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WO1992000314A1 - Composes tricyclo, procede servant a les preparer et composition pharmaceutique contenant ces composes - Google Patents

Composes tricyclo, procede servant a les preparer et composition pharmaceutique contenant ces composes Download PDF

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Publication number
WO1992000314A1
WO1992000314A1 PCT/JP1991/000885 JP9100885W WO9200314A1 WO 1992000314 A1 WO1992000314 A1 WO 1992000314A1 JP 9100885 W JP9100885 W JP 9100885W WO 9200314 A1 WO9200314 A1 WO 9200314A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
represent
independently represent
substituted
compound
Prior art date
Application number
PCT/JP1991/000885
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 WO1992000314A1 publication Critical patent/WO1992000314A1/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 immuno ⁇ uppr ⁇ ssive 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 synthetic process.
  • 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.
  • vakushimaensis No. 7238 (FERM 3P-928).
  • 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-N R11 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 20a,H) and (R21a,H) respectively;
  • R 20 a and R 21 a independently represent OH, O-alkyl or OCH 2 OCH 2 CH 2 OCH 2 , 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, hydroxyl, alkyl substituted by one or more hydroxyl groups, O-alkyl, benzyl and
  • R 24 is lower alkyl which may be substituted by
  • 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, xylyi, 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.
  • Suitable "lower alkyl which may be substituted by suitable substituents” may include aforementioned lower alkyl, which may be substituted by one or more, preferably one or two suitable substituents such as hydroxyl, aryl as mentioned above, and the like.
  • R 1 and R 2 are each hydrogen
  • 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
  • R 8 is hydrogen
  • R 9 is hydroxyl
  • R 10 is propyl
  • R 14 , R 15 , R 16 , R 17 , R 18 and R 19 are each methyl
  • R 20 is [R 20 a,H], wherein R 20 a is methoxy
  • R 21 is [R 21 a,H], wherein R 21 a is hydroxy;
  • R 22 is methyl
  • R 23 is hydrogen
  • R 24 is propyl, 3-hydroxypropyl or benzyl
  • Y is oxo
  • the object tricyclo compounds (I) can be prepared by the following process.
  • R 1 to R 10 , R 14 to R 24 , Y and n are each as defined above, and
  • R 25 is lower alkyl, preferably methyl.
  • the compound (I) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound ( III ) .
  • the compound (III) can be prepared by reacting the compound R 24 -NH 2 with AS,(R 25 ) 3 in a conventional solvent at the temperature of cooling to warming.
  • 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, hexane, or a mixture thereof.
  • reaction temperature of this reaction is not critical and the reaction is usually conducted under from warming 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,
  • Suitable salts of the compounds (I) and (II) may include pharmaceutically acceptable salts such as basic salts, for example, alkali metal salt (e.g. sodium salt, potassium salt, etc.), alkaline earth metal salt (e.g.
  • the starting compounds (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 compounds can be prepared by a conventional manner.
  • the tricyclo compounds (I) possess pharmacological activities such as immunosuppressive activity,
  • antimicrobial activity and the like, and therefore are useful for the treatment and prevention of immune-mediated diseases controlled by a immun ⁇ suppressant such as the resistance by transplantation of organs or tissue such as heart, kidney, liver, medulla ossiur ⁇ , 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 the treatment and the prophylaxis of inflammatory and hyperproliferative skin diseases and cutaneous
  • immunol ⁇ gically-mediated illnesses suc as, psoriasis, atopical dermatitis, contact dermatitis an further eczematous dermatitises, seborrhoeis dermatitis, Lichen planus, Pemphigus, bullous Pemphigoid, Epidermolys bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupus erythematosus, acne and Alooecia areata; various eye diseases such as autoimmune diseases and so on (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,
  • 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;
  • Atherosclerosis aortitis syndrome, polvarteritis 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 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- 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, and
  • lactose lactose
  • gum acacia gelatin
  • mannitol 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.
  • 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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • 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 se rapporte à des composés représentés par la formule (I), ainsi qu'à des sels pharmaceutiquement acceptables de ces composés. Des procédés permettant de produire ces composés et une composition pharmaceutique contenant ces composés sont également décrits.
PCT/JP1991/000885 1990-07-02 1991-06-27 Composes tricyclo, procede servant a les preparer et composition pharmaceutique contenant ces composes WO1992000314A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9014681.2 1990-07-02
GB909014681A GB9014681D0 (en) 1990-07-02 1990-07-02 Tricyclo compounds,a process for their production and a pharmaceutical composition containing the same

Publications (1)

Publication Number Publication Date
WO1992000314A1 true WO1992000314A1 (fr) 1992-01-09

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1991/000885 WO1992000314A1 (fr) 1990-07-02 1991-06-27 Composes tricyclo, procede servant a les preparer et composition pharmaceutique contenant ces composes

Country Status (4)

Country Link
EP (1) EP0537354A1 (fr)
JP (1) JPH06501922A (fr)
GB (1) GB9014681D0 (fr)
WO (1) WO1992000314A1 (fr)

Cited By (2)

* 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
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection

Citations (2)

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

Patent Citations (2)

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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Journal of Organic Chemistry, vol. 56, no. 8, 12 April 1991, (Washington D.C., US), M.J. Fisher et al.:"On the Remarkable Propensity for Carbon-Carbon Bond Cleavage Reactions in the C8-C10 Region of FK-506", pages 2900-2907, see scheme VII, page 2904 *

Cited By (2)

* 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
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
JPH06501922A (ja) 1994-03-03
EP0537354A1 (fr) 1993-04-21
GB9014681D0 (en) 1990-08-22

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