WO1994029295A1 - Derives heterocycliques a activite immunomodulante - Google Patents

Derives heterocycliques a activite immunomodulante Download PDF

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Publication number
WO1994029295A1
WO1994029295A1 PCT/JP1994/000824 JP9400824W WO9429295A1 WO 1994029295 A1 WO1994029295 A1 WO 1994029295A1 JP 9400824 W JP9400824 W JP 9400824W WO 9429295 A1 WO9429295 A1 WO 9429295A1
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Prior art keywords
hydroxy
compound
hydrogen
alkoxy
salt
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PCT/JP1994/000824
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English (en)
Inventor
Masaaki Matsuo
Kiyoshi Tsuji
Katsuya Nakamura
Glen W. Spears
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Fujisawa Pharmaceutical Co., Ltd.
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Priority to JP7501557A priority Critical patent/JPH08511514A/ja
Priority to AU66585/94A priority patent/AU6658594A/en
Publication of WO1994029295A1 publication Critical patent/WO1994029295A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61P35/00—Antineoplastic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • This invention relates to new heterocyclic
  • This invention relates to new heterocyclic
  • this invention relates to new heterocyclic derivatives and pharmaceutically
  • composition comprising the same and a use of the same.
  • one object of this invention is to provide the new and useful heterocyclic derivatives and pharmaceutically acceptable salts thereof which possess a strong immunomodulating activity (e.g. an inhibitory activity on the production of an autoantibody, etc.), anti-inflammatory activity and anti-cancer activity.
  • a strong immunomodulating activity e.g. an inhibitory activity on the production of an autoantibody, etc.
  • Another object of this invention is to provide processes for preparation of the heterocyclic derivatives and salts thereof.
  • a further object of this invention is to provide a pharmaceutical composition comprising said heterocyclic derivatives or a pharmaceutically acceptable salt thereof. Still further object of this invention is to provide a use of said heterocyclic derivatives or a
  • the object heterocyclic derivatives of the present invention are novel and can be represented by the
  • R 3 is lower alkyl
  • R 6 is hydroxy, protected hydroxy or halogen
  • Y is a bivalent radical selected from the group consisting of
  • R 1 is hydrogen or lower alkoxy
  • R 2 is hydrogen, lower alkyl, lower alkoxy, halogen, mono(or di or tri)halo(lower)alkoxy, amino, protected amino, mono (or di)( lower alkyl)amino, protected (lower)- alkylamino, hydroxy, protected hydroxy, aryloxy, heterocyclic group, or nitro
  • R 1 is hydrogen or lower alkoxy
  • R 2 is hydrogen, lower alkyl, lower alkoxy, halogen, mono(or di or tri)halo(lower)alkoxy, amino, protected amino, mono (or di)( lower alkyl)amino, protected (lower)- alkylamino, hydroxy, protected hydroxy, aryloxy, heterocyclic group, or nitro
  • R 3 is hydrogen, halogen or lower
  • R 2 and R 3 are linked together to form lower alkylene or a group of the formula : ,
  • R 4 is hydrogen or lower alkoxy, or
  • R 4 and R 5 are linked together to form lower alkylene
  • R 7 is lower alkyl
  • R 5 and R 7 are linked together to form lower alkylene).
  • the object compound (I) of the present invention canepared by the following processes.
  • R 2 a is protected ( lower)alkylamino
  • R 2 b is lower alkylamino
  • R 6 a is protected hydroxy
  • R 8 is lower alkyl
  • Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt,
  • a salt with an inorganic base for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt
  • a salt with an organic base for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt,
  • ethanolamine salt triethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.
  • an inorganic acid addition salt e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • an organic carboxylic or sulfonic acid addition salt e.g., formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.
  • a salt with a basic or acidic amino acid e.g., arginine, aspartic acid, glutamic acid, etc.
  • lower is used to intend a group having 1 to 6, preferably 1 to 4, carbon atom(s), unless otherwise provided.
  • alkylamino and “protected (lower)alkylamino” may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, hexyl, and the like, preferably one having 1 to 4 carbon atom(s).
  • Suitable "lower alkoxy” and “lower alkoxy moiety" in the term “mono(or di or tri)halo(lower) alkoxy” may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like.
  • Suitable “protected amino” may include an acylamino or an amino group substituted by a conventional protecting group such as ar( lower)alkyl which may have suitable substituent(s) (e.g., benzyl, trityl, etc.) or the like.
  • acylamino may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or heterocyclic ring, which is referred to as heterocyclic acyl.
  • Suitable example of said acyl may be illustrated as follows : Carbamoyl ;
  • Aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2, 2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.);
  • alkanoyl e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2, 2-dimethylpropanoy
  • alkoxycarbonyl e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.
  • alkylsulfonyl e.g., methylsulfonyl, ethylsulfonyl, etc.
  • alkoxysulfonyl e.g., methoxysulfonyl, ethoxysulfonyl, etc.; or the like;
  • Aromatic acyl such as
  • aroyl e.g., benzoyl, toluoyl, naphthoyl, etc.
  • ar( lower) alkanoyl e.g., phenyl ( lower) alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl,
  • phenylisobutanoyl phenylpentanoyl, phenylhexanoyl, etc.
  • naphthyl( lower) alkanoyl e.g., naphthylacetyl
  • ar(lower)alkanoyl e.g., phenyl(lower)alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc.),
  • naphthyl(lower)alkenoyl e.g., naphthylpropenoyl
  • ar(lower)alkoxycarbonyl e.g., phenyl(lower)alkoxycarbonyl
  • aryloxycarbonyl e.g., phenoxycarbonyl
  • aryloxy(lower)alkanoyl e.g., phenoxyacetyl
  • arylcarbamoyl e.g., phenylcarbamoyl, etc.
  • arylthiocarbamoyl e.g., phenylthiocarbamoyl, etc.
  • arylglyoxyloyl e.g., phenylglyoxyloyl
  • arylsulfonyl e.g., phenylsulfonyl, p-tolylsulfonyl, etc.; or the like;
  • Heterocyclic acyl such as
  • heterocyclic(lower)alkanoyl e.g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl,
  • heterocyclic (lower) alkenoyl e.g., heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl,
  • heterocyclichexenoyl etc.
  • heterocyclicglyoxyloyl or the like
  • heterocycliccarbonyl "heterocyclic(lower)alkyl”
  • heterocyclic(lower)alkenoyl and "heterocyclicglyoxyloyl” as mentioned above means, in more detail, saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like.
  • heterocyclic group may be heterocyclic group such as
  • nitrogen atom(s) for example, pyrrolyl, pyrrolinyl,
  • nitrogen atom(s) for example, pyrrolidinyl
  • oxazolyl isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.),etc.;
  • thiazolyl isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;
  • acyl moiety as stated above may have one to ten, same or different, suitable substituerit(s) such as lower alkyl (e.g., methyl, ethyl, propyl, etc.); lower alkoxy
  • cyclo( lower) alkyl e.g., cyclopentyl, cyclohexyl, etc.
  • cyclo( lower)alkenyl e.g., cyclohexenyl, etc.
  • amino ( lower ) alkyl e.g., aminomethyl, aminoethyl, etc.
  • carbamoyloxy e.g., hydroxymethyl, 1 or 2-hydroxyethyl, 1 or 2 or 3-hydroxypropyl, etc., or the like.
  • protected hydroxy may include acyl as mentioned above, phenyl(lower)alkyl which may have one or more suitable substituent(s) (e.g., benzyl, 4-methoxybenzyl, trityl, etc.), trisubstituted silyl [e.g., tri(lower)alkylsilyl
  • protected (lower)alkylamino may include acyl as mentioned above, and the like.
  • Suitable "aryl moiety” in the term “aryloxy” may include phenyl, naphthyl and the like.
  • Suitable “leaving group” may include acid residue and the like, and suitable examples of “acid residue” may be halogen (e.g., fluorine, chlorine, bromine, iodine), acyloxy [e.g., sulfonyloxy (e.g., phenylsulfonyloxy, tosyloxy, mesyloxy, etc.), lower alkanoyloxy (e.g., acetyloxy, propionyloxy, etc.), etc.] or the like.
  • halogen e.g., fluorine, chlorine, bromine, iodine
  • acyloxy e.g., sulfonyloxy (e.g., phenylsulfonyloxy, tosyloxy, mesyloxy, etc.), lower alkanoyloxy (e.g., acetyloxy, propionyloxy, etc.), etc.] or the like.
  • Suitable "halogen” and “halogen moiety” in the term “mono (or di or tri)halo(lower) alkoxy” may include
  • Suitable "lower alkylene” may include straight or branched one such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene,
  • methylmethylene, ethylethylene, propylene, and the like in which more preferable example may be C 1 -C 4 alkylene.
  • Suitable "bicyclic heterocyclic group containing at least one nitrogen atom” may include isoindolyl, indolyl, indazolyl, indolinyl, isoindolinyl, 1,2-dihydroguinolyl, tetrahydroquinolyl [e.g., 1,2,3,4-tetrahydroguinolyl, etc.], benzoxazinyl [e.g., 4H-1,4-benzoxazinyl, etc.], dihydrobenzoxazinyl [e.g., 3,4-dihydro-2H-1,4-benzoxazinyl, 2,3-dihydro-4H-1,3-benzoxazinyl, etc.], benzothiazinyl [e.g., 4H-1,4-benzothiazinyl, etc.], dihydrobenzothiazinyl [e.g.
  • Suitable "heterocyclic group” can be referred to the ones as exemplified above.
  • heterocyclic group containing at least one nitrogen atom which may have suitable substituent(s) " may include lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, t-pentyl, hexyl, etc.), lower alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, t-butoxy, pentyloxy, neopentyloxy, t-pentyloxy, hexyloxy, etc.), lower alkenyl (e.g., vinyl, 1-propenyl, allyl, 1-meth ⁇ lallyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl, etc.), lower alkynyl (e.g.
  • propargyl 1-methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or 5-hexynyl, etc.
  • mono(or di or tri)halo (lower) alkyl e.g., fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,
  • dibromomethyl tribromomethyl, 1 or 2-fluoroethyl, 1 or 2-bromoethyl, 1 or 2-chloroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, etc.), halogen (e.g., chlorine, bromine, fluorine, iodine), carboxy, protected carboxy, hydroxy, protected hydroxy, aryl (e.g., phenyl, naphthyl, etc.), ar(lower)alkyl such as phenyl(lower)alkyl (e.g., benzyl, phenethyl, phenylpropyl, etc.), carboxy(lower)alkyl, protected carboxy(lower)alkyl, nitro, amino, protected amino, di ( lower) alkylamino (e.g., dimethylamino,
  • lower alkylthio e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.
  • the compound (I) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the carboxy group, or a salt thereof with the compound (III) or its reactive derivative at the imino group, or a salt thereof.
  • Suitable reactive derivative at the imino group of the compound (III) may include a silyl derivative formed by the reaction of the compound (III) with a silyl
  • Suitable reactive derivative at the carboxy group of the compound (II) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like.
  • Suitable examples of the reactive derivatives may be an acid chloride; an acid azide;
  • a mixed acid anhydride with an acid such as substituted phosphoric acid [e.g. dialkylphosphoric acid,
  • dibenzylphosphoric acid dibenzylphosphoric acid, halogenated phosphoric acid, etc.] dialkylphosphorous acid, sulfurous acid,
  • dimethylpyrazole triazole or tetrazole
  • an activated ester e.g. methyl ester, cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl ester, vinyl ester, ethyl ester, propargyl ester, p-nitrophenyl ester, 2, 4-dinitrophenyl ester, trichlorophenyl ester,
  • phenylazophenyl ester phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-guinolyl thioester, etc.], or an ester with a N-hydroxy compound [e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole, etc.], and the like.
  • These reactive derivatives can optionally be selected from them according to the kind of the compound (II) to be used.
  • the reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, toluene, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely
  • a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, toluene, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely
  • a conventional condensing agent such as N,N' -dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide;
  • N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide; N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;
  • 1-alkoxy-1-chloroethylene trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride; lower alkyl haloformate [e.g. ethyl chloroformate, isopropyl chloroformate, etc.]; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide
  • 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)alkylmorpholine, 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)alkylmorpholine, 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 (Ib) or a salt thereof can be prepared by subjecting the compound (Ia) or a salt thereof to elimination reaction of the hydroxy protective group.
  • This reaction is carried out in accordance with a conventional method such as hydrolysis, reduction or the like.
  • the hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
  • Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. sodium, potassium, etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonate thereof, trialkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicycl[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, or the like.
  • Suitable acid may include an organic acid [e.g.
  • Lewis acid such as trihaloacetic acid [e.g. trichloroacetic acid, trifluoroacetic acid, etc.] or the like is preferably carried out in the presence of cation trapping agent [e.g. anisole, phenol, etc.],
  • the reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely affect the reaction.
  • a liquid base or acid can be also used as the solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
  • the reduction method applicable for the elimination reaction may include chemical reduction and catalytic reduction.
  • Suitable reducing agents to be used in chemical reduction are a combination of metal [e.g. tin, zinc, iron, etc.] or metallic compound [e.g. chromium chloride, chromium acetate, etc.] and an organic or inorganic acid [e.g. formic acid, acetic acid, propionic acid,
  • Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts [e.g. platinum plate, spongy platinum, platinum black, colloidal 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
  • 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.
  • the reduction is usually carried out in a
  • catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc., or a mixture thereof.
  • reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.
  • the compound (Id) or a salt thereof can be prepared by subjecting the compound (Ic) or a salt thereof to elimination reaction of the amino protective group.
  • the compound (If) or a salt thereof can be prepared by reacting the compound (Ie) or a salt thereof with the compound (IV) or a salt thereof.
  • This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, diethyl ether or any other solvent which does not
  • the reaction is usually carried out in the presence of an inorganic or an organic base such as an alkali metal (e.g., sodium, potassium, etc.), an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), an alkali metal hydrogencarbonate (e.g., sodium, potassium, etc.), sodium bicarbonate (e.
  • alkali metal carbonate e.g., sodium carbonate, potassium carbonate, etc.
  • tri( lower)alkylamine e.g.,
  • alkali metal hydride e.g, sodium hydride, etc.
  • alkali metal (lower)alkoxide e.g., sodium methoxide, sodium ethoxide, etc.
  • pyridine lutidine, picoline, dimethylaminopyridine, N-(lower)alkylmorpholine, N,N-di(lower)al
  • the base and/or the starting compound are in liquid, they can be used also as a solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under warming to heating.
  • Suitable salts of the object and starting compounds and their reactive derivatives in Processes (1) ⁇ (4) can be referred to the ones as exemplified for the compound (I).
  • pharmaceutically acceptable salt thereof of the present invention possess a strong immunomodulating activity (e.g. an inhibitory activity on the production of an
  • immunomodulating agent e.g. an inhibitor on the
  • the new heterocyclic derivatives (I) and a pharmaceutically acceptable salt thereof can be used for the treatment and/or prevention of inflammatory disorders
  • rheumatoid arthritis rheumatoid 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 condition of the gastrointestinal tract associated with inflammation [e.g. aphthous ulcer, Crohn's disease, atrophic gastritis, gastritis varialoforme, ulcerative colitis, coeliac disease, regional ileitis, irritable bowel syndrome, etc.], gingivitis,
  • spondytis inflammatory chronic renal condition
  • glomerulonephritis membranous nephritis, etc.
  • rheumatic fever Sjogren's syndrome
  • Behcet disease thyroiditis
  • type I diabetes type I diabetes
  • dermatomyositis chronic active
  • hepatitis myasthenia gravis, idiopathic sprue, Grave's disease, multiple sclerosis, primary biliary cirrhosis, Reiter's syndrome, autoimmune hematological disorders
  • heterocyclic derivatives (I) 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, cancer [e.g. lung carcinoma, stomach carcinoma, colon cancer, renal carcinoma, hepatoma, etc.] and the like.
  • pharmacological test data of the representative compound of the heterocyclic derivatives (I) are illustrated in the following.
  • a conventional pharmaceutical preparation in admixture with a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration.
  • a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration.
  • the pharmaceutical preparation may be compounded in a solid form such as granule, capsule, tablet, dragee or suppository, or in a liquid form such as solution,
  • auxiliary substance such as stabilizing agent, wetting or emulsifying agent, buffer or any other commonly used additives.
  • the effective ingredient may usually be administered with a unit dose of 0.01 mg/kg to 500 mg/kg, preferably 0.01 mg/kg to 10 mg/kg, 1 to 4 times a day.
  • the above dosage may be increased or decreased according to age, weight and conditions of the patient or the
  • Preferred embodiments of the object compound (I) are as follows.
  • R 5 is lower alkyl
  • R 6 is hydroxy
  • phenyl(lower)alkoxy which may have one or more suitable substituent(s) [more preferably
  • substituent(s) selected from the group consisting of halogen, lower alkoxy and lower alkylthio (more preferably indolinyl which may have halogen, lower alkoxy or lower alkylthio); tetrahydroquinolyl;
  • Y is a bivalent radical selected from the group
  • R 2 is hydrogen, lower alkyl, lower alkoxy, halogen, trihalo(lower)alkoxy, amino, acylamino [more preferably lower alkanoylamino], mono(or di)(lower alkyl)amino, N-acyl-N- lower alkylamino [more preferably N- lower alkanoyl-N-lower alkylamino], hydroxy, phenyl(lower)alkoxy which may have one or more suitable substituent(s) [more preferably benzyloxy], phenyloxy, pyrrolyl or nitro,
  • R 3 is hydrogen, halogen or lower alkoxy, or
  • R 4 is hydrogen or lower alkoxy, or
  • R 4 and R 5 are linked together to form
  • R 7 is lower alkyl
  • R 5 and R 7 are linked together to form lower alkylene).
  • dichloromethane (0.5 ml) was added dropwise to a solution of 1,2-dihydro-3-carboxy-4-chloro-6-methoxy-1-methyl-2-oxoquinoline (0.27 g) and triethylamine (0.29 ml) in dichloromethane (2 ml) at -10°C. The mixture was stirred at -5°C for 1 hour. 4,5,6,7-Tetrahydropyrazolo[1,5-a]pyrimidine (0.15 g) was added thereto, and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was washed with water, dried and

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Abstract

Dérivés hétérocycliques de la formule (I) dans laquelle R5 est un alkyle inférieur; R6 est un hydroxy, un hydroxy protégé ou un halogène; (a) est un groupe hétérocyclique bicyclique renfermant au moins un atome d'azote, qui peut avoir un ou plusieurs substituants appropriés; et Y est un radical bivalent (b) (dans lequel R1 est l'hydrogène ou un alcoxy inférieur; R2 est l'hydrogène, un alkyle inférieur, un alcoxy inférieur, un halogène, etc.; R3 est l'hydrogène, un halogène ou un alcoxy inférieur, etc.; R4 est l'hydrogène ou un alcoxy inférieur, etc.), etc; et sel pharmaceutiquement acceptable de ces dérivés, qui peuvent être utilisés comme médicament.
PCT/JP1994/000824 1993-06-04 1994-05-24 Derives heterocycliques a activite immunomodulante WO1994029295A1 (fr)

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JP7501557A JPH08511514A (ja) 1993-06-04 1994-05-24 免疫調節作用を有する複素環誘導体
AU66585/94A AU6658594A (en) 1993-06-04 1994-05-24 Heterocyclic derivatives with immunomodulating activity

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995024395A1 (fr) * 1994-03-07 1995-09-14 Fujisawa Pharmaceutical Co., Ltd. Derives de quinoline utilises comme immunomodulateurs
WO1997035565A1 (fr) * 1996-03-27 1997-10-02 Toray Industries, Inc. Derives de cetone et usage medicinal
WO1999015524A1 (fr) * 1997-09-23 1999-04-01 Fujisawa Pharmaceutical Co., Ltd. Derives de thiazole
WO2000053605A1 (fr) * 1999-03-11 2000-09-14 Merck & Co., Inc. Inhibiteurs de tyrosine kinase
WO2005123744A1 (fr) * 2004-06-18 2005-12-29 Active Biotech Ab Carboxamides de thiénopyridone et leur utilisation médicale
EP1746994A2 (fr) * 2004-05-17 2007-01-31 Epix Delaware, Inc. Composes de thieno-pyridinone et procedes de traitement associes
WO2011150682A1 (fr) * 2010-06-04 2011-12-08 中国人民解放军军事医学科学院毒物药物研究所 Dérivés de 4-hydroxyquinoléine-3-amide, leurs méthodes de synthèse et leurs utilisations
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection
US8962598B2 (en) 2010-10-14 2015-02-24 Immunahr Ab 1,2-dihydro-4-hydroxy-2-oxo-quinoline-3-carboxanilides as AHR activators

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7737314B2 (en) 2007-02-12 2010-06-15 Exxonmobil Chemical Patents Inc. Production of high purity ethylbenzene from non-extracted feed and non-extracted reformate useful therein

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0059698A1 (fr) * 1981-03-03 1982-09-08 Ab Leo Carboxamides hétérocycliques, compositions contenant de tels composés, procédés pour leur préparation et méthodes pour le traitement à l'aide de ceux-ci
JPH02152966A (ja) * 1988-12-05 1990-06-12 Otsuka Pharmaceut Co Ltd ４−ヒドロキシカルボスチリル誘導体
WO1990015052A1 (fr) * 1989-06-09 1990-12-13 Pharmacia Ab Derives de quinoline-3-carboxanilide
WO1992018483A1 (fr) * 1991-04-22 1992-10-29 Fujisawa Pharmaceutical Co., Ltd. Derives de quinoleine
WO1993015083A1 (fr) * 1992-01-27 1993-08-05 Fujisawa Pharmaceutical Co., Ltd. Derives heterotricycliques, leur procede de preparation, et compositions pharmaceutiques les contenant

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0059698A1 (fr) * 1981-03-03 1982-09-08 Ab Leo Carboxamides hétérocycliques, compositions contenant de tels composés, procédés pour leur préparation et méthodes pour le traitement à l'aide de ceux-ci
JPH02152966A (ja) * 1988-12-05 1990-06-12 Otsuka Pharmaceut Co Ltd ４−ヒドロキシカルボスチリル誘導体
WO1990015052A1 (fr) * 1989-06-09 1990-12-13 Pharmacia Ab Derives de quinoline-3-carboxanilide
WO1992018483A1 (fr) * 1991-04-22 1992-10-29 Fujisawa Pharmaceutical Co., Ltd. Derives de quinoleine
WO1993015083A1 (fr) * 1992-01-27 1993-08-05 Fujisawa Pharmaceutical Co., Ltd. Derives heterotricycliques, leur procede de preparation, et compositions pharmaceutiques les contenant

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 113, no. 23, 3 December 1990, Columbus, Ohio, US; abstract no. 211864z, YOSHIZAKI, SHIRO ET AL.: "4-Hydroxycarbostyrils as antiinflammatory and antiallergy agents." *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995024395A1 (fr) * 1994-03-07 1995-09-14 Fujisawa Pharmaceutical Co., Ltd. Derives de quinoline utilises comme immunomodulateurs
WO1997035565A1 (fr) * 1996-03-27 1997-10-02 Toray Industries, Inc. Derives de cetone et usage medicinal
WO1999015524A1 (fr) * 1997-09-23 1999-04-01 Fujisawa Pharmaceutical Co., Ltd. Derives de thiazole
WO2000053605A1 (fr) * 1999-03-11 2000-09-14 Merck & Co., Inc. Inhibiteurs de tyrosine kinase
US6544988B1 (en) 1999-03-11 2003-04-08 Merck & Co., Inc. Tyrosine kinase inhibitors
EP1746994A2 (fr) * 2004-05-17 2007-01-31 Epix Delaware, Inc. Composes de thieno-pyridinone et procedes de traitement associes
EP1746994A4 (fr) * 2004-05-17 2008-01-23 Epix Delaware Inc Composes de thieno-pyridinone et procedes de traitement associes
WO2005123744A1 (fr) * 2004-06-18 2005-12-29 Active Biotech Ab Carboxamides de thiénopyridone et leur utilisation médicale
US7553849B2 (en) 2004-06-18 2009-06-30 Active Biotech Ab Compounds
CN1980937B (zh) * 2004-06-18 2011-08-10 活跃生物技术有限公司 噻吩并吡啶酮甲酰胺及其医药用途
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection
WO2011150682A1 (fr) * 2010-06-04 2011-12-08 中国人民解放军军事医学科学院毒物药物研究所 Dérivés de 4-hydroxyquinoléine-3-amide, leurs méthodes de synthèse et leurs utilisations
US8962598B2 (en) 2010-10-14 2015-02-24 Immunahr Ab 1,2-dihydro-4-hydroxy-2-oxo-quinoline-3-carboxanilides as AHR activators

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AU6658594A (en) 1995-01-03
GB9311562D0 (en) 1993-07-21
HU9403465D0 (en) 1995-03-28
JPH08511514A (ja) 1996-12-03
HUT71352A (en) 1995-11-28

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