h2 were m / z 379.1 (MH). -It was.

[0162] (Example 36) To a DMF solution (1 ml) containing a mixture of compounds 5c and 6c (36 mg, 0.11 mmol) and 3-(bromomethyl)-3-methyloxetane (53 mg, 0.32 mmol) as the second-stage esterification agent, K2CO3 (29 mg, 0.21 mmol) was added at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was neutralized with 1N HCl at room temperature and purified by preparative HPLC (YMC-Triart C18, eluted with acetonitrile-water containing 0.1% trifluoroacetic acid). The desired fractions were lyophilized to obtain compound (I)-h1 and compound (I)-h2 (23 mg, 54 μmol, 51%, 96% purity) as a colorless oil. The molecular weights of compound (I)-h1 and compound (I)-h2 were m / z 421.1 (MH). - It was.

[0163] [ka]

[0164] Synthesis Example 4-1: Synthesis of diamide The hydroxycitric acid derivative of Example 49 was synthesized by the following procedure. To a solution of (2S,3S)-3-hydroxy-5-oxotetrahydrofuran-2,3-dicarboxylic acid (compound 1, 50 mg, 0.26 mmol) and HATU (0.20 g, 0.53 mmol) in DMF (1 mL) was added DIPEA (0.18 mL, 1.1 mmol) at room temperature. After stirring for 5 min at room temperature, the amidating reagent N-methylbenzylamine (compound 7c, 80 mg, 0.66 mmol) was added to the reaction mixture. The residue was purified by preparative HPLC (YMC-Triart C18, eluted with HO in acetonitrile containing 10 mM ammonium bicarbonate). The desired fraction was lyophilized to give compound (III) (5.0 mg, 11 μmol, 4.3%, 90% purity) as a white powder.

[0165] [ka]

[0166] Synthesis Example 4-2: Synthesis of diamide The hydroxycitric acid derivatives of Examples 50 to 54 were synthesized by the following procedure. The amidation reagent amine compound (7a-i, 1.1 mmol) was dissolved in DMA (1 mL) with (2S,3S)-3-hydroxy-5-oxotetrahydrofuran-2,3-dicarboxylic acid (compound 1, 80 mg, 0.42 mmol). (Note: An insoluble precipitate in the DMA was removed.) DIPEA (0.29 mL, 1.7 mmol) and a suspension of HATU (0.32 g, 0.84 mmol) in DMA (1 mL) were added. The mixture was stirred overnight at room temperature and purified by preparative HPLC (YMC-Triart C18, eluted with HO in acetonitrile containing 10 mM ammonium bicarbonate). The desired fraction was lyophilized to give compound (III) (diamide) as a white or pale pink powder.

[0167] [ka]

[0168] Synthesis Example 5: Synthesis of acylated compounds 25 mg (67.5 μmol) of compound 1 and acid chloride RCOCl (675 μmol) were added to a test tube and stirred at an external temperature of 80°C for 3 hours. After cooling, 200 μL of methanol was added and the mixture was concentrated under reduced pressure. The resulting residue was purified by reverse phase chromatography to obtain compound 4. Next, compound 4 and 200 μL of tetrahydrofuran were added to a test tube and the mixture was stirred under a nitrogen atmosphere using an ASCA-2 (water-containing) column (manufactured by NE Chemcat). (R) The test tube was replaced with a hydrogen atmosphere and stirred for 2 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure to obtain the target compound (IV).

[0169] [ka]

[0170] Identification of hydroxycitric acid derivatives Each of the obtained hydroxycitric acid derivatives was analyzed using deuterated chloroform or deuterated dimethyl sulfoxide as a solvent and TMS as a standard substance. 1 Identification was performed by H NMR (400 MHz, 600 MHz, or 1300 MHz, Bruker AVANCE 400) or mass spectrometry (Shimazu UFLC-Mass Spectrometer System (LC-MS) using a L-column 2 ODS (3.0 mm ID x 30 mm L, 3 mM, CERI, Japan for Examples 1 to 54; Waters ACQUITY UPLC, BEH C18 1.7 μm, 2.1 mm x 50 mm for Examples 55 to 66).

[0171] Example 1 (Homodiester) obtained 1 The H NMR is shown in Figure 1. 1H NMR (400 MHz, CDCl3, 300 K) δ 1.27-1.34 (6H, m), 2.80 (1H, d, J = 17.6 Hz), 3.13 (1H, d, J = 17.6 Hz), 4.17-4.37 (4H, m), 4.87 (1H, s). MS m / z 264.1 (M+HO) + , 245.1 (MH) - Example 2 (Homodiester) MS m / z 292.1 (M+HO) + , 273.0 (MH) - Example 3 (Homodiester) MS m / z 320.2 (M+HO) + , 301.1 (MH) - Example 4 (Homodiester) MS m / z 376.2 (M+HO) + , 357.2 (MH) -

[0172] Example 5 (Homodiester) obtained 1 The H NMR is shown in Figure 2. 1H NMR (400 MHz, CDCl3, 300 K) δ 1.67 (6H, td, J = 18.6, 4.5 Hz), 2.90 (1H, d, J = 17.6 Hz), 3.15 (1H, d, J = 17.6 Hz), 3.88 (1H, s), 4.22-4.47 (4H, m), 4.99 (1H, s). MS m / z 364.1 (M+HO) + , 345 (MH) -

[0173] Example 6 (Homodiester) obtained 1 The H NMR is shown in Figure 3. 1H NMR (400 MHz, CDCl3, 300 K) δ 1.26-1.35 (12H, m), 2.81 (1H, d, J = 17.6 Hz), 3.06 (1H, d, J = 17.4 Hz), 3.88 (1H, br s), 4.83 (1H, s), 5.02-5.14 (2H, m). MS m / z 292.1 (M+HO) + , 273.0 (MH) - Example 7 (Homodiester) MS m / z 320.1 (M+HO) + , 301.1 (MH) -

[0174] Example 8 (Homodiester) obtained 1 The H NMR is shown in Figure 4. 1H NMR (400 MHz, CDCl3, 300 K) δ 0.95 (18H, d, J = 1.0 Hz), 1.55-1.62 (4H, m), 2.79 (1H, d, J = 17.6 Hz), 3.11 (1H, d, J = 17.6 Hz), 3.88 (1H, s), 4.14-4.38 (4H, m), 4.85 (1H, s). MS m / z 376.2 (M+HO) + , 357.2 (MH) - Example 9 (Homodiester) MS m / z 316.1 (M+HO) + , 297.0 (MH) - Example 10 (Homodiester) obtained 1 The H NMR is shown in Figure 5. 1H NMR (400 MHz, CDCl3) δ 1.55-1.95 (m, 16H), 2.81 (d, 1H, J = 17.5), 3.02 (d, 1H, J = 17.5), 3.91 (s, 1H), 4.82 (s, 1H), 5.20-5.28 (m, 2H) MS m / z 344.1 (M+HO) + , 325.1 (MH) - Example 11 (Homodiester) MS m / z 396.2 (M+HO) + , 377.2 (MH) - Example 12 (Homodiester) MS m / z 476.3 (M+HO) + , 457.2 (MH) -

[0175] Example 13 (Homodiester) obtained 1 The H NMR is shown in Figure 6. 1H NMR (400 MHz, CDCl3, 296 K) δ 0.25-0.36 (4H, m), 0.58-0.65 (4H, m), 1.08-1.19 (2H, m), 2.83 (1H, d, J = 17.6 Hz), 3.17 (1H, d, J = 17.6 Hz), 3.93-4.06 (3H, m), 4.12 (1H, dd, J = 11.2, 7.6 Hz), 4.91 (1H, s). MS m / z 316.1 (M+HO) + , 297.1 (MH) - Example 14 (Homodiester) MS m / z 372.2 (M+HO) + , 353.1 (MH) - Example 15 (Homodiester) MS m / z 344.1 (M+HO) + , 325.2 (MH) -

[0176] Example 16 (Homodiester) obtained 1 The H NMR is shown in Figure 7. 1H NMR (400 MHz, CDCl3) δ 2.68 (1H, d, J = 17.6 Hz), 2.80-3.02 (5H, m), 3.85 (1H, br s), 4.14(1H, dt, J = 10.8, 6.7 Hz), 4.21-4.35 (2H, m), 4.39 (1H, dt, J = 10.8, 7.3 Hz), 4.84 (1H, s), 7.13-7.38 (10H, m). MS m / z 416.1 (M+NH4) + Example 17 (Homodiester) MS m / z 416.2 (M+HO) + , 397.1 (MH) - Example 18 (Homodiester) MS m / z 416.2 (M+HO) + , 397.1 (MH) - Example 19 (Homodiester) MS m / z 444.2 (M+HO) + , 425.2 (MH) - Example 20 (Homodiester) MS m / z 444.2 (M+HO) + , 407.1 (M-H2O) - Example 21 (Homodiester) MS m / z 456.1 (M+HO) + , 437.1 (MH) - Example 22 (Homodiester) MS m / z 456.1 (M+HO) + , 437.0 (MH) - Example 23 (Homodiester) MS m / z 452.1 (M+HO) + , 415.1 (M-H2O) - Example 24 (Homodiester) MS m / z 452.2 (M+HO) + , 415.1 (M-H2O) - Example 25 (Homodiester) MS m / z 584.2 (M+HO) + , 547.1 (M-H2O) - Example 26 (Homodiester) MS m / z 476.2 (M+HO) + , 457.2 (MH) - Example 27 (Homodiester) MS m / z 357.1 (M−H) -

[0177] Example 28 (Homodiester) obtained 1 The H NMR is shown in Figure 8. 1H NMR (400 MHz, CDCl3, 296 K) δ 1.78-1.89 (8H, m), 2.81 (1H, d, J = 17.6 Hz), 3.10 (1H, d, J = 17.6 Hz), 3.89 (1H, br s), 3.97 (4H, t, J = 5.6 Hz), 4.19-4.39 (4H, m), 4.87 (1H, s), 6.85-6.96 (6H, m), 7.25 (1H, s), 7.27-7.30 (3H, m). MS m / z 485.1 (M−H) - Example 29 (Homodiester) MS m / z 652.3 (M+HO) + , 633.2 (MH) -

[0178] Example 30 (heterodiester, compound shown on the right side in Table 3) obtained 1 The H NMR is shown in Figure 9. 1H NMR (400 MHz, CDCl3, 300 K) δ 1.14-1.22 (3H, m), 2.75-2.87 (1H, m), 3.02-3.15 (1H, m), 3.90-4.04 (2H, m), 4.15 (1H, dq, J = 10.8, 7.1 Hz), 4.86-4.93 (1H, m), 5.12-5.30 (2H, m), 7.33-7.42 (5H, m). MS m / z 307.1 (M−H) -

[0179] Example 31 (heterodiester, compound shown on the right side in Table 3) obtained1 The H NMR is shown in Figure 10. 1H NMR (400 MHz, CDCl3, 296 K) δ 0.91-0.97 (3H, m), 1.67 (2H, sxt, J = 7.1 Hz), 1.79-1.95 (4H, m), 2.77-2.86 (1H, m), 3.07-3.15 (1H, m), 3.99 (2H, t, J = 5.6 Hz), 4.05-4.42 (4H, m), 4.86-4.91 (1H, m), 6.86-6.91 (2H, m), 6.92-6.98 (1H, m), 7.27-7.33 (2H, m). MS m / z 379.2 (M−H) -

[0180] Example 32 (heterodiester, compound shown on the right side in Table 3) MS m / z 337.1 (M−H) -

[0181] Example 33 (heterodiester, compound shown on the right side in Table 3) obtained 1 The H NMR is shown in Figure 11. 1H NMR (400 MHz, CDCl3, 296 K) δ 1.22-1.32 (6H, m), 1.81-1.91 (4H, m), 2.75-2.88 (1H, m), 3.00-3.12 (1H, m), 3.99 (2H, t, J = 5.6 Hz), 4.19-4.47 (2H, m), 4.81-4.92 (1H, m), 5.01-5.13 (1H, m), 6.86-6.90 (2H, m), 6.92-7.00 (1H, m), 7.26-7.33 (2H, m). MS m / z 379.1 (M−H) -

[0182] Example 34 (heterodiester, compound shown on the right side in Table 3) MS m / z 363.1 (M−H) -

[0183] Example 35 (heterodiester, compound shown on the right side in Table 3) MS m / z 399.1 (M−H) -

[0184] Example 36 (heterodiester, compound shown on the right side in Table 3) obtained 1 The H NMR is shown in Figure 12. 1H NMR (400 MHz, CDCl3, 296 K) δ 1.27-1.37 (3H, m), 1.80-1.97 (4H, m), 2.81-2.94 (1H, m), 3.05-3.17 (1H, m), 3.97-4.05 (2H, m), 4.15-4.40 (6H, m), 4.44-4.54 (4H, m), 4.90-5.01 (1H, m), 6.86-6.92 (2H, m), 6.92-6.99 (1H, m), 7.26-7.31 (2H, m). MS m / z 421.1 (M−H) -

[0185] Example 37 (Triester) MS m / z 335.1(M+H) + Example 38 (Triester) MS m / z 377.2(M+H) + Example 39 (Triester) MS m / z 461.3(M+H) + Example 40 (Triester) MS m / z 447.2(M+Na) + Example 41 (Triester) MS m / z 377.2(M+H) + Example 42 (Triester) obtained 1 The H NMR is shown in Figure 13. 1H NMR (400 MHz, CDCl3) δ 0.93 (s, 9H), 0.95 (s, 9H), 0.96 (s, 9H), 1.51-1.66 (m, 6H), 3.00 (s, 2H), 3.26 (d, 1H, J = 8.5 Hz), 3.96 (s, 1H), 4.10-4.16 (m, 2H), 4.25 (d, 1H, J = 8.0 Hz), 4.28-4.34 (m, 4H) MS m / z 461.3(M+H) + Example 43 (Triester) obtained 1 The H NMR is shown in Figure 14. 1H NMR (400 MHz, CDCl3) δ1.53-1.94 (m, 24H), 2.96 (s, 2H), 3.25 (d, 1H, J = 8.5 Hz), 3.89 (s, 1H), 4.18 (d, 1H, J = 9.0 Hz), 5.14-5.18 (m, 1H), 5.29-5.34 (m, 2H) MS m / z 413.2(M+H) + Example 44 (Triester) MS m / z 513.3(M+Na) + Example 45 (Triester) MS m / z 455.2(M+H) +

[0186] Example 46 (Triester) obtained 1 The H NMR is shown in Figure 15. 1H NMR (400 MHz, CDCl3, 300 K) δ 2.29-2.49 (8H, m), 2.61-2.78 (7H, m), 3.06 (2H, s), 3.26 (1H, d, J = 8.3 Hz), 3.88 (1H, s), 4.11-4.17 (2H, m), 4.27-4.41 (5H, m). MS m / z 543.2(M+Na) + Example 47 (Triester) obtained 1 The H NMR is shown in Figure 16. 1H NMR (400 MHz, CDCl3) δ 2.82-3.05 (8H, m), 3.23 (1H, d, J = 8.8 Hz), 3.88 (1H, s), 4.12-4.33 (3H, m), 4.36-4.51 (4H, m), 7.13-7.33 (15H, m). MS m / z 521.2 (M+H) + Example 48 (Triester) MS m / z 525.3(M+Na) +

[0187] Example 49 (Diamide) obtained 1 The H NMR is shown in Figure 17. 1H NMR (600 MHz, DMSO-d6, 300 K) δ 2.54-2.84 (3H, m), 3.01-3.10 (4H, m), 3.41-3.63 (1H, m), 4.28-5.10 (4H, m), 5.30-5.62 (1H, m), 6.78-7.08 (1H, m), 7.19-7.54 (11H, m). MS m / z 397.1 (M+H) + , 395.1 (MH) -

[0188] Example 50 (Diamide) MS m / z 399.1 (M+H) + , 397.1 (MH) -

[0189] Example 51 (Diamide) obtained 1 The H NMR is shown in Figure 18. 1H NMR (400 MHz, CDCl3, 298 K) δ 2.66-2.80 (4H, m), 2.83 (1H, d, J = 17.1 Hz), 2.91 (1H, d, J = 16.9 Hz), 3.36-3.47 (2H, m), 3.47-3.59 (2H, m), 3.88 (6H, s), 4.24 (1H, br s), 4.68 (1H, s), 6.55-6.60 (1H, m), 6.75-6.81 (1H, m), 6.87 (2H, d, J = 8.3 Hz), 7.07 (1H, dd, J = 8.3, 2.2 Hz), 7.10 (1H, br dd, J = 8.3, 2.2 Hz), 7.22-7.25 (2H, m). MS m / z 525.1 (M+H) + , 523.1 (MH) -

[0190] Example 52 (Diamide) MS m / z 517.1 (M+H) + , 515.0 (MH) -

[0191] Example 53 (Diamide) obtained 1 The H NMR is shown in Figure 19. 1H NMR (400 MHz, CDCl3) δ2.89 (d, 1H, J = 17.5 Hz), 3.11-3.16 (m, 8H), 3.21-3.24 (m, 1H), 3.32 (d 1H, J = 17.5 Hz), 3.72-3.85 (m, 8H), 5.18 (s, 1H), 6.77-6.84 (m, 4H), 7.20-7.23 (m, 4H) MS m / z 547.1 (M+H) + , 545.1 (MH) -

[0192] Example 54 (Diamide) obtained 1 The H NMR is shown in Figure 20. MS m / z 421.1 (M+H) + , 419.1 (MH) -

[0193] Example 55 (Acyl derivative) MS m / z 247 (M+H) + Example 56 (Acyl derivative) MS m / z 303 (M+H) + Example 57 (Acyl derivative) MS m / z 317 (M+H) + Example 58 (Acyl derivative) MS m / z 289 (M+H) + Example 59 (Acyl derivative) MS m / z 289 (M+H) + Example 60 (Acyl derivative) MS m / z 315 (M+H) + Example 61 (Acyl derivative) MS m / z 295 (M+H) + Example 62 (Acyl derivative) MS m / z 325 (M+H) + Example 63 (Acyl derivative) MS m / z 325 (M+H) + Example 64 (Acyl derivative) MS m / z 311 (M+H) + Example 65 (Acyl derivative) MS m / z 319 (M+H) + Example 66 (Acyl derivative) MS m / z 333 (M+H) +

[0194] [Test Example 2] The hydroxycitric acid derivative obtained in Test Example 1 was subjected to a CYSLTR2 inhibitory activity test (in vitro) as follows.

[0195] Test Overview Number of target receptors: 1 Target receptor: human CYSLTR2 Test compounds: hydroxycitric acid derivatives of Examples 1 to 66 (for heterodiesters, a mixture of two compounds shown in Table 2 was used in each Example). Final test concentrations: 333 μM (all test compounds), and 100 μM and / or 30 μM (some test compounds). Assay mode: antagonist n=2

[0196] Test Procedure (1) Plating 1. Reporter cells (Tansoh Biosciences, Inc.) were cultured in DMEM supplemented with 10% FCS and penicillin-streptomycin according to standard procedures. 2. Cells were released using trypsin-EDTA and suspended in DMEM containing 10% dialyzed FCS. 3. The suspended cells were seeded into a 96-well white microplate at 24,000 cells per well. 4. The seeded cells were cultured overnight at 37°C in the presence of 5% CO2 so that they could adhere to the bottom of the microplate.

[0197] (2) Transfection 1. Plasmids expressing GPCR, Gα protein, and luciferase reporter were mixed and transfected using transfection reagent (FuGENE 6, Promega) at a total of 100 ng per well. The cells were cultured overnight at 37°C in the presence of 2.5% CO2.

[0198] (3) Preparation of test compound solution Immediately before the assay, the hydroxycitric acid derivative (test compound) synthesized in Test Example 1 was diluted with DMEM containing 10% dialyzed FCS to a concentration six times the final test concentration to prepare a test compound solution.

[0199] (4) Antagonist test 1. A freshly prepared 6x concentrated test compound solution was added to each well to achieve the desired final test concentration. The final carry-over concentration of test compound solvent was 0.3%. 2. Immediately after the addition of the test compound, a standard agonist solution was added to each well so that the final concentration would be EC80. The cells were cultured for 6 hours at 37°C in the presence of 3.5% CO2.

[0200] (5) Activity measurement After 1.6 hours of test compound stimulation, the medium was aspirated. 2. Luciferase assay reagent (Steady-Glo, Promega) was added to the wells. 3. The amount of luciferase luminescence was measured using a plate reader (Victor Nivo, Perkin Elmer).

[0201] (6) Evaluation of CYSLTR2 inhibitory activity of test compounds The antagonist activity (Inhibition (%)) of the test compound was calculated by the following formula: where NC and PC represent the solvent control and the standard agonist control, respectively.

[0202]

number

[0203] Separately, hydroxycitric acid was used instead of the test compound (hydroxycitric acid derivative) to determine antagonist activity in the same manner as above. The value (%) obtained by subtracting the antagonist activity (%) of hydroxycitric acid from the antagonist activity (%) of the test compound was used as an evaluation index for the "CYSLTR2 inhibitory activity" of the test compound. The higher the value of the evaluation index for CYSLTR2 inhibitory activity, the higher the CYSLTR2 inhibitory effect can be evaluated.

[0204] result The results are shown in Tables 6 to 8. As shown in Tables 6 to 8, the hydroxycitric acid derivatives of all the Examples exhibited stronger CYSLTR2 inhibitory activity than hydroxycitric acid.

[0205] [Table 6]

[0206] [Table 7]

[0207] [Table 8]

[0208] [Test Example 3] The hydroxycitric acid derivative obtained in Test Example 1 was subjected to a CYSLTR2 inhibitory activity test (in vivo) as follows.

[0209] Test Overview BALB / C mice were intraperitoneally sensitized with ovalbumin (OVA) to create an allergic (asthma) mouse model. Hydroxycitric acid derivatives were then orally administered via gavage. At 12, 24, 48, or 72 hours after administration, the mice were sacrificed, and the expression levels of CYSLTR2 in lung tissue and inflammatory cells were assessed by Western blot, flow cytometry, and immunochemistry. Furthermore, the release of interleukins (IL-4, IL-5, and IL-13) from inflammatory cells was also assessed.

[0210] result The hydroxycitric acid derivatives of each Example were found to exhibit stronger CYSLTR2 inhibitory activity than hydroxycitric acid in an allergy (asthma)-induced mouse model. In particular, the hydroxycitric acid derivatives of Examples 25, 39, 42, and 45 exhibited stronger CYSLTR2 inhibitory activity. Furthermore, the hydroxycitric acid derivatives of each Example were found to exhibit stronger interleukin release inhibitory activity (anti-allergy activity) than hydroxycitric acid in an allergy (asthma)-induced mouse model. In particular, the hydroxycitric acid derivatives of Examples 25, 39, 42, and 45 exhibited stronger interleukin release inhibitory activity (anti-allergy activity).

Claims

1. A hydroxycitric acid derivative or a salt thereof represented by any one of the following formulas (I) to (IV): 【Chemical 1】 (In formula (I), R 1 and R 2 may be the same or different and may have a substituent, and are [A] a linear alkyl group, [B] a branched alkyl group, [C] a cycloalkyl group, [D] a cycloalkylalkyl group, [E] an aralkyl group, [F] a heterocycloalkylalkyl group, [G] an aryloxyalkyl group, and / or [H] an aralkylpolyoxyalkylene group). 【Chemistry 2】 (In formula (II), R 3 , R 4 and R 5 may be the same or different and may have a substituent, and are [A] a linear alkyl group, [B] a branched alkyl group, [C] a cycloalkyl group, [D] a cycloalkylalkyl group, [E] an aralkyl group, and / or [F] a heterocycloalkylalkyl group). 【Chemistry 3】 (In formula (III), R 61 , R 62 and R 63 And, R 71 , R 72 and R 73 may be the same or different from each other, R 61 and R 71 is [I] hydrogen, [A] a linear alkyl group and / or [B] a branched alkyl group, R 62 and R 72 is a [J] alkylene group and / or a [K] alkyleneimino group, and R 63 and R 73 is an optionally substituted [L]aryl group, or R 61 and R 62 and / or R 71 and R 72 are bonded to each other to form a nitrogen-containing aliphatic ring [AB / JK] together with the nitrogen atom to which they are attached, and / or R 61 and R 63 and / or R 71 and R 73 are bonded to each other, and each represents R 61 and / or R 71 The nitrogen atom to which R is bonded 63 and / or R 73 R to which 62 and / or R 72 together form a nitrogen-containing aliphatic ring [AB / L / JK]). 【Chemistry 4】 (In formula (IV), R 8 is [A] a linear alkyl group, [B] a branched alkyl group, [D] a cycloalkylalkyl group or [L] an aryl group which may have a substituent, [M] an acyloxyalkyl group, or [N] an alkoxycarbonylalkyl group).

2. The hydroxycitric acid derivative or salt thereof according to claim 1, wherein in formula (I), the substituents are [a] an alkyl group, [b] a halogen group, [c] a halogenated alkoxy group, and / or [d] an alkoxy group.

3. In the formula (I), The R 1 and R 2 the substituent that the linear alkyl group (A) may have is an alkyl group, a halogen group, a halogenated alkoxy group, or an alkoxy group; and The R 1 and R 2 The hydroxycitric acid derivative or salt thereof according to claim 1, wherein the substituent that the other of the linear alkyl groups [A] may have is an alkyl group [a], a halogen group [b], and / or a halogenated alkoxy group [c].

4. In the formula (I), 2. The hydroxycitric acid derivative or salt thereof according to claim 1, wherein the linear alkyl group [A] has two or more carbon atoms.

5. 2. The hydroxycitric acid derivative or salt thereof according to claim 1, wherein in formula (I), the substituent that the [D] cycloalkylalkyl group may have is an [a] alkyl group.

6. The hydroxycitric acid derivative or salt thereof according to claim 1, wherein, in formula (I), when the [E] aralkyl group has the [d] alkoxy group as a substituent, the number of the [d] group substituted is one.

7. The hydroxycitric acid derivative or salt thereof according to claim 1, wherein, in formula (I), when the [E] aralkyl group has the [b] halogen group as a substituent, the [b] group is a chloro group.

8. In the formula (I), the R 1 and R 2 are each the above-mentioned [E] aralkyl group, Any of the [E] groups is an aryl (C2 or greater) alkyl group, or The hydroxycitric acid derivative or salt thereof according to claim 1, wherein at least one of the [E] groups is an aryl (C1 or higher) alkyl group and at least one of the [E] groups has the substituent.

9. 2. The hydroxycitric acid derivative or salt thereof according to claim 1, wherein in formula (I), the [F] heterocycloalkylalkyl group is an oxetanylalkyl group.

10. 2. The hydroxycitric acid derivative or salt thereof according to claim 1, wherein, in the formula (I), the number of repeating oxyalkylene groups in the [H]aralkylpolyoxyalkylene group is 3 or more.

11. The hydroxycitric acid derivative or salt thereof according to claim 1, wherein in the formula (II), the substituents are [b] a halogen group and / or [d] an alkoxy group.

12. The hydroxycitric acid derivative or salt thereof according to claim 1, wherein in the formula (III), the substituents are [b] a halogen group and / or [d] an alkoxy group.

13. 2. The hydroxycitric acid derivative or salt thereof according to claim 1, wherein in the formula (III), the [AB / JK] nitrogen-containing aliphatic ring is a piperidine ring, a piperazine ring, a pyrrolidine ring, and / or an imidazolidine ring.

14. 2. The hydroxycitric acid derivative or salt thereof according to claim 1, wherein in the formula (III), the [AB / L / JK] nitrogen-containing aliphatic ring is a piperidine ring and / or a piperazine ring.

15. The hydroxycitric acid derivative or salt thereof according to claim 1, wherein in the formula (IV), the substituents are [d] an alkoxy group and / or [e] a hydroxyl group.

16. 2. The hydroxycitric acid derivative or salt thereof according to claim 1, wherein in formula (IV), the branched alkyl group [B] is a 1,1-dimethylpropyl group or an isopentyl group.

17. The hydroxycitric acid derivative or salt thereof according to claim 1, wherein in the formula (IV), the [N]alkoxycarbonylalkyl group is an [N]alkoxycarbonyl (C3 or higher) alkyl group.

18. 2. The hydroxycitric acid derivative or salt thereof according to claim 1, wherein in formula (IV), the substitution position of the substituent that the [L]aryl group may have is the ortho position and / or the para position.

19. A cysteinyl leukotriene receptor 2 inhibitor comprising the hydroxycitric acid derivative or its salt according to any one of claims 1 to 18.

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