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WO1995003053A1 - Oxophtalazine de traitement de la cachexie - Google Patents

Oxophtalazine de traitement de la cachexie Download PDF

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Publication number
WO1995003053A1
WO1995003053A1 PCT/JP1994/001179 JP9401179W WO9503053A1 WO 1995003053 A1 WO1995003053 A1 WO 1995003053A1 JP 9401179 W JP9401179 W JP 9401179W WO 9503053 A1 WO9503053 A1 WO 9503053A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
ester
compound
oxophthalazine
carboxy
Prior art date
Application number
PCT/JP1994/001179
Other languages
English (en)
Inventor
Fumihiko Sakai
Nobuchika Yamamoto
Kunio Nakahara
Harumi Yamazaki
Yoshitada Notsu
Yoshio Kawai
Hitoshi Yamazaki
Yoshito Abe
Teruo Oku
Original Assignee
Fujisawa 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 claimed from GB939315422A external-priority patent/GB9315422D0/en
Priority claimed from GB939322283A external-priority patent/GB9322283D0/en
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to JP7505053A priority Critical patent/JPH09506068A/ja
Priority to AU71955/94A priority patent/AU7195594A/en
Publication of WO1995003053A1 publication Critical patent/WO1995003053A1/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a new use of the oxophthalazine compounds or pharmaceutically acceptable salts thereof.
  • the present invention is useful for the medical care.
  • the oxophthalazine compounds to be used in the present invention may include the novel and known ones disclosed in the publications such as Japanese Patent Application laid-open No. 54-95582, or the like; and the like.
  • the present invention relates to a new use of the oxophthalazine compounds or pharmaceutically acceptable salts thereof.
  • oxophthalazine compounds for the prophylactic and/or therapeutic treatment of cachexia (e.g. oligotropha, anorexia, syntexis, etc.) such as cancer cachexia [e.g. alimentary cancer cachexia (e.g. cancer cachexia of stomach, cancer cachexia of pancreas, etc.)]; cachexia in case of chronic infectious diseases (e.g. AIDS, trypanosoma infection, etc.); shock (e.g.
  • cachexia e.g. oligotropha, anorexia, syntexis, etc.
  • cancer cachexia e.g. alimentary cancer cachexia (e.g. cancer cachexia of stomach, cancer cachexia of pancreas, etc.)]
  • cachexia in case of chronic infectious diseases e.g. AIDS, trypanosoma infection, etc.
  • shock e.g.
  • septic shock hemorrhagic shock, burn shock, anaphylactic shock, etc.
  • disseminated intravascular coagulation DIC
  • hypertriglycemia hyperglyce ia
  • arteriosclerosis arteriosclerosis
  • osteoporosis degradation of bone and cartilage in case of rheumatoid arthritis, osteoarthritis, etc.
  • rejection by transplantation asthma; specific autoimmune diseases (e.g.
  • aplastic anaemia pure red cell anaemia, idiopathic thrombocytopenia, etc.
  • systemic lupus erythematosus egener granulamotosis; chronic active hepatitis; myasthenia gravis; psoriasis; idiopathic sprue; multiple sclerosis; primary biliary cirrhosis; juvenile diabetes (diabetes ellitus type I); Reiter's syndrome; thrombosis and the like in a human being or an animal.
  • one object of the present invention is to provide a pharmaceutical composition for the prophylactic and/or therapeutic treatment of above- mentioned diseases in a human being or an animal comprising, as an active ingredient, the oxophthalazine compounds or pharmaceutically acceptable salts thereof.
  • Another object of the present invention is to provide a method for the prophylactic and/or therapeutic treatment of above-mentioned diseases in a human being or an animal which comprises administering the oxophthalazine compounds to a human being or an animal.
  • a further object of the present invention is to provide a use of the oxophthalazine compounds for the manufacture of a medicament for the prophylactic and/or therapeutic treatment of above-mentioned diseases in a human being or an animal.
  • An additional object of the present invention is to provide a use of the oxophthalazine compounds for the prophylactic and/or therapeutic treatment of above- mentioned diseases in a human being or an animal.
  • the inventors of the present invention have found the oxophthalazine compounds and pharmaceutically acceptable salts thereof are useful for the prophylactic and/or therapeutic treatment of above-mentioned diseases in a human being or an animal and have completed the present inventio .
  • oxophthalazine compounds used in the present invention can be represented by following general formula
  • R ⁇ is ar(lower)alkyl which may have one or more suitable substituent(s) , and R ⁇ is carboxy(lower)alkyl or protected carboxy(lower)alkyl, or a pharmaceutically acceptable salt thereof.
  • the oxophthalazine compounds to be used in the present invention may include the novel and known ones disclosed in the publications such as Japanese laid-open No. 54-95582, or the like; and the like.
  • novel oxophthalazine compound (I) can be prepared, for example, according to the procedures disclosed in Preparations and Examples as mentioned later in the present specification.
  • Suitable pharmaceutically acceptable salts of the oxophthalazine compound (I) to be used in the present invention are conventional ones and include a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), an organic acid - 4 -
  • a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,
  • salt e.g. acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.
  • an inorganic acid salt e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.
  • a salt with an amino acid e.g. arginine, aspartic acid, glutamic acid, etc.
  • Suitable example of "ar(lower)alkyl” may include mono-(or di- or tri-)phenyl(lower)alky1 (e.g. benzyl, phenethy1, 2-phenylpropyl, 4-phenylbuty1, 2-pheny1-1,1- dimethylethyl, 1-phenylpentyl, 6-phenylhexyl, benzhydryl, trityl, etc.) and the like, in which the preferred one may be phenyl(C ⁇ -C4)alkyl and the most preferred one may be benzyl.
  • benzyl e.g. benzyl, phenethy1, 2-phenylpropyl, 4-phenylbuty1, 2-pheny1-1,1- dimethylethyl, 1-phenylpentyl, 6-phenylhexyl, benzhydryl, trityl, etc.
  • Suitable substituent(s)" in the term of "ar(lower)alkyl which may have one or more suitable substituent(s) " may include lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc.), halogen (e.g. chloro, bromo, fluoro, iodo), mono-(or di- or tri-)halo(lower)alkyl (e.g. trifluoromethyl, 2-iodoethyl, 2,2,2-trichloroethyl, etc.).
  • Suitable number of the substituent(s) on said "ar(lower)alkyl” may be 1 to 3, preferably 2.
  • Suitable example of “carboxy(lower)alkyl” may include carboxymethyl, 1-carb ⁇ xyethyl, 2-carboxypropyl, l-(carboxymethyl)ethyl, 4-carboxybutyl, 3-carboxy ⁇ entyl, 2-carboxyhexyl, etc., in which the preferred one may be carboxy(C1-C4)alkyl and the more preferred one may be carboxymethyl.
  • Suitable example of "protected carboxy” in the term of “protected carboxy(lower)alkyl” may be an esterified carboxy group, or the like, and concrete examples of the ester moiety in said esterified carboxy group may be the ones such as lower alkyl ester [e.g.
  • ester methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.
  • suitable substituent(s) for example, lower alkanoyloxy(lower)alkyl ester [e.g.
  • benzyl ester 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)meth l ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-tert- butylbenzyl ester, etc.]; aryl ester which may have suitable substituent(s) [e.g. phenyl ester, 4-chl ⁇ rophenyl ester, tolyl ester, 4-tert- butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.]; or the like.
  • suitable substituent(s) e.g. phenyl ester, 4-chl ⁇ rophenyl ester, tolyl ester, 4-tert- butylphenyl ester, xylyl ester, mesityl ester,
  • the preferred one may be lower alkoxycarbonyl(lower)alkyl, the more preferred one may be (C1-C4)alkoxycarbonyl(C1-C4)- alkyl and the most preferred one may be ethoxycarbonylmethyl.
  • the preferred one may be the compound (I) wherein R* is phenyl(lower)alkyl which may have 1 to 3 suitable substituent(s) selected from the group consisting of lower alkyl, halogen and tri- halo(lower)alkyl, and R ⁇ is carboxy(lower)alkyl or esterified carboxy(lower)alkyl; ii) the more preferred one may be the compound (I) wherein R 1 is phenyl(lower)alkyl which may have 1 to 3 halogen, and R ⁇ is carboxy(lower)alkyl or lower alkoxycarbonyl(lower)alkyl; iii) the much more preferred one may be the compound (I) wherein R ⁇ is phenyl(C ⁇ C4)alkyl having 2 halogen, and R ⁇ is carboxy(C1-C4)alkyl; iv) the most preferred one may be 2-[3-
  • the pharmaceutical composition of the present invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the oxophthalazine compound (I) or a pharmaceutically acceptable salt thereof, as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for rectal, pulmonary (nasal or buccal inhalation), nasal, ocular, external (topical), oral or parenteral (including subcutaneous, intravenous and intramuscular) administrations or insufflation.
  • a pharmaceutical preparation for example, in solid, semisolid or liquid form, which contains the oxophthalazine compound (I) or a pharmaceutically acceptable salt thereof, as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for rectal, pulmonary (nasal or buccal inhalation), nasal, ocular, external (topical), oral or parenteral (including subcutaneous, intravenous and intramuscular) administrations or insufflation.
  • the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, troches, capsules, suppositories, creams, ointments, aerosols, powders for insufflation, solutions, emulsions, suspensions, and any other form suitable for use. And, if necessary, in addition, auxiliary, stabilizing, thickening and coloring agents and perfumes may be used.
  • the oxophthalazine compound (I) or pharmaceutical acceptable salts thereof is/are included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the diseases.
  • the pharmaceutical composition of the present invention can be manufactured by the conventional method in this field of the art. If necessary, the technique generally used in this field of the art for improving the bioavailability of a drug can be applied to the pharmaceutical composition of the present invention.
  • composition for applying the composition to a human being or an animal, it is preferable to apply it by intravenous (including i.v. infusion), intramuscular, pulmonary, or oral administration, or insufflation.
  • intravenous including i.v. infusion
  • intramuscular including i.v. infusion
  • pulmonary including pulmonary pulmonary
  • oral administration or insufflation.
  • While the dosage of therapeutically effective amount of the oxophthalazine compound (I) varies from and also depends upon the age and condition of each individual patient to be treated, in the case of intravenous administration, a daily dose of 0.01-100 g of the oxophthalazine compound (I) per kg weight of a human being or an animal, in the case of intramuscular administration, a daily dose of 0.01-100 mg of the oxophthalazine compound (I) per kg weight of a human being or an animal, in case of oral administration, a daily dose of 0.01-200 mg of the oxophthalazine compound (I) per kg weight of a human being or an animal is generally given for the prophylactic and/or therapeutic treatment of above-mentioned diseases in a human being or an animal.
  • Test Compound (I) 2-[3-(2-Fluoro-4-bromobenzyl)-3,4-dihydro-4- oxophthalazin-1-yl]acetic acid. (This compound is disclosed in Example 7 of Japanese Patent Application laid-open No. 54-95582.) [hereinafter referred to as Test Compound (I) ]
  • Test 1 in vitro activity :
  • IL-1 levels were quantified by a commercial ELISA kit (prepared by Ohtuka assay, Japan) using a sandwich technique.
  • the sensitivity levels for the detection of IL-l ⁇ were 20 pg/ml.
  • the inhibitory concentration that caused a 50% inhibition was calculated by regression analysis of the dose-response data.
  • 3T3-L ⁇ adipocytes were induced by the method of (J. Biolo. Che ., 253 (20), 7570 (1978)) and the fully differentiated 3T3-L ⁇ adipocytes showed lipoprotein lipase (LPL) activity.
  • the LPL activity was suppressed more than 80% by the addition of rabbit serum injected with LPS to 3T3-L ⁇ adipocytes.
  • test compound (1) was added at concentration of 1.6 ⁇ g/ml, the increase of intracellular lipids accumulation and a two times increase in LPL activity compared with that incubated in the presence of LPS injected rabbit serum only were observed.
  • LPL activity were determined by the method of (J. Lipid Res., 17,536 (1976)) with minor modification. This result apparently shows the increase on lipoprotein lipase (LPL) because of the oxophthalazine compound (I).
  • the rabbit model was prepared according to the methods of (FASEB J., 5 (3), 338-343 (1991)) with minor modification.
  • Female New Zealand White (3 kg) were housed for a minimum of a week in the animal care facilities were free of infections.
  • the rabbits were anesthetized with 1% halothane.
  • Catheters were placed in the abdominal aorta from the left femoral artery, to continuously record mean arterial pressure.
  • LPS were resuspended with 10 ml of sterile saline, and then infused into the left femoral vena cava for 20 minutes beginning to 0 minute.
  • the saline-treated (vehicle-matched) control received saline intravenous injection as a 10 ml bolus 15 minutes before LPS infusion, then continuous infusion at a constant rate (3 ml/hr) for 4 hours.
  • Test compound treated group received test compound intravenous injection as a 10 ml bolus (3.2 mg/kg) at 15 minutes before LPS infusion, followed by a constant rate (3.2 mg/kg/hr) for 4 hours. 2.
  • Test Compound (1) 100 81.2 ⁇ 4.4*
  • test compound (1) was suspended in 0.5% carboxymethylcellulose and administered orally at a dosage of from 32 to 100 mg/kg. After 16 hours, the LPL activity in the epididymal fat pads were determined by the method of (J. Lipid Res., 17,536 (1976) with minor modification.
  • Mouse cancer cachexia model is induced by intraperitoneal injection of B16 mice melanoma 1.5 x 10" cells/head into female C57BL/6 mice.
  • food intake, epididymal fat pad weight and body weight were significantly decreased. This situation is similar to that observed in cancer patients.
  • Epididymal fat pad weight started to decrease approximately 7 days after transplantation. After 10-12 days the epididymal fat pad weight loss were measured.
  • Test compound (1) was suspended in 0.5% carboxymethylcellulose and administered orally for 10-12 days at dosage rate of from 3.2 to 10 mg/kg/day.
  • mice Data were presented as the mean ⁇ S.E. for eight mice.
  • Test method This tumor bearing mice is induced by intraperitoneal injection of B16 melanoma 10 ⁇ cells/head into female C57 BL/6 mice. Test compound (I) was suspended in 0.5% carboxymethyl cellulose and administered orally at dosage of 32 mg/kg/day.
  • mice Female db/db mice (7 weeks old) were administered orally test compound (I) at dosage of 100 mg/kg/day for 12 days before measurement. Blood sample were collected from the heart, were obtained to measure plasma glucose and free fatty acid for 6 hours after the last administration. The plasma glucose and free fatty acid were markedly decreased in treated mice. - 14 -
  • mice control 100 mg/kg
  • the results of above-mentioned test apparently shows the utility of the oxophthalazine compound (I) for the prophylactic and/or therapeutic treatment of cachexia (e.g. oligotrophia, anorexia, syntexis, etc.) such as cancer cachexia [e.g. alimentary cancer cachexia (e.g. cancer cachexia of stomach, cancer cachexia of pancreas, etc.)]; cachexia in case of chronic infectious disease (e.g. AIDS, trypanosoma infection, etc.); shock (e.g.
  • cachexia e.g. oligotrophia, anorexia, syntexis, etc.
  • cancer cachexia e.g. alimentary cancer cachexia (e.g. cancer cachexia of stomach, cancer cachexia of pancreas, etc.)]
  • cachexia in case of chronic infectious disease e.g. AIDS, trypanosoma infection, etc.
  • shock e.g.
  • septic shock hemorrhagic shock, burn shock, anaphylactic shock, etc.
  • disseminated intravascular coagulation DIC
  • hypertriglycemia hyperglycemia
  • arteriosclerosis arteriosclerosis
  • osteoporosis degradation of bone and cartilage in case of rheumatoid arthritis, osteoarthritis, etc.
  • rejection by transplantation asthma; specific autoimmune diseases (e.g.
  • aplastic anaemia pure red cell anaemia, idiopathic thrombocytopenia, etc.
  • systemic lupus erythematosus Wegener granulomatosis; chronic active hepatitis; myasthenia gravis; psoriasis; idiopathic sprue; multiple sclerosis; primary biliary cirrhosis; juvenile diabetes (diabetes mellitus type I); Reiter's syndrome; thrombosis and the like in a human being or an animal.
  • the oxophthalazine compound (I) is useful for the prophylactic and/or therapeutic treatment of cachexia and shock.
  • Example 4 The following compound was obtained according to a similar manner to that of Example 1.
  • Example 5 to 19 The following compounds in Example 5 to 19 were obtained according to a similar manner to that of Example or any process known in the field of the art for preparing structurally analogous compounds thereto.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Saccharide Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Nouvelle application de composés d'oxophtalazine ou de leurs sels pharmaceutiquement acceptables à la prévention et/ou au traitement thérapeutique de la cachexie ou analogue. Ces composés d'oxophtalazine répondent à la formule générale (I), dans laquelle R1 représente aralkyle (inférieur) ayant un ou plusieurs substituants appropriés, et R2 représente carboxyalkyle (inférieur) ou carboxyalkyle (inférieur) protégé.
PCT/JP1994/001179 1993-07-26 1994-07-18 Oxophtalazine de traitement de la cachexie WO1995003053A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP7505053A JPH09506068A (ja) 1993-07-26 1994-07-18 悪液質治療のためのオキソフタラジン類
AU71955/94A AU7195594A (en) 1993-07-26 1994-07-18 Oxophthalazines for treating cachexia

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB939315422A GB9315422D0 (en) 1993-07-26 1993-07-26 New use
GB9315422.7 1993-10-29
GB939322283A GB9322283D0 (en) 1993-10-29 1993-10-29 New use
GB9322283.4 1993-10-29

Publications (1)

Publication Number Publication Date
WO1995003053A1 true WO1995003053A1 (fr) 1995-02-02

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1994/001179 WO1995003053A1 (fr) 1993-07-26 1994-07-18 Oxophtalazine de traitement de la cachexie

Country Status (3)

Country Link
JP (1) JPH09506068A (fr)
AU (1) AU7195594A (fr)
WO (1) WO1995003053A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015181394A1 (fr) * 2014-05-30 2015-12-03 INSERM (Institut National de la Santé et de la Recherche Médicale) Nouveaux composés antagonistes des récepteurs de l'il-2/il-15 et leurs utilisations pour le traitement de maladies auto-immunes et inflammatoires ou du rejet de greffe

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0002895A1 (fr) * 1977-12-29 1979-07-11 Imperial Chemical Industries Plc Dérivés de l'acide phtalazinyl-4-acétique inhibiteurs d'enzymes, compositions pharmaceutiques les contenant et leur procédé de préparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0002895A1 (fr) * 1977-12-29 1979-07-11 Imperial Chemical Industries Plc Dérivés de l'acide phtalazinyl-4-acétique inhibiteurs d'enzymes, compositions pharmaceutiques les contenant et leur procédé de préparation
JPS5495582A (en) * 1977-12-29 1979-07-28 Ici Ltd Phthalazinee44yl acetic acid derivative*its manufacture and medical composition containing said derivative and having aldose reductase control activity

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
A.S. REDDI ET AL.: "Aldose reductase inhibition by ponalrestat (Statil) does not prevent proteinuria in long-term diabetic rats", J. DIAB. COMP., vol. 7, no. 3, 1993, pages 233 - 240 *
E. BRUERA: "Current pharmacological management of anorexia in cancer patients", ONCOLOGY, vol. 6, no. (1), 1992, pages 125 - 130 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015181394A1 (fr) * 2014-05-30 2015-12-03 INSERM (Institut National de la Santé et de la Recherche Médicale) Nouveaux composés antagonistes des récepteurs de l'il-2/il-15 et leurs utilisations pour le traitement de maladies auto-immunes et inflammatoires ou du rejet de greffe

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Publication number Publication date
AU7195594A (en) 1995-02-20
JPH09506068A (ja) 1997-06-17

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