Pseudo-glycolipid derivatives, their synthetic intermediates, production methods, and uses

Abstract

The present invention relates to: a compound represented by formula (I) (in the formula, X denotes -CH2- or -NH-; R1 and R3 each independently denote a substituted or unsubstituted hydrocarbon group having 5-30 carbon atoms, with any -CH2- moiety in said hydrocarbon group able to be replaced by a carbonyl group, a sulfonyl group, -O-, -S-, -COO-, -OCO-, -CONH-, -NHCO- or -NH- (however, this excludes a -CH2- adjacent to X in a case where X is -NH-); R2 denotes a hydrogen atom or a substituted or unsubstituted alkyl group having 1-6 carbon atoms, but in a case where R2 is a hydrogen atom or a substituted or unsubstituted alkyl group having 1 carbon atom, R1 includes 1 or more substituted or unsubstituted aromatic rings, or X denotes -NH-) or a salt thereof; and a synthesis intermediate, a production method and an application of the compound.

Description

Technical Field

[0001] The present invention relates to novel pseudo-glycolipid derivatives, their synthetic intermediates, production methods, and uses.

Background Art

[0002] α-Galactosylceramide is a sphingoglycolipid in which galactose is bound in an α-configuration to a ceramide formed by acylating a sphingosine base with a long-chain fatty acid. Various analogs have been synthesized so far, and the correlation between their structures and activities has been investigated. Among a series of synthetic analogs, for example, α-galactosylceramide (hereinafter referred to as "α-GalCer" or "KRN7000") represented by the following formula (a) exhibits the strongest activity, and furthermore, it has been clarified that the corresponding β-form (β-GalCer) does not show immunostimulatory activity (Non-Patent Document 1).

[0003]

Chemical Formula

[0004] Patent Document 1 discloses the following formula for a novel carbohydrate derivative:

Chemical Formula

[0005] RCAI-56 was shown to preferentially induce IFN-γ and only a small amount of IL-4 was induced simultaneously in comparison with α-GalCer (for example, FIGS. 1 to 2 in Patent Document 1).

[0006] In Non-Patent Document 2, a synthesis method of RCAI-101 in which the 6-position hydroxyl group of the carbosugar of RCAI-56 is methylated has been reported. However, since the methylation of the 6-position hydroxyl group of the carbosugar is carried out at the initial stage of the synthesis, a multi-step reaction is required to obtain the final product RCAI-101 from there (the following formula). Furthermore, the IFN-γ-inducing ability of RCAI-101 was weaker than that of RCAI-56 (for example, Fig. 2A in Non-Patent Document 2).

[0007]

Chemical formula

Prior art documents

Patent documents

[0008]

Patent Document 1

Non-patent documents

[0009]

Non-Patent Document 1

Non-Patent Document 2

Summary of the invention

Problems to be solved by the invention

[0010] An object of the present invention is to provide a novel and efficient synthesis method of a novel pseudo-glycolipid derivative and an intermediate useful for efficient synthesis. Another object of the present invention is to provide a novel pseudo-glycolipid derivative useful as a medicine, particularly a medicine having an immunostimulatory action. [Means for Solving the Problem]

[0011] The inventors of the present invention have succeeded in efficiently synthesizing a compound in which the 6-position of carbose is converted, such as RCAI-101, in a shorter process than the method described in Non-Patent Document 2. Furthermore, when the performance of inducing IFN-γ of the pseudo-glycolipid derivative obtained by this method was evaluated, it was found that the performance was equal to or higher than that of RCAI-56, and the present invention was completed.

[0012] That is, the gist of the present invention is as follows. (1) The following formula (I): [Chemical Formula] (In the formula, X represents -CH2- or -NH-; R 1 and R 3 each independently represents a substituted or unsubstituted hydrocarbon group having 5 to 30 carbon atoms, and any -CH2- in the hydrocarbon group (however, when X is -NH-, the -CH2- adjacent to X is excluded) may be replaced by a carbonyl group, a sulfonyl group, -O-, -S-, -COO-, -OCO-, -CONH-, -NHCO- or -NH-; R 2 represents a hydrogen atom or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, provided that when R 2 is a hydrogen atom or a substituted or unsubstituted alkyl group having 1 carbon atom, R 1 contains one or more substituted or unsubstituted aromatic rings, or X represents -NH-.) A compound represented by the formula or a salt thereof. (2) The following formula (II): [Chemical Formula] (In the formula, BN represents a substituted or unsubstituted benzyl group, and X, R 1 , R 2 and R 3 have the same meanings as in (1) above.) A compound represented by the formula or a salt thereof. (3) The following formula (III): [Chemical Formula] (wherein, BN has the same meaning as described in the above (2), and X, R 1 and R 3 have the same meaning as described in the above (1).) A compound represented by the formula or a salt thereof. (4) The following formula (IV):

Chemical formula

Chemical formula

Chemical formula

[0013] (7) A method for producing the compound described in the above (1) or a salt thereof, which comprises debenzylating the compound described in the above (2) or a salt thereof by catalytic reduction. (8) The following formula (VII):

Chemical formula

Chemical formula

[0014] (9) A compound having an amino group protected with a substituted or unsubstituted benzyl group and a hydroxyl group protected with a substituted or unsubstituted benzyl group is represented by the following formula: RO2CN=NCO2R (In the formula, R represents an alkyl group having 1 to 5 carbon atoms.) After treatment with a dialkyl azodicarboxylate represented by the formula, treatment with aminooxyacetic acid or a salt thereof is carried out to selectively eliminate the substituted or unsubstituted benzyl group protecting the amino group. A method for N-benzyl group selective debenzylation. (10) An IFN-γ production inducer containing at least one of the compound or a salt thereof described in the above (1) as an active ingredient. (11) An anticancer agent containing at least one of the compound or a pharmaceutically acceptable salt thereof described in the above (1) as an active ingredient.

Advantages of the Invention

[0015] The compound of the present invention is a novel pseudo-glycolipid derivative showing IFN-γ inducing ability. According to the production method and novel intermediate of the present invention, a pseudo-glycolipid derivative can be efficiently synthesized.

Modes for Carrying Out the Invention

[0016] Hereinafter, the present invention will be described in detail.

[0017] As used herein, the term "acyl group" refers to, for example, a formyl group; an alkyl-carbonyl group (e.g., an alkyl-carbonyl group in which the alkyl moiety is a linear or branched alkyl group having 1 to 31 carbon atoms (preferably 1 to 12 carbon atoms), such as an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, a pivaloyl group, a hexanoyl group); a cycloalkyl-carbonyl group (e.g., a cycloalkyl-carbonyl group in which the cycloalkyl moiety is a cycloalkyl group having 3 to 10 carbon atoms); an alkenyl-carbonyl group (e.g., an alkenyl-carbonyl group in which the alkenyl moiety is a linear or branched alkenyl group having 2 to 12 carbon atoms, such as an acryloyl group, a methacryloyl group); an aryl-carbonyl group (e.g., an aryl-carbonyl group in which the aryl moiety is an aryl group having 6 to 14 carbon atoms, such as a benzoyl group, a naphthoyl group), and the like. The aryl group in the aryl-carbonyl group refers to, for example, a monocyclic to tricyclic aromatic hydrocarbon group, and specifically, for example, a phenyl group, a naphthyl group, an anthryl group, and a phenanthryl group are exemplified. Among them, as the acyl group, a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a benzoyl group, a naphthoyl group, and the like are preferable, and an acetyl group and a benzoyl group are more preferable.

[0018] In formula (I), X represents -CH2- or -NH-.

[0019] In formula (I), R 1 and R 3 each independently represent a substituted or unsubstituted hydrocarbon group having 5 to 30 carbon atoms. As used herein, the term "hydrocarbon group" is a concept that includes substituted or unsubstituted alkyl groups having 5 to 30 carbon atoms, alkenyl groups having 5 to 30 carbon atoms, alkynyl groups having 5 to 30 carbon atoms, cycloalkyl groups having 5 to 30 carbon atoms, cycloalkenyl groups having 5 to 30 carbon atoms, aryl groups having 5 to 30 carbon atoms, and combinations thereof, and may be in any of linear, branched, and cyclic forms, and may be a saturated hydrocarbon group or an unsaturated hydrocarbon group, and may have an unsaturated bond either in the molecule or at the terminal. Among them, R 1 and R 3As for this, a substituted or unsubstituted alkyl group having 5 to 30 carbon atoms and a substituted or unsubstituted arylalkyl group having 5 to 30 carbon atoms are preferable.

[0020] R 1 or R 3 As substituents of the hydrocarbon group represented by, a halogen atom (preferably a chlorine atom, a fluorine atom); an alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a tert-butoxy group (preferably having 1 to 24 carbon atoms, more preferably having 1 to 16 carbon atoms, still more preferably having 1 to 10 carbon atoms, particularly preferably having 1 to 4 carbon atoms); an aryloxy group such as a phenoxy group (preferably having 6 to 14 carbon atoms); a hydroxyl group; an amino group; an alkylamino group such as a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group (the alkyl moiety is preferably 1 to 24 carbon atoms, more preferably 1 to 16 carbon atoms, still more preferably 1 to 10 carbon atoms, particularly preferably 1 to 4 carbon atoms each); a cycloalkylamino group (preferably having 3 to 6 carbon atoms); an alkylcarbonylamino group such as an acetamido group (the number of carbon atoms in the alkyl moiety is preferably 1 to 24 carbon atoms, more preferably 1 to 16 carbon atoms, still more preferably 1 to 10 carbon atoms, particularly preferably 1 to 4 carbon atoms); a cycloalkylcarbonylamino group (the number of carbon atoms in the cycloalkyl moiety is preferably 3 to 6); an arylcarbonylamino group such as a benzoylamino group (preferably an arylcarbonylamino group in which the aryl moiety has 6 to 14 carbon atoms), etc., an electron-donating group, further a carboxyl group; an alkoxycarbonyl group (the number of carbon atoms in the alkyl moiety is preferably 1 to 24 carbon atoms, more preferably 1 to 16 carbon atoms, still more preferably 1 to 10 carbon atoms, particularly preferably 1 to 4 carbon atoms); an acyl group (as the acyl group is as described above. Preferably an alkyl-carbonyl group in which the alkyl moiety is a linear or branched alkyl group having 1 to 24 carbon atoms); a carbamoyl group; an electron-withdrawing group such as a trifluoromethyl group are exemplified.

[0021] Examples of the alkyl portion of the alkylamino group and alkylcarbonylamino group include linear or branched alkyl groups such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group (preferably having 1 to 24 carbon atoms, more preferably 1 to 16 carbon atoms, still more preferably 1 to 10 carbon atoms, and particularly preferably 1 to 4 carbon atoms).

[0022] Examples of the cycloalkyl portion of the cycloalkylamino group and cycloalkylcarbonylamino group include cycloalkyl groups such as cyclopentyl group and cyclohexyl group (preferably having 3 to 24 carbon atoms, more preferably 3 to 16 carbon atoms, still more preferably 3 to 10 carbon atoms, and particularly preferably 3 to 6 carbon atoms).

[0023] Examples of the alkoxy portion of the alkoxycarbonyl group are the same as those of the alkoxy group described above.

[0024] The above-mentioned substituents may be further substituted at substitutable positions with at least one of a halogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, a phenyl group, an alkoxy group, a hydroxyl group, an amino group, an alkylamino group, and a cycloalkylamino group.

[0025] Examples of the halogen atom, alkoxy group, alkylamino group, and cycloalkylamino group are the same as those described above.

[0026] R 1 and R 3Examples of the alkyl group independently represented by each of them include alkyl groups such as pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group (preferably having 10 to 30 carbon atoms, 15 to 30 carbon atoms, 15 to 28 carbon atoms, or 18 to 28 carbon atoms).

[0027] R 1 and R 3 Examples of the cycloalkyl group independently represented by each of them include cycloalkyl groups such as cyclopentyl group, cyclohexyl group (preferably having 5 to 24 carbon atoms, 5 to 16 carbon atoms, or 5 to 10 carbon atoms).

[0028] R 1 and R 3 Examples of the alkenyl group independently represented by each of them preferably include alkenyl groups having 10 to 30 carbon atoms, 15 to 30 carbon atoms, 15 to 28 carbon atoms, or 18 to 28 carbon atoms.

[0029] R 1 and R 3 Examples of the alkynyl group independently represented by each of them preferably include alkynyl groups having 10 to 30 carbon atoms, 15 to 30 carbon atoms, 15 to 28 carbon atoms, or 18 to 28 carbon atoms.

[0030] R 1 and R 3 Examples of the aryl group independently represented by each of them include aryl groups having 6 to 30 carbon atoms such as phenyl group, naphthyl group, etc.

[0031] R 1 and R 3 Examples of the aralkyl group independently represented by each of them include groups obtained by combining each of the examples of the aryl group and each of the examples of the alkyl group.

[0032] R 1 or R 3Any -CH2- in the hydrocarbon group represented by (however, when X is -NH-, the -CH2- adjacent to X is excluded) may be replaced by a carbonyl group, a sulfonyl group, -O-, -S-, -COO-, -OCO-, -CONH-, -NHCO- or -NH-.

[0033] For example, as a group in which any -CH2- in the hydrocarbon group is replaced by -NH-, groups represented by -NH-R (wherein R represents a substituted or unsubstituted hydrocarbon group having 1 to 27 carbon atoms, preferably an alkyl group) can be mentioned.

[0034] Among them, R 1 is preferably a substituted or unsubstituted alkyl group, and its carbon number is preferably 10 to 30, 15 to 30, 15 to 28, or 18 to 28. R 1 Specifically, for example, -(CH2) 23 -CH3, -(CH2) 24 -CH3, -(CH2) 25 -CH3 and the like can be mentioned.

[0035] Also, as R 1 -(CH2) n -Phe (wherein Phe represents a phenyl group or a substituted phenyl group (for example, a 4-halophenyl group, preferably a 4-fluorophenyl group), n is an integer of 1 or more, preferably 1 to 24, 1 to 20, 5 to 20, or 5 to 18) is also a suitable aralkyl group.

[0036] Also, as R 3 is preferably a substituted or unsubstituted alkyl group, and its carbon number is preferably 5 to 28, 5 to 25, 5 to 20, 10 to 20 or 10 to 18. Also, as R 3 a linear alkyl group is preferred. As R 3 Specifically, for example, -(CH2) 11 -CH3, -(CH2) 12 -CH3, -(CH2) 13 -CH3, -(CH2) 14 -CH3, -(CH2) 15-CH3, -(CH2) 16 -CH3, -(CH2) 17 Examples thereof include -CH3 and the like.

[0037] In the formula (I), R 2 represents a hydrogen atom or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, provided that when R 2 is a hydrogen atom or a substituted or unsubstituted alkyl group having 1 carbon atom (i.e., a substituted or unsubstituted methyl group), R 1 contains one or more substituted or unsubstituted aromatic rings, or X represents -NH-.

[0038] R 2 Examples of the alkyl group having 1 to 6 carbon atoms represented by R include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group, etc., preferably an ethyl group and an n-propyl group. The alkyl group may be linear, branched or cyclic. When it is an alkyl group having 2 or more carbon atoms, the ability to induce IFN-γ tends to be higher.

[0039] R 2Examples of the substituent of the alkyl group having 1 to 6 carbon atoms represented by include a halogen atom (preferably a chlorine atom or a fluorine atom); an alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a tert-butoxy group (preferably having 1 to 24 carbon atoms, more preferably 1 to 16 carbon atoms, still more preferably 1 to 10 carbon atoms, particularly preferably 1 to 4 carbon atoms); an aryloxy group such as a phenoxy group (preferably having 6 to 14 carbon atoms); a hydroxyl group; an amino group; an alkylamino group such as a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group; a cycloalkylamino group; an alkylcarbonylamino group such as an acetamido group; a cycloalkylcarbonylamino group; an arylcarbonylamino group such as a benzoylamino group (preferably an arylcarbonylamino group in which the aryl moiety is an aryl group having 6 to 14 carbon atoms) and other electron-donating groups, and further a carboxyl group; an alkoxycarbonyl group; an acyl group (as described above for the acyl group. Preferably an alkyl-carbonyl group in which the alkyl moiety is a linear or branched alkyl group having 1 to 24 carbon atoms); a carbamoyl group; an electron-withdrawing group such as a trifluoromethyl group.

[0040] However, when R 2 is a hydrogen atom or a substituted or unsubstituted alkyl group having 1 carbon atom (i.e., a substituted or unsubstituted methyl group), R 1 is a group containing one or more substituted or unsubstituted aromatic rings (preferably, the aromatic ring is a benzene ring.), (preferably, the group represented by -(CH2) n -Phe), or X represents -NH-.

[0041] Examples of the compound represented by the formula (I) include the following compounds.

[0042]

Chemical formula

[0043]

Chemical formula

[0044]

Chem.

[0045]

Chem.

[0046] In the above formulas (II) to (VII), the substituted or unsubstituted benzyl group represented by BN is not particularly limited as long as it can be used as a protecting group for a hydroxyl group or an amino group. For example, benzyl (Bn) group, p-methoxybenzyl (PMB) group, 2,4-dimethoxybenzyl group, 3,4-dimethoxybenzyl group, preferably Bn group, PMB group, etc. are exemplified.

[0047] Each example of the compound represented by the above formulas (II) to (V) includes a compound in which a predetermined OH group in the above compounds (I)-1 to (I)-22 exemplified as an example of the compound of the above formula (I) is substituted with an OBN group.

[0048] Each example of the compound represented by the above formulas (VI) to (VII) includes a compound in which a predetermined OH group in the above compounds (I)-1 to (I)-22 exemplified as an example of the compound of the above formula (I) is substituted with an OBN group and -NH-C=O-R 1 is substituted with -NH2 or -NH-BN, respectively.

[0049] As the salts of the compounds represented by the above formulas (I) to (VII), pharmaceutically acceptable salts are preferred. For example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.; organic acid salts such as succinate, fumarate, acetate, methanesulfonate, toluenesulfonate, etc.; alkali metal salts such as sodium salt, potassium salt, etc.; alkaline earth metal salts such as magnesium salt, calcium salt, etc.; ammonium salts such as ammonium salt, alkylammonium salt, etc. can be mentioned.

[0050] The compounds of the present invention can be produced by various methods. However, in order to efficiently synthesize them in a short process, a method using the compound represented by the formula (VII) as a starting material is preferred.

[0051] Among the compounds represented by the formula (VII), the following formula (VIIa):

Chemical formula

[0052] Taking the case of using the compound represented by the formula (VIIa) as the compound represented by the formula (VII) as an example, the synthesis method of the compound represented by the formula (I) will be described below.

[0053]

Chemical formula

[0054] (N-Benzyl group selective debenzylation of compound (VIIa)) By treating compound (VIIa) with an oxidizing agent in an organic solvent, an imine form (-N=CH-Ph) in which only the N-benzyl group (-NH-BN, that is, -NH-CH2-Ph (Ph is a phenyl group)) in the formula is selectively oxidized can be obtained. Examples of the oxidizing agent include organic oxidizing agents. A preferred example of the oxidizing agent is a dialkyl azodicarboxylate represented by the following formula. More specifically, diisopropyl azodicarboxylate (DIAD), di-tert-butyl azodicarboxylate (DBAD), diethyl azodicarboxylate (DEAD), etc.

[0055] RO2CN=NCO2R (In the formula, R represents an alkyl group having 1 to 5 carbon atoms, preferably 1 to 4 carbon atoms.)

[0056] Also, other examples of the oxidizing agent include 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) and N-tert-butylbenzenesulfinimidoyl chloride.

[0057] The amount of the oxidizing agent (e.g., dialkyl azodicarboxylate represented by the above formula) used is usually 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to the compound (VIIa).

[0058] Examples of the solvent include halogenated hydrocarbons such as dichloromethane; ethers, especially cyclic ethers such as tetrahydrofuran (THF) and 2-methyltetrahydrofuran; esters such as ethyl acetate and isopropyl acetate; and aromatic hydrocarbons such as toluene. Two or more of these may be mixed and used. The amount of the solvent used is usually 1 to 20 times the volume, preferably 5 to 10 times the volume, relative to the compound (VIIa).

[0059] The reaction temperature is usually from 20°C to the heating reflux temperature, preferably from room temperature to the heating reflux temperature, and the reaction time is usually 3 to 18 hours, preferably 3 to 5 hours.

[0060] After treating the compound of the formula (VIIa) with an oxidizing agent to allow the oxidation reaction to proceed and / or after the oxidation reaction is completed, at least one selected from the group consisting of hydroxylamine and its derivatives, and hydrazine and its derivatives is allowed to act on the imine form to convert the imine form (-N=CH-Ph) to an amine form (-NH2). Thereby, the N-benzyl group can be selectively debenzylated to obtain the amine compound (VIa).

[0061] Examples of the derivatives of the hydroxylamine (HO-NH2) include the group of compounds represented by R a O-NH2. R a represents a substituted or unsubstituted C1-C10 hydrocarbon group (e.g., a C1-C5 alkyl group and a C6-C10 aromatic hydrocarbon group), and examples of the substituent include a carboxyl group or its salt, a hydroxyl group, and an amino group. Ra It may have two or more same or different substituents. Examples of the hydroxylamine derivative include methoxylamine (MeO-NH2), aminooxyacetic acid (HOOCCH2O-NH2) and salts thereof. Among them, aminooxyacetic acid or its salt is preferable.

[0062] Examples of the derivative of the hydrazine (H2N-NH2) include a group of compounds represented by R b NH-NH2. R b represents a substituted or unsubstituted C1-C10 hydrocarbon group (for example, a C1-C5 alkyl group and a C6-C10 aromatic hydrocarbon group), and examples of the substituent include a carboxyl group or its salt, a hydroxyl group, and an amino group. R b may have two or more same or different substituents. Examples of the hydrazine derivative include methylhydrazine (MeHN-NH2) and phenylhydrazine (C6H5HN-NH2). Among them, hydrazine is preferable.

[0063] Examples of the solvent include water, 1,4-dioxane, THF, ethanol, and methanol, and two or more of these may be mixed and used. Preferably, a water-THF-ethanol mixed solvent is mentioned. The usage amount of the solvent is usually 1 to 20 times the volume, preferably 5 to 10 times the volume, relative to the compound (VIIa).

[0064] The reaction temperature is usually 0 to 80 °C, preferably room temperature to 50 °C, and the reaction time is usually 3 to 24 hours, preferably 3 to 18 hours.

[0065] The above-mentioned selective debenzylation of the N-benzyl group is not limited to the compound (VII), and can be widely applied to a compound having an amino group protected by a substituted or unsubstituted benzyl group and a hydroxyl group protected by a substituted or unsubstituted benzyl group. In particular, it can be preferably applied to a compound containing a sugar residue having a hydroxyl group protected by a substituted or unsubstituted benzyl group.

[0066] (Acylation of Compound (VIa)) This step is to react compound (VIa) with an acid halide, preferably an acid chloride, to obtain compound (Va). Specifically, compound (VIa) is reacted with an acid halide (e.g., R 1 -COX’ (wherein R 1 is as defined above, and X’ is, for example, a chlorine atom.)) in a solvent in the presence of a base. The amount of the acid halide used is usually 1 to 2 equivalents, preferably 1 to 1.2 equivalents, relative to compound (VIa).

[0067] The solvent is not particularly limited as long as it does not inhibit this reaction. For example, ethers, especially cyclic ethers such as THF and 2-methyltetrahydrofuran; halogenated hydrocarbons such as chloroform are preferably used. The amount of the solvent used is usually 1 to 20 times the volume of compound (VIa), preferably 5 to 10 times the volume.

[0068] Examples of the base include 4-(N,N-dimethylamino)pyridine and triethylamine, and among them, triethylamine is preferred. The amount of the base used is usually 1 to 5 equivalents, preferably 2 to 3 equivalents, relative to compound (VIa).

[0069] The reaction temperature is usually from 0 °C to the heating reflux temperature, preferably from 0 °C to room temperature, and the reaction time is usually from 10 minutes to 48 hours, preferably from 1 to 20 hours.

[0070] (Benzylation of compound (Va)) This step is to react compound (Va) with benzyl halide, preferably benzyl bromide, in an organic solvent in the presence of a base to obtain compound (IVa). The amount of benzyl halide used is usually 2 to 3 equivalents, preferably 2.2 to 2.8 equivalents, relative to compound (Va).

[0071] Examples of the solvent include aprotic solvents such as N,N-dimethylformamide (DMF), ethers (e.g., diethyl ether, THF), etc., and a mixed solvent of DMF and THF is preferably used. The amount of the solvent used is usually 1 to 20 times the volume, preferably 5 to 10 times the volume, relative to the compound (Va).

[0072] Examples of the base include alkali metal hydrides (e.g., sodium hydride, potassium hydride), alkali metal alkoxides (e.g., sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium propoxide, potassium propoxide, sodium isopropoxide, potassium isopropoxide), strongly basic organic amines (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]nona-5-ene (DBN)), organic amine alkali metal salts (e.g., lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide), strongly basic alkyl alkali metal salts (e.g., methyllithium, butyllithium). Among them, sodium hydride is preferably used. The amount of the base used is usually 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to the compound (Va).

[0073] (Selective debenzylation of compound (IVa)) This step is a step of obtaining compound (IIIa) by selectively converting only the benzyloxy group at the 6-position of the carbosugar of compound (IVa) to an acetoxy group and then converting the acetoxy group to a hydroxyl group. Specifically, compound (IVa) is reacted in acetic anhydride - acetic acid in the presence of zinc chloride to convert it into a compound in which only the hydroxyl group at the 6-position of the carbosugar of compound (IVa) is acetylated, and then reacted in an alcohol solvent (e.g., methanol, ethanol) in the presence of a base (e.g., sodium methoxide, sodium ethoxide) to obtain compound (IIIa).

[0074] The amount of zinc chloride used is usually 1 to 20 equivalents, preferably 7.5 to 10 equivalents, based on the compound (IVa). The mass ratio of acetic anhydride to acetic acid is usually 1:1 to 1:10, preferably 2:1 to 3:1.

[0075] The amount of the base such as sodium methoxide used is usually 1 to 10 equivalents, preferably 2 to 3 equivalents, based on the compound (IVa).

[0076] The reaction temperature is usually 0 to 40 °C, preferably room temperature to 30 °C, and the reaction time is usually 1 to 5 hours, preferably 2 to 4 hours.

[0077] (Alkylation of compound (IIIa)) This step is a step of alkylating the hydroxyl group at the 6-position of the carbose of compound (IIIa) to obtain compound (IIa). Specifically, for example, compound (IIIa) is (i) In a solvent such as methylene chloride, in the presence of 1,8-bis(dimethylamino)naphthalene (Proton-sponge TM ), treated with a trialkyloxonium tetrafluoroborate represented by the following formula: R 2 3O + BF4 - (wherein R 2 represents a substituted or unsubstituted alkyl group having 1 to 2 carbon atoms).) (Meyer's reagent; for example, triethyloxonium tetrafluoroborate (Et3OBF4)); or (ii) In a solvent (for example, aprotic solvents such as DMF, ethers (such as diethyl ether, THF), preferably a mixed solvent of DMF and THF), in the presence of an alkali metal hydride (such as sodium hydride, potassium hydride), reacted with an alkyl iodide represented by the following formula: R 2 -I (wherein R 2 represents a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms).), compound (IIa) can be obtained.

[0078] (Debenzylation of compound (IIa)) This step involves catalytic hydrogenolysis of compound (IIa) in a solvent in the presence of a reducing catalyst to obtain compound (Ia).

[0079] Examples of the solvent include ethers (e.g., diethyl ether, THF), alcoholic solvents (e.g., methanol, ethanol), and mixed solvents of ethers and alcoholic solvents (e.g., a mixed solvent of THF and ethanol). The amount of the solvent used is usually 1 to 100 times the volume of compound (IIa), preferably 10 to 50 times the volume.

[0080] Examples of the reducing catalyst include palladium hydroxide, palladium - C, platinum oxide, Raney nickel, etc. The amount of the reducing catalyst used may be a catalytic amount relative to compound (IIa).

[0081] To purify the product obtained in each step as described above, commonly used methods may be employed, for example, column chromatography using silica gel or the like as a carrier, or recrystallization using methanol, ethanol, chloroform, dimethyl sulfoxide, n - hexane - ethyl acetate, water, etc. Examples of the elution solvent for column chromatography include methanol, ethanol, chloroform, acetone, hexane, dichloromethane, ethyl acetate, and mixed solvents thereof.

[0082] The compound (I) of the present invention obtained as described above can be converted into the desired salt by a method known per se or a method analogous thereto.

[0083] Next, the pharmaceutical use of the present invention will be described.

[0084] By administering the compound (I) of the present invention or a salt thereof, it forms a complex with the CD1d protein of APC and is presented to NKT cells. NKT cells can recognize this complex via TCR and selectively and abundantly produce IFN-γ, which is a kind of cytokine that activates the function of immune cells among its own immunomodulatory functions. Therefore, the compound (I) of the present invention or a salt thereof is useful as an immunostimulant that induces IFN-γ production.

[0085] The administration subjects of the compound (I) of the present invention or a salt thereof include mammals such as humans.

[0086] When the compound (I) of the present invention or a salt thereof is administered to humans, it can be mixed with itself or a pharmaceutically acceptable carrier (e.g., excipient, diluent, etc.) and orally or parenterally and safely administered as a pharmaceutical composition such as an oral dosage form (e.g., powder, granule, tablet, capsule) or a parenteral dosage form (e.g., injection, suppository (e.g., rectal suppository, vaginal suppository)). These preparations can be manufactured by conventionally known methods.

[0087] Examples of injections include subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, or drip infusion. The injection can also be made into an aqueous injection according to a conventional method together with the compound (I) of the present invention or a salt thereof, a solubilizing agent (e.g., β-cyclodextrins), a dispersing agent (e.g., carboxymethyl cellulose, sodium alginate), a preservative (e.g., methylparaben, propylparaben, benzyl alcohol, chlorobutanol), an isotonic agent (e.g., sodium chloride, glycerin, sorbitol, glucose), etc. Further, it can be dissolved, suspended, or emulsified in a vegetable oil (e.g., olive oil, sesame oil, peanut oil, cottonseed oil, corn oil), propylene glycol, etc. to make an oily injection.

[0088] An oral dosage form can be produced by appropriately adding, for example, excipients (such as lactose, sucrose, starch), disintegrants (such as starch, calcium carbonate), binders (such as starch, gum arabic, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose), or lubricants (such as talc, magnesium stearate, polyethylene glycol) to the compound (I) of the present invention or a salt thereof, followed by compression molding, and then, if necessary, coating with hydroxypropyl methylcellulose or the like. A suppository can be produced by mixing the compound (I) of the present invention or a salt thereof with a non-irritating excipient (such as polyethylene glycol, glyceride of higher fatty acid).

[0089] The dosage of the compound (I) of the present invention or a salt thereof varies depending on age, body weight, symptoms, dosage form, administration method, administration period, etc. For example, for a patient (adult, body weight about 60 kg), it is usually 0.1 to 1 mg / kg body weight per day, preferably 0.5 to 1 mg / kg body weight, more preferably 0.8 to 1 mg / kg body weight, and this can be administered orally or parenterally in one to several divided doses.

[0090] This specification includes the content described in the specification of Japanese Patent Application No. 2020-188511, which is the basis of the priority of the present application.

Example

[0091] Hereinafter, the present invention will be described more specifically by way of examples, but the present invention is not limited to the following examples.

[0092] (Example 1) (2S,3S,4R)-2-Amino-1-({(1S,2S,3S,4S,5R)-2,3,4-Tris(benzyloxy)-5-[(benzyloxy)methyl]cyclohexyl}oxy)octadecane-3,4-diol (Compound (VIa))

Chemical formula

[0093] The raw material (compound (VIIa)) (7.607 g) and DIAD (1.775 ml) were dissolved in toluene (41 ml) and heated at 110 °C for 3 hours. After allowing to cool to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in THF (7 ml), water (5 ml), and ethanol (30 ml), 2-(aminooxy)acetic acid 1 / 2 hydrochloride (2.690 g) was added, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, 0.1 N aqueous sodium hydroxide solution and saturated brine were added, and then extracted with diisopropyl ether. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. Hexane was added to the obtained residue, and the mixture was heated to 42 °C and stirred to solidify the crude product. The solvent was distilled off and further solidified by cooling overnight at 0 °C. After allowing to cool to room temperature, diisopropyl ether was added, and the mixture was stirred and filtered to obtain the title compound (4.500 g (66%)) as a colorless solid. HRMS (ESI) calcd for C 53 H 76 NO7[M + H] + 838.5622, found 838.5617.

[0094] (Example 2) N-[(2S,3S,4R)-3,4-dihydroxy-1-({(1S,2S,3S,4S,5R)-2,3,4-tris(benzyloxy)-5-[(benzyloxy)methyl]cyclohexyl}oxy)octadecane-2-yl]hexacosamide

Chemical formula

[0095] Serotic acid (1.345 g) and oxalyl chloride (2.92 ml) were added to benzene (15 ml), and the mixture was stirred at 60 °C for 2 hours. After allowing to cool to room temperature, the solvent was distilled off under reduced pressure. The resulting residue was dissolved in THF (15 ml), and the solution was added dropwise to a solution of the starting material (the compound obtained in Example 1) (2.710 g) and triethylamine (1.5 ml) in THF (15 ml) at 0 °C. After the addition, the temperature was raised to room temperature and the mixture was stirred for 30 minutes as it was. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in chloroform. The solution was washed successively with dilute hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform - 20% methanol / chloroform = 100:0 to 97:3) to obtain the title compound (3.854 g (98%)) as a colorless solid. HRMS (ESI) calcd for C 79 H 125 NO8Na [M + Na] + 1238.9303, found 1238.9299.

[0096] (Example 3) N-[(2S,3S,4R)-3,4-bis(benzyloxy)-1-({(1S,2S,3S,4S,5R)-2,3,4-tris(benzyloxy)-5-[(benzyloxy)methyl]cyclohexyl}oxy)octadecane-2-yl]hexacosaneamide

Chemical formula

[0097] The starting material (the compound obtained in Example 2) (4.812 g) and benzyl bromide (1.893 ml) were added to a mixed solution of DMF (20 ml) and THF (20 ml), and sodium hydride (60%, dispersed in liquid paraffin) (633 mg) was added at 0 °C. After raising the temperature to room temperature, the mixture was stirred overnight as it was. An aqueous saturated ammonium chloride solution was added under ice cooling, and the mixture was extracted with ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane - ethyl acetate = 100:0 to 85:15) to obtain the title compound (4.968 g (90%)). HRMS (ESI) calcd for C 93 H 137 NO8Na [M + Na] + 1420.0276, found 1420.0251.

[0098] (Example 4) N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-{[(1S,2S,3S,4S,5R)-2,3,4-tris(benzyloxy)-5-(hydroxymethyl)cyclohexyl]oxy}octadecane-2-yl)hexacosamide

Chemical formula

[0099] To a mixed solution of acetic anhydride - acetic acid (2:1, 20 ml) of the starting material (the compound obtained in Example 3) (2.834 g), a mixed solution of zinc chloride (2.846 g) in acetic anhydride - acetic acid (2:1, 14 ml) was added dropwise. After stirring at room temperature for 3 hours, it was heated at 40 °C for 1 hour and further stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and after adding toluene, the solvent was distilled off under reduced pressure again. The obtained residue was dissolved in chloroform, washed with saturated brine, saturated sodium bicarbonate solution, and again with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in a mixed solvent of methanol (17 ml) and THF (11 ml), sodium methoxide (301 mg) was added, and it was stirred overnight at room temperature. A saturated aqueous ammonium chloride solution was added, and it was extracted with ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate = 100:0 to 67:33) to obtain the title compound (2.227 g (84%)). HRMS (ESI) calcd for C 86 H 131 NO8Na [M + Na] + 1328.9773, found 1328.9752.

[0100] (Example 5) N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-{[(1S,2S,3S,4S,5R)-2,3,4-tris(benzyloxy)-5-(ethoxymethyl)cyclohexyl]oxy}octadecane-2-yl)hexacosamide

Chemical formula

[0101] The raw material (the compound obtained in Example 4) (247 mg) was dissolved in dichloromethane (2 ml), proton sponge (81 mg) and triethyloxonium tetrafluoroborate (15% dichloromethane solution, about 1 mol / L) (378 μl) were added, and the mixture was stirred at room temperature for 1 hour. Further, proton sponge (94 mg) and triethyloxonium tetrafluoroborate (15% dichloromethane solution, about 1 mol / L) (378 μl) were added, and the mixture was stirred at room temperature for 1 hour. Further, proton sponge (105 mg) and triethyloxonium tetrafluoroborate (15% dichloromethane solution, about 1 mol / L) (378 μl) were added, and the mixture was stirred at room temperature for 1 hour. Dichloromethane was added, and the mixture was washed successively with dilute hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate = 100:0 to 80:20) to obtain the title compound (129 mg (51%)). HRMS (ESI) calcd for C 88 H 135 NO8Na [M + Na] + 1357.0085, found 1357.0088.

[0102] (Example 6) N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-{[(1S,2S,3S,4S,5R)-2,3,4-tris(benzyloxy)-5-(propoxymethyl)cyclohexyl]oxy}octadecane-2-yl)hexacosamide

Chemical formula

[0103] To a mixed solution of the raw material (the compound obtained in Example 4) (275 mg) in THF (1.5 ml) - DMF (1.5 ml), 1-iodopropane (31 μl) was added, and sodium hydride (60%, dispersed in liquid paraffin) (13 mg) was added. After stirring at room temperature for 2 hours, 1-iodopropane (102 μl) was further added, and sodium hydride (60%, dispersed in liquid paraffin) (42 mg) was added. The same operation was carried out 3 times until the raw material disappeared. An aqueous saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate = 100:0 to 85:15) and amino silica gel column chromatography (hexane - ethyl acetate = 100:0 to 85:15) to obtain the title compound (198 mg (70%)). HRMS (ESI) calcd for C 89 H 137 NO8Na [M + Na] + 1371.0242, found 1371.0212.

[0104] (Example 7) N-((2S,3S,4R)-1-{[(1S,2R,3S,4S,5R)-5-(ethoxymethyl)-2,3,4-trihydroxycyclohexyl]oxy}-3,4-dihydroxyoctadecane-2-yl)hexacosamide (Compound (I)-1)

Chemical formula

[0105] To a mixed solution of the raw material (the compound obtained in Example 5) (90 mg) in THF (2 ml) - ethanol (2 ml), 50% hydrous 20% palladium hydroxide / carbon (19 mg) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. A chloroform - methanol (10:1) mixed solution was added to the reaction solution and stirred at room temperature. After filtering off the catalyst, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform - 20% methanol / chloroform = 95:5 to 75:25) to obtain the title compound (54.5 mg (91%)). 1 H NMR (500 MHz, pyridine - d5) δ ppm 8.38 (br d, J = 8.6 Hz, 1 H), 6.80 (br s, 1 H), 6.08 - 6.38 (m, 2 H), 6.00 (br s, 1 H), 5.85 (br s, 1 H), 5.09 - 5.19 (m, 1 H), 4.34 - 4.51 (m, 3 H), 4.25 - 4.32 (m, 2 H), 4.13 - 4.25 (m, 3 H), 3.77 (t, J = 8.6 Hz, 1 H), 3.36 - 3.46 (m, 3 H), 2.36 - 2.48 (m, 3 H), 2.19 - 2.35 (m, 1 H), 1.76 - 1.96 (m, 6 H), 1.61 - 1.74 (m, 1 H), 1.20 - 1.47 (m, 66 H), 1.12 (t, J = 7.0 Hz, 3 H), 0.85 (t, J = 6.7 Hz, 6 H) HRMS (ESI) calcd for C 53 H 105 NO8Na [M + Na] + 906.7738, found 906.7722.

[0106] (Example 8) N - ((2S,3S,4R) - 3,4 - Dihydroxy - 1 - {[(1S,2R,3S,4S,5R) - 2,3,4 - Trihydroxy 5 - (propoxymethyl) cyclohexyl] oxy} octadecane - 2 - yl) hexacosaneamide (Compound (I) - 2)

Chemical Structure

[0107] In the same manner as in Example 7, 80 mg (82%) of the title compound was obtained from 146 mg of the raw material (the compound obtained in Example 6). 1 H NMR (500 MHz, pyridine-d5) δ ppm 8.37 (br d, J = 8.6 Hz, 1 H), 6.78 (br s, 1 H), 6.11 - 6.49 (m, 2 H), 5.98 (br s, 1 H), 5.82 (br s, 1 H), 5.10 (br dd, J = 8.2, 4.0 Hz, 1 H), 4.31 - 4.50 (m, 3 H), 4.23 - 4.30 (m, 2 H), 4.10 - 4.23 (m, 3 H), 3.76 (br t, J = 8.6 Hz, 1 H), 3.27 - 3.46 (m, 3 H), 2.41 (br t, J = 7.3 Hz, 3 H), 2.16 - 2.32 (m, 1 H), 1.74 - 1.95 (m, 6 H), 1.60 - 1.70 (m, 1 H), 1.53 (dq, J = 13.9, 7.0 Hz, 2 H), 1.20 - 1.42 (m, 66 H), 0.81 - 0.89 (m, 9 H) HRMS (ESI) calcd for C 54 H 107 NO8Na [M + Na] + 920.7894, found 920.7885.

[0108] (Example 9) N-[(2S,3S,4R)-3,4-Dihydroxy-1-({(1S,2S,3S,4S,5R)-2,3,4-Tris(benzyloxy)-5-[(benzyloxy)methyl]cyclohexyl}oxy)octadecane-2-yl]-11-(4-fluorophenyl)undecanamide

Chemical formula

[0109] Using 11-(4-fluorophenyl)undecanoic acid as the carboxylic acid, in the same manner as in Example 2, 3.369 g (95%) of the title compound was obtained from 2.690 g of the raw material (the compound obtained in Example 1). HRMS (ESI) calcd for C 70 H 98 FNO8Na [M + Na] + 1122.7174, found 1122.7173.

[0110] (Example 10) N-[(2S,3S,4R)-3,4-bis(benzyloxy)-1-({(1S,2S,3S,4S,5R)-2,3,4-tris(benzyloxy)-5-[(benzyloxy)methyl]cyclohexyl}oxy)octadecane-2-yl]-11-(4-fluorophenyl)undecanamide

Chemical formula

[0111] In the same manner as in Example 3, 2.229 g (71%) of the title compound was obtained from 2.707 g of the raw material (the compound obtained in Example 9). HRMS (ESI) calcd for C 84 H 110 FNO8Na [M + Na] + 1302.8113, found 1302.8085.

[0112] (Example 11) N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-{[(1S,2S,3S,4S,5R)-2,3,4-tris(benzyloxy)-5-(hydroxymethyl)cyclohexyl]oxy}octadecane-2-yl)-11-(4-fluorophenyl)undecanamide

Chemical formula

[0113] In the same manner as in Example 4, 628.5 mg (76%) of the title compound was obtained from 872 mg of the raw material (the compound obtained in Example 10). HRMS (ESI) calcd for C 77 H 104 FNO8Na [M + Na] + 1212.7644, found 1212.7625.

[0114] (Example 12) N-((2S,3S,4R)-3,4-Bis(benzyloxy)-1-{[(1S,2S,3S,4S,5R)-2,3,4-Tris(benzyloxy)-5-(methoxymethyl)cyclohexyl]oxy}octadecane-2-yl)-11-(4-fluorophenyl)undecanamide

Chemical formula

[0115] Using trimethyloxonium tetrafluoroborate as the alkylating agent, 240 mg (84%) of the title compound was obtained from 281 mg of the raw material (the compound obtained in Example 11) in the same manner as in Example 5. HRMS (ESI) calcd for C 78 H 106 FNO8Na [M + Na] + 1226.7800, found 1226.7788.

[0116] (Example 13) N-((2S,3S,4R)-3,4-Bis(benzyloxy)-1-{[(1S,2S,3S,4S,5R)-2,3,4-Tris(benzyloxy)-5-(ethoxymethyl)cyclohexyl]oxy}octadecane-2-yl)-11-(4-fluorophenyl)undecanamide

Chemical formula

[0117] In the same manner as in Example 5, 190 mg (81%) of the title compound was obtained from 229 mg of the raw material (the compound obtained in Example 11). HRMS (ESI) calcd for C 79 H 109 FNO8[M + H] + 1218.8137, found 1218.8127.

[0118] (Example 14) N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-{[(1S,2S,3S,4S,5R)-2,3,4-tris(benzyloxy)-5-(propoxymethyl)cyclohexyl]oxy}octadecane-2-yl)-11-(4-fluorophenyl)undecanamide

Chemical formula

[0119] In the same manner as in Example 6, 231 mg (72%) of the title compound was obtained from 308 mg of the raw material (the compound obtained in Example 11). HRMS (ESI) calcd for C 80 H 110 FNO8Na [M + Na] + 1254.8113, found 1254.8097.

[0120] (Example 15) N-((2S,3S,4R)-3,4-dihydroxy-1-{[(1S,2R,3S,4S,5R)-2,3,4-trihydroxy 5-(hydroxymethyl)cyclohexyl]oxy}octadecane-2-yl)-11-(4-fluorophenyl)undecanamide (Compound (I)-3)

Chemical formula

[0121] In the same manner as in Example 7, 100 mg (85%) of the title compound was obtained from 174 mg of the raw material (the compound obtained in Example 10). 11H NMR (500 MHz, pyridine-d5) δ ppm 8.40 (d, J=8.6 Hz, 1 H), 7.15 - 7.18 (m, 2 H), 7.06 - 7.12 (m, 2 H), 6.80 (br s, 1 H), 6.15 - 6.40 (m, 2 H), 6.05 (br s, 1 H), 5.96 (br s, 2 H), 5.07 - 5.25 (m, 1 H), 4.64 - 4.73 (m, 1 H), 4.38 - 4.51 (m, 2 H), 4.15 - 4.34 (m, 6 H), 3.98 (br dd, J=10.1, 5.7 Hz, 1 H), 2.37 - 2.55 (m, 5 H), 2.19 - 2.33 (m, 1 H), 2.04 - 2.14 (m, 1 H), 1.85 - 2.01 (m, 3 H), 1.79 (dt, J=15.2, 7.6 Hz, 2 H), 1.62 - 1.73 (m, 1 H), 1.50 (quin, J=7.3 Hz, 2 H), 1.12 - 1.45 (m, 34 H), 0.84 (t, J=7.5 Hz, 3 H) HRMS (ESI) calcd for C 42 H 74 FNO8Na [M + Na] + 762.5296, found 762.5296.

[0122] (Example 16) N-((2S,3S,4R)-3,4-Dihydroxy-1-{[(1S,2R,3S,4S,5R)-2,3,4-Trihydroxy-5-(methoxymethyl)cyclohexyl]oxy}octadecane-2-yl)-11-(4-fluorophenyl)undecanamide (Compound (I)-4)

Chemical Structure

[0123] In the same manner as in Example 7, 112 mg (91%) of the title compound was obtained from 196 mg of the starting material (the compound obtained in Example 12). 11H NMR (500 MHz, pyridine-d5) δ ppm 8.38 (broad doublet, J = 8.3 Hz, 1 H), 7.15 - 7.18 (multiplet, 2 H), 7.06 - 7.12 (multiplet, 2 H), 6.81 (broad singlet, 1 H), 6.30 (broad singlet, 2 H), 6.02 (broad singlet, 1 H), 5.88 (broad singlet, 1 H), 5.10 - 5.19 (multiplet, 1 H), 4.41 - 4.48 (multiplet, 2 H), 4.31 - 4.41 (multiplet, 1 H), 4.29 (broad singlet, 2 H), 4.11 - 4.25 (multiplet, 3 H), 3.71 (triplet, J = 8.3 Hz, 1 H), 3.34 - 3.43 (multiplet, 1 H), 3.24 (singlet, 3 H), 2.47 - 2.54 (multiplet, 2 H), 2.42 (broad triplet, J = 7.3 Hz, 3 H), 2.18 - 2.33 (multiplet, 1 H), 1.85 - 1.98 (multiplet, 3 H), 1.75 - 1.84 (multiplet, 3 H), 1.61 - 1.73 (multiplet, 1 H), 1.50 (quintet, J = 7.3 Hz, 2 H), 1.15 - 1.44 (multiplet, 34 H), 0.84 (triplet, J = 7.5 Hz, 3 H) HRMS (ESI) calculated for C 43 H 76 FNO8Na [M + Na] + 776.5453, found 776.5453.

[0124] (Example 17) N-((2S,3S,4R)-1-{[(1S,2R,3S,4S,5R)-5-(ethoxymethyl)-2,3,4-trihydroxycyclohexyl]oxy}-3,4-dihydroxyoctadecan-2-yl)-11-(4-fluorophenyl)undecanamide (Compound (I)-5)

Chemical Structure

[0125] In the same manner as in Example 7, 83.7 mg (78%) of the title compound was obtained from 150 mg of the raw material (the compound obtained in Example 13). 1 H NMR (500 MHz, CDCl3) δ ppm 7.10 (t, J = 6.6 Hz, 2 H), 6.87 - 7.01 (m, 2 H), 6.62 (br d, J = 8.8 Hz, 1 H), 4.89 (br s, 1 H), 4.54 - 4.70 (m, 2 H), 4.11 (br s, 2 H), 3.93 (br d, J = 5.1 Hz, 1 H), 3.73 - 3.82 (m, 4 H), 3.66 (br d, J = 17.1 Hz, 3 H), 3.45 - 3.55 (m, 3 H), 3.40 (br dd, J = 9.2, 4.8 Hz, 1 H), 2.81 (br s, 1 H), 2.51 - 2.60 (m, 2 H), 2.18 (br t, J = 7.6 Hz, 2 H), 1.94 - 2.08 (m, 1 H), 1.51 - 1.66 (m, 8 H), 1.42 (br d, J = 9.0 Hz, 2 H), 1.23 - 1.32 (m, 34 H), 1.18 (t, J = 7.0 Hz, 3 H), 0.88 (t, J = 7.0 Hz, 3 H) HRMS (ESI) calcd for C 44 H 78 FNO8Na [M + Na] + 790.5609, found 790.5595.

[0126] (Example 18) N-((2S,3S,4R)-3,4-Dihydroxy-1-{[(1S,2R,3S,4S,5R)-2,3,4-Trihydroxy-5-(propoxymethyl)cyclohexyl]oxy}octadecane-2-yl)-11-(4-fluorophenyl)undecanamide (Compound (I)-6)

Chemical formula

[0127] In the same manner as in Example 7, 91.0 mg (82%) of the title compound was obtained from 174 mg of the raw material (the compound obtained in Example 14). 1 H NMR (500 MHz, pyridine-d5) δ ppm 8.40 (br d, J=8.1 Hz, 1 H), 7.17 (br d, J=5.9 Hz, 2 H), 7.06 - 7.13 (m, 2 H), 6.85 (br s, 1 H), 6.15 - 6.39 (m, 2 H), 6.03 (br s, 1 H), 5.89 (br s, 1 H), 5.15 (br s, 1 H), 4.34 - 4.52 (m, 3 H), 4.29 (br s, 2 H), 4.14 - 4.25 (m, 3 H), 3.78 (br t, J=8.6 Hz, 1 H), 3.44 (dd, J=8.8, 6.1 Hz, 1 H), 3.25 - 3.39 (m, 2 H), 2.36 - 2.55 (m, 5 H), 2.16 - 2.33 (m, 1 H), 1.75 - 2.00 (m, 6 H), 1.63 - 1.71 (m, 1 H), 1.47 - 1.57 (m, 4 H), 1.14 - 1.46 (m, 34 H), 0.85 (t, J=10 Hz, 3 H), 0.84 (t, J=10 Hz, 3 H) HRMS (ESI) calcd for C 45 H 80 FNO8Na [M + Na] + 804.5765, found 804.5760.

[0128] (Example 19) N-[(2S,3S,4R)-3,4-Dihydroxy-1-({(1S,2S,3S,4S,5R)-2,3,4-Tris(benzyloxy)-5-[(benzyloxy)methyl]cyclohexyl}oxy)octadecane-2-yl]-8-phenyloctanamide [Chemical formula]

[0129] Using 8-phenyloctanoic acid as the carboxylic acid, 3.216 g (72%) of the title compound was obtained from 3.615 g of the raw material (the compound obtained in Example 1) in the same manner as in Example 2. HRMS (ESI) calcd for C 67 H 93 NO8Na [M + Na] + 1062.6799, found 1062.7686.

[0130] (Example 20) N-[(2S,3S,4R)-3,4-bis(benzyloxy)-1-({(1S,2S,3S,4S,5R)-2,3,4-tris(benzyloxy)-5-[(benzyloxy)methyl]cyclohexyl}oxy)octadecane-2-yl]-8-phenyloctanamide

Chemical formula

[0131] In the same manner as in Example 3, 2.036 g (86%) of the title compound was obtained from 2.023 g of the raw material (the compound obtained in Example 19). HRMS (ESI) calcd for C 81 H 105 NO8Na [M + Na] + 1242.7738, found 1242.7725.

[0132] (Example 21) N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-{[(1S,2S,3S,4S,5R)-2,3,4-tris(benzyloxy)-5-[(hydroxymethyl)cyclohexyl]oxy}octadecane-2-yl)-8-phenyloctanamide

Chemical formula

[0133] In the same manner as in Example 4, 1.354 g (78%) of the title compound was obtained from 1.866 g of the raw material (the compound obtained in Example 20). HRMS (ESI) calcd for C 74 H 99 NO8Na [M + Na] + 1152.7268, found 1152.7252.

[0134] (Example 22) N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-{[(1S,2S,3S,4S,5R)-2,3,4-tris(benzyloxy)-5-[(methoxymethyl)cyclohexyl]oxy}octadecane-2-yl)-8-phenyloctanamide

Chemical formula

[0135] Using trimethyloxonium tetrafluoroborate as the alkylating agent, 178 mg (87%) of the title compound was obtained from 201 mg of the starting material (the compound obtained in Example 21) by the same method as in Example 5. HRMS (ESI) calcd for C 75 H 101 NO8Na [M + Na] + 1166.7424, found 1166.7406.

[0136] (Example 23) N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-{[(1S,2S,3S,4S,5R)-2,3,4-tris(benzyloxy)-5-[(ethoxymethyl)cyclohexyl]oxy}octadecane-2-yl)-8-phenyloctanamide

Chemical formula

[0137] Using ethyl iodide as the alkylating agent, 78.6 mg (55%) of the title compound was obtained from 140.3 mg of the starting material (the compound obtained in Example 21) by the same method as in Example 6. HRMS (ESI) calcd for C 76 H 103NO8Na [M + Na] + 1180.7582, found 1180.7567.

[0138] (Example 24) N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-{[(1S,2S,3S,4S,5R)-2,3,4-tris(benzyloxy)-5-[(propoxymethyl)cyclohexyl]oxy}octadecane-2-yl)-8-phenyloctanamide

Chemical Structure

[0139] Using the same method as in Example 6, 82.5 mg (56%) of the title compound was obtained from 141.6 mg of the starting material (the compound obtained in Example 21). HRMS (ESI) calcd for C 77 H 106 NO8[M + H] + 1172.7919, found 1172.7920.

[0140] (Example 25) N-((2S,3S,4R)-3,4-dihydroxy-1-{[(1S,2R,3S,4S,5R)-2,3,4-trihydroxy-5-(hydroxymethyl)cyclohexyl]oxy}octadecane-2-yl)-8-phenyloctanamide (Compound (I)-7)

Chemical Structure

[0141] Using the same method as in Example 7, 86 mg (86%) of the title compound was obtained from 153 mg of the starting material (the compound obtained in Example 20). 11H NMR (500 MHz, pyridine-d5) δ ppm 8.38 (broad doublet, J = 8.6 Hz, 1 H), 7.28 - 7.35 (multiplet, 2 H), 7.17 - 7.22 (multiplet, 3 H), 6.33 (broad singlet, 1 H), 5.94 (broad singlet, 3 H), 5.02 - 5.31 (multiplet, 3 H), 4.62 - 4.71 (multiplet, 1 H), 4.39 - 4.50 (multiplet, 2 H), 4.15 - 4.32 (multiplet, 6 H), 3.92 - 4.02 (multiplet, 1 H), 2.36 - 2.53 (multiplet, 5 H), 2.21 - 2.31 (multiplet, 1 H), 2.08 (broad doublet, J = 13.7 Hz, 1 H), 1.85 - 2.01 (multiplet, 3 H), 1.63 - 1.80 (multiplet, 3 H), 1.45 - 1.50 (multiplet, 2 H), 1.33 - 1.43 (multiplet, 2 H), 1.17 - 1.30 (multiplet, 26 H), 0.84 (triplet, J = 7.0 Hz, 3 H) HRMS (ESI) calculated for C 39 H 69 NO₈Na [M + Na] + 702.4921, found 702.4918.

[0142] (Example 26) N-((2S,3S,4R)-3,4-Dihydroxy-1-{[(1S,2R,3S,4S,5R)-2,3,4-Trihydroxy-5-(methoxymethyl)cyclohexyl]oxy}octadecane-2-yl)-8-phenyloctanamide (Compound (I)-8)

Chemical Structure

[0143] Using the same method as in Example 7, 80 mg (89%) of the title compound was obtained from 148 mg of the starting material (the compound obtained in Example 22). 11H NMR (500 MHz, pyridine-d5) δ ppm 8.38 (d, J=8.6 Hz, 1 H), 7.29 - 7.34 (m, 2 H), 7.19 - 7.23 (m, 3 H), 6.82 (br s, 1 H), 6.15 - 6.40 (m, 2 H), 6.04 (br s, 1 H), 5.90 (br s, 1 H), 5.15 (dq, J=8.4, 4.2 Hz, 1 H), 4.41 - 4.50 (m, 2 H), 4.39 (dd, J=9.8, 3.2 Hz, 1 H), 4.29 (br s, 2 H), 4.13 - 4.23 (m, 3 H), 3.70 (t, J=8.4 Hz, 1 H), 3.38 (dd, J=9.0, 6.4 Hz, 1 H), 3.24 (s, 3 H), 2.47 - 2.56 (m, 2 H), 2.33 - 2.47 (m, 3 H), 2.19 - 2.31 (m, 1 H), 1.73 - 1.96 (m, 6 H), 1.63 - 1.71 (m, 1 H), 1.44 - 1.53 (m, 2 H), 1.32 - 1.44 (m, 2 H), 1.17 - 1.29 (m, 26 H), 0.79 - 0.88 (t, J=7.5 Hz, 3 H) HRMS (ESI) calcd for C 40 H 71 NO8Na [M + Na] + 716.5078, found 716.5070.

[0144] (Example 27) N-((2S,3S,4R)-1-{[(1S,2R,3S,4S,5R)-5-(ethoxymethyl)-2,3,4-trihydroxycyclohexyl]oxy}-3,4-dihydroxyoctadecan-2-yl)-8-phenyloctanamide (Compound (I)-9)

Chemical formula

[0145] In the same manner as in Example 7, 29.5 mg (71%) of the title compound was obtained from 68 mg of the raw material (the compound obtained in Example 23). 1 H NMR (500 MHz, pyridine-d5) δ ppm 8.38 (br d, J=7.3 Hz, 1 H), 7.31 (t, J=7.0 Hz, 2 H), 7.21 (br d, J=7.3 Hz, 3 H), 6.81 (br s, 1 H), 6.12 - 6.39 (m, 2 H), 6.03 (br s, 1 H), 5.86 (br s, 1 H), 5.09 - 5.16 (m, 1 H), 4.47 (br s, 1 H), 4.34 - 4.45 (m, 2 H), 4.28 (br s, 2 H), 4.19 (br s, 2 H), 4.15 (br s, 1 H), 3.76 (br t, J=8.4 Hz, 1 H), 3.35 - 3.45 (m, 3 H), 2.44 - 2.56 (m, 2 H), 2.39 (br t, J=7.3 Hz, 3 H), 2.24 (br s, 1 H), 1.71 - 1.97 (m, 6 H), 1.66 (br s, 1 H), 1.45 - 1.52 (m, 2 H), 1.33 - 1.43 (m, 2 H), 1.17 - 1.29 (m, 26 H), 1.10 (t, J=7.0 Hz, 3 H), 0.83 (t, J=6.8 Hz, 3 H) HRMS (ESI) calcd for C 41 H 73 NO8Na [M + Na] + 730.5234, found 730.5233.

[0146] (Example 28) N-((2S,3S,4R)-3,4-dihydroxy-1-{[(1S,2R,3S,4S,5R)-2,3,4-trihydroxy-5-(propoxymethyl)cyclohexyl]oxy}octadecane-2-yl)-8-phenyloctanamide (Compound (I)-10)

Chemical Structure

[0147] In the same manner as in Example 7, 189.6 mg (78%) of the title compound was obtained from 397 mg of the raw material (the compound obtained in Example 24). 1 H NMR (500 MHz, pyridine-d5) δ ppm 8.39 - 8.47 (m, 1 H), 7.18 - 7.34 (m, 5 H), 6.91 (br s, 1 H), 6.36 (br s, 2 H), 6.09 (br s, 1 H), 5.95 (br s, 1 H), 5.13 - 5.21 (m, 1 H), 4.39 - 4.53 (m, 3 H), 4.31 (br s, 2 H), 4.14 - 4.26 (m, 3 H), 3.73 - 3.83 (m, 1 H), 3.39 - 3.48 (m, 1 H), 3.27 - 3.35 (m, 2 H), 2.36 - 2.55 (m, 5 H), 2.22 - 2.32 (m, 1 H), 1.73 - 1.96 (m, 6 H), 1.64 - 1.72 (m, 1 H), 1.13 - 1.60 (m, 32 H), 0.85 (t, J=7.5 Hz, 3 H), 0.84 (t, J=10 Hz, 3 H) HRMS (ESI) calcd for C 42 H 75 NO8Na [M + Na] + 744.5391, found 744.5384.

[0148] (Example 29) N-[(2S,3S,4R)-3,4-Dihydroxy-1-({(1S,2S,3S,4S,5R)-2,3,4-Tris(benzyloxy)-5-[(benzyloxy)methyl]cyclohexyl}oxy)octadecane-2-yl]-11-phenylundecanamide [Chemical formula]

[0149] Using 11-phenylundecanoic acid as the carboxylic acid, 3.615 g (92%) of the title compound was obtained from 3.035 g of the raw material (the compound obtained in Example 1) in the same manner as in Example 2. HRMS (ESI) calcd for C 70 H 99 NO8Na [M + Na] + 1104.7268, found 1104.7236.

[0150] (Example 30) N-[(2S,3S,4R)-3,4-bis(benzyloxy)-1-({(1S,2S,3S,4S,5R)-2,3,4-tris(benzyloxy)-5-[(benzyloxy)methyl]cyclohexyl}oxy)octadecane-2-yl]-11-phenylundecanamide

Chemical formula

[0151] In the same manner as in Example 3, 3.531 g (91%) of the title compound was obtained from 3.327 g of the raw material (the compound obtained in Example 29). HRMS (ESI) calcd for C 84 H 111 NO8Na [M + Na] + 1284.8207, found 1284.8191.

[0152] (Example 31) N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-{[(1S,2S,3S,4S,5R)-2,3,4-tris(benzyloxy)-5-(hydroxymethyl)cyclohexyl]oxy}octadecane-2-yl)-11-phenylundecanamide

Chemical formula

[0153] In the same manner as in Example 4, 2.688 g (87%) of the title compound was obtained from 3.322 g of the raw material (the compound obtained in Example 30). HRMS (ESI) calcd for C 77 H 105 NO8Na [M + Na] + 1194.7738, found 1194.7732.

[0154] (Example 32) N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-{[(1S,2S,3S,4S,5R)-2,3,4-tris(benzyloxy)-5-(methoxymethyl)cyclohexyl]oxy}octadecane-2-yl)-11-phenylundecanamide

Chemical formula

[0155] Using trimethyloxonium tetrafluoroborate as the alkylating agent, 175 mg (86%) of the title compound was obtained from 202 mg of the starting material (the compound obtained in Example 31) in the same manner as in Example 5. HRMS (ESI) calcd for C 78 H 107 NO8Na [M + Na] + 1208.7894, found 1208.7888.

[0156] (Example 33) N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-{[(1S,2S,3S,4S,5R)-2,3,4-tris(benzyloxy)-5-(ethoxymethyl)cyclohexyl]oxy}octadecane-2-yl)-11-phenylundecanamide

Chemical formula

[0157] Using ethyl iodide as the alkylating agent, 116.0 mg (54%) of the title compound was obtained from 211.0 mg of the starting material (the compound obtained in Example 31) in the same manner as in Example 6. HRMS (ESI) calcd for C 79 H 110 NO8[M + H]+ 1200.8231, found 1200.8232.

[0158] (Example 34) N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-{[(1S,2S,3S,4S,5R)-2,3,4-tris(benzyloxy)-5-(propoxymethyl)cyclohexyl]oxy}octadecane-2-yl)-11-phenylundecanamide

Chemical Structure

[0159] Using the same method as in Example 6, 120.5 mg (52%) of the title compound was obtained from 225.1 mg of the starting material (the compound obtained in Example 31). HRMS (ESI) calcd for C 80 H 111 NO8Na [M + Na] + 1236.8207, found 1236.8207.

[0160] (Example 35) N-((2S,3S,4R)-3,4-dihydroxy-1-{[(1S,2R,3S,4S,5R)-2,3,4-trihydroxy-5-(hydroxymethyl)cyclohexyl]oxy}octadecane-2-yl)-11-phenylundecanamide (Compound (I)-11)

Chemical Structure

[0161] Using the same method as in Example 7, 110 mg (89%) of the title compound was obtained from 185 mg of the starting material (the compound obtained in Example 30). 11H NMR (500 MHz, pyridine-d5) δ ppm 8.40 (broad doublet, J = 8.6 Hz, 1 H), 7.33 (triplet, J = 7.0 Hz, 2 H), 7.20 - 7.26 (multiplet, 3 H), 6.78 (broad singlet, 1 H), 6.31 - 6.38 (multiplet, 1 H), 6.25 (broad singlet, 1 H), 6.04 (broad singlet, 1 H), 5.94 (broad singlet, 2 H), 5.16 (broad doublet of doublets, J = 8.1, 3.9 Hz, 1 H), 4.66 (broad singlet, 1 H), 4.39 - 4.50 (multiplet, 2 H), 4.29 (broad singlet, 2 H), 4.16 - 4.26 (multiplet, 4 H), 3.97 (broad doublet of doublets, J = 9.9, 5.7 Hz, 1 H), 2.55 (broad triplet, J = 7.7 Hz, 2 H), 2.38 - 2.50 (multiplet, 3 H), 2.21 - 2.31 (multiplet, 1 H), 2.08 (broad doublet, J = 13.7 Hz, 1 H), 1.97 (broad triplet, J = 13.3 Hz, 1 H), 1.85 - 1.93 (multiplet, 2 H), 1.78 (quintet, J = 7.5 Hz, 2 H), 1.62 - 1.72 (multiplet, 1 H), 1.54 (doublet of triplets, J = 14.7, 7.3 Hz, 2 H), 1.15 - 1.45 (multiplet, 34 H), 0.84 (triplet, J = 7.5 Hz, 3 H) HRMS (ESI) calculated for C 42 H 75 NO8Na [M + Na] + 744.5391, found 744.5393.

[0162] (Example 36) N-((2S,3S,4R)-3,4-Dihydroxy-1-{[(1S,2R,3S,4S,5R)-2,3,4-Trihydroxy-5-(methoxymethyl)cyclohexyl]oxy}octadecane-2-yl)-11-phenylundecanamide (Compound (I)-12)

Chemical Structure

[0163] In the same manner as in Example 7, 75 mg (83%) of the title compound was obtained from 145 mg of the raw material (the compound obtained in Example 32). 1 H NMR (500 MHz, pyridine-d5) δ ppm 8.40 (d, J=8.3 Hz, 1 H), 7.31 - 7.36 (m, 2 H), 7.19 - 7.26 (m, 3 H), 6.85 (br s, 1 H), 6.33 (br d, J=5.6 Hz, 1 H), 6.28 (br s, 1 H), 6.05 (br s, 1 H), 5.92 (br s, 1 H), 5.16 (br dd, J=8.4, 4.3 Hz, 1 H), 4.43 - 4.48 (m, 2 H), 4.39 (br dd, J=9.8, 2.9 Hz, 1 H), 4.30 (br s, 2 H), 4.14 - 4.24 (m, 3 H), 3.71 (t, J=8.4 Hz, 1 H), 3.39 (dd, J=9.0, 6.4 Hz, 1 H), 3.24 (s, 3 H), 2.51 - 2.60 (m, 2 H), 2.37 - 2.47 (m, 3 H), 2.20 - 2.31 (m, 1 H), 1.86 - 1.97 (m, 3 H), 1.75 - 1.85 (m, 3 H), 1.63 - 1.72 (m, 1 H), 1.55 (dt, J=14.9, 7.6 Hz, 2 H), 1.14 - 1.44 (m, 34 H), 0.84 (t, J=5.0 Hz, 3 H) HRMS (ESI) calcd for C 43 H 77 NO8Na [M + Na] + 758.5574, found 758.5543.

[0164] (Example 37) N-((2S,3S,4R)-1-{[((1S,2R,3S,4S,5R)-5-(ethoxymethyl)-2,3,4-trihydroxycyclohexyl]oxy}-3,4-dihydroxyoctadecane-2-yl)-11-phenylundecanamide (Compound (I)-13)

Chemical Structure

[0165] Using the same method as in Example 7, 48.2 mg (79%) of the title compound was obtained from 98.0 mg of the starting material (the compound obtained in Example 33). 1 H NMR (500 MHz, pyridine-d5) δ ppm 8.38 (br d, J=7.8 Hz, 1 H), 7.29 - 7.36 (m, 2 H), 7.20 - 7.27 (m, 3 H), 6.80 (br s, 1 H), 6.31 (br s, 1 H), 6.20 (br s, 1 H), 6.02 (br s, 1 H), 5.85 (br s, 1 H), 5.14 (br s, 1 H), 4.35 - 4.51 (m, 3 H), 4.29 (br s, 2 H), 4.12 - 4.24 (m, 3 H), 3.77 (br t, J=8.1 Hz, 1 H), 3.35 - 3.46 (m, 3 H), 2.56 (br t, J=7.5 Hz, 2 H), 2.41 (br t, J=6.6 Hz, 3 H), 2.25 (br s, 1 H), 1.86 - 1.98 (m, 3 H), 1.74 - 1.85 (m, 3 H), 1.67 (br s, 1 H), 1.50 - 1.60 (m, 2 H), 1.14 - 1.37 (m, 34 H), 1.10 - 1.14 (m, 3 H), 0.84 (br t, J=6.4 Hz, 3 H) HRMS (ESI) calcd for C 44 H 79 NO8Na [M + Na] + 772.5703, found 772.5692.

[0166] (Example 38) N-((2S,3S,4R)-3,4-dihydroxy-1-{[(1S,2R,3S,4S,5R)-2,3,4-trihydroxy-5-(propoxymethyl)cyclohexyl]oxy}octadecane-2-yl)-11-phenylundecanamide (Compound (I)-14) [Chemical formula]

[0167] In the same manner as in Example 7, 55.5 mg (86%) of the title compound was obtained from 102.0 mg of the starting material (the compound obtained in Example 34). 1 H NMR (500 MHz, pyridine-d5) δ ppm 8.40 (d, J=8.6 Hz, 1 H), 7.19 - 7.35 (m, 5 H), 6.82 (br s, 1 H), 6.32 (br d, J=6.1 Hz, 1 H), 6.13 - 6.28 (m, 1 H), 6.03 (br s, 1 H), 5.87 (br s, 1 H), 5.11 - 5.18 (m, 1 H), 4.37 - 4.52 (m, 3 H), 4.27 - 4.34 (m, 2 H), 4.15 - 4.27 (m, 3 H), 3.78 (t, J=8.6 Hz, 1 H), 3.44 (dd, J=9.0, 6.1 Hz, 1 H), 3.28 - 3.36 (m, 2 H), 2.56 (t, J=7.7 Hz, 2 H), 2.37 - 2.49 (m, 3 H), 2.20 - 2.32 (m, 1 H), 1.76 - 1.97 (m, 6 H), 1.62 - 1.73 (m, 1 H), 1.54 (dquin, J=13.8, 6.9, 6.9, 6.9, 6.9 Hz, 4 H), 1.14 - 1.44 (m, 34 H), 0.85 (t, J=10 Hz, 3 H), 0.84 (t, J=10 Hz, 3 H) HRMS (ESI) calcd for C 45 H81 NO8Na [M + Na] + 786.5860, found 786.5856.

[0168] (Example 39) N-[(2S,3S,4R)-3,4-Dihydroxy-1-({(1S,2S,3S,4S,5R)-2,3,4-Tris(benzyloxy)-5-[(benzyloxy)methyl]cyclohexyl}oxy)octadecane-2-yl]-8-(4-fluorophenyl)octanamide

Chemical formula

[0169] Using 8-(4-fluorophenyl)octanoic acid as the carboxylic acid, in the same manner as in Example 2, 2.87 g (68%) of the title compound was obtained from 3.341 g of the starting material (the compound obtained in Example 1). HRMS (ESI) calcd for C 67 H 92 FNO8Na [M + Na] + 1080.6704, found 1080.6688.

[0170] (Example 40) N-[(2S,3S,4R)-3,4-Bis(benzyloxy)-1-({(1S,2S,3S,4S,5R)-2,3,4-Tris(benzyloxy)-5-[(benzyloxy)methyl]cyclohexyl}oxy)octadecane-2-yl]-8-(4-fluorophenyl)octanamide

Chemical formula

[0171] In the same manner as in Example 3, 2.752 g (91%) of the title compound was obtained from 2.580 g of the starting material (the compound obtained in Example 39). HRMS (ESI) calcd for C 81 H 104 FNO8Na [M + Na] +1260.7644, found 1260.7615.

[0172] (Example 41) N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-{[(1S,2S,3S,4S,5R)-2,3,4-tris(benzyloxy)-5-(hydroxymethyl)cyclohexyl]oxy}octadecane-2-yl)-8-(4-fluorophenyl)octanamide

Chemical formula

[0173] Using the same method as in Example 4, 1.923 g (82%) of the title compound was obtained from 2.517 g of the raw material (the compound obtained in Example 40). HRMS (ESI) calcd for C 74 H 99 FNO8 [M + H] + 1148.7355, found 1148.7350.

[0174] (Example 42) N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-{[(1S,2S,3S,4S,5R)-2,3,4-tris(benzyloxy)-5-(methoxymethyl)cyclohexyl]oxy}octadecane-2-yl)-8-(4-fluorophenyl)octanamide

Chemical formula

[0175] Using trimethyloxonium tetrafluoroborate as the alkylating agent, 150 mg (71%) of the title compound was obtained from 209 mg of the raw material (the compound obtained in Example 41) by the same method as in Example 5. HRMS (ESI) calcd for C 75 H 100 FNO8Na [M + Na] + 1184.7330, found 1184.7300.

[0176] (Example 43) N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-{[(1S,2S,3S,4S,5R)-2,3,4-tris(benzyloxy)-5-(ethoxymethyl)cyclohexyl]oxy}octadecane-2-yl)-8-(4-fluorophenyl)octanamide

Chemical formula

[0177] Using ethyl iodide as the alkylating agent, 92.3 mg (41%) of the title compound was obtained from 220.0 mg of the starting material (the compound obtained in Example 41) in the same manner as in Example 6. HRMS (ESI) calcd for C 76 H 103 FNO8[M + H] + 1176.7667, found 1176.7664.

[0178] (Example 44) N-((2S,3S,4R)-3,4-bis(benzyloxy)-1-{[(1S,2S,3S,4S,5R)-2,3,4-tris(benzyloxy)-5-(propoxymethyl)cyclohexyl]oxy}octadecane-2-yl)-8-(4-fluorophenyl)octanamide

Chemical formula

[0179] 117.5 mg (54%) of the title compound was obtained from 210.5 mg of the starting material (the compound obtained in Example 41) in the same manner as in Example 6. HRMS (ESI) calcd for C 77 H 105 FNO8[M + H] + 1190.7825, found 1190.7809.

[0180] (Example 45) N-((2S,3S,4R)-3,4-Dihydroxy-1-{[(1S,2R,3S,4S,5R)-2,3,4-Trihydroxy-5-(hydroxymethyl)cyclohexyl]oxy}octadecane-2-yl)-8-(4-fluorophenyl)octanamide (Compound (I)-15) [Chemical formula]

[0181] In the same manner as in Example 7, 113 mg (91%) of the title compound was obtained from 188 mg of the starting material (the compound obtained in Example 40). 1 H NMR (500 MHz, pyridine-d5) δ ppm 8.39 (br d, J=8.6 Hz, 1 H), 7.11 - 7.16 (m, 2 H), 7.05 - 7.10 (m, 2 H), 6.78 (br s, 1 H), 6.17 - 6.40 (m, 2 H), 6.05 (br s, 1 H), 5.95 (br s, 2 H), 5.16 (br d, J=3.9 Hz, 1 H), 4.67 (br s, 1 H), 4.39 - 4.52 (m, 2 H), 4.16 - 4.31 (m, 6 H), 3.92 - 4.02 (m, 1 H), 2.37 - 2.48 (m, 5 H), 2.21 - 2.31 (m, 1 H), 2.08 (br d, J=13.7 Hz, 1 H), 1.97 (br t, J=13.3 Hz, 1 H), 1.85 - 1.93 (m, 2 H), 1.77 (dt, J=14.7, 7.4 Hz, 2 H), 1.61 - 1.72 (m, 1 H), 1.19 - 1.46 (m, 30 H), 0.84 (br t, J=6.8 Hz, 3 H) HRMS (ESI) calcd for C 39 H 68 FNO8Na [M + Na] + 720.4827, found 720.4814.

[0182] (Example 46) N-((2S,3S,4R)-3,4-Dihydroxy-1-{[(1S,2R,3S,4S,5R)-2,3,4-Trihydroxy-5-(methoxymethyl)cyclohexyl]oxy}octadecane-2-yl)-8-(4-fluorophenyl)octanamide (Compound (I)-16) [Chemical Structure]

[0183] In the same manner as in Example 7, 64 mg (91%) of the title compound was obtained from 115 mg of the starting material (the compound obtained in Example 42). 1 H NMR (500 MHz, pyridine-d5) δ ppm 8.39 (d, J=8.2 Hz, 1 H), 7.12 - 7.16 (m, 2 H), 7.05 - 7.11 (m, 2 H), 6.84 (br s, 1 H), 6.31 (br s, 2 H), 6.04 (br s, 1 H), 5.91 (br s, 1 H), 5.11 - 5.19 (m, 1 H), 4.35 - 4.48 (m, 3 H), 4.29 (br s, 2 H), 4.13 - 4.24 (m, 3 H), 3.70 (t, J=8.4 Hz, 1 H), 3.38 (dd, J=8.9, 6.5 Hz, 1 H), 3.24 (s, 3 H), 2.38 - 2.48 (m, 5 H), 2.20 - 2.31 (m, 1 H), 1.85 - 1.97 (m, 3 H), 1.73 - 1.84 (m, 3 H), 1.61 - 1.71 (m, 1 H), 1.18 - 1.47 (m, 30 H), 0.84 (t, J=7.0 Hz, 3 H) HRMS (ESI) calcd for C 40 H 70 FNO8Na [M + Na] + 734.4983, found 734.4975.

[0184] (Example 47) N-((2S,3S,4R)-1-{[(1S,2R,3S,4S,5R)-5-(ethoxymethyl)-2,3,4-trihydroxyhexyl]oxy}-3,4-dihydroxyoctadecane-2-yl)-8-(4-fluorophenyl)octanamide (Compound (I)-17)

Chemical Structure

[0185] In the same manner as in Example 7, 33.04 mg (64%) of the title compound was obtained from 83.0 mg of the starting material (the compound obtained in Example 43). 1 H NMR (500 MHz, pyridine-d5) δ ppm 8.38 (d, J = 8.6 Hz, 1 H), 7.12 - 7.17 (m, 2 H), 7.05 - 7.11 (m, 2 H), 6.83 (br s, 1 H), 6.11 - 6.39 (m, 2 H), 6.03 (br s, 1 H), 5.88 (br s, 1 H), 5.15 (br dd, J = 8.2, 4.0 Hz, 1 H), 4.37 - 4.51 (m, 3 H), 4.29 (br s, 2 H), 4.14 - 4.25 (m, 3 H), 3.77 (t, J = 8.6 Hz, 1 H), 3.34 - 3.47 (m, 3 H), 2.37 - 2.49 (m, 5 H), 2.20 - 2.30 (m, 1 H), 1.74 - 1.96 (m, 6 H), 1.63 - 1.72 (m, 1 H), 1.33 - 1.49 (m, 4 H), 1.17 - 1.31 (m, 26 H), 1.11 (t, J = 7.0 Hz, 3 H), 0.84 (t, J = 6.8 Hz, 3 H) HRMS (ESI) calcd for C 41 H 72 FNO8Na [M + Na] + 748.5140, found 748.5132.

[0186] (Example 48) N-((2S,3S,4R)-3,4-Dihydroxy-1-{[(1S,2R,3S,4S,5R)-2,3,4-Trihydroxy-5-(propoxymethyl)cyclohexyl]oxy}octadecane-2-yl)-8-(4-fluorophenyl)octanamide (Compound (I)-18)

Chemical Structure

[0187] In the same manner as in Example 7, 46.6 mg (79%) of the title compound was obtained from 94.4 mg of the starting material (the compound obtained in Example 44). 1 H NMR (500 MHz, pyridine-d5) δ ppm 8.38 (d, J = 8.6 Hz, 1 H), 7.06 - 7.17 (m, 4 H), 6.81 (br s, 1 H), 6.31 (br d, J = 6.1 Hz, 1 H), 6.21 (br s, 1 H), 6.03 (br s, 1 H), 5.87 (br s, 1 H), 5.04 - 5.18 (m, 1 H), 4.36 - 4.51 (m, 3 H), 4.26 - 4.33 (m, 2 H), 4.13 - 4.26 (m, 3 H), 3.78 (t, J = 8.6 Hz, 1 H), 3.44 (dd, J = 8.8, 6.1 Hz, 1 H), 3.27 - 3.36 (m, 2 H), 2.36 - 2.50 (m, 5 H), 2.21 - 2.32 (m, 1 H), 1.73 - 1.96 (m, 6 H), 1.63 - 1.72 (m, 1 H), 1.49 - 1.57 (m, 2 H), 1.33 - 1.49 (m, 4 H), 1.15 - 1.32 (m, 26 H), 0.85 (t, J = 7.5 Hz, 3 H), 0.84 (t, J = 10 Hz, 3 H) HRMS (ESI) calcd for C 42 H 74 FNO8Na [M + Na] + 762.5296, found 762.5300.

[0188] (Example 49) 1-[(2S,3S,4R)-3,4-Dihydroxy-1-({(1S,2S,3S,4S,5R)-2,3,4-Tris(benzyloxy)-5-[(benzyloxy)methyl]cyclohexyl}oxy)octadecane-2-yl]-3-tetracosylurea [Chemical formula]

[0189] Pentacosanoic acid (984 mg), diphenylphosphoryl azide (DPPA) (664 μl), and triethylamine (896 μl) were heated at 80 °C for 30 minutes in benzene (8 ml). After allowing to cool to room temperature, a solution of the starting material (the compound obtained in Example 1) (1.918 g) in THF (8 ml) was added dropwise, and the mixture was stirred overnight at room temperature. Saturated brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate = 90:10 to 50:50) to obtain the title compound (2.575 g (92%)). HRMS (ESI) calcd for C 78 H 125 NO8[M + H] + 1217.9436, found 1217.9438.

[0190] (Example 50) 1-[(2S,3S,4R)-3,4-Bis(benzyloxy)-1-({(1S,2S,3S,4S,5R)-2,3,4-Tris(benzyloxy)-5-[(benzyloxy)methyl]cyclohexyl}oxy)octadecane-2-yl]-3-tetracosylurea [Chemical formula]

[0191] In the same manner as in Example 3, 2.546 g (91%) of the title compound was obtained from 2.430 g of the starting material (the compound obtained in Example 49). HRMS (ESI) calcd for C 92 H 136 N2O8Na [M + Na] + 1421.0228, found 1421.0206.

[0192] (Example 51) 1 - ((2S,3S,4R)-3,4-bis(benzyloxy)-1-{[(1S,2S,3S,4S,5R)-2,3,4-tris(benzyloxy)-5-(hydroxymethyl)cyclohexyl]oxy}octadecane-2-yl)-3-tetracosylurea

Chemical formula

[0193] Using the same method as in Example 4, 1.922 g (85%) of the title compound was obtained from 2.404 g of the starting material (the compound obtained in Example 50). HRMS (ESI) calcd for C 85 H 130 N2O8Na [M + Na] + 1329.9725, found 1329.9712.

[0194] (Example 52) 1 - ((2S,3S,4R)-3,4-bis(benzyloxy)-1-{[(1S,2S,3S,4S,5R)-2,3,4-tris(benzyloxy)-5-(methoxymethyl)cyclohexyl]oxy}octadecane-2-yl)-3-tetracosylurea

Chemical formula

[0195] Using trimethyloxonium tetrafluoroborate as the alkylating agent and the same method as in Example 5, 108 mg (44%) of the title compound was obtained from 241 mg of the starting material (the compound obtained in Example 51). HRMS (ESI) calcd for C 86 H 133 N2O8[M + H] +1322.0062, found 1322.0051.

[0196] (Example 53) 1-((2S,3S,4R)-3,4-bis(benzyloxy)-1-{[(1S,2S,3S,4S,5R)-2,3,4-tris(benzyloxy)-5-(ethoxymethyl)cyclohexyl]oxy}octadecane-2-yl)-3-tetracosylurea

Chemical Structure

[0197] Using ethyl iodide as the alkylating agent, 174.8 mg (85%) of the title compound was obtained from 202.1 mg of the starting material (the compound obtained in Example 51) in the same manner as in Example 6. HRMS (ESI) calcd for C 87 H 135 N2O8[M + H] + 1336.0219, found 1336.0201.

[0198] (Example 54) 1-((2S,3S,4R)-3,4-bis(benzyloxy)-1-{[(1S,2S,3S,4S,5R)-2,3,4-tris(benzyloxy)-5-(propoxymethyl)cyclohexyl]oxy}octadecane-2-yl)-3-tetracosylurea

Chemical Structure

[0199] 179.4 mg (87%) of the title compound was obtained from 200.3 mg of the starting material (the compound obtained in Example 51) in the same manner as in Example 6. HRMS (ESI) calcd for C 88 H 137 N2O8[M + H] + 1350.0375, found 1350.0365.

[0200] (Example 55) 1-((2S,3S,4R)-3,4-Dihydroxy-1-{[(1S,2R,3S,4S,5R)-2,3,4-Trihydroxy-5-(hydroxymethyl)cyclohexyl]oxy}octadecane-2-yl)-3-tetracosylurea (Compound (I)-19)

Chemical Structure

[0201] In the same manner as in Example 7, 95 mg (67%) of the title compound was obtained from 200 mg of the starting material (the compound obtained in Example 50). 1 H NMR (500 MHz, pyridine-d5) δ ppm 6.76 (t, J=5.6 Hz, 1 H), 6.62 (d, J=8.8 Hz, 1 H), 6.35 - 6.58 (m, 1 H), 5.63 - 6.16 (m, 5 H), 4.96 (dq, J=8.6, 4.1 Hz, 1 H), 4.58 (br s, 1 H), 4.35 (dd, J=9.7, 3.5 Hz, 2 H), 4.10 - 4.27 (m, 6 H), 3.93 (dd, J=10.3, 5.6 Hz, 1 H), 3.37 - 3.52 (m, 2 H), 2.34 (br d, J=6.1 Hz, 1 H), 2.18 - 2.28 (m, 1 H), 1.99 - 2.07 (m, 1 H), 1.80 - 1.97 (m, 3 H), 1.61 - 1.70 (m, 1 H), 1.57 (quin, J=7.3 Hz, 2 H), 1.35 - 1.43 (m, 2 H), 1.20 - 1.31 (m, 62 H), 0.86 (t, J=6.8 Hz, 6 H) HRMS (ESI) calcd for C 50 H 100 N2O8Na [M + Na] + 879.7377, found 879.7361.

[0202] (Example 56) 1-((2S,3S,4R)-3,4-Dihydroxy-1-{[(1S,2R,3S,4S,5R)-2,3,4-Trihydroxy-5-(methoxymethyl)cyclohexyl]oxy}octadecane-2-yl)-3-tetracosylurea (Compound (I)-20)

Chem.

[0203] In the same manner as in Example 7, 50 mg (88%) of the title compound was obtained from 86 mg of the raw material (the compound obtained in Example 52). 1 H NMR (500 MHz, pyridine-d5) δ ppm 6.80 (br t, J=5.6 Hz, 1 H), 6.75 (br d, J=5.9 Hz, 1 H), 6.65 (d, J=9.0 Hz, 1 H), 6.12 (br s, 2 H), 5.95 (br s, 1 H), 5.82 (br s, 1 H), 5.02 (br dd, J=8.3, 4.2 Hz, 1 H), 4.33 - 4.43 (m, 3 H), 4.27 (br d, J=7.3 Hz, 1 H), 4.17 - 4.24 (m, 2 H), 4.11 - 4.15 (m, 1 H), 4.08 (dd, J=9.5, 2.7 Hz, 1 H), 3.69 (t, J=8.6 Hz, 1 H), 3.46 (quind, J=13.2, 13.2, 13.2, 13.2, 7.0 Hz, 2 H), 3.36 (dd, J=8.8, 6.4 Hz, 1 H), 3.25 (s, 3 H), 2.34 (br d, J=7.3 Hz, 1 H), 2.21 - 2.29 (m, 1 H), 1.82 - 1.93 (m, 3 H), 1.74 - 1.81 (m, 1 H), 1.61 - 1.70 (m, 1 H), 1.57 (quin, J=7.3 Hz, 2 H), 1.35 - 1.43 (m, 2 H), 1.19 - 1.30 (m, 62 H), 0.85 (t, J=7.5 Hz, 6 H) HRMS (ESI) calcd for C 51 H 103 N2O8[M + H] + 871.7714, found 871.7712.

[0204] (Example 57) 1-((2S,3S,4R)-1-{[(1S,2R,3S,4S,5R)-5-(ethoxymethyl)-2,3,4-trihydroxycyclohexyl]oxy}-3,4-dihydroxyoctadecane-2-yl)-3-tetracosylurea (Compound (I)-21)

Chemical formula

[0205] In the same manner as in Example 7, 88.1 mg (91%) of the title compound was obtained from 146.5 mg of the starting material (the compound obtained in Example 53). 11H NMR (500 MHz, pyridine-d5) δ ppm 6.83 (broad t, J = 5.5 Hz, 1 H), 6.70 - 6.81 (m, 1 H), 6.67 (broad d, J = 8.8 Hz, 1 H), 6.16 (broad s, 2 H), 5.97 (broad s, 1 H), 5.82 (broad s, 1 H), 5.03 (broad s, 1 H), 4.42 (broad s, 1 H), 4.35 (broad d, J = 9.0 Hz, 2 H), 4.26 (broad s, 1 H), 4.19 (broad d, J = 6.4 Hz, 2 H), 4.12 (broad s, 1 H), 4.07 (broad d, J = 9.8 Hz, 1 H), 3.74 (t, J = 8.6 Hz, 1 H), 3.36 - 3.52 (m, 5 H), 2.28 - 2.39 (m, 1 H), 2.24 (broad s, 1 H), 1.81 - 1.91 (m, 3 H), 1.73 - 1.81 (m, 1 H), 1.60 - 1.68 (m, 1 H), 1.55 (quin, J = 7.3 Hz, 2 H), 1.19 - 1.40 (m, 64 H), 1.12 (t, J = 7.0 Hz, 3 H), 0.84 (t, J = 7.5 Hz, 6 H) HRMS (ESI) calcd for C 52 H 105 N2O8[M + H] + 885.7871, found 885.7863.

[0206] (Example 58) 1 - ((2S,3S,4R)-3,4 - Dihydroxy - 1 - {[(1S,2R,3S,4S,5R)-2,3,4 - Trihydroxy - 5 - (propoxymethyl)cyclohexyl]oxy}octadecane - 2 - yl)-3 - tetracosylurea (Compound (I)-22)

Chemical Structure

[0207] In the same manner as in Example 7, 90.0 mg (90%) of the title compound was obtained from 151 mg of the raw material (the compound obtained in Example 54). 1 H NMR (500 MHz, pyridine-d5) δ ppm 6.84 (br t, J=5.6 Hz, 2 H), 6.69 (d, J=9.0 Hz, 1 H), 6.18 (br s, 2 H), 6.00 (br s, 1 H), 5.84 (br s, 1 H), 5.03 (br s, 1 H), 4.45 (br s, 1 H), 4.34 - 4.43 (m, 2 H), 4.25 - 4.32 (m, 1 H), 4.21 (br d, J=6.4 Hz, 2 H), 4.15 (br s, 1 H), 4.09 (br d, J=9.5 Hz, 1 H), 3.77 (t, J=8.7 Hz, 1 H), 3.40 - 3.54 (m, 3 H), 3.30 - 3.38 (m, 2 H), 2.33 - 2.42 (m, 1 H), 2.21 - 2.31 (m, 1 H), 1.76 - 1.95 (m, 4 H), 1.63 - 1.73 (m, 1 H), 1.48 - 1.63 (m, 4 H), 1.16 - 1.39 (m, 64 H), 0.83 - 0.93 (m, 9 H) HRMS (ESI) calcd for C 53 H 106 N2O8Na [M + Na] + 921.7847, found 921.7845.

[0208] (Example 59) Synthesis of various pseudo-glycolipid derivatives According to the method of the above examples, the following compounds were synthesized.

[0209]

Table 1

[0210] (Example 60) Analysis of in vivo cytokine production ability Compound (I)-1 of the present invention, KRN7000 (α-GalCer), and RCAI-56 were each dissolved in DMSO, and then diluted 5-fold with a phosphate buffer containing 0.5% Tween-80 to prepare aqueous solutions with a final concentration of 200 μg / mL, respectively. After diluting each aqueous solution with physiological saline (manufactured by Otsuka Pharmaceutical Factory, Inc.), 10 ng / 100 μL was administered to the tail vein of 7-week-old female C57BL / 6J mice (Charles River). On the first day after administration, blood was collected from the orbital cavity, and the cytokine IFN-γ concentration (pg / ml) in the plasma component was measured by a multiplex cytokine assay method (Luminex TM ). The results are shown in Table 2.

[0211]

Table 2

[0212] From the results shown in Table 2, it can be understood that compound (I)-1 of the present invention has a significantly higher IFN-γ production ability compared to KRN7000 (α-GalCer) and RCAI-56.

[0213] (Example 61) Evaluation of in vitro cytokine production ability Each compound represented by formula (I) of the present invention shown below was dissolved in DMSO, and then diluted 5-fold with a phosphate buffer containing 0.5% Tween-80 to prepare an aqueous solution with a final concentration of 200 μg / mL, which was used as each sample.

[0214] As a comparative example, samples were prepared in the same manner for RCAI-56 having the structure shown below.

[0215] The spleens of C57BL / 6J female mice (7 weeks old) were excised, and the whole cells were placed in 1 well of a 96-well microtiter plate at 2x10 5Cells and 100 μL of cell culture medium (RPMI containing 10% fetal bovine serum) were added. Each sample prepared as described above was added to each well so that the final concentration was 100 ng / mL. After culturing for 3 days in a 37 °C incubator filled with 5% CO2, the cytokine (IFN-γ) concentration in the culture supernatant was measured by Luminex TM and the results are shown in Table 3.

[0216]

Table 3

[0217] From the results shown in Table 3, it can be understood that all of the compounds according to the present invention exhibit an INF-γ production ability equivalent to that of RCAI-56.

[0218] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

Claims

1. A compound represented by the following formula (I): 【Chemical 1】 (wherein X represents -CH ２ - or -NH-; R1 represents an unsubstituted alkyl group having 5 to 30 carbon atoms, or a phenylalkyl group having 5 to 30 carbon atoms which may be substituted with a halogen atom or is unsubstituted and contains a phenyl group; R3 represents an unsubstituted alkyl group having 5 to 30 carbon atoms; R ２ represents an unsubstituted alkyl group having 2 to 6 carbon atoms.) or a salt thereof.

2. A compound represented by the following formula (II): 【Chemical Formula 2】 (In the formula, BN represents a substituted or unsubstituted benzyl group, and X, R １ , R ２ and R ３ are as defined in claim 1.) or a salt thereof.

3. A compound represented by the following formula (III): [Chemical Formula 3] (wherein BN has the same meaning as in claim 2, and X, R １ and R ３ have the same meaning as in claim 1.) or a salt thereof.

4. A compound represented by the following formula (IV): 【Chemical Formula 4】 (wherein, BN is synonymous with Claim 2, and X, R １ and R ３ are synonymous with Claim 1.) or a salt thereof.

5. A compound represented by the following formula (V): 【Chemical Formula 5】 (wherein BN is synonymous with claim 2, and X, R １ and R ３ are synonymous with claim 1.) or a salt thereof.

6. The compound or a salt thereof according to any one of Claims 1 to 5, wherein R1 represents an unsubstituted alkyl group having 5 to 30 carbon atoms, or a phenylalkyl group having 5 to 30 carbon atoms containing a 4-halophenyl group or an unsubstituted phenyl group.

7. The compound or a salt thereof according to any one of Claims 1 to 5, wherein R1 represents an unsubstituted alkyl group having 5 to 30 carbon atoms, or a phenylalkyl group having 5 to 30 carbon atoms containing a 4-fluorophenyl group or an unsubstituted phenyl group.

8. A compound represented by the following formula (VI): 【Chemical Formula 6】 (wherein, BN is synonymous with claim 2, and R ３ is synonymous with claim 1.) or a salt thereof.

9. A method for producing the compound or a salt thereof according to Claim 1, comprising debenzylating the compound or a salt thereof according to Claim 2 by catalytic reduction.

10. A step of treating a compound represented by the following formula (VII): with an oxidizing agent to selectively oxidize -NH-BN in the formula (VII) to obtain an imine form, and [Chemical Formula 7] (wherein BN has the same meaning as in claim 2, and R ３ has the same meaning as in claim 1.) a step of allowing at least one selected from the group consisting of hydroxylamine and its derivatives, and hydrazine and its derivatives to act on the imine form while and / or after proceeding with the above step, wherein the derivative of hydroxylamine is represented by RaO-NH2, and Ra is a C1-C5 alkyl group which may be substituted or unsubstituted by at least one selected from the group consisting of a carboxyl group and its salt, a hydroxyl group, and an amino group, or a C6-C10 aromatic hydrocarbon group which may be substituted or unsubstituted by at least one selected from the group consisting of a carboxyl group and its salt, a hydroxyl group, and an amino group.

11. The method for producing a compound or a salt thereof according to Claim 10, wherein the oxidizing agent is selected from the group consisting of m-chloroperbenzoic acid, peracetic acid, and hydrogen peroxide. A derivative of hydrazine is represented by RbNH-NH2, where Rb is a C1-C5 alkyl group which may or may not be substituted by at least one selected from the group consisting of a carboxyl group and its salts, a hydroxyl group, and an amino group, or a C6-C10 aromatic hydrocarbon group which may or may not be substituted by at least one selected from the group consisting of a carboxyl group and its salts, a hydroxyl group, and an amino group. The following formula (VI) [Chemical Formula 8] (wherein, BN and R ３ are as defined in the above formula (VII).) A method for producing a compound represented thereby or a salt thereof.

11. The oxidizing agent is the following formula: RO ２ CN=NCO ２ R (In the formula, R represents an alkyl group having 1 to 5 carbon atoms.) The production method according to claim 10, wherein the oxidizing agent is a dialkyl azodicarboxylate represented by the formula, and at least one selected from the group consisting of the hydroxylamine and its derivatives, and hydrazine and its derivatives is aminooxyacetic acid or a salt thereof.

12. An IFN-γ production inducer containing at least one of the compound according to claim 1 or a salt thereof as an active ingredient.

13. An anticancer agent containing at least one of the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

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