JP2001172250A - Glucopyranose derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a compound represented by general formula (I) useful as a prophylactic and/or a therapeutic agents for HIV infectious diseases, asthma, atopic dermatitis, rhinitis, conjunctivitis, allergic bronchopulmonary aspergillosis, allergic eosinophilic gastroenteropathy, nephritis, nephropathy, hepatitis, arthritis, rheumatoid arthritis, rejection of transplanted organs and shock during bacterial infection. SOLUTION: This glucopyranose derivative is represented by the general formula (I) [wherein A is O or CH2; R0 and R1 are each H, OH, a (phenyl- substituted) alkoxy, an alkylthio, a halogen, t-butyldimethylsilyloxy, t- butyldiphenylsilyloxy or OSO3H; R2 and R3 are each a group represented by formula (II), formula (III) or formula (IV); E is OCO or E-R3 is H, OH, a (phenyl- substituted) alkoxy, t-butyldimethylsilyloxy or t-butyldiphenylsilyloxy; and R4 is H, a halogen or CH2-R10] or its salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to (1) a compound represented by the general formula (I):

Embedded image (Wherein all symbols have the same meanings as described below), a glucopyranose derivative or a non-toxic salt thereof, (2) a method for producing the same, and (3) a compound containing the compound as an active ingredient. About drugs.

[0002]

BACKGROUND OF THE INVENTION Acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus (hereinafter abbreviated as HIV) infection has been the most coveted treatment in recent years. Is one of the diseases.
Once HIV infects CD4 + cells, the primary target cell, HIV repeats its growth in the patient's body and eventually catastrophically destroys the T cells responsible for immune function. During this process, the immune function gradually decreases, and various immunodeficiency states such as fever, diarrhea, swelling of lymph nodes, etc. are exhibited, and various opportunistic infections, such as carinii pneumonia, are likely to occur in due course.
It is well known that such a condition is referred to as the onset of AIDS and induces a malignant tumor such as carbodisarcoma and becomes serious. Currently, various prevention and treatment methods for AIDS (for example, (1) suppression of HIV proliferation by administration of a reverse transcriptase inhibitor or a protease inhibitor, (2) prevention of opportunistic infection by administration of a drug having an immunostimulating effect, Relaxation, etc.)
Have been tried.

[0003] HIV mainly infects helper T cells, which play a central role in the immune system. It has been known since 1985 to use the protein molecule CD4 expressed on the membrane of T cells at that time (Cell, 52 , 631 (1985)). The CD4 molecule is composed of 433 amino acid residues. In addition to mature helper T cells, macrophages, some B cells, vascular endothelial cells, Langerhans cells in skin tissue, dendritic cells in lymphoid tissue, glial cells in central nervous system And the like. But C
As it has become clear that HIV infection cannot be established only with the D4 molecule, it has been suggested that there may be factors other than the CD4 molecule involved in HIV infection of cells. In 1996, in addition to the CD4 molecule, a cell membrane protein called Fusin was identified as a factor required for HIV to infect cells (Science, 272 , 872 (199
6)). This fusin molecule is a stromal cell-derived factor-
1 (abbreviated as SDF-1) (i.e., CXCR4), and furthermore, in vitro, SDF-1 has T cell tropism (X4) HIV It has been shown in a timely manner to specifically suppress infection (Nature, 382 , 829 (19
96), Nature, 382 , 833 (1996)). That is, SDF-
It is presumed that HIV-1 was first bound to CXCR4, thereby losing a foothold for HIV to infect cells and inhibiting HIV infection. At the same time, another chemokine receptor, RANTES, MIP-1α, MIP-
CCR5, a receptor for 1β, has also been discovered to be utilized during infection of macrophage tropic (R5) HIV (Science, 272 , 1955 (1996)).

[0004] Therefore, any substance that can compete with HIV for CXCR4 or CCR5 or that binds to HIV virus and renders the virus incapable of binding to CXCR4 or CCR5 could be an HIV infection inhibitor. In some cases, low-molecular compounds initially discovered as inhibitors of HIV infection have been shown to be actually CXCR4 antagonists (Nature Medicine,
4 , 72 (1998)).

[0005] In addition, chemokines are activated through their receptors.
Prior to being shown to be deeply involved in IV infection, chemokines have been known to be basic and strongly heparin-binding proteins having endogenous leukocyte chemotaxis and activation. Chemokine research has been spurred since the time it was shown to be related to HIV, and much knowledge has been accumulated. Currently, chemokines not only control infiltration of specific leukocytes during inflammatory and immune reactions, but also It has been considered to be involved in homing of lymphocytes, migration of blood cell precursor cells and somatic cells under physiological conditions.

[0006] Differentiation, proliferation and cell death of blood cells are controlled by various cytokines. Inflammation is observed locally in the body, and lymphocyte differentiation, maturation, and the like are performed in a specific site. In other words, a series of inflammatory / immune reactions occur when various required cells accumulate at a specific site by migration. Therefore, in addition to cell differentiation, proliferation, and death, cell migration is also an essential phenomenon for the immune system.

[0007] The migration of blood cells in a living body begins with the transition of hematopoiesis that begins in the AGM region during development to permanent hematopoiesis in the bone marrow via the fetal liver. In addition, fetal liver
Progenitor cells of T cells and thymic dendritic cells migrate from the bone marrow to the thymus and differentiate in the thymus environment. T cells that have undergone clone selection migrate to secondary lymphoid tissues and participate in the immune response in the periphery. The Langerhans cells of the activated and differentiated skin that capture the antigen migrate to the T cell area of the local lymph node,
Activate naive T cells as dendritic cells. Memory T cells home again to lymph nodes via lymphatic vessels and blood vessels. In addition, B cells, intestinal epithelial T cells, γδ T cells, NKT cells, and dendritic cells migrate and differentiate from the bone marrow without passing through the thymus, and participate in the immune response.

[0008] Chemokines are deeply involved in the migration of such various cells. For example, MIP-3β, SLC and its receptor, CCR7, are involved in the migration and homing of both dendritic cells and naive T cells, which have captured antigens, to local lymphoid tissues in order to efficiently meet both cells. It plays an important role. T cells and dendritic cells required to control an antigen-specific immune response are hardly observed in the secondary lymph nodes of PLT mice deficient in SLC expression (J. Exp. Med., 189 (3) , 451 (1999)). M
DC, TARC and its receptor, CCR4, are Th2
Th to the local area where immune and inflammatory reactions involving cells are induced
It plays an important role in the movement of two cells. In a rat fulminant hepatitis model (P. acnes + LPS), anti-TARC antibody increases blood ALT levels and hepatic TNFα and FasL.
Increased the expression of, and further improved the rat mortality (J. Clin. Invest., 102 , 1933 (1998)). In a mouse OVA-induced airway hyperreactivity model, the anti-MDC antibody suppressed the number of eosinophils accumulated in the lung interstitium and suppressed airway hypersensitivity (J. Immunology, 163 , 403 (1999)).

[0009] As described above, chemokines and chemokine receptors are inflammatory by a mechanism in which chemokine receptors are expressed at specific times of various specific cells, and their effector cells accumulate at the locations where chemokines are produced. -It is known that it is greatly involved in the control of immune response.

[0010]

2. Description of the Related Art 1) Japanese Patent Publication No. 4-74359 discloses a general formula (X).

Embedded image The glucopyranose derivative represented by the following formula or a non-toxic salt thereof is represented by the following general formula (Y):

Embedded image The glucopyranose derivative or a non-toxic salt thereof represented by the following formula 3) is disclosed in JP-A-63-297357.

Embedded image Are cyclolipid derivatives or non-toxic salts thereof, each of which has a lipid A-like activity, and has an immunostimulating effect (macrophage activating effect, B cell blastogenesis effect, non-specific antibody producing effect, cell-mediated immunostimulating effect). Etc.) and antitumor effects (interferon-inducing activity, interleukin-producing activity, TNFα production-inducing activity, etc.).

4) JP-A-6-41175 discloses a compound represented by the general formula (X-
1)

Embedded image 2-deoxy-2- [3S- (9-phenylnonanoyloxy) tetradecanoyl] amino-3-O represented by
-(9-phenylnonanoyl) -4-O-sulfo-D-
Various non-toxic salts of glucopyranose have been disclosed.

[0012]

The present inventors have focused on the fact that HIV binds to and invades CD4-positive cells via a chemokine receptor, which is a membrane protein on CD4-positive cells, and inhibits HIV activity by inhibiting it. Are expected to inhibit the action of various chemokines to control the movement of effector cells, and to suppress the enhanced inflammatory and immune reactions. Have been found to achieve the object of the present invention, and have completed the present invention.
In addition, they have found that the glucopyranose derivative represented by the general formula (I) or a non-toxic salt thereof does not show a TNFα production inducing action.

As a result, the compound of the present invention has an effect of inhibiting the binding between CXCR4 (SDF-1 receptor) and SDF-1 on CD4-positive cells,
It has an action of inhibiting the binding of CR5 (RANTES, MIP-1α, MIP-1β receptor) to RANTES, and an action of binding to the HIV virus gp120 protein-related portion and inhibiting the binding of gp120 to target cells. Is considered to be useful for the prevention and / or treatment of acquired immunodeficiency syndrome [HIV infection (AIDS)].

Further, the compounds of the present invention can be used for various chemokine receptors and their ligands (particularly CXCR4 and SDF-1α or SDF) on blood cells involved in inflammation and immunity, for example, on T cells, dendritic cells or macrophages.
-1β, CCR4 and MDC or TARC, CCR7 and MIP-3β or SLC or CCR5 and RANT
It has an effect of inhibiting binding to ES, MIP-1α or MIP-1β), and is therefore considered to be useful for treating inflammatory and immune diseases.

Accordingly, the compound of the present invention is useful for obtaining acquired immunodeficiency syndrome [HIV infection (AIDS)], asthma, atopic dermatitis (including urticaria), rhinitis, conjunctivitis, allergic bronchopulmonary aspergillosis, allergic It is considered to be useful as a prophylactic and / or therapeutic agent for eosinophilic gastroenteropathy, nephritis, nephropathy, hepatitis, arthritis, rheumatoid arthritis, transplant organ rejection, and shock during bacterial infection.

[0016]

DISCLOSURE OF THE INVENTION The present invention provides: 1) a compound represented by the general formula (I):

Embedded image [In the formula, A represents an oxygen atom or a methylene group, R ⁰
And R ¹ are each independently a hydrogen atom, a hydroxyl group,
A C1-8 alkoxy group, a C1-8 alkylthio group, a halogen atom, a C1-4 alkoxy group substituted with a phenyl group, a t-butyldimethylsilyloxy group, a t-butyldiphenylsilyloxy group, or a sulfate group (—OSO ₃ H
R ² and R ³ are each independently

Equation (1)

Embedded image (In the formula, G represents a single bond, a C2-30 oxycarbonylalkylene group, a C3-30 oxycarbonylalkenylene group or a C3-30 oxycarbonylalkynylene group, and R ⁵ represents a hydrogen atom or a formula

Embedded image (Wherein, T ring represents a C5~15 carbon ring, R ⁷ is a hydrogen atom, C1-8 alkyl group, an C1-8 alkoxy group or a halogen atom, m represents. 1, 2 or 3) J represents a C1-30 alkylene group, a C2-30 alkenylene group or a C2-30 alkynylene group (however, a C1-30 alkylene group, a C2
—CH ₂ — in the 30 alkenylene group or the C 2-30 alkynylene group may be replaced by —O—, —S— or —NR ⁹ —. R ⁹ represents a hydrogen atom or a C1-8 alkyl group. And R ⁶ is a hydrogen atom or a formula

Embedded image (Wherein, W ring represents a C5~15 carbocycle, R ⁸ represents a hydrogen atom, C1-8 alkyl group, an C1-8 alkoxy group or a halogen atom, n represents. 1, 2 or 3) Represents the group shown. ),

Equation (2)

Embedded image (Wherein, Y represents a single bond or a C1-8 alkylene group, p and q each independently represent an integer of 6-12), or

Equation (3)

Embedded image (In the formula, J and J ¹ each independently represent the same meaning as J, and R ⁶ and R ⁶¹ each independently represent the same meaning as R ^6. ) E represents -OCO- or -ER ³
Represents a hydrogen atom, a hydroxyl group, a C1-8 alkoxy group, a C1-4 alkoxy group substituted with a phenyl group, a t-butyldimethylsilyloxy group or a t-butyldiphenylsilyloxy group, and R ⁴ represents a hydrogen atom, a halogen atom represents an atom or -CH ₂ -R ¹⁰ group, R ¹⁰ is a hydrogen atom, a hydroxyl group, C1-8 alkoxy group, a phenyl group and a substituted C
1-4 alkoxy group, t-butyldimethylsilyloxy group, t-butyldiphenylsilyloxy group, sulfate group (-
OSO ₃ H group), - OCOR ¹² group (wherein, R ¹² is the R ²
Or, has the same meaning as R ³ . Or R ¹⁰ and R ^{1 taken} together represent -O-,

Embedded image Represents a single bond or a double bond.

Wherein (1) when G represents a C2-30 oxycarbonylalkylene group, a C3-30 oxycarbonylalkenylene group or a C3-30 oxycarbonylalkynylene group, R ⁵ is bonded to the alkyl group in G; (2) at least one of R ⁰ , R ¹ , and R ¹⁰ represents a sulfate group (—OSO ₃ H group);
(3) R ⁰ , R ¹ , —OCOR ² , and —ER ³ groups are not bonded to the same carbon atom. Or a non-toxic salt thereof, 2) a method for producing them, and 3) a drug containing these compounds as an active ingredient.

In the general formula (I), R ⁰ , R ¹ , R ⁷ , R ⁸ , R
The C1~8 alkoxy group represented by ¹⁰ and -E-R ^3, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, and octyloxy groups, and isomers thereof.

In the general formula (I), examples of the C1-8 alkylthio group represented by R ⁰ and R ¹ include methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, and isomers thereof. .

In the general formula (I), examples of the halogen atom represented by R ⁰ , R ¹ , R ⁴ , R ⁷ and R ⁸ include chlorine, bromine, fluorine and iodine atoms.

In the general formula (I), R ⁰ , R ¹ , R ¹⁰ and-
C1~ the E-R ³ Therefore phenyl group represented is substituted
4-Alkoxy groups include methoxy, ethoxy, propoxy, butoxy groups and isomers thereof substituted by one phenyl group.

In the general formula (I), the C1-8 alkyl group represented by R ⁷ , R ⁸ and R ⁹ is methyl,
Ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl groups and isomers thereof.

In the general formula (I), C represented by G
The 2-30 oxycarbonylalkylene group is represented by the formula

Embedded image And R ⁵ is bonded to the alkylene group side chain. Here, as the C1-29 alkylene group, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, undecamethylene, dodecamethylene, tridecamethylene, tetradecamethylene, Pentadecamethylene, hexadecamethylene, heptadecamethylene, octadecamethylene, nonadecamethylene, icosamethylene, henicosamethylene, docosamethylene, tricosamethylene, tetracosamethylene, pentacosamethylene, hexacosamethylene, heptacosamethylene, octacamethylene , A nonacosamethylene group and isomers thereof.

In the general formula (I), C represented by G
The 3-30 oxycarbonylalkenylene group is of the formula

Embedded image And R ⁵ is bonded to the alkenylene group side chain. Here, the C2-29 alkenylene group means a C2-29 alkylene group which may have 1 to 14 double bonds. For example, vinyl, propenyl, butenyl,
Pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, icosenyl, henicosenyl, docosenyl, hexacenyl, octacenyl, hexacenyl, octanoyl
Butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl, undecadienyl, dodecadienyl, tridecadienyl, tetradecadienyl, pentadecadienyl, hexadecadienyl, heptadecadienyl, hexadecadienyl, hexadecadienyl Trienyl, heptatrienyl, octatrienyl, nonatrienyl, decatrienyl, undecatrienyl, dodecatrienyl, tridecatrienyl, tetradecatrienyl, pentadecatrienyl, hexadecatrienyl, heptadecatrienyl, octadecatrienyl, Examples include nonadecatrienyl, icosatrienyl and isomers thereof.

In the general formula (I), C represented by G
The 3-30 oxycarbonylalkynylene group is of the formula

Embedded image And R ⁵ is bonded to the alkynylene group side chain. Here, the C2-29 alkynylene group means a C2-29 alkylene group which may have 1 to 14 triple bonds. For example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, noninyl, decynyl, undecynyl, dodecynyl,
Tridecynyl, tetradecynyl, pentadecynyl, hexadecynyl, heptadecynyl, octadecynyl, nonadecinyl, icosinyl, henicosinyl, docosynyl, tricosinyl, tetracosynyl, pentacosynyl, hexacosynyl, heptacosynyl, octacosynyl, nonacosynyl, butadinyl, pentazinyl, pentazinyl
Heptadiynyl, octadiynyl, nonadiynyl, decadinyl, undecadiinyl, dodecadiinyl, tridecadiinyl, tetradecadiinyl, pentadecadiinyl, hexadecadiinyl, heptadecadiinyl, octadecadinyl, nonadecadinyl, icosazinyl, hexatriainyl, hexatriainyl Triinyl, nonatriinyl, decatriinyl, undecatriinyl, dodecatriinyl, tridecatriinyl, tetradecatriinyl, pentadecatriinyl, hexadecatriinyl, heptadecatriinyl, octadecatriinyl, nonadecatriinyl, icosatriinyl Groups and isomer groups thereof.

[0029] In the formula (I), a C1~30 alkylene group represented by J and J ^1, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl , Tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosanil, henicosanil, docosanil, tricosanil,
Tetracosanyl, pentacosanyl, hexacosanyl, heptacosanyl, octacosanyl, nonacosanyl, triacontyl and isomers thereof.

[0030] In the formula (I), is C2~30 alkenylene group represented by J and J ^1, the double bond 1
It means a C2-30 alkylene group which may have up to 15 groups. For example, vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl,
Decenyl, undecenyl, dodecenyl, tridecenyl,
Tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, icosenyl, henicocenyl, docosenyl, tricosenyl, tetracosenyl, pentacosenyl, hexacosenyl, heptacosenyl, octacocenyl, nonacoenyl, hexadienyl, pentadienyl, pentadienyl, pentadienyl, pentadienyl, pentadienyl, pentadienyl, pentadienyl, pentadienyl, pentadienyl, pentadienyl
Decadienyl, undecadienyl, dodecadienyl, tridecadienyl, tetradecadienyl, pentadecadienyl, hexadecadienyl, heptadecadienyl, octadecadienyl, nonadecadienyl, icosadienyl,
Hexatrienyl, heptatrienyl, octatrienyl, nonatrienyl, decatrienyl, undecatrienyl, dodecatrienyl, tridecatrienyl, tetradecatrienyl, pentadecatrienyl, hexadecatrienyl, heptadecatrienyl, octadecatrienyl , Nonadecatrienyl, icosatrienyl and isomers thereof.

In the general formula (I), the C2-30 alkynylene group represented by J and J ¹ is a group having one triple bond.
It means a C2-30 alkylene group which may have up to 15 groups. For example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, noninyl, decynyl, undecynyl, dodecynyl, tridecynyl, tetradecynyl, pentadecynyl, hexadecynyl, heptadecynyl, octadecynyl, nonadecynyl,
Icosynyl, henicosinyl, docosynyl, tricosynyl, tetracosynyl, pentacosynyl, hexacosynyl, heptacosynyl, octacosynyl, nonacosynyl,
Triacontinyl, butadiynyl, pentadiynyl, hexadiynyl, heptadiynyl, octadiynyl, nonadiynyl, decadinyl, undecadinyl, dodecadinyl, tridecadinyl, tetradecadinyl, pentadecadinyl, hexadecadinyl, heptadecadinyl, octadecadinyl, octadecadinyl , Icosadiynyl, hexatriynyl, heptatriynyl, octatriynyl, nonatriynyl, decatriinyl, undecatriynyl, dodecatriynyl, tridecatriinyl, tetradecatriinyl, pentadecatriinyl, hexadecatriinyl, heptacatriinyl, octatrilinyl, octa Decatriinyl, nonadecatriinyl, icosatriynyl groups, and isomers thereof.

In the general formula (I), C represented by Y
1 to 8 alkylene groups include methyl, ethyl, propyl,
Butyl, pentyl, hexyl, heptyl, octyl and isomers thereof.

[0033] In the general formula (I), T ring in R ^5, and C5~15 carbocyclic ring represented by W ring in R ⁶ and R ⁶¹ are, C5～1
5 means a monocyclic, bicyclic or tricyclic aromatic carbocyclic ring, a partially saturated carbocyclic ring and a fully saturated carbocyclic ring. Examples of the C5 to C15 monocyclic, bicyclic and tricyclic aromatic carbocycles include, for example, benzene, naphthalene, indene,
Fluorene and anthracene ring. C5 above
Examples of the 15 monocyclic, bicyclic or tricyclic aromatic carbocyclic rings in which a part of the aromatic carbocyclic rings are saturated include cyclopentene, cyclohexene, cyclohexadiene, cycloheptene, cycloheptadiene, 1,2,3,4-tetrahydronaphthalene , Indane, 1,2,3,4-tetrahydrofluorene ring and the like. As the carbocycle in which all of the C5 to C15 monocyclic, bicyclic and tricyclic aromatic carbocycles are saturated,
C5-7 cycloalkyl rings such as cyclopentyl, cyclohexyl and cycloheptyl rings, decahydronaphthalene, dodecahydrofluorene rings.

In the present invention, all isomers are included unless otherwise indicated. For example, the alkyl group, the alkoxy group and the alkylene group include straight-chain and branched ones. Further, isomers (E, Z, cis, trans) in double bonds, rings and condensed rings, isomers due to the presence of asymmetric carbon (R, S, α, β, enantiomers, diastereomers) , An optically active substance having optical activity (D, L, d, l-form), polar forms (high-polarity forms, low-polarity forms) by chromatographic separation, equilibrium compounds, mixtures of any ratio thereof, and racemic mixtures All are included in the present invention.

In the present invention, unless otherwise specified.
Symbol as obvious to the person skilled in the art

Embedded image Indicates that it is connected to the other side of the paper (ie, α-configuration),

Embedded image Indicates that it is connected to the near side of the paper (that is, β-configuration),

Embedded image Represents α-, β- or a mixture thereof.

[0036]

[Salt] The compound represented by formula (I) used in the present invention is converted into a corresponding salt by a known method. Non-toxic, water-soluble salts are preferred. Suitable salts include salts of alkali metals (sodium, potassium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts, and pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine) , Dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, lysine, arginine, N-
Methyl-D-glucamine, tris (hydroxymethyl)
Methylamine and the like). The compound represented by the general formula (I) used in the present invention or a salt thereof is
It can also be converted to a hydrate by a known method.

In the general formula (I), R ⁰ and R ¹ are preferably a hydroxyl group, a C1-8 alkoxy group or a C1-8 alkylthio group, a C1-4 alkoxy group substituted with a phenyl group, or a sulfate group (—OSO ₃ H ), more preferably hydroxyl, C1 -4 alkoxy or C1 -4 alkylthio group, C1 -4 alkoxy group in which the phenyl group is substituted, -OSO ₃ H group, i.e. a hydroxyl group, methoxy, ethoxy, propoxy, butoxy, methylthio , Ethylthio, propylthio, butylthio, benzyloxy, -O
SO ₃ H group.

In the general formula (I), R ² or R ³ is
Equation (1)

Embedded image Are preferred.

As G in the R ² or R ³ group,
A single bond, a C5-15 oxycarbonylalkylene group, more preferably a single bond, a C12-18 oxycarbonylalkylene group, i.e., a single bond, oxycarbonyldodecamethylene, oxycarbonyltridecamethylene, oxycarbonyltetradecamethylene, Oxycarbonylpentadecamethylene, oxycarbonylhexadecamethylene, oxycarbonylheptadecamethylene or oxycarbonyloctadecamethylene group. R ²
Alternatively, a hydrogen atom is preferable as R ⁵ in the R ³ group.

J and J ¹ in the R ² or R ³ groups are preferably C5-18 alkylene, C7-20 alkenylene, C7-20 alkynylene, more preferably C10-16 alkylene, C12 -18 alkenylene, C12-18 alkynylene, i.e., decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, dodecadienyl, tetradecadienyl, tetradecenyl Decadienyl, hexadecadienyl, heptadecadienyl, octadecadienyl, dodecatrienyl, tridecatrienyl, tetradecatrienyl, pentadecatrienyl, hexadecato Enyl, hepta tetradecatrienyl,
Octadecatrienyl, dodecinyl, tridecinyl, tetradecynyl, pentadecynyl, hexadecynyl, heptadecynyl, octadecynyl, dodecadinyl, tridecadinyl, tetradecadinyl, pentadecadinyl, hexadecadinyl, heptadecadinyl, octadecadinyl, dodecadelinyl Tridecatriinyl, tetradecatriinyl, pentadecatriinyl, hexadecatriinyl, heptadecatriinyl or octadecatriinyl. As R ⁶ and R ⁶¹ in the R ² or R ³ group, a hydrogen atom is preferable.

In the general formula (I), E is preferably-
OCO- group. In the general formula (I), the case where A represents an oxygen atom is represented by the general formula (IA)

Embedded image (Wherein all symbols have the same meanings as described above). In this case, R ⁴ is preferably —CH ₂ —R ¹⁰ , and R ¹⁰ is preferably a hydroxyl group or a C1-8 alkoxy group,
A sulfuric acid group (—OSO ₃ H), more preferably —O
H, methoxy, ethoxy, propoxy, butoxy, -O
SO ₃ H group.

On the other hand, when A represents a methylene group, the compound represented by the general formula (IB)

Embedded image (Wherein all symbols have the same meanings as described above). In this case, R ⁴ is preferably a hydrogen atom.

Among the compounds of the present invention represented by the general formula (I), preferred compounds are those represented by the general formula (Ia)

Embedded image (Wherein, R ² and R ³ represent the same meaning as described above),

Formula (Ib)

Embedded image (Wherein, R ² and R ³ represent the same meaning as described above),

Formula (Ic)

Embedded image (Wherein, R ² and R ³ represent the same meaning as described above),

Formula (Id)

Embedded image (Wherein, R ² and R ³ represent the same meaning as described above),

Formula (Ie)

Embedded image (Wherein, R ² and R ³ represent the same meaning as described above),

Formula (If)

Embedded image (Wherein, R ² and R ³ represent the same meaning as described above),

Formula (Ig)

Embedded image (Wherein, R ² and R ³ represent the same meaning as described above),

Formula (Ih)

Embedded image (Wherein, R ² and R ³ represent the same meaning as described above),

Formula (Ii)

Embedded image (Wherein, R ² and R ³ represent the same meaning as described above),

Formula (Ij)

Embedded image (Wherein, R ² and R ³ represent the same meaning as described above),

Formula (Ik)

Embedded image (Wherein, R ² and R ³ represent the same meaning as described above),

Formula (Im)

Embedded image (Wherein, R ² and R ³ represent the same meaning as described above),

Formula (In)

Embedded image (Wherein, R ² and R ³ represent the same meaning as described above),

Formula (Io)

Embedded image (Wherein, R ² and R ³ represent the same meaning as described above),

Formula (Ip)

Embedded image (Wherein, R ² and R ³ represent the same meaning as described above),

Formula (Iq)

Embedded image (Wherein, R ² and R ³ represent the same meaning as described above),

Formula (Ir)

Embedded image (Wherein, R ² and R ³ represent the same meaning as described above),

Formula (Is)

Embedded image (Wherein, R ² and R ³ represent the same meaning as described above),

Formula (It)

Embedded image (Wherein, R ² and R ³ represent the same meaning as described above),

Formula (Iu)

Embedded image (Wherein, R ² and R ³ represent the same meaning as described above),

Formula (Iv)

Embedded image (Wherein, R ² and R ³ represent the same meaning as described above),

Formula (Iw)

Embedded image (Wherein, R ² and R ³ represent the same meaning as described above),

Formula (Ix)

Embedded image (Wherein, R ² and R ³ represent the same meaning as described above),

Formula (I-y)

Embedded image (Wherein, R ² and R ³ represent the same meaning as described above),

Formula (Iz)

Embedded image (Wherein R ² and R ¹² represent the same meaning as described above),

Formula (I-aa)

Embedded image (Wherein R ² and R ¹² represent the same meaning as described above),

Formula (I-ab)

Embedded image (Wherein R ² and R ¹² represent the same meaning as described above),

Formula (I-ac)

Embedded image (Wherein R ² and R ¹² represent the same meaning as described above),

Formula (I-ad)

Embedded image (Wherein, R ² and R ³ represent the same meaning as described above),

Formula (I-ae)

Embedded image (Wherein, R ² and R ³ represent the same meaning as described above),

Formula (I-af)

Embedded image (Wherein, R ² and R ³ represent the same meaning as described above),

Formula (I-ag)

Embedded image (Wherein, R ² and R ³ represent the same meaning as described above) or

Formula (I-ah)

Embedded image (Wherein, R ² and R ³ have the same meanings as described above), and non-toxic salts thereof.

Specific compounds represented by the general formula (I) used in the present invention include the compounds prepared in Examples described later, the compounds shown in the following Tables 1 to 33, and non-toxic salts thereof. Can be

[0077]

[Table 1]

[0078]

[Table 2]

[0079]

[Table 3]

[0080]

[Table 4]

[0081]

[Table 5]

[0082]

[Table 6]

[0083]

[Table 7]

[0084]

[Table 8]

[0085]

[Table 9]

[0086]

[Table 10]

[0087]

[Table 11]

[0088]

[Table 12]

[0089]

[Table 13]

[0090]

[Table 14]

[0091]

[Table 15]

[0092]

[Table 16]

[0093]

[Table 17]

[0094]

[Table 18]

[0095]

[Table 19]

[0096]

[Table 20]

[0097]

[Table 21]

[0098]

[Table 22]

[0099]

[Table 23]

[0100]

[Table 24]

[0101]

[Table 25]

[0102]

[Table 26]

[0103]

[Table 27]

[0104]

[Table 28]

[0105]

[Table 29]

[0106]

[Table 30]

[0107]

[Table 31]

[0108]

[Table 32]

[0109]

[Table 33]

[Production Method of the Compound of the Present Invention] The compound of the present invention represented by the general formula (I) and a non-toxic salt thereof can be produced by the following methods or the methods described in Examples.

[1] Among the compounds of the present invention represented by the general formula (I), the compound in which the R ¹⁰ group in R ⁰ , R ¹ , —E—R ³ and R ⁴ does not represent a hydroxyl group, ie, the general formula (I) I-1)

Embedded image (Wherein R ^0-1 , R ^1-1 , E ¹ , R ^3-1 and R ^4-1 represent R ⁰ ,
It has the same meaning as R ¹ , E, R ³ and R ⁴ . However,
Any of R ^0-1 , R ^1-1 , -E ¹ -R ^3-1 and R ^4-1 does not represent a hydroxyl group-containing group, and R ^0-1 , R ^1-1 ,
At least one of R ^4-1 represents a group containing a sulfate group, and the other symbols have the same meanings as described above. The compound of the present invention represented by the general formula (II)

[0111]

Embedded image ( ^Where R ^0-1-2 , R ^1-1-2 , E ^1-2 , R ^3-1-2 and R
^4-1-2 has the same meaning as R ⁰ , R ¹ , E, R ³ and R ⁴ . However, none of the groups R ^0-1-2 , R ^1-1-2 and R ^4-1-2 represent a group containing a sulfate group, and -E ^1-2 -R
^3-1-2 does not represent a hydroxyl group, and R ^0-1-2 , R ^1-1-2 , R
^4-1-2 , at least one group represents a hydroxyl group,
Other symbols have the same meaning as described above. ) Can be produced by subjecting the compound of the formula (1) to a sulfation reaction.

This sulfation reaction is known (JP-B 4-74).
No. 359, Patent No. 2514070, JP-A-63-297357, JP-A-6-297357
-41175), for example, in an inert solvent (tetrahydrofuran, dichloromethane, ethyl acetate, etc.) or without solvent,
Using an excess amount of sulfur trioxide / pyridine complex in the presence of a tertiary amine (pyridine, triethylamine, etc.),
The reaction is performed at a temperature of 0 to 60 ° C.

[2] Among the compounds of the present invention represented by the general formula (I), compounds wherein at least one of R ¹⁰ groups in R ⁰ , R ¹ , -E R ³ and R ⁴ represents a hydroxyl group That is, the general formula (I-2)

Embedded image (Wherein R ^0-2 , R ^1-2 , E ² , R ^3-2 and R ^4-2 are R ⁰ ,
It has the same meaning as R ¹ , E, R ³ and R ⁴ . However,
At least one of R ^0-2 , R ^1-2 , -E ² -R ^3-2 and R ^4-2 represents a group containing a hydroxyl group;
^0-2, R ^1-2, one of R ^4-2, represents a group with at least one group containing a sulfate group, the other symbols have the same meanings as described above. The compound represented by the general formula (I-1) produced by the above method is represented by R ^0-1 , R
^1-1 , -E ¹ -R ^3-1 and at least one of R ^10-1 groups among R ^4-1 groups is a benzyloxy group, a t-butyldimethylsilyloxy group or a t-butyldiphenylsilyl group. represents an oxy group, and R ^0-1, R ^1-1, one of R ^4-1, compounds representative of the group with at least one group containing a sulfate group, namely the general formula (I-1-a)

[0114]

Embedded image (Wherein R ^0-1-a , R ^1-1-a , E ^1-a , R ^3-1-a and R ^3-1-a
4-1-a has the same meaning as R ⁰ , R ¹ , E, R ³ and R ⁴ . However, at least one of R ^10-1-a groups in R ^0-1-a , R ^1-1-a , -E ^1-a -R ^3-1-a and R ^4-1-a groups The group represents a benzyloxy group, a t-butyldimethylsilyloxy group or a t-butyldiphenylsilyloxy group, and at least one of R ^0-1-a , R ^1-1-a and R ^4-1-a One group represents a group containing a sulfate group, and the other symbols have the same meanings as described above. ) Is subjected to a deprotection reaction.

The deprotection reaction of the benzyloxy group is known and includes, for example, an inert solvent [ether (eg, tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.), alcohol (eg, methanol, ethanol, etc.), and benzene. (Eg, benzene, toluene, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), nitriles (eg, acetonitrile, etc.),
Amide type (for example, dimethylformamide, etc.), water, ethyl acetate, acetic acid, or a mixed solvent of two or more thereof]
In the presence of a hydrogenation catalyst (e.g., palladium-carbon, palladium black, palladium, palladium hydroxide, platinum dioxide, nickel, Raney nickel, etc.), an inorganic acid (e.g., hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid, In the presence or absence of tetrafluoroboric acid or the like or an organic acid (eg, acetic acid, p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid, formic acid, etc.), under a hydrogen atmosphere under normal pressure or pressure, or ammonium formate The reaction is carried out at a temperature of 0 to 200 ° C in the presence. When an acid is used, its salt may be used.

T-butyldimethylsilyloxy or t-butyldimethylsilyloxy
The deprotection reaction of -butyldiphenylsilyloxy group is known, and in a water-miscible organic solvent (such as tetrahydrofuran or acetonitrile), tetrabutylammonium fluoride, an aqueous solution of hydrogen fluoride or an organic acid (acetic acid,
(Trifluoroacetic acid, p-toluenesulfonic acid, etc.) at a temperature of 0 to 40 ° C.

It will be apparent to those skilled in the art that the protecting group for the hydroxyl group may be a benzyloxy group, a t-
Any group other than the butyldimethylsilyl group and the t-butyldiphenylsilyl group may be used as long as it can be easily and selectively eliminated, and is not particularly limited. For example, TW Greene, Protec
tive Groups in Organic Synthesis, Wiley, New York,
The one described in 1991 is used. Also, as can be easily understood by those skilled in the art, the intended compound of the present invention can be easily produced by properly using these deprotection reactions.

[3] Among the compounds represented by the general formula (I), only the R ¹⁰ group out of the R ⁴ groups represents a sulfate group, that is, the compound represented by the general formula (I-3)

Embedded image (Wherein all symbols have the same meanings as described above) are represented by the general formula (III)

[0119]

Embedded image (Wherein all symbols have the same meanings as described above). The compound can also be produced by subjecting the compound to a sulfation reaction.

This sulfation reaction is carried out in the same manner as the above-mentioned sulfation reaction. However, the excess amount of the sulfur trioxide / pyridine complex is performed using one equivalent of the sulfur trioxide / pyridine complex.

[0121]

[Pharmacological activity] The compound of the present invention represented by the general formula (I) is H
It was proved by the following experiments that they have an inhibitory effect on IV infection or an inhibitory effect on the binding between various chemokine receptors and their respective ligands.

As described above, in order to screen for a compound that inhibits the binding of HIV to CXCR4 or CCR5, which is a receptor on CD4-positive cells, it is more preferable to use an HIV virus-based assay system. It is a direct method. However, the use of HIV virus for large-scale screening is not practical because of its difficulty in handling. On the other hand, T cell tropism (X4) H
Since both IV and SDF-1 bind to CXCR4, it is expected that the CXCR4 binding sites on both the HIV side and the SDF-1 side, and the SDF-1 and HIV binding sites on the CXCR4 side have some common features. You.
Therefore, to find compounds that inhibit the adsorption of HIV virus to cells, which have a different mechanism of action from existing anti-AIDS drugs (reverse transcription inhibitors and protease inhibitors),
SDF which is the original ligand of CXCR4 instead of V
Assay systems using -1 are available. Specifically, as a system for screening a compound that inhibits the binding between SDF-1 and CXCR4, for example, CXCR4 is G
Since it is a protein-coupled seven-transmembrane receptor, SDF-
A system is possible in which 1 measures the effect of Ca ions induced via CXCR4 on transient elevations. Macrophage tropism (R5) HIV-1 and RANTES, MI
Since both P-1α and MIP-1β bind to CCR5, a similar concept is possible.

[0123]Experiment on inhibition of binding between SDF-1 and CXCR4 (For SDF-1 Ca ion transient increase inducing activity
Inhibition experiment) [Experimental method] 5 × 10⁶CXCR to become
4 expressing human T cells, such as CCRF-HSB
2 cells (ATCC No. CCL-120.1) as RP
MI1640 medium, FBS (10%), Fura-2AM
(5μM) (Dojindo, cat # 343-05401), probeneshi
(Probenecid) (2.5 mM), HEPES (20 m
M, pH 7.4) and 30 ° C at 37 ° C in the dark.
Warmed for minutes. And 4 to 8 times 1 × Hanks, HE
PES (20 mM, pH 7.4), Probenecid (2.5 mM)
And warmed for an additional 30 minutes. 1 x Hanks, HE
PES (20 mM, pH 7.4), Probenecid (2.5 mM)
After washing the cells with the same solution, add 2 × 10⁶Pieces / ml
Resuspended so that This Fura-2AM
T cells that were dissolved in PBS (-)
Transient of Ca induced by addition of recombinant SDF-1β
Increased sex was detected using a suitable Ca detector. Obstruction
In the test, SDF-1β was added 3 minutes after the addition of the test compound.
For example, adding a final concentration of 30 nM,
a The inhibition rate of the test compound against the transient increase was determined,
C ₅₀Values were calculated. Inhibition rate (%) is calculated from the following formula
Issued.

[0124]

## EQU1 ## Inhibition rate = {(Ec−Ea) / Ec} × 100 In the formula, the meanings of the respective symbols are as follows. Ec: measured value of Ca transient increase by SDF-1β, Ea: C by SDF-1β when test compound was added
a Measured transient rise.

Table 34 shows the results.

[Table 34]

Binding of MIP-3β / ELC to CCR7
Inhibition experiment ( Inhibition experiment on the activity of MIP-3β / ELC to induce transient increase of Ca ion) [Experimental method] CCR7 was adjusted to 5 × 10 ⁶ cells / ml.
T cells expressing, for example, CCRF-HSB2
Cells (ATCC No. CCL-120.1) were converted to RPM
I1640 medium, FBS (10%), Fura-2AM (5
μM) (Dojindo, cat # 343-05401), Probenecid (2.5
mM), suspended in HEPES (20 mM, pH 7.4),
Heated at 37 ° C. for 30 minutes in the light-shielded state. And 4 ~
Eight times 1 × Hanks, HEPES (20 mM, pH 7.
4), Probenecid (2.5 mM) was added, and the mixture was further heated for 30 minutes. 1 × Hanks, HEPES (20 mM, pH 7.
4) After washing the cells with a solution of Probenecid (2.5 mM),
The same solution was resuspended at 2 × 10 ⁶ cells / ml.
For the T cells loaded with Fura-2AM,
Recombinant MIP-3β / ELC dissolved in PBS (-)
The transient increase in Ca induced by the addition of was detected using a suitable Ca detector. In the inhibition experiment, 3 minutes after the addition of the test compound, MIP-3β / ELC was added at a final concentration of, for example, 30 nM, and CIP by MIP-3β / ELC was added.
a The inhibition rate of the test compound against the transient increase was determined,
The _C50 value was calculated. The inhibition rate (%) was calculated by the following formula.

[0127]

## EQU2 ## Inhibition rate = {(Ec−Ea) / Ec} × 100 In the formula, the meanings of the respective symbols are as follows. Ec: measured value of Ca transient increase by MIP-3β / ELC, Ea: MIP-3β / ELC when test compound was added
Measurement of Ca transients due to

As a result, the compound of Example 2 had an IC ₅₀
0.17 μM.

Inhibition experiment on binding between MDC and CCR4 ( inhibition experiment on MDC transient increase inducing activity of MDC) [Experimental method] CCR4 was adjusted to 5 × 10 ⁶ cells / ml.
T cells expressing, for example, CCRF-HSB2
Cells (ATCC No. CCL-120.1) were converted to RPM
I1640 medium, FBS (10%), Fura-2AM (5
μM) (Dojindo, cat # 343-05401), Probenecid (2.5
mM), suspended in HEPES (20 mM, pH 7.4),
Heated at 37 ° C. for 30 minutes in the light-shielded state. And 4 ~
Eight times 1 × Hanks, HEPES (20 mM, pH 7.
4), Probenecid (2.5 mM) was added, and the mixture was further heated for 30 minutes. 1 × Hanks, HEPES (20 mM, pH 7.
4) After washing the cells with a solution of Probenecid (2.5 mM),
The same solution was resuspended at 2 × 10 ⁶ cells / ml.
For the T cells loaded with Fura-2AM,
The transient increase in Ca induced by the addition of recombinant MDC dissolved in PBS (-) was detected using a suitable Ca detector. In the inhibition experiment, MDC was added 3 minutes after the addition of the test compound, for example, at a final concentration of 30 nM, and MD was added.
The inhibition rate of the test compound against the transient increase in Ca caused by C was measured, and the IC ₅₀ value was calculated. The inhibition rate (%) was calculated by the following formula.

[0130]

## EQU3 ## Inhibition rate = {(Ec-Ea) / Ec} × 100 In the formula, the meanings of the symbols are as follows. Ec: Measured value of Ca transient increase by MDC, Ea: Measured value of Ca transient increase by MDC when test compound was added.

As a result, the compound of Example 2 had an IC ₅₀
0.8 μM.

Inhibition experiment of binding between RANTES and CCR5 ( Inhibition experiment on RANTES activity for inducing transient increase of Ca ion) [Experimental method] CCR5 was adjusted to 5 × 10 ⁶ cells / ml.
, Such as THP-1 cells (ATCC No. TIB-202) or human C
CHO cells incorporating the CR5 expression vector were
1640 medium, FBS (10%), Fura-2AM (5μ
M) (Dojindo, cat # 343-05401), Probenecid (2.5m
M), and suspended in HEPES (20 mM, pH 7.4) and heated at 37 ° C. for 30 minutes in the dark. And 4-8
1x Hanks, HEPES (20 mM, pH 7.
4), Probenecid (2.5 mM) was added, and the mixture was further heated for 30 minutes. 1 × Hanks, HEPES (20 mM, pH 7.
4) After washing the cells with a solution of Probenecid (2.5 mM),
The same solution was resuspended at 2 × 10 ⁶ cells / ml.
For the cells loaded with Fura-2AM, P
The transient increase in Ca induced by the addition of recombinant RANTES dissolved in BS (-) was detected using a suitable Ca detector. Inhibition experiments were performed 3 days after addition of the test compound.
At the elapse of minutes, RANTES was added, for example, at a final concentration of 30 nM, and the inhibition rate of the test compound against the transient increase in Ca due to RANTES was measured, and the IC ₅₀ value was calculated. The inhibition rate (%) was calculated by the following formula.

[0133]

## EQU4 ## Inhibition rate = {(Ec-Ea) / Ec} × 100 In the formula, the meanings of the symbols are as follows. Ec: measured value of Ca transient increase by RANTES, Ea: C by RANTES when test compound was added
a Measured transient rise.

As a result, the compound of Example 2 had an IC ₅₀ of
2.0 μM.

The HIV virus binds to the target cell CD4 protein and chemokine receptor via its envelope protein gp120. Those that bind to the HIV gp120 protein are those that inhibit the binding and fusion of HIV to target cells. Therefore, the following experiment confirmed that the compound of the present invention binds to the gp120 protein.

In vitro HIV using BIAcore 2000
a gp120 protein and an anti-gp120 (loop3) antibody
Inhibition of binding of neutralizing antibodies to HIV-induced cell fusion
Harm Experimental [Experimental Method] Anti gp120 (loop3) an antibody HI
Neutralizing antibody against V-induced cell fusion (Advanced Bio
technologies) (10 μg / ml).
The solution diluted with mM acetate buffer (pH 4.0) was
Sensor chip CM5 injected and set to 0
Immobilized. 5 μg / ml recombinant gp-120 (INTRA
CEL) and 3 μM of the compound at room temperature for 3 hours.
Under the condition that the S-EP buffer was used as a running buffer, 15 μL of the mixture was injected at a flow rate of 5 μL / min. The inhibitory effect was expressed as the inhibition ratio of the compound with respect to the value obtained by subtracting the resonance unit obtained without gp120 from the resonance unit obtained only with gp120 as 100%. As a result, the compound of Example 2 was inhibited by 66%, the compound of Example 2 (1) was inhibited by 99%, and the compound of Example 15 was inhibited by 71%.

From the above results, the glucopyranose derivative represented by the general formula (I) or a non-toxic salt thereof was obtained from CD4
CXCR4 (SDF-1 receptor) and SDF on positive cells
-1 binding inhibition or CCR5 on CD4-positive cells (RANTES, MIP-1α, MIP-
1β receptor) and RANTES, and has the effect of binding to the HIV virus gp120 protein infection-related portion and inhibiting the binding of gp120 to target cells. [HI
V infection (AIDS)].

The glucopyranose derivative represented by the general formula (I) or a non-toxic salt thereof can be combined with various chemokine receptors on blood cells involved in inflammation and immunity, for example, on T cells, dendritic cells or macrophages. Ligands (especially CXCR4 and SDF-1α or SDF
-1β, CCR4 and MDC or TARC, CCR7 and MIP-3β or SLC or CCR5 and RANT
It has an effect of inhibiting binding to ES, MIP-1α or MIP-1β), and is therefore considered to be useful for treating inflammatory and immune diseases.

Therefore, specifically, acquired immunodeficiency syndrome [HIV infection (AIDS)], asthma, atopic dermatitis (including hives), rhinitis, conjunctivitis, allergic bronchopulmonary aspergillosis, allergic disorders It is considered to be useful as a prophylactic and / or therapeutic agent for acidophilic gastroenteropathy, nephritis, nephropathy, hepatitis, arthritis, rheumatoid arthritis, transplant organ rejection, and shock during bacterial infection.

[0140]

[Toxicity] The toxicity of the compound represented by formula (I) used in the present invention is extremely low, and it can be judged that the compound is sufficiently safe for use as a medicament.

[0141]

[Application to pharmaceutical products] The compounds represented by the general formula (I) used in the present invention include acquired immunodeficiency syndrome [HIV infection (AIDS)], asthma, atopic dermatitis (including urticaria), rhinitis, Useful for prevention and / or treatment of conjunctivitis, allergic bronchopulmonary aspergillosis, allergic eosinophilic gastroenteropathy, nephritis, nephropathy, hepatitis, arthritis, rheumatoid arthritis, transplant rejection, shock in bacterial infection It is. In order to use the compound represented by the general formula (I), a non-toxic salt thereof or a hydrate thereof for the above-mentioned purpose, it is usually administered systemically or locally in an oral or parenteral form. Is done. The dose varies depending on age, body weight, symptoms, therapeutic effect, administration method, processing time, etc.
Usually 1mg to 1000m per adult
g orally once to several times a day, or 1 mg to 100 mg per adult per dose
Parenteral administration once to several times a day (preferably,
Intravenous administration) or continuous intravenous administration for 1 hour to 24 hours per day. Of course, as described above, the dose varies depending on various conditions, so that a dose smaller than the above-mentioned dose may be sufficient, or may be required beyond the range.

When the compound represented by the formula (I) is administered, solid compositions, liquid compositions and other compositions for oral administration and injections, external preparations and suppositories for parenteral administration are administered. Used as an agent and the like. Solid compositions for oral administration include tablets, pills, capsules, powders, granules and the like. Capsules include hard capsules and soft capsules. In such a solid composition, the one or more active substances comprise at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminum metasilicate. It is mixed with magnesium acid. The composition may contain, in a conventional manner, additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose glycolate, a stabilizer such as lactose, glutamic acid or asparagine. A solubilizing agent such as an acid may be contained. The tablet or pill may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or may be coated with two or more layers, if necessary. . Also included are capsules of absorbable materials such as gelatin.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, syrups, elixirs and the like. In such liquid compositions, one or more active substances are contained in commonly used inert diluents (eg, purified water, ethanol). The composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives. Other compositions for oral administration include sprays which contain one or more active substances and are formulated in a manner known per se. The composition may further comprise a buffering agent which, in addition to the inert diluent, provides isotonicity with stabilizers such as sodium bisulfite,
For example, they may contain isotonic agents such as sodium chloride, sodium citrate or citric acid. Methods for producing sprays are described in detail, for example, in US Pat. Nos. 2,868,691 and 3,095,355.

The injections for parenteral administration according to the present invention include sterile aqueous and / or non-aqueous solutions, suspensions and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline.
Examples of the water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and Polysorbate 80 (registered trademark). In addition, sterile aqueous and non-aqueous solutions, suspensions, and emulsions may be mixed and used. Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing (eg, lactose) and solubilizing agents (eg, glutamic acid, aspartic acid). . These are sterilized by filtration through a bacteria retaining filter, blending of a bactericide or irradiation. They can also be used to produce sterile solid compositions, for example, sterilized or dissolved in sterile distilled water for injection or other solvents before use of the lyophilized product. Other compositions for parenteral administration include one or more active substances,
It includes external solutions, ointments, liniments, suppositories for rectal administration, and pessaries for vaginal administration, etc., which are formulated in a conventional manner.

[0145]

EXAMPLES The present invention will be described in detail below with reference examples and examples, but the present invention is not limited to these examples.
The solvent in parentheses shown in the column of separation by chromatography and TLC indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio. Unless otherwise specified, Merck 7734 silica gel was used for column chromatography.

Reference Example 1 Methyl 4,6-O-isopropylidene-α-D-glucopyranoside

Embedded image Methyl α-D-glucopyranoside (10 g) in dimethylformamide (40 ml) and dioxane (40 ml)
In a mixed solution, pyridinium p-toluenesulfonic acid (650 mg) and acetone dimethyl acetal (37.8 m
l) was added. The reaction mixture was stirred at 50 ° C. for 2 days.
The reaction mixture was cooled to room temperature, triethylamine was added and concentrated. The obtained residue is subjected to silica gel column chromatography (dichloromethane: methanol = 20:
Purified in 1) to give the title compound (9.03
g) was obtained. TLC: Rf 0.11 (hexane: ethyl acetate = 1: 1).

Reference Example 2 Methyl 2-O-tetradecanoyl-3-O-tetradecanoyl-4,6-O-isopropylidene-α-D-glucopyranoside

Embedded image Compound (1.64 g) produced in Reference Example 1, myristic acid (3.98 g), 2-chloro-1-methylpyridinium iodide (17.48 g), dimethylaminopyridine (171 m)
To a solution of g) in dichloromethane (70 ml) was added triethylamine (4 ml). The reaction mixture was stirred at room temperature for 15 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1 → 6: 1) to give the title compound (0.99 g) having the following physical data. TLC: Rf 0.50 (hexane: ethyl acetate = 4: 1).

Reference Example 3 Methyl 2-O-tetradecanoyl-3-O-tetradecanoyl-α-D-glucopyranoside

Embedded image In a mixed solution of the compound (1.60 g) produced in Reference Example 2 in tetrahydrofuran (12 ml) and methanol (12 ml), p-toluenesulfonic acid monohydrate (116 mg) was added.
Was added. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated to give the title compound (1.53 g) having the following physical data. TLC: Rf 0.20 (hexane: ethyl acetate = 2: 1).

Reference Example 4 Methyl 2-O-tetradecanoyl-3-O-tetradecanoyl-6-O- (t-butyldimethylsilyl) -α
-D-glucopyranoside

Embedded image To a solution of the compound (1.49 g) produced in Reference Example 3 in dichloromethane (24 ml) was added imidazole (364 m 2) under ice-cooling.
g) and t-butyldimethylsilyl chloride (550 m
g) was added. The reaction mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and concentrated to give the title compound (2.01 g) having the following physical data. TLC: Rf 0.85 (hexane: ethyl acetate = 4: 1).

Example 1 Methyl 2-O-tetradecanoyl-3-O-tetradecanoyl-4-O-sulfo-6-O- (t-butyldimethylsilyl) -α-D-glucopyranoside sodium salt

Embedded image The compound (1.88 g) produced in Reference Example 4 was treated with pyridine (26
ml) solution, sulfur trioxide / pyridine complex (1.23 g) was added. The reaction mixture was stirred at 50 ° C. for 1.5 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated to give the compound of the present invention (1.92 g) having the following physical data. TLC: Rf 0.52 (chloroform: methanol: water = 4
0: 10: 1).

Example 2 Methyl 2-O-tetradecanoyl-3-O-tetradecanoyl-4-O-sulfo-α-D-glucopyranoside sodium salt

Embedded image Acetic acid (6) was added to a mixed solution of the compound (1.82 mg) produced in Example 1 in tetrahydrofuran (6 ml) and water (2 ml).
ml) was added. The reaction mixture was stirred at 50 C for 30 minutes. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to make it alkaline, and extracted with tetrahydrofuran. The extract is dried over anhydrous sodium sulfate,
Concentrated. The obtained residue was purified by silica gel column chromatography (Fuji Silysia Chemical BW-235, chloroform: methanol: water = 9: 1: 0.07 → 40: 10: 1) to give the compound of the present invention (1.25) having the following physical data. g) was obtained. TLC: Rf 0.38 (chloroform: methanol: water = 4
0: 10: 1), IR (KBr): ν 3490, 2921, 2851, 1742, 1638, 146
9, 1378, 1259, 1169,1117, 1031, 989, 809, 755, 72
1,609 cm ^-1 .

Examples 2 (1) to 2 (6) Reference examples 2 → Reference examples 3 → Reference examples 4 → Examples 1 → Same as in Example 2 by using corresponding carboxylic acids instead of myristic acid. By the operation, the following compound of the present invention was obtained.

Example 2 (1) Methyl 2-O- (9-phenylnonanoyl) -3-O
-(9-phenylnonanoyl) -4-O-sulfo-α-
D-glucopyranoside sodium salt

Embedded image TLC: Rf 0.35 (ethyl acetate: methanol = 10:
1), IR (KBr): ν 3516, 2925, 2852, 1743, 1604, 149
6, 1454, 1252, 1125,1054, 920, 857 cm ^-1 .

Example 2 (2) Methyl 2-O-heptanoyl-3-O-heptanoyl-4-O-sulfo-α-D-glucopyranoside sodium salt

Embedded image TLC: Rf 0.17 (chloroform: methanol: acetic acid =
15: 2: 1), IR (KBr): ν 3483, 2931, 2859, 1740, 1637, 146
7, 1376, 1263, 1167,1104, 1032, 991, 925, 850, 80
8, 753, 607 cm ^-1 .

Example 2 (3) Methyl 2-O-eicosanoyl-3-O-eicosanoyl-4-O-sulfo-α-D-glucopyranoside sodium salt

Embedded image TLC: Rf 0.35 (chloroform: methanol: acetic acid =
15: 2: 1), IR (KBr): ν 3466, 2918, 2850, 1744, 1637, 146
9, 1416, 1378, 1262,1167, 1115, 1034, 989, 927, 80
7, 753, 721, 609, 472, 419 cm ^-1 .

Example 2 (4) Methyl 2-O-oleoyl-3-O-oleoyl-4
-O-sulfo-α-D-glucopyranoside sodium salt

Embedded image TLC: Rf 0.28 (chloroform: methanol: water = 1
00: 20: 1), IR (KBr): ν 3483, 3006, 2925, 2854, 1742, 163
8, 1466, 1376, 1246,1168, 1121, 1053, 993, 925, 85
6, 813, 754, 722, 607, 473 cm ^-1 .

Example 2 (5) Methyl 2-O- [5- (heptyloxy) pentanoyl] -3-O- [5- (heptyloxy) pentanoyl] -4-O-sulfo-α-D-glucopyranoside. Sodium salt

Embedded image TLC: Rf 0.42 (chloroform: methanol: water = 4
0: 10: 1), IR (KBr): ν 3453, 2928, 2856, 1738, 1640, 145
4, 1378, 1241, 1165,1119, 1031, 992, 811, 758, 69
7, 604 cm ^-1 .

Example 2 (6) Methyl 2-O- [5- (N-methyl-N-heptylamino) pentanoyl] -3-O- [5- (N-methyl-
N-heptylamino) pentanoyl] -4-O-sulfo-α-D-glucopyranoside sodium salt

Embedded image TLC: Rf 0.32 (chloroform: methanol: water = 4
0: 10: 1), IR (KBr): ν 3388, 2928, 2856, 1740, 1467, 137
7, 1163, 1052, 918, 756 cm ^-1 .

Example 3 (1) to (4) Instead of methyl β-D-glucopyranoside, benzyl β-D-glucopyranoside, methyl β-D-thioglucopyranoside, 1,5-anhydro-D-glucitol, methyl β Using -L-glucopyranoside, the same operation as in Reference Example 1 → Reference Example 2 → Reference Example 3 → Reference Example 4 → Example 1 → Example 2 was performed to obtain the present compound shown below.

Example 3 (1) Benzyl 2-O-tetradecanoyl-3-O-tetradecanoyl-4-O-sulfo-β-D-glucopyranoside sodium salt

Embedded image TLC: Rf 0.28 (chloroform: methanol: water = 1
00: 20: 1), IR (KBr): ν 3472, 2924, 2853, 1747, 1637, 146
7, 1377, 1260, 1158,1115, 1079, 1047, 987, 822, 73
1, 698, 596, 486 cm ^-1 .

Example 3 (2) Methyl 2-O-tetradecanoyl-3-O-tetradecanoyl-4-O-sulfo-β-D-thioglucopyranoside sodium salt

Embedded image TLC: Rf 0.39 (chloroform: methanol: water = 4
0: 10: 1), IR (KBr): ν 3472, 2921, 2851, 1746, 1637, 146
9, 1258, 1168, 1084, 1037, 987, 797 cm ^-1 .

Example 3 (3) 2-O-tetradecanoyl-3-O-tetradecanoyl-4-O-sulfo-1,5-anhydro-D-glucitol sodium salt

Embedded image TLC: Rf 0.39 (chloroform: methanol: water = 4
0: 10: 1), IR (KBr): ν 3477, 2956, 2919, 2850, 1742, 163
8, 1469, 1257, 1172,1102, 1068, 1021, 983, 801, 72
1, 621 cm ^-1 .

Example 3 (4) Methyl 2-O-tetradecanoyl-3-O-tetradecanoyl-4-O-sulfo-β-L-glucopyranoside sodium salt

Embedded image TLC: Rf 0.43 (chloroform: methanol: water = 4
0: 10: 1), IR (KBr): ν 3477, 2956, 2920, 2851, 1739, 163
9, 1469, 1259, 1169,1116, 1031, 989, 807, 754, 72
1,609 cm ^-1 .

Reference Example 5 Methyl 2-O-tetradecanoyl-3-O-tetradecanoyl-4,6-O-benzylidene-α-D-glucopyranoside

Embedded image Instead of the compound prepared in Reference Example 1, methyl 4,6
The same operation as in Reference Example 2 was carried out using -O-benzylidene-α-D-glucopyranoside to obtain the title compound having the following physical data. TLC: Rf 0.52 (hexane: ethyl acetate = 4: 1).

Reference Example 6 Methyl 2-O-tetradecanoyl-3-O-tetradecanoyl-6-O-benzyl-α-D-glucopyranoside

Embedded image To a solution of the compound (1 g) prepared in Reference Example 5 and triethylsilane (1.14 ml) in dichloromethane (10 ml) was added trifluoroacetic acid (0.55 ml) under ice-cooling.
The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (Fuji Silysia Chemical BW-235, hexane: ethyl acetate = 5: 1) to give the title compound (785 mg) having the following physical data. TLC: Rf 0.60 (hexane: ethyl acetate = 2: 1).

Example 4 Methyl 2-O-tetradecanoyl-3-O-tetradecanoyl-4-O-sulfo-6-O-benzyl-α-D
-Glucopyranoside sodium salt

Embedded image The same operation as in Example 1 was carried out using the compound produced in Reference Example 6, and further converted into a sodium salt using an aqueous sodium hydrogen carbonate solution to obtain a compound of the present invention having the following physical properties. TLC: Rf 0.46 (chloroform: methanol: acetic acid =
15: 2: 1), IR (KBr): ν 3467, 2922, 2851, 1736, 1636, 146
8, 1267, 1171, 1116,1045, 984, 924, 815, 749, 698,
610 cm ^-1 .

Reference Example 7 Methyl 2-O-tetradecanoyl-3-O-tetradecanoyl-4-O-benzyl-α-D-glucopyranoside

Embedded image To a solution of the compound (1 g) prepared in Reference Example 5 in anhydrous tetrahydrofuran (70 ml) was added dropwise a solution of a 1.0 M borane-tetrahydrofuran complex in tetrahydrofuran (7.1 ml) under an argon atmosphere under ice cooling. The mixture was stirred at the same temperature for 5 minutes. A 1.0 M solution of dibutylborane triflate in dichloromethane (1.42 ml) was added dropwise to the reaction mixture.
The reaction mixture was stirred at 0 ° C. for 2 hours. Triethylamine was added to the reaction mixture, methanol was further added, and the mixture was concentrated. The obtained residue was purified by silica gel column chromatography (Fuji Silysia Chemical BW-235, hexane: ethyl acetate = 5: 1 → 3: 1 → 2: 1) to give the title compound (332 mg) having the following physical data. Obtained. TLC: Rf 0.36 (hexane: ethyl acetate = 2: 1).

Reference Example 8 Methyl 2-O-tetradecanoyl-3-O-tetradecanoyl-4-O-benzyl-6-O-methyl-α-D
-Glucopyranoside

Embedded image To a solution of the compound (134 mg) produced in Reference Example 7 in dimethylformamide (1 ml), 60% sodium hydride (18 mg) was added, and further, methyl iodide (0.1 m2) was added.
l) was added. The reaction mixture was stirred at room temperature for 30 minutes.
A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with water, a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (Fuji Silysia Chemical BW-235, hexane: ethyl acetate = 5: 1) to give the title compound (87 mg) having the following physical data. TLC: Rf 0.69 (hexane: ethyl acetate = 2: 1).

Reference Example 9 Methyl 2-O-tetradecanoyl-3-O-tetradecanoyl-6-O-methyl-α-D-glucopyranoside

Embedded image A solution of the compound (86 mg) produced in Reference Example 8 in tetrahydrofuran (1.5 ml) was added to a 10% palladium carbon (8
0 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 days. The reaction mixture was filtered through Celite (trade name)
The filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (Fuji Silysia Chemical BW-235, hexane: ethyl acetate = 4: 1) to give the title compound (76 mg) having the following physical data. TLC: Rf 0.39 (hexane: ethyl acetate = 2: 1).

Example 5 Methyl 2-O-tetradecanoyl-3-O-tetradecanoyl-4-O-sulfo-6-O-methyl-α-D-
Glucopyranoside sodium salt

Embedded image The same operation as in Example 1 was performed using the compound produced in Reference Example 9, and further converted into a sodium salt using an aqueous sodium hydrogen carbonate solution to obtain a compound of the present invention having the following physical properties. TLC: Rf 0.32 (chloroform: methanol: water = 1
00: 20: 1), IR (KBr): ν 3456, 2924, 2853, 1740, 1648, 146
7, 1376, 1236, 1162,1119, 1082, 1045, 998, 921, 83
9, 817, 756, 721, 606, 582, 478 cm ^-1 .

Reference Example 10 Methyl 3,4-O-isopropylidene-β-L-arabinopyranoside

Embedded image The same operation as in Reference Example 1 was carried out using methyl β-L-arabinopyranoside instead of methyl β-D-glucopyranoside to obtain the title compound having the following physical data. TLC: Rf 0.15 (hexane: ethyl acetate = 3: 2).

Reference Example 11 Methyl 2-O- [3RS- (tetradecanoyloxy) tetradecanoyl] -3,4-O-isopropylidene-β-L-arabinopyranoside

Embedded image The same operation as in Reference Example 2 was performed using the compound produced in Reference Example 10 and 3RS- (tetradecanoyloxy) tetradecanoic acid to obtain the title compound having the following physical data. TLC: Rf 0.67 (hexane: ethyl acetate = 3: 2).

Reference Example 12 Methyl 2-O- [3RS- (tetradecanoyloxy) tetradecanoyl] -β-L-arabinopyranoside

Embedded image The same operation as in Example 2 was performed using the compound produced in Reference Example 11 to obtain the title compound having the following physical data. TLC: Rf 0.29 (hexane: ethyl acetate = 1: 1).

Reference Example 13 Methyl 2-O- [3RS- (tetradecanoyloxy) tetradecanoyl] -3-O-tetradecanoyl-
β-L-arabinopyranoside

Embedded image The same operation as in Reference Example 2 was performed using the compound prepared in Reference Example 12 to obtain the title compound having the following physical data. TLC: Rf 0.15 (hexane: ethyl acetate = 4: 1).

Example 6 Methyl 2-O- [3RS- (tetradecanoyloxy) tetradecanoyl] -3-O-tetradecanoyl-
4-O-sulfo-β-L-arabinopyranoside Calcium, sodium, magnesium salt

Embedded image Using the compound produced in Reference Example 13, the same operation as in Example 1 was performed, and the compound was further purified by silica gel column chromatography to obtain the compound of the present invention having the following physical data. TLC: Rf 0.31 (dichloromethane: methanol = 1
7: 3), IR (CHCl ₃ ): ν 3530, 1735, 1465, 1275, 1137, 10
73, 1000, 915 cm ^-1 .

Example 6 (1) Methyl 2-O- [3RS- (tetradecanoyloxy) tetradecanoyl] -3-O-tetradecanoyl-
4-O-sulfo-β-D-arabinopyranoside Calcium, sodium, magnesium salt

Embedded image Reference Example 10 was repeated using methyl β-D-arabinopyranoside instead of methyl β-L-arabinopyranoside.
→ Reference Example 11 → Reference Example 12 → Reference Example 13 → The same operation as in Example 6 was carried out to obtain the compound of the present invention having the following physical property values. TLC: Rf 0.12 (dichloromethane: methanol = 9:
1), IR (CHCl ₃ ): ν 3470, 2940, 2860, 1735, 1462, 12
80, 1200, 1135, 1176, 1000 cm ^-1 .

Reference Example 14 Methyl 2-O-tetradecanoyl-3,4-O-isopropylidene-β-L-arabinopyranoside

Embedded image The same operation as in Reference Example 2 was performed using the compound prepared in Reference Example 10 to obtain the title compound having the following physical data. TLC: Rf 0.60 (hexane: ethyl acetate = 3: 2).

Reference Example 15 Methyl 2-O-tetradecanoyl-β-L-arabinopyranoside

Embedded image The same operation as in Reference Example 12 was performed using the compound produced in Reference Example 14, to obtain the title compound having the following physical data. TLC: Rf 0.16 (hexane: ethyl acetate = 1: 1).

Reference Example 16 Methyl 2-O-tetradecanoyl-3-O- [3-
(Tetradecanoyloxy) tetradecanoyl] -β-
Highly polar and low polar L-arabinopyranosides

Embedded image The same operation as in Reference Example 11 was carried out using the compound prepared in Reference Example 15 to give the title compound having the following physical data. Highly polar TLC: Rf 0.27 (hexane: ethyl acetate = 4: 1,2
Times). Low polar TLC: Rf 0.32 (hexane: ethyl acetate = 4: 1,2
Times).

Example 7 Methyl 2-O-tetradecanoyl-3-O- [3-
(Tetradecanoyloxy) tetradecanoyl] -4-
O-Sulfo-β-L-arabinopyranoside Highly polar form of a mixed salt of calcium, sodium and magnesium

Embedded image The same operation as in Example 1 was carried out using the highly polar compound of the compound produced in Reference Example 16, and the compound was further purified by silica gel column chromatography to obtain the compound of the present invention having the following physical data. TLC: Rf 0.33 (dichloromethane: methanol = 1
7: 3), IR (CHCl ₃ ): ν 3500, 2940, 2860, 1735, 1462, 12
72, 1138, 1075, 1040, 1000 cm ^-1 .

Example 7 (1) and (2) Reference Example 10 was repeated using methyl β-D-arabinopyranoside instead of methyl β-L-arabinopyranoside.
→ Reference Example 14 → Reference Example 15 → Reference Example 16 → Perform the same operation as in Example 7, or use the low-polar form of the compound produced in Reference Example 16, and perform the same operation as in Example 7, Was obtained.

Example 7 (1) Methyl 2-O-tetradecanoyl-3-O- [3-
(Tetradecanoyloxy) tetradecanoyl] -4-
O-sulfo-β-L-arabinopyranoside low polarity form of a mixed salt of calcium, sodium and magnesium

Embedded image TLC: Rf 0.33 (dichloromethane: methanol = 1
7: 3), IR (CHCl ₃ ): ν 3500, 2930, 2855, 1735, 1460, 12
68, 1134, 1070, 1035, 999 cm ^-1 .

Example 7 (2) Methyl 2-O-tetradecanoyl-3-O- [3-
(Tetradecanoyloxy) tetradecanoyl] -4-
O-sulfo-β-D-arabinopyranoside Highly polar compound of a mixed salt of calcium, sodium and magnesium

Embedded image TLC: Rf 0.16 (dichloromethane: methanol = 9:
1), IR (CHCl ₃ ): ν 3500, 2940, 2860, 1735, 1460, 12
70, 1220, 1135, 1075, 1037, 1000 cm ^-1 .

Reference Example 17 Methyl 3-O-tetradecanoyl-α-D-xyloside

Embedded image Methyl D-xyloside (5.47 g) in benzene (30 m
l) To the solution, phenylboronic acid (4.47 g) and camphorsulfonic acid (10 mg) were added. Reaction mixture at 80 ° C
And generate water by a Dean-Stark trap.
an-Stark trap). The reaction mixture was stirred for 1.5 hours. The reaction mixture was cooled to room temperature and concentrated. The obtained residue was dissolved in dichloromethane (50 ml), and pyridine (4 ml) and tetradecanoyl chloride (11 ml) were added under ice cooling. The reaction mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture and extracted. Extract 1N
The extract was washed with an aqueous hydrochloric acid solution (× 3) and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was dissolved in tetrahydrofuran (50 ml), and a saturated aqueous sodium hydrogen carbonate solution (50 ml) was added under ice cooling.
0% aqueous hydrogen peroxide (10 ml) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with a mixed solution of hexane: ethyl acetate = 1: 1. The extract was washed with a 1N aqueous sodium hydroxide solution (× 3) and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to give the title compound (2.87 g) having the following physical data. TLC: Rf 0.35 (hexane: ethyl acetate = 1: 1).

Reference Example 18 Methyl 2-O- [3RS- (tetradecanoyloxy) tetradecanoyl] -3-O-tetradecanoyl-
α-D-xyloside

Embedded image The same operation as in Reference Example 11 was performed using the compound prepared in Reference Example 17 to give the title compound having the following physical data. TLC: Rf 0.48 (hexane: ethyl acetate = 2: 1).

Example 8 Methyl 2-O- [3RS- (tetradecanoyloxy) tetradecanoyl] -3-O-tetradecanoyl-
4-O-sulfo-α-D-xyloside-mixed salt of calcium, sodium and magnesium

Embedded image Using the compound produced in Reference Example 18, the same operation as in Example 1 was performed, and the product was further purified by silica gel column chromatography to obtain the compound of the present invention having the following physical data. TLC: Rf 0.14 (dichloromethane: methanol = 9:
1), IR (CHCl ₃ ): ν 3520, 2937, 2860, 1738, 1468, 13
30-1135, 1040, 996 cm ^-1 .

Example 8 (1) 2-O- [3RS- (tetradecanoyloxy) tetradecanoyl] -3-O-tetradecanoyl-4-O-sulfo-1,5-anhydroxylitol calcium ,
Mixed salt of sodium and magnesium

Embedded image The same operation as in Reference Example 17 → Reference Example 18 → Example 8 was performed using 1,5-anhydroxylitol instead of methyl D-xyloside to obtain the compound of the present invention having the following physical property values. IR (CHCl ₃ ): ν 3500, 2935, 2860, 1736, 1465, 12
67, 1210, 1160, 1112, 1072, 1032, 992 cm ^-1 .

Examples 9 (1) and 9 (2) Reference Example 11 → Reference Example using methyl 3-O-benzyl-4,6-O-isopropylidene-α-D-glucopyranoside and 3RS-hydroxytetradecanoic acid. Example 9 → Reference Example 2 → Reference Example 3 → Reference Example 4 → Example 1 → The same operation as in Example 2 was performed to obtain the present compound shown below.

Example 9 (1) Methyl 2-O- [3- (tetradecanoyloxy) tetradecanoyl] -3-O-tetradecanoyl-4-O
-Sulfo-α-D-glucopyranoside Low polarity form of a mixed salt of calcium, sodium and magnesium

Embedded image TLC: Rf 0.35 (dichloromethane: methanol = 1
7: 3), IR (CHCl ₃ ): ν 3500, 2925, 2857, 1734, 1460, 12
50, 1162, 1116, 1082, 1048, 1028, 992, 818, 598 cm
^-1 .

Example 9 (2) Methyl 2-O- [3- (tetradecanoyloxy) tetradecanoyl] -3-O-tetradecanoyl-4-O
-Sulfo-α-D-glucopyranoside, a highly polar form of a mixed salt of calcium, sodium and magnesium

Embedded image TLC: Rf 0.37 (dichloromethane: methanol = 1
7: 3), IR (CHCl ₃ ): ν 3450, 2924, 2855, 1736, 1460, 12
72, 1160, 1113, 1086, 988, 595 cm ^-1 .

Reference Example 19 1,6-Anhydro-2,3-O-isopropylidene-
4-O-benzyl-β-D-mannopyranoside

Embedded image A suspension of 60% sodium hydride (208 mg) in dimethylformamide (10 ml) was added under an argon atmosphere.
1,6-anhydro-2,3-O-isopropylidene-
A solution of β-D-mannopyranoside (1 g) in dimethylformamide (10 ml) was added. After stirring the reaction mixture for 10 minutes, benzyl bromide (0.59 ml) was added. The reaction mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water (× 3), a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated to give the title compound (1.
5 g) were obtained. TLC: Rf 0.83 (hexane: ethyl acetate = 1: 1).

Reference Example 20 1,6-Anhydro-4-O-benzyl-β-D-mannopyranoside

Embedded image A 90% aqueous trifluoroacetic acid solution (10 ml) was added to the compound (1.35 g) produced in Reference Example 19. The reaction mixture was stirred at room temperature for 15 minutes, and the reaction mixture was concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (0.83 g) having the following physical data. TLC: Rf 0.19 (hexane: ethyl acetate = 1: 1).

Reference Example 21 1,6-anhydro-2-O-tetradecanoyl-3-
O-tetradecanoyl-4-O-benzyl-β-D-mannopyranoside

Embedded image The same operation as in Reference Example 2 was performed using the compound prepared in Reference Example 20, to give the title compound having the following physical data. TLC: Rf 0.61 (hexane: ethyl acetate = 3: 1).

Reference Example 22 1,6-Anhydro-2-O-tetradecanoyl-3-
O-tetradecanoyl-β-D-mannopyranoside

Embedded image The same operation as in Reference Example 9 was performed using the compound prepared in Reference Example 21 to give the title compound having the following physical data. TLC: Rf 0.59 (hexane: ethyl acetate = 1: 1).

Example 10 1,6-Anhydro-2-O-tetradecanoyl-3-
O-tetradecanoyl-4-O-sulfo-β-D-mannopyranoside sodium salt

Embedded image The same operation as in Example 1 was carried out using the compound produced in Reference Example 22, and further converted into a sodium salt using an aqueous sodium hydrogen carbonate solution to obtain a compound of the present invention having the following physical properties. TLC: Rf 0.58 (chloroform: methanol: water = 4
0: 10: 1), IR (KBr): ν 3489, 2956, 2919, 2850, 1744, 163
8, 1469, 1379, 1258,1158, 1116, 1077, 1036, 991, 9
03, 825, 808, 721, 592 cm ^-1 .

Reference Example 23 3-benzyloxy-1-cyclohexene

Embedded image 1,6-anhydro-2,3-O-isopropylidene-
The same operation as in Reference Example 19 was performed using 2-cyclohexen-1-ol instead of β-D-mannopyranoside to obtain the title compound having the following physical data. TLC: Rf 0.75 (hexane: ethyl acetate = 8: 1).

Reference Example 24 2,3 (anti) -epoxy-1-benzyloxycyclohexane (1) and 2,3 (syn) -epoxy-1-benzyloxycyclohexane (2)

Embedded image To a solution of the compound (5 g) produced in Reference Example 23 in dichloromethane (150 ml) was added m-chloroperbenzoic acid (6.69 g) at 0 ° C. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was washed with a 10% aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution, a 1N aqueous sodium hydroxide solution, water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1 → 4: 1) to give the title compound (1) (3.07 g) and the title compound (2) (1.19) having the following physical data.
g) were obtained. Reference Example 24 (1) TLC: Rf 0.79 (hexane: ethyl acetate = 2:
1). Reference Example 24 (2) TLC: Rf 0.66 (hexane: ethyl acetate = 2:
1).

Reference Example 25 3 (syn) -hydroxy-2 (anti) -hydroxy-1-benzyloxycyclohexane

Embedded image Dimethylsulfoxide (30 ml) and dioxane (40 ml) of compound (1) (3.17 g) produced in Reference Example 24
To the solution was added a 2N aqueous sodium hydroxide solution (78 ml). The reaction mixture was stirred at 100 ° C. for 17 hours. The reaction mixture was adjusted to pH 3 with a 2N aqueous hydrochloric acid solution, and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated to give the title compound (3.19 g) having the following physical data. TLC: Rf 0.10 (hexane: ethyl acetate = 2:
1).

Reference Example 26 3 (syn) -tetradecanoyloxy-2 (ant)
i) -Tetradecanoyloxy-1-benzyloxycyclohexane

Embedded image The same operation as in Reference Example 2 was carried out using the compound produced in Reference Example 25 to obtain the title compound having the following physical data. TLC: Rf 0.86 (hexane: ethyl acetate = 4:
1).

Reference Example 27 3 (syn) -tetradecanoyloxy-2 (ant)
i) -tetradecanoyloxycyclohexanol

Embedded image The same operation as in Reference Example 9 was carried out using the compound prepared in Reference Example 26 to give the title compound having the following physical data. TLC: Rf 0.34 (hexane: ethyl acetate = 4:
1).

Example 11 3 (syn) -tetradecanoyloxy-2 (ant)
i) -Tetradecanoyloxycyclohex-1-yl-O-sulfonic acid sodium salt

Embedded image The same operation as in Example 1 was carried out using the compound produced in Reference Example 27, and further converted into a sodium salt using an aqueous sodium hydrogen carbonate solution to obtain a compound of the present invention having the following physical properties. TLC: Rf 0.38 (chloroform: methanol: water =
40: 10: 1), IR (KBr): ν 3484, 2919, 2850, 1739, 1640, 146
9, 1378, 1232, 1173,1109, 1074, 996, 953, 889, 85
7, 806, 721, 620 cm ^-1 .

Example 11 (1) 3 (anti) -tetradecanoyloxy-2 (sy
n) -Tetradecanoyloxycyclohex-1-yl-O-sulfonic acid sodium salt

Embedded image Reference Example 2 Using the compound produced in Reference Example 24 (2), Reference Example 2
5 → Reference Example 26 → Reference Example 27 → The same operation as in Example 11 was performed to obtain the compound of the present invention having the following physical data. TLC: Rf 0.47 (chloroform: methanol: water =
40: 10: 1), IR (KBr): ν 3459, 2920, 2851, 1737, 1723, 147
0, 1414, 1347, 1258,1213, 1166, 1114, 1053, 988, 9
23, 890, 859, 802, 719, 684 cm ^-1 .

Reference Example 28 2,3-O-isopropylidenecyclohexane-1-ol

Embedded image The same operation as in Reference Example 1 was performed using cyclohexane-1,2,3-triol to obtain the title compound having the following physical data. TLC: Rf 0.38 (hexane: ethyl acetate = 1:
1).

Reference Example 29 2,3 (syn) -O-isopropylidenecyclohexane-1-benzyloxycyclohexane

Embedded image Using the compound produced in Reference Example 28, the same operation as in Reference Example 19 was performed to obtain the title compound having the following physical data. TLC: Rf 0.78 (hexane: ethyl acetate = 1:
1).

Reference Example 30 2 (syn) -hydroxy-3 (syn) -hydroxy-1-benzyloxycyclohexane

Embedded image The same operation as in Reference Example 3 was performed using the compound produced in Reference Example 29, to give the title compound having the following physical data. TLC: Rf 0.31 (hexane: ethyl acetate = 1:
1).

Example 12 3 (syn) -tetradecanoyloxy-2 (syn)
-Tetradecanoyloxycyclohex-1-yl-O
-Sulfonic acid / sodium salt

Embedded image Using the compound produced in Reference Example 30, the same operation as in Reference Example 26 → Reference Example 27 → Example 11 was carried out, and further converted to a sodium salt using an aqueous sodium hydrogen carbonate solution. A compound of the present invention having TLC: Rf 0.25 (chloroform: methanol: water =
40: 10: 1), IR (neat): ν 3457, 2922, 2853, 1739, 1466, 125
8, 1121, 1078, 1035,985, 889, 812, 721, 604 cm ^-1 .

Example 13 Methyl 2-O-tetradecanoyl-3-O-tetradecanoyl-4-O- (diphenyloxy) phosphono-6
—O- (t-butyldimethylsilyl) -α-D-glucopyranoside

Embedded image To a solution of the compound (211 mg) produced in Reference Example 4 in benzene (2 ml) was added dimethylaminopyridine (141 m2).
g), pyridine (0.093 ml) and diphenyl phosphorochloridate (311 mg) were added. The reaction mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated to give the compound of the present invention (240 mg) having the following physical data. TLC: Rf 0.57 (hexane: ethyl acetate = 5:
1).

Example 14 Methyl 2-O-tetradecanoyl-3-O-tetradecanoyl-4-O- (diphenyloxy) phosphono-α
-D-glucopyranoside

Embedded image The same operation as in Example 2 was performed using the compound prepared in Example 13 to obtain the compound of the present invention (19) having the following physical data.
0 mg). TLC: Rf 0.13 (hexane: ethyl acetate = 3:
1).

Example 15 Methyl 2-O-tetradecanoyl-3-O-tetradecanoyl-4-O-phosphono-α-D-glucopyranoside

Embedded image Platinum dioxide (30 mg) was added to a mixed solution of the compound (170 mg) produced in Example 14 in methanol (2 ml) and tetrahydrofuran (1 ml). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 3 days. The reaction mixture was filtered through Celite (trade name), and the filtrate was concentrated to give the compound of the present invention (117 mg) having the following physical data. TLC: Rf 0.33 (dichloromethane: methanol = 7:
3), IR (CHCl ₃ ): ν 3300, 2930, 2855, 1737, 1460, 13
80, 1240, 1148, 1112, 1035, 952, 905 cm ^-1 .

Example 16 (1) to (3) Instead of myristic acid, using the corresponding carboxylic acid and the compound produced in Reference Example 1, Reference Example 2 → Reference Example 3 → Reference Example 4 → Example 1 → By performing the same operation as in Example 2, the following compound of the present invention was obtained.

Example 16 (1) Methyl 2-O-decanoyl-3-O-decanoyl-4
-O-sulfo-α-D-glucopyranoside sodium salt

Embedded image TLC: Rf 0.39 (chloroform: methanol: water =
40: 10: 1), IR (KBr): ν 3476, 2926, 2854, 1742, 1639, 146
8, 1378, 1251, 1166,1115, 1052, 991, 810, 754, 607
cm ^-1 .

Example 16 (2) Methyl 2-O-hexadecanoyl-3-O-hexadecanoyl-4-O-sulfo-α-D-glucopyranoside sodium salt

Embedded image TLC: Rf 0.31 (chloroform: methanol: water =
40: 10: 1), IR (KBr): ν 3488, 2919, 2850, 1743, 1638, 146
9, 1378, 1266, 1169,1117, 1051, 989, 810, 755, 72
1, 611 cm ^-1 .

Example 16 (3) Methyl 2-O-dodecanoyl-3-O-dodecanoyl-4-O-sulfo-α-D-glucopyranoside sodium salt

Embedded image TLC: Rf 0.49 (chloroform: methanol: water =
40: 10: 1), IR (KBr): ν 3486, 2922, 2852, 1741, 1638, 146
8, 1260, 1116, 1032,990, 809, 754, 721, 607 cm ^-1 .

Reference Example 31 Methyl 4,6-O-benzylidene-α-D-galactopyranoside

Embedded image To a suspension of methyl α-D-galactopyranoside (2 g) and benzaldehyde dimethyl acetal (1.72 g) in chloroform (20 ml) was added camphorsulfonic acid (23 m 2).
g) was added. The reaction mixture was refluxed for 5 hours. The reaction mixture was concentrated. The obtained residue was purified by silica gel column chromatography (Fuji Silysia Chemical BW-235, chloroform: methanol = 10: 1) to give the title compound (2.40 g) having the following physical data. TLC: Rf 0.50 (chloroform: methanol: water =
100: 20: 1).

Reference Example 32 Methyl 2-O-tetradecanoyl-3-O-tetradecanoyl-4,6-O-benzylidene-α-D-galactopyranoside

Embedded image The same operation as in Reference Example 2 was performed using the compound produced in Reference Example 31, to give the title compound having the following physical data. TLC: Rf 0.35 (hexane: ethyl acetate = 4:
1).

Reference Example 33 Methyl 2-O-tetradecanoyl-3-O-tetradecanoyl-α-D-galactopyranoside

Embedded image The same operation as in Reference Example 20 was performed using the compound prepared in Reference Example 32 to obtain the title compound having the following physical data. TLC: Rf 0.44 (hexane: ethyl acetate = 1:
1).

Example 17 Methyl 2-O-tetradecanoyl-3-O-tetradecanoyl-4-O-sulfo-α-D-galactopyranoside sodium salt

Embedded image Using the compound produced in Reference Example 33, the same operation as in Reference Example 4 → Example 1 → Example 2 was performed to obtain the compound of the present invention having the following physical property values. TLC: Rf 0.34 (chloroform: methanol: water =
100: 20: 1), IR (KBr): ν 3474, 2923, 2852, 1738, 1636, 146
8, 1378, 1258, 1164,1116, 1042, 949, 895, 852, 82
5, 694, 579 cm ^-1 .

Example 17 (1) Methyl 2-O-tetradecanoyl-3-O-tetradecanoyl-4-O-sulfo-α-D-mannopyranoside sodium salt

Embedded image Using methyl α-D-mannopyranoside instead of methyl α-D-galactopyranoside, Reference Example 31 →
Reference Example 32 → Reference Example 33 → The same operation as in Example 17 was performed to obtain the compound of the present invention having the following physical data. TLC: Rf 0.31 (chloroform: methanol: water =
100: 20: 1), IR (KBr): ν 3461, 2920, 2851, 1734, 1469, 129
2, 1214, 1141, 1065,1007, 920, 849, 771, 721, 591,
419 cm ^-1 .

Reference Example 34 Methyl 2-O-tetradecanoyl-4,6-O-isopropylidene-α-D-glucopyranoside

Embedded image Instead of methyl 4,6-O-isopropylidene-α-D-glucopyranoside, methyl 3-O-benzyl-
Using 4,6-O-isopropylidene-α-D-glucopyranoside, the same operation as in Reference Example 2 → Reference Example 9 was performed,
The title compound having the following physical properties was obtained. TLC: Rf 0.13 (hexane: ethyl acetate = 4:
1).

Example 18 Methyl 2-O-tetradecanoyl-3-O- (9-phenylnonanoyl) -4-O-sulfo-α-D-glucopyranoside sodium salt

Embedded image Reference Example 2 → Reference Example 3 using 9-phenylnonanoic acid and the compound produced in Reference Example 34 instead of myristic acid.
→ Reference Example 4 → Example 1 → The same operation as in Example 2 was performed to obtain the compound of the present invention having the following physical property values. TLC: Rf 0.33 (chloroform: methanol: water =
40: 10: 1), IR (KBr): ν 3503, 2925, 2853, 1742, 1638, 146
7, 1250, 1168, 1122,1052, 991, 813, 748, 698, 607
cm ^-1 .

Example 19 Methyl 2-O-tetradecanoyl-3-O-tetradecanoyl-6-O-sulfo-α-D-glucopyranoside sodium salt

Embedded image The same operation as in Example 1 was carried out using the compound produced in Reference Example 3 to obtain a compound of the present invention having the following physical data. TLC: Rf 0.34 (chloroform: methanol: water =
40: 10: 1), IR (KBr): ν 3480, 2956, 2918, 2850, 1737, 147
0, 1253, 1229, 1171, 1062, 1004, 828, 719 cm ^-1 .

Example 19 (1) Methyl 2-O-dodecanoyl-3-O-dodecanoyl-6-O-sulfo-α-D-glucopyranoside sodium salt

Embedded image Instead of the compound prepared in Reference Example 3, methyl 2-O
Using -dodecanoyl-3-O-dodecanoyl-α-D-glucopyranoside, the same operation as in Example 19 was performed,
The compound of the present invention having the following physical properties was obtained. TLC: Rf 0.20 (chloroform: methanol: water =
40: 10: 1), IR (KBr): ν 3482, 2918, 2850, 1736, 1639, 147
1, 1416, 1382, 1239,1172, 1112, 1063, 1006, 942, 8
29, 718 cm ^-1 .

Example 20 Methyl 2-O-tetradecanoyl-3-O-tetradecanoyl-4-O-sulfo-6-O-sulfo-α-D-
Glucopyranoside disodium salt

Embedded image The same operation as in Example 1 was performed using the compound prepared in Example 19 to obtain the compound of the present invention having the following physical data. TLC: Rf 0.42 (chloroform: methanol: water =
40: 10: 1), IR (KBr): ν 3505, 2925, 2853, 1740, 1631, 146
8, 1380, 1239, 1157,1065, 1034, 963, 845, 755, 617
cm ^-1 .

Example 20 (1) Methyl 2-O-dodecanoyl-3-O-dodecanoyl-4-O-sulfo-6-O-sulfo-α-D-glucopyranoside disodium salt

Embedded image Using the compound prepared in Example 19 (1), Example 2
The same operation as in Example 1 was carried out to obtain the compound of the present invention having the following physical data. TLC: Rf 0.12 (chloroform: methanol: water =
40: 10: 1), IR (KBr): ν 3502, 2925, 2854, 1739, 1630, 146
6, 1379, 1239, 1158,1113, 1085, 1065, 1035, 845, 7
54, 616 cm ^-1 .

Example 21 2-O-tetradecanoyl-3-O-tetradecanoyl-6-O-sulfo-D-glucose sodium salt

Embedded image Using the compound prepared in Example 3 (1), the same operation as in Reference Example 9 was carried out to obtain the compound of the present invention having the following physical properties. TLC: Rf 0.16 (chloroform: methanol: water =
40: 10: 1), IR (KBr): ν 3460, 2918, 2850, 1738, 1470, 125
7, 1174, 1037, 985, 815, 768, 720, 614 cm ^-1 .

Reference Example 35 Methyl 2-O-benzyl-4,6-O-isopropylidene-α-D-glucopyranoside and methyl 2-O
-Benzyl-3-O-benzyl-4,6-O-isopropylidene-α-D-glucopyranoside

Embedded image To a solution of the compound (468 mg) produced in Reference Example 1 in dimethylformamide (10 ml) was added 60% sodium hydride (80 mg). Benzyl bromide was added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 1: 1) to give the title compound (1) (456 mg) and the title compound (2) (141 mg) having the following physical data. Was obtained respectively. Reference Example 35 (1) TLC: Rf 0.64 (hexane: ethyl acetate = 1:
1). Reference Example 35 (2) TLC: Rf 0.91 (hexane: ethyl acetate = 1:
1).

Reference Example 36 Methyl 2-O-benzyl-3-O-tetradecanoyl-4-O-tetradecanoyl-6-O- (t-butyldimethylsilyl) -α-D-glucopyranoside

Embedded image Reference Example 3 using compound (1) produced in Reference Example 35
→ Reference Example 4 → The same operation as in Reference Example 2 was carried out to obtain the title compound having the following physical properties. TLC: Rf 0.74 (hexane: ethyl acetate = 4:
1).

Example 22 Methyl 2-O-benzyl-3-O-tetradecanoyl-4-O-tetradecanoyl-6-O-sulfo-α-D
-Glucopyranoside sodium salt

Embedded image Using the compound produced in Reference Example 36, the same operation as in Example 2 → Example 1 was performed to obtain the compound of the present invention having the following physical property values. TLC: Rf 0.62 (chloroform: methanol: water =
40: 10: 1), IR (KBr): ν 3602, 2920, 2850, 1741, 1469, 125
6, 1164, 1109, 1068,1005, 948, 832, 759, 696 c
m ^-1 .

Example 23 Methyl 3-O-tetradecanoyl-4-O-tetradecanoyl-6-O-sulfo-α-D-glucopyranoside sodium salt

Embedded image Using the compound produced in Example 22, the same operation as in Reference Example 9 was carried out to obtain the compound of the present invention having the following physical data. TLC: Rf 0.29 (chloroform: methanol: water =
40: 10: 1), IR (KBr): ν 3470, 2918, 2850, 1745, 1634, 147
0, 1416, 1374, 1254,1180, 1071, 1057, 1011, 818, 7
53, 719, 584 cm ^-1 .

Example 24 Methyl 3-O-tetradecanoyl-4-O-tetradecanoyl-2-O-sulfo-α-D-glucopyranoside sodium salt

Embedded image Using the compound prepared in Reference Example 36, the same operation as in Reference Example 9 → Example 1 → Example 2 was performed to obtain the compound of the present invention having the following physical properties. TLC: Rf 0.37 (chloroform: methanol: water =
40: 10: 1), IR (KBr): ν 3542, 2957, 2920, 2851, 1747, 163
9, 1469, 1255, 1173,1114, 1025, 826, 721, 586 c
m ^-1 .

Example 25 Methyl 2-O-benzyl-3-O-tetradecanoyl-4-O-sulfo-α-D-glucopyranoside sodium salt

Embedded image Using the compound produced in Reference Example 35, the same operation as in Reference Example 2 → Reference Example 3 → Reference Example 4 → Example 1 → Example 2 was carried out to obtain a compound of the present invention having the following physical properties. TLC: Rf 0.47 (chloroform: methanol: water =
40: 10: 1).

Example 26 Methyl 3-O-tetradecanoyl-4-O-sulfo-
α-D-glucopyranoside sodium salt

Embedded image Using the compound produced in Example 25, the same operation as in Reference Example 9 was performed to obtain the compound of the present invention having the following physical data. TLC: Rf 0.22 (chloroform: methanol: water =
40: 10: 1), IR (KBr): ν 3448, 2925, 2854, 1732, 1468, 137
7, 1258, 1051, 1023, 993, 798, 753, 607 cm ^-1 .

Example 27 Methyl 3-O- (2-tetradecanyl) hexadecanoyl-4-O-sulfo-6-O-sulfo-α-D-glucopyranoside disodium salt

Embedded image Instead of myristic acid, using (2-tetradecanyl) hexadecanoic acid and the compound (1) produced in Reference Example 35, the same operation as in Reference Example 2 → Reference Example 3 → Example 1 → Reference Example 9 was performed, The compound of the present invention having the following physical properties was obtained. TLC: Rf 0.10 (chloroform: methanol: water =
40: 10: 1), IR (KBr): v 3529, 2920, 2851, 1720, 1639, 146
8, 1242, 1036, 1000,792, 741, 609 cm ^-1 .

Reference Example 37 Methyl 4-O-tetradecanoyl-6-O-tetradecanoyl-α-D-glucopyranoside

Embedded image Reference Example 3 using compound (2) produced in Reference Example 35
→ Reference Example 2 → The same operation as in Reference Example 9 was performed to obtain the title compound having the following physical data. TLC: Rf 0.13 (hexane: ethyl acetate = 4:
1).

Example 28 Methyl 4-O-tetradecanoyl-6-O-tetradecanoyl-2-O-sulfo-α-D-glucopyranoside sodium salt (1) and methyl 4-O-tetradecanoyl- 6-O-tetradecanoyl-2-O-sulfo-3-O-sulfo-α-D-glucopyranoside disodium salt (2)

Embedded image The same operation as in Example 1 was carried out using the compound produced in Reference Example 37, and the compound of the present invention (1) having the following physical data was obtained.
And the present compound (2) were obtained.

Example 28 (1) TLC: Rf 0.35 (chloroform: methanol: water =
40: 10: 1), IR (KBr): ν 3362, 2919, 2850, 1749, 1469, 141
3, 1392, 1255, 1178,1157, 1083, 1063, 990, 829, 75
5, 719, 669, 626, 577 cm ^-1 .

Example 28 (2) TLC: Rf 0.23 (chloroform: methanol: water =
40: 10: 1), IR (KBr): ν 3507, 2922, 2851, 1739, 1637, 146
9, 1377, 1231, 1170,1053, 997, 922, 828, 736, 587
cm ^-1 .

Reference Example 38 2-O-tetradecanoyl-3-O-tetradecanoyl-4,6-O-isopropylidene-1-O-sulfo-α
-D-glucopyranoside sodium salt

Embedded image Reference Example 1 → Reference Example 2 → Reference Example 9 → The same operation as in Example 1 was performed using benzyl α-D-glucopyranoside instead of methyl α-D-glucopyranoside, and the title compound having the following physical property values was obtained. I got TLC: Rf 0.51 (chloroform: methanol: water =
40: 10: 1).

Example 29 2-O-Tetradecanoyl-3-O-tetradecanoyl-1-O-sulfo-α-D-glucopyranoside sodium salt

Embedded image The same operation as in Reference Example 3 was carried out using the compound produced in Reference Example 38 to obtain the compound of the present invention having the following physical data. TLC: Rf 0.17 (chloroform: methanol: water =
40: 10: 1), IR (KBr): ν 3468, 2920, 2851, 1744, 1637, 147
0, 1235, 1170, 1113,1086, 1034, 923, 848, 720, 607
cm ^-1 .

Reference Example 39 D-Glucal

Embedded image 3,4,6-tri-O-acetyl-D-glucal (3
To a solution of g) in methanol (55 ml) was added sodium methoxide (1.79 g). The reaction mixture was stirred at room temperature for 1 hour. Add resin (Bio-Rad AG 50W-X) to the reaction mixture.
8, H ⁺ body) to make it neutral. The reaction mixture was filtered and concentrated to give the title compound having the following physical data. TLC: Rf 0.23 (chloroform: methanol: water =
40: 10: 1).

Reference Example 40 3-O-tetradecanoyl-4-O-tetradecanoyl-D-glucal

Embedded image Using the compound prepared in Reference Example 39, the same operation as in Reference Example 4 → Reference Example 2 → Example 2 was performed to obtain the title compound having the following physical data. TLC: Rf 0.33 (hexane: ethyl acetate = 4:
1).

Example 30 3-O-tetradecanoyl-4-O-tetradecanoyl-6-O-sulfo-D-glucal sodium salt

Embedded image The same operation as in Example 1 was performed using the compound produced in Reference Example 40 to obtain the compound of the present invention having the following physical data. TLC: Rf 0.49 (chloroform: methanol: water =
40: 10: 1), IR (KBr): ν 3581, 2957, 2919, 2850, 1736, 165
5, 1469, 1232, 1180,1107, 1073, 1011, 818, 721, 58
6 cm ^-1 .

Example 30 (1) 3-O-tetradecanoyl-4-O-tetradecanoyl-6-O-sulfo-D-galactal sodium salt

Embedded image Reference Example 39 → Reference Example 40 → Example 30 using 3,4,6-tri-O-acetyl-D-galactal instead of 3,4,6-tri-O-acetyl-D-glucal
By the same operation as described above, the compound of the present invention having the following physical properties was obtained. TLC: Rf 0.39 (chloroform: methanol: water =
40: 10: 1), IR (KBr): ν 3486, 2919, 2850, 1743, 1657, 146
9, 1380, 1233, 1180,1071, 1010, 807, 721, 579 c
m ^-1 .

Example 31 1,2-Dideoxy-3-O-tetradecanoyl-4-
O-tetradecanoyl-6-O-sulfo-D-glucose sodium salt

Embedded image The same operation as in Reference Example 9 was performed using the compound prepared in Example 30, to obtain the compound of the present invention having the following physical data. TLC: Rf 0.50 (chloroform: methanol: water =
40: 10: 1), IR (KBr): ν 3488, 2917, 2850, 1738, 1641, 147
0, 1256, 1231, 1178, 1103, 1058, 949, 809, 719, 67
2, 604 cm ^-1 .

Reference Example 41 2 (anti)-(2-decanyl) dodecanoyloxy-1-hydroxycyclohexane

Embedded image The same operation as in Reference Example 2 was carried out using (2-decanyl) dodecanoic acid and trans-1,2-cyclohexanediol instead of myristinic acid to obtain the title compound having the following physical data. TLC: Rf 0.68 (hexane: ethyl acetate = 4:
1).

Example 32 2 (anti)-(2-Decanyl) dodecanoyloxycyclohex-1-yl-O-sulfonic acid sodium salt

Embedded image Using the compound produced in Reference Example 41, the same operation as in Example 1 was performed to obtain the compound of the present invention having the following physical data. TLC: Rf 0.40 (chloroform: methanol: water =
40: 10: 1), IR (KBr): ν 3499, 2924, 2854, 1731, 1644, 146
4, 1379, 1265, 1160,1065, 972, 869, 780, 617 c
m ^-1 .

Reference Example 42 (1R, 3S, 4S, 6R, 9S, 10R) -9-methoxy-10-hydroxy-3,4-dimethoxy-3,4
-Dimethyl-2,5,8-trioxabicyclo [4.
4.0] Decane (1) and (1S, 3R, 4R, 6
(R, 7S, 10R) -7-methoxy-10-hydroxy-3,4-dimethoxy-3,4-dimethyl-2,5,8
-Trioxabicyclo [4.4.0] decane (2)

Embedded image Methyl β-D-xylopyranoside (1 g) and 2,2
To a solution of 3,3-tetramethoxybutane (1.6 g) in methanol (15 ml) was added trimethyl orthoformate (2.6 ml) and camphorsulfonic acid (70 mg) under an argon atmosphere. The reaction mixture was refluxed for 8 hours.
Sodium bicarbonate was added to the reaction mixture, which was concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 1) to give a mixture (1.64) of the title compound having the following physical data.
g) was obtained. TLC: Rf 0.35 (hexane: ethyl acetate = 1:
1).

Reference Example 43 (1R, 3S, 4S, 6R, 9S, 10R) -9-methoxy-10-benzyloxy-3,4-dimethoxy-
3,4-dimethyl-2,5,8-trioxabicyclo [4.4.0] decane (1) and (1S, 3R, 4
R, 6R, 7S, 10R) -7-methoxy-10-benzyloxy-3,4-dimethoxy-3,4-dimethyl-
2,5,8-trioxabicyclo [4.4.0] decane (2)

Embedded image The same operation as in Reference Example 19 was carried out using the mixture of the compounds produced in Reference Example 42 to give the title compounds having the following physical data. Reference Example 43 (1) TLC: Rf 0.25 (hexane: ethyl acetate = 5:
1). Reference Example 43 (2) TLC: Rf 0.18 (hexane: ethyl acetate = 5:
1).

Example 33 Methyl 3-O-tetradecanoyl-4-O-tetradecanoyl-2-O-sulfo-β-D-xylopyranoside

Embedded image Reference Example 2 using compound (1) produced in Reference Example 43
0 → Reference Example 2 → Reference Example 9 → Perform the same operation as in Example 1,
The compound of the present invention having the following physical properties was obtained. TLC: Rf 0.43 (chloroform: methanol: water =
80: 20: 1), IR (KBr): ν 3474, 2919, 2850, 1742, 1638, 146
9, 1379, 1257, 1169,1074, 995, 922, 800, 721, 613
cm ^-1 .

Example 33 (1) Methyl 2-O-tetradecanoyl-3-O-tetradecanoyl-4-O-sulfo-β-D-xylopyranoside

Embedded image TLC: Rf 0.33 (chloroform: methanol: water =
80: 20: 1), IR (KBr): ν 3449, 2919, 2850, 1751, 1728, 163
8, 1470, 1274, 1169,1073, 994, 814, 718, 584 c
m ^-1 .

[0251]

Formulation Example Formulation Example 1 After mixing the following components by a conventional method, the solution is sterilized by a conventional method, filled into ampoules in 1 ml portions, freeze-dried by a conventional method, and contains 50 mg of active ingredient in one ampule. 100 ampoules were obtained.・ Methyl 2-O-tetradecanoyl-3-O-tetradecanoyl-4-O-sulfo-α-D-glucopyranoside sodium salt… 5.00 g 55% ethanol… 100 ml

Formulation Example 2 The following components were mixed in a conventional manner, and the mixture was tableted to give 100 tablets each containing 5 mg of the active ingredient.・ Methyl 2-O-tetradecanoyl-3-O-tetradecanoyl-4-O-sulfo-α-D-glucopyranoside sodium salt 500 mg ・ Carboxymethylcellulose calcium 200 mg ・ Magnesium stearate 100 mg・ Microcrystalline cellulose …… 9.2 g

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 309/30 C07D 309/30 4H050 C07F 9/09 C07F 9/09 K C07H 13/04 C07H 13/04 / / A61K 31/215 A61K 31/215 31/351 31/351 31/7024 31/7024 A61P 1/00 A61P 1/00 1/16 1/16 11/02 11/02 11/06 11/06 13/12 13/12 27/02 27/02 29/00 29/00 101 101 31/18 31/18 37/00 37/00 F term (reference) 4C057 BB02 CC03 DD03 GG02 GG03 HH03 JJ03 4C062 AA17 AA19 4C086 AA02 AA03 BA07 EA03 MA04 NA14 ZB09 ZB26 ZC55 4C206 AA02 AA03 DB11 JA02 MA04 ZB09 ZB26 ZC55 4H006 AA01 AA03 AB20 4H050 AA01 AB20

Claims (3)

[Claims] 1. A compound of the general formula (I) [In the formula, A represents an oxygen atom or a methylene group, R ⁰
And R ¹ are each independently a hydrogen atom, a hydroxyl group,
A C1-8 alkoxy group, a C1-8 alkylthio group, a halogen atom, a C1-4 alkoxy group substituted with a phenyl group, a t-butyldimethylsilyloxy group, a t-butyldiphenylsilyloxy group, or a sulfate group (—OSO ₃ H
R ² and R ³ are each independently
(1) Formula (In the formula, G represents a single bond, a C2-30 oxycarbonylalkylene group, a C3-30 oxycarbonylalkenylene group or a C3-30 oxycarbonylalkynylene group, and R ⁵ represents a hydrogen atom or a compound represented by the formula: (Wherein, T ring represents a C5~15 carbon ring, R ⁷ is a hydrogen atom, C1-8 alkyl group, an C1-8 alkoxy group or a halogen atom, m represents. 1, 2 or 3) J represents a C1-30 alkylene group, a C2-30 alkenylene group or a C2-30 alkynylene group (however, a C1-30 alkylene group, a C2
—CH ₂ — in the 30 alkenylene group or the C 2-30 alkynylene group may be replaced by —O—, —S— or —NR ⁹ —. R ⁹ represents a hydrogen atom or a C1-8 alkyl group. And R ⁶ is a hydrogen atom or a formula (Wherein, W ring represents a C5~15 carbocycle, R ⁸ represents a hydrogen atom, C1-8 alkyl group, an C1-8 alkoxy group or a halogen atom, n represents. 1, 2 or 3) Represents the group shown. ), (2)
Formula (Wherein Y represents a single bond or a C1-8 alkylene group, p and q each independently represent an integer of 6 to 12), or a group represented by the formula (3): (In the formula, J and J ¹ each independently represent the same meaning as J, and R ⁶ and R ⁶¹ each independently represent the same meaning as R ^6. ) E represents -OCO- or -ER ³
Represents a hydrogen atom, a hydroxyl group, a C1-8 alkoxy group, a C1-4 alkoxy group substituted with a phenyl group, a t-butyldimethylsilyloxy group or a t-butyldiphenylsilyloxy group, and R ⁴ represents a hydrogen atom, a halogen atom represents an atom or -CH ₂ -R ¹⁰ group, R ¹⁰ is a hydrogen atom, a hydroxyl group, C1-8 alkoxy group, a phenyl group and a substituted C
1-4 alkoxy group, t-butyldimethylsilyloxy group, t-butyldiphenylsilyloxy group, sulfate group (-
OSO ₃ H group), - OCOR ¹² group (wherein, R ¹² is the R ²
Or, has the same meaning as R ³ . ) Or R ¹⁰ and R ^{1 taken} together represent -O-, Represents a single bond or a double bond. However, (1)
G is a C2-30 oxycarbonylalkylene group, C3
30 oxycarbonylalkenylene group or C3-30
R ⁵ represents G when representing an oxycarbonylalkynylene group;
(2) R ⁰ , R ¹ ,
At least one group of R ¹⁰ is a sulfate group (—OSO ₃ H
(3) R ⁰ , R ¹ , -OCO
The R ² and -ER ³ groups are not bonded to the same carbon atom. Or a non-toxic salt thereof. 2. The compound of formula (IA) (Wherein all symbols have the same meanings as defined in claim 1). The glucopyranose derivative or a non-toxic salt thereof according to claim 1, which is represented by the formula: 3. A compound of the formula (IB) (Wherein all symbols have the same meanings as defined in claim 1) or the non-toxic salt thereof according to claim 1.