WO1991013899A1 - Composes tricyclo - Google Patents

Composes tricyclo Download PDF

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Publication number
WO1991013899A1
WO1991013899A1 PCT/JP1991/000314 JP9100314W WO9113899A1 WO 1991013899 A1 WO1991013899 A1 WO 1991013899A1 JP 9100314 W JP9100314 W JP 9100314W WO 9113899 A1 WO9113899 A1 WO 9113899A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
hydroxy
och
symbol
oxo
Prior art date
Application number
PCT/JP1991/000314
Other languages
English (en)
Inventor
Chiyoshi Kasahara
Takehiko Ohkawa
Masashi Hashimoto
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 GB909005521A external-priority patent/GB9005521D0/en
Priority claimed from GB909017450A external-priority patent/GB9017450D0/en
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Publication of WO1991013899A1 publication Critical patent/WO1991013899A1/fr

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/01Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • A61P37/06Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • R is hydroxy or alkoxy
  • X is oxo or (H, OH)
  • n is an integer of 1 or 2
  • the symbol of a line and dotted line is a single bond or a double bond.
  • R , R , R , R , x and n are each as defined above.
  • Suitable alkyl moiety in "alkoxy" and "lower alkyl which may have one or more hydroxy” may include a straigh or branched lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like. And particularly, the preferable “alkoxy” is methoxy, and the preferable "lower alkyl which may have one or more - 6 -
  • hydroxy is propyl or propyl having one or two hydroxy such as 2-hydroxypropyl and 2,3-dihydroxypropyl.
  • Suitable "aryl which may have suitable substituent(s)” may include phenyl, tolyl, xylyl, mesityl, naphthyl, and the like, which may have suitable substituent(s) such as halogen (e.g. fluoro, chloro, bromo, iodo) , and the like.
  • halogen e.g. fluoro, chloro, bromo, iodo
  • the compound (I) or a salt thereof can be prepared by introducing "R NHCO-" group into the compound (II) or its reactive derivative at the hydroxy group or a salt thereof.
  • Suitable introducing agent of "R NHCO-" group used in this reaction may be a conventional one such as carbamic acid and their reactive derivative, for example, an acid halide, an acid anhydride, an activated amide, an activated ester, isocyanate, and the like.
  • reactive derivative may include acid chloride, acid bromide, a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, alkyl carbonate (e.g.
  • aliphatic carboxylic acid e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-eth ⁇ lbutyric acid, trichloroacetic trifluoroacetic acid, etc.
  • aromatic carboxylic acid e.g. benzoic acid, etc.
  • a symmetrical acid anhydride an activated acid amide wit a heterocyclic compound containing imino function such as imidazole, 4-substituted imidazole, dimethylpyrazole, triazole and tetrazole, an activated ester (e.g.
  • R is as defined above, preferably aryl which ma have suitable substituent(s) , and
  • R is as defined above, preferably hydrogen or lower alkyl which may have one or more hydroxy.
  • Suitable reactive derivative at the hydroxy group of the compound (II) may be conventional one which is capable ooff rreeppllaacciinngg aa hhyyddrrooxxyy ggrroouupp wwiitthh '"R NHCOO-" such as an activated ester as mentioned above,
  • the reaction is preferably conducted in the presence of an organic or inorganic base such as 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 carbonate (e.g. sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal alkoxide (e.g.
  • 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,
  • alkali metal alkanoic acid e.g. sodium acetate, etc.
  • trialkylamine e.g. triethylamine, etc.
  • pyridine compound e.g. pyridine, lutidine, picoline, 4-N,N-dimeth ⁇ laminopyridine, etc.
  • quinoline and the like.
  • the reaction is usually conducted in a conventional solvent which does not adversely influence the reaction such as water, acetone, dichloromethane, alcohol (e.g. methanol, ethanol, etc.), tetrahydrofuran, pyridine, benzene, N,N-dimethylformamide, etc., or a mixture thereof, and further in case that the base or the iinnttrroodduucciinngg aaggeenntt ooff tthhee RR NNHHCCO- group is in liquid, it can also be used as a solvent.
  • the reaction temperature is not critical and the reaction is usually conducted under from cooling to heating.
  • this process also includes, within a scope thereof, a case that the compound (II) having a partial structure of the formula :
  • Reduction in this process can be conducted by a conventional method which is capable of reducing an allyl group to a propyl group, such as catalytic reduction, or the like.
  • Suitable catalysts used in catalytic reduction are conventional ones such as platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloida platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g. reduced cobalt, Raney cobalt, etc.), iron catalysts (e.g. reduced iron, Raney iron, etc.), copper catalysts (e.g. reduced copper, Raney copper, Ullman copper, etc. ) , and the like.
  • reaction temperature of this reduction is not critical and the reaction is usually conducted under from cooling to warming.
  • This process includes, within a scope thereof, a cas that the double bond defined by the symbol of a line and dotted line may occasionally be reduced during the reaction to give a single bond.
  • the tricyclo compounds (I) are also useful in the topical administration for the treatment an the prophylaxis of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of i munologically-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 and Alopecia areata.
  • i munologically-mediated illnesses such as, psoriasis, atopical dermatitis, contact dermatitis and further eczematous dermatitises, seborrhoeis dermatitis, Lichen planus, Pemphigus
  • bronchial asthma allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma
  • chronic or inveterate asthma e.g. late asthma and airway hyper-responsiveness
  • bronchitis and the like nephrotic syndrome such as glomerulonephritis
  • hemolytic-uremic syndrome e.g., hemolytic-uremic syndrome
  • photoallergic sensitivity e.g. male pattern alopecia or alopecia senilis; etc.
  • the pharmacological test data of the tricyclo compounds (I) is illustrated in the following.
  • the MLR test was preformed in microtiter plates, with each well containing 5 x 10 C57BL/6 responder cells
  • I C value (mol concentration to suppress 50% or MLR) was calculated by a conventional method, which is shown in the following Table 1.
  • Table 1 I C CQ value of MLR test on tricyclo compounds (I)
  • 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 tricyclo compounds (I), 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, cre e 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, 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 an coloring agents and perfumes may be used.
  • a solubilizin 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 pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • this composition for applying this composition to human, it is preferable to apply it by parenteral or enteral administration.
  • 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.

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

Abstract

Composés de la formule (I) dans laquelle R1 représente hydrogène, alkyle inférieur pouvant avoir un ou plusieurs hydroxy, ou aryle pouvant avoir un/des substituant(s) approprié(s), R2 représente hydrogène, hydroxy ou hydroxy protégé, R3 représente méthyle, étyle, propyle ou allyle, R4 représente hdyroxy ou alcoxy, R5 représente oxo, (H, OH) ou (H, alcoxy), X représente oxo ou (H, OH), n représente un nombre entier de 1 ou de 2, et le symbole d'une ligne ou d'une ligne pointillée représente une seule liaison ou une double liaison, et sels, de ces composés. Procédés de production de ces composés, compositions contenant ces composés, et utilisation de ces composés comme agents immunosuppresseurs.
PCT/JP1991/000314 1990-03-12 1991-03-08 Composes tricyclo WO1991013899A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9005521.1 1990-03-12
GB909005521A GB9005521D0 (en) 1990-03-12 1990-03-12 Tricyclo compounds,a process for their production and a pharmaceutical composition containing the same
GB909017450A GB9017450D0 (en) 1990-08-09 1990-08-09 Tricyclo compounds,a process for their production and a pharmaceutical composition containing the same
GB9017450.9 1990-08-09

Publications (1)

Publication Number Publication Date
WO1991013899A1 true WO1991013899A1 (fr) 1991-09-19

Family

ID=26296777

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1991/000314 WO1991013899A1 (fr) 1990-03-12 1991-03-08 Composes tricyclo

Country Status (2)

Country Link
JP (1) JPH05504956A (fr)
WO (1) WO1991013899A1 (fr)

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5143918A (en) * 1990-10-11 1992-09-01 Merck & Co., Inc. Halomacrolides and derivatives having immunosuppressive activity
US5162334A (en) * 1991-05-13 1992-11-10 Merck & Co., Inc. Amino O-alkyl, O-alkenyl and O-alkynlmacrolides having immunosuppressive activity
US5189042A (en) * 1991-08-22 1993-02-23 Merck & Co. Inc. Fluoromacrolides having immunosuppressive activity
EP0515071A3 (en) * 1991-05-13 1993-03-03 Merck & Co. Inc. O-aryl, o-alkyl, o-alkenyl and o-alkynylmacrolides having immunosuppressive activity
US5208241A (en) * 1991-09-09 1993-05-04 Merck & Co., Inc. N-heteroaryl, n-alkylheteroaryl, n-alkenylheteroaryl and n-alkynylheteroarylmacrolides having immunosuppressive activity
US5262533A (en) * 1991-05-13 1993-11-16 Merck & Co., Inc. Amino O-aryl macrolides having immunosuppressive activity
US5262423A (en) * 1992-10-29 1993-11-16 American Home Products Corporation Rapamycin arylcarbonyl and alkoxycarbonyl carbamates as immunosuppressive and antifungal agents
US5284877A (en) * 1992-06-12 1994-02-08 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
US5302584A (en) * 1992-10-13 1994-04-12 American Home Products Corporation Carbamates of rapamycin
EP0642516A4 (fr) * 1991-09-05 1994-06-15 Abbott Lab Immunomodulateurs macrocycliques.
US5434260A (en) * 1992-10-13 1995-07-18 American Home Products Corporation Carbamates of rapamycin
US5463048A (en) * 1994-06-14 1995-10-31 American Home Products Corporation Rapamycin amidino carbamates
US5480989A (en) * 1992-10-13 1996-01-02 American Home Products Corporation Carbamates of rapamycin
US5480988A (en) * 1992-10-13 1996-01-02 American Home Products Corporation Carbamates of rapamycin
EP0689546A1 (fr) * 1993-03-17 1996-01-03 Abbott Laboratories Carbamates macrocycliques immunomodulateurs
US5484791A (en) * 1992-10-13 1996-01-16 American Home Products Corporation Carbamates of rapamycin
US5532248A (en) * 1991-05-13 1996-07-02 Merck Co., Inc. O-aryl,O-alkyl, and O-alkenyl-macrolides having immunosuppressive activity
US5534632A (en) * 1991-09-05 1996-07-09 Abbott Laboratories Macrocyclic carbamate immunomodulators
WO1996031514A1 (fr) * 1995-04-06 1996-10-10 Novartis Ag Ascomycines
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
US6352998B2 (en) 1994-10-26 2002-03-05 Novartis Ag Pharmaceutical compositions
EP1687283A2 (fr) * 2003-11-21 2006-08-09 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
US9402802B2 (en) 1998-12-03 2016-08-02 Meda Pharma Sarl Topical compositions comprising ascomycins

Citations (3)

* 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
EP0293892A2 (fr) * 1987-06-05 1988-12-07 Fujisawa Pharmaceutical Co., Ltd. Anticorps anti-FR-900506, substance et procédé d'essai enzymatique immunologique de haute sensibilité
EP0315978A2 (fr) * 1987-11-09 1989-05-17 Sandoz Ag Utilisation de dérivés de 11,28-dioxa-4-azatricyclo[22.3.1.0 4,9]octacos-18-ène et compositions pharmaceutiques les contenant

Patent Citations (3)

* 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
EP0293892A2 (fr) * 1987-06-05 1988-12-07 Fujisawa Pharmaceutical Co., Ltd. Anticorps anti-FR-900506, substance et procédé d'essai enzymatique immunologique de haute sensibilité
EP0315978A2 (fr) * 1987-11-09 1989-05-17 Sandoz Ag Utilisation de dérivés de 11,28-dioxa-4-azatricyclo[22.3.1.0 4,9]octacos-18-ène et compositions pharmaceutiques les contenant

Cited By (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5143918A (en) * 1990-10-11 1992-09-01 Merck & Co., Inc. Halomacrolides and derivatives 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
US5162334A (en) * 1991-05-13 1992-11-10 Merck & Co., Inc. Amino O-alkyl, O-alkenyl and O-alkynlmacrolides having immunosuppressive activity
EP0515071A3 (en) * 1991-05-13 1993-03-03 Merck & Co. Inc. O-aryl, o-alkyl, o-alkenyl and o-alkynylmacrolides having immunosuppressive activity
US5250678A (en) * 1991-05-13 1993-10-05 Merck & Co., Inc. O-aryl, O-alkyl, O-alkenyl and O-alkynylmacrolides having immunosuppressive activity
US5262533A (en) * 1991-05-13 1993-11-16 Merck & Co., Inc. Amino O-aryl macrolides having immunosuppressive activity
US5189042A (en) * 1991-08-22 1993-02-23 Merck & Co. Inc. Fluoromacrolides having immunosuppressive activity
EP0642516A4 (fr) * 1991-09-05 1994-06-15 Abbott Lab Immunomodulateurs macrocycliques.
EP0642516A1 (fr) * 1991-09-05 1995-03-15 Abbott Laboratories Immunomodulateurs macrocycliques
US5708002A (en) * 1991-09-05 1998-01-13 Abbott Laboratories Macrocyclic immunomodulators
US5534632A (en) * 1991-09-05 1996-07-09 Abbott Laboratories Macrocyclic carbamate immunomodulators
US5208241A (en) * 1991-09-09 1993-05-04 Merck & Co., Inc. N-heteroaryl, n-alkylheteroaryl, n-alkenylheteroaryl and n-alkynylheteroarylmacrolides having immunosuppressive activity
US5284877A (en) * 1992-06-12 1994-02-08 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
US5504204A (en) * 1992-10-13 1996-04-02 American Home Products Corporation Carbamates of rapamycin
US5559119A (en) * 1992-10-13 1996-09-24 American Home Products Corporation Carbamates of rapamycin
US5480988A (en) * 1992-10-13 1996-01-02 American Home Products Corporation Carbamates of rapamycin
US5302584A (en) * 1992-10-13 1994-04-12 American Home Products Corporation Carbamates of rapamycin
US5484791A (en) * 1992-10-13 1996-01-16 American Home Products Corporation Carbamates of rapamycin
US5484790A (en) * 1992-10-13 1996-01-16 American Home Products Corporation Carbamates of rapamycin
US5486522A (en) * 1992-10-13 1996-01-23 American Home Products Corporation Carbamates of rapamycin
US5486523A (en) * 1992-10-13 1996-01-23 American Home Products Corporation Carbamates of rapamycin
US5486524A (en) * 1992-10-13 1996-01-23 American Home Products Corporation Carbamates of rapamycin
US5488054A (en) * 1992-10-13 1996-01-30 American Home Products Corporation Carbamates of Rapamycin
US5489595A (en) * 1992-10-13 1996-02-06 American Home Products Corporation Carbamates of rapamycin
US5489680A (en) * 1992-10-13 1996-02-06 American Home Products Corporation Carbamates of rapamycin
US5480989A (en) * 1992-10-13 1996-01-02 American Home Products Corporation Carbamates of rapamycin
US5559120A (en) * 1992-10-13 1996-09-24 American Home Products Corporation Carbamates of rapamycin
US5508399A (en) * 1992-10-13 1996-04-16 American Home Products Corporation Carbamates of rapamycin
US5559227A (en) * 1992-10-13 1996-09-24 American Home Products Corporation Carbamates of rapaycin
US5516780A (en) * 1992-10-13 1996-05-14 American Home Products Corporation Carbamates of rapamycin
US5530121A (en) * 1992-10-13 1996-06-25 American Home Products Corporation Carbamates of rapamycin
US5530007A (en) * 1992-10-13 1996-06-25 American Home Products Corporation Carbamates of rapamycin
US5559112A (en) * 1992-10-13 1996-09-24 American Home Products Corporation Carbamates of rapamycin
US5532355A (en) * 1992-10-13 1996-07-02 American Home Products Corporation Carbamates of rapamycin
US5434260A (en) * 1992-10-13 1995-07-18 American Home Products Corporation Carbamates of rapamycin
US5550133A (en) * 1992-10-13 1996-08-27 American Home Products Corporation Carbamates of rapamycin
US5262423A (en) * 1992-10-29 1993-11-16 American Home Products Corporation Rapamycin arylcarbonyl and alkoxycarbonyl carbamates as immunosuppressive and antifungal agents
EP0689546A4 (fr) * 1993-03-17 1996-04-03 Abbott Lab Carbamates macrocycliques immunomodulateurs
EP0689546A1 (fr) * 1993-03-17 1996-01-03 Abbott Laboratories Carbamates macrocycliques immunomodulateurs
US5541191A (en) * 1994-06-14 1996-07-30 American Home Products Corporation Rapamycin amidino carbamates
US5541192A (en) * 1994-06-14 1996-07-30 American Home Products Corporation Rapamycin amidino carbamates
US5508286A (en) * 1994-06-14 1996-04-16 American Home Products Corporation Rapamycin amidino carbamates
US5463048A (en) * 1994-06-14 1995-10-31 American Home Products Corporation Rapamycin amidino carbamates
US5637590A (en) * 1994-06-14 1997-06-10 American Home Products Corporation Rapamycin amidino carbamates
US5693648A (en) * 1994-09-30 1997-12-02 Merck & Co., Inc. O-aryl, O-alkyl, O-alkenyl and O-alkynyl-macrolides having immunosuppressive activity
US6352998B2 (en) 1994-10-26 2002-03-05 Novartis Ag Pharmaceutical compositions
WO1996031514A1 (fr) * 1995-04-06 1996-10-10 Novartis Ag Ascomycines
US5925649A (en) * 1995-04-06 1999-07-20 Novartis Ag Ascomycins
US9402802B2 (en) 1998-12-03 2016-08-02 Meda Pharma Sarl Topical compositions comprising ascomycins
EP1687283A2 (fr) * 2003-11-21 2006-08-09 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
EP1687283A4 (fr) * 2003-11-21 2008-09-24 Siemens Healthcare Diagnostics 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

Also Published As

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