WO1992011275A1 - Derive de 13-dimethyle fr-900506 et son utilisation en tant qu'agent immunosuppresseur - Google Patents

Derive de 13-dimethyle fr-900506 et son utilisation en tant qu'agent immunosuppresseur Download PDF

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Publication number
WO1992011275A1
WO1992011275A1 PCT/JP1991/001726 JP9101726W WO9211275A1 WO 1992011275 A1 WO1992011275 A1 WO 1992011275A1 JP 9101726 W JP9101726 W JP 9101726W WO 9211275 A1 WO9211275 A1 WO 9211275A1
Authority
WO
WIPO (PCT)
Prior art keywords
substance
diseases
liters
hexane
silica gel
Prior art date
Application number
PCT/JP1991/001726
Other languages
English (en)
Inventor
Kanji Hayami
Kazuto Yonetani
Takeshi Kawagita
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.
Publication of WO1992011275A1 publication Critical patent/WO1992011275A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen
    • 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

Definitions

  • This invention relates to a novel compound having pharmacological activities, hereinafter entitled FR-901429 substance, to a process for its production, to a pharmaceutical composition containing the same and to a use thereof.
  • FR-901429 substance which has pharmacological activities such as immunosuppressive activity, antimicrobial activity, and the like, to a process for its production, to a
  • composition containing the same and to a use thereof as a medicament.
  • one object of this invention is to provid the novel compound, FR-901429 substance which is of use for treating and preventing rejection by transplantation, graft-versus-host diseases by medulla ossium
  • Another object of this invention is to provide a process for production of the FR-901429 substance by fermen tation of a FR-901429 substance-producing strain belonging to the genus Streptomyces in a nutrient medium.
  • a further object of this invention is to provide a pharmaceutical composition containing, as an active
  • Still further object of this invention is to provide a use of the FR-901429 substance for treating and preventing rejection by transplantation, graft-versus-host diseases by medulla ossium transplantation, autoimmune diseases, infectious diseases, and the like.
  • This invention is originated from the newly discovered
  • FR-900506 substance [chemical name: 17-allyl-1,14-dihydroxy- 12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25- dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo- [22.3.1.0 4,9 ]octacos-18-ene-2,3,10,16-tetraone] which was newly isolated in pure form from culture broth obtained by fermentation of new species belonging to genus Streptomyces.
  • the FR-901429 substance of the present invention sses the following physical and chemical properties,
  • the FR-901429 substance is inferred to have the following plan structural formula.
  • the FR-901429 substance of this invention can be produced by fermentation of a FR-901429 substance-producing strain belonging to the genus Streptomyces such as
  • Streptomyces tsukubaensis No. 9993 in a nutrient medium Streptomyces tsukubaensis No. 9993 in a nutrient medium.
  • novel FR-901429 substance is not limited to the use of the particular organism described above, which is given for the illustrative purpose only.
  • This invention also includes the use of any mutants which are capable of producing the
  • FR-901429 substance including natural mutants as well as artificial mutants which can be produced from the.described organism by conventional means such as irradiation of
  • the FR-901429 substance can be produced by culturing the FR-901429 substance-producing strain in an aqueous nutrient medium containing sources of assimilable carbon and nitrogen, preferably under aerobic conditions (e.g. shaking culture, submerged culture, etc.).
  • sources of assimilable carbon and nitrogen preferably under aerobic conditions (e.g. shaking culture, submerged culture, etc.).
  • the preferred sources of carbon in the nutrient mediu are carbohydrates such as glucose, xylose, galactose, glycerin, starch, dextrin, and the like.
  • Other sources whi may be included are maltose, rhamnose, raffinose, arabinos mannose, salicin, sodium succinate, and the like.
  • the preferred sources of nitrogen are yeast extract, peptone, gluten meal, cottonseed meal, soybean meal, corn steep liquor, dried yeast, wheat germ, feather meal, peanut powder etc., as well as inorganic and organic nitrogen compounds such as ammonium salts (e.g. ammonium nitrate, ammonium sulfate, ammonium phosphate, etc.), urea, amino acid, and the like.
  • ammonium salts e.g. ammonium nitrate, ammonium sulfate, ammonium phosphate, etc.
  • urea amino acid, and the like.
  • the carbon and nitrogen sources though advantageously employed in combination, need not 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.
  • the medium mineral salts such as sodium or calcium carbonate, sodium or potassium phosphate, sodium or potassium chloride, sodium or potassium iodide, magnesium salts, copper salts, cobalt salt and the like. If .necessary especially when the culture medium foams seriously, a defoaming agent, such as liquid paraffin, fatty oil, plant oil, mineral oil or silicone may be added.
  • the conditions for the production of the FR-901429 substance in massive amounts submerged aerobic cultural conditions are preferred therefor.
  • a shaking or surface culture in a flask or bottle is employed.
  • the vegetative form of the organism for inoculation in the production tanks in order to avoid growth lag in the process of production of the FR-901429 substance. Accordingly, it is desirable first to produce a vegetative inoculum of the organism by
  • the medium, in which the vegetative inoculum is produced, is
  • Agitation and aeration of the culture mixture may be accomplished in a variety of ways. Agitation may be provided by a propeller or similar mechanical agitation equipment, by revolving or shaking the fermentor, by various pumping equipment or by the passage of sterile air through the medium. Aeration may be effected by passing sterile air through the fermentation mixture.
  • the fermentation is usually conducted at a temperature between about 20°C and 40°C, preferably 25-35°C, for a period of about 50 hours to 250 hours, preferably 100 hours to 200 hours which may be varied according to fermentation conditions and scales.
  • FR-901429 substance can be recovered from the culture medium by conventional means which are commonly used for the recovery of other known biologically active substances.
  • the FR-901429 substance produced is found in the cultured mycelium and filtrate, and accordingly the
  • FR-901429 substance can be isolated and purified from the mycelium and the filtrate, which are obtained by filtering or centrifuging the cultured broth, by a conventional method such as concentration under reduced pressure,
  • lyophilization extraction with a conventional solvent, pH adjustment, treatment with a conventional resin (e.g. anion or cation exchange resin, non-ionic adsorption resin, etc. treatment with a conventional adsorbent (e.g. activated charcoal, silicic acid, silica gel, cellulose, alumina, etc.), crystallization, recrystallization, and the like.
  • a conventional resin e.g. anion or cation exchange resin, non-ionic adsorption resin, etc.
  • a conventional adsorbent e.g. activated charcoal, silicic acid, silica gel, cellulose, alumina, etc.
  • the FR-901429 substance possesses pharmacological activities such as immunosuppressive activity, antimicrobial 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, intestinum ***, limb, muscle, nervus, etc.;
  • autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's
  • thyroiditis multiple sclerosis, myasthenia gravis, type I diabetes, and the like; and further infectious diseases caused by pathogenic microorganisms.
  • FR-901429 substance is also useful for the treatment and the prophylaxis of inflammatory and
  • immunologically-mediated illnesses such as, psoriasis, atopical dermatitis, contact dermatitis and further eczematous dermatitises, seborrhoeis dermatitis, Lichen planus.
  • autoimmune diseases e.g. keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren's ulcer,
  • 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.g. late asthma and airway hyper-responsiveness), 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 enterocolitis, intestinal lesions associated with thermal burns, leukotriene B 4 -mediated diseases;
  • intestinal inflammations/allergies such as Coeliac disease, proctitis, eosnophilic gastroenteritis, mastocytosis,
  • renal diseases such as interstitial nephritis
  • Guillain-Barre syndrome Meniere's disease, polyneuritis, multiple neuritis, mononeuritis and radiculopathy;
  • hematic diseases such as pure red cell aplasia,
  • thrombocytopenic purpura autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia and anerythroplasia
  • bone diseases such as osteoporosis
  • respiratory diseases such as sarcoidosis, fibroid lung and idiopathic interstitial pneumonia;
  • Periodontal disease such as lesion of gingiva, periodontium, alveolar bone, substantia ossea dentis
  • nephrotic syndrome such as glomerulonephritis
  • active oxgen-mediated diseases for example, organ injury such as ischemia-reperfusion injury of organs
  • ischemic diseases e.g. heart, liver, kidney, digestive tract
  • 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 drug (e.g. paracort,bleomycins), lung cancer, pulmonary diseases
  • emphysema ocular diseases such as cataracta, siderosis, retinitis, pigmentosa, senile macular degeneration, vitreal scarring, corneal alkali burn: dermatitis such as erythema multiforme, linear IgA ballous dermatitis, cement
  • dermatitis and others such as gingvatis, periodontitis. sepsis, pancreatitis, diseases caused by environmental pollution(e.g. air pollution), aging, carcinogenis,
  • 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.
  • FR-901429 substance has liver
  • hepatic diseases such as immunogenic diseases (e.g. chronic autoimmune liver diseases such as the group consisting of autoimmune
  • ⁇ holangitis partial liver resection
  • acute liver necrosis e.g. necrosis caused by toxins, viral hepatitis, shock or anoxia
  • B-virus hepatitis non-A/non-B hepatitis
  • cirrhosis e.g. alcoholic cirrhosis
  • hepatic failure such as fulminant hepatic failure, late-onset hepatic failure and "acute-on-chronic" liver failure (acute liver failure on chronic liver diseases).
  • the FR-901429 substance is useful for various diseases because of its useful pharmaceutical activity such as augmenting activity of chemotherapeutic effect, preventing or treating activity of cytomegalovirus infection, anti-inflammatory activity, and so on.
  • the pharmaceutical composition of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the FR-901429 substance, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications.
  • 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, corn starch, keratin, colloida silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing,
  • solubilizing, thickening and coloring agents and perfumes may be used.
  • the active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of diseases. For applying this composition to human, it is
  • a daily dose of about 0.01-1000 mg, preferably 0.1-500 mg and more preferably 0.5-100 mg, of the active ingredient is generally given for treating diseases, and an average single dose of about 0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 250 mg and 500 mg is generally administered.
  • Example 1 The following examples are given for the purpose of illustrating the present invention.
  • Example 1 The following examples are given for the purpose of illustrating the present invention.
  • Fermentation A culture medium (100 ml) containing corn starch (1%), glycerin (1%), glucose (0.5%), cottonseed meal (1%), dried yeast (0.5%), corn steep liquor (0.5%) and calcium carbonate (0.2%) (adjusted to pH 6.5) was poured into each of eight 500 ml-Erlenmeyer flasks and sterilized at 120°C for 30 minutes. A loopful of slant culture of Streptomyces
  • FERM P-7886 was inoculated to each of the media and cultured at 30°C for 72 hours on a rotary shaker.
  • the seed culture was transferred to the same seed medium (160 liters) added Adekanol (defoaming agent. Trade Mark, maker; Asahi Denka Co.) (0.05%) and Silicone
  • the fermentation was carried out at 25°C for 168 hours under aeration of 1500 liters/minute and agitation at 140 rpm.
  • Figure 1 shows 13 C Nuclear Magnetic Resonance Spectrum of the FR-901429 substance.
  • Figure 2 shows 1 H Nuclear Magnetic Resonance Spectrum of the FR-901429 substance.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biotechnology (AREA)
  • Medicinal Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Transplantation (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

Composé répondant à la formule (I); son procédé de production; composition le contenant; et son utilisation en tant qu'agent immunosuppresseur.
PCT/JP1991/001726 1990-12-19 1991-12-18 Derive de 13-dimethyle fr-900506 et son utilisation en tant qu'agent immunosuppresseur WO1992011275A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9027471.3 1990-12-19
GB909027471A GB9027471D0 (en) 1990-12-19 1990-12-19 Novel compound

Publications (1)

Publication Number Publication Date
WO1992011275A1 true WO1992011275A1 (fr) 1992-07-09

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ID=10687204

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1991/001726 WO1992011275A1 (fr) 1990-12-19 1991-12-18 Derive de 13-dimethyle fr-900506 et son utilisation en tant qu'agent immunosuppresseur

Country Status (3)

Country Link
JP (1) JPH06503327A (fr)
GB (1) GB9027471D0 (fr)
WO (1) WO1992011275A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0184162A2 (fr) * 1984-12-03 1986-06-11 Fujisawa Pharmaceutical Co., Ltd. Composés tricycliques, procédé pour leur préparation et composition pharmaceutique les contenant
EP0323042A1 (fr) * 1987-12-09 1989-07-05 FISONS plc Procédé pour macrolides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0184162A2 (fr) * 1984-12-03 1986-06-11 Fujisawa Pharmaceutical Co., Ltd. Composés tricycliques, procédé pour leur préparation et composition pharmaceutique les contenant
EP0323042A1 (fr) * 1987-12-09 1989-07-05 FISONS plc Procédé pour macrolides

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Publication number Publication date
GB9027471D0 (en) 1991-02-06
JPH06503327A (ja) 1994-04-14

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