WO1996041636A1

WO1996041636A1 - Antiasthmatic agent

Info

Publication number: WO1996041636A1
Application number: PCT/JP1996/001534
Authority: WO
Inventors: Kou Okumura; Tomoyasu Ra; Kazunori Kato; Shohei Makino; Hironori Sagara; Naofumi Takahashi; Hisami Shinohara
Original assignee: The Nisshin Oil Mills, Ltd.
Priority date: 1995-06-13
Filing date: 1996-06-06
Publication date: 1996-12-27
Also published as: AU5911196A

Abstract

An antiasthmatic agent containing a glycolipid derivative represented by general formula (I) or a pharmaceutically acceptable salt thereof as the active ingredient, wherein X represents either of the groups of formulae (A) and (B); n is an integer of 0 to 10, and R represents a branched C19-C39 hydrocarbon chain.

Description

Specification

Name of the invention

Anti-asthma drugs

Technical field

The present invention relates to an anti-asthmatic drug containing a glycolipid derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

Background art

Asthma attacks include an immediate asthmatic response (IAR) followed by a delayed asthmatic response (LAR). Mast cells play a major role in the immediate asthmatic response. That is, the inhaled antigen binds to a specific IgE antibody on the surface of the mast cell, causes cross-linking (pludging) of multiple IgE antibodies, activates the fertile cells, and degranulates. Newly synthesized leukotrienes C ₄ and D ₄ (LTC _4. LTD ₄ ), platelet activating factor (PAF), prostaglandin D ₂ (PGD ₂ ) and thromboxane A ₂ (TXA ₂ ) from activated mast cells It is released, and vasoactive substances such as histamine, bronchial smooth muscle contractile substances, and granulocyte chemotactic factor are released from the granules. These chemical mediators cause airway constriction, edema of the airway mucosa, and enhanced airway secretion, resulting in the appearance of IAR. In addition, migratory actives cause inflammatory cells, such as eosinophils and neutrophils, to migrate to the airway mucosa, preparing for the subsequent delayed asthmatic response. In late asthmatic response, infiltration of the airway mucosa of eosinophils is characteristic, leukotriene B _4, which also has vascular permeability enhancing effect of activated eosinophils (LTB ₄₎ and the bronchial smooth muscle contraction action LTC 4 is released, causing edema and airway constriction again. LTB ₄ is also eosinophil chemotactic activity, these reactions are amplified. Thus, in bronchial asthma, repeated exposure to antigens releases various chemical mediators from the dilated cells, and IAR and LAR are repeated in the respiratory tract. In particular, in LAR, eosinophils accumulate in the respiratory tract and, when activated, release various cytotoxic factors Is thought to cause airway inflammation by causing damage to the airway epithelial cells, which in turn enhances the airway response, exacerbates asthma, and causes chronic disease. Emphasis is placed on the suppression of eosinophil migration. Basic therapeutic drugs that suppress bronchial smooth muscle contraction (the main pathological condition of IAR) include sympathomimetic drugs and xanthine derivative-anticorin drugs, which can effectively suppress bronchoconstriction. On the other hand, there are problems such as side effects such as hand tremor and arrhythmia, and drowsiness when the substance has an antihistaminic effect. On the other hand, a therapeutic drug targeting eosinophils has not yet been developed and marketed for allergic inflammation such as LAR. In recent years, the importance of adhesion molecules in the inflammatory response has been discussed, and the involvement of adhesion molecules in LAR has also been studied in asthma classified as allergic unilateral inflammation. Adhesion molecules E-selectin (ELAM-1), ICAM-1 and VCAM-1 are expressed on vascular endothelial cells, and by blocking these, eosinophil infiltration is suppressed and LAR is reduced. There is a concept of suppression, and the possibility of drug development that can effectively suppress LAR has emerged. Examples of these are disclosed in Japanese Patent Publication No. 6-502195 (W093 / 02702), WO 93/15098 and Japanese Patent Publication No. 5-507923 (W091 / 19501).

Japanese Patent Application Publication No. 6-502195 describes the use of an antibody capable of binding to ELAM-1 for the treatment of asthma, but there is no specific description of the use of glycolipids in the block of adhesion molecules. Is not disclosed. WO 93/15098 also states that Lewis-type sugar chain derivatives can be used for the treatment and prevention of asthma, but does not show any pharmacological data on these sugar chain derivatives.

In addition, Japanese Patent Application Publication No. 5-507923 describes that a compound having a selectin-binding oligosaccharide component can be used for treating asthma, but does not provide data on the therapeutic effect of asthma. On the other hand, no information has been available on the relevance of adhesion molecules for the suppression of IAR.

Furthermore, Japanese Patent Application Laid-Open No. 6-80667, which is assigned to the present applicant, discloses a compound represented by the general formula (I):

[Where X is

and

COOH

Selected from the group consisting of H ₃ C, n is an integer from 0 and 1 to 10, and R is a branched hydrocarbon chain having from 19 to 39 carbon atoms.)

It is disclosed that the glycolipid derivative represented by and a pharmaceutically acceptable salt thereof are useful as a ligand binding to ELAM-1, and can be used as an anti-inflammatory agent, a therapeutic agent for rheumatoid arthritis and a cancer metastasis inhibitor. . However, it does not teach the possibility of suppressing the immediate allergic reaction and the subsequent delayed allergic reaction.

Summary of the Invention

The present invention provides an anti-allergic reaction which suppresses an immediate allergic reaction and a subsequent delayed allergic reaction using the glycolipid derivative of the general formula (I). Lergi monotherapy, especially for providing anti-asthmatics.

The present inventors further studied the mechanism of action of the glycolipid derivative represented by the general formula (I), and confirmed that the instantaneous and late asthmatic reactions were markedly suppressed. This has led to the present invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the inhibitory effect of guinea pigs on airway resistance after antigen exposure. FIG. 2 shows the inhibitory effect on eosinophil infiltration in guinea pig airway tissue.

FIG. 3 shows the appearance rate of eosinophils in bronchial blood vessels in guinea pigs.

FIG. 4 shows the incidence of eosinophils in pulmonary blood vessels of guinea pigs.

FIG. 5 shows the mechanism of action of the glycolipid derivative of the present invention.

FIG. 6 shows the mechanism of action of the glycolipid derivative of the present invention.

FIG. 7 shows the inhibitory effect of guinea pigs on airway resistance after antigen exposure. FIG. 8 shows the histamine concentration in the blood of a guinea pig immediately after the confirmation of the immediate asthmatic reaction.

FIG. 9 shows the inhibitory effect on eosinophil infiltration in guinea pig airway tissue.

Disclosure of the invention

According to the present invention, the following general formula (I)

(Where X is

and

COOH

Wherein n is an integer of 0 and 1 to 10, and R is a branched hydrocarbon chain having a carbon number of 19 to 39] or a pharmaceutically acceptable derivative thereof. An anti-asthmatic drug comprising a salt acceptable as an active ingredient is provided.

In the above general formula (I), the residue represented by RC (O) is a branched fatty acid residue having 20 to 40 carbon atoms. As a specific example of the corresponding fatty acid, 2-hexylte Tradecanoic acid, 2-year-old cutilte tradecanic acid, 2-decylte tradecanic acid, 2-dodecylte tradecanic acid, 2-dodecylhexadecanoic acid, 2-dodecyloctadecanoic acid, 2-dodecyleicosanoic acid, 2-tetradecyl Hexadecanoic acid, 2-tetradecyloctadecanoic acid, 2-tetradecyleicosanoic acid, 2-hexadecyloctadecanoic acid, 2 monohexadecyleicosanoic acid, 2-year-old kutadecyleicosanoic acid , 3- to quinlute trdecanoic acid, 3- to octylte toradecanoic acid, 3- to decylte tradecanoic acid, 3- to dodecylte toradecanoic acid, 3- to dodecylhexadecanoic acid, Acid, 3-dodecyleicosanoic acid, 3-tetradecylhexadecanoic acid, 3-tetradecyloctadecanoic acid, 3-tetradecyleicosanoic acid, 3-hexadecyloctadecanoic acid, 3-hexene Examples include sadesyl eicosanoic acid and 3-octadecyl eicosanoic acid.

Examples of the pharmaceutically acceptable salt of the glycolipid derivative represented by the general formula (I) include salts of alkaline metals such as sodium and potassium and salts of alkaline earth metals such as calcium and magnesium. I can give it.

In place of the compounds of the general formula (I) which can be used as active ingredients in the present invention Tabular examples are listed below.

D- (5-acetamido-3,5-dideoxy-D-glycero-D-galacto-2-nonurobilanosylic acid)-(2-3) -0- / 3-D -galacttopyranosyl (1 → 4) —0— [Na-ichi-L-fucopyrano shiro (1 → 3)] -1- 0- 3-D-Darcovirano shiro (1 → 1) ii 2--0—Paraller (2-dodecylte-tradecanoyl) Ndyl monoethane-1,2-diol

0— (5-acetamido 3,5-dideoxy D—glycero-one D—galacto 2-nonurobilanosylic acid) — (2 → 3) -0- ^ -D—galact topyranosyl (1 → 4) 1-0— [Naichi L-fucopyranosyl 1 (1 → 3)) 1-0—1D—glucovirano shiro (1 → 1) 1 5—0—Parr (2—dodecylte toradecanyl) ami nobenziru 3-oxanthan-1,5-diol

0— (5-acetamido-3,5-didequine D-glycero α-D-galacto-2-nonurobilanosylic acid) one (2 → 3) -0- ^ -D —galactobirano shiro (1 → 4) 1-0 [α-L-fucopyrano shiro (1 → 3)] 1-0—; 3—D-glucoviranone (1 → 1) 1 8-0—Parallel (2—dodecylte tradacanyl) ami nobenziru 3,6-dioxaoctane-1,8-diol

0— (5-acetamido 3, 5-dideoxy D—glycemic α-

D—Galactone 2-Nonuloviranosyl acid) One (2 → 3) -0- / 3-D —Galactone tovilanosyl one (1 → 4) One 0— [a—L—Fucopyrano siro (1 → 3)] 1-0-1 D-glucovirano shiro (1 → 1)-11 -0- Parr (2-dodecylte toradecanol) aminobenzyl-1,3,6,9-trioxanedecane-1,1,11-diol

0— (5-acetamido-1,3—dideoxy D-glycero-α—D—galacto-2-nonurobilanosylic acid) 1 (2 → 3) -0- 3-D —Galac Tovirano Shiro (1 → 4) -0- [One L—Fucopyranosyl 1 (1 → 3)] One 0—3—D—Darcopyranosyl 1 (1 → 1) — 14—0— 2—dodecylte toradecanol) aminobenzyl 3.6, 9. 12—te tolaxatetradecane 1,14-diol

0- (5-acetamido-3,5-dideoxy-D-glycero-one D-galacto-2-nonurobilanosylic acid)-(2 → 3) -0- / 3-D-galactoviranosyl (1 → 4) — 0— (Naichi L—Fucopyrano shiro (1 → 3)) One 0— / S—D—Glucobiranonelu (1 → 1) — 20—0— Parr (2-Dodecylte Tradecanoyl) Aminobenzyl 3, 6, 9, 12, 15, 18-hexaoxicosan-1,1,20-diol

0— (5-acetamido) 3.5—dideoxy D—glycerol 1—D—galacto 1—nonurobilanosylic acid 1— (2—3) -0- / 3-D—galactovirano shiro (1 → 4) —0— [α— L—fucopyranosyl (1 → 3)) 1 0 — ^ — D—Darcovirano sirou (1 → 1) -26-0- Parr (2— dodecylte toradecanyl) ami nobenziru 3, 6, 9. 12. 15, 18, 21. 24—Octoxaxa 1, 1, 26—Diol

0— (5-acetamido) 3.5—dideoxy D—glycerol α—D—galacto-2-nonurobilanosylic acid 1 (2 → 3) — 0— — D—galactoviranosyl 1 (1 → 4) 1 0— [α—L—Fucopyranosyl (1 → 3)] 1 0—3—D—Darcovirano Siro (1 → 1)-32-0- Parr (2—Dodecylte Tradecanoyl) Aminobenzyl 1 3, 6, 9, 12, 15, 18, 21, 24, 27, 30-decaoxide triacontan-1, 32-diol

0— (5-acetamide 3,5—dideoxy D—glycemic monohydrate D—galacto 2-nonurobilanosilic acid) 1 (2 → 3) -0-^-D—galactovirano shiro (1 → 4 ) -0- [Hiichi L-Fucopyranosyl (1 → 3)] 1-0— / S—D—Darcovirano shiro (1 → 1) 1—2—0—Par (2—Tetradecylhexadecanoyl) ami benzoylethane 1,2-diol

0— (5-acetamido) 3.5—dideoxy D—glycemic D-galactol 2-nonuloviranosylic acid) — (2 → 3) -0-yS-D galactopyranosyl (1 → 4) One 0— [One L-fucopyrano shiro (1 → 3)] One 0 — ^ — D—Dalcopyranosyl 1 (1 → 1) — 5—0—Parallel (2-Tetradecylhexadecanoyl) Njiru 3-oxo sapentane 1,5-diol

0— (5-acetamido-3,5-dideoxy D—glycerol α—D—galacto-2-nonurobilanosylic acid) 1 (2 → 3) — 0— ー D—galactobirano shiro (1 → 4) — 0— [α-L-fucopyrano shiro (1 → 3)] 1 0—S—D—glucovirano shiro (1 → 1) 1 8—0—para (2—tetradecylhexadecanoyl) aminobenzyl-3 6-dioxaoctane-1,8-diol

0— (5-acetamido-3,5-dideoxy D—glycerol α—D—galacto-2-nonuloviranosylate) 1 (2 → 3) — 0—S—D 1 galactovirano shiro (1 → 4) —◦1 Ο— L-fucopyrano siro (1-3)] 1 0— / 3— D-glucopyranosil 1 (1 → 1) —1 1 1 Ο—Parallel (2-tetradecylhexadecanoyl) amino Benzyl-3,6.9 Trioxanedecane-1,11-1

0— (5-acetamido-3,5-dideoxy-D-glycerol α-D—galacto-2-nonurobilanosylic acid) 1 (2—3) —0— — D —galactopyrano siro (1 → 4) — 0— [α-L-fucopyrano shiro (1 → 3)] 1 0— ^ — D-glucovirano shiro (1 → 1)-14 -0- p- (2-tetradecylhexadecanoyl) amino Benziru 3, 6, 9, 12—te Traoxate Toradecan-1.14-diol 0— (5-acetamide-1,3—dideoxy D-glycemic D-galactone 2-nonurobilanosylic acid) 1 (2 → 3) -0-β-Ό (1 → 4) -0- [cr—L—fucopyrano shiro (1 → 3)] 1 0 — ^ — D—darcopyrano shiro (1 → 1) —20—0—para (2—tetradecylhexadecanoyl) ) Ami nobenzil 1, 3,6,9 1 2.1,5,18-hexaoxysaicosan 1, 20-diol

0— (5-acetamido) 3.5—didequinone D—glycerol α—D—galacto-2-nonurobilanosylic acid) 1 (2 → 3) —0— ^ 1 D galactotopyranosyl (1 → 4) 1 0-[1: L-fucopyrano shiro (1 → 3)] 1 0-3-D-darcovirano shiro (1 → 1)-26-0-para (2-tetradecylhexadecanoyl) Novenziru 3, 6, 9. 1 2. 1 5, 1 8, 2 1, 2 4 1-year-old kutoxaxa 1-, 26-diol

0— (5-acetamido-3,5-dideoxy-1 D-glycero α-D—galacto-2-nonurobilanosylic acid) 1 (2-3) -0- ^ -D —galactobyranosyl 1 (1 → 4) One 0— [α—L—Fucopyranosyl (1 → 3)] One 0—One D—Glucopyranosyl (1—1) —32—0—Para (2—tetradecylhexadecanoyl) amino Benziru 3, 6, 9, 1 2, 1 5. 1 8, 2 1.2 4, 2 7, 3 0—Decaoxadotriacontan-1,1,32-diol

0— (5-acetamido 3.5-dideoxy D-glycerol D-galacto 2-nonuloviranosylic acid) ― (2-3) -O-^-D —galactopyranosyl ( 1 → 4) —0— [a—L—Fucopyrano siro (1 → 3)] 1—0— / 9—D—Darcopyranosyl (1—1) —2—0—Parallel (2-hexadecyllo) Kutadecanoyl) ami nobenjiruethane-1, 2-diol

0— (5—acetamide 3,5—dideoxy D—glycemic α- D—Galacto 2—Nonulovirano silicic acid) 1 (2—3) — 0— ^ — D—Galac tovirano shiro (1 → 4) —0— [α—L-fucopyranosyl (1 → 3)) 1 0— 3—D—Glucopyranosyl mono (1 → 1) —5—0—Parallel (2-hexadecylloctadecanoyl) aminobenzyl-1-3-oxosapentane-1,5-diol

0- (5-acetamido-3,5-dideoxy-1 D-glycerol α-D-galacto-2-nonurobilanosylate) 1 (2 → 3) -0- β-Ό 1-galacttopyranosyl 1 (1 → 4) — 0— [Hiichi L-fucopyrano shiro (1 → 3)] 1—0—) 3—D-glucovirano shiro (1 → 1) 1—8—0—Parallel (2-hexadecyloctadecanoyl) ) Aminobenzyl-3,6-dioxaoctane-1,8-diol

0— (5-acetamido-3,5-dideoxy D—glycerol mono D—galacto 2-nonurobiranosylic acid) mono (2 → 3) -0- / 3-D monogalact 1 → 4) 1 0— [α-L-fucopyranosyl 1 (1 → 3)] 1 0— / δ—D—glucovirano siro (1 → 1) -1 1 1 0—Parallel (2-hexadecyl) 3,6,9—Trioxanedecane-1,1,1—diol

0— (5-acetamido) 3.5—dideoxy D—glycerol α—D—galactone 2-nonurobilanosylic acid) one (2—3) -0- -Ό one galactovirano shiro (1 → 4) -0- [α-L-fucopyrano shiro (1 → 3)] 10- ー D-glucovirano shiro (1 → 1)-1 4 -0- 1- (2-hexadecyloktadecanoyl) 1,6,9,12 2-Tetraoxate Tradecane-1,1,4-diol

0— (5-acetamido-1,3—dideoxy D—glycerol—D—galacto-2-nonurobilanosylic acid) — (2—3) -0-β-Ό—galactobirano shiro (1 → 4) One 0— [α—L—Fucopyrano shiro (1-3)] One 0— / 9—D—Glucovirano shiro (1 → 1) One 20—0— Parr (2-hexadecyloctadecanoyl) ami nobenziru 3,6,9,12,15,18-hexaoxysaicosan-1,20-diol

0— (5-acetamido-3,5-dideoxy-D-glycerol α-D-galacto-2-nonurobilanosylic acid) 1 (2 → 3) -0- / 3-D 1-galacttopyranosyl (1 → 4) —0— [“One L—Fucopyrano shiro (1 → 3)] One——D—Dalcopyrano syl (1 → 1) — 26— 0—Nora one (2—Hexadecylococtadeca) Noir) Ami Novenziru 3, 6, 9, 12, 15, 18, 21, 24—Taxioxahexacosan-1,26—Diol

0— (5-acetamido 3, 5-dideoxy D—glycerol α—

D—Galacto 2—Nonuloviranosylic acid) 1 (2 → 3) -0-) SD—Galact Topyrano siro (1 → 4)-0— [α-L-fucopyrano siro (1 → 3)] 1 0—j8—D—Darcopyrano sill (1 → 1)-32-0- Parr (2—Hexadecylloctadecanoyl) Ami Nobenziru 3, 6, 9, 12, 15, 18, 21 , 24, 27, 30—Decaoxadotriacontan-1, 32—diol

0— (5-acetamido) 3.5—dideoxy D—glycerol α—D—galacto 2-nonurobiranosylic acid) 1 (2—3) -O-^-D — 4) -0- [α-L-fucopyrano syl (1 → 3)] 1 0— — D-glucovirano shiro (1 → 1) — 2—0—para 1 (2-octadecyl icosanoyl) Aminobenzyl monoethane-1,2-diol

0- (5-acetamido-3,5-didequin-1 D-glycerol α-D-galacto-2-nonurobilanosyl acid) 1 (2-3) — 0-^ — D —galactobiranosyl 1 (1 → 4) -0- [α-L-fucopyrano shiro (1 → 3)] 1 0— — D-glucopyranosyl 1 (1 → 1) 1 5-0—para 1 (2-octadecyl icosanoyl) ) Aminobenzyl-3-oxa 1,5-Diol

0— (5-acetamido) 3.5—dideoxy D—glyceroyl D—galacto 1—nonurobilanosylic acid 1— (2 → 3) — 0——D galactobyranosyl 1 (1 → 4) One 0-[Hiichi L-Fucopyranosyl 1 (1 → 3)] 1-0-/ 3-D-Glucovirano shiro (1-1) 1 8-0-Parr (2-year-old Kuta decyl icosanoy) Le) ami nobenjiru 3, 6-dioxatan-1,8-diol

0— (5-acetamido-3,5-didequin-1 D-glyceroquinone D—galacto-2-nonurobilanosylic acid) one (2-3) one Q—β— Ό one galact topirano shiro (1 ~ * 4) — 0— [α—L—fucopyrano shiro (1 → 3)] 1 0—; S—D—Dalcopyrano shiro (1 → 1) — 1 1 -0- no, rah (2-octadecyl) Icosanoyl) ami nobenjiru 3,6,9—trioxanedecane-1,1,1—diol

0— (5-acetamido-3,5-dideoxy-D-glycerol α-D-galacto-2-nonurobilanosylic acid) 1 (2 → 3) — 0—; 9 1-D-galactobyranosyl (1 → 4) One 0— [Naichi L-Fucovirano Shiru (1 → 3)] One 0— / 3— D—Darcovirano Shiru (1 → 1)-1 4 -0- Parrer (2-year-old Kutadecsil Ikosanol) ) Aminobenzyl-3, 6, 9. 1 2—te Traoxate Tradecane 1,1 4—diol

0- (5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-2-nonurobilanosylic acid) 1 (2-3) -0- 0-D —galactobyranosyl 1 (1 → 4) — 0— [α-L-fucopyrano syl (1 → 3)] 1 0—; 3—D-darcopyrano syl 1 (1 → 1)-2 0—0— Parr (2-octadecyl icosano 3,7,9,1,2,1,5,18-hexaoxicosan-san 1.20-diol

0— (5-acetamido-3,5-dideoxy D—glycemic α-D—galacto 2-nonurobilanosylic acid) 1 (2 → 3) -0-β-Ό One galact Tovirano shiro (1 → 4) — 0— [One L—Fukopyranosyl one (1 → 3)] One 0— — D—Dalcovirano shiro (1 → 1)-26-0-no. Ra (2-octadecyl icosanoyl) amino benzyl 3, 6, 9, 12, 15, 18, 21, 24-octaoxahexacosan-1, 26-diol

0— (5-acetamido-1,3-dideoxy D-glycero α-D—galacto-2-nonurobilanosylic acid) 1 (2 → 3) -0- / 3-D —galactobiranosyl (1 → 4) -0- [α- L-fucopyrano syl (1 → 3)] 1 0-/?-1 D-glucovirano sylou (1 → 1) -32-0- Parr (2-octadecyl ico Sanoyl) ami nobenziru 3,6,9,12,15,18.21.24,27,30-decaoxadotriacontan-1,32-diol

3— 0— [1 (S) -carboxyethyl] 1 S— D—Galactopyrano silou (1 → 4) — 0— [Na-1 L-fucopyrano syl (1 → 3)] 1 0— 3— D—Darcovirano Shiro (1 → 1) — 2—O—Para (21 Dodecylte Tradecanoyl) Aminobenzyl 1-Ethane 1,2-Diol

3—0— [11 (S) -carboxyethyl] 1 / 9—D—galactopyranosyl (1 → 4) 1 0— [α—L—fucopyranosyl 1 (1 → 3)] 1 0 1; S—D—Darcopyrano shiro (1 → 1) — 5—0—Par (2—dode sylte tradecanol) ami nobenziru 3-oxapentane-1,5-diol

3-0- [1 (S) -carboxyethyl] 1-D-galact Tovirano siro (1-4) 1 0- [α-L-fucopyranosyl 1 (1 → 3)] 1 0 1 / 3- D—Darcoviranone (1 → 1) — 8—0—Para (2—dodecylte toradecanol) aminobenziru 3,6—Dioxaoctane-1,8-diol 3-0- [1— (S) —Carboxyethyl] 1 3— D—Galactovirano shiro (1—4) 1 0— [1 L—Fucopyrano shiro (1—3)] 1 0 1 ^ —D— Glucobilano shiro (1 → 1) 1 1 1-0-Par (2-dodecylte toradecanol) Aminobenzyl-1 3,6,9-Trioxazine Decane 1, 11-Diol

3-0- [1- (S) -carboxyethyl] 1 / 3- D-galactovirano shiro (1 → 4) —0— [naichi L-fucopyrano shiro (1 → 3)] 10-1-D —Darcovirano shiro (1 → 1) 1 14—0—Par (2—dodecylte toradecanol) aminobenzyl 1 3,6.9,12—Te traoxate tradecane 1 1.14—Diol

3-0- [1-1 (S) -carboxyethyl] 1-D-Galactovirano shiro (i → 4) 1 0— [α-L-fucopyranosyl 1 (1 → 3)] 1 0 1—D— Glucobilanone (1 → 1) — 20— 0—Para (2—dodecylte toradecanol) ami nobenjiru 3, 6, 9, 12, 15, 18 Diol

3-0- [1- (S) -carboxyethyl] 1 3- D-galactovirano shiro (1 → 4) 1 0— [cr-L-fucopyranosyl (1 → 3)] 1 0 — — D-gluco Vilanosyl (1 → 1) 1 26—0—Par (2—dodecylte toradecanol) Aminobenzyl 3,6,9,12,15,18,21,24—Octoxaxahexacosan-1,1,26—Diol

3-0- [1- (S) -carboxyethyl] -1 3-D-galactobyranosyl-1 (1 → 4) -0- [α-L-fucopyranosyl-1 (1 → 3)] 1-0-1; S—D—Darcovirano Sirou (1 → 1) 1—32—0—Para (2—dodecylte Toradecanol) Ami Novenziru 3, 6, 9, 12, 15, 18, 21, 24.27, 30—Decaoxadot Rear Kontan 1, 32—diol

3-0- [1- (S) -carboxyethyl] 1 / 3- D-galacto virano Syl 1 (1 → 4) —0— [α—L—Fucopyrano Siro (1 → 3)] 1 0 —; 9— D—Darcobirano Siro (1 → 1) — 2—0—Para 1 (2—te Radecylhexadecanoyl) aminobenzyl-1-ethane 1.2-diol

3-0- [1— (S) -carboxyethyl] 1 — D—galactovirano shiro (1-4) —0— [naichi L—fucopyrano shiro (1 → 3)] -0 — yS— D— Darcovirano Shiro (1 → 1) —5—0—Par (2—Tetradecylhexadecanoyl) Aminobenzyl-1,3-oxapentane-1,5-Diol

3-0- [1- (S) -carboxyethyl] 1; 3-D-galact Tovirano shiro (1 → 4) -0- [N-L-fucopyrano shiro (1 → 3)] 1 0 1/9 1 D—Darcoviranone (1 → 1) 1 8—0—Par (2—Tetradecylhexadecanoyl) aminobenziru 3,6—Dioxaoctane 1 1,8—diol

3-0- [1- (S) -carboxyethyl] 1 / 3- D-galactobiranosil-1 (1 → 4) -0- [na-1 L-fucopyranosil-1 (1 → 3)] 1 0 1 / 91-D-glucopyranosyl 1 (1 → 1) 1 1 1 1 0-para (2-tetradecylhexadecanoyl) aminobenziru 3,6,9-trioxanedecane-1,1,11-diol

3 -0- [1- (S) -carboxyethyl] 1 9-1 D-galactoviranosyl (1 → 4) —0— [na 1 L-fucopyranosyl (1 → 3)] 1 0 1; 3—D—Glucobilanone (1 → 1) -1 14-0—Par (2-tetradecylhexadecanoyl) aminobenzyl-1,3,6,9,12—Tetraoxate tradecan-1 1,14-diol

3 -0- [11- (S) -carboxyethyl] 1; 9-1 D-galactopyranosyl 1 (1 → 4) —0— [α-L-fucopyranosyl 1 (1 → 3)] 1 0 One 3—D—Darcovirano Shiro (1 → 1) — 20—0—Parr (2—te Tradecylhexadecanoyl) aminobenzyl-1. 6, 9, 12. 15, 18

3—0— [1 (S) -carboxyethyl] 1—3—D—Galacto pyrano siro (1 → 4) — 0— [1 L—fucopyrano siro (1 → 3)] — 0— / S — D—glucoviranosyl (1 → 1) — 26— 0—para (2—tetradecylhexadecanoyl) aminobenzyl 1,3,6,9,12,15,18,21,24—year-old One 1, 26—Diol

3-0- [1- (S) -carboxyethyl] 1 yS- D-galact Tovirano shiro (1 → 4) 1 0— [Na 1 L-1 fucopyrano shiro (1 → 3)] 1◦ 1 D— Glucobilanosyl (1 → 1) —32— 0—para (2-tetradecylhexadecanoyl) aminobenzyl 1 3, 6, 9, 12, 15, 18. 21. 24. 27. 30—decaoxadotriacontan 1, 32—diol

3-0- [11- (S) -carboxyethyl] 13-D-Galact Tovirano Shiro (1 → 4) 1 0- [Na-L-Fucopyrano Shiro (1 → 3)] 10-1-1; 3- D-glucovirano shiro (1 · 1) 1 2–0—para (2—hexadecyloctadecanoyl) ami-nobenjiruetane 1,2-diol

3 -0- [1- (S) -carboxyethyl] 1 3-D-Galactovirano shiro (1 → 4) —0— [α-L-fucopyrano shiro (1-3)) 1 0 1; S— D-glucovirano shiro (1 → 1) 1-5-0-para (2-hexadecylococtadecanol) ami-nobenziru 3-oxoxanthan 1.5-diol

3— 0— [1— (S) —Carboxyethyl] 1 3— D—Galacto virano shiro (1 → 4) — 0— 〔Naichi L—Fucopyrano shiro (1—3)] 1 0 1; S — D—Darcopyrano sill (1 → 1) 1 8—0—Para 1 (2—Heki Sadesiloctadecanoyl) Aminobenzyl-3,6-dioxactan-1 1,8-diol

3— 0— [1— (S) —carboxyethyl] 1 3— D—galactopyranosyl (1 → 4) — 0— [α—L-fucopyranosyl (1 → 3)] 1 0 — / S—D—Darcovirano syl 1 (1 → 1) —1 1 1 1 0—Para 1 (2-Hexadesylloctadecanoyl) ami nobenziru 3, 6, 9-1 Trioxanedecane 1 1, 11-diol

3— 0— [1 (S) -carboxyethyl] 1 3— D—Galactoviranosil 1 (1 → 4) -0- [α—L—Fucopyrano siro (1 → 3)] -0 — / S — D—glucovirano shiro (1 → 1) — 14-1 0—para (2—hexadecylloctadecanoyl) ami nobenziru 3,6,9,12—tetraxatetradecane 1, 14 -Diol

3-0- [1-1 (S) -carboxyethyl] 1 9-1 D-Galact Tovirano shiro (1 → 4) -0- [α-L-fucopyrano shiro (1-3)] 10-S-D —Darcovirano shiro (1 → 1) 1 20—0—Par (2—Hexadecylloctadecanoyl) Aminobenzyl-3, 6.9, 12, 15,

18-hexaoxicosan-1,20-diol

3— Ο— [1— (S) —Carboxyethyl] 1 — D—Galactovirano shiro (1 → 4) —0— [α—L-fucopyranosyl 1 (1 → 3)] 1 0 1 9 1 D— Darcopyrano shiro (1-1) -26-〇-para- (2-hexadecylloctadecanoyl) aminobenzyl-3,6,9,12,15,18,18

21.24-Octoxaxahexacosan-1,26-diol

3-0- [1- (S) -carboxyethyl] 1; 9- D-galactovirano shiro (1 → 4)-0- [Na-L-fucopyrano shiro (1 → 3)] 1 0 —; 9 1 D—Darcopyranosyl 1 (1 → 1) — 32—0—Par (2—Xadecylloctadecanoyl) Aminobenzyl 3, 6, 9, 12, 15,

18. 21, 24. 27, 30—Decaoxadotriacontan-1, 32— Diol

3-0- [1- (S) -carboxyethyl] 1-D-galactoviranosyl 1 (1 → 4) — 0— [α-L-fucopyrano siro (1 → 3)] 1 0— ^ 1 D —Glucopyrano syl 1 (1 ~ 1) 1 2— 0—Par (2—Octadesi noreikosanoyl) ami nobenziruetane 1,2—diol

3-0- [1- (S) -Carboxyethyl] 1 — D-Galactoviranosyl 1 (1 → 4) 1 0— [1: L-Fucopyranosyl (1 → 3)] 1 0 — — D-glucopyrano Syl-1 (1 → 1) 1 5-0 —Par (2-octadedecylicosanoyl) aminobenzyl-1-3-oxapentane-1,5-diol

3-0- [1- (S) -carboxyethyl] 1-D-galact Tovirano shiro (1 → 4) 1 0- [α-L-fucopyrano shiro (1 → 3)] 1 0 1; 3-D —Darkoviranonruh (1 → 1) —8—0—Par (2-Octadecylicosanoyl) Ami Nobenziru 3,6-Dioxaoctane 1.8—Diol

3-0- [1 (S) -carboxyethyl] 1 ^ -1 D-galactoviranosyl (1 → 4) — 0— [1 L-fucovirano silu (1 → 3)] 1 0 — — D—Darco Vilanosyl (1 → 1) 1 11 1 Ο-Par (2 years old Kutadecyl icosanoyl) Aminobenzyl-3,6,9—Trioxazine Decane 1-1,11-Diol

3--0- [1- (S) -carboxyethyl] 1; 5-D-galactovirano shiro (1 → 4) 1 0- [HI-1 L-fucopyrano shiro (1 → 3)] 1 0 —; 9 — D—Glucopyranosyl 1 (1 → 1) 1 14—0—Para 1 (2—Kutadecyl icosanoyl) ami Nobenziru 3,6,9,12—Tetraoxate tradecane 1.14-diol

3-0- [1- (S) -carboxyethyl] 1 3-D-Galactoviranosil 1 (1 → 4) -0- [Na-1 L-fucopyranosil 1 (1 → 3)] — 0 96/3 1 3— D—Darcopyranosyl (1 → 1) — 20—0—Par (2—Kutadecylicosanoyl) Aminobenzyl—3, 6, 9. 12, 15 and 18 — 1.20—Diol

3 -0- [1- (S) -carboxyethyl] 1 D-Galact Tovirano Siro (1 → 4) — 0— [α-L-Fucopyrano Siro (1 → 3)] 1 0 — 3— D— Glucovirano Shiru (1 → 1) — 26— 0—Para 1 (2-year-old Kutadecyl Icosanoyl) Ami Novengiru 3, 6, 9, 12, 1 5, 18, 21, 24 Kisakosan-1, 26-diol

3 -0- [1 (S) -carboxyethyl] 1; 3-D-galactovirano shiro (1 → 4) — 0— [N-1 L-1 fucopyrano shiro (1 → 3)] 1 0 1 ^ 1 D—Darcovirano Shiro (1 → 1) — 32— 0—Para (2—year-old Kutadecylikosanoyl) Ami Nobenziru 3, 6, 9, 9, 12, 1 5, 18, 21, 24.27, 30— Decaoxadotriacontan-1,32-diol.

〔Mechanism of action〕

The action mechanism of the glycolipid derivative of the general formula (I) that can be used as an active ingredient in the present invention is considered as follows.

L AR is caused by the infiltration of inflammatory cells, mainly eosinophils, into the airway tissues. The mechanism of this infiltration is that glycolipids expressed on the surface of eosinophils in the bloodstream (SLex, etc.) Binds to the adhesion molecule (ELAM-1 etc., see Fig. 5) expressed on activated vascular endothelial cells.

As shown in Fig. 6, the process of eosinophil infiltration into airway tissue is divided into three stages: (1) rolling, (2) adhesion, and (3) passage through the vascular endothelial cell gap. In Fig. 6, (2) adhesion and (3) vascular endothelial cell gap clearance are shown separately for cases where vascular endothelial cells were activated by IL-1, TNF, and those activated by IL-4. It is. In each case, the upper row shows the adhesion molecules on the eosinophil side, and the lower row shows the adhesion molecules on the vascular endothelial cell side. The glycolipid derivative of the general formula (I) in the present invention acts at this rolling stage (and at the stage of adhesion), acts antagonistically to the glycolipid on eosinophils, and is expressed in vascular endothelial cells. It is believed that adhesion to adhesion molecules is blocked. The eosinophils blocked in the rolling stage stay in the blood without passing through the following stages (2) adhesion and (3) vascular endothelial cell gap, that is, infiltration is suppressed. LAR is suppressed by this suppression of eosinophil infiltration.

- the person, I AR is a reaction which occurs immediately after antigen challenge by antigen molecules corresponding to I gE antibodies on mast cells of the airway mucosa binding, Hisuta Mi emissions, such as LTC _{_₄} ZD ₄ / E ₄ It is known that the chemical mediator is released, and as a result, airway contraction occurs due to contraction of bronchial smooth muscle, increased vascular permeability, and increased secretion. The mechanism of action of the compound of the present invention for inhibiting IAR is not yet known in detail, but the histamine level in blood was reduced by administration of the compound of the present invention. It is conceivable that the compound of the present invention may suppress the release of a chemical messenger from the mast cell. In addition, LAR breaks down the airway mucosal epithelium by infiltrating eosinophils activated by chemical mediators released in the IAR into the airway epithelium and subepithelial airway and releasing cytotoxic granular proteins. It is caused by causing airway hyperreactivity. Furthermore it is also known that LTC _4, PAF was production of eosinophils is acting as增悪factor asthmatic response. Therefore, there are two possible mechanisms by which the compounds of the present invention suppress LAR: the first is the indirect inhibitory effect of IAR suppression, and the second is eosinophils via adhesion molecules. It is a direct inhibitory effect by blocking the adhesion of Eosinophils to the airway mucosa by blocking the adhesion between E. coli and vascular endothelial cells.

(Pharmacological test)

Representative compounds selected from the compounds of the general formula (I) used in the present invention Compound (branched hydrocarbon chain of ^X -C ₂₉ )

0— (5-acetoamido 3,5—dideoxy D—glycerose—α-D—galacto 2-nonurobilano silicic acid) 1 (2 → 3) — 0—β—galactopyrano siro (1 → 4)-0-[Na-1 L-fucopyrano syl (1 → 3)] 1 0—S—D—Glucopyrano siro (1 → 1) 1 8 1 0—para (2—tetradecylhexadecanoyl) amino As a result of a pharmacological test on benzyl 3,6-dioxaoctane-1,8-diol (hereinafter abbreviated as "Sialyl Lewis X derivative (LX 0104)") as shown in Examples 1 and 2 below, immediate results were obtained. A remarkable effect of suppressing the asthmatic and late asthmatic responses was confirmed.

The administration of the antiasthmatic drug of the present invention is effective not only as a preventive drug before antigen sensitization but also as a therapeutic drug. Specifically, when the pathological condition of asthma is considered in the long term, the period of asymptomatic period from the time of sensitization to the antigen until the inhalation of the antigen (寬 resolution period) and the asthma response period after inhalation of the antigen (active period) The drug of the present invention is a prophylactic drug administered before inhalation of the antigen, and is also a therapeutic drug that suppresses the transition from the peptic phase to the active phase. In addition, administration at the onset of (or shortly after) asthma symptoms is also effective in reducing the duration and extent of the symptoms.

The anti-asthmatic drug of the present invention can be formulated according to a conventional formulation method. Various forms can be arbitrarily selected as the pharmaceutical preparation depending on the administration form of oral administration and parenteral administration. Representative examples are powders, granules, tablets, capsules, pills, liquids, Suspensions, fat emulsions, injections, liposomes and the like.

In preparing these preparations, conventional additives for formulation such as excipients, stabilizers, preservatives, dissolving agents, wetting agents, emulsifiers, lubricants, sweeteners, Formulations can be made by adding coloring agents, flavoring agents, tonicity adjusting agents, buffers, antioxidants and the like.

The administration method is not particularly limited, and it can be administered by a method according to various formulation forms, the age and sex of the patient, other conditions, the degree of the disease, and the like. For example, parenteral administration typified by injection (intravenous, intramuscular, subcutaneous, etc.), oral administration such as enteral and sublingual or nasal administration can be mentioned. The agent of the present invention is preferably administered by oral inhalation with an oral spray or an aerosol for oral cavity, and is also preferably administered into the nose with a nasal spray or a swab. In particular, if rapid action is expected, that is, if suppression of IAR is also expected, administration by inhalation is preferable. In order to control the duration of action, the preparation may be in the form of a controlled-release preparation. In preparing the aerosol, a surfactant and a propellant are used. The surfactant is preferably non-toxic and soluble in the propellant, such as anionic surfactants (alkyl sulfates, sulfosuccinates, etc.), thiothion surfactants (quaternary ammonium salts, etc.), nonionics Surfactants (sucrose fatty acid ester, polyethylene glycol fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, polyoxyethylene hardened castor oil, polyoxyethylene sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene alkyl Ether, block polymer type, polyquinethylene alkyl aryl ether) or amphoteric surfactant (soy lecithin etc.). On the other hand, the propellant exists as a gas at room and normal temperatures, and has a property of easily liquefying by lowering the temperature below the boiling point or increasing the pressure, for example, ethane, propane, butane, and preferably Examples include dichlorodichloromethane, dichlorotetrafluorophenol, trichloro monophenylphenol, and the like. The composition ratio of these agents is 0.05 to 30% by weight, preferably 1 to 10% by weight, and 0.1 to 10% by weight of a surfactant. It is suitable that the propellant occupies 〜20% by weight, preferably 0.25-5% by weight. In addition, if necessary, stabilizers, buffers, flavoring agents, suspending agents, preservatives, solubilizers and other additives can be added to the drug. It is particularly necessary to prepare the aerosol under sterile conditions.

Further, the usual dose of the drug is preferably in the range of about 0.5 mg / kg (body weight) to 50 mg kg (body weight). A dose outside this range can be administered depending on the condition of the patient, but the dose can be appropriately adjusted depending on factors such as the condition, age, sex, and weight of the patient to be administered. Naturally, it will vary depending on the method of administration. The number of times of administration is preferably once to three times a day. When administering by injection, continuous infusion or single or frequent administration may be used.

In addition, a lipid emulsion / liposome can be used as a suitable preparation. Fat emulsions can be prepared by using natural fats and oils such as soybean oil as an oil component and soybean lecithin or egg yolk lecithin as an emulsifier. In addition to the above components, for example, glycerin may be used as a tonicity agent, and various surfactants may be used as an emulsifying aid. This fat emulsion can be used, for example, as an injection or spray for intravenous, intramuscular, or subcutaneous administration.

Liposomes are formed from standard vesicle-forming lipids. The major lipids used to make liposomes include phosphatidylcholine and sphingomyelin, to which dicetyl phosphate, phosphatidic acid, and phosphatidylserine are added to stabilize the liposomes by charging them. Methods for preparing ribosomes include the ultrasonic method, ethanol injection method, and reverse-phase evaporation method. Also, in addition to the agent of the present invention, a desired drug, enzyme or the like can be encapsulated in the ribosome.

The agents of the present invention may be used alone or in combination with one or more additional anti-asthmatics, eg, other anti-asthmatics (such as theophylline) Can also be used. Thereby, the dose of the drug can be reduced.

BEST MODE FOR CARRYING OUT THE INVENTION

Next, the present invention will be further described with reference to pharmacological experimental examples and formulation examples.

Example 1

A. Materials and Methods

Animals: The animals used in this experiment were male guinea pigs (Dunkin-Hartley guinea pig), weighing 250 g and weighing 300 g (Doken Laboratory Animals, Saitama, Japan) ₀ Each animal was equipped with an automatic washing device Three animals were placed in a closed all-net cage, and food and water were given ad libitum.

Test compound: The above-mentioned sialyl Lewis X derivative (LX 0104) was synthesized as an antagonist to ELAM-1 receptor according to the method described in Example 2 of JP-A-6-80687. That is, 0— (methyl 5-acetamide 4,7,8,9-tetra-0-acetyl-3.5-dideoxy D-glycero α-D-galacto 2-nonuroviranosilonate) 1 (2-3) — 0— (4-10—acetyl-2,6-di-1 0—benzoyl-D—galact topyranosyl) 1 (1 → 4) 1 0— {(2,3,4-tree 0 -Acetyl-α-L-fucopyranosyl)-(1 → 3)} —0— (2,6-di-1 0-benzoyl-α-D-darcopyranosyl) trichloroacetimidate (90mg, 0.053mmol) and 1-para (2-Tetradecylhexadecanol) Aminobenzyl-3,6-dioxaoctane-1,8-diol (73 mg, 0.106 mmol) was dissolved in methylene chloride (3 ml), MS4A AW300 (2 g) was added, and the mixture was added at room temperature for 40 minutes. Stirred. Ice-cold after their, BF ₃ · 0Et ₂ a (0.04ml), and the mixture was stirred for 3 hours.

After confirming the completion of the reaction with TLC (methylene chloride: methanol = 30: 1), the reaction mixture was filtered through celite, and the filtrate and washing were combined and extracted with methylene chloride. Was. The organic layer is washed with _{_{_{Na 2 C0 3, H 2 0}}} , dehydrated with N a ₂ S 0 _4, which was separated by filtration, and concentrated under reduced pressure. The resulting syrup was subjected to column chromatography, and the effluent (methylene chloride: methanol = 30: 1) was used as the eluate (methyl 5-acetoamide 4,7,8,9-tetra-0-acetyl-3,5-1 didoxy). 1-D-glycerose α-D-galacto 2-nonurobilanosylonate 1- (2 → 3)-0— (4-10-acetyl-1 2,6-di-0-benzylol; 9-D-galactoviranosyl ) One (1 → 4) one 0— {(2,3,4 one tree 0_acetyl-α-L-fucopyranosyl) one (1 → 3)} — 0 one (2,6-di-one 0—Benzolu) 5-D-glucopyranosyl) 1 (1 → 1) -8-0-para (2-tetradecylhexadecanoyl) aminobenziru 3,6-dioxactan-1.8-diol (73 mg, 61.9%) was obtained. . This compound (72 mg, 0.0325 mmol) was dissolved in methanol (5 ml), 28% sodium methoxide (10 drops) was added, and the mixture was stirred at room temperature for 10 hours. Then, water (0.5 ml) was added, and the mixture was stirred as it was for 6 hours. After confirming the completion of the reaction by TLC (butanol: methanol: water = 3: 2: 1), the mixture was neutralized with ion-exchange resin IR-120 (H +), filtered, and concentrated under reduced pressure. . The obtained syrup was subjected to gel filtration with Sephadex LH-20, and the test compounds LX 0104, 0- (5-acetamido 3,5-dideoxy-1 D-glycerol α-D-galact-1) 2-nonyl pyranosyl acid) 1 (2 → 3) — 0— 1 D—galactopyranosyl 1 (1—4) -0— {α—L—fucopyranosyl (1 → 3)} — 0—3—D—glu 1-copyranosyl (1 → 1) — 8-0-para- (2-tetradecylhexadecanoyl) aminobenziru 3,6-dioxacoctane 1,8-diol (45.5 rag. 96.6%) was obtained.

This test compound was dissolved in physiological saline (final concentration lOmgZml) immediately before intravenous injection into the lower limb vein.

For inhaled administration, dissolve in physiological saline immediately before inhalation. The final concentration was 0.6 mgZnil).

Antigen inhalation sensitization: For antigen inhalation sensitization, ovalbumin (OA, Sigma Chemical Co.. St. Louis, MO) was added to 1 OmgZinl using a micronebulizer (manufactured by Meiko I). Those prepared with water were administered. The antigen was administered to each animal twice a day for the first 10 consecutive days and then once a week. Each sensitization was performed for 10 minutes with a flow of 6 liters of Zmin, and animals that showed a PCA (passive skin pananaphylaxin) reaction of more than 30 times were used in the experiments.

Rrs measurement: The measurement of respiratory resistance (Rrs: cmHzO / ml / sec) is based on the oscillation method described by Mead et al. (Mead et al., J. Appl. Physiol. 15: 325 (I960)). The paper was partially modified [Yukawa et al., Allergy 1: 227 (1987); Terashi et al., Allergy 37: 980 (1988)]. In other words, in a specially designed chamber-box, a sinusoidal wave of about 18 Hz from the rear of the guinea pig [Leader Electronics Model LFG-1300 Function Oscillator is passed through a trio integrating power amplifier (Model KA900). To a Coral Model 12L-70 woofer speaker to generate a sine wave. On the other hand, the respiratory flow of the guinea pig is extracted through a conical plastic mask screen by a differential converter (Validyne Engineering, Model MP45-18), and passed through an amplifier (Shizu Medical) to an oscilloscope (San-Eikki). 2G46), recorded on a polygraph (Surgical Monitor 125, manufactured by San-Ei Keiki), and measured from the ratio of chamber internal pressure and respiratory flow.

Detection of eosinophils by tissue staining: 24 hours after antigen exposure, the mice were sacrificed by blood removal, and the trachea and lungs were removed. It was fixed in formalin, embedded in paraffin, sectioned into 3 m sections, and Hansel stained for microscopy. Eosinophil infiltration numbers were calculated as iota Iotapaiiotaita number of eosinophils infiltrating into the bronchial wall per ^2. In addition, the eosinophil appearance rate in the trachea and intrapulmonary blood vessels was The percentage of blood vessels in which eosinophils were confirmed was determined as a percentage.

Number of blood vessels in which eosinophils were confirmed out of 100

—— X 100

1 0 0 exposed blood vessels

Drug administration and evaluation: Each animal was anesthetized by inhalation with ether, and once administered intravenously with the sialyl Lewis X derivative (LX 0104) or carrier (saline) synthesized by the above method from the right lower limb vein. The baseline of respiratory resistance (R rs: cmH ₂₀ / ml / sec) was monitored for approximately 3 minutes. Each animal was returned to the cage, and one hour later, one dose of intraperitoneal injection of cloltlimetone (chlorpheniramin maleate, 10 mg / kg: Schering-Brow) was given, and 15 minutes later, antigen exposure was performed. Was done. Thereafter, Rrs for 15 minutes, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 24 hours were monitored for 3 minutes, and immediate and delayed asthmatic responses were recorded. . After 24 h of Rrs measurement, bronchi and lungs were removed and stained for tissue.

Statistical analysis: All data are expressed as mean ± standard deviation, and the number of animals (N) used in each experiment is 6. For the test of significance, Student's test was used, and p-value <0.05 was considered significant.

B. Result

First, guinea pig airway resistance for up to 24 hours post-antigen challenge _{(Rrs: cmH 2 0 / ml} / sec) shows the results of measured over time in Table 1 and Figure 1 below. Immediately after antigen exposure (15 min) (immediate asthmatic response), there was no significant difference from the control group, but this drug significantly increased the respiratory resistance observed in the control group after 2 hours. Suppression (time 2 and 3: p <0.05; time 4 and 6: p <0.01).

In addition, by performing Hansel staining (eosinophil-specific staining) of airway tissue sections, the number of eosinophils in the guinea pig airway epithelium and in the subepithelial tissue 24 hours after antigen exposure was measured. See Table 2 below and Figure 2. Figure 2 shows that eosinophil infiltration was observed in the drug-administered group compared to the control group. (Epithelium: p <0.01; subepithelial: p <0.05) o Conversely, the rate of eosinophils in bronchial and alveolar blood vessels is As shown in the following Table 3 (FIG. 3) and Table 4 (FIG. 4), it was confirmed that there was a significant increase in the drug administration group (FIGS. 3 and 4; p

(Table 1) Effect of suppressing guinea pig airway resistance

Sample of the present invention αχ 0104) Control sample

(Average spear) (average spear)

Before antigen exposure 1.4 6 1.5 9

15 minutes after antigen exposure 2.2 3 2.4 4

1 hour 1.5 6 1.5 6

2 hours 1. 2 7 1. 6 1

3 hours 1.4 2 2. 1 2

4 hours 1.5 3 2.3 5

5 hours 1.5 5 1.7 7

6 hours 1.3 4 2.09

7 hours 1.4 9 1.7 7

8 hours 1.5 8 1.4 9

9 hours 1.40 1.50

10 hours 1.3 6 1.4 9

2 4 hours 1. 5 7 1. 6 8 Airway resistance 表示 (R rs) (Meet 2) Eosinophil count in guinea pig airway 糍

Epithelium (mean implantation) Subepithelial (mean value) Sample of the present invention (LX 0104) 11.91 14.58

Control sample 478.57 194.91

Displayed as the number of eosinophils per unit area (mm ² ) (force / nun ² )

(Table 3) Eosinophil appearance in guinea pig bronchial vessels

Average value

Sample of the present invention (LX 0104) 39.3

Control sample 20.9

Eosinophil appearance rate in bronchial vessels is displayed as percentage (%)

(Table 4)

Eosinophil appearance rate in guinea pig lung blood vessels

Average

Sample of the present invention (LX 0104) 28.3

Control sample 8.1

Example 2: Appearance rate of eosinophils in pulmonary blood vessels is displayed as percentage (%).

Drug administration and evaluation method: Each animal was inhaled with a sialyl Lewis X derivative (LX 0104) or a carrier (saline) synthesized by the method described in Example 1 using a Devilbis 646 nebulizer for 10 minutes, and then breathed. The baseline of resistance (Rrs: cmHzO / ml / sec) was monitored for approximately 3 minutes. LX 0104 Intra-peritoneal injection of chlortrimetone (chlorpheniramine maleate, 10 rag / kg: Sealing 'Blau) 15 minutes after the start of inhalation A single dose was administered by injection, and antigen exposure was performed for 15 minutes after 15 minutes. Then, at 15 minutes, 1, 2, 3, 4, 5, 6, 7, and 8 hours, Rrs was monitored for 3 minutes, and changes in respiratory resistance due to immediate and delayed asthmatic responses were observed. Method for detecting histamine concentration in the blood: Immediate asthmatic response was confirmed 15 minutes after antigen exposure, and whole blood was collected from guinea pigs, and histamine concentration in plasma was measured by HPLC.

Eosinophil detection method by tissue staining; 8 hours after antigen exposure, the mice were sacrificed by blood removal, and the trachea was removed. It was fixed in formalin, embedded in paraffin, sectioned into 3 m sections, and Hansel stained for microscopy. Eosinophil infiltration numbers were calculated as number of eosinophils was Hita涠into the bronchial wall of or 1 ² Ah.

^ Mouth ;;

First, guinea pig airway resistance (R rs: cinH ₂₀ mlZsec) was measured over time up to 8 hours after antigen exposure, and the results are shown in Table 5 and Fig. 7 below. In the group to which the sample of the present invention was administered, immediately after antigen exposure (immediate asthmatic reaction), the increase in airway resistance was significantly suppressed as compared to the control group (p <0.001). It also clearly suppressed the delayed asthmatic response observed after the first hour (1st, 3rd and 7th hours: p <0.05).

Next, the blood histamine concentration immediately after the confirmation of the immediate asthmatic reaction was measured, and the results are shown in Table 6 and FIG. In the group to which the sample of the present invention was administered, it was found that the blood histamine concentration was clearly lower than the control group.

Furthermore, Hansel staining (eosinophil-specific staining) of airway tissue sections was performed to measure the number of eosinophils in the guinea pig airway epithelium and in the subepithelial tissue 8 hours after antigen exposure. The results are shown in Table 7 below and FIG. In the group to which the sample of the present invention was administered, the number of eosinophils infiltrating into the respiratory tract was dramatically reduced as compared to the control group. (Table 5)

Lumot airway resistance suppression effect

Sample of the present invention (X0104) Reference sample (mean) (mean) Before antigen exposure 2.12 2.22 15 minutes after antigen exposure 2.40 3.02

1 hour 2.26 2.59 2 hours 2.3 1 2.56 3 hours 2.20 2.58 4 hours 2.28 2.36 5 hours 2.12 2.39 6 hours 2.16 2.48 7 hours 2.10 2.55 8 hours 2.22 2.37 Displayed as airway resistance (Rrs)

(Table 6)

Blood histamine level immediately after immediate asthmatic reaction

Sample of the present invention (LX 0104) Reference sample

(Average value) (Average value)

2.25 0.3 1 Displayed as histamine amount (ngZml) per unit volume (ml)

(Table 7)

Eosinophil counts in guinea pig airway tissue

Epithelial displayed as (average value) subepithelial (average value) samples of the invention (LX 0104) 21 22 vs. irradiation specimen 370 16 1 unit volume (隨²⁾ the number of eosinophils per (count ZMM ²⁾ Implementation cool 3

Preparation of ribosome

200 ml of phosphatidylcholine, 100 g of cholesterol, 7.5 ^ g of dicetylphosphate and 50 βg of the compound of the present invention were added to a solution (about lml) of a form / methanol == 2Z1 solution containing mouth mouth. After drying under reduced pressure, 0.25 ml of physiological phosphate solution was added, and sonication (output 90 watts) was performed for 5 minutes, and agitation treatment (vortex mixer) was performed for 5 minutes to prepare liposomes. did.

Example 4

Preparation of fat emulsion

A mixed solution containing 6 mg of egg yolk lecithin (manufactured by Nakarai Tesque), soybean oil of the Japanese Pharmacopoeia (manufactured by Yoshida Pharmaceutical Co., Ltd.) 30/1, distilled water for injection (manufactured by Otsuka Pharmaceutical Co., Ltd.) 470 1, and 125 g of the compound of the present invention. The mixture was subjected to sonication (output 90 liters) for 10 minutes to produce a fat emulsion. Further, the fat emulsion was passed through a polycarbonate membrane filter (manufactured by Millipore) having an average pore size of 0.2 / ζπ to adjust the average particle size to 0.2 m.

Claims

The scope of the claims

The following general formula (I)

(Where X is

and

COOH

H is a group selected from the group consisting of H ₃ C ^, n is an integer of 0 and 1 to 10, and R is a branched hydrocarbon chain having 19 to 39 carbon atoms.]

An anti-respiratory drug comprising, as an active ingredient, a glycolipid derivative represented by or a pharmaceutically acceptable salt thereof.

2. In the general formula (I), X is

2. The anti-asthmatic drug according to claim 1, which is

3. In the general formula (I), X is

COOH

H, C 2. The anti-asthmatic agent according to claim 1, which is:

4. In the general formula (I), X is

The anti-asthmatic agent according to claim 1, wherein n is 0 and an integer of 1 to 10 and R represents a branched hydrocarbon chain having 19 to 39 carbon atoms.

5. The anti-asthmatic agent according to claim 4, wherein in the general formula (I), n is 2 and R represents a branched hydrocarbon chain having 29 carbon atoms.

6. The anti-asthmatic drug according to any one of claims 1 to 5, which acts on allergic inflammation caused by eosinophils.

7. The anti-asthmatic drug according to claim 6, which suppresses late asthmatic reaction.

8. The anti-asthmatic drug according to claim 6, which suppresses an immediate asthmatic reaction.