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WO1993012125A1 - Ester d'acide phosphorique d'un compose heterocyclique a titre de medicament - Google Patents

Ester d'acide phosphorique d'un compose heterocyclique a titre de medicament Download PDF

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Publication number
WO1993012125A1
WO1993012125A1 PCT/JP1992/001654 JP9201654W WO9312125A1 WO 1993012125 A1 WO1993012125 A1 WO 1993012125A1 JP 9201654 W JP9201654 W JP 9201654W WO 9312125 A1 WO9312125 A1 WO 9312125A1
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WO
WIPO (PCT)
Prior art keywords
substance
wf11231a
salt
diseases
medicament
Prior art date
Application number
PCT/JP1992/001654
Other languages
English (en)
Inventor
Eisaku Tsujii
Tomoko Nakanishi
Shigehiro Takase
Michio Yamashita
Shizue Izumi
Masakuni Okuhara
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
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to JP5510788A priority Critical patent/JPH07506332A/ja
Publication of WO1993012125A1 publication Critical patent/WO1993012125A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/14—Fungi; Culture media therefor
    • C12N1/145—Fungal isolates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
    • C12P17/182—Heterocyclic compounds containing nitrogen atoms as the only ring heteroatoms in the condensed system
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/645—Fungi ; Processes using fungi

Definitions

  • the present invention relates to a new bioactive compound, hereinafter entitled WF11231A substance.
  • WF11231A substance or a salt thereof which has immunosupressing activity
  • a process for preparation thereof to a pharmaceutical composition comprising the same, which is useful as immunosupressing agents, and to a use thereof as a medicament.
  • one object of this invention is to provide the novel compound, F11231A substance or a salt thereof which is of use for treating and preventing rejection by transplantation, graft-versus-host diseases by medulla ossium transplantation, autoimmune diseases, and the like.
  • Another object of this invention is to provide a process for production of the WF11231A substance or a salt thereof by fermentation of a WF11231A substance-producing strain belonging to the genus Cladobotrvum in a nutrient medium.
  • a further object of this invention is to provide a pharmaceutical composition containing, as an active ingredient, the WF11231A substance or a salt thereof.
  • Still further object of this invention is to provide a use of the WF11231A substance or a salt thereof for treating and preventing rejection by transplantation, graft-versus-host diseases by medulla ossium transplantation, autoimmune diseases, and the like.
  • the WF11231A substance of the present invention can be represented by the following formula:
  • Suitable salt of the WF11231A substance (I) is conventional pharmaceutically acceptable salt and include a metal salt such as an alkali metal salt (e. g. sodium salt, potassium salt, etc.) and 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 salt (e. g.
  • a metal salt such as an alkali metal salt (e. g. sodium salt, potassium salt, etc.) and 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
  • 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.
  • the WF11231A substance can be produced by fermentation of the WF11231A substance-producing strain belonging to the genus Cladobotryum such as Cladobotrvum sp. No. 11231 in a nutrient medium.
  • the production of the WF11231A substance is not limited to the use of the particular organism described herein, which is given for the illustrative purpose only.
  • This invention also includes the use of any mutants which are capable of producing the WF11231A substance including natural mutants as well as artificial mutants which can be produced from the described organism by conventional means such as irradiation of X-ray, ultra-violet radiation, treatment which N-methyl-N'-nitro-N-nitrosoguanidine, 2- aminopurine, and the like.
  • Cladobotrvum sp. No. 11231 is as follows:
  • the fungus strain No.11231 was originally isolated from a litter, collected at Iwaki-shi, Fukushima-ken, Japan. This organism grew very rapidly on various culture media and formed yellow to red colonies. Strain No.11231 formed anamorph, consisting of micronematous conidiophores branching subverticillately with hyaline and septated conidia formed retrogressively on various agar media. The conidiogenesis was holoblastic. This strain did not produce teleomorph structures. On the basis of its morphological characteristics, the strain appears to belong the hyphomycete genus Cladobotrvum Nees ex Steud. 1924 ⁇ . Its mycological characteristics were as follows.
  • the morphological characteristics were determined on basis of the cultures on mushroom agar ⁇ 1) .
  • the conidial structures were micronematous, mononematous, hyaline, smooth, septate.
  • Conidiophores were fragile, hyaline, smooth, often over 1 mm long, and up to 15 ⁇ m wide. They branched subverticillately, whorls on main stalks contained 2-3 branches, and ultimate branches bore 2-7 fertile cells verticiUately.
  • Conidiogenous cells were straight, subulate to cylindrical, 20-45 ⁇ m long, 3.0-6.0 ⁇ m wide above the base, tapering slightly towards the 1.0-3.0 ⁇ m wide apex, and formed conidia retrogressively. The conidia were 1-3 septated, straight, smooth, obclavate to cylindrical, and 18.0-28.5 x 7.0-11.0 ⁇ m, with rounded apices and acuminate bases.
  • the vegetative hyphae were smooth, septate, hyaline and branched.
  • the hyphal cells were cylindrical and 2.0-8.0 ⁇ m in diameter.
  • Strain No.11231 was able to grow at the temperature range from 4 to 32 °C with the growth optimum at 23 to 26 °C. These temperature data were determined on potato dextrose agar (made by Nissui).
  • strain No.11231 resembled Cladobotryum-state of Hypomyces dactylarioides G. Arnold 1971. But this strain did not produce teleomorph structures, then we named the producing strain Cladobotrvum sp. No.11231. And it was deposited in the Fermentation Research Institute, Agency of Industrial Science and Technology (1-3, Higashi 1-chome, Tsukuba-shi, Ibaraki, Japan) as FERM BP-3665 (deposited date: December 4, 1991). Table 1. Cultural characteristics of strain No.11231
  • Potato dextrose G Spreading broadly, >8.5 cm agar (Difco 0013)
  • S Cottony, produced red soluble pigment, formed conidial structures, dark blond
  • Czapek's solution G Spreading broadly, >8.5 cm agar (Raper and S: Irregular, cottony, formed conidial Thorn 1949) structures, yellowish white (3A2), at the center pastel pink (11 A4) R: Yellowish white (3A2), at the center pastel pink (11A4)
  • Oatmeal agar G Spreading broadly, >8.5 cm (Difco 0552) S: Felty to cottony, abundantly formed conidial structures, reddish white (7A2) R: Brownish orange (6C5) Medium Cultural characteristics
  • Emerson Yp Ss agar G Spreading broadly, >8.5 cm (Difco 0739)
  • S Cottony, abundantly formed conidial structures, light brown (7D4), at the margin reddish white (8A2), at the center brownish red (10C6)
  • R Grayish red (10B5)
  • Com meal agar G Spreading broadly, >8.5 cm (Difco 0386) S: Plane, thin, abundantly formed conidial structures, reddish white (8A2) R: Reddish white (8A2)
  • MY20 agar* G Spreading broadly, 5.0-5.5 cm
  • G growth, measuring colony size in diameter
  • S colony surface
  • R reverse
  • MY20 agar 5 g peptone, 3 g yeast extract, 3 g malt extract, 200 g glucose and 20 g agar per liter of water
  • the WF11231A substance are produced when the WF11231A substance-producing strain belonging the genus Cladobotrvum is grown in a nutrient medium containing sources of assimilable carbon and nitrogen under aerobic conditions (e. g. shaking culture, submerged culture, etc.).
  • the preferred sources of carbon in the nutrient medium are carbohydrates such as glucose, sucrose, starch, fructose or glycerin, or the like.
  • the preferred sources of nitrogen are yeast extract, peptone, gluten meal, cotton seed flour, soybean meal, com steep liquor, dried yeast, wheat germ, etc., as well as inorganic and organic nitrogen compounds such as ammonium salts (e. g. ammonium nitrate, ammonium sulfate, ammonium phosphate, etc.), urea or amino acid, or the like.
  • ammonium salts e. g. ammonium nitrate, ammonium sulfate, ammonium phosphate, etc.
  • urea or amino acid or the like.
  • the carbon and nitrogen sources though advantageously employed in combination, need not to be used in their pure form because less pure materials, which contain traces of growth factors and considerable quantities of mineral nutrients, are also suitable for use.
  • medium mineral salts such as sodium or calcium carbonate, sodium or potassium phosphate, sodium or potassium chloride, sodium or potassium iodide, magnesium slats, copper salts, zinc salts, or salts, or cobalt salts, or the like.
  • a defaming agent such as liquid paraffin, fatty oil, plant oil, mineral oil or silicone, or the like may be added.
  • Agitation and aeration of the culture mixture may be accomplished in a variety of ways, such as agitation by a propeller or similar mechanical agitation equipment, by revolving or shaking the fermenter, and the like.
  • the fermentation is usually conducted at a temperature between about 10°C and 40°C, preferably 20°C to 30°C, for a period of about 50 hours to 150 hours, which may be varied according to fermentation conditions and scales.
  • the culture broth is then subjected for recovery of the WF11231A substance to various procedures conventionally used for recovery and purification of biological active substance, for instance, solvent extraction with an appropriate solvent or a mixture of some solvents, chromatography or recrystallization from an appropriate solvent or a mixture thereof.
  • the salt of the WF11231A substance can be prepared by a conventional manner, during or after the recovery and purification of the WF11231 A substance.
  • the hydrochloric acid salt of the WF11231A substance as obtained has the following physico-chemical properties:
  • the WF11231A substance is inferred to have the following plane structural formula.
  • the WF11231A substance (I) possesses pharmacological activities such as immunosuppressive activity, and the like, and therefore are useful for the treatment and prevention of immune-mediated diseases such as the resistance by transplantation of organs or tissue such as heart, kidney, liver, medulla ossium, skin, cornea, lung, pancreas, - f -
  • intestinum ***, limb, muscle, nervus, etc. graft-versus-host diseases by medulla ossium transplantation
  • autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, and the like.
  • the WF11231A substance (I) is also useful for the treatment and the prophylaxis of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically-mediated illnesses, such as, psoriasis, atopical dermatitis, contact dermatitis and further eczematous dermatitises, seborrhoeis dermatitis, Lichen planus, Pemphigus, bullous Pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupus erythematosus, acne and Alopecia areata; various eye diseases such as autoimmune diseases and so on (e.
  • keratoconjunctivitis vernal conjunctivitis, uveitis associated with Behcet's diseases, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis comeae, comeal leukoma, ocular pemphigus, Mooren's ulcer, Scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, etc.); reversible obstructive airways disease, which includes conditions such as asthma (e. g. bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma), particularly chronic or inveterate asthma (e.
  • asthma e. g. bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma
  • chronic or inveterate asthma e.
  • bronchitis and the like inflammation of mucosa and blood vessels such as gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel disease, inflammatory bowel disease, necrotizing enterocblitis, intestinal lesions associated with thermal bums, leukotriene B ⁇ -mediated diseases; intestinal inflammations/allergies such as Coeliac disease, proctitis, eosnophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis; food related allergic diseases which have symptomatic manifestation remote form the gastro-intestinal tract, for example migraine, rhinitis and eczema; renal diseases such as interstitial nephritis, Goodpasture's syndrome, hemolytic-uremic syndrome and diabetic nephropathy; nervous diseases such as multiple myositis, Guillain-Barr ⁇ syndrome, Meniere's disease, polyneuritis, multiple neuritis,
  • autoimmune myocarditis e.g. autoimmune myocarditis, vims myocarditis); collagen diseases such as scleroderma, Wegener's granuloma and Sjogren's syndrome; adiposis; eosinophilic fasciitis; periodontal disease such as lesion of gingiva, periodontium, alveolar bone, substantia ossea dentis; nephrotic syndrome such as glomerulonephritis; male pattern alopecia or alopecia senilis; muscular dystrophy; Pyoderma and Sezary's syndrome; Addison's disease; active oxygen-mediated diseases, for example, organ injury such as ischemia-reperfusion injury of organs (e. g.
  • ischemic diseases e. g. thrombosis, cardiac infarction
  • intestinal diseases such as endotoxin-shock, pseudomembranous colitis, colitis caused by drug or radiation
  • renal diseases such as ischemic acute renal insufficiency, chronic renal insufficiency
  • pulmonary diseases such as toxinosis caused by lung- oxygen or drag (e, g.
  • pulmonary emphysema ocular diseases such as cataracta, siderosis, retinitis, pigmentosa, senile macular degeneration, vitreal scarring, comeal alkali bum: dermatitis such as erythema multiforme, linear IgA baUous dermatitis, cement dermatitis: and others such as gingvatis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution (e. g. air pollution), aging, carcinogenis, metastasis of carcinoma, hypobaropathy; diseases caused by histamine or leukotriene ⁇ release; and Behcet's disease such as intestinal-, vasculo-, or neuro-
  • Behcet's disease and also the one which affects oral cavity, skin, eye, vulva, articulation, epididymis, lung, kidney and so on; and so on.
  • the WF11231A substance (I) may have liver regenerating activity and/or activities of stimulating hypertrophy and hyperplasia of hepatocytes. Therefore, they are useful for treatment and prevention of hepatic diseases such as immunogenic diseases (e. g. chronic autoimmune liver diseases such as the group consisting of autoimmune hepatitis, primary biliary cirrhosis and sclerosing cholangitis), partial liver resection, acute liver necrosis (e. g.
  • immunogenic diseases e. g. chronic autoimmune liver diseases such as the group consisting of autoimmune hepatitis, primary biliary cirrhosis and sclerosing cholangitis
  • partial liver resection e. g.
  • the WF11231A substance (I) may be useful for various diseases because of its useful pharmaceutical activity such as augmenting activity of chemotherapeutic effect, preventing of treating activity of cytomegalovirus infection, anti-inflammatory activity, and so on.
  • Test 1 Effect of the WF11231A substance on concanavalin A-induced lymphocyte proliferation
  • Spleens from Balb/c mice were taken under sterile conditions and gently dissociated in RPMI 1640 medium supplemented with penicillin (100 units/ml) and streptomycin (100 ⁇ g/ml). Cells were pelleted by centrifugation at 1,000 rpm for 5 minutes. Containing erythrocytes were removed by treating the pellet with ammonium chloride lysing buffer for 2 minutes at room temperature and washed. Washed spleen cells were finally resuspended in RPMI 1640 medium supplemented with 10% fetal bovine serum, 50 ⁇ M 2-mercaptoethanol, penicillin (100 units/ml) and streptomycin (100 ⁇ g/ml).
  • Concanavalin A was added at 10 ⁇ g/ml.
  • the cell suspension was immediately distributed into 96 well round-bottomed microculture plates at 50 ⁇ l/well.
  • the hydrochloric acid salt of the WF11231A substance, hereinafter entitled WF11231A • HC1, of this invention was dissolved in water, further diluted in RPMI 1640 medium and added in triplicate wells at 50 ⁇ l/well to give the below-indicated final concentration.
  • MTT [3-(4,5- dimethylthiazolyl-2-yl)-2,5-diphenyltetrazolium bromide] dye reduction assay.
  • MTT was dissolved in phosphate buffer at 5 mg/ml.
  • Ten ⁇ l of MTT solution was added to all wells of an assay and plates were incubated at 37 °C for 4 hours.
  • Vental allografts from donor (Lewis) rats were grafted onto the lateral thoracic area of recipient (F344) rats.
  • the dressings were removed 5 days after the skin transplantation.
  • the grafts were inspected daily until rejection which was defined as more than 90% necrosis of the graft epithelium.
  • the WF11231A • HQ was dissolved in saline and administered intraperitoneally either for 14 consecutive days in rats treated at doses of 0, 0.1 and 0.3 mg/kg, for 9 consecutive days in rats treated at 1 mg/kg or for 5 consecutive days in rats treated at 3 mg/kg, beginning at the day of transplantation.
  • the pharmaceutical composition of this invention can be used in the form of pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the WF11231A substance or its pharmaceutically acceptable salt, as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral administrations.
  • the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, injections, ointments, liniments, eye drops, lotion, gel, creme, and any other form suitable for use.
  • the carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, com starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening, solubilizing and coloring agents and perfumes may be used.
  • the composition for applying the composition to human, it is preferable to apply it by intravenous, intramuscular, topical or oral administration.
  • the dosage of therapeutically effective amount of the WF11231A substance varies from and also depends upon the age and condition of each individual patient to be treated, in the case of individual patient to be treated, in the case of intravenous administration, a daily dose of 0.01 - 10 mg of the WF11231A substance per kg weight of human being, in the case of intramuscular administration, a daily dose of 0.1 - 10 mg of the WF11231A substance per kg weight of human being, in case of oral administration, a daily dose of 0.5 - 50 mg of the WF11231A substance of human being is generally given for treating.
  • aqueous seed medium 120 ml containing sucrose 4%, cotton seed flour 2%, dried yeast 1%, peptone 1%, KH 2 P0 4 0.2%, CaC0 3 0.2% and Tween 80 0.1% was poured into each of twenty 500 ml-Erlenmyer flasks and sterilized at 121 °C for 30 minutes.
  • a loopful of Cladobotrvum sp. No.11231 was inoculated from a slant culture into each of the flasks. The flasks were shaken on a rotary shaker at 25 °C for 3 days.
  • the resultant seed culture was inoculated to 150 liters of sterile production medium consisting of modified starch 4 %, glucose 1 %, cotton seed flour 2 %, soybean flour 2 %, (NH 4 ) 2 P0 4 1%,
  • the amount of the WF11231A in the fermentation broth was quantified by both its immunosuppressing activity in the in vitro concanavarin A-induced lymphocyte proliferation and HPLC analysis.
  • the cultured broth 160 liters was filtered with the aid of diatomaseous earth (1 kg). The filtrate was discarded. 80 liters of methanol was added to the mycelium cake with stirring. The mixture was allowed to stand for 1 hour and was then filtered. The filtrate was concentrated to 20 liters under reduced pressure and the solution was passed through a column (6 liters) of polymeric adsorbent, SEPABEADS SP-207 (Mitsubishi Kasei Co., Ltd.). The column was washed with 18 liters of water, 18 liters of 50 % aqueous methanol and was eluted with 18 liters of 50 % aqueous methanol containing 0.14 % ammonium hydroxide.
  • the eluate was concentrated to 10 liters under reduced pressure. After adjusting the pH to 3.0 with 1 N HCI, the aqueous solution was passed through a column (0.35 liter) of a cation exchange resin, Diaion SK-1B (NH 4 + -type, Mitsubishi Kasei
  • the resultant crude powder was further purified by preparative HPLC column packed with YMC gel (ODS-AM 120-S50, 1.5 cmID 50 cm, made by Yamamura Chemical Institute), mobile phase, acetonitrile- acid (6:94:0.1, v/v).
  • the eluate was monitored by

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Abstract

Composé répondant à la formule (I), et ses sels pharmaceutiquement acceptables, utilisés comme médicament.
PCT/JP1992/001654 1991-12-18 1992-12-17 Ester d'acide phosphorique d'un compose heterocyclique a titre de medicament WO1993012125A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP5510788A JPH07506332A (ja) 1991-12-18 1992-12-17 医薬としての複素環化合物のリン酸エステル

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB919126870A GB9126870D0 (en) 1991-12-18 1991-12-18 Novel compound
GB9126870.6 1991-12-18

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WO1993012125A1 true WO1993012125A1 (fr) 1993-06-24

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0673646A3 (fr) * 1994-03-22 1995-12-27 Behringwerke Ag Utilisation de déoxypergualin dans la fabrication d'un médicament pour le traitement des affections de l'hypersensibilité-inflammatoire.
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
No relevant documents disclosed *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0673646A3 (fr) * 1994-03-22 1995-12-27 Behringwerke Ag Utilisation de déoxypergualin dans la fabrication d'un médicament pour le traitement des affections de l'hypersensibilité-inflammatoire.
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection

Also Published As

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JPH07506332A (ja) 1995-07-13
GB9126870D0 (en) 1992-02-19

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