WO1996041636A1 - Agent antiasthmatique - Google Patents

Agent antiasthmatique Download PDF

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Publication number
WO1996041636A1
WO1996041636A1 PCT/JP1996/001534 JP9601534W WO9641636A1 WO 1996041636 A1 WO1996041636 A1 WO 1996041636A1 JP 9601534 W JP9601534 W JP 9601534W WO 9641636 A1 WO9641636 A1 WO 9641636A1
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WO
WIPO (PCT)
Prior art keywords
shiro
diol
acid
asthmatic
fucopyrano
Prior art date
Application number
PCT/JP1996/001534
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English (en)
Japanese (ja)
Inventor
Kou Okumura
Tomoyasu Ra
Kazunori Kato
Shohei Makino
Hironori Sagara
Naofumi Takahashi
Hisami Shinohara
Original Assignee
The Nisshin Oil Mills, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Nisshin Oil Mills, Ltd. filed Critical The Nisshin Oil Mills, Ltd.
Priority to AU59111/96A priority Critical patent/AU5911196A/en
Publication of WO1996041636A1 publication Critical patent/WO1996041636A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/06—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages

Definitions

  • 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.
  • Asthma attacks include an immediate asthmatic response (IAR) followed by a delayed asthmatic response (LAR).
  • IAR immediate asthmatic response
  • LAR delayed asthmatic response
  • 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.
  • vasoactive substances such as histamine, bronchial smooth muscle contractile substances, and granulocyte chemotactic factor are released from the granules.
  • vasoactive substances such as histamine, bronchial smooth muscle contractile substances, and granulocyte chemotactic factor are released from the granules.
  • vasoactive substances such as histamine, bronchial smooth muscle contractile substances, and granulocyte chemotactic factor are released from the granules.
  • vasoactive substances such as histamine, bronchial smooth muscle contractile substances, and granulocyte chemot
  • 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.
  • 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 include sympathomimetic drugs and xanthine derivative-anticorin drugs, which can effectively suppress bronchoconstriction.
  • side effects such as hand tremor and arrhythmia, and drowsiness when the substance has an antihistaminic effect.
  • 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.
  • 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.
  • Japanese Patent Application Laid-Open No. 6-80667 which is assigned to the present applicant, discloses a compound represented by the general formula (I):
  • n is an integer from 0 and 1 to 10
  • R is a branched hydrocarbon chain having from 19 to 39 carbon atoms.
  • 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. .
  • it does not teach the possibility of suppressing the immediate allergic reaction and the subsequent delayed allergic reaction.
  • 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.
  • 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.
  • n is an integer of 0 and 1 to 10
  • 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.
  • the residue represented by RC (O) is a branched fatty acid residue having 20 to 40 carbon atoms.
  • 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
  • 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.
  • 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.
  • 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.
  • (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.
  • the upper row shows the adhesion molecules on the eosinophil side
  • 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.
  • 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
  • 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.
  • 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 ⁇ 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.
  • 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.
  • the period of asymptomatic period from the time of sensitization to the antigen until the inhalation of the antigen ⁇ resolution period
  • 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.
  • 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.
  • 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.
  • parenteral administration typified by injection (intravenous, intramuscular, subcutaneous, etc.)
  • oral administration such as enteral and sublingual or nasal administration
  • 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.
  • rapid action is expected, that is, if suppression of IAR is also expected, administration by inhalation is preferable.
  • the preparation may be in the form of a controlled-release preparation.
  • 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.).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • additional anti-asthmatics eg, other anti-asthmatics (such as theophylline) Can also be used.
  • mice 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 ⁇ -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- ⁇ -L-fucopyranosyl)-(1 ⁇ 3) ⁇ —0— (2,6-di-1 0-benzoyl- ⁇ -D-darcopyranosyl) trichloroacetimidate (90mg, 0.053mmol)
  • 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 ⁇ -D-galact-1) 2-nonyl pyranosyl acid) 1 (2 ⁇ 3) — 0— 1 D—galactopyranosyl 1 (1—4) -0— ⁇ —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.
  • 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.
  • PCA passive skin pananaphylaxin
  • 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).
  • 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.
  • 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.
  • guinea pig airway resistance for up to 24 hours post-antigen challenge shows the results of measured over time in Table 1 and Figure 1 below.
  • antigen exposure 15 min
  • 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).
  • Eosinophil appearance rate in bronchial vessels is displayed as percentage (%)
  • Example 2 Appearance rate of eosinophils in pulmonary blood vessels is displayed as percentage (%).
  • 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 ⁇ into the bronchial wall of or 1 2 Ah.
  • 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.
  • 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).
  • 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
  • Epithelial displayed as (average value) subepithelial (average value) samples of the invention (LX 0104) 21 22 vs. irradiation specimen 370 16 1 unit volume ( ⁇ 2) the number of eosinophils per (count ZMM 2) Implementation cool 3
  • 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 / ⁇ to adjust the average particle size to 0.2 m.

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Abstract

La présente invention concerne un agent antiasthmatique contenant comme principe actif un dérivé de glycolipide représenté par la formule générale (I) ou l'un de ses sels admis en pharmacologie. Dans cette formule, X représente l'un ou l'autre des groupes représentés par les formules spécifiques (A) et (B); n est un nombre entier de 0 à 10 et R représente une chaîne hydrocarbure en C19-C39 ramifiée.
PCT/JP1996/001534 1995-06-13 1996-06-06 Agent antiasthmatique WO1996041636A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU59111/96A AU5911196A (en) 1995-06-13 1996-06-06 Antiasthmatic agent

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP14646095 1995-06-13
JP7/146460 1995-06-13

Publications (1)

Publication Number Publication Date
WO1996041636A1 true WO1996041636A1 (fr) 1996-12-27

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PCT/JP1996/001534 WO1996041636A1 (fr) 1995-06-13 1996-06-06 Agent antiasthmatique

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WO (1) WO1996041636A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10869936B2 (en) 2016-12-23 2020-12-22 The Board Of Trustees Of The Leland Stanford Junior University Activity-based probe compounds, compositions, and methods of use

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06502195A (ja) * 1991-07-31 1994-03-10 ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド 内皮性白血球粘着分子−１およびそれに対する抗体の喘息治療における使用
JPH0680687A (ja) * 1992-07-15 1994-03-22 Nisshin Oil Mills Ltd:The 新規糖脂質誘導体およびその用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06502195A (ja) * 1991-07-31 1994-03-10 ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド 内皮性白血球粘着分子−１およびそれに対する抗体の喘息治療における使用
JPH0680687A (ja) * 1992-07-15 1994-03-22 Nisshin Oil Mills Ltd:The 新規糖脂質誘導体およびその用途

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10869936B2 (en) 2016-12-23 2020-12-22 The Board Of Trustees Of The Leland Stanford Junior University Activity-based probe compounds, compositions, and methods of use

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