WO1995024395A1 - Derives de quinoline utilises comme immunomodulateurs - Google Patents

Derives de quinoline utilises comme immunomodulateurs Download PDF

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Publication number
WO1995024395A1
WO1995024395A1 PCT/JP1995/000263 JP9500263W WO9524395A1 WO 1995024395 A1 WO1995024395 A1 WO 1995024395A1 JP 9500263 W JP9500263 W JP 9500263W WO 9524395 A1 WO9524395 A1 WO 9524395A1
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WIPO (PCT)
Prior art keywords
alkyl
alkoxy
methyl
hydroxy
compound
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PCT/JP1995/000263
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English (en)
Inventor
Masaaki Matsuo
Kiyoshi Tsuji
Glen W. Spears
Takashi Ogino
Hiroaki Nishimura
Takashi Tojo
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Fujisawa Pharmaceutical Co., Ltd.
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Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to AU18235/95A priority Critical patent/AU1823595A/en
Priority to JP7523351A priority patent/JPH09509957A/ja
Publication of WO1995024395A1 publication Critical patent/WO1995024395A1/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
    • C07D401/04—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 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
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D417/12—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 linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to new qumolme derivatives and pharmaceutically acceptable salts thereof which are useful as a medicament.
  • This invention relates to new qumolme derivatives. More particularly, this invention relates to new qumolme derivatives and pharmaceutically acceptable salts thereof which have pnarmacological activities, processes for preparation thereof, a pharmaceutical composition comprising tne same and a use of the same.
  • one object of this invention is to provide the new and useful qumolme derivatives and pharmaceutically acceptable salts thereof which possess a strong immunomodulatmg activity (e.g. an inhibitory activity on the production of an autoantiDody, etc.), anti-mflammatory activity and anti-cancer activity.
  • Another object of this invention is to provide processes for preparation of the qumolme derivatives and salts thereof.
  • a further object of this invention is to provide a pharmaceutical composition comprising said qumolme derivatives or a pharmaceutically acceptable salt thereof. Still further object of this invention is to provide a use of said qumolme derivatives or a pharmaceutically acceptable salt thereof as a medicament for the treatment and/or prevention of inflammatory conditions, various pains, collagen diseases, autoimmune diseases, various immunity diseases, cancer and the like in human being and animals .
  • R 1 is hydrogen, halogen, lower alkyl, lower alkoxy, mono (or di or tri) halo (lower) alkoxy or heterocyclic group
  • R- is hydroxy or protected hydroxy
  • R IS lower alkyl
  • R 4 is lower alkyl, lower alkenyl, lower alkoxy (lower) alkyl, cyclo (lower) alkyl or lower alkoxy (lower) alkoxy(lower) - - 3 - alkyl, and R ⁇ is aryl which may have suitable substituent (s) or heterocyclic group) , or
  • R° is hydrogen or lower alkyl
  • R J and R° are linked together to form a bivalent radical of the formula :
  • Z is 0 or S.
  • the object compound (I) of the present invention can be prepared by the following processes.
  • R 6 and X 1 are each a leaving group.
  • the starting compounds of the present invention can be prepared by the following processes.
  • ⁇ 2 is a leaving group
  • 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, ethanolamine 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, tart
  • lower is used to intend a group having 1 to 6, preferably 1 to 4, carbon atom(s), unless otherwise provided.
  • Suitable "lower alkyl” and “lower alkyl moiety" in the terms “lower alkoxy(lower) alkyl” and “lower alkoxy(lower) alkoxy(lower) alkyl” 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, and in which more preferable example may be C1-C5 alkyl.
  • Suitable "lower alkenyl” may include vinyl, 1- (or 2-)propenyl, 1- (or 2- or 3-)butenyl, 1- (or 2- or 3- or 4-)pentenyl, 1- (or 2- or 3- or 4- or 5-)hexenyl, methylvinyl, ethylvinyl, l-(or 2- or 3-)methyl-l- (or 2-)- propenyl, 1- (or 2- or 3-) ethyl-1- (or 2-)propenyl, 1- (or 2- or 3- or 4-)methyl-1- (or 2- or 3-)butenyl, and the like, in which more preferable example may be C2-C4 alkenyl.
  • Suitable “lower alkynyl” may include ethynyl, 1-propynyl, 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, and the like.
  • Suitable "lower alkoxy” and “lower alkoxy moiety" in the terms “mono (or di or tri) halo (lower) alkoxy”, “lower alkoxy(lower) lkyl” and “lower alkoxy(lower) alkoxy- (lower) alkyl” may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like.
  • Suitable “cyclo (lower) alkyl” may include cyclopropyl, cyclopentyl, cyclohexyl and the like.
  • Suitable “cyclo (lower) alkenyl” may include cyclohexenyl, cyclohexadienyl and the like.
  • Suitable "aryl” may include phenyl, naphthyl and the like.
  • Suitable "halogen” and “halogen moiety” in the term “mono (or di or tri) halo (lower) alkoxy” may include fluorine, bromine, chlorine and iodine.
  • Suitable “leaving group” may include acid residue, lower alkoxy as exemplified above, amino substituted with lower alkyl and aryl which may have suitable substituent (s) wherein lower alkyl moiety and aryl moiety are each as exemplified above, and the like.
  • Suitable "acid residue” may include halogen, acyloxy and the like.
  • Suitable "protected carboxy” may include esterified carboxy and the like.
  • suitable example of said ester may be the ones such as lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, etc.) ; lower alkenyl ester (e.g., vinyl ester, allyl ester, etc.) ; lower alkynyl ester (e.g., ethynyl ester, propynyl ester, etc.) ; lower alkoxy (lower) alkyl ester (e.g., methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester
  • - I I - phenyl (lower) alkyl ester which may have one or more suitable substituent (s) (e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis (methoxyphenyl)methyl ester, 3, 4-dimethoxybenzyl ester, 4-hydroxy-3, 5-di-t-butylbenzyl ester, etc.) ; aryl ester which may have one or more suitable substituent (s) such as substituted or unsubstituted phenyl ester (e.g., phenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, esityl ester, cumenyl ester, 4-chlorophenyl ester,
  • suitable substituent (s) e.g., benzyl ester
  • Suitable "hydroxy protective group” in the term “protected hydroxy” may include acyl, 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 (e.g., trimethylsilyl, t-butyldimethylsilyl, etc.), etc.], tetrahydropyranyl and the like.
  • suitable substituent e.g., benzyl, 4-methoxybenzyl, trityl, etc.
  • trisubstituted silyl e.g., tri (lower) alkylsilyl (e.g., trimethylsilyl, t-butyldimethylsilyl, etc.), etc.
  • Suitable “protected amino” may include 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.
  • suitable substituent e.g., benzyl, trityl, etc.
  • acyloxy and “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 :
  • alkanoyl e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl,
  • lower or higher alkoxycarbonyl e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.
  • lower or higher alkylsulfonyl e.g., methylsulfonyl, ethylsulfonyl, etc.
  • lower or higher alkoxysulfonyl e.g., methoxysulfonyl, ethoxysulfonyl, etc.
  • cyclo (lower) alkylcarbonyl e.g., cyclopentylcarbonyl, cyclohexylcarbonyl, etc.
  • Aromatic acyl such as aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.); ar (lower) alkanoyl [e.g., phenyl (lower) alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, pnenyiisobutanoyl,
  • aryloxycarbonyl e.g., phenoxycarbonyl, naphthyloxycarbonyl, etc.
  • aryloxy(lower) alkanoyl e.g., phenoxyacetyl, phenoxypropionyl, etc.
  • arylglyoxyloyl e.g., phenylglyoxyloyl, naphthylglyoxyloyl, etc.
  • arylsulfonyl e.g., phenylsulfonyl, p-tolylsulfonyl, etc.
  • or the like e.g., benzyloxycarbonyl, etc.
  • Heterocyclic acyl such as heterocycliccarbonyl; heterocyclic (lower) alkanoyl (e.g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl, heterocyclichexanoyl, etc.) ; heterocyclic (lower) alkenoyl (e.g., heterocyclicpropenoyl, he erocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl, etc.) ; heterocyclicglyoxyloyl; or the like; in which suitable "heterocyclic moiety" in the terms "heterocycliccarbonyl", “heterocyclic (lower) alkanoyl", heterocyclic (lower) alkenoyl” and “heterocyclicglyoxyloyl” as mentioned above means, in more detail, saturated or unsaturated, monocyclic or polycyclic hetero
  • heterocyclic group may be heterocyclic group such as unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4- triazolyl, 1H-1, 2, 3-triazolyl, 2H-1, 2, 3-triazolyl, etc.), tetrazolyl (e.g., IH-tetrazolyl, 2H-tetrazolyl, etc.), etc.
  • heterocyclic group such as unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrol
  • the acyl moiety as stated above may have one to ten, same or different, suitable substituent (s) such as lower alkyl as exemplified above, lower alkoxy as exemplified above, lower alkylthio wherein lower alkyl moiety is as exemplified above, lower alkylamino wherein lower alkyl moiety is as exemplified above, cyclo (lower) alkyl as exemplified above, cyclo (lower) alkenyl as exemplified above, halogen as exemplified above, aryl as exemplified above, amino, protected amino as exemplified above, hydroxy, protected hydroxy as exemplified above, cyano, nitro, carboxy, protected carboxy as exemplified above, sulfo, sulfamoyl, imino, oxo, amino (lower) alkyl wherein lower alkyl moiety is as exemplified above, carb
  • Suitable "substituent” in the term “aryl which may have suitable substituent (s) " may include lower alkyl as exemplified above, lower alkoxy as exemplified above, lower alkenyl as exemplified above, lower alkynyl as exemplified above, mono (or di or tri) halo (lower) alkyl wherein halogen moiety and lower alkyl moiety are each as exemplified above, mono (or di or tri) halo (lower ⁇ alkoxy wnerem halogen moiety and lower alkoxy moiety are each as exemplified above, lower alkoxy(lower) alkoxy wnerem lower alkoxy moiety is as exemplified above, cyclo (lower) alkyl as exemplified above, cyclo (lower) alkenyl as exemplified above, halogen as exemplified above, carboxy, protected carboxy as exemplified above,
  • Suitable "N-containmg heterocyclic group” may include unsaturated 3 to 8-membered (more preferably 5 or ⁇ -membered heteromonocyclic group containing 1 to 4- nitrogen atom(s), for example, pyrrolyl, pyrrolmyl, imidazolyl, pyrazolyl, dihydropyridyl, triazolyl (e.g. 4H- 1,2, 4-t ⁇ azolyl, 1H-1, 2, 3-tr ⁇ azolyl, 2H-1, 2, 3-tr ⁇ azolyl, etc.), tetrazolyl (e.g. IH-tetrazolyl, 2H-tetrazolyl, etc. ) , etc.
  • unsaturated 3 to 8-membered more preferably 5 or ⁇ -membered heteromonocyclic group containing 1 to 4- nitrogen atom(s)
  • pyrrolyl pyrrolmyl
  • imidazolyl pyrazolyl
  • amino substituted with lower alkyl and aryl which may have suitable substituent (s) may be N-lower alkyl-N-phenylamino, N-lower alkyl-N-halophenylamino and N-lower alkyl-N-lower alkoxyphenylam o.
  • the object compound (la) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (III) or a salt thereof.
  • Tne reaction is usually carried out m a conventional solvent such as chloroform, ether, tetranydrofuran, benzene, N,N-dimethylformamide, N,N-dimethylacetamide or any other solvents which do not adversely influence the reaction, or the mixture thereof.
  • a conventional solvent such as chloroform, ether, tetranydrofuran, benzene, N,N-dimethylformamide, N,N-dimethylacetamide or any other solvents which do not adversely influence the reaction, or the mixture thereof.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the reaction is usually carried out m the presence of an inorganic or an organic base such as an alkali metal hydroxide, an alkali metal hvdrogencarbonate, alkali metal carbonate, alkali metal hydride (e.g., sodium hydride, etc.), alkali metal acetate, di (lower) alkylamme (e.g., diisopropylamme, etc.), tri (lower) alkylamme, pyridme, lutidme, picolme, dimethylammopyridme, N- (lower) alkylmorpholme, N-N-di (lower) alkylbenzylamme, N,N-di (lower) alkylamlme or the like.
  • an inorganic or an organic base such as an alkali metal hydroxide, an alkali metal hvdrogencarbonate, alkali metal carbonate, alkali metal hydride (e.g., sodium
  • the compound (la) or a salt thereof can be prepared by subjecting the compound (VI) or a salt thereof to cyclization reaction.
  • This reaction is usually carried out m a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichlo ⁇ de, chloroform, 5/24395
  • a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichlo ⁇ de, chloroform, 5/24395
  • the reaction temperature is net critical and the reaction is usually carried out under cooling to heating.
  • the reaction is usually carried out by a method using 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 hydrogencarbonate, potassium hydrogencarbonate, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), tri (lower) alkylamine (e.g., trimethylamine, triethylamine, diisopropylethylamine, etc.), alkali metal hydride (e.g., sodium hydride, etc.), alkali metal (lower) alkoxide (e.g., sodium methoxide, sodium ethoxide, etc.), pyridine, lutidine, picoline, dimethylaminopyridine, N-
  • the compound (III) or a salt thereof can be prepared by reacting the compound (IV) or a salt thereof with the compound (V) 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, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • the reaction temperature is not critical and the reaction is usually carried out under warming to heating. When the starting compounds are in liquid, they can be used also as a solvent.
  • the compound (VI) or a salt thereof can be prepared by reacting the compound (VII) or its reactive derivative at the i ino group, or a salt thereof with the compound (VIII) or its reactive derivative, or a salt thereof.
  • Suitable reactive derivative at the imino group of the compound (VII) may include a silyl derivative formed by the reaction of the compound (VII) with a silyl compound such as N, O-bis (trimethylsilyl) acetamide, N-trimethylsilylacetamide or the like; a derivative formed by the reaction of the compound (VII) with phosphorus trichloride or phosgene, and the like.
  • Suitable reactive derivative of the compound (VIII) may include an acid halide, an acid anhydride, an activated ester, and the like.
  • the suitable example may be an acid chloride; acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, alkanesulfonic acid (e.g., methanesulfonic acid, ethanesulfonic acid, etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g., pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.); aromatic carboxylic acid (e.g., benzoic acid, etc.); a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole
  • N-hydroxyphthalimide 1-hydroxy-6-chloro-lH-benzotriazole, etc.
  • reactive derivatives can optionally be selected from them accordingly to the kind of the compound (VIII) to be used.
  • the reaction is usually carried out m a conventional solvent such as acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, -dimethylformamide, pyridine or any other organic solvents which do not a ⁇ versely affect the reaction, or the mixture thereof.
  • a conventional solvent such as acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, -dimethylformamide, pyridine or any other organic solvents which do not a ⁇ versely affect the reaction, or the mixture thereof.
  • the reaction is preferably carried out m the presence of the dehydrating agent such as Molecular Sieves
  • the reaction is preferably carried out the presence of a conventional condensing agent such as N,N 1 -dicyclohexylcarbodnmide;
  • the reaction may be also be carried out in the
  • an organic or inorganic base such as an alkali metal bicarbonate, tri (lower) alkylamme, pyridine, N- (lower) alkylmorphorme, N,N-di (lower) alkylbenzylamme, or the like.
  • reaction temperature is not critical, and the l*-** 1 reaction is usually carried out under cooling to heating.
  • Preferred embodiments of the object compound (I) are as follows.
  • R 1 is hydrogen, halogen, lower alkyl, lower alkoxy, mono (or di or tri) halo (lower) alkoxy(more preferably trihalo (lower) alkoxy) or pyrrolyl,
  • R 2 is hydroxy or acyloxy
  • R 3 is lower alkyl, is a group of the formula
  • R 4 is lower alkyl, lower alkenyl, lower alkoxy (lower) alkyl, cyclo (lower) alkyl or lower 5 alkoxy (lower) alkoxy (lower) alkyl, and R is phenyl which may have 1 to 3 (more preferably one or two) suitable substituent (s) [more preferably substituent (s) selected from the group consisting of lower alkyl, lower alkoxy, halogen, mono (or di or tri) halo (lower) alkyl (more preferably trihalo (lower) alkyl) , mono (or di or tri)halo (lower) alkoxy (more preferably
  • R' is hydrogen or halogen
  • R is hydrogen or lower alkyl, or
  • R and R° are linked together to form a bivalent radical 0 of the formula :
  • Z is 0 or S. 5
  • More preferred embodiments of the object compound (. ' are as follows.
  • R- * - is hydrogen, halogen, lower alkyl, lower alkoxy, 0 trihalo (lower) alkoxy or pyrrolyl, R-2 is hydroxy, R 3 is lower alkyl, is a group of the formula : 5 - 24 -
  • R 4 is lower alkyl, lower alkenyl, lower alkoxy(lower) alkyl, cyclo (lower) alkyl or lower alkoxy(lower) alkoxy(lower) alkyl
  • R 5 is phenyl, lower alkylphenyl, lower alkoxyphenyl, more (or di)halophenyl, trihalo (lower) alkylphenyl, trihalo (lower) alkoxyphenyl, lower alkoxy(lower) alkoxyphenyl, lower alkylthiazolylphenyl, thienyl or methylenedioxyphenyl
  • R is hydrogen or halogen
  • R is hydrogen or lower alkyl, or
  • R J and R° are linked together to form a bivalent radical of the formula :
  • Z is 0 or S.
  • Suitable salts of the object and starting compounds in Processes (1), (2), (A) and (B) can be referred to the ones as exemplified for the compound (I) .
  • the new quinoline derivatives (I) and a pharmaceutically acceptable salt thereof of the present invention pcssess a strong immunomodulating activity (e.g. an inhibitory activity on the production of an autoantibody, an inhibitory activity on the production of an antibody, etc.), anti-inflammatory activity and anti- cancer activity and therefore are useful as an immunomodulat g agent (e.g. an inhibitor on the production of an autoantibody, an inhibitor on the production of an antibody, etc.), anti-mfiammatory agent and anti-cancer agent.
  • a strong immunomodulating activity e.g. an inhibitory activity on the production of an autoantibody, an inhibitory activity on the production of an antibody, etc.
  • an immunomodulat g agent e.g. an inhibitor on the production of an autoantibody, an inhibitor on the production of an antibody, etc.
  • anti-mfiammatory agent e.g. an inhibitor on the production of an autoantibody, an inhibitor on the production of an antibody, etc.
  • the new qumolme derivatives (I) and a pharmaceutically acceptable salt thereof can be used for the treatment and/or prevention of inflammatory conditions, various pains, collagen diseases, autoimmune diseases, various immunity diseases, cancer, and the like human bemgs or animals, and more particularly for the treatment and/or prevention of inflammation and pain m joint and muscle [e.g. 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 m which inflammation is involved [e.g.
  • asthma wheezing fever
  • bronchitis pigeon fancier's disease
  • farmer's lung etc.
  • condition of the gastrointestinal tract associated with inflammation e.g. aphthous ulcer, Crohn's disease, atrophic gastritis, gastritis va ⁇ aloforme, ulcerative colitis, coeliac disease, regional lleitis, irritable bowel syndrome, etc.
  • gingivitis (inflammation, pain and tumescence after operation or injury) , pyrexia, pain and other conditions associated w th inflammation, rejection by transplantation, systemic lupus erythematosus, scleroderma, polymyositis, polychondritis, periarteritis nodosa, ankylosmg spondytis, inflammatory chronic renal condition [e.g.
  • glomeruloneph ⁇ tis membranous nephritis, etc.
  • rheumatic fever Sjogren's syndorome
  • Behcet disease thyroiditis
  • type I diabetes dermatomyositis
  • chronic active hepatitis 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.
  • myasthenia gravis uveitis, contact dermatitis, psoriasis, Kawasaki disease, sarco dosis, Wegner's granulomatosis, Hodgkm's disease, cancer [e.g. lung carcinoma, stomach carcinoma, colon cancer, renal carcinoma, nepatoma, etc.], and the like.
  • mice Six weeks old female (57BL/6 x DBA/2) F 1 and DBA/2 mice were used. Graft-versus-host (GVH) disease was induced m (57BL/6 x DBA/2) F ] _ mice witn two injections of DBA/2 spleen cells given 5 days apart. Each injection contained 5 x 10 7 cells. From 3 days after the second cell injection, drug was administered orally once a day for 8 weeks .
  • VH graft-versus-host
  • mice Female (C57BL/6 x DBA/2) Fi mice (6 weeks old) were immunized i.v. with 2, , 6-trinitrophenol-conjugated lipopolysaccharide (TNP-LPS) (10 ⁇ g/mouse) on day 0. Mice were bled on day 4 after immunization, and anti-TNP IgM levels in each serum were determined by ELISA.
  • TNP-LPS 6-trinitrophenol-conjugated lipopolysaccharide
  • mice were randomly divided after immunization (7 mice/group) and were injected P.O. with the test compound on day 0 and day 1.
  • - 28 - acceptable salts can usually be administered to mammals including human being in the form of a conventional pharmaceutical composition such as oral dosage form (e.g., capsule, micro-capsule, tablet, granule, powder, troche, syrup, aerosol, inhalation, suspension, emulsion, etc.), injection dosage form, suppository, ointment, or the like.
  • oral dosage form e.g., capsule, micro-capsule, tablet, granule, powder, troche, syrup, aerosol, inhalation, suspension, emulsion, etc.
  • injection dosage form e.g., suppository, ointment, or the like.
  • the pharmaceutical composition of this invention can contain various organic or inorganic carrier materials, which are conventionally used for pharmaceutical purpose such as excipient (e.g., sucrose, starch, mannit, sorbit, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, etc.), binding agent (e.g., cellulose, methyl cellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arable, polyethyleneglycol, sucrose, starch, etc.), disintegrator (e.g., starch, carboxymethyl cellulose, calcium salt of carboxymethyl cellulose, hydroxypropylstarch, sodium glycolestarch, sodium bicarbonate, calcium phosphate, calcium citrate, etc.), lubricant (e.g., magnesium stearate, talc, sodium laurylsulfate, etc.), flavoring agent (e.g., citric acid, mentol, glycme, orange powders, etc.), preserv
  • IR (Film) 3400, 2990, 2900, 2820, 1680, 1620,
  • the gummy insoluble material was collected by filtration, washed with water, and dissolved in dichloromethane, and extracted with 0.83 equivalent (7 mmol) of sodium hydroxide solution. To the resulting aqueous phase was added 0.12 equivalent (1 mmol) hydrochloric acid, and the solution was washed with dichloromethane. This process (addition of 0.12 equivalent hydrochloric acid, then dichloromethane wash) was repeated. The desired dichloromethane fractions (the first two washes) were combined, dried and evaporated.
  • N,N'-dimethyl-N,N*- diphenylmalondithioamide (3.14 g) in N,N-dimethylacetamide (40 ml) was added sodium hydride (60%, 0.42 g) at 5°C.
  • the mixture was stirred at room temperature for 1 hour.
  • 6-chloro-l-methyl-2H-3, l-benzoxazine-2, 4 (IH) -dione (2,12 g) was added thereto and the resulting mixture was stirred at 120°C for 30 minutes.
  • the reaction mixture was poured into ice-water (400 ml) and acidified with 3N hydrochloric acid (10 ml) .
  • Example 3 The following compounds were obtained according to similar manners to those of Examples 1 and 2.
  • Example 5 To a solution of ethyl 5-chloro-2- [N- [3- [N-methyl- N- (2-tn ⁇ enyl) ammo] -3-th ⁇ oxoprop ⁇ onyl] -N- methylammo]benzoate (278 mg) in ethanol (3.4 ml) at 5°C was adde ⁇ sodium ethoxide (60 mg) . The mixture was stirred at 5°C for 20 minutes and 3N hydrochloric acid (1 ml), then water (30 ml) were added thereto.

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Abstract

L'invention concerne des dérivés de quinoline de formule (I) ainsi qu'un sel pharmaceutiquement acceptable de ces derniers, utilisés comme médicament. Dans ladite formule (I), R1 représente hydrogène, halogène, alkyle inférieur, etc., R2 représente hydroxy ou hydroxy protégé, R3 représente alkyle inférieur, etc., (a) est un groupe de formule (i) (dans laquelle R4 représente alkyle inférieur, alcényle inférieur, alcoxy inférieur-alkyle (inférieur), cyclo-alkyle (inférieur) ou alcoxy inférieur alcoxy-alkyle(inférieur), et R5 représente aryle ayant éventuellement un ou plusieurs substituant(s) ou un groupe hétérocycliques appropriés), etc., R7 représente hydrogène ou halogène, R8 représente hydrogène ou alkyle inférieur, etc., et Z correspond à O ou S.
PCT/JP1995/000263 1994-03-07 1995-02-22 Derives de quinoline utilises comme immunomodulateurs WO1995024395A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU18235/95A AU1823595A (en) 1994-03-07 1995-02-22 Quinoline derivatives as immunomodulators
JP7523351A JPH09509957A (ja) 1994-03-07 1995-02-22 免疫調節剤としてのキノリン誘導体

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9404378A GB9404378D0 (en) 1994-03-07 1994-03-07 Quinoline derivatives
GB9404378.3 1994-03-07

Publications (1)

Publication Number Publication Date
WO1995024395A1 true WO1995024395A1 (fr) 1995-09-14

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JP (1) JPH09509957A (fr)
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GB (1) GB9404378D0 (fr)
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WO (1) WO1995024395A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000003992A1 (fr) * 1998-07-15 2000-01-27 Active Biotech Ab Derives de quinoline
WO2000003991A1 (fr) * 1998-07-15 2000-01-27 Active Biotech Ab Derives de quinoline
US6121287A (en) * 1998-07-15 2000-09-19 Active Biotech Ab Quinoline derivatives
US6133285A (en) * 1998-07-15 2000-10-17 Active Biotech Ab Quinoline derivatives
WO2001030758A1 (fr) * 1999-10-25 2001-05-03 Active Biotech Ab Medicaments de traitement de tumeurs malignes
US6395750B1 (en) 1999-10-25 2002-05-28 Active Biotech Ab Drugs for the treatment of malignant tumors
EP1447094A1 (fr) * 2001-10-22 2004-08-18 Santen Pharmaceutical Co., Ltd. Remedes contre le prurit
US7317107B2 (en) 2002-02-15 2008-01-08 Astellas Pharma Inc. Imidazole 4-carboxamide compounds with adenosine deaminase inhibiting activity

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HUP0100407A3 (en) * 1997-12-15 2002-01-28 Fujisawa Pharmaceutical Co Process for producing quinoline carbamoyl and thio carbamoyl derivatives and intermediates
JP2007191495A (ja) * 2001-10-22 2007-08-02 Santen Pharmaceut Co Ltd 掻痒治療剤

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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
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
WO1994029295A1 (fr) * 1993-06-04 1994-12-22 Fujisawa Pharmaceutical Co., Ltd. Derives heterocycliques a activite immunomodulante

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
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
WO1994029295A1 (fr) * 1993-06-04 1994-12-22 Fujisawa Pharmaceutical Co., Ltd. Derives heterocycliques a activite immunomodulante

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6593343B2 (en) 1998-07-15 2003-07-15 Active Biotech Ab Quinoline derivatives
AP1366A (en) * 1998-07-15 2005-01-26 Active Biotech Ab Quinoline derivatives.
US6121287A (en) * 1998-07-15 2000-09-19 Active Biotech Ab Quinoline derivatives
US6133285A (en) * 1998-07-15 2000-10-17 Active Biotech Ab Quinoline derivatives
HRP20010039B1 (en) * 1998-07-15 2009-04-30 Active Biotech Ab Quinoline derivatives
CZ300229B6 (cs) * 1998-07-15 2009-03-25 Active Biotech Ab Deriváty chinolinu
WO2000003991A1 (fr) * 1998-07-15 2000-01-27 Active Biotech Ab Derives de quinoline
US6605616B1 (en) 1998-07-15 2003-08-12 Active Biotech Ab Quinoline derivatives
WO2000003992A1 (fr) * 1998-07-15 2000-01-27 Active Biotech Ab Derives de quinoline
CN1114597C (zh) * 1998-07-15 2003-07-16 活跃生物技术有限公司 喹啉衍生物
US6395750B1 (en) 1999-10-25 2002-05-28 Active Biotech Ab Drugs for the treatment of malignant tumors
WO2001030758A1 (fr) * 1999-10-25 2001-05-03 Active Biotech Ab Medicaments de traitement de tumeurs malignes
EP1447094A1 (fr) * 2001-10-22 2004-08-18 Santen Pharmaceutical Co., Ltd. Remedes contre le prurit
EP1447094A4 (fr) * 2001-10-22 2005-10-26 Santen Pharmaceutical Co Ltd Remedes contre le prurit
US7317107B2 (en) 2002-02-15 2008-01-08 Astellas Pharma Inc. Imidazole 4-carboxamide compounds with adenosine deaminase inhibiting activity

Also Published As

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TW350838B (en) 1999-01-21
CA2214521A1 (fr) 1995-09-14
JPH09509957A (ja) 1997-10-07
AU1823595A (en) 1995-09-25
GB9404378D0 (en) 1994-04-20

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