WO1998046229A1 - Inhibiteurs de la production d'il-8 et du mcaf - Google Patents

Inhibiteurs de la production d'il-8 et du mcaf Download PDF

Info

Publication number
WO1998046229A1
WO1998046229A1 PCT/JP1997/001283 JP9701283W WO9846229A1 WO 1998046229 A1 WO1998046229 A1 WO 1998046229A1 JP 9701283 W JP9701283 W JP 9701283W WO 9846229 A1 WO9846229 A1 WO 9846229A1
Authority
WO
WIPO (PCT)
Prior art keywords
mcaf
production
formula
carbon
bond
Prior art date
Application number
PCT/JP1997/001283
Other languages
English (en)
Japanese (ja)
Inventor
Akira Matsumori
Original Assignee
Otsuka Pharmaceutical Co., 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
Priority to JP07154923A priority Critical patent/JP3008010B2/ja
Priority claimed from JP07154923A external-priority patent/JP3008010B2/ja
Application filed by Otsuka Pharmaceutical Co., Ltd. filed Critical Otsuka Pharmaceutical Co., Ltd.
Priority to PCT/JP1997/001283 priority patent/WO1998046229A1/fr
Publication of WO1998046229A1 publication Critical patent/WO1998046229A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms

Definitions

  • the present invention provides a pharmaceutically useful carbostyryl derivative represented by the following general formula (1) and / or a salt thereof as an active ingredient, an IL-8 (Interleukin-8) production inhibitor, and MCAF (Monocyte hemorrhage and
  • IL-8 Interleukin-8
  • MCAF Monocyte hemorrhage and
  • the present invention relates to a method for inhibiting the production of IL-18 and a method for inhibiting the production of MCAF using the same.
  • Inflammation is a host defense reaction that occurs to maintain homeostasis in tissue damage caused by various stimuli (physical, chemical, microbial, etc.).
  • the inflammation includes multiple forms such as enhanced vascular permeability, inflammatory cell infiltration of neutrophils and macrophages, lymphocyte infiltration as an immune response, and tissue repair.
  • a variety of cells are involved in this inflammation, such as various cells constituting an inflammation field, and leukocytes infiltrating into an inflammatory focus through blood vessels.
  • the polypeptide-acting factor produced by these cells and involved in the formation of a complex inflammatory response is called inflammatory cytokin.
  • inflammatory cytokin a number of site kinases with leukocyte chemotaxis have recently been discovered, Their structures and functions have been elucidated.
  • the site cytokines are collectively called chemokines and have been found to play an important role in leukocyte infiltration in inflammation.
  • chemokine was given at the International Leukocyte Chemotactic Factor Symposium in 1992 for polypeptide factors having chemotactic activity specifically for leukocytes. These factors have high amino acid sequence homology, have structurally four cystine residues, and have a common feature of a molecular weight of about 10,000. Chemokines are currently classified into two subfamilies, Cys-X-Cys and Cys-Cys, according to the binding mode of cystine (Cys), and IL-8 (Interleukin-8) is The former, MCAF (Monocyte Chemoattractant Protein-1), also known as MCP-1 (Monocyte Chemoattractant Protein-1), is a typical site-power factor of the latter. It is said that both of these sites bind to hormone-type receptors. Of these, IL-18 is a polypeptide having a molecular weight of 8 KDa and is composed of 72 amino acids.
  • IL-8 (aka NAP-1: eutrophil Activating Peptide-1) is a human peripheral blood that was stimulated by LPS in 1987. Isolated and purified as neutrophil chemoattractant (NCF) from mononuclear cell culture supernatant [Yoshimura, T., et al., Proc. Natl. Acad. Sci., USA, 84, 9233 ( 1987)], and subsequently the T-lymphocyte chemotactic factor (TCF) was also isolated and purified.
  • NCF neutrophil chemoattractant
  • TCF T-lymphocyte chemotactic factor
  • the IL-8 induces neutrophil migration and activates neutrophils.
  • IL-18 not only enhances neutrophil chemotaxis, but also promotes degranulation and production of peroxide, enhances lysosomal enzyme release,
  • CDllabc CD18
  • IL-8 Diseases that may involve IL-8 include psoriasis of the skin, rheumatoid arthritis, bronchial asthma, acute myocardial infarction, adult respiratory distress syndrome (ARDS), sepsis, vascular inflammation, and liver Flames have been cited [Masafumi Takahashi, Clinician, 19 (9), 42-45 (1993)].
  • MCAF monocyte chemotactic factor
  • monocytes stimulated by LPS and vascular endothelial cells, fibroblasts, and vascular infiltrating muscle cells stimulated by inflammatory site forces such as IL-1 and TNF. It is reported to have chemotactic and activating effects, and further to enhance the chemotactic ability of T lymphocytes and basophils.
  • MCAF promotes the production of sono and mono-oxide, enhances the release of lysosomal enzymes, enhances antitumor activity, enhances the production of cytokinin, enhances the expression of adhesion molecules (CD11bc), It has been reported that histamine release from basophils is enhanced.
  • the diseases in which the MCAF is involved include arterial sclerosis, rheumatoid arthritis, pulmonary fibrosis, malignant glioma, melanoma, fibrosarcoma, malignant fibrous histiocytoma [Takahashi Takafumi Clinicians, 19 (9), 42-45 (1993)].
  • An object of the present invention is to suppress the abnormal production of IL-8 and / or the abnormal production of MCAF, or to inhibit IL-18.
  • a new IL-8 production inhibitor which can treat various diseases caused by abnormal production of IL-18 and / or MCAF by simultaneous suppression of abnormal production with MCAF;
  • An object of the present invention is to provide a MCAF production inhibitor.
  • the present inventors have conducted intensive studies on the above object.
  • the carbostyril derivative represented by the following general formula (1) and a compound or a salt thereof, which have been previously developed as a cardiotonic active ingredient, are desired.
  • the present inventors have found that it has an inhibitory effect on IL-8 production and also has an inhibitory effect on MCAF production, and is effective as a drug meeting the above-mentioned object, and thus completed the present invention.
  • R represents a benzoyl group which may have a lower alkoxy group on the phenyl ring.
  • Carbostyril skeleton 3 The carbon-carbon bond between the 4-position and the 4-position indicates a single bond or a double bond.
  • the IL-8 production inhibitor and the MCAF production inhibitor which contain the carbostyril derivative represented by these formulas and / or its salt as an active ingredient together with a nontoxic pharmaceutical carrier are provided.
  • the carbostyril derivative used as the active ingredient of the present invention may be, for example, a cardiotonic agent as described in Japanese Patent Publication No. 1443747 and US Patent No.US Pat. It is already known to be useful.
  • the carbostyril derivative and Z or one of its salts have been demonstrated to improve hemodynamic parameters and exercise tolerance in patients with congestive heart failure [Inoue et al., Heart Vessels, 2, 166-171 (1986); Sasayma et al., Heart Vessels, 2, 23-28 (1986); Feldman et al., Am ..
  • carbostyril derivative has an effect of improving virus-induced myocardial injury and an inhibitory effect on natural killer cells (NK cells) during the improvement of myocardial injury [Matsui S., et al. , J. Clin. Invest. 94.
  • carbostyril derivative represented by the general formula (1) and / or a salt thereof has an IL-8 production inhibitory action and a MCAF production inhibitory action as described above.
  • the above-mentioned rubostyryl derivative as a particularly preferred active ingredient compound is 6- [4- (3,4-dimethoxy). Benzoinole) 1 1 —Piperazinyl] — 3,4 —Dihydrocarbostyril.
  • Each of the groups represented by the above general formula (1) representing the carbostyril derivative as an active ingredient of the drug of the present invention can be more specifically exemplified by the following groups.
  • examples of the lower alkoxy group include straight-chain or branched-chain groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy groups.
  • An alkoxy group can be exemplified.
  • Benzoyl groups which may have a lower alkoxy group as a substituent on the phenyl group include, for example, benzoinole, 2-methoxybenzoyl, 3-methoxybenzoyl, 4-methoxybenzoyl, 2-ethoxybenzoyl, 3-ethoxybenzoinole, 4-ethoxybenzoinole, 3-isopropoxybenzoyl, 4-butoxyquinyl, 2 1-Pentinoleoxybenzoyl, 3—Hexinoleoxybenzyl, 3,4—Dimethoxybenzoinole, 2,5—Dimethoxybenzoinole, 3,4,5—Trimethoxybenzoyl Examples thereof include benzoyl groups having from 1 to 6 straight or branched alkoxy groups having 1 to 6 carbon atoms as substituents on the phenyl ring, such as a group.
  • the carbostyril derivative represented by the general formula (1) includes a pharmacologically acceptable acid addition salt.
  • the acidic compound that forms the salt include inorganic acids such as sulfuric acid, phosphoric acid, nitric acid, hydrochloric acid, and hydrobromic acid, oxalic acid, maleic acid, fumaric acid, and lingic acid. And organic acids such as tartaric acid, citric acid and benzoic acid.
  • the carbostyryl derivative represented by the general formula (1), which is an active ingredient of the drug of the present invention, and nose or a salt thereof are usually used in the form of a general pharmaceutical preparation.
  • Such preparations are prepared using commonly used non-toxic preparation carriers, for example, diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants, and lubricants. Is done.
  • diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants, and lubricants.
  • this pharmaceutical preparation Can be selected from various forms according to the purpose of treatment. Representative examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions) , Suspensions and the like), eye drops and the like.
  • any of the above carriers which are conventionally known in the art can be widely used, such as lactose, saccharose, sodium chloride, glucose, urea, starch, canolecum carbonate, and kao.
  • Excipients such as phosphorus, microcrystalline cellulose, gay acid, etc., water, ethanol, propanol, single syrup, glucose solution, starch solution, gelatin solution, carboxymethyl phenol resin, cerac, Binders such as methinoresenorelose, potassium phosphate, polyvinylpyrrolidone, dried starch, sodium alginate, carpet powder, laminarane powder, sodium hydrogencarbonate, carbonate Calcium, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, milk Disintegrators such as sugar, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc., absorption promoters such as quaternary ammonium
  • the tablet can be a tablet coated with a usual coating, if necessary, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet or a double tablet or a multilayer tablet.
  • carriers conventionally known in this field can be used as carriers, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and evening oil.
  • carriers such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and evening oil.
  • Excipients binders such as arabic gum powder, tragacanth powder, gelatin and ethanol, disintegrants such as lamina lanthanum and the like can be used.
  • a wide variety of conventionally known carriers can be used, such as polyethylene glycol, cocoa butter, higher alcohols, higher alcohol esters, gelatin, and semi-synthetic materials. Glyceride etc. can be used.
  • liquids, emulsions, suspensions, etc. are preferably sterilized and isotonic with blood, and formed into the form of these liquids, emulsions, suspensions, etc.
  • any diluent commonly used in this field can be used. Examples include water, ethyl alcohol, propylene glycol, ethoxy diisostearyl alcohol, polyoxylated isostearyl lanolechol, and polyquinethylene sorbitan fatty acid ester. And the like.
  • the pharmaceutical preparation may contain a sufficient amount of salt, glucose, glycerin, etc. to prepare an isotonic solution, and may use a usual dissolution aid or buffer. Agents, soothing agents and the like may be added. Further, if necessary, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent, and other pharmaceuticals may be contained in the pharmaceutical preparation.
  • the amount of the compound of the general formula (1) contained as an active ingredient in the drug of the present invention is not particularly limited and may be appropriately selected from a wide range, but is usually about 1 to 70% by weight of the whole composition, preferably It is suitably in the range of about 1 to 30% by weight.
  • the administration method of the pharmaceutical preparation of the present invention is not particularly limited, and is determined according to various preparation forms, the age and sex of the patient, other conditions, and the degree of the disease.
  • a pharmaceutical preparation in the form of an injection can be administered by intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal or intravaginal administration, if necessary. It can also be administered intravenously after mixing with a replacement fluid.
  • the pharmaceutical preparation of the present invention in a solid form such as a tablet, a pill, a granule, a capsule or a liquid form for oral administration can be administered orally or enterally. Suppositories can be administered rectally. Eye drops can also be applied to the eyes.
  • the dose of the drug of the present invention can be appropriately selected from a wide range, and is not particularly limited.
  • the dosage unit form is a carbostyryl derivative (and salt thereof) represented by the general formula (1) ⁇
  • the administration of the drug of the present invention can be divided into once a day or 3 to 4 times a day.
  • Figure 1 is a graph showing the results of the test according to Pharmacological Test Example 1.o
  • Figure 2 is a graph showing the results of the test according to Pharmacological Test Example 1.
  • Figure 3 is a graph showing the results of the test according to Pharmacological Test Example 2.
  • Figure 4 is a graph showing the results of the test according to Pharmacological Test Example 2.
  • finolem coating agent consisting of castor oil and methanol
  • the above active ingredient compound, citrate, lactose, dicalcium phosphate, pull nick F-68 and sodium lauryl sulfate are mixed.
  • the above mixture is sieved with a No. 60 screen, and wet granulated with an alcoholic solution containing polyvinylpyrrolidone, Carbox 1500 and Carbox 600. .
  • the dried particles are sieved with a No. 16 screen, dried sodium lauryl sulfate and dried magnesium stearate are added, mixed, and compression-molded into a desired shape using a tableting machine.
  • the core is treated with varnish and talc is sprayed to prevent moisture absorption.
  • An undercoat layer is coated around the core. Apply a sufficient number of varnish coats for internal use.
  • a subbing layer and a smooth coating In order to make the tablet completely round and smooth, further apply a subbing layer and a smooth coating.
  • the colored coating is applied until the desired shade is obtained. After drying, polish the coating agent to prepare tablets with uniform gloss.
  • compound 1 6- [4— (3,4-dimethoxybenzoinole) -1-1-piperazinyl] -13,4-dihydroforce rubostyril (hereinafter referred to as “compound 1”) as the test compound.
  • compound 1 6- [4— (3,4-dimethoxybenzoinole) -1-1-piperazinyl] -13,4-dihydroforce rubostyril
  • PBMC peripheral blood mononuclear cells
  • FBS heat-inactivated fetal calf serum
  • Zml penicillin 100; g / ml RPMI containing Streptomycin (manufactured by Gibco) and 50 M 2 —Mercaptoethanol — resuspended in 1640 medium (manufactured by Gibco) and 5% C 0
  • the cells were cultured at 37 ° C under 2 .
  • Compound 1 was dissolved in 1N hydrochloric acid, diluted with FBS to a concentration of 1 mg Zml, and stored at 120 ° C.
  • the stock solution was further diluted with medium and adjusted to pH 7.0 with INNaOH.
  • Lipoposaccharide (LPS: manufactured by Difco) was prepared in PBS as a 3 mg noml storage solution.
  • PBMC peripheral blood mononuclear cells
  • 2 xl 0 6 cells Zm l 2 xl 0 6 cells Zm l
  • l O ⁇ gZm l Stimulation with LPS and lOng Zml PMA 5 M and 15 zM concentrations of Compound 1 were added simultaneously with LPS stimulation. After incubation for 24 hours, the supernatant was obtained and stored at ⁇ 20 ° C. until measurement of the cytokin. Culture was performed twice, and a total of 10 samples were measured. In addition, the gel stimulated without the addition of Compound 1 was used as a control.
  • the amount of IL-8 and MCAF produced by the stimulation was measured using a commercially available IL-8 and MCAF measurement kit (both manufactured by Toray Industries, Inc.).
  • the IL-8 and MCAF measurements were performed according to the measurement procedure attached to the kit, the absorbance at 450 nm was measured, calibration curves were obtained from the measured values of both standard solutions, and the human IL in each sample was measured. One-eight and MC AF concentrations were read.
  • Fig. 1 the vertical axis indicates the control (only for LPS stimulation
  • the amount of MCAF produced (shown as LPS), the amount of MCAF when added (shown as Ves_5), and the amount of MCAF (shown as Ves-3X5) when added (1). pg / m 1).
  • the vertical axis indicates control (only for LPS stimulation
  • Human umbilical vein endothelial cells were isolated using a method modified from the method of Gimbrone et al. [Gimbrone MA et al., J. Cell Biol., 60, 673-684 (1974)], and 20% Using fetal bovine serum (FCS), an endothelial cell growth promoter (ECGS; Sigma), and a medium of 199 medium (Sigma) containing 90 g nom 1 of heparin Culture was performed as follows.
  • the umbilical vein was extracted and subjected to a 0.05% collagenase solution ( ⁇ Sinton 'Nokiochemi Canole' Corporation: Worthington Biochemical Corporation, USA) at 37 ° C. For 20 minutes. The contents were poured into a conical tube containing the medium and centrifuged. Pellet cells were cultured seeded onto tissue culture plastic Kupure preparative you have Pureko bets with gelatin, in 5% C 0 2 below, 3 7 ° C in tissue culture Lee Nkyubeta PT / JP9701283
  • HUVECs used in this study included three to five levels.
  • Compound 1 was dissolved in hydrochloric acid, diluted with FBS to a concentration of 1 mg no ml, and stored at ⁇ 20 ° C. The stock solution was further diluted with medium and the pH was adjusted to 7.0 with INNaOH. IL-1 (manufactured by Genzyme) and TNF-a (manufactured by R & D Systems) were diluted with the above culture solution, and adjusted to have a concentration of l Ong Zml.
  • the vertical axis is the control (unstimulated, shown as-), Compound 1 only (shown as V 26), IL-11 stimulation only (shown as IL-1), TNF- ⁇ stimulation only
  • the vertical axis indicates control (no stimulation, shown as —), only compound 1 added (shown as V26), only IL-1 stimulation (shown as IL-1), only TNF- ⁇ stimulation
  • the IL-18 production inhibitor and MCAF production inhibitor of the present invention suppress abnormal production of IL-18 and MCAF, and cause diseases caused by these abnormal production, such as psoriasis of the skin, vasculitis, and pulmonary fibrosis. Effective for prevention and treatment.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des inhibiteurs de la production d'IL-8 (interleukine 8) et du MCAF (facteur monocytaire activant les neutrophiles), qui inhibent la production anormale d'IL-8 et de MCAF et sont par conséquent efficaces pour prévenir et traiter les maladies résultant de cette production anormale, par ex. le psoriasis, l'angéite et le poumon fibreux. Ces inhibiteurs contiennent, comme principe actif, des dérivés de carbostyryle de formule générale (1), et/ou leurs sels. Dans la formule, R représente benzoyle pouvant comporter un alcoxy inférieur sur le noyau phénylique; et la liaison entre les atomes de carbone en position 3 et 4, du squelette carbostyryle, est une liaison simple ou double. L'invention concerne également un procédé pour inhiber la production d'IL-8 et du MCAF.
PCT/JP1997/001283 1995-06-21 1997-04-14 Inhibiteurs de la production d'il-8 et du mcaf WO1998046229A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP07154923A JP3008010B2 (ja) 1995-06-21 1995-06-21 Ｉｌ−８産生抑制剤及びｍｃａｆ産生抑制剤
PCT/JP1997/001283 WO1998046229A1 (fr) 1995-06-21 1997-04-14 Inhibiteurs de la production d'il-8 et du mcaf

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP07154923A JP3008010B2 (ja) 1995-06-21 1995-06-21 Ｉｌ−８産生抑制剤及びｍｃａｆ産生抑制剤
PCT/JP1997/001283 WO1998046229A1 (fr) 1995-06-21 1997-04-14 Inhibiteurs de la production d'il-8 et du mcaf

Publications (1)

Publication Number Publication Date
WO1998046229A1 true WO1998046229A1 (fr) 1998-10-22

Family

ID=26438168

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1997/001283 WO1998046229A1 (fr) 1995-06-21 1997-04-14 Inhibiteurs de la production d'il-8 et du mcaf

Country Status (1)

Country Link
WO (1) WO1998046229A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993000902A1 (fr) * 1991-07-03 1993-01-21 Otsuka Pharmaceutical Co., Ltd. Regulateur d'apoptose
WO1993011769A1 (fr) * 1991-12-10 1993-06-24 Otsuka Pharmaceutical Co., Ltd Agent anticancereux
JPH05320133A (ja) * 1991-07-18 1993-12-03 Japan Tobacco Inc ３，４−ジヒドロ−２（１ｈ）−キノリノン誘導体
WO1994004504A1 (fr) * 1992-08-19 1994-03-03 Otsuka Pharmaceutical Co., Ltd. Regulateur d'apoptose

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993000902A1 (fr) * 1991-07-03 1993-01-21 Otsuka Pharmaceutical Co., Ltd. Regulateur d'apoptose
JPH05320133A (ja) * 1991-07-18 1993-12-03 Japan Tobacco Inc ３，４−ジヒドロ−２（１ｈ）−キノリノン誘導体
WO1993011769A1 (fr) * 1991-12-10 1993-06-24 Otsuka Pharmaceutical Co., Ltd Agent anticancereux
WO1994004504A1 (fr) * 1992-08-19 1994-03-03 Otsuka Pharmaceutical Co., Ltd. Regulateur d'apoptose

Similar Documents

Publication Publication Date Title
US6300349B1 (en) Inhibition of tumor necrosis factor alpha
EP1248604B2 (fr) Combinaisons comprenant un inhibiteur de la dipeptidylpeptidase - iv
TW449473B (en) Compositions for inhibition of the pathophysiologic actions in mammals of tumor necrosis factor-alpha
US5672603A (en) Apoptosis regulating composition
JP2006502152A (ja) 線維性疾患治療用の併用療法
JP2002363094A (ja) 肝線維化抑制剤
KR20230145439A (ko) Irak4 분해제 및 이의 용도
JPH0575729B2 (fr)
JP2005529927A (ja) 新規な組み合わせ
KR20010107927A (ko) 면역 조절용 약학 조성물
JP3008010B2 (ja) Ｉｌ−８産生抑制剤及びｍｃａｆ産生抑制剤
WO1998046229A1 (fr) Inhibiteurs de la production d'il-8 et du mcaf
KR102377420B1 (ko) 피리메타민을 유효성분으로 포함하는 류마티스 관절염의 치료 또는 예방용 약학 조성물
TWI344366B (en) Pharmaceutical compositions for the treatment of renal dysfunction, disease or disorder, in particular in diabetic patients
WO1994020107A1 (fr) Inhibiteur de rejet pour transplantations et inhibiteur de production d'interleukine 1
JP2946377B2 (ja) ＴＮＦ−α及びＩＬ−６産生抑制剤
JP3944257B2 (ja) 肝実質細胞増殖因子産生増加剤
JPH05194217A (ja) 抗高血圧組み合わせ医薬
WO2002011725A1 (fr) Inhibiteurs de production de cytokine inflammatoire
JP2000136139A (ja) 有機ゲルマニウム化合物を有効成分とするｍｃｐ−１受容体拮抗剤、及びｍｃｐ−１が関与する炎症性疾患及び臓器障害の発症予防または治療剤
JPH0873453A (ja) サイトカイン阻害剤
CN115645405B (zh) 顺苯磺酸阿曲库铵在制备抗结核抗生素增效剂中的应用
JP2010111581A (ja) ドーパミンｄ２様受容体アゴニストを有効成分とする医薬及びスクリーニング方法
JPH06192095A (ja) Ａｒｄｓ治療剤
WO2007000771A2 (fr) Derives de la quinazolinone fondue et leurs utilisations

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA US

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
NENP Non-entry into the national phase

Ref country code: CA