EP0533930A1 - Utilisation d'un compose de macrolide tel que le fk 506 pour fabriquer un medicament destine a traiter la purpura thrombocytopenique idiopathique et la maladie de basedow - Google Patents

Utilisation d'un compose de macrolide tel que le fk 506 pour fabriquer un medicament destine a traiter la purpura thrombocytopenique idiopathique et la maladie de basedow

Info

Publication number
EP0533930A1
EP0533930A1 EP91911491A EP91911491A EP0533930A1 EP 0533930 A1 EP0533930 A1 EP 0533930A1 EP 91911491 A EP91911491 A EP 91911491A EP 91911491 A EP91911491 A EP 91911491A EP 0533930 A1 EP0533930 A1 EP 0533930A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
disease
basedow
thrombocytopenic purpura
idiopathic thrombocytopenic
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP91911491A
Other languages
German (de)
English (en)
Inventor
T. 3-2-1-61-904 Minatojimanakamachi Honbo
Hachiro 12-1 Sengokuhigashimachi Seno
Michihisa 2-6-15-502 Iguchido Nishiyama
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fujisawa Pharmaceutical Co Ltd
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 GB909012954A external-priority patent/GB9012954D0/en
Priority claimed from GB909012958A external-priority patent/GB9012958D0/en
Priority claimed from GB909012942A external-priority patent/GB9012942D0/en
Priority claimed from GB909012961A external-priority patent/GB9012961D0/en
Priority claimed from GB909012959A external-priority patent/GB9012959D0/en
Priority claimed from GB909012956A external-priority patent/GB9012956D0/en
Priority claimed from GB909012957A external-priority patent/GB9012957D0/en
Priority claimed from GB909012951A external-priority patent/GB9012951D0/en
Priority claimed from GB909012952A external-priority patent/GB9012952D0/en
Priority claimed from GB909012953A external-priority patent/GB9012953D0/en
Priority claimed from GB909012960A external-priority patent/GB9012960D0/en
Priority claimed from GB909012955A external-priority patent/GB9012955D0/en
Priority claimed from GB909017701A external-priority patent/GB9017701D0/en
Application filed by Fujisawa Pharmaceutical Co Ltd filed Critical Fujisawa Pharmaceutical Co Ltd
Publication of EP0533930A1 publication Critical patent/EP0533930A1/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • This invention relates to a new use of macrolide compounds for idiopathic thrombocytopenic purpura and
  • this invention provides a new use of the macrolide compounds for preventing or treating idiopathic thrombocytopenic purpura and Basedow's disease.
  • this invention provides a prophylactic or therapeutic agent for idiopathic thrombocytopenic purpura and Basedow's disease, which comprises the macrolide compounds.
  • this invention provides a method for preventing or treating idiopathic thrombocytopenic purpura and Basedow's disease, which comprises administering said macrolide compounds to mammals.
  • the macrolide compounds used in this invention are known and disclosed, for example, in European Patent
  • Those known macrolide compounds include the
  • fermentation products such as FR-900506, FR-900520,
  • macrolide compounds were indicated inter alia for use in the treatment of rejection to transplantation, autoimmune diseases and infectious diseases.
  • the inventors of this invention have surprisingly found that the macrolide compounds mentioned hereinbelow are useful for preventing or treating idiopathic
  • the macrolide compounds used in this invention can be represented by the following general formula (I).
  • a) represent two vicinal hydrogen atoms
  • R 2 may represent an alkyl group
  • R 8 and R 9 independently represent H or OH
  • X represents O, (H,OH), (H,H) or -CH2O-;
  • Y represents O, (H,OH), (H,H), N-NR 11 R 12 or N-OR 13 ;
  • R 11 and R 12 independently represent H, alkyl, aryl or tosyl
  • R 20 and R 21 independently represent O, or they may independently represent (R 20 a,H) and (R 21 a,H) respectively; R 20 a and R 21 a independently represent OH, O-alkyl or
  • R 20 a and R 21 a may together represent an oxygen atom in an epoxide ring
  • n 1, 2 or 3;
  • Y, R 10 and R 23 together with the carbon atoms to which they are attached, may represent a 5- or 6- membered N-, S- or O-containing heterocyclic ring, which may be saturated or unsaturated, and which may be substituted by one or more groups selected from alkyl, hydroxy, alkyl substituted by one or more hydroxyl groups, O-alkyl, benzyl and
  • Suitable " alkyl” means straight or branched saturated aliphatic hydrocarbon residue and may include lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl, hexyl, and the like.
  • Suitable " alkenyl” means straight or branched
  • unsaturated aliphatic hydrocarbon residue having one double bond may include lower alkenyl such as vinyl, propenyl, butenyl, methylpropenyl, pentenyl, hexenyl, and the like.
  • Suitable " aryl” may include phenyl, tolyl, xylyl, cumenyl, mesityl, naphthyl, and the like.
  • protected hydroxyl group may include:
  • alkylthiomethyl groups e.g. methylthiomethyl
  • tri-substituted silyl groups such as tri(lower)-alkylsilyl groups (e.g. trimethylsilyl, triethylsilyl, tributylsilyl, tert-butyl-dimethylsilyl,
  • lower alkyl-diarylsilyl groups e.g. methyldiphenylsilyl, ethyldiphenylsilyl, propyldiphenylsilyl, tert-butyldiphenylsilyl, etc.
  • acyl groups such as aliphatic acyl groups, aromatic acyl groups and aliphatic acyl. groups substituted by aromatic groups, which are derived from carboxylic acids, sulfonic acids or carbamic acids.
  • the aliphatic acyl group may includes lower alkanoyl groups which may optionally have one or more suitable substituents such as carboxy (e.g. formyl, acetyl,
  • lower alkyl e.g. cyclopropyloxyacetyl, cyclobutyloxypropionyl, cycloheptyloxybutyryl, menthyloxyacetyl, menthyloxypropion
  • camphorsulfonyl lower
  • alkylcarbamoyl groups having one or more suitable
  • substituents such as carboxy or protected carboxy, for example carboxy(lower)alkylcarbamoyl groups( e.g.
  • the aromatic acyl group may include aroyl groups which may optionally have one or more suitable substituents such as nitro (e.g. benzoyl, toluoyl, xyloyl, naphthoyl,
  • arenesulfonyl groups which may optionally have one or more suitable substituent(s) such as halogen (e.g.
  • the aromatic group-substituted aliphatic acyl group may include ar(lower)alkanoyl groups which may optionally 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-trifluoromethyl2-propoxy-2-phenylacetyl, etc.), and so on.
  • suitable substituent(s) e.g. phenylacetyl, phenylpropionyl, phenylbutyryl, 2-trifluoromethyl-2-methoxy-2-phenylacetyl, 2-ethyl-2-trifluoromethyl-2-phenylacetyl, 2-trifluoromethyl2-propoxy-2-phenylacetyl,
  • desirable acyl groups are C 1 -C 4 alkanoyl groups which may optionally be substituted by carboxy, cyclo(C 5 -C 6 )alkyloxy-(C 1 -C 4 )alkanoyl groups having two (C 1 -C 4 )alkyl groups in the cycloalkyl moiety, camphorsulfonyl, carboxy(C 1 -C 4 )alkylcarbamoyl groups, tri(C 1 -C 4 )alkylsilyl(C 1 -C 4 )alkoxycarbonyl-(C 1 -C 4 )alkylcarbamoyl groups, benzoyl which may have one or two nitro groups, halogen-substituted benzenesulfonyl groups, phenyl(C 1 -C 4 )alkanoyl groups having C 1 -C 4 alkoxy and trihalo(C 1 -C 4 )alkyl groups.
  • acetyl carboxypropionyl, menthyloxyacetyl, camphorsulfonyl, benzoyl, nitrobenzoyl, dinitrobenzoyl, iodobenzenesulfonyl and 2-trifluoromethyl-2-methoxy-2-phenylacetyl.
  • Suitable " 5- or 6-membered N-, S- or O-containing heterocyclic ring” may include pyrrolyl, tetrahydrofuryl, and the like.
  • R 1 and R 2 are each hydrogen or combined to form a second bond
  • R 3 and R 4 are combined to form a second bond
  • R 5 and R 6 are combined to form a second bond
  • R 7 is hydrogen, hydroxy, O-lower alkyl such as methoxy or protected hydroxy
  • R 8 is hydrogen
  • R 9 is hydroxy
  • R 10 is methyl, ethyl, propyl or allyl
  • R 14 , R 15 , R 16 , R 17 , R 18 and R 19 are each methyl
  • R 20 is oxo or [R 20 a,H], wherein R 20 a is hydroxy or methoxy;
  • R 21 is [R 21 a,H], wherein R 21 a is hydroxy or protected hydroxy;
  • R 23 is hydrogen
  • X is oxo, (H,OH) or (H,H); Y is oxo; and
  • n 1 or 2.
  • the pharmaceutically acceptable salt of the compound (I) is a nontoxic salt, which may be the corresponding salt with an inorganic or organic base such as alkali metal salts (e.g. sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g. calcium salt, magnesium salt, etc.), ammonium salt and amine salts (e.g. triethylamine salt,.
  • alkali metal salts e.g. sodium salt, potassium salt, etc.
  • alkaline earth metal salts e.g. calcium salt, magnesium salt, etc.
  • ammonium salt and amine salts e.g. triethylamine salt,.
  • conformers or one pair or more of stereoisomers such as optical and geometrical isomers due to the asymmetric carbon or the double bond.
  • Such conformers and isomers also fall within the scope of the invention.
  • the macrolide compounds of the present invention may be administered as pure compounds or mixtures of compounds or preferably, in a pharmaceutical vehicle or carrier.
  • compositions of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the macrolide compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral,
  • the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable, carriers for tablets, pellets, capsules, suppositories, solutions
  • the carriers which can be used are water, glucose, lactose, gum. acacia, gelatin, mannitol, starch paste, 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 and coloring agents and perfumes may be used.
  • the active compound is included in the pharmaceutical composition in an effective amount sufficient to produce the desired effect upon the process or condition of the disease.
  • Mammals which may be treated using the method of the present invention include livestock mammals such as cows, horses, etc. , domestic animals such as dogs, cats, rats, etc. and humans.
  • 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 0.2-0.5 mg, 1 mg, 5 mg, 10 mg,
  • 50 mg, 100 mg, 250 mg and 500 mg is generally administered.
  • Daily doses for chronic administration in humans will be in the range of about 0.3 mg/kg/day.
  • macrolide compounds (I) used in the present invention are also useful for treating or preventing renal diseases selected from interstitial nephritis,
  • nervous diseases selected from multiple myositis
  • endocrine diseases selected from hyperthyroidism
  • hematic diseases selected from pure red cell aplasia, aplastic anemia, hypoplastic anemia, autoimmune hemolytic anemia, agranulocytosis and anerythroplasia;
  • bone diseases such as osteoporosis
  • respiratory diseases selected from sarcoidosis, fibroid lung and idiopathic interstitial pneumonia;
  • eye diseases selected from herpetic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukmas, ocular pemphigus, Mooren's ulcer, scleritis and Grave's ophthalmopathy;
  • skin diseases selected from dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity and cutaneous T cell lymphoma;
  • collagen diseases selected from scleroderma, Wegener's granuloma and Sjogren's syndrome;
  • Croscarmellose sodium (Ac-Di-Sol) 1 g
  • the FK 506 (1 g) was dissolved in ethanol (10 ml), and thereto was added hydroxypropyl methylcellulose 2910 (TC-5R) (1 g) to prepare a suspension.
  • TC-5R hydroxypropyl methylcellulose 2910
  • dichloromethane 5 ml
  • Lactose (2 g) and croscarmellose sodium (Trade Mark:
  • a tablet was prepared in a conventional manner by using the solid dispersion composition (49.75 mg) mentioned above and magnesium stearate (0.25 mg) .
  • the tablet prepared in (1) was coated with the composition containing the following compounds in a conventional manner. Titanium oxide 0.85 mg

Landscapes

  • 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)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (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)

Abstract

Sont décrits des composés de macrolide tels que le FR-900506 et ses composés connexes pour la prévention ou le traitement de la purpura thrombocytopénique idiopathique et de la maladie de Basedow. Une composition renfermant de tels composés est également décrite.
EP91911491A 1990-06-11 1991-06-07 Utilisation d'un compose de macrolide tel que le fk 506 pour fabriquer un medicament destine a traiter la purpura thrombocytopenique idiopathique et la maladie de basedow Withdrawn EP0533930A1 (fr)

Applications Claiming Priority (26)

Application Number Priority Date Filing Date Title
GB9012956 1990-06-11
GB9012960 1990-06-11
GB909012942A GB9012942D0 (en) 1990-06-11 1990-06-11 New use of macrolide compounds for eosinophilic fasciitis
GB9012952 1990-06-11
GB9012951 1990-06-11
GB9012954 1990-06-11
GB909012961A GB9012961D0 (en) 1990-06-11 1990-06-11 New use of macrolide compounds for renal diseases
GB909012952A GB9012952D0 (en) 1990-06-11 1990-06-11 New use of macrolide compounds for adiposis
GB909012956A GB9012956D0 (en) 1990-06-11 1990-06-11 New use of macrolide compounds for respiratory diseases
GB909012951A GB9012951D0 (en) 1990-06-11 1990-06-11 New use of macrolide compounds for collagen diseases
GB9012955 1990-06-11
GB9012942 1990-06-11
GB909012960A GB9012960D0 (en) 1990-06-11 1990-06-11 New use of macrolide compounds for nervous diseases
GB909012954A GB9012954D0 (en) 1990-06-11 1990-06-11 New use of macrolide compounds for skin diseases
GB909012953A GB9012953D0 (en) 1990-06-11 1990-06-11 New use of macrolide compounds for circulatory diseases
GB9012958 1990-06-11
GB9012957 1990-06-11
GB9012961 1990-06-11
GB909012958A GB9012958D0 (en) 1990-06-11 1990-06-11 New use of macrolide compounds for hematic diseases
GB9012959 1990-06-11
GB909012955A GB9012955D0 (en) 1990-06-11 1990-06-11 New use of macrolide compounds for eye diseases
GB9012953 1990-06-11
GB909012957A GB9012957D0 (en) 1990-06-11 1990-06-11 New use of macrolide compounds for bone diseases
GB909012959A GB9012959D0 (en) 1990-06-11 1990-06-11 New use of macrolide compounds for endocrine diseases
GB9017701 1990-08-13
GB909017701A GB9017701D0 (en) 1990-08-13 1990-08-13 New use of macrolide compounds for periodontal disease

Publications (1)

Publication Number Publication Date
EP0533930A1 true EP0533930A1 (fr) 1993-03-31

Family

ID=27584060

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91911491A Withdrawn EP0533930A1 (fr) 1990-06-11 1991-06-07 Utilisation d'un compose de macrolide tel que le fk 506 pour fabriquer un medicament destine a traiter la purpura thrombocytopenique idiopathique et la maladie de basedow

Country Status (3)

Country Link
EP (1) EP0533930A1 (fr)
JP (1) JPH05507915A (fr)
WO (1) WO1991019495A1 (fr)

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US5250678A (en) 1991-05-13 1993-10-05 Merck & Co., Inc. O-aryl, O-alkyl, O-alkenyl and O-alkynylmacrolides having immunosuppressive activity
ZA926812B (en) 1991-09-09 1993-04-28 Merck & Co Inc O-heteroaryl,o-alkylheteroaryl,o-alkenylheteroaryl and o-alkynylheteroaryl macrolides having immunosupressive activity
CA2091194A1 (fr) * 1992-04-08 1993-10-09 Richard D. Connell Derives 2-oxoethyliques utilises comme immunosuppresseurs
AT408520B (de) * 1993-05-27 2001-12-27 Novartis Erfind Verwalt Gmbh Galenische formulierungen
CH686761A5 (de) 1993-05-27 1996-06-28 Sandoz Ag Galenische Formulierungen.
GB2308546B (en) 1994-10-26 1999-06-02 Novartis Ag Topical macrolide compositions
AR004480A1 (es) * 1995-04-06 1998-12-16 Amico Derin C D Compuestos de ascomicina que poseen actividad antiinflamatoria, pro cedimiento para prepararlos, uso de dichos compuestos para preparar agentesfarmaceuticos y composiciones farmaceuticas que los incluyen
DK2198858T3 (da) 1998-03-26 2011-10-03 Astellas Pharma Inc Præparat med opretholdt frigivelse af en makrolidforbindelse såsom tacrolimus
GB9826656D0 (en) 1998-12-03 1999-01-27 Novartis Ag Organic compounds
US7063857B1 (en) 1999-04-30 2006-06-20 Sucampo Ag Use of macrolide compounds for the treatment of dry eye
EP1389480A1 (fr) * 2002-08-14 2004-02-18 Mondobiotech Interferon SA Utilisation thérapeutique de guanylhydrazones pour l'inhibition des procédés dépendant du CD83 et de la maturation des cellules dendritiques
US7014227B2 (en) * 2003-05-09 2006-03-21 The Langenau Manufacturing Company Wedge bar locking mechanism
US20110104186A1 (en) 2004-06-24 2011-05-05 Nicholas Valiante Small molecule immunopotentiators and assays for their detection
WO2006068932A2 (fr) 2004-12-20 2006-06-29 Wyeth Analogues de rapamycine et leurs utilisations dans le traitement de troubles neurologiques, proliferatifs, et inflammatoires
RU2007119585A (ru) 2004-12-20 2009-01-27 Вайет (Us) Производные рапамицина и их применение при лечении неврологических заболеваний
TW200932240A (en) 2007-10-25 2009-08-01 Astellas Pharma Inc Pharmaceutical composition containing lipophilic substance which inhibits IL-2 production
CN107106588B (zh) 2014-10-28 2020-08-11 山口晃史 用于改善妊娠状态的药剂及其使用
CN106074367A (zh) * 2016-07-20 2016-11-09 中山大学中山眼科中心 含fk506类化合物/fkbp蛋白二聚体的药物组合物及其制备方法
JP7465806B2 (ja) 2018-08-10 2024-04-11 晃史 山口 母体と胎児との関係における液性免疫関連疾患の治療薬
CN113226331A (zh) 2018-12-18 2021-08-06 山口晃史 用于改善不孕不育症或妊娠状态的药物

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US4894366A (en) * 1984-12-03 1990-01-16 Fujisawa Pharmaceutical Company, Ltd. Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same
DE3853477T2 (de) * 1987-12-09 1995-11-09 Fisons Plc Makrozyklische verbindungen.
DK603988D0 (da) * 1988-10-28 1988-10-28 Klaus Bendtzen Farmaceutisk praeparat

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Also Published As

Publication number Publication date
WO1991019495A1 (fr) 1991-12-26
JPH05507915A (ja) 1993-11-11

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