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WO1993016083A1 - Composes macrocycliques et utilisation de ces derniers en tant que produits pharmaceutiques - Google Patents

Composes macrocycliques et utilisation de ces derniers en tant que produits pharmaceutiques Download PDF

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Publication number
WO1993016083A1
WO1993016083A1 PCT/GB1993/000231 GB9300231W WO9316083A1 WO 1993016083 A1 WO1993016083 A1 WO 1993016083A1 GB 9300231 W GB9300231 W GB 9300231W WO 9316083 A1 WO9316083 A1 WO 9316083A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
compounds
pharmaceutically acceptable
diseases
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.)
Ceased
Application number
PCT/GB1993/000231
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English (en)
Inventor
Mark Furber
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.)
Fisons Ltd
Original Assignee
Fisons 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 Fisons Ltd filed Critical Fisons Ltd
Publication of WO1993016083A1 publication Critical patent/WO1993016083A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • 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

Definitions

  • This invention relates to a novel macrocyclic compound and its pharmaceutically acceptable derivatives, their use as pharmaceuticals, and pharmaceutical formulations containing them.
  • European Patent Application 184162 discloses a number of macrocyclic compounds isolated from microorganisms belonging to the genus Streptomyces. The compounds are numbered FR-900506, FR-900520, FR-900523 and FR-900525, and the preparation of some of their derivatives is also described. The compounds are indicated as immunosuppressive agents.
  • the compound of formula I may be prepared by the method of Example 1 below.
  • the compounds of the invention have the advantage that they are less toxic, more efficacious, longer acting, have a broader range of activity, are more potent, are more stable, produce fewer side effects, are more easily absorbed, are more soluble, or have other more useful physical or pharmacological properties, than compounds of the prior art.
  • esters may be prepared by conventional methods, for example reaction with a carboxylic acid and a coupling agent, or an acyl chloride.
  • carbamates may also be prepared by conventional methods, for example reaction with an isocyanate. Specific esters and carbamates are CH 3 CO 2 -, C 6 H 5 CO 2 -, H 2 NCO 2 - and CH 3 NHCO 2 -.
  • the compounds of the invention are useful because they possess pharmacological activity in animals: in particular they are useful because they possess immunosuppressive activity, e.g. as indicated in Tests A, B, C and D below.
  • the compounds of the invention are indicated for use in the treatment or prevention of resistance to transplanted organs or tissues, such as kidney, heart, lung, bone marrow, skin, cornea, liver, medulla ossium, pancreas, intestinum ***, limb.
  • organs or tissues such as kidney, heart, lung, bone marrow, skin, cornea, liver, medulla ossium, pancreas, intestinum ***, limb.
  • rheumatoid arthritis lupus erythematosus, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type 1 diabetes, uveitis, nephrotic syndrome, psoriasis, atopical dermatitis, contact dermatitis and further eczematous dermatitides, seborrheic dermatitis, Lichen planus, Pemphigus, bullous Pemphigoid, Epidermolysis bullosa.
  • the compounds of the invention are also indicated in the treatment of respiratory diseases, for example sarcoidosis, fibroid lung, idiopathic interstitial pneumonia and reversible obstructive airways disease which latter 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.
  • respiratory diseases for example sarcoidosis, fibroid lung, idiopathic interstitial pneumonia and reversible obstructive airways disease
  • respiratory diseases for example sarcoidosis, fibroid lung, idiopathic interstitial pneumonia and reversible obstructive airways disease which latter 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-
  • the compound of the invention is also indicated in certain eye diseases such as keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren's ulcer, Scleritis, Graves' ophthalmopathy and the like.
  • eye diseases such as keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren's ulcer, Scleritis, Graves' ophthalmopathy and the like.
  • the compounds of the invention are also indicated in the treatment of inflammation of mucosa and blood vessels such as gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel disease, inflarr-matory bowel disease, necrotizing enterocolitis, intestinal lesions associated with thermal burns and leukotriene B4-mediated diseases.
  • the compounds of the invention are also indicated in the treatment of renal diseases including interstitial nephritis, Goodpasture's syndrome, hemolytic-uremic syndrome and diabetic nephropathy; nervous diseases including multiple myositis, Guillain-Barre syndrome, Meniere's disease and radiculopathy; endocrine diseases including hyperthyroidism and Basedow's disease; hematic diseases including pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis and anerythroplasia; bone diseases such as osteoporosis; skin diseases including dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity and cutaneous T-cell lymphoma; circulatory diseases selected from arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa and myocardosis;
  • the compounds of the invention are indicated in the treatment of diseases including intestinal inflammations/allergies such as Coeliac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis; and food related allergic diseases which have symptomatic manifestation remote from the gasto-intestinal tract, for example migraine, rhinitis and eczema.
  • diseases including intestinal inflammations/allergies such as Coeliac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis
  • food related allergic diseases which have symptomatic manifestation remote from the gasto-intestinal tract, for example migraine, rhinitis and eczema.
  • the compounds of the invention also have liver regenerating activity and/or activity in 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 autoimmune liver diseases including autoimmune hepatitis, primary biliary s 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.
  • immunogenic diseases e.g. chronic autoimmune liver diseases including autoimmune hepatitis, primary biliary s cirrhosis and sclerosing cholangitis
  • partial liver resection e.g. necrosis caused by toxins, viral hepatitis, shock or anoxia
  • B-virus hepatitis e.g
  • the compounds of the invention are also indicated for use as antimicrobial agents, and o thus may be used in the treatment of diseases caused by pathogenic microorganisms and the like.
  • the compounds of the invention are further indicated in the prophylactic treatment of acquired immunodeficiency syndrome (AIDS), by which we mean delay of the onset of 5 disease symptoms in patients infected with the human immunodeficiency virus (HIV)
  • AIDS acquired immunodeficiency syndrome
  • HAV human immunodeficiency virus
  • the dosage administered will, of course, vary with the mode of administration, the treatment desired (eg topical, parenteral or oral) and the disease indicated.
  • the compounds of the inventions are administered at a daily dosage of from 0.001 to 20mg per kg of animal body weight.
  • unit dosage forms suitable for adrninistration comprise from O.Olmg to 500mg, and preferably 0.5mg to lOOmg of a compound of the invention preferably admixed with a solid or liquid pharmaceutically acceptable diluent, carrier or adjuvant.
  • a pharmaceutical formulation comprising preferably less than 80%, and more preferably less than 50% by weight, of a compound of the invention in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • Suitable adjuvants, diluents or carriers are: for tablets, capsules and dragees - microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and/or gelatin; for suppositories - natural or hardened oils or waxes; for inhalation formulations - coarse lactose.
  • the compounds of the invention are preferably in a form having a mass median diameter of from 0.01 to lO ⁇ m.
  • the formulations may also contain suitable preserving, stabilising and wetting agents, solubilisers (eg a water-soluble cellulose polymer such as hydroxypropyl methylcellulose, or a water-soluble glycol such as propylene glycol), sweetening and colouring agents and flavourings.
  • solubilisers eg a water-soluble cellulose polymer such as hydroxypropyl methylcellulose, or a water-soluble glycol such as propylene glycol
  • sweetening and colouring agents and flavourings may, if desired, be formulated in sustained release form.
  • the compounds of the invention for the treatment of reversible obstructive airways disease, we prefer the compounds of the invention to be administered by inhalation to the lung, especially in the form of a powder.
  • a method of effecting immunosuppression which comprises administering a therapeutically effective amount of a compound of the invention to a patient.
  • the compounds of the invention have a number of chiral centres and may exist in a variety of stereoisomers.
  • the invention provides all optical and stereoisomers.
  • the isomers may be resolved or separated by conventional techniques.
  • the MLR test was performed in microtitre plates, with each well containing 5x10 s
  • BALB/C stimulator cells H-2 d
  • BALB/C stimulator cells H-2 d
  • RPMI 1640 medium supplemented with 10% fetal calf serum, 2mM sodium hydrogen carbonate, penicillin (50 ⁇ g/ml) and streptomycin (50 ⁇ g/ml).
  • the cells were incubated at 37°C in a 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.
  • the compound of the invention was dissolved in ethanol s and further diluted in RPMI 1640 medium and added to the cultures to give final concentrations of O.l ⁇ g/ml or less.
  • the compound under test was dissolved at lOmg/ml in ethanol and further diluted in
  • RPMI 1640 The cells were incubated at 37°C in a humidified atmosphere at 5% s carbon dioxide for 96 hours. 3H-thymidine (0.5 ⁇ Ci) was added for the final 24 hours of the incubation to provide a measure of proliferation.
  • graft versus Host Assay f GVH 0 Spleen cells from DA and DAxLewis Fl hybrid rats were prepared at approximately 10 s cells/ml. 0.1ml of these suspensions were injected into the rear footpads of DAxLewis Fl rats (left and right respectively). Recipient animals were dosed with the compound under test, either orally or subcutaneously, on days 0-4. The assay was te ⁇ ninated on day 7 when the popliteal lymph nodes of the animals were removed and weighed. The 5 increase in weight of the left node relative to the weight of the right gave a measure of the GVH response.
  • Example 1 The title compound of Example 1 was tested following the method of test D above, and s the concentration of the compound required to inhibit IL-2 secretion by 50% (IC ⁇ ) was found to be 5xlO- 10 M.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne le composé de formule (I) et ses dérivés pharmaceutiquement acceptables qui sont indiqués, entre autres, comme immunosuppresseurs.
PCT/GB1993/000231 1992-02-15 1993-02-04 Composes macrocycliques et utilisation de ces derniers en tant que produits pharmaceutiques Ceased WO1993016083A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB929203265A GB9203265D0 (en) 1992-02-15 1992-02-15 Pharmaceutically active compound
GB9203265.5 1992-02-15

Publications (1)

Publication Number Publication Date
WO1993016083A1 true WO1993016083A1 (fr) 1993-08-19

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ID=10710476

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1993/000231 Ceased WO1993016083A1 (fr) 1992-02-15 1993-02-04 Composes macrocycliques et utilisation de ces derniers en tant que produits pharmaceutiques

Country Status (3)

Country Link
AU (1) AU3458393A (fr)
GB (1) GB9203265D0 (fr)
WO (1) WO1993016083A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0673646A3 (fr) * 1994-03-22 1995-12-27 Behringwerke Ag Utilisation de déoxypergualin dans la fabrication d'un médicament pour le traitement des affections de l'hypersensibilité-inflammatoire.
US5496831A (en) * 1994-05-13 1996-03-05 The General Hospital Corporation Inhibition of insulin-induced adiposis
US6346546B1 (en) 1997-06-13 2002-02-12 Galderma Research & Development Biaromatic compounds and pharmaceutical and cosmetic compositions comprising them
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989005304A1 (fr) * 1987-12-09 1989-06-15 Fisons Plc Composes macrocycliques
EP0413532A2 (fr) * 1989-08-18 1991-02-20 FISONS plc Composés macrocycliques
WO1992003441A1 (fr) * 1990-08-18 1992-03-05 Fisons Plc Composes macrocycliques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989005304A1 (fr) * 1987-12-09 1989-06-15 Fisons Plc Composes macrocycliques
EP0413532A2 (fr) * 1989-08-18 1991-02-20 FISONS plc Composés macrocycliques
WO1992003441A1 (fr) * 1990-08-18 1992-03-05 Fisons Plc Composes macrocycliques

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0673646A3 (fr) * 1994-03-22 1995-12-27 Behringwerke Ag Utilisation de déoxypergualin dans la fabrication d'un médicament pour le traitement des affections de l'hypersensibilité-inflammatoire.
US5496831A (en) * 1994-05-13 1996-03-05 The General Hospital Corporation Inhibition of insulin-induced adiposis
US6346546B1 (en) 1997-06-13 2002-02-12 Galderma Research & Development Biaromatic compounds and pharmaceutical and cosmetic compositions comprising them
US6849658B2 (en) 1997-06-13 2005-02-01 Galderma Research & Development Biaromatic compounds and pharmaceutical and cosmetic compositions comprising them
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
GB9203265D0 (en) 1992-04-01
AU3458393A (en) 1993-09-03

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