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WO1992000980A1 - Composes tricyclo, procede servant a leur production et composition pharmaceutique contenant ces composes - Google Patents

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

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Publication number
WO1992000980A1
WO1992000980A1 PCT/JP1991/000899 JP9100899W WO9200980A1 WO 1992000980 A1 WO1992000980 A1 WO 1992000980A1 JP 9100899 W JP9100899 W JP 9100899W WO 9200980 A1 WO9200980 A1 WO 9200980A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
represent
independently represent
substituted
och
Prior art date
Application number
PCT/JP1991/000899
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
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Publication of WO1992000980A1 publication Critical patent/WO1992000980A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • This invention relates to 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 to 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 synthetic process.
  • a further object of this invention is to provide 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 to transplantation, graft-versus-host diseases by medulla ossium
  • Such macrolides are particularly numbered FR-900506, FR-900520,
  • a) represent two vicinal hydrogen atoms
  • R 2 may
  • R 8 and R 9 independently represent H or OH
  • 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 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 22 and R 23 independently represent H or alkyl
  • R 20 and R 21 independently represent O, or they may independently represent (R 20 a,H) and (R 21 a,H)
  • R 20 a and R 21 a independently represent OH, O-alkyl or OCH 2 OCH 2 CH 2 OCH 3 or R 21 a represents protected hydroxy;
  • R 20 a and R 21 a may together represent an oxygen atom in an epoxide ring
  • n 1, 2 or 3;
  • Y, R 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
  • the object tricyclo compounds (I) can be prepared by the following process.
  • R 1 to R 10 , R 14 to R 23 Y and n are each as
  • 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.
  • 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.
  • Suitable "protected hydroxy” may include 1-(lower alkylthio)(lower) alkyl, trisubstituted silyl and acyl as exemplified in European Patent Publication No. 0184162.
  • 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
  • Y is oxo
  • Salts of the tricyclo compounds of the present invention include all pharmaceutically acceptable salts without limitation.
  • the compound (I) or a salt thereof can be prepared by subjecting the compound (II) or a salt thereof to
  • the reaction may be carried out in a conventional manner using Grignard reagent, and the like, which is explained in detail in the below example.
  • the reaction can also be carried out in the presence of Lewis acid.
  • the reaction is usually conducted in a conventional solvent which does not adversely influence the reaction such as water, acetone, dichloromethane, alcohol (e.g.
  • the reaction temperature is not critical and the reaction is usually conducted under from cooling to heating.
  • the object tricyclo compounds (I) obtained according to the process as explained above can be isolated and purified in a conventional manner, for example,
  • 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.; graft-versus-host diseases by medulla ossium
  • 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 fo 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, vasculitidas, erythemas, cutaneous eosinophilias, 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 ), particularly chronic or inveterate asthma (e.g. late asthma and airway hyper-responsiveness), bronchitis and the like;
  • inflammation of mucosa and blood vessels such as gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel disease, inflammatory bowel disease, necrotizing enterocolitis, intestinal lesions associated with thermal burns, leukotriene B 4 -mediated diseases;
  • intestinal inflammations/allergies such as Coeliac disease, proctitis, eosnophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis; food related allergic diseases which have symptomatic manifestation remote from the gastro-intestinal tract, for example migraine, rhinitis and eczema;
  • 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 S jogren ' s syndrome;
  • nephrotic syndrome such as gloraerulonephritis
  • 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 immunogeni ⁇ diseases (e.g. chronic hepatic diseases (e.g. chronic hepatic diseases (e.g. chronic hepatic diseases (e.g. chronic hepatic diseases (e.g. chronic hepatic diseases (e.g. chronic hepatocytes), and so on.
  • 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 immunogeni ⁇ diseases (e.g. chronic hepatic diseases (e.g. chronic hepatic diseases (e.g. chronic hepatic diseases (e.g. chronic hepatic diseases (e.g. chronic hepatic diseases (e.g. chronic hepatic
  • autoimmune liver diseases selected from the group consisting 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.
  • the tricyclo compounds (I) are useful for various diseases because of its useful pharmaceutical activity such as augmenting activity of chemotherapeutic effect.
  • 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
  • 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,
  • suspensions injections, ointments, liniments, eye drops lotion, gel, creme and any other form suitable for use.
  • the carriers which can be used are water, glucose lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, 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 solubilizing agent there may be
  • 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.
  • 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)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Transplantation (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

L'invention se rapporte à des composés représentés par la formule (I), ainsi qu'à des sels pharmaceutiquement acceptables de ces composés. Des procédés servant à les produire et une composition pharmaceutique contenant de tels composés sont également décrits.
PCT/JP1991/000899 1990-07-05 1991-07-03 Composes tricyclo, procede servant a leur production et composition pharmaceutique contenant ces composes WO1992000980A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9014881.8 1990-07-05
GB909014881A GB9014881D0 (en) 1990-07-05 1990-07-05 Tricyclo compounds,a process for their production and a pharmaceutical composition containing the same

Publications (1)

Publication Number Publication Date
WO1992000980A1 true WO1992000980A1 (fr) 1992-01-23

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1991/000899 WO1992000980A1 (fr) 1990-07-05 1991-07-03 Composes tricyclo, procede servant a leur production et composition pharmaceutique contenant ces composes

Country Status (4)

Country Link
EP (1) EP0537353A1 (fr)
JP (1) JPH06501923A (fr)
GB (1) GB9014881D0 (fr)
WO (1) WO1992000980A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US5686424A (en) * 1992-04-08 1997-11-11 Miles Inc. 2-oxoethyl derivatives as immunosuppressants
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0323042A1 (fr) * 1987-12-09 1989-07-05 FISONS plc Procédé pour macrolides

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0323042A1 (fr) * 1987-12-09 1989-07-05 FISONS plc Procédé pour macrolides

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Tetrahedron Letters, vol. 30, no. 45, Pergamon Press, Oxford, GB; D. Askin et al.: "A mechanistic study of the FK-506 tricarbonyl system rearrangement: synthesis of C.9 labeled FK-506", pages 6121-6124, see page 6122 *
Tetrahedron Letters, vol. 30, no. 6, February 1989, Pergamon Press, Oxford, GB; D. Askin et al.: "Chemistry of FK-506: benzilic acid rearrangement of the tricarbonyl system", pages 671-674, see page 672 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5686424A (en) * 1992-04-08 1997-11-11 Miles Inc. 2-oxoethyl derivatives as immunosuppressants
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
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
GB9014881D0 (en) 1990-08-22
EP0537353A1 (fr) 1993-04-21
JPH06501923A (ja) 1994-03-03

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