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WO1992000313A1 - Composes tricyclo, leur procede de production et composition pharmaceutique contenant ces composes - Google Patents

Composes tricyclo, leur procede de production et composition pharmaceutique contenant ces composes Download PDF

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Publication number
WO1992000313A1
WO1992000313A1 PCT/JP1991/000811 JP9100811W WO9200313A1 WO 1992000313 A1 WO1992000313 A1 WO 1992000313A1 JP 9100811 W JP9100811 W JP 9100811W WO 9200313 A1 WO9200313 A1 WO 9200313A1
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WIPO (PCT)
Prior art keywords
alkyl
hydroxy
compound
aryl
alkenyl
Prior art date
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Ceased
Application number
PCT/JP1991/000811
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English (en)
Inventor
Chiyoshi Kasahara
Takehiko Ohkawa
Masashi Hashimoto
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Fujisawa Pharmaceutical Co Ltd
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Fujisawa Pharmaceutical Co Ltd
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Publication of WO1992000313A1 publication Critical patent/WO1992000313A1/fr
Anticipated expiration legal-status Critical
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    • 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 novel tricyclo compounds having pharmacological activities, to a process for their production and to a pharmaceutical composition containing the same.
  • novel tricyclo compounds which have pharmacological activities such as immunosuppressive activity, antimicrobial activity, and the like, to a process for their production, to a
  • composition containing the same and to a use thereof as a medicament.
  • one object of this invention is to provide the novel tricyclo compounds, which are useful for treatment and prevention of resistance by transplantation, graft-versus-host diseases by medulla ossium
  • Another object of this invention is to provide a process for production of the tricyclo compounds by
  • a further object of this invention is to provide a pharmaceutical composition containing, as active
  • Still further object of this invention is to provide a use of the tricyclo compounds as a medicament for treating and preventing resistance by transplantation, graft-versus-host diseases by medulla ossium
  • R 1 is hydrogen or acyl
  • R 2 is hydrogen, hydroxy, alkoxy or acyloxy
  • R 3 is (C 3 -C 7 )alkyl, aryl(C 2 -C 7 ) alkyl, protected carboxy ( C 2 -C 7 ) alkyl, 1-(C 3 -C 7 )alkenyl, aryl-1-(C 2 -C 7 )alkenyl or protected
  • R 4 is hydroxy or alkoxy
  • R 5 is hydrogen and R 6 is hydroxy or methoxy, or R 5 and R 6 are combined to form oxo,
  • A is methylene, hydroxymethylene or carbonyl, n is an integer of 1 or 2, and
  • the object tricyclo compounds (I) can be prepared by the following processes in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A and n are each as defined above,
  • R 7 is (C 2 -C 6 ) alkyl, aryl(C 1 -C 8 )alkyl or protected carboxy(C 1 -C 6 )alkyl,
  • R 8 is aryl
  • R 9 is protected carboxy
  • R 10 is (C 2 -C 8 )alkylidene, aryl(C 1 -C 8 )alkylidene or protected carboxy(C 1 -C 8 )alkylidene, and
  • X is halogen
  • Suitable "acyl” and acyl group in the “acyloxy” may include aliphatic acyl, aromatic acyl and aliphatic acyl substituted with aromatic group, which are derived from carboxylie, sulfonic and carbamic acids; and the like.
  • the aliphatic acyl may include lower alkanoyl which may have one or more suitable substituent(s) such as carboxy (e.g. formyl, acetyl, propionyl, butyryl,
  • camphorsulfonyl lower alkylcarbamoyl having one or more suitable substituent(s) such as carboxy, protected carboxy and hydroxy for example, carboxy(lower) alkylcarbamoyl (e.g. carboxymethylcarbamoyl, carboxyethylcarbamoyl, carboxypropylcarbamoyl, carboxybutylcarbamoyl,
  • hydroxy(lower)alkylcarbamoyl e.g. hydroxymethylcarbamoyl, hydroxyethylcarbamoyl, hydroxypropylcarbamoyl,
  • the aromatic acyl may include aroyl which may have one or more suitable substituent(s) such as nitro (e.g. benzoyl, toluoyl, xyloyl, naphthoyl, nitrobenzoyl,
  • suitable substituent(s) such as nitro (e.g. benzoyl, toluoyl, xyloyl, naphthoyl, nitrobenzoyl,
  • dinitrobenzoyl, nitronaphthoyl, etc. arenesulfonyl which may have one or more suitable substituent(s) such as halogen (e.g. benzenesulfonyl, toluenesulfonyl,
  • arylcarbamoyl which may have one or more suitable
  • substituent(s) such as halogen (e.g. phenylcarba-moyl, fluorophenylcarbamoyl, chlorophenylcarbamoyl, etc.), and the like.
  • halogen e.g. phenylcarba-moyl, fluorophenylcarbamoyl, chlorophenylcarbamoyl, etc.
  • the heterocyclic acyl may include heterocyclic carbonyl (e.g. furoyl, thenoyl, nicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl,
  • heterocyclic carbonyl e.g. furoyl, thenoyl, nicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl
  • the aliphatic acyl substituted with aromatic group may include ar(lower) alkanoyl which may have one or more suitable substituent(s) such as lower alkoxy and
  • trihalo(lower) alkyl e.g. phenylacetyl, phenylpropionyl, phenylbutyryl, 2-trifluoromethyl-2-methoxy-2-phenylacetyl, 2-ethyl-2-trifluoromethyl-2-phenylacetyl, 2-trifluoro-methyl-2-propoxy-2-phenylacetyl, etc.
  • lower alkyl e.g. phenylacetyl, phenylpropionyl, phenylbutyryl, 2-trifluoromethyl-2-methoxy-2-phenylacetyl, 2-ethyl-2-trifluoromethyl-2-phenylacetyl, 2-trifluoro-methyl-2-propoxy-2-phenylacetyl, etc.
  • the more preferred acyl group thus defined may be C 1 -C 4 alkanoyl which may have carboxv, cyclo(C 5 -C 6 )- alkyloxy(C 1 -C 4 ) alkanoyl having two (C 1 -C 4 ) alkyl groups on the cycloalkyl moiety, camphorsulfonyl, carboxy(C 1 -C 4 )- alkylcarbamoyl, hydroxy(C 1 -C 4 )alkylcarbamoyl,
  • menthyloxyacetyl camphorsulfonyl, hydroxypropylcarbamoyl, benzoyl, nitrobenzoyl, dinitrobenzoyl,
  • Suitable alkoxy may be lower alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, neopentoxy, hexyloxy and the like, in which the preferred one is C 1 -C 4 alkoxy.
  • Suitable "(C 3 -C 7 )alkyl” may include straight or branched one such as propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and the like, in which more preferred example may be (C 3 -C 5 )alkyl and the most preferred one may be propyl and pentyl.
  • Suitable "(C 2 -C 6 ) alkyl” may include straight or branched one such as ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, and the like, in which more preferred example may be (C 2 -C 4 ) alkyl and the most preferred one may be ethyl and butyl.
  • Suitable "aryl(C 2 -C 7 ) alkyl” may include
  • Suitable "protected carboxy(C 2 -C 7 ) alkyl” may include aforementioned (C 3 -C 7 )alkyl and ethyl, which is
  • Suitable "1-(C 3 -C 7 ) alkenyl” may include straight or branched one such as 1-propenyl, 1-isopropenyl, 1-butenyl, 1-isobutenyl, 1-pentenyl, 1-isopentenyl, 1-neopentenyl, 1-hexenyl, 1-heptenyl, and the like, in which more
  • preferred example may be 1-(C 3 -C 5 ) alkenyl and the most preferred one may be 1-propenyl and 1-pentenyl.
  • Suitable "aryl-1-(C 2 -C 7 ) alkenyl” may include
  • Suitable "protected carboxy-1-(C 2 -C 7 ) alkenyl” may include aforementioned 1-(C 3 -C 7 ) alkenyl and ethenyl, which is substituted with protected carboxy as mentioned below, wherein more preferred example may be
  • Suitable "aryl(C 1 -C 8 ) alkyl” may include straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, and the like, which is substituted with aryl as mentioned below, wherein more preferred example may be
  • Suitable "protected carboxy(C 1 -C 8 ) alkyl” may include straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, and the like, which is substituted with protected carboxy as mentioned below, wherein more preferred example may be (C 1 -C 4 )alkoxycarbonyl(C 1 -C 4 )alkyl.
  • Suitable "(C 2 -C 6 )alkylidene” may include straight or branched one such as ethylidene, propylidene,
  • (C 2 -C 4 )alkylidene and the most preferred one may be ethylidene and butylidene.
  • Suitable "aryl(C 1 -C 8 )alkylidene” may include
  • Suitable "protected carboxy(C 1 -C 8 )alkylidene” may include aforementioned (C 2 -C 6 )alkylidene and methylene, which are substituted with protected carboxy as mentioned below, wherein more preferred example may be (C 1 -C 4 )alkoxycarbonyl(C 1 -C 4 )alkylidene and the most preferred one may be methoxycarbonylmethylene.
  • Suitable “leaving group” may include an acid residue and the like, and suitable examples of “acid residue” may be halogen (e.g. chlorine, bromine, iodine, etc.), sulfonyloxy (e.g. methanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy, etc.) or the like.
  • Suitable “protected carboxy” may include esterified carboxy such as lower alkoxycarbonyl (e.g.
  • Suitable "aryl” may include phenyl, tolyl, xylyl, cumenyl, mesityl, naphthyl, and the like, in which the preferred example may be phenyl.
  • Suitable "halogen” may be chlorine bromine, fluorine and iodine, in which the preferred one may be chlorine and bromine.
  • the compound (Ia) or a salt thereof can be prepared by hydroxylating the compound ( II ) or a salt thereof.
  • the hydroxylating agent applicable to this process may be a conventional one which is capable of introducing hydroxy group(s) into the allyl moiety of starting
  • compound (II) for example, alkali metal permanganate (e.g. potassium permanganate, etc.), osmium tetroxide optionally in the presence of a suitable oxidizing agent to regenerate osmium tetroxide (e.g. N-methylmorpholine N-oxide, sodium chlorate, etc.), hydrogen peroxide, and the like.
  • alkali metal permanganate e.g. potassium permanganate, etc.
  • osmium tetroxide optionally in the presence of a suitable oxidizing agent to regenerate osmium tetroxide (e.g. N-methylmorpholine N-oxide, sodium chlorate, etc.), hydrogen peroxide, and the like.
  • This reaction is usually conducted in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, pyridine, ethyl acetate, N,N-dimethylformamide, dichloromethane, ethyl ether, isopropyl ether, 1,4-dioxane or a mixture thereof.
  • a conventional solvent which does not adversely influence the reaction
  • the reaction temperature of this reaction is not critical and the reaction is usually conducted under from cooling to warming.
  • the compound (lb) or a salt thereof can be prepared by oxidizing the compound (la) or a salt thereof to an aldehyde.
  • the oxidizing agent applicable to this process may be a conventional one which is capable of oxidizing vicinal diols to an aldehyde, for example, perhalogenic acid or a salt thereof (e.g. periodic acid, sodium metaperiodate, etc.), lead tetra(lower alkanoate) (e.g. lead
  • This reaction is usually conducted in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, pyridine, ethyl acetate, N,N-dimethylformamide, dichloromethane, ethyl ether, isopropyl ether, 1,4-dioxane, or a mixture thereof.
  • a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, pyridine, ethyl acetate, N,N-dimethylformamide, dichloromethane, ethyl ether, isopropyl ether, 1,4-dioxane, or a mixture thereof.
  • the reaction temperature is not critical and the reaction is usually conducted under from cooling to warming.
  • the compound (Ic) or a salt thereof can be prepared by reacting the compound (lb) or a salt thereof with the compound (IlIa) or (Illb).
  • this reaction can preferably be carried out in the presence of an organic or inorganic base such as lower alkylalkalimetal (e.g. methyllithium, butyllithium, etc.), alkali metal (e.g. lithium, sodium, potassium, etc.), alkaline earth metal (e.g. calcium, etc.), alkali metal hydride (e.g. sodium hydride, etc.), alkaline earth metal hydride (e.g. calcium hydride, etc.), alkali metal
  • hydroxide e.g. sodium hydroxide, potassium hydroxide, etc.
  • alkali metal carbonate e.g. sodium carbonate, potassium carbonate, etc.
  • alkali metal hydrogen e.g. sodium hydroxide, potassium hydroxide, etc.
  • alkali metal alkoxide e.g. sodium methoxide, sodium ethoxide, potassium
  • alkali metal alkanoic acid e.g. sodium acetate, etc.
  • trialkylamine e.g. triethylamine, etc.
  • pyridine compound e.g. pyridine, lutidine, picoline, 4-N,N-dimethylaminopyridine, etc.
  • guinoline and the like.
  • the reaction is usually conducted in a conventional solvent which does not adversely influence the reaction such as acetone, dichloromethane, alcohol (e.g. methanol, ethanol, etc.), tetrahydrofuran, pyridine, benzene,
  • the reaction temperature is not critical and the reaction is usually conducted under from cooling to warming.
  • the compound (Id) or a salt thereof can be prepared by reducing the compound (Ic) or a salt thereof.
  • the reduction method applicable for this reaction is a conventional one which is capable of hydrogenating olefinic bond and may include, for example, reduction by using a combination of a metal (e.g. zinc, zinc amalgam, etc.) or a chrome compound (e.g. chromous chloride, chromous acetate, etc.) and an organic or inorganic acid (e.g. acetic acid, prop ⁇ onic acid, hydrochloric acid, sulfuric acid, etc.); and conventional catalytic reduction in the presence of a conventional metallic catalyst such as palladium catalysts (e.g.
  • solvent which does not adversely influence the reaction
  • water alcohol (e.g. methanol, ethanol, propanol, etc.), dioxane, tetrahydrofuran, acetic acid, buffer solution (e.g. phosphate buffer, acetate buffer, etc.), benzene, toluene, xylene, and the like, or a mixture thereof.
  • alcohol e.g. methanol, ethanol, propanol, etc.
  • dioxane etrahydrofuran
  • acetic acid e.g. phosphate buffer, acetate buffer, etc.
  • buffer solution e.g. phosphate buffer, acetate buffer, etc.
  • benzene toluene
  • xylene e.g. benzene, toluene, xylene, and the like, or a mixture thereof.
  • the reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.
  • the object tricyclo compounds (I), obtained according to the processes as explained above can be isolated and purified in a conventional manner, for example,
  • Suitable salts of the compounds (I), (la), (lb), (Ic), (Id) and (II) may include pharmaceutically
  • salts such as basic salts, for example, alkali metal salt (e.g. sodium salt, potassium salt, etc.), alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), ammonium salt, amine salt (e.g. triethylamine salt, N-benzyl-N-methylamine salt, etc.) and other salts.
  • alkali metal salt e.g. sodium salt, potassium salt, etc.
  • alkaline earth metal salt e.g. calcium salt, magnesium salt, etc.
  • ammonium salt e.g. triethylamine salt, N-benzyl-N-methylamine salt, etc.
  • amine salt e.g. triethylamine salt, N-benzyl-N-methylamine salt, etc.
  • the starting compound (II) in the process mentioned above contains known and novel compounds, and the known compounds are disclosed, for example, in European Patent Publication Nos. 184162 and 323042 and the new compound can be prepared by a conventional manner.
  • the tricyclo compounds (I) possess pharmacological activities such as immunosuppressive activity,
  • immunosuppressant 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.
  • tricyclo compounds (I) are also useful for the treatment and the prophylaxis of inflammatory and hyperproliferative skin diseases and cutaneous
  • 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 e ⁇ sinophilias, Lupus erythematosus, acne and Alopecia areata;
  • 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
  • asthma e.g. bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma
  • chronic or inveterate asthma e.g. late asthma and airway hyper-responsiveness
  • bronchitis e.g. chronic or inveterate asthma 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 selected from interstitial nephritis,
  • nervous diseases selected from multiple myositis
  • endocrine diseases selected from hyperthyroidism and
  • hematic diseases selected from pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic
  • thrombocytopenic purpura autoimmune hemolytic anemia, agranulocytosis and anerythroplasia
  • bone diseases such as osteoporosis
  • respiratory diseases selected from sarcoidosis, fibroid lung and idiopathic interstitial pneumonia; skin diseases selected from dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity and cutaneous T cell lymphoma;
  • circulatory diseases selected from arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa and myocardosis;
  • collagen diseases selected from scleroderma, Wegener's granuloma and Sjogren's syndrome;
  • nephrotic syndrome such as glomerulonephritis
  • the tricyclo compounds (I) have liver regenerating activity and/or activities of stimulating hypertrophy and hyperplasia of hepatocytes. Therefore, they are useful for the treatment and prevention of hepatic diseases such as immunogenic diseases (e.g. chronic hepatic diseases).
  • autoimmune liver diseases selected from the group consistin of autoimmune hepatitis, primary biliary cirrhosis and sclerosing cholangitis), 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 and cirrhosis.
  • tricyclo compounds (I) are useful for various diseases because of its useful pharmaceutical activity such as augmenting activity of chemotherapeutic effect.
  • the MLR test was performed in microtiter plates, with each well containing 5 ⁇ 10 5 C57BL/6 responder cells
  • 1640 medium supplemented with 10% fetal calf serum, 2mM sodium bicarbonate, penicillin (50 unit/ml) and
  • streptomycin 50 ⁇ g/ml.
  • the cells were incubated at 37°C in humidified atmosphere of 5% carbon dioxide and 95% of air for 68 hours and pulsed with 3 H-thymidine (0.5 ⁇ Ci) 4 hours before the cells were collected.
  • 3 H-thymidine 0.5 ⁇ Ci
  • the IC 50 value (mol concentration to suppress 50% of MLR) was calculated by a conventional method, which is shown in the following Table 1.
  • composition of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which
  • the 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,
  • the carriers which can be used are water, glucose,
  • lactose lactose
  • gum acacia gelatin
  • mannitoi starch paste
  • magnesium trisilicate magnesium trisilicate
  • talc corn 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.
  • a solubilizing agent there may be exemplified water-soluble cellulose polymer (i.e. hydroxypropyl methylcellulose, etc.), water-soluble glycol (i.e. propylene glycol, etc.), etc.
  • the active object compound is included in the
  • composition in an amount, sufficient to produce the desired effect upon the process or condition of diseases.
  • 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.
  • 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.
  • n-butyltriphen ⁇ lphosphonium bromide (505 mg) in diethyl ether (9.2 ml) at 0°C was added 1.4 M methyllithium in hexane (0.9 ml). The orange reaction mixture was warmed to room temperature and stirred for 2 hours.

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  • Health & Medical Sciences (AREA)
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  • 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)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

L'invention concerne des composés de la formule (I), dans laquelle R1 représente hydrogène ou acyle, R2 représente hydrogène, hydroxy, alcoxy ou acyloxy, R3 est (C¿3?-C7)alkyle, aryl(C2-C7), carboxy(C2-C7)alkyle protégé, 1-(C3-C7)alcényle, aryl-1-(C2-C7)alcényle, R?4¿ représente hydroxy ou alcoxy, R5 représente hydrogène et R6 est hydroxy ou méthoxy ou bien R5 et R6 sont combinés pour former oxo, A représente méthylène, hydroxyméthylène ou carbonyle, n est un nombre entier valant 1 ou 2, et le symbole constitué d'une ligne et d'une ligne en pointillé représente une liaison simple ou double. L'invention concerne aussi des sels de ces composés, des procédés de production desdits composés ainsi que des compositions pharmaceutiques contenant ces composés.
PCT/JP1991/000811 1990-06-25 1991-06-18 Composes tricyclo, leur procede de production et composition pharmaceutique contenant ces composes Ceased WO1992000313A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9014136.7 1990-06-25
GB909014136A GB9014136D0 (en) 1990-06-25 1990-06-25 Tricyclo compounds,a process for their production and a pharmaceutical composition containing the same

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Publication Number Publication Date
WO1992000313A1 true WO1992000313A1 (fr) 1992-01-09

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JP (1) JPH06501920A (fr)
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Cited By (15)

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US5247076A (en) * 1991-09-09 1993-09-21 Merck & Co., Inc. Imidazolidyl macrolides having immunosuppressive activity
US5252732A (en) * 1991-09-09 1993-10-12 Merck & Co., Inc. D-heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynylheteroarylmacrolides having immunosuppressive activity
US5262533A (en) * 1991-05-13 1993-11-16 Merck & Co., Inc. Amino O-aryl macrolides having immunosuppressive activity
GB2267707A (en) * 1992-06-12 1993-12-15 Merck & Co Inc Alkyl and alkenyl macrolides having immunosuppressive activity
US5284840A (en) * 1992-06-12 1994-02-08 Merck & Co., Inc. Alkylidene macrolides having immunosuppressive activity
EP0642516A4 (fr) * 1991-09-05 1994-06-15 Abbott Lab Immunomodulateurs macrocycliques.
US5496831A (en) * 1994-05-13 1996-03-05 The General Hospital Corporation Inhibition of insulin-induced adiposis
US5532248A (en) * 1991-05-13 1996-07-02 Merck Co., Inc. O-aryl,O-alkyl, and O-alkenyl-macrolides having immunosuppressive activity
US5693648A (en) * 1994-09-30 1997-12-02 Merck & Co., Inc. O-aryl, O-alkyl, O-alkenyl and O-alkynyl-macrolides having immunosuppressive activity
US5708002A (en) * 1991-09-05 1998-01-13 Abbott Laboratories Macrocyclic immunomodulators
US5880280A (en) * 1994-06-15 1999-03-09 Merck & Co., Inc. Aryl, alkyl, alkenyl and alkynylmacrolides having immunosuppressive activity
WO2005052542A3 (fr) * 2003-11-21 2005-12-01 Dade Behring Inc Procede et composition servant a determiner fk 506
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection
CN109923118A (zh) * 2016-11-10 2019-06-21 诺华股份有限公司 Bmp增效剂
CN113614091A (zh) * 2019-01-23 2021-11-05 约翰霍普金斯大学 非免疫抑制性fk506类似物及其用途

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US6503594B2 (en) 1997-02-13 2003-01-07 Samsung Electronics Co., Ltd. Silicon wafers having controlled distribution of defects and slip
US6485807B1 (en) 1997-02-13 2002-11-26 Samsung Electronics Co., Ltd. Silicon wafers having controlled distribution of defects, and methods of preparing the same

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EP0323042A1 (fr) * 1987-12-09 1989-07-05 FISONS plc Procédé pour macrolides

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US5262533A (en) * 1991-05-13 1993-11-16 Merck & Co., Inc. Amino O-aryl macrolides having immunosuppressive activity
US5532248A (en) * 1991-05-13 1996-07-02 Merck Co., Inc. O-aryl,O-alkyl, and O-alkenyl-macrolides having immunosuppressive activity
EP0642516A4 (fr) * 1991-09-05 1994-06-15 Abbott Lab Immunomodulateurs macrocycliques.
US5708002A (en) * 1991-09-05 1998-01-13 Abbott Laboratories Macrocyclic immunomodulators
US5252732A (en) * 1991-09-09 1993-10-12 Merck & Co., Inc. D-heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynylheteroarylmacrolides having immunosuppressive activity
US5247076A (en) * 1991-09-09 1993-09-21 Merck & Co., Inc. Imidazolidyl macrolides having immunosuppressive activity
US5284840A (en) * 1992-06-12 1994-02-08 Merck & Co., Inc. Alkylidene macrolides having immunosuppressive activity
US5284877A (en) * 1992-06-12 1994-02-08 Merck & Co., Inc. Alkyl and alkenyl macrolides having immunosuppressive activity
GB2267707A (en) * 1992-06-12 1993-12-15 Merck & Co Inc Alkyl and alkenyl macrolides having immunosuppressive activity
US5496831A (en) * 1994-05-13 1996-03-05 The General Hospital Corporation Inhibition of insulin-induced adiposis
US5880280A (en) * 1994-06-15 1999-03-09 Merck & Co., Inc. Aryl, alkyl, alkenyl and alkynylmacrolides having immunosuppressive activity
US5693648A (en) * 1994-09-30 1997-12-02 Merck & Co., Inc. O-aryl, O-alkyl, O-alkenyl and O-alkynyl-macrolides having immunosuppressive activity
WO2005052542A3 (fr) * 2003-11-21 2005-12-01 Dade Behring Inc Procede et composition servant a determiner fk 506
US7186518B2 (en) * 2003-11-21 2007-03-06 Dade Behring Inc. Method and composition useful for determining FK 506
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection
CN109923118A (zh) * 2016-11-10 2019-06-21 诺华股份有限公司 Bmp增效剂
CN113614091A (zh) * 2019-01-23 2021-11-05 约翰霍普金斯大学 非免疫抑制性fk506类似物及其用途
JP2022518555A (ja) * 2019-01-23 2022-03-15 ザ・ジョンズ・ホプキンス・ユニバーシティ 非免疫抑制性ｆｋ５０６類似体およびその使用

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GB9014136D0 (en) 1990-08-15
EP0536401A1 (fr) 1993-04-14
JPH06501920A (ja) 1994-03-03

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