WO1999015524A1 - Derives de thiazole - Google Patents

Derives de thiazole Download PDF

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Publication number
WO1999015524A1
WO1999015524A1 PCT/JP1998/004275 JP9804275W WO9915524A1 WO 1999015524 A1 WO1999015524 A1 WO 1999015524A1 JP 9804275 W JP9804275 W JP 9804275W WO 9915524 A1 WO9915524 A1 WO 9915524A1
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WO
WIPO (PCT)
Prior art keywords
nmr
mass
pyridyl
thiazol
similar manner
Prior art date
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PCT/JP1998/004275
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English (en)
Inventor
Kiyoshi Tsuji
Seiichiro Tabuchi
Yoshiteru Eikyu
Takashi Tojo
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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.)
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Publication date
Priority claimed from AUPO9367A external-priority patent/AUPO936797A0/en
Priority claimed from AUPP3591A external-priority patent/AUPP359198A0/en
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to AU90966/98A priority Critical patent/AU9096698A/en
Priority to JP2000512829A priority patent/JP2001517666A/ja
Publication of WO1999015524A1 publication Critical patent/WO1999015524A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This inventio n relates to new thiazole derivatives or a pharmaceutically acceptable salts thereof which are useful as a medicament.
  • This invention relates to new thiazole derivatives. More particularly, this invention relates to new thiazole derivatives and a pharmaceutically acceptable salt thereof which have pharmacological activities, processes for preparation thereof, a pharmaceutical composition comprising the same and a use of the same.
  • one object of this invention is to provide the useful thiazole derivatives and a pharmaceutically acceptable salt thereof which possess an anti-inflammatory activity, an immunomodulating activity, an inhibitory activity on the production of gamma interferon (IFN- 7 ) and an inhibitory activity on the production of tumor necrosis factor (TNF).
  • IFN- 7 gamma interferon
  • TNF tumor necrosis factor
  • Another object of this invention is to provide processes for preparation of the thiazole derivatives and a salt thereof.
  • a further object of this invention is to provide a pharmaceutical composition comprising said thiazole derivatives or a pharmaceutically acceptable salt thereof.
  • Still further object of this invention is to provide a use of said thiazole derivatives or a pharmaceutically acceptable salt thereof as a medicament for prophylactic and/or therapeutic treatment of inflammatory conditions, various pains, collagen diseases, autoimmune diseases, IFN- 7 mediated diseases, TNF mediated diseases and the like in human being and animals.
  • R 1 is amino; lower alkylamino ; heterocyclic ring containing nitrogen which may be substituted with halogen(s), amino(s), N-oxide, lower alkoxy(s), lower alkyl(s), lower alkoxycarbonyl(s), halo(lower)- alkoxycarbonyl(s), cyano(s), cyclo(lower)alkylamino(s), lower alkylamino(s), heterocyclic ring containing nitrogen(s), or oxo; or lower alkyl substituted with heterocyclic ring containing nitrogen;
  • R 2 is hydrogen; hydroxy; lower alkyl; or lower alkoxy;
  • R is hydrogen; lower alkyl which may be subst ituted with acyl(s), N-mono(or di)(lower)alkylamino(s), lower alkylthio(s), lower alkoxy(s), carboxy(s), heterocyclic ring containing nitrogen(s), lower alkynyl(s
  • the object compound (I) may include one or more stereoisomers due to asymmetric carbon atom(s) and double bond, and all of such isomers and a mixture thereof are included within the scope of the present invention.
  • isomerization or rearrangement of the object compound (I) may occur due to the effect of the light, acid, base or the like, and the compound obtained as the result of said isomerization or rearrangement is also included within the scope of the present invention.
  • the new thiazole derivatives (I) may be prepared by the processes which are mainly illustrated in the following scheme, and in the same as or the similar manners to those of the working Examples as mentioned below.
  • R 1 , R 2 ,R 3 , R 4 , X and Y are each as defined above, R 3a is hydrogen, R 3b is lower alkyl, R 4a is halogen, R 4b is lower alkylthio, M is alkaline metal, X 1 is lower alkylene,
  • X 2 is cyclo(lower)alkylene
  • X 3 is lower alkylene which may have alkyl or cycloalkyl
  • Y 1 is carbonyl
  • Y 2 is methylene
  • Z is acid residue.
  • Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and include a metal salts such as an alkali metal salt (e.g., sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylene diamine salt, etc.), an organic acid salt (e.g., acetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate, etc.), an inorganic acid salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.), a salt with an amino acid (e.g
  • lower is intended to mean 1 to 7 carbon atom(s), unless otherwise indicated, preferably 1 to 6 carbon atom(s), more preferably 1 to 4 carbon atom(s).
  • Suitable “lower alkyl” and “lower alkyl moiety” in the terms “lower alkylamino”, “cyclo(lower)alkylamino”, “cyclo(lower)alkyl”, “lower alkylthio", “N-mono(or di)(lower)alkylcarbamoyl", “N-mono(or di) (lower)alkylamino”, “N-mono(or di) (lower)alkylamino(lower)- alkylidene”, and “lower(alkyl)sulfonyl” may include straight or branch one such as methyl, ethyl, propyl, 1-ethylpropyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, pentyl, neopentyl, t-pentyl, hexyl
  • Suitable "heterocyclic ring containing nitrogen” and “heterocyclic moiety” in the term “heterocyclic carbonyl” may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one nitrogen atom.
  • heterocyclic ring containing nitrogen may be ones such as unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, tetrahydropyridyl (e.g., 1 ,2,3,6- tetrahydropyridyl, 1,4,5,6-tetrahydropyridyl, etc.), pyrimidinyl, pyrazinyl, dihydropyridazinyl, tetrahydropyridazinyl, triazolyl (e.g., lH- l ,2,4-triazolyl, lH-l,2,3-triazolyl, 2H- l ,2,3-triazolyl, etc.), tetrazolyl (e.g., lH-t
  • Suitable "acyl” may include aliphatic acyl group and acyl group containing an aromatic or heterocyclic ring.
  • suitable examples of the said acyl may be lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.); aroyl (e.g. benzoyl, naphthoyl, etc.); lower alkoxyaroyl (e.g.
  • ar(lower)alkoxycarbonyl e.g. benzyloxy- carbonyl, phenethyloxycarbonyl, etc.
  • heterocyclic carbonyl e.g. benzyloxy- carbonyl, phenethyloxycarbonyl, etc.
  • heterocyclic carbonyl e.g. benzyloxy- carbonyl, phenethyloxycarbonyl, etc.
  • heterocyclic carbonyl e.g. benzyloxy- carbonyl, phenethyloxycarbonyl, etc.
  • bridged cyclic(lower)alkanecarbonyl e.g.
  • cyclopropane carbonyl cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, etc.
  • carbamoyl which may be substituted with mono- or di-(lower)alkyl (e.g. dimethylcarbamoyl, etc.), sulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.) and the like.
  • halo(lower)alkoxycarbonyl and “lower alkoxyimino” may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy, t- pentyloxy, hexyloxy, heptyloxy and the like.
  • Suitable "lower alkylene” may include straight or branched one having 1 to 7 carbon atom(s), such as methylene, ethylene, dimethylethylene, trimethylene, 1-methyltrimethylene, 1, 1- dimethyltrimethylene, 2,2-dimethyltrimethylene, 1 -ethyltrimethylene, (l, l-di ⁇ ropyl)trimethylene, ( 1, 1 -diet hyl)trimethylene, tetramethylene, pentamethylene, hexamehylene, or the like, preferably one having 1 to 6 carbon atom(s), more preferably one having 1 to 4 carbon atom(s).
  • Suitable "halogen” and “halogen moiety” in t he terms “mono(or di or tri)halo(lower)alkyl” and “halo(lower)alkoxycarbonyl” may include chlorine, bromine, fluorine and iodine.
  • Suitable “alkaline metal” may include lithium, sodium, potassium, and the like.
  • Suitable "cyclo(lower)alkylidene” may include cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclohexylidene, cycloheptylidene, and the like.
  • Suitable “lower alkynyl” may include ethynyl, propynyl, propenyl, butynyl, pentynyl, hexynyl, heptynyl, and the like.
  • Suitable "aryl” may include phenyl, lower alkylphenyl (e.g. tolyl, ethylphenyl, propylphenyl, etc.), naphthyl, or the like.
  • Suitable “lower alkylidene moiety” in the terms “phenyl(lower)- alkylidene”, “cyclo(lower)alkylidene", “N-mono(or di) (lower)- alkylamino(lower)alkylidene”, and “hydroxy(lower)alkylidene” may include methylidene, ethylidene, propylidene, butylidene, pentylidene, hexylidene, heptylidene, or the like.
  • Suitable "cyclo(lower)alkyl” and “cyclo(lower)alkyl moiety" in the term “cyclo(lower)alkylamino” may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • Suitable “lower alkenylene” may include straight or branched one having 2 to 7 carbon atom(s), such as vinylene, propenylene, 1- pentenylene, 2-pentenylene, 1-butenylene, 2-butenylene, 1-hexenylene, 2-hexenylene, 3-hexenylene, 1-heptenylene, 2-heptenylene, 3- heptenylene, or the like.
  • R 1 is amino ; lower alkylamino ; heterocyclic ring containing nitrogen which may be substituted with halogen(s), amino(s), N-oxide, lower alkoxy(s), lower alkyl(s), lower alkoxycarbonyl(s), halo(lower)- alkoxycarbonyl(s), cyano(s), cyclo(lower)alkylamino(s), lower alkylamino(s), heterocyclic ring containing nitrogen(s), or oxo; or lower alkyl substituted with heterocyclic ring containing nitrogen;
  • R 2 is hydrogen; hydroxy; lower alkyl; or lower alkoxy;
  • R 3 is hydrogen; lower alkyl which may be substituted with lower alkanoyl(s), cyclo(lower)alkanecarbonyl(s), bridged cyclic(lower)alkylcarbonyl(s), aroyl(s), lower alkoxyaroy
  • R 1 is amino; methylamino; or pyridyl, [l,2,4]triazolo[4,3-a]pyridin-5-yl, 1,2,3,6- tetrahydropyridin-4-yl, imidazo[l,2-a]pyrazin-2-yl, 4- pyrimidinyl, 2-chloro-4-pyridyl, 2-chloro-5-pyridyl, 2-amino-5- pyridyl, pyridine-l-oxide-4-yl, pyridine- l -oxide-3-yl, 2- methoxypyridin-4-yl, l -methyl-l,2,3,6-tetrahydropyridin-4-yl, l-methyl-2-oxopyridin-4-yl, 2-methylpyridin-5-yl, 3- methylpyridin-4-yl, 2-ethoxycarbonylpyridin-4-yl, 1-(1- chloroethoxy carbonyl
  • R 2 is hydrogen; hydroxy; methyl; or methoxy
  • R 3 is hydrogen; methyl, ethyl, propyl, 1-ethylpropyl, isopropyl, butyl, sec-butyl, pentyl, neopentyl, hexyl, propionylmethyl, pivaloylmethyl, adamantylcarbonylmethyl, benzoyl, m-methoxybenzoylmethyl, isonicotinoylmethyl, ethoxycarbonylmethyl, 2-(N,N- dimethylamino)ethyl, 2-methylthio ethyl, 2-methoxyethyl, carboxymethyl, (N,N-dimethylcarbamoyl)methyl, (pyridin-4-yl)- methyl, (pyridin-3-yl)methyl, (pyridin-2-yl)methyl, carbamoylmethyl, 2-propynyl, 2,2-difluoroethyl, or benzyl; acetyl or methyl
  • R 2 and R 3 may be linked together to form ethylene
  • R 4 is hydrogen; methyl; chloro; bromo; or methylthio;
  • X is methylene, ethylene, 1-methyltrimethylene, 1, 1- dimethyltrimethylene, 2,2-dimethyltrimethylene, trimethylene, tetramethylene, (l-ethyl)trimethylene, (1 , 1-dipropyl)- trimethylene, (l , l-diethyl)trimethylene, l-(l-imidazolyl)- trimethylene, fluoromethylene, difluoromethylene, hydroxymethylene, styrylidene, 2-(N, N-dimethylamino)- ethylidene, hydroxyethylidene, or methoxyiminomethylene; cyclopropylidene, cyclobutylidene, cyclopentylidene, or cyclohexylidene; carbonyl; or thio ;
  • Y is methylene, 1-oxoethylene, 1-oxotrimethylene, carbonyl, or thiocarbonyl; and X and Y may be linked together to form vinylene,
  • R 1 is heterocyclic ring containing nitrogen
  • R 2 is hydrogen or lower alkyl
  • R 3 is lower alkyl
  • R 4 is hydrogen
  • X is lower alkylene
  • Y is carbonyl
  • R 1 is pyridyl
  • R 2 , R 3 , R 4 , X and Y are each as defined above
  • the most preferred embodiments of the object compound(I) are 1 -isoproy 1-8- met hy 1-7- [2-(4- pyridyl) thiazol-4-yl]- 1,3, 4,5- tetrahydro- 2H- l-benzazepin-2-one or l -isoproyl-5,5-dimethyl-7-[2-(4- pyridyl)thiazol-4-yl]- 1,3,4,5- tetrahydro-2H-l-benzazepin-2-one.
  • the compound (I) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the amino group or a salt thereof with the compound (III) or a salt thereof.
  • Suitable reactive derivative at the amino group of the compound (II) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (II) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as N,N-bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide or the like; a derivative formed by the reaction of the compound (II) with phosphorus trichloride or phosgene and the like.
  • Suitable salts of the compounds (II) and (III) can be referred to the ones as exemplified for the compound (I).
  • Suitable acid residue may include inorganic acid residue (e.g., halogen such as chlorine, bromine, fluorine or iodine); organic acid residue (e.g., acyloxy such as acetoxy; sulfonyloxy such as benzenesulfonyloxy, tosyloxy, methanesulfonyloxy).
  • inorganic acid residue e.g., halogen such as chlorine, bromine, fluorine or iodine
  • organic acid residue e.g., acyloxy such as acetoxy
  • sulfonyloxy such as benzenesulfonyloxy, tosyloxy, methanesulfonyloxy
  • the reaction is usually carried out in a conventional so lvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydro furan, ethyl acetate, N,N- dimethylformamide, pyridine or any other organic so lvents which do not adversely affect the reaction.
  • a conventional so lvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydro furan, ethyl acetate, N,N- dimethylformamide, pyridine or any other organic so lvents which do not adversely affect the reaction.
  • a conventional so lvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydro furan, ethyl acetate,
  • the reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)aklylmorphorine, N,N- di(lower)alkylbenzylamine, or the like.
  • an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)aklylmorphorine, N,N- di(lower)alkylbenzylamine, or the like.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
  • the compound (III) or a salt thereo f can be prepared in accordance with the method disclosed in the Preparations described later or similar manners thereto.
  • the reaction can be referred to that of Examples 1-7, 32-34, 37, 39, 41 , 44, 46, 50, 53, 59, 60, 78, 94-97, 99, 104, 107, 109, 111, 113, 115, 117, 129.
  • the compound (lb) or a salt thereof can be prepared by reducing the compound (la) or a salt thereof.
  • Suitable salts of the compounds (la) and (lb) can be referred to the ones as exemplified for the compound (I).
  • This reaction can be referred to that of Examples 1-(1), 2-(l), 8- (2), 36, 38, 40, 42, 45, 63, 80, 131.
  • the compound (Id) or a salt thereof can be prepared by subjecting the compound (Ic) or a salt thereof to
  • This reaction can be referred to that of Examples 6-(l), 6-(2), 8- (1 ), 9-22, 23-(l ), 24-(l), 25-( l), 26-(l ), 27-(l), 28-( l ), 29-(l ), 30-(l), 31-( 1 ), 48, 72-77, 79, 81, 83-88, 91 , 98, 100, 105, 108, 110, 112, 114, 116, 118-124, 127, 128, 130, 132 [(a-1 )], Example 3-(l) [(a-2)], Example 5-(l), 61 , 62 [(b)].
  • the compound (If) or a salt thereof can be prepared by halogenating the compound (Ie) or a salt thereof.
  • Suitable salts of the compounds (If) and (Ie) can be referred to the ones as exemplified for the compound (I).
  • the compound (Ig) or a salt thereof can be prepared by reacting the compound (If) or a salt thereof with the compound (Ig) or a salt thereof.
  • Suitable salts of the compounds (Ig) can be referred to the ones as exemplified for the compound (I).
  • Example 35 the following processes of Examples can be referred to those of Example 35 ; 43(including Examples 51, 89, 106, 126, and 133); 47; 49; 52; 54(including Example 101); 55-58; 64-71 ; 82(including Example 125); 90; 92; 93; 102(including Example 103).
  • mice Female BALB/c mice were purchased from the Shizuoka Experimental Animal Center (Shizuoka, Japan), and were used at 7- 10 week of age.
  • Con A (Vector Laboratories, Inc.) was dissolved in pyrogen-free saline and administered to mice via the tail vein at a dose of 0.3 mg/mouse. Drugs suspended in 0.1 % methylcellulose were administered to mice orally (p.o.) 1 hour before Con A injection.
  • Plasma from individual mice was obtained 24hr after Con A injection. Plasma transaminase activity was measured by the standard photometric method using a bichromatic analyzer (model 100; Abbott Laboratories).
  • Test Compound (a) 6-[2-(4-pyridyl)thiazol-4-yl]-3,4-dihydro- l-methyl-2(lH)- quinolinone [Example 2]
  • Spleens from BALB/c mice were removed, and single cell suspensions were prepared in culture medium (RPMI 1640 containing 2 mmol/1 L-glutamine, 50 units/ml penicillin, and 50 g/ml streptomycin, 5 X 10 "5 mol/1 2-mercaptoethanol and 10% fatal calf serum).
  • the cells were seeded into 24-well culture plates at a concentration of 2 X 10 6 cells per well in a volume of 1 ml culture medium and stimulated with 2 /Z g/ml of concanavalin A.
  • Drugs dissolved in dimethylsulfoxide (DMSO) were diluted in culture medium and added at the initiation of culture. After 24 hr incubation in a humidified incubator (37°C, 5 % CO,), culture supernatants were obtained. TNF and IFN- 7 concentrations in the supernatants were determined by enzyme-linked immunosorbent assay (ELISA).
  • ELISA enzyme-linked immunosorbent assay
  • the thiazole derivatives (I) and a pharmaceutically acceptable salt thereof of the present invention possess an anti-inflammatory activity, an immunomodulating activity, an inhibitory activity on the production of gamma interferon (IFN- 7 ) and an inhibitory activity on the production of tumor necrosis factor (TNF).
  • IFN- 7 gamma interferon
  • TNF tumor necrosis factor
  • the thiazole derivatives (I) and a pharmaceutically acceptable salt thereof can be used for prophylactic and/or therapeutic treatment of inflammatory conditions, various pains, collagen diseases, autoimmune diseases, I FN- 7 mediated diseases, TNF mediated diseases and the like in human beings or animals, and more particularly for prophylactic and/or therapeutic treatment of inflammation and pain in joint and muscle [e.g. rheumatoid arthritis, rheumatois spondylitis, osteoarthritis, gouty arthritis, etc. ], inflammatory skin condition [e.g. sunburn, eczema, etc.], inflammatory eye condition [e.g. conjunctivitis, etc. ], lung disorder in which inflammation is involved [e.g.
  • asthma wheezing aphthous ulcer, Crohn 's disease, atrophic gastritis, gastritis varialoforme, ulcerative colitis, coeliac disease, regional ileitis, irritable bowel syndrome, etc.
  • gingivitis inflammation, pain and tumescence after operation or injury
  • pyrexia pain and other conditions associated with inflammation
  • rejection by transplantation systemic lupus erythematosus, scleroderma, polymyositis, polychondritis, periarteritis nodosa, ankylosing spondytis, inflammatory chronic renal condition [e.g.
  • diabetes e.g. diabetes mellitus type I, diabetes mellitus type II, etc.
  • dermatomyositis e.g. acute hepatitis, chronic active hepatitis, etc.
  • myasthenia gravis idiopathic sprue, Grave ' s disease, multiple sclerosis, primary billiary cirrhoris, Reiter 's syndrome, autoimmune hematological disorders [e.g.
  • hemolytic anemia pure red cell anemia, idiopathic thrombocytopenia, aplastic anemia, etc.
  • uveitis contact dermatitis, psoriasis, Kawasaki disease, sarcoidosis, Wegner's granulomatosis, Hodgkin 's disease, emphysema, chronic bronchiolitis, osteoporosis, eosinophilia, cystic fibrosis, pancreatitis, nephritis, atopic dermatitis, idiopathic sprue, endocrine ophthalmopathy, non infection uveitis, autoimmune keratitis (e.g.
  • keratoconjunctivitis sicca vernal keratoconjunctivitis, etc.
  • interstitial lung fibrosis psoriatic arthritis
  • cancer cachexia AIDS cachexia
  • thrombosis chronic granulomutotic diseases
  • tuberculosis leprosy
  • meurological inflammatory conditions graft versus host disease and atherosclerosis
  • shock e.g. septic shock, hemorrhagic shock, burn shock, anaphylactic shock, etc.
  • the pharmaceutical composition of the present invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the object compound (I) or a pharmaceutically acceptable salt thereof, as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for rectal, pulmonary (nasal or buccal inhalation), nasal, ocular, external (topical), oral or parenteral (including subcutaneous, intravenous, intramuscular and intra-articular) administrations or insufflation.
  • a pharmaceutical preparation for example, in solid, semisolid or liquid form, which contains the object compound (I) or a pharmaceutically acceptable salt thereof, as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for rectal, pulmonary (nasal or buccal inhalation), nasal, ocular, external (topical), oral or parenteral (including subcutaneous, intravenous, intramuscular and intra-articular) administrations or insufflation.
  • the active ingredient may be used in admixture with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, troches, capsules, suppositories, creams, ointments, aerosols, powders for insufflation, solutions, emulsions, suspensions, and any other form suitable for use. And, if necessary, in addition, auxiliary, stabilizing, thickening and coloring agents and perfumes may be used.
  • the object compound (I) or a pharmaceutically acceptable salt thereof is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the diseases.
  • the pharmaceutical composition of the present invention can be prepared by the conventional method in this field of the art. If necessary, the technique generally used in this field of the art for improving the bioavailability of a drug can be applied to the pharmaceutical composition of the present invention. For applying the composition to a human being or an animal, it is preferable to apply it by intravenous (including i.v. infusion), intramuscular, pulmonary, or oral administration, or insufflation including aerosols from metered dose inhalator, nebulizer or dry powder inhalator.
  • intravenous including i.v. infusion
  • intramuscular, pulmonary, or oral administration or insufflation including aerosols from metered dose inhalator, nebulizer or dry powder inhalator.
  • the dosage of therapeutically effective amount of the object compound (I) varies from and also depends upon the age and condition of each individual patient to be treated, the preferred daily dosage can generally be selected from the range of 0.001 -lOOmg of the object compound (I) per kg weight of a human being or an animal, for the prophylactic and/or therapeutic treatment of aforesaid diseases in a human being or an animal.
  • Oxalyl chloride (4.4ml) was added dropwise to an ice-cooled solution of 4-(l -indolinyl)-4-oxobutanoic acid (lOg) and N,N- dimethylformamide (1 drop) in 1 ,2-dichloroethane (100ml). Then, aluminum chloride (30.4g) was added, and the whole mixture was stirred at 50°C overnight. The mixture was poured into a mixture of ice water and ethyl acetate, and the insoluble product was removed by filtration. The resulted organic layer was dried and evaporated.
  • Example 1- (1) The following compound was obtained in a similar manner to that of Example 1- (1).
  • Methanesulfonyl chloride (39.6 Z 1) was added to a solution of 5- [2-(4-pyridyl)thiazol-4-yl]indoline dihydrochloride (0.15g) in pyridine (3 ml). The mixture was stirred overnight at room temperature and evaporated. The residue was dissolved in a mixture of methylene chloride and water. The resultant organic layer was separated, dried, and evaporated. The residue was recrystallized from ethanol to afford l-(methanesulfonyl)-5-[2-(4-pyridyl)thiazol-4-yl]indoline (0.10 g) as pale yellow crystals. mp : 199-201 °C
  • the residual oil was chromatographed [a mixture of toluene and ethyl acetate (2:1)] over silica gel, and the product was crystallized from diisopropyl ether to give l-isopropyl-5,5-dimethyl-7-[2-(2-cyclopropylamino-4- pyridyl)thiazol-4-yl]-l,3,4,5-tetrahydro-2H-l-benzazepin-2-one (45 mg) as a pale brown powder.

Abstract

L'invention concerne des dérivés de thiazole, ou leurs sels pharmaceutiquement acceptables, représentés par la formule (I). Dans ladite formule, R1 est amino; alkylamino inférieur; un anneau hétérocyclique contenant azote éventuellement substitué par halogène(s), amino(s), N-oxyde, alcoxy(s) inférieur(s), alkyle(s) inférieur(s), alcoxycarbonyle(s) inférieur(s), haloalcoxycarbonyle(s) (inférieur(s)), cyano(s), cycloalkylamino(s) (inférieur(s)), alkylamino(s) inférieur(s), un anneau hétérocyclique contenant azote(s), ou oxo; ou alkyle inférieur substitué par un anneau hétérocyclique contenant azote; R2 est hydrogène; hydroxy, alkyle inférieur; ou alcoxy inférieur; R3 est hydrogène; alkyle inférieur éventuellement substitué par acyle(s), N-mono (ou di)alkylamino(s) (inférieur(s)), alkylthio(s) inférieur(s) alcoxy(s) inférieur(s), carboxy(s), un anneau hétérocyclique contenant azote(s), alkynyle(s) inférieur(s), halogène(s), ou aryle(s); acyle; ou cycloalkyle inférieur; R2 et R3 peuvent être liés pour former alkylène inférieur, R4 est hydrogène; alkyle inférieur; halogène; ou alkylthio inférieur; X est alkylène inférieur éventuellement substitué par un anneau hétérocyclique contenant azote(s), halogène(s), hydroxy(s), phénylalkylidène(s) inférieur(s), N-mono (ou di)alkylamino (inférieur) alkylidène(s) (inférieur(s)), hydroxyalkylidène(s) (inférieur(s)), ou alcoxyimino(s) inférieur(s); cycloalkylidène (inférieur); carbonyle; ou thio; Y est alkylène inférieur éventuellement substitué par oxo, ou thioxo, et X et Y peuvent être liés pour former alcénylène inférieur, X et N étant respectivement liés aux atomes de carbone attenants sur le noyau benzénique. Les dérivés en question, ou leurs sels pharmaceutiquement acceptables, sont utiles comme médicaments.
PCT/JP1998/004275 1997-09-23 1998-09-22 Derives de thiazole WO1999015524A1 (fr)

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AU90966/98A AU9096698A (en) 1997-09-23 1998-09-22 Thiazole derivatives
JP2000512829A JP2001517666A (ja) 1997-09-23 1998-09-22 チアゾール誘導体

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AUPO9367A AUPO936797A0 (en) 1997-09-23 1997-09-23 Thiazole derivatives
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AUPP3591A AUPP359198A0 (en) 1998-05-19 1998-05-19 Thiazole derivatives
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US6358948B1 (en) * 1999-05-04 2002-03-19 American Home Products Corporation Quinazolinone and benzoxazine derivatives as progesterone receptor modulators
US6498154B1 (en) 1999-05-04 2002-12-24 Wyeth Cyclic regimens using quinazolinone and benzoxazine derivatives
WO2005095366A1 (fr) * 2004-03-24 2005-10-13 Wyeth Derives de 7-aryl 1,5-dihydro-4,1-benzoxazepine-2(3h)-one et leurs utilisations comme modulateurs du recepteur de la progesterone
WO2009033033A3 (fr) * 2007-09-06 2009-04-30 Boston Biomedical Inc Compositions d'inhibiteurs de kinase et leur utilisation pour le traitement du cancer et d'autres maladies liées aux kinases
US7645761B2 (en) * 1999-05-04 2010-01-12 Wyeth Indoline derivatives
US7722886B2 (en) 2003-05-20 2010-05-25 Wyeth Compositions and methods for treatment of severe acute respiratory syndrome (SARS)
EP2241328A1 (fr) 2000-05-12 2010-10-20 Immunex Corporation Inhibiteurs d'interleukine 1 dans le traitement de maladies
US8410060B2 (en) 1999-04-19 2013-04-02 Immunex Corporation Soluble tumor necrosis factor receptor treatment of medical disorders
US8685960B2 (en) 2008-05-06 2014-04-01 Elexopharm Gmbh 6-pyridin-3-yl-3,4-dihydro-1h-quinolin-2-one derivatives and related compounds as inhibitors of the human aldosterone synthase CYP11B2
WO2014202528A1 (fr) * 2013-06-20 2014-12-24 Boehringer Ingelheim International Gmbh Oxindoles substitués par oléfine ayant une activité sur ampk
US9096546B2 (en) 2007-05-10 2015-08-04 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzo-1,4-diazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
KR20150097511A (ko) * 2012-12-19 2015-08-26 하. 룬드벡 아크티에셀스카브 6-클로로-3-(페닐-ｄ5)-인덴-1-온 및 이의 용도
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US9713613B2 (en) 2007-02-02 2017-07-25 Motonari Uesugi Methods and compositions for the treatment of cancer and related hyperproliferative disorders
CN112047964A (zh) * 2020-09-07 2020-12-08 宋喂 格氏试剂制备方法与应用
US11535600B2 (en) 2018-12-03 2022-12-27 H. Lundbeck A/S Prodrugs of 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine and 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine

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US8410060B2 (en) 1999-04-19 2013-04-02 Immunex Corporation Soluble tumor necrosis factor receptor treatment of medical disorders
US6358948B1 (en) * 1999-05-04 2002-03-19 American Home Products Corporation Quinazolinone and benzoxazine derivatives as progesterone receptor modulators
US6498154B1 (en) 1999-05-04 2002-12-24 Wyeth Cyclic regimens using quinazolinone and benzoxazine derivatives
US7645761B2 (en) * 1999-05-04 2010-01-12 Wyeth Indoline derivatives
EP2241328A1 (fr) 2000-05-12 2010-10-20 Immunex Corporation Inhibiteurs d'interleukine 1 dans le traitement de maladies
US7722886B2 (en) 2003-05-20 2010-05-25 Wyeth Compositions and methods for treatment of severe acute respiratory syndrome (SARS)
US7892563B2 (en) 2003-05-20 2011-02-22 Wyeth Holdings Corporation Methods for treatment of severe acute respiratory syndrome (SARS)
WO2005095366A1 (fr) * 2004-03-24 2005-10-13 Wyeth Derives de 7-aryl 1,5-dihydro-4,1-benzoxazepine-2(3h)-one et leurs utilisations comme modulateurs du recepteur de la progesterone
US7323455B2 (en) 2004-03-24 2008-01-29 Wyeth 7-aryl 1,5-dihydro-4,1-benzoxazepin-2(3H)-one derivatives and their use as progesterone receptor modulators
US7598237B2 (en) 2004-03-24 2009-10-06 Wyeth 7-aryl 1,5-dihydro-4,1-benzoxazepin-2(3H)-one derivatives and their use as progesterone receptor modulators
US9713613B2 (en) 2007-02-02 2017-07-25 Motonari Uesugi Methods and compositions for the treatment of cancer and related hyperproliferative disorders
US9096546B2 (en) 2007-05-10 2015-08-04 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzo-1,4-diazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US8299106B2 (en) 2007-09-06 2012-10-30 Boston Biomedical, Inc. Compositions of kinase inhibitors and their use for treatment of cancer and other diseases related to kinases
EP3037419A1 (fr) * 2007-09-06 2016-06-29 Boston Biomedical, Inc. Compositions d'inhibiteurs de kinase et leur utilisation pour le traitement du cancer et d'autres maladies liées aux kinases
US9725444B2 (en) 2007-09-06 2017-08-08 Boston Biomedical, Inc Compositions of kinase inhibitors and their use for treatment of cancer and other diseases related to kinases
WO2009033033A3 (fr) * 2007-09-06 2009-04-30 Boston Biomedical Inc Compositions d'inhibiteurs de kinase et leur utilisation pour le traitement du cancer et d'autres maladies liées aux kinases
EP2197878A2 (fr) * 2007-09-06 2010-06-23 Boston Biomedical, Inc. Compositions d'inhibiteurs de kinase et leur utilisation pour le traitement du cancer et d'autres maladies liées aux kinases
EP2197878A4 (fr) * 2007-09-06 2012-02-08 Boston Biomedical Inc Compositions d'inhibiteurs de kinase et leur utilisation pour le traitement du cancer et d'autres maladies liées aux kinases
US8685960B2 (en) 2008-05-06 2014-04-01 Elexopharm Gmbh 6-pyridin-3-yl-3,4-dihydro-1h-quinolin-2-one derivatives and related compounds as inhibitors of the human aldosterone synthase CYP11B2
JP2016501901A (ja) * 2012-12-19 2016-01-21 ハー・ルンドベック・アクチエゼルスカベット ６−クロロ−３−（フェニル−ｄ５）インデン−１−オンおよびその使用
KR20150097511A (ko) * 2012-12-19 2015-08-26 하. 룬드벡 아크티에셀스카브 6-클로로-3-(페닐-ｄ5)-인덴-1-온 및 이의 용도
KR102212096B1 (ko) * 2012-12-19 2021-02-04 하. 룬드벡 아크티에셀스카브 6-클로로-3-(페닐-ｄ5)-인덴-1-온 및 이의 용도
WO2014202528A1 (fr) * 2013-06-20 2014-12-24 Boehringer Ingelheim International Gmbh Oxindoles substitués par oléfine ayant une activité sur ampk
CN105884607A (zh) * 2014-05-05 2016-08-24 上海合全药业股份有限公司 一种环丙丙酸的制备方法
US11535600B2 (en) 2018-12-03 2022-12-27 H. Lundbeck A/S Prodrugs of 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine and 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine
CN112047964A (zh) * 2020-09-07 2020-12-08 宋喂 格氏试剂制备方法与应用

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