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WO1992018483A1 - Quinoline derivatives - Google Patents

Quinoline derivatives Download PDF

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Publication number
WO1992018483A1
WO1992018483A1 PCT/JP1992/000510 JP9200510W WO9218483A1 WO 1992018483 A1 WO1992018483 A1 WO 1992018483A1 JP 9200510 W JP9200510 W JP 9200510W WO 9218483 A1 WO9218483 A1 WO 9218483A1
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WO
WIPO (PCT)
Prior art keywords
compound
methyl
salt
hydroxy
formula
Prior art date
Application number
PCT/JP1992/000510
Other languages
French (fr)
Inventor
Masaaki Matsuo
Kiyoshi Tsuji
Katsuya Nakamura
Glen W. Spears
Original Assignee
Fujisawa Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to AU15487/92A priority Critical patent/AU656576B2/en
Priority to EP92908346A priority patent/EP0639182A1/en
Priority to JP4507784A priority patent/JPH06506925A/en
Publication of WO1992018483A1 publication Critical patent/WO1992018483A1/en

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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
    • C07D215/36—Sulfur atoms
    • 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
    • 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
    • C07D401/02—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
    • 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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • 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
    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • C07D417/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • 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

Definitions

  • This invention relates to new quinoline derivatives and pharmaceutically acceptable salts thereof which are useful as a medicament.
  • guinoline derivatives have been known as described, for example, in U.S. Patent 4,547,511 and U.S. Patent 4,127,574.
  • This invention relates to new guinoline derivatives. More particularly, this invention relates to new guinoline derivatives and pharmaceutically acceptable salts thereof which have pharmacological activities, processes for preparation thereof, a pharmaceutical composition
  • one object of this invention is to provide the new and useful guinoline 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 guinoline derivatives and salts thereof.
  • a further object of this invention is to provide a pharmaceutical composition comprising said guinoline derivatives or a pharmaceutically acceptable salt thereof.
  • Still further object of this invention is to provide a use of said guinoline 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.
  • the object guinoline derivatives of the present invention are novel and can be represented by the
  • R 1 is lower alkyl or aryl which may have suitable substituent(s),
  • R 2 is hydroxy, protected hydroxy, lower alkoxy, halogen, amino, substituted amino, mercapto or protected mercapto,
  • R 3 is hydrogen, lower alkyl, lower alkoxy(lower)- alkyl or ar( lower)alkyl and
  • R 8 is hydrogen, or
  • R 3 and R 8 are linked together to form lower alkylene
  • R 4 is an organic group
  • Z is O or S
  • n 0, 1 or 2.
  • the object compound (I) of the present invention can be prepared by the following processes.
  • Process (1) (1)
  • R 1 , R 2 , R 3 , R 4 , R 8 , Z and n are each as defined above,
  • R 2 a is halogen
  • R 2 b is amino or substituted amino
  • R 2 c is protected mercapto
  • R 2 d is lower alkoxy
  • R 4 a is protected carboxy
  • R 4 a is acyl having protected carboxy
  • R 4 c is acyl having carboxy
  • R 2 d is acyl having nitro
  • R 4 e is acyl having amino
  • R f 4 is acyl having acylammo
  • R 6 is a leaving group
  • X 1 , X 2 and X 3 are each as a leaving group, M 1 and M 2 are each as an alkali metal and m is 1 or 2.
  • the starting compounds or salts thereof can be prepared by the following processes.
  • R 1 , R 3 , R 4 , R 2 , R 8 , X , Z and n are each as
  • R 2 a is lower alkyl, lower alkoxy(lower)alkyl
  • R 2 , R 9 , R 10 , X 4 , X 5 and X are each as a leaving group
  • R 12 is protected carboxy.
  • Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and may include e.g. 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,
  • 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, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.
  • a salt with a basic or acidic amino acid e.g.
  • lower is used to intend a group having 1 to 6 carbon atom(s), unless otherwise provided.
  • Suitable "lower alkyl” and “lower alkyl moiety" in the terms “lower alkoxy( lower) alkyl and “ar( lower) alkyl” may include straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl,
  • neopentyl, hexyl, and the like in which more preferable example may be C 1 -C 5 alkyl.
  • Suitable "lower alkoxy” and “lower alkoxy moiety" in the term “lower alkoxy( lower) alkyl may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like.
  • aromatic( lower) alkyl may include phenyl, naphthyl and the like.
  • Suitable "lower alkylene” may include straight or branched one such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene,
  • methyImethylene, ethylethylene, propylene, and the like in which more preferable example may be C 1 -C 4 alkylene and the most preferable one may be ethylene.
  • Suitable "halogen” may include chlorine, bromine, iodine and fluorine.
  • Suitable "alkali metal” may include sodium, potassium and the like.
  • Suitable substituent in the term "aryl which may have suitable substituent(s)" may include lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, tert-pentyl, hexyl, etc.), lower alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, tert-butoxy, pentyloxy, ne ⁇ pentyloxy,
  • lower alkyl e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, ne ⁇ pentyloxy,
  • lower alkenyl e.g., vinyl, 1-propenyl, allyl, 1-methylallyl, 1 or 2 or
  • bromomethyl dibromomethy1, tribromomethyl, 1 or
  • halogen e.g., chlorine, bromine, fluorine and iodine
  • phenyl(lower) alkyl e.g., benzyl, phenethyl, phenylpropyl, etc.
  • carboxy(lower) alkyl wherein lower alkyl moiety can be referred to the ones as exemplified above
  • protected carboxy(lower) alkyl wherein lower alkyl moiety can be referred to the ones as exemplified above
  • protected carboxy moiety can be referred to the ones as exemplified below
  • amino, protected amino, di( lower)alkylamino e.g., dimethylamino, diethylamino, diisopropylamino
  • ethylisopropylamino, etc. hydroxy(lower) alkyl, protected hydroxy(lower) alkyl, nitro, acyl, cyano, mercapto, lower alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.), imino, and the like.
  • Suitable "acyl” may include carbamoyl, thiocarbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or
  • heterocyclic acyl which is referred to as heterocyclic acyl.
  • Suitable example of said acyl may be illustrated as follows :-
  • Aliphatic acyl such as lower or higher alkanoyl (e.g.
  • alkoxycarbonyl e.g. methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.
  • alkylsulfonyl e.g. methylsulfonyl, ethylsulfonyl, etc.
  • alkoxysulfonyl e.g. methoxysulfonyl, ethoxysulfonyl, etc.
  • aminosulfonyl 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,
  • phenylisobutylyl phenylpentanoyl, phenylhexanoyl, etc.
  • naphthyl(lower)alkanoyl e.g. naphthylacetyl
  • ar(lower) alkenoyl e.g. phenyl(lower) alkenoyl (e.g. phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc.),
  • naphthyl(lower) alkenoyl e.g. naphthylpropenoyl
  • phenyl(lower) alkoxycarbonyl e.g. benzyloxycarbonyl, etc., etc.
  • ar(lower)cycloalkylcarbonyl e.g.
  • phenyl(lower) cycloalkylcarbonyl e.g., 1-phenyl-1- cyclopropylcarbonyl, 1-phenyl-1-cyclopentylcarbonyl, etc., etc.
  • aryloxycarbonyl e.g., phenoxycarbonyl
  • aryloxy(lower)alkanoyl e.g. phenoxyacetyl
  • arylglyoxyloyl e.g. phenylglyoxyloyl
  • arenesulfonyl e.g. benzenesulfonyl
  • ar(lower)alkylsulfonyl e.g.
  • phenyl(lower)alkylsulfonyl (e.g. benzylsulfonyl, etc.), etc.]; or the like.
  • Heterocyclic acyl such as
  • heterocyclic(lower)alkanoyl e.g., heterocyclicacetyl, heterocyclcpropanoyl, heterocyclicbutanoyl,
  • heterocyclic(lower)alkenoyl e.g. heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl, etc.
  • heterocyclicglyoxyloyl e.g. thiazolylglyoxyloyl
  • heterocycliccarbonyl heterocyclic(lower) alkanoyl
  • 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
  • 4-nitrogen atom( s ) for example , pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide,
  • triazolyl e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.
  • tetrazolyl e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.
  • 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.
  • unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) for example, benzodioxolyl (e.g.
  • acyl moiety as stated above may have one to ten, 1 same or different, suitable substituent(s) such as lower alkyl;
  • lower alkylthio e.g. methylthio, ethylthio, etc.
  • lower alkylamino e.g. methylamino, etc.
  • cycloalkyl e.g. cyclopentyl, cyclohexyl, etc.
  • lower cycloalkenyl e.g. cyclohexenyl, etc.
  • halogen amino; protected amino; hydroxy; protected hydroxy; cyano; nitro; carboxy; protected carboxy; sulfo; sulfamoyl; imino; oxo; amino(lower)alkyl (e.g. aminomethyl, aminoethyl, etc.); carbamoyloxy; hydroxy(lower)alkyl (e.g. hydroxymethyl, 1 or 2-hydroxyethyl, 1 or 2 or 3-hydroxypropyl, etc.);
  • ar( lower)alkyl e.g. phenyl(lower)alkyl (e.g., benzyl, phenylpropyl, phenylbutyl, etc.), etc.];
  • aryl which may have 1 to 3, same or different, suitable substituent(s) [e.g., lower alkyl; halogen; lower alkoxy; lower alkylthio, di ( lower) alkylamino (e.g., dimethylamino, diethylamino, dipropylamino, etc.); cyano; mono(or di or tri)halo(lower) alkyl (e.g., fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, dichloromethyl,
  • suitable substituent(s) e.g., lower alkyl; halogen; lower alkoxy; lower alkylthio, di ( lower) alkylamino (e.g., dimethylamino, diethylamino, dipropylamino, etc.); cyano; mono(or di or tri)halo(lower) alkyl (e.g., fluoromethyl, chloromethyl, bromomethyl, difluoromethyl,
  • carboxy ; protected carboxy [e.g., esterified carboxy ⁇ e.g. lower alkoxycarbonyl (e.g., methoxycarbonyl,
  • acyl e.g., lower alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, etc.), etc.]; nitro; amino; protected amino
  • acylamin ⁇ ⁇ e.g., lower alkanoylamino (e.g.,
  • heterocyclic group which may have suitable substituent(s) [e.g., lower alkyl; lower alkoxy; lower alkylthio; lower alkylamino; lower cycloalkyl; lower cycloalkenyl; halogen; amino; protected amino, etc.]; or the like.
  • Suitable "protected hydroxy” may be acyloxy group or the like.
  • Suitable "protected mercapto" may be acylthio group or the like.
  • Suitable “substituted amino” may be protected amino or lower alkylamino or the like.
  • Suitable "protected amino” may be acylamino group or the like.
  • acyl moiety in the terms “acyloxy”, “acylthio” and “acylamino” can be referred to the ones as exemplified above.
  • lower alkyl moiety in the term “lower alkylamino” can be referred to the ones as exemplified above.
  • Suitable “leaving group” may include lower alkoxy
  • aryloxy e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, etc.
  • aryloxy e.g.
  • acid residue may be halogen (e.g. chlorine, bromine, iodine, etc.), sulfonyloxy (e.g.
  • Suitable “amidated carboxy” may include carbamoyl which may be substituted with one or two suitable
  • Suitable “organic group” may include lower alkyl, lower alkenyl, lower alkynyl, aryl, ar(lower) alkyl, carboxy, ar(lower)alkylsulfinyl, ar( lower)alkylthio, cyano, acyl, heterocyclic group which may have suitable substituent(s), and the like.
  • Suitable "lower alkenyl” may include vinyl,
  • Suitable "lower alkynyl” may include ethynyl,
  • aromatic(lower)alkylthio can be referred to the ones as exemplified above.
  • acyl can be referred to the ones as exemplified above.
  • Suitable "heterocyclic group” can be referred to the ones as exemplified above.
  • Suitable "substituent" in the term “heterocyclic group which may have suitable substituent(s)” may include lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl,
  • lower alkoxy e.g., methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, tert-butoxy, pentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, etc.
  • lower alkenyl e.g., vinyl, 1- ⁇ ropenyl, allyl
  • lower alkynyl e.g., ethynyl, 1-propynyl, propargyl
  • 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 and 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.),
  • halogen e.g., chlorine, bromine, fluorine and iodine
  • carboxy protected carboxy, hydroxy, protected hydroxy, aryl (e.g., phenyl, naphthyl, etc.), ar( lower)alkyl such as
  • ethylisopropylamino, etc. hydroxy( lower)alkyl, protected hydroxy( lower)alkyl, nitro, acyl, cyano, mercapto, lower alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.), imino, and the like.
  • substituent(s)" may include lower alkyl
  • lower alkylthio e.g. methylthio, ethylthio, etc.
  • lower alkylamino e.g. methylamino, etc.
  • cycloalkyl e.g. cyclopentyl, cyclohexyl, etc.
  • hydroxy(lower) alkyl e.g. hydroxymethyl, 1 or 2-hydroxyethyl, 1 or 2 or 3
  • ar( lower) alkyl e.g., phenyl (lower) alkyl (e.g., benzyl, phenylpropyl, phenylbutyl, etc.), etc.];
  • aryl which may have 1 to 3, same or different, suitable substituent( s) [e.g., lower alkyl; halogen; lower alkoxy; lower alkylthio; di(lower)alkylamino (e.g., dimethylamino, diethylamino, dipropylamino, etc.); cyano;
  • suitable substituent( s) e.g., lower alkyl; halogen; lower alkoxy; lower alkylthio; di(lower)alkylamino (e.g., dimethylamino, diethylamino, dipropylamino, etc.); cyano;
  • mono(or di or tri)halo(lower) alkyl e.g., fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl,
  • carboxy protected carboxy [e.g. esterified carboxy ⁇ e.g., lower alkoxycarbonyl (e.g., methoxycarbonyl,
  • acyl e.g., lower alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, etc.), etc.]; nitro; amino; protected amino
  • acylamino ⁇ e.g., lower alkanoylamino (e.g.,
  • A is lower alkylene as exemplified above; or heterocyclic group which may have suitable substituent(s) [e.g. lower alkyl; lower alkoxy; lower alkylthio;
  • Suitable "heterocyclic group” can be referred to the ones as exemplified above.
  • Suitable “protected carboxy” may include esterified carboxy and the like.
  • An suitable examples of said ester moiety 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, 1-cyclopropylethyl ester, etc.);
  • lower alkenyl ester e.g., vinyl ester, allyl ester, etc.
  • lower alkynyl ester e.g., ethynyl ester, propynyl ester, etc .
  • lower alkoxyalkyl ester e.g., methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, etc.
  • lower alkylthioalkyl ester e.g., methylthiomethy1 ester, ethylthiomethyl ester, ethylthioethyl ester,
  • mono(or di or tri)halo(lower,)alkyl ester e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.
  • lower alkanoyloxy( lower)alkyl ester e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester,
  • lower alkanesulfonyl(lower)alkyl ester e.g. mesylmethyl ester, 2-mesylethyl ester etc.
  • ar( lower) alkyl ester for example, phenyl(lower)alkyl ester which may have one or more suitable substituent(s)
  • benzyl ester 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis (methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester,
  • substituent(s) such as substituted or unsubstituted phenyl ester (e.g., phenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester,
  • lower alkylthioester e.g. methylthioester
  • Suitable "heterocyclic group containing at least one nitrogen atom” may include
  • 4-nitrogen atom(s) for example, pyrrolyl, pyrr ⁇ linyl, imidazolyl, pyrazolyl, dihydropyridyl, pyrazinyl,
  • nitrogen atom(s) for example pyrrolidinyl
  • dihydrobenzoxazinyl e.g. 2H-3,4-dihydro-1,4-benzoxazinyl, etc.
  • dihydrobenzothiazinyl e.g., 2H-3,4-dihydrobenzothiazinyl, etc.
  • dihydrobenzothiazinyl e.g., 2H-3,4-dihydrobenzothiazinyl, etc.
  • 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.
  • reaction is usually carried out in a conventional solvent such as chloroform, ether, tetrahydrofuran, benzene, N,N-dimethylformamide, N,N-dimethylacetamide or any other organic solvent which does not adversely
  • a conventional solvent such as chloroform, ether, tetrahydrofuran, benzene, N,N-dimethylformamide, N,N-dimethylacetamide or any other organic solvent which does not adversely
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the reaction is usually carried out in the presence of an inorganic or an organic base such as an alkali .metal hydroxide, an alkali metal hydrogencarbonate, alkali metal carbonate, alkali metal hydride (e.g., sodium hydride, etc.), alkali metal acetate, di ( lower) alkylamine (e.g., diisopropylamine, etc.), tri (lower) alkylamine, pyridine base (e.g., pyridine, lutidine, picoline,
  • an inorganic or an organic base such as an alkali .metal hydroxide, an alkali metal hydrogencarbonate, alkali metal carbonate, alkali metal hydride (e.g., sodium hydride, etc.), alkali metal acetate, di ( lower) alkylamine (e.g., diisopropylamine, etc.), tri (lower) alkylamine, pyridine base (e.g., pyridine,
  • N-(lower) alkylmorpholine N,N-di(lower) alkylbenzylamine, N,N-di(lower) alkylaniline or the like.
  • the compound (Ic) or a salt thereof can be prepared by subjecting the compound (lb) or a salt thereof to oxidation reaction.
  • Oxidation is carried out in a conventional manner, which is capable of oxidizing a sulfur atom to an oxidized sulfur atom
  • suitable oxidizing reagent may be oxygen acid such as periodate (e.g. sodium periodate, potassium periodate, etc.), peroxy acid such as peroxybenzoic acids (e.g. peroxybenzoic acid, m-chloroperoxybenzoic acid, etc.), and the like.
  • the reaction is usually carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, dichloromethane, chloroform, N,N-dimethyl acetamide, N,N-dimethylformamide or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, dichloromethane, chloroform, N,N-dimethyl acetamide, N,N-dimethylformamide or any other organic solvent which does not adversely influence the reaction.
  • alcohol e.g., methanol, ethanol, isopropyl alcohol, etc.
  • tetrahydrofuran e.g., methanol, ethanol, isopropyl alcohol, etc.
  • reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the compound (Ie) or a salt thereof can be prepared by subjecting the compound (Id) or its reactive derivative at the carboxy group or a salt thereof to amidation reaction.
  • Suitable amidating reagent to be used in the present amidation reaction may include a compound of the formula :
  • Suitable reactive derivative of the compound (XXIII) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (XXIII) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (XXIII) with a silyl compound such as
  • Suitable reactive derivative at the carboxy group of the compound (Id) 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,
  • 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
  • N-hydroxyphthalimide 1-hydroxy-1H-benzotriazole, etc.]
  • These reactive derivatives can optionally be selected from them according to the kind of the
  • 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'-dicyclohexyl ⁇ arbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide;
  • N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide; N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;
  • oxychloride phosphoryl chloride
  • phosphorus trichloride phosphorus trichloride
  • thionyl chloride phosphorus trichloride
  • 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.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
  • the compound (Id) or a salt thereof can be prepared by subjecting the compound (If) or a salt thereof to elimination reaction of the carboxy protective group in R a 4 .
  • 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,
  • an alkali metal e.g. sodium, potassium, etc.
  • an alkaline earth metal e.g. magnesium, calcium, etc.
  • trialkylamine e.g. trimethylamine, triethylamine, etc.
  • picoline 1,5-diazabicyclo[4.3.0]non-5-ene
  • 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.].
  • 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 liguid 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
  • N,N-dimethylformamide or a mixture thereof.
  • a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc., or a mixture thereof.
  • the reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to heating.
  • the compound (Ih) or a salt thereof can be prepared by subjecting the compound (Ig) or a salt thereof to elimination reaction of the carboxy protective group in This elimination can be carried out in a similar manner to that of the aforementioned Process (4), and therefore the reagents to be used and the reaction
  • the compound (Ii) 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, diethyl ether or any other solvent which does not
  • the reaction temperature is not critical and the reaction is usually carried out under warming to heating.
  • the starting compound when in liquid, it can be also used as a solvent.
  • the compound (Ia) 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 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 solvent which does not adversely affect the reaction.
  • 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 solvent which does not adversely affect the reaction.
  • solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene,
  • the reaction temperature is not 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
  • an alkali metal hydroxide e.g., sodium hydroxide, potassium hydroxide, etc.
  • an alkali metal hydrogencarbonate e.g., sodium
  • alkali metal carbonate e.g., sodium carbonate, potassium carbonate, etc.
  • tri(lower)alkylamine e.g., sodium carbonate, potassium carbonate, etc.
  • alkali metal hydride e.g., sodium hydride, etc.
  • alkali metal ( lower)alkoxide e.g., sodium methoxide, sodium ethoxide, etc.
  • pyridine e.g., pyridine
  • N-(lower)alkylmorpholine N,N-di(lower)alkylbenzylamine, N,N-di(lower)alkylaniline or the like.
  • the base and/or the starting compound are in liquid, they can be used also as a solvent.
  • the compound (Ij) or a salt thereof can be prepared by subjecting the compound (Ia) or a salt thereof to halogenation reaction.
  • This halogenation is usually carried out by using a conventional halogenating agent such as halogen (e.g., chlorine, bromine, etc.), phosphorus trihalide (e.g., phosphorus tribromide, phosphorus trichloride, etc.), phosphorus pentahalide, (e.g., phosphorus pentachloride, phosphorus pentabromide, etc.), phosphorus oxychloride (e.g., phosphoryl trichloride, phosphoryl monochloride, etc.), thionyl halide (e.g., thionyl chloride, thionyl bromide, etc.), oxalyl halide (e.g., oxalyl chloride, oxalyl bromide, etc.) and the like.
  • halogen e.g., chlorine, bromine, etc.
  • phosphorus trihalide e.g., phosphorus tribromide,
  • This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), benzene, dioxane, N,N-dimethylformamide, tetrahydrofuran, methylene chloride, ethylene dichloride, chloroform, diethyl ether or any other solvent which does not adversely affect the reaction.
  • a solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), benzene, dioxane, N,N-dimethylformamide, tetrahydrofuran, methylene chloride, ethylene dichloride, chloroform, diethyl ether or any other solvent which does not adversely affect the reaction.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the starting compound when in liquid, it can be also used as a solvent.
  • the compound (Il) or a salt thereof can be prepared by reacting the compound (Ik) or a salt thereof with the compound (VII) 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 temperature is not critical and the reaction is usually carried out under warming to heating.
  • the starting compound when in liguid, it can be also used as a solvent.
  • the compound (Im) or a salt thereof can be prepared by reacting the compound (Ik) or a salt thereof with the compound (VIII) 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, acetone, ethylene dichloride,
  • a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, acetone, ethylene dichloride,
  • reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the compound (In) or a salt thereof can be prepared by subjecting the compound (Im) or a salt thereof to elimination reaction of the mercapto protective group.
  • the compound (Io) or a salt thereof can be prepared by reacting the compound (Ik) or a salt thereof with the compound (IX) 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 temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the compound (Iq) or a salt thereof can be prepared by subjecting the compound (Ip) or a salt thereof to reduction reaction.
  • Reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction.
  • Suitable reducing reagent to be used in chemical reduction are hydrides (e.g., hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, etc.) or a combination of a metal (e.g., tin, zinc, iron, etc.) or metallic compound (e.g., chromium chloride, chromium acetate, etc.) and an organic acid or an inorganic acid (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).
  • a metal e.g., tin, zinc, iron, etc.
  • metallic compound e.g., chromium chloride, chromium acetate, etc.
  • organic acid or an inorganic acid e.g., formic acid, acetic acid, propionic
  • 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, palladium on barium
  • 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, palladium on barium
  • 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
  • N,N-dimethylformamide or a mixture thereof.
  • a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc. or a mixture thereof.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
  • the compound (Ir) or a salt thereof can be prepared by subjecting the compound (Iq) or its reactive derivative at the amino group or a salt thereof to acylation reaction.
  • Suitable acylating agent to be used in the present acylation reaction may include the compound of the formula
  • R 11 - OH (XXI) (wherein R 11 is acyl) or its reactive derivative or a salt thereof.
  • Suitable reactive derivative at the amino group of the compound (Iq) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (Iq) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (Iq) with a silyl compound such as N,O-bis(trimethylsilyl) acetamide,
  • Suitable reactive derivative of the compound (XXI) may include an acid halide, an acid anhydride, an
  • the suitable example may be an acid chloride, an 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,
  • substituted phosphoric acid e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.
  • methanesulfonic acid ethanesulfonic acid, etc.
  • sulfuric acid alkylcarbonic acid
  • aliphatic carboxylic acid e.g. pivalic acid, pentanoic acid, isopentanoic acid
  • a symmetrical acid anhydride an activated amide with imidazole, 4-substituted imidazole, dimethyIpyrazole, triazole or tetrazole; or an activated ester (e.g.
  • N-hydroxy compound e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide,
  • the reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride,
  • reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;
  • N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide N,N'-diethylcarbodiimide; N,N'-diisopropylcarbodiimide; N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;
  • N,N-carbonylbis-(2-methylimidazole) pentamethyleneketene- N-cyclohexylimine, diphenylketene-N-cyclohexylimine;
  • ethoxyacetylene 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride;
  • triphenylphosphine 2-ethyl-7-hydroxybenzisoxazolium salt
  • 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,
  • the compound (IIb) or a salt thereof can be prepared by reacting the compound (IIa) or a salt thereof with the compound (X) or a salt thereof.
  • the reaction is usually carried out in a conventional solvent.
  • a conventional solvent such as alcohols (e.g. methanol, ethanol, ethylene glycol, etc.), chloroform, ether, tetrahydrofuran, benzene, N,N-dimethylformamide, N,N-dimethylacetamide or any other organic solvent which does not adversely
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the reaction is usually carried out in the presence of an inorganic or an organic base such as an alkali metal hydroxide, an alkali metal hydrogencarbonate, alkali metal carbonate, alkali metal hydride (e.g. sodium hydride, etc.), alkali metal acetate, tri (lower) alkylamine,
  • an inorganic or an organic base such as an alkali metal hydroxide, an alkali metal hydrogencarbonate, alkali metal carbonate, alkali metal hydride (e.g. sodium hydride, etc.), alkali metal acetate, tri (lower) alkylamine,
  • pyridine base e.g. pyridine, lutidine, picoline
  • N-(lower)alkylmorpholine N,N-di(lower)alkylbenzylamine, N,N-di (lower)alkylaniline or the like.
  • the base and/or the starting compound are in liquid, they can be used also as a solvent.
  • the compound (III) or a salt thereof can be prepared by reacting the compound (XI) or a salt thereof with the compound (XII) or a salt thereof.
  • the reaction is usually carried out in a conventional solvent such as alcohols (e.g. methanol, ethanol, ethylene glycol, etc.), chloroform, ether, tetrahydrofuran,
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
  • the reaction is usually carried out in the presence of an inorganic or an organic base such as an alkali metal hydroxide, an alkali metal hydrogencarbonate, alkali metal carbonate, alkali metal acetate, tri (lower) alkylamine, lower alkyl alkali metal (e.g. n-butyl lithium, etc.), pyridine base (e.g. pyridine, lutidine, picoline,
  • an inorganic or an organic base such as an alkali metal hydroxide, an alkali metal hydrogencarbonate, alkali metal carbonate, alkali metal acetate, tri (lower) alkylamine, lower alkyl alkali metal (e.g. n-butyl lithium, etc.), pyridine base (e.g. pyridine, lutidine, picoline,
  • the compound (XV) or a salt thereof can be prepared by reacting the compound (XIII) or a salt thereof with the compound (XIV) 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 solvent which does not adversely affect the reaction.
  • 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 solvent which does not adversely affect the reaction.
  • solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene,
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • 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., sodium carbonate, potassium carbonate, etc.
  • alkali metal hydride e.g., sodium hydride, etc.
  • alkali metal (lower) alkoxide e.g., sodium methoxide, sodium ethoxide, etc.
  • pyridine e.g., pyridine
  • N-(lower)alkylmorpholine N,N-di(lower)alkylbenzylamine, N,N-di(lower)alkylaniline or the like.
  • the compound (XVIb) or a salt thereof can be prepared by subjecting the compound (XV) or a salt thereof to reduction reaction.
  • This reaction can be carried out in the manner disclosed in Preparation 5 or similar manners thereto.
  • the compound (II) or a salt thereof can be prepared by reacting the compound (XVIa) or a salt thereof with the compound (XVII) 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 solvent which does not adversely affect the reaction.
  • 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 solvent which does not adversely affect the reaction.
  • solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene,
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • 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.g., sodium, sodium, potassium, etc.), sodium bicarbonate (e.g., sodium, sodium, potassium, etc.), an alkali metal hydrogencarbonate (e.g., sodium
  • alkali metal carbonate e.g., sodium carbonate, potassium carbonate, etc.
  • tri( lower)alkylamine e.g., sodium carbonate, potassium carbonate, etc.
  • alkali metal hydride e.g., sodium hydride, etc.
  • alkali metal ( lower) alkoxide e.g., sodium methoxide, sodium ethoxide, etc.
  • pyridine e.g., pyridine
  • N-(lower) alkylmorpholine N,N-di(lower) alkylbenzylamine, N,N-di(lower) alkylaniline or the like.
  • the base and/or the starting compound and in liquid they can be used also as a solvent.
  • the compound (VI) or a salt thereof can be prepared by reacting the compound (XVIc) or its reactive
  • Suitable reactive derivative of the compound (XVIc) may include Schiff 's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (XVIc) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (XVIc) with a silyl compound such as
  • Suitable reactive derivative of the compound (XVIII) may include a conventional one such as 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.
  • halogenated phosphoric acid, etc. dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [e.g. methanesulfonic acid, etc.], aliphatic carboxylic acid [e.g. acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylic acid [e.g. benzoic acid, etc.]; a symmetrical acid anhydride; an activated amide with imidazole, 1-hydroxy-1H-benzotriazole,
  • phenylazophenyl ester phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, benzothiazolyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl 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.]
  • These reactive derivatives can optionally be selected from them according to the kind of the
  • the reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform,
  • a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform,
  • reaction when the compound (XVIII) is used in a free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide;
  • a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide;
  • oxychloride phosphoryl chloride
  • phosphorus trichloride phosphorus trichloride
  • thionyl chloride phosphorus trichloride
  • 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
  • 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.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
  • the compound (XV) or a salt thereof can be prepared by reacting the compound (XIX) or a salt thereof with the compound (XX) or a salt thereof.
  • This reaction can be carried out in the manner disclosed in Preparation 11 or similar manners thereto.
  • Suitable salts of the object and starting compounds and their reactive derivatives in Processes (1) ⁇ (13) and (A) ⁇ (H) 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
  • an immunomodulating agent e.g. an inhibitor on the
  • the new quinoline derivatives (I) and a pharmaceutically acceptable salt thereof can be used for the treatment and/or prevention of inflammatory
  • cancer e.g. lung carcinoma, stomach carcinoma, colon cancer, renal
  • 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, 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 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. glomerulonephritis, 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, sarc ⁇ idosis, Wegner's
  • granulomatosis e.g. lung carcinoma, stomach carcinoma, colon cancer, renal
  • carcinoma hepatoma, etc.]
  • DBA/2 spleen cells given 5 days apart. Each injection contained 5 ⁇ 10 7 cells. From 3 days after the second cell injection, drug was administered orally once a day for 8 weeks.
  • the animals were sacrificed at day 16 and tumor colonies established in lung were counted in a dissection microscope.
  • test compound was administered orally once a day.
  • 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
  • R 1 is lower alkyl or phenyl which may have suitable
  • substituent(s) [more preferably phenyl which may have halogen; most preferably phenyl or halophenyl],
  • R 2 is hydroxy, protected hydroxy [more preferably acyloxy], lower alkoxy, halogen, amino, lower alkylamino, protected amino [more preferably acylamino], mercapto, or protected mercapto [more preferably acylthio; most preferably lower alkanoylthio],
  • R 3 is hydrogen, lower alkyl, lower alkoxy( lower) alkyl, or ar( lower) alkyl [more preferably phenyl ( lower) alkyl; most preferably benzyl],
  • R 8 is hydrogen, or
  • R 3 and R 8 are linked together to form lower alkylene
  • R 4 is acyl [more preferably carbamoyl which may be
  • phenyl which may have 1 to 3 (more preferably 1 or 2) suitable substituent(s) selected from the group
  • thiocarbamoyl which may be substituted with one or two suitable substituent(s) selected from the group consisting of lower alkyl and aryl;
  • aminosulfonyl which may be substituted with one or two suitable substituent(s) selected from the group consisting of lower alkyl and aryl;
  • ar(lower)alkylsulfonyl or heterocycliccarbonyl
  • carbamoyl which may be substituted with one or two suitable substituent(s) selected from the group consisting of lower alkyl, phenyl, mono(or
  • aminosulfonyl which may be substituted with one or two suitable substituent(s) selected from the group consisting of lower alkyl and phenyl;
  • ar(lower)alkylsulfinyl [more preferably phenyl(lower)- alkylsulfinyl; most preferably benzylsulfinyl];
  • ar(lower) alkylthio [more preferably phenyl(lower)- alkylthio; most preferably benzylthio]; cyano;
  • Z is O or S
  • n 0, 1 or 2.
  • Phosphorus trichloride (0.347 ml) was added dropwise to a solution of N-methyl-4-fluoroaniline (2.99 g) in toluene (18 ml) under stirring. After stirring was continued at room temperature for 30 minutes, to the resultant solution 1-methyl-2-oxo-3-carboxy-4-hydroxy-6-methylthio-1,2-dihydroquinoline (2.11 g) was added. The mixture was heated at 100°C for 2 hours arid then cooled down. The reaction mixture was extracted with 2N sodium hydroxide solution. The extract was acidified with hydrochloric acid and extracted with chloroform. The extract obtained above was dried over magnesium sulfate, filtered and evaporated to dryness.

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Abstract

Quinoline derivatives of formula (I), wherein R1 is lower alkyl or aryl which may have suitable substituent(s), R2 is hydroxy, protected hydroxy, lower alkoxy, etc., R3 is hydrogen, lower alkyl, lower alkoxy(lower)- alkyl or ar(lower)alkyl and R8 is hydrogen, or R3 and R¿8? are linked together to form lower alkylene, R?4¿ is an organic group, Z is O or S, and n is 0, 1 or 2; and pharmaceutically acceptable salts thereof which are useful as a medicament.

Description

DESCRIPTION QUINOLINE DERIVATIVES
TECHNICAL FIELD
This invention relates to new quinoline derivatives and pharmaceutically acceptable salts thereof which are useful as a medicament.
BACKGROUND ART
Some guinoline derivatives have been known as described, for example, in U.S. Patent 4,547,511 and U.S. Patent 4,127,574.
DISCLOSURE OF INVENTION
This invention relates to new guinoline derivatives. More particularly, this invention relates to new guinoline derivatives and pharmaceutically acceptable salts thereof which have pharmacological activities, processes for preparation thereof, a pharmaceutical composition
comprising the same and a use of the same.
Accordingly, one object of this invention is to provide the new and useful guinoline 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.
Another object of this invention is to provide processes for preparation of the guinoline derivatives and salts thereof.
A further object of this invention is to provide a pharmaceutical composition comprising said guinoline derivatives or a pharmaceutically acceptable salt thereof.
Still further object of this invention is to provide a use of said guinoline 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.
The object guinoline derivatives of the present invention are novel and can be represented by the
following general formula (I) :
Figure imgf000004_0001
wherein R 1 is lower alkyl or aryl which may have suitable substituent(s),
R 2 is hydroxy, protected hydroxy, lower alkoxy, halogen, amino, substituted amino, mercapto or protected mercapto,
R 3 is hydrogen, lower alkyl, lower alkoxy(lower)- alkyl or ar( lower)alkyl and
R 8 is hydrogen, or
R 3 and R8 are linked together to form lower alkylene,
R 4 is an organic group,
Z is O or S, and
n is 0, 1 or 2.
The object compound (I) of the present invention can be prepared by the following processes. Process (1)
Figure imgf000005_0003
Figure imgf000005_0004
Figure imgf000005_0002
Process (2)
Figure imgf000005_0001
Figure imgf000006_0001
Process (3)
Figure imgf000006_0002
Figure imgf000006_0003
Process (4)
Figure imgf000007_0001
Figure imgf000007_0002
Process (5)
Figure imgf000007_0003
Figure imgf000008_0001
Process (6)
Figure imgf000008_0002
Figure imgf000008_0003
Process (7)
Process (8)
Figure imgf000009_0002
Figure imgf000010_0001
Process (9)
Figure imgf000010_0002
Figure imgf000011_0001
Process (10)
Figure imgf000011_0002
Figure imgf000011_0003
Figure imgf000011_0004
Figure imgf000012_0001
Process (11)
Figure imgf000012_0002
Figure imgf000012_0003
Figure imgf000013_0001
Process (12)
Figure imgf000013_0002
Process (13)
Figure imgf000014_0001
Figure imgf000014_0002
wherein R 1, R 2, R 3, R 4, R 8, Z and n are each as defined above,
R 2 a is halogen,
R 2 b is amino or substituted amino,
R 2 c is protected mercapto,
R 2 d is lower alkoxy,
R 4 a is protected carboxy,
R 4 a is acyl having protected carboxy, R 4 c is acyl having carboxy,
R 2 d is acyl having nitro, R4 e is acyl having amino,
Rf 4 is acyl having acylammo,
R 6 is a leaving group,
a group of the formula : -CO-R 6
is amidated carboxy,
X 1, X2 and X3 are each as a leaving group, M 1 and M2 are each as an alkali metal and m is 1 or 2. The starting compounds or salts thereof can be prepared by the following processes.
Process (A)
Figure imgf000015_0001
Figure imgf000015_0002
Process (B)
Figure imgf000016_0001
Figure imgf000016_0002
Figure imgf000016_0003
Process (C)
Figure imgf000016_0004
Figure imgf000016_0005
Figure imgf000017_0001
Process (D)
Figure imgf000017_0002
Figure imgf000017_0003
Process (E)
Figure imgf000017_0004
Figure imgf000018_0002
Process (F)
Figure imgf000018_0003
Figure imgf000018_0004
Figure imgf000019_0001
Process (G)
Figure imgf000019_0002
Figure imgf000019_0003
Figure imgf000019_0004
Process (H)
Figure imgf000020_0001
Figure imgf000020_0002
wherein R 1, R 3, R 4, R 2, R 8, X , Z and n are each as
defined above,
R 2 a is lower alkyl, lower alkoxy(lower)alkyl,
or ar(lower)alkyl,
R 2, R9, R10, X4, X5 and X are each as a leaving group, and
R12 is protected carboxy.
Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and may include e.g. 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, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g.
arginine, aspartic acid, glutamic acid, etc.).
In the above and subsequent descriptions of the present specification, suitable example and illustration of the various definitions which the present invention intends to include within the scope thereof are explained in detail as follows.
The term "lower" is used to intend a group having 1 to 6 carbon atom(s), unless otherwise provided.
The term "higher" is used to intend a group having 7 to 20 carbon atoms, unless otherwise provided.
Suitable "lower alkyl" and "lower alkyl moiety" in the terms "lower alkoxy( lower) alkyl and "ar( lower) alkyl" may include straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl,
neopentyl, hexyl, and the like, in which more preferable example may be C1-C5 alkyl.
Suitable "lower alkoxy" and "lower alkoxy moiety" in the term "lower alkoxy( lower) alkyl may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like.
Suitable "aryl" and "aryl moiety" in the term
"ar( lower) alkyl" may include phenyl, naphthyl and the like.
Suitable "lower alkylene" may include straight or branched one such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene,
methyImethylene, ethylethylene, propylene, and the like, in which more preferable example may be C1-C4 alkylene and the most preferable one may be ethylene.
Suitable "halogen" may include chlorine, bromine, iodine and fluorine.
Suitable "alkali metal" may include sodium, potassium and the like.
Suitable substituent in the term "aryl which may have suitable substituent(s)" may include lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, tert-pentyl, hexyl, etc.), lower alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, tert-butoxy, pentyloxy, neσpentyloxy,
tert-pentyloxy, hexyloxy, etc.), lower alkenyl (e.g., vinyl, 1-propenyl, allyl, 1-methylallyl, 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., 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, etc.), mono(or di or tri)halo( lower) alkyl (e.g. fluoromethyl, difluoromethyl, trifluoromethyl,
chloromethyl, dichloromethyl, trichloromethyl,
bromomethyl, dibromomethy1, tribromomethyl, 1 or
2-fluoroethyl, 1 or 2-bromoethyl, 1 or 2-chloroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, etc.), mono(or di or tri)halo(lower)alkoxy (e.g., fluoromethoxy,
difluoromethoxy, trifluoromethoxy, chloromethoxy,
dichloromethoxy, trichloromethoxy, bromomethoxy,
dibromomethoxy, tribromαmethoxy, etc.), halogen (e.g., chlorine, bromine, fluorine and 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 wherein lower alkyl moiety can be referred to the ones as exemplified above, protected carboxy(lower) alkyl wherein lower alkyl moiety can be referred to the ones as exemplified above and protected carboxy moiety can be referred to the ones as exemplified below, amino, protected amino, di( lower)alkylamino (e.g., dimethylamino, diethylamino, diisopropylamino,
ethylmethylamino, isopropylmethylamino,
ethylisopropylamino, etc.), hydroxy(lower) alkyl, protected hydroxy(lower) alkyl, nitro, acyl, cyano, mercapto, lower alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.), imino, and the like.
Suitable "acyl" may include carbamoyl, thiocarbamoyl, 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; Thiocarbamoyl;
Aliphatic acyl such as lower or higher alkanoyl (e.g.
formyl, aσetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.);
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.); aminosulfonyl; 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,
phenylisobutylyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthyl(lower)alkanoyl (e.g. naphthylacetyl,
naphthylpropanoyl, naphthylbutanoyl, etc.), etc.];
ar(lower) alkenoyl [e.g. phenyl(lower) alkenoyl (e.g. phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc.),
naphthyl(lower) alkenoyl (e.g. naphthylpropenoyl,
naphthylbutenoyl, naphthylpentenoyl, etc.), etc.];
ar(lower)alkoxycarbonyl [e.g.
phenyl(lower) alkoxycarbonyl (e.g. benzyloxycarbonyl, etc.), etc.];
ar(lower)cycloalkylcarbonyl [e.g.
phenyl(lower) cycloalkylcarbonyl (e.g., 1-phenyl-1- cyclopropylcarbonyl, 1-phenyl-1-cyclopentylcarbonyl, etc.), etc.];
aryloxycarbonyl (e.g., phenoxycarbonyl,
naphthyloxycarbonyl, etc.);
aryloxy(lower)alkanoyl (e.g. phenoxyacetyl,
phenoxypropionyl, etc.);
arylglyoxyloyl (e.g. phenylglyoxyloyl,
naphthylglyoxyloyl, etc.);
arenesulfonyl (e.g. benzenesulfonyl,
p-toluenesulfonyl, etc.);
ar(lower)alkylsulfonyl [e.g.
phenyl(lower)alkylsulfonyl, (e.g. benzylsulfonyl, etc.), etc.]; or the like.
Heterocyclic acyl such as
heterocycliccarbonyl;
heterocyclic(lower)alkanoyl (e.g., heterocyclicacetyl, heterocyclcpropanoyl, heterocyclicbutanoyl,
heterocyclicpentanoyl, heterocyclichexanoyl, etc.);
heterocyclic(lower)alkenoyl (e.g. heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl, etc.);
heterocyclicglyoxyloyl (e.g. thiazolylglyoxyloyl,
thienylglyoxyloyl, etc.); 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 heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like.
And, especially preferable 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 and its N-oxide,
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. 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4
nitrogen atom(s), for example, pyrrolidinyl,
imidazolidinyl, piperidyl, piperazinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, guinolyl,
isoquinolyl, indazolyl, benzotriazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example,
oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc.;
saturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 oxygen atom(s-) and 1 to 3 nitrogen atom(s), for example,
morpholinyl, sydnonyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, benzoxazinyl (e.g.
2H-1,4-benzoxazinyl, etc.), dihydrobenzoxazinyl (e.g.
2H-3,4-dihydro-1,4-benzoxazinyl, etc.), etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example,
thiazolyl, isothiazolyl, thiadiazolyl (e.g.
1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2, 5-thiadiazolyl, etc.),
dihydrothiadiazolyl, etc.;
saturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example,
thiazolidinyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 sulfur atom(s), for example, thienyl, dihydrodithiinyl,
dihydrodithionyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, benzothiazinyl (e.g. 2H-1,4-benzothiazinyl, etc.), dihydrobenzothiazinyl (e.g. 2H-3,4-dihydrobenzothiazinyl, etc.), etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom, for example, furyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s), for example, benzodioxolyl (e.g.
1,3-benzodioxolyl, etc.), etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example,
dihydrooxathiinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s), for example, benzothienyl, benzodithiinyl, etc.;
unsaturated condensed heterocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example
benzoxathiinyl, etc.; and the like. The acyl moiety as stated above may have one to ten,1 same or different, suitable substituent(s) such as lower alkyl;
lower alkoxy (e.g. methoxy, ethoxy, propoxy, etc.);
lower alkylthio (e.g. methylthio, ethylthio, etc.);
lower alkylamino (e.g. methylamino, etc.); lower
cycloalkyl (e.g. cyclopentyl, cyclohexyl, etc.); lower cycloalkenyl (e.g. cyclohexenyl, etc.); halogen; amino; protected amino; hydroxy; protected hydroxy; cyano; nitro; carboxy; protected carboxy; sulfo; sulfamoyl; imino; oxo; amino(lower)alkyl (e.g. aminomethyl, aminoethyl, etc.); carbamoyloxy; hydroxy(lower)alkyl (e.g. hydroxymethyl, 1 or 2-hydroxyethyl, 1 or 2 or 3-hydroxypropyl, etc.);
ar( lower)alkyl [e.g. phenyl(lower)alkyl (e.g., benzyl, phenylpropyl, phenylbutyl, etc.), etc.];
aryl which may have 1 to 3, same or different, suitable substituent(s) [e.g., lower alkyl; halogen; lower alkoxy; lower alkylthio, di ( lower) alkylamino (e.g., dimethylamino, diethylamino, dipropylamino, etc.); cyano; mono(or di or tri)halo(lower) alkyl (e.g., fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, dichloromethyl,
dibromomethyl, trifluoromethyl, trichloromethyl,
tribromomethyl, 1-(or 2-)fluoroethyl, 1-(or
2-) chloromethyl, 1-(or 2-)bromomethyl, etc.);
mono( or di or tri)halo( lower)alkoxy (e.g., fluoromethoxy, chloromethoxy, bromomethoxy,
difluoromethoxy, dichloromethoxy, dibromomethoxy,
trifluoromethoxy, trichloromethoxy, tribromomethoxy, 1-(or 2-)fluoroethoxy, 1-(or 2-)chloroethoxy, 1-(or
2-)bromoethoxy, etc.);
carboxy; protected carboxy [e.g., esterified carboxy {e.g. lower alkoxycarbonyl (e.g., methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, etc.), etc.}, etc.]; acyl [e.g., lower alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, etc.), etc.]; nitro; amino; protected amino
[e.g. acylaminσ {e.g., lower alkanoylamino (e.g.,
formylamino, acetylamino, etc.), etc.}, etc.]; etc.];
a group of the formula :
Figure imgf000028_0001
(in which A is lower alkylene as exemplified above); heterocyclic group which may have suitable substituent(s) [e.g., lower alkyl; lower alkoxy; lower alkylthio; lower alkylamino; lower cycloalkyl; lower cycloalkenyl; halogen; amino; protected amino, etc.]; or the like.
Suitable "protected hydroxy" may be acyloxy group or the like.
Suitable "protected mercapto" may be acylthio group or the like.
Suitable "substituted amino" may be protected amino or lower alkylamino or the like.
Suitable "protected amino" may be acylamino group or the like.
Suitable "acyl moiety" in the terms "acyloxy", "acylthio" and "acylamino" can be referred to the ones as exemplified above.
Suitable "lower alkyl moiety" in the term "lower alkylamino" can be referred to the ones as exemplified above.
Suitable "leaving group" may include lower alkoxy
(e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, etc.), aryloxy (e.g.
phenoxy, napthoxy, etc.), an acid residue or the like, and suitable examples of "acid residue" may be halogen (e.g. chlorine, bromine, iodine, etc.), sulfonyloxy (e.g.
methanesulfonyloxy, benzenesulfonyloxy,
toluenesulfonyloxy, etc.) or the like.
Suitable "amidated carboxy" may include carbamoyl which may be substituted with one or two suitable
substituent(s), a group of the formula :
(wherein a group of the formula :
Figure imgf000029_0002
Figure imgf000029_0001
is a heterocyclic group containing at least one nitrogen atom), and the like.
Suitable "organic group" may include lower alkyl, lower alkenyl, lower alkynyl, aryl, ar(lower) alkyl, carboxy, ar(lower)alkylsulfinyl, ar( lower)alkylthio, cyano, acyl, heterocyclic group which may have suitable substituent(s), and the like.
Suitable "lower alkyl" and "lower alkyl moiety" in the terms "ar(lower)alkyl", "ar(lower) alkylsulfinyl" and
"ar(lower) alkylthio" can be referred to the ones as exemplified above.
Suitable "lower alkenyl" may include vinyl,
1-propenyl, allyl, 1-methylallyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl and the like.
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 "aryl" and "aryl moiety" in the terms "ar(lower)alkyl", "ar( lower) alkylsulfinyl" and
"ar(lower)alkylthio" can be referred to the ones as exemplified above.
Suitable "acyl" can be referred to the ones as exemplified above.
Suitable "heterocyclic group" can be referred to the ones as exemplified above.
Suitable "substituent" in the term "heterocyclic group which may have suitable substituent(s)" may include lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl,
tert-pentyl, hexyl, etc.), lower alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, tert-butoxy, pentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, etc.), lower alkenyl (e.g., vinyl, 1-ρropenyl, allyl,
1-methylallyl, 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., 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, etc.), mono(or di or tri)halo(lower) alkyl (e.g. fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl,
dichloromethyl, trichloromethyl, bromomethyl,
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 and 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 wherein lower alkyl moiety can be referred to the ones as exemplified above, protected carboxy(lower)alkyl wherein lower alkyl moiety can be referred to the ones as exemplified above and protected carboxy moiety can be referred to the ones as exemplified below, amino , protected amino , di ( lower ) alkylamino ( e . g . , dimethylamino, diethylamino, diisopropylamino,
ethylmethylamino, isopropylmethylamino,
ethylisopropylamino, etc.), hydroxy( lower)alkyl, protected hydroxy( lower)alkyl, nitro, acyl, cyano, mercapto, lower alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.), imino, and the like.
Suitable "substituent" in the term "carbamoyl which may be substituted with one or two suitable
substituent(s)" may include lower alkyl;
lower alkoxy (e.g. methoxy, ethoxy, propoxy, etc.);
lower alkylthio (e.g. methylthio, ethylthio, etc.);
lower alkylamino (e.g. methylamino, etc.);
lower cycloalkyl (e.g. cyclopentyl, cyclohexyl, etc.);
lower cycloalkenyl (e.g. cyclohexenyl, etc.); halogen;
amino; protected amino; hydroxy; protected hydroxy; cyano; nitro; carboxy; protected carboxy; sulfo; sulfamoyl;
imino; oxo; amino(lower)alkyl (e.g. aminomethyl,
aminoethyl, etc.); carbamoyloxy; hydroxy(lower) alkyl (e.g. hydroxymethyl, 1 or 2-hydroxyethyl, 1 or 2 or 3
hydroxypropyl, etc.);
ar( lower) alkyl [e.g., phenyl (lower) alkyl (e.g., benzyl, phenylpropyl, phenylbutyl, etc.), etc.];
aryl which may have 1 to 3, same or different, suitable substituent( s) [e.g., lower alkyl; halogen; lower alkoxy; lower alkylthio; di(lower)alkylamino (e.g., dimethylamino, diethylamino, dipropylamino, etc.); cyano;
mono(or di or tri)halo(lower) alkyl (e.g., fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl,
tribromomethyl, 1- ( or 2- ) f luoroethyl, 1- ( or
2-)chloromethyl, 1-(or 2-)bromomethyl etc.);
mono(or di or tri)halo(lower) alkoxy (e.g.,
fluoromethoxy, chloromethoxy, bromomethoxy, difluoromethoxy, dichloromethoxy, dibromomethoxy,
trifluoromethoxy, trichloromethoxy, tribromomethoxy, l-(or 2-)fluoroethoxy, 1-(or 2-)chloroethoxy, 1-(or
2-)bromoethoxy, etc.);
carboxy; protected carboxy [e.g. esterified carboxy {e.g., lower alkoxycarbonyl (e.g., methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, etc.), etc.}, etc.], acyl [e.g., lower alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, etc.), etc.]; nitro; amino; protected amino
[e.g. acylamino {e.g., lower alkanoylamino (e.g.,
formylamino, acetylamino, etc.), etc.}, etc.], etc.];
a group of the formula :
Figure imgf000032_0001
(in which A is lower alkylene as exemplified above); or heterocyclic group which may have suitable substituent(s) [e.g. lower alkyl; lower alkoxy; lower alkylthio;
lower alkylamino; lower cycloalkyl, lower cycloalkenyl;
halogen; amino; protected amino, etc.]; or the like.
Suitable "heterocyclic group" can be referred to the ones as exemplified above.
Suitable "protected carboxy" may include esterified carboxy and the like. An suitable examples of said ester moiety 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, 1-cyclopropylethyl ester, etc.);
lower alkenyl ester (e.g., vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g., ethynyl ester, propynyl ester, etc . ) ;
lower alkoxyalkyl ester (e.g., methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, etc.);
lower alkylthioalkyl ester (e.g., methylthiomethy1 ester, ethylthiomethyl ester, ethylthioethyl ester,
isopropylthiomethyl ester, etc.);
mono(or di or tri)halo(lower,)alkyl ester (e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.);
lower alkanoyloxy( lower)alkyl ester (e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester,
hexanoyloxymethyl ester, 2-acetoxyethyl ester,
2-propionyloxyethyl ester, etc.);
lower alkanesulfonyl(lower)alkyl ester (e.g. mesylmethyl ester, 2-mesylethyl ester etc.);
ar( lower) alkyl ester, for example, 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, mesityl ester, cumenyl ester,
4-chlorophenyl ester, 4-methoxyphenyl ester, etc.);
tri (lower)alkyl silyl ester;
lower alkylthioester (e.g. methylthioester,
ethylthioester, etc.) and the like.
Suitable "heterocyclic group containing at least one nitrogen atom" may include
unsaturated 3 to 8-membered (more preferably 5 or
6-membered) heteromonocyclic group containing 1 to
4-nitrogen atom(s), for example, pyrrolyl, pyrrσlinyl, imidazolyl, pyrazolyl, dihydropyridyl, pyrazinyl,
pyridazinyl, triazolyl (e.g. 4H-l,2,4-triazolyl,
1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;
saturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 4
nitrogen atom(s), for example pyrrolidinyl,
imidazolidinyl, piperidyl, piperazinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl, benzimidazolyl, indazolyl, benzotriazolyl, etc.; saturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example,
morpholinyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example,
dihydrothiazinyl, etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, benzoxazinyl,
dihydrobenzoxazinyl (e.g. 2H-3,4-dihydro-1,4-benzoxazinyl, etc.);
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example benzothiazolyl, benzothiadiazolyl, benzothiazinyl,
dihydrobenzothiazinyl (e.g., 2H-3,4-dihydrobenzothiazinyl, etc.), etc.; and the like.
The processes for preparing the object and starting compounds are explained in detail in the following. Process ( 1 )
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.
The reaction is usually carried out in a conventional solvent such as chloroform, ether, tetrahydrofuran, benzene, N,N-dimethylformamide, N,N-dimethylacetamide or any other organic solvent which does not adversely
influence the reaction.
The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
The reaction is usually carried out in the presence of an inorganic or an organic base such as an alkali .metal hydroxide, an alkali metal hydrogencarbonate, alkali metal carbonate, alkali metal hydride (e.g., sodium hydride, etc.), alkali metal acetate, di ( lower) alkylamine (e.g., diisopropylamine, etc.), tri (lower) alkylamine, pyridine base (e.g., pyridine, lutidine, picoline,
dimethylaminopyridine, etc.), N-(lower) alkylmorpholine, N,N-di(lower) alkylbenzylamine, N,N-di(lower) alkylaniline or the like.
Process (2)
The compound (Ic) or a salt thereof can be prepared by subjecting the compound (lb) or a salt thereof to oxidation reaction.
Oxidation is carried out in a conventional manner, which is capable of oxidizing a sulfur atom to an oxidized sulfur atom, and suitable oxidizing reagent may be oxygen acid such as periodate (e.g. sodium periodate, potassium periodate, etc.), peroxy acid such as peroxybenzoic acids (e.g. peroxybenzoic acid, m-chloroperoxybenzoic acid, etc.), and the like.
The reaction is usually carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, dichloromethane, chloroform, N,N-dimethyl acetamide, N,N-dimethylformamide or any other organic solvent which does not adversely influence the reaction. Among these solvents, hydrophilic solvents may be used in a mixture with water.
The reaction temperature is not critical and the reaction is usually carried out under cooling to heating. Process (3)
The compound (Ie) or a salt thereof can be prepared by subjecting the compound (Id) or its reactive derivative at the carboxy group or a salt thereof to amidation reaction.
Suitable amidating reagent to be used in the present amidation reaction may include a compound of the formula :
H - R6 (XXIII) (wherein R6 is as defined above)
or its reactive derivative or a salt thereof, and the like.
Suitable reactive derivative of the compound (XXIII) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (XXIII) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (XXIII) with a silyl compound such as
bis(trimethylsilyl) acetamide, mono(trimethylsilyl)-acetamide [e.g. N-(trimethylsilyl)acetamide],
bis(trimethylsilyl)urea or the like;
a derivative formed by reaction of the compound (XXIII) with phosphorus trichloride or phosgene, and the like.
Suitable reactive derivative at the carboxy group of the compound (Id) 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,
phenylphosphoric acid, diphenylphosphoric acid,
dibenzylphosphoric acid, halogenated phosphoric acid, etc.], dialkylphosphorous acid, sulfurous acid,
thiosulfuric acid, sulfuric acid, sulfonic acid [e.g.
methanesulfonic acid, etc.], aliphatic carboxylic acid
[e.g. acetic acid, propionic acid, butyric acid,
isobutyric acid, pivalic acid, pentanoic acid,
isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylic acid [e.g. benzoic acid, etc.]; a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethyIpyrazole, triazole or tetrazole; or an activated ester [e.g.
cyanomethyl ester, methoxymethyl ester,
dimethyliminomethyl ester, vinyl ester,
Figure imgf000037_0001
ethyl ester, propargyl ester, p-nitrophenyl ester,
2,4-dinitrophenyl ester, trichlorophenyl ester,
pentachlorophenyl ester, mesylphenyl 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-dimethyl hydroxylamine,
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 (Id) 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
influence the reaction. These conventional solvent may also be used in a mixture with water. When the base and/or the starting compound are in liguid, they can be used also as a solvent.
In this reaction, when the compound (Id) is used in a free acid form or its salt form, the reaction is
preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylσarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide;
N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide; N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide; N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;
N,N'-carbonyl-bis(2-methylimidazole);
pentamethyleneketene-N-cyclohexylimine;
diphenylketene-N-cyclohexylimine; ethoxyacetylene;
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
intramolecular salt; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc.; or the like.
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. The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
Process (4)
The compound (Id) or a salt thereof can be prepared by subjecting the compound (If) or a salt thereof to elimination reaction of the carboxy protective group in Ra 4.
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-diazabicyclo[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.
formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.]. The
elimination using 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 liguid 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,
trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.].
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, palladium on barium
carbonate, etc.], 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.] and the like.
The reduction is usually carried out in a
conventional solvent which does not adversely affect the reaction such as water, methanol, ethanol, propanol,
N,N-dimethylformamide, or a mixture thereof.
Additionally, in case that the above-mentioned acids to be used in chemical reduction are in liquid, they can also be used as a solvent, further, a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc., or a mixture thereof. The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to heating. Process (5)
The compound (Ih) or a salt thereof can be prepared by subjecting the compound (Ig) or a salt thereof to elimination reaction of the carboxy protective group in This elimination can be carried out in a similar manner to that of the aforementioned Process (4), and therefore the reagents to be used and the reaction
conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process (4).
Process (6)
The compound (Ii) 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, diethyl ether or any other solvent which does not
adversely affect the reaction.
The reaction temperature is not critical and the reaction is usually carried out under warming to heating.
When the starting compound is in liquid, it can be also used as a solvent.
Process (7)
The compound (Ia) 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 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 solvent which does not adversely affect the reaction. These conventional solvent may also be used in a mixture with water.
The reaction temperature is not 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 (e.g., pyridine,
lutidine, picoline, dimethylaminopyridine, etc.),
N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, N,N-di(lower)alkylaniline or the like.
When the base and/or the starting compound are in liquid, they can be used also as a solvent.
Process (8)
The compound (Ij) or a salt thereof can be prepared by subjecting the compound (Ia) or a salt thereof to halogenation reaction.
This halogenation is usually carried out by using a conventional halogenating agent such as halogen (e.g., chlorine, bromine, etc.), phosphorus trihalide (e.g., phosphorus tribromide, phosphorus trichloride, etc.), phosphorus pentahalide, (e.g., phosphorus pentachloride, phosphorus pentabromide, etc.), phosphorus oxychloride (e.g., phosphoryl trichloride, phosphoryl monochloride, etc.), thionyl halide (e.g., thionyl chloride, thionyl bromide, etc.), oxalyl halide (e.g., oxalyl chloride, oxalyl bromide, etc.) and the like.
This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), benzene, dioxane, N,N-dimethylformamide, tetrahydrofuran, methylene chloride, ethylene dichloride, chloroform, diethyl ether or any other solvent which does not adversely affect the reaction.
The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
When the starting compound is in liquid, it can be also used as a solvent.
Process (9)
The compound (Iℓ) or a salt thereof can be prepared by reacting the compound (Ik) or a salt thereof with the compound (VII) 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
adversely affect the reaction.
The reaction temperature is not critical and the reaction is usually carried out under warming to heating.
When the starting compound is in liguid, it can be also used as a solvent.
Process (10) - ①
The compound (Im) or a salt thereof can be prepared by reacting the compound (Ik) or a salt thereof with the compound (VIII) 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, acetone, ethylene dichloride,
chloroform, diethyl ether or any other solvent which does not adversely affect the reaction.
The reaction temperature is not critical and the reaction is usually carried out under cooling to heating. Process (10) -②
The compound (In) or a salt thereof can be prepared by subjecting the compound (Im) or a salt thereof to elimination reaction of the mercapto protective group.
This elimination can be carried out in a similar manner to that of the aforementioned Process (4)4 and therefore the reagents to be used and the reaction
conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process (4). Process (11)
The compound (Io) or a salt thereof can be prepared by reacting the compound (Ik) or a salt thereof with the compound (IX) 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
adversely affect the reaction.
The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
Process (12)
The compound (Iq) or a salt thereof can be prepared by subjecting the compound (Ip) or a salt thereof to reduction reaction.
Reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction.
Suitable reducing reagent to be used in chemical reduction are hydrides (e.g., hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, etc.) or a combination of a metal (e.g., tin, zinc, iron, etc.) or metallic compound (e.g., chromium chloride, chromium acetate, etc.) and an organic acid or an inorganic acid (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).
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, palladium on barium
carbonate, etc.), 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.) and the like.
The reduction is usually carried out in a
conventional solvent which does not adversely influence the reaction such as water, alcohol (e.g., methanol, ethanol, propanol, etc.), tetrahydrofuran, dioxane,
N,N-dimethylformamide, or a mixture thereof.
Additionally, in case that the above-mentioned acids to be used in chemical reduction are in liquid, they can also be used as a solvent.
Further, a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc. or a mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
Process (13)
The compound (Ir) or a salt thereof can be prepared by subjecting the compound (Iq) or its reactive derivative at the amino group or a salt thereof to acylation reaction.
Suitable acylating agent to be used in the present acylation reaction may include the compound of the formula
R11 - OH (XXI) (wherein R11 is acyl) or its reactive derivative or a salt thereof.
Suitable reactive derivative at the amino group of the compound (Iq) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (Iq) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (Iq) 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 (Iq) with phosphorus
trichloride or phosgene, and the like.
Suitable reactive derivative of the compound (XXI) may include an acid halide, an acid anhydride, an
activated amide, an activated ester, isocyanate, and the like. The suitable example may be an acid chloride, an 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 or trichloroacetic acid, etc.) or aromatic carboxylic acid (e.g. benzoic acid, etc.);
a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethyIpyrazole, triazole or tetrazole; or an activated ester (e.g.
cyanomethyl ester, methoxymethyl ester,
dimethyliminomethyl
Figure imgf000047_0001
ester, vinyl ester,., propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl 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-hydroxybenzotriazole, N-hydroxyphthalimide,
1-hydroxy-6-chloro-1H-benzotriazole, etc.);
substituted or unsubstituted aryl isocyanate;
substituted or unsubstituted aryl isothiocyanate, and the like. These reactive derivatives can optionally be selected from them according to the kind of the compound (XXI) to be used.
The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride,
tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvents which do not adversely influence the reaction. These conventional solvents may also be used in a mixture with water. When the compound (XXI) is used in free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of 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;
N,N-carbonylbis-(2-methylimidazole); pentamethyleneketene- N-cyclohexylimine, diphenylketene-N-cyclohexylimine;
ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride;
triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide
intra-molecular salt; 1-(p-chlorobenzenesulfonyloxy)-6- chloro-1H-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride, etc.; or the like.
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)alkylmorphorine, 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. Process (A)
The compound (IIb) or a salt thereof can be prepared by reacting the compound (IIa) or a salt thereof with the compound (X) or a salt thereof.
The reaction is usually carried out in a conventional solvent. such as alcohols (e.g. methanol, ethanol, ethylene glycol, etc.), chloroform, ether, tetrahydrofuran, benzene, N,N-dimethylformamide, N,N-dimethylacetamide or any other organic solvent which does not adversely
influence the reaction.
The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
The reaction is usually carried out in the presence of an inorganic or an organic base such as an alkali metal hydroxide, an alkali metal hydrogencarbonate, alkali metal carbonate, alkali metal hydride (e.g. sodium hydride, etc.), alkali metal acetate, tri (lower) alkylamine,
pyridine base (e.g. pyridine, lutidine, picoline,
dimethylaminopyridine, etc.), N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, N,N-di (lower)alkylaniline or the like. When the base and/or the starting compound are in liquid, they can be used also as a solvent.
Process (B)
The compound (III) or a salt thereof can be prepared by reacting the compound (XI) or a salt thereof with the compound (XII) or a salt thereof.
The reaction is usually carried out in a conventional solvent such as alcohols (e.g. methanol, ethanol, ethylene glycol, etc.), chloroform, ether, tetrahydrofuran,
benzene, hexane or any other organic solvent which does not adversely influence the reaction.
The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
The reaction is usually carried out in the presence of an inorganic or an organic base such as an alkali metal hydroxide, an alkali metal hydrogencarbonate, alkali metal carbonate, alkali metal acetate, tri (lower) alkylamine, lower alkyl alkali metal (e.g. n-butyl lithium, etc.), pyridine base (e.g. pyridine, lutidine, picoline,
dimethylaminopyridine, etc.), N-(lower)alkylmorpholine, N,N-di(lower) alkylbenzylamine, N,N-di(lower) alkylaniline or the like. When the base and/or the starting compound are in liquid, they can be used also as a solvent. Process (C)
The compound (XV) or a salt thereof can be prepared by reacting the compound (XIII) or a salt thereof with the compound (XIV) 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 solvent which does not adversely affect the reaction. These conventional solvent may also be used in a mixture with water.
The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
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
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 (e.g., pyridine,
lutidine, picoline, dimethylaminopyridine, etc.),
N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, N,N-di(lower)alkylaniline or the like.
When the base and/or the starting compound are in liquid, they can be used also as a solvent. Process ( D )
The compound (XVIb) or a salt thereof can be prepared by subjecting the compound (XV) or a salt thereof to reduction reaction.
This reaction can be carried out in the manner disclosed in Preparation 5 or similar manners thereto.
Process (E)
The compound (II) or a salt thereof can be prepared by reacting the compound (XVIa) or a salt thereof with the compound (XVII) 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 solvent which does not adversely affect the reaction. These conventional solvent may also be used in a mixture with water.
The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
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
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 (e.g., pyridine,
lutidine, picoline, dimethylaminopyridine, etc.),
N-(lower) alkylmorpholine, N,N-di(lower) alkylbenzylamine, N,N-di(lower) alkylaniline or the like. When the base and/or the starting compound and in liquid, they can be used also as a solvent.
Process (F)
The compound (VI) or a salt thereof can be prepared by reacting the compound (XVIc) or its reactive
derivative, or a salt thereof with the compound (XVIII) or its reactive derivative, or a salt thereof.
Suitable reactive derivative of the compound (XVIc) may include Schiff 's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (XVIc) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (XVIc) with a silyl compound such as
bis(trimethylsilyl) acetamide, mono(trimethylsilyl)- acetamide [e.g. N-(trimethylsilyl)acetamide],
bis(trimethylsilyl)urea or the like; a derivative formed by reaction of the compound (XVIc) with phosphorus
trichloride or phosgene, and the like.
Suitable reactive derivative of the compound (XVIII) may include a conventional one such as 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, phenylphosphoric acid,
diphenylphosphoric acid, dibenzylphosphoric acid,
halogenated phosphoric acid, etc.], dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [e.g. methanesulfonic acid, etc.], aliphatic carboxylic acid [e.g. acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylic acid [e.g. benzoic acid, etc.]; a symmetrical acid anhydride; an activated amide with imidazole, 1-hydroxy-1H-benzotriazole,
4-substituted imidazole, dimethyIpyrazole, triazole or tetrazole; or an activated ester [e.g. cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl
Figure imgf000053_0001
ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester,
pentachlorophenyl ester, mesylphenyl ester,
phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, benzothiazolyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl 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 (XVIII) 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, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. These conventional solvent may also be used in a mixture with water.
In this reaction, when the compound (XVIII) is used in a free acid form or its salt form, the reaction is preferably carried out in the presence of 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;
N,N'-carbonyl-bis(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine;
diphenylketene-N-cyclohexylimine; ethoxyacetylene;
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
intramolecular salt; 1-(p-chlorobenzenesulfonyloxy)-6- chloro-1H-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc.; or the like.
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.
The reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
Process (G)
The compound (XV) or a salt thereof can be prepared by reacting the compound (XIX) or a salt thereof with the compound (XX) or a salt thereof.
This reaction can be carried out in the manner
disclosed in Preparation 9 or similar manners thereto. Process (H)
The compound (XVIIIa) or a salt thereof can be
prepared by subjecting the compound (XXII) or a salt thereof to elimination reaction of the carboxy protective group.
This reaction can be carried out in the manner disclosed in Preparation 11 or similar manners thereto.
Suitable salts of the object and starting compounds and their reactive derivatives in Processes (1)~(13) and (A)~(H) can be referred to the ones as exemplified for the compound (I).
The new guinoline derivatives (I) and a
pharmaceutically acceptable salt thereof of the present invention possess a strong immunomodulating activity (e.g. an inhibitory activity on the production of an
autoantibody, etc.), anti-inflammatory activity and anti-cancer activity and and therefore are useful as an immunomodulating agent (e.g. an inhibitor on the
production of an autoantibody, etc.), anti-inflammatory agent and anti-cancer agent.
Accordingly, the new quinoline 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 [e.g. lung carcinoma, stomach carcinoma, colon cancer, renal
carcinoma, hepatoma, etc.], and the like in human beings or animals, and more particularly for the treatment and/or prevention of inflammation and pain in 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 in which inflammation is involved [e.g. asthma, 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 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. glomerulonephritis, 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, sarcσidosis, Wegner's
granulomatosis, Hodgkin's disease, cancer [e.g. lung carcinoma, stomach carcinoma, colon cancer, renal
carcinoma, hepatoma, etc.], and the like.
In order to show the utilities of the guinoline derivatives (I) and a pharmaceutically acceptable salt thereof of the present invention, pharmacological test data of the representative compound of the quinoline derivatives (I) are illustrated in the following.
Inhibitory activity on the production of an
anti-DNA-antibody and on the leakage of a proteinuria.
1. Test method
Six weeks old female (57BL/6 × DBA/2)F1 and DBA/2 mice were used. Graft-varsus-host (GVH) disease was induced in (57BL/6 × DBA/2) F1 mice with two injections of
DBA/2 spleen cells given 5 days apart. Each injection contained 5 × 107 cells. From 3 days after the second cell injection, drug was administered orally once a day for 8 weeks.
As an indication of autoimmune disease, 4 weeks after the last cell injection anti-single strand DNA antibodies were measured by enzyme-linked immunosorbent assay (ELISA) using the procedure reported by T. Fujitsu et al.
(International J. Immunopharmacol, 8 897 (1986)). To assess the renal disease, 8 weeks after the last cell injection proteinuria were measured. The concentration of serum albumin in the urine was determined by the single radial immunodiffusion method using rabbit anti-mouse serum albumin antiserum. Ten mice were used per group. The activity of the compound was expressed as a %
inhibition of anti-DNA antibody and proteinuria.
2. Test compound
1-Methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4-hydroxy-6-methylsulfinyl-1,2-dihydroguinoline
3. Test result
Figure imgf000057_0001
Inhibitory activity on B16 melanoma metastases
1. Test Method
According to the experimental schedule as exemplified below, the experiment was carried out.
Mouse B16 melanoma cells (5×10 cells) were
inoculated intravenously to 8 weeks old female (C57BL/6) mice on day 0.
The animals were sacrificed at day 16 and tumor colonies established in lung were counted in a dissection microscope.
The test compound was administered orally once a day.
Effects of test compound on tumors were assessed by the numbers of colonies compared to control. experimental schedule
Figure imgf000058_0001
Test compound
1-methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl) -4- hydroxy-6-methylthio-1, 2-dihydr oquinoline
3. Test result
Figure imgf000058_0002
For therapeutic administration, the object compounds (I) of the present invention and pharmaceutically
acceptable salts thereof are used in a form of the
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. 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,
suspension or emulsion for injection, ingestion, eye drops, etc. If needed, there may be included in the above preparation 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. However, the above dosage may be increased or decreased according to age, weight and conditions of the patient or the
administering method.
Preferred embodiments of the object compound (I) are as follows. R 1 is lower alkyl or phenyl which may have suitable
substituent(s) [more preferably phenyl which may have halogen; most preferably phenyl or halophenyl],
R 2 is hydroxy, protected hydroxy [more preferably acyloxy], lower alkoxy, halogen, amino, lower alkylamino, protected amino [more preferably acylamino], mercapto, or protected mercapto [more preferably acylthio; most preferably lower alkanoylthio],
R 3 is hydrogen, lower alkyl, lower alkoxy( lower) alkyl, or ar( lower) alkyl [more preferably phenyl ( lower) alkyl; most preferably benzyl],
R 8 is hydrogen, or
R 3 and R8 are linked together to form lower alkylene,
R 4 is acyl [more preferably carbamoyl which may be
substituted with one or two suitable substituent(s) selected from the group consisting of lower alkyl;
phenyl which may have 1 to 3 (more preferably 1 or 2) suitable substituent(s) selected from the group
consisting of lower alkyl, halogen, lower alkoxy, lower alkylthio, acyl, di(lower) alkylamino, cyano, mono(or di or tri)halo(lower)alkyl, mono(or di or tri)halo(lower)- alkoxy, carboxy, protected carboxy, nitro, amino and acylamino; heterocyclic group which may have lower alkyl; phenyl(lower) alkyl; lower cycloalkyl and a group of the formula :
Figure imgf000060_0001
(in which A is lower alkylene);
thiocarbamoyl which may be substituted with one or two suitable substituent(s) selected from the group consisting of lower alkyl and aryl;
lower alkoxycarbonyl;
aminosulfonyl which may be substituted with one or two suitable substituent(s) selected from the group consisting of lower alkyl and aryl;
aroyl; ar(lower)cycloalkylcarbonyl;
ar(lower)alkylsulfonyl; or heterocycliccarbonyl;
most preferably carbamoyl which may be substituted with one or two suitable substituent(s) selected from the group consisting of lower alkyl, phenyl, mono(or
di) (lower)alkylphenyl, mono(or di)halophenyl,
( lower)alkoxyphenyl, lower alkylthiophenyl, lower alkanoylphenyl, di(lower) alkylaminophenyl, cyanophenyl, trihalo( lower) alkylphenyl, trihalo( lower)alkoxyphenyl, carboxyphenyl, lower alkoxycarbonylphenyl, nitrophenyl, aminophenyl, lower alkanoylaminophenyl, pyridyl, lower alkylpyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, benzodioxolyl, phenyl(lower) alkyl, lower cycloalkyl and indanyl; thiocarbamoyl which may be substituted with one or two suitable substituent(s) selected from the group consisting of lower alkyl and phenyl;
lower alkoxycarbonyl;
aminosulfonyl which may be substituted with one or two suitable substituent(s) selected from the group consisting of lower alkyl and phenyl;
benzoyl; phenyl( lower) cycloalkylcarbonyl;
phenyl(lower)alkylsulfonyl;
indolinylcarbonyl, dihydrobenzoxazinylcarbonyl; or dihydrobenzothiazinylcarbonyl]; carboxy;
ar(lower)alkylsulfinyl [more preferably phenyl(lower)- alkylsulfinyl; most preferably benzylsulfinyl];
ar(lower) alkylthio [more preferably phenyl(lower)- alkylthio; most preferably benzylthio]; cyano;
heterocyclic group which may have suitable
substituent(s) [more preferably unsaturated 3 to
8-membered (more preferably 5 or 6-membered)
heteromonocyclic group containing 1 to 4 nitrogen atom(s) which may have aryl,
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2-oxygen atom(s) and 1 to 3 nitrogen atom(s) which may have aryl, or
unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s) which may have lower alkyl;
most preferably imidazolinyl, phenylimidazolinyl, tetrazolyl, phenyltetrazolyl, oxadiazolyl,
phenyloxadiazolyl, benzimidazolyl, lower
alkylbenzimidazolyl, guinolyl or isoguinolyl],
Z is O or S and
n is 0, 1 or 2.
The following Preparations and Examples are given for the purpose of illustrating the present invention in more detail. Preparation 1
To a solution of 6-methylthio-2H-3,l-benzoxazine- 2,4(1H)-dione (13 g) in N,N-dimethylacetamide (130 ml), sodium hydride (2.74 g, 60% in mineral oil) was slowly added and the mixture was stirred for 1 hour at room temperature. Methyl iodide (4.26 ml) was added and the reaction was allowed to stir for 3 hours at room temperature. The reaction mixture was poured into ice-water (650 ml). The precipitates were filtered, washed with water, and dried to give yellow crystals of
1-methyl-6-methylthio-2H-3,1-benzoxazine-2,4(1H)-dione
(12.8 g).
mp : 183-191°C
IR (Nujol) : 1770, 1720, 1610, 1590 cm-1
NMR (DMSO-d6, δ) : 2.54 (3H, s), 3.45 (3H, s),
7.3-7.8 (3H, m)
Preparation 2
To a solution of N-methyl-N-phenylmethanesulfonamide (25 g) in tetrahydrofuran (250 ml) was added dropwise 1.6M n-butyllithium in hexane (89 ml), keeping the temperature of the reaction below 20°C. Then a solution of diethyl carbonate (8.2 ml) in tetrahydrofuran (40 ml) was added dropwise, keeping the temperature of the reaction below
-30°C. The mixture was allowed to warm to room
temperature and concentrated in vacuo. Water was added to the residue, and the resulting solution was acidified and extracted with chloroform. Removal of the solvent
furnished an oil (30 g), which was purified by column
chromatography on silica gel (200 g) eluting with toluene to give a yellow oil of ethyl (N-methyl-N-phenylamino)- sulfonylacetate (12.5 g).
IR (Film) : 1740, 1600, 1495, 1355 cm-1
NMR (CDCl3, δ) : 1.31 (3H, t, J=7.1Hz), 3.41 (3H,
s), 3.94 (2H, s), 4.25 (2H, q, J=7.1Hz), 7.1-7.6 (5H, m)
Mass (m/z) : 257 (M+)
Preparation 3
The following compounds were obtained according to a similar manner to that of Preparation 1.
( 1 ) 6-Ethylthio-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione mp : 143-150°C
IR (Nujol) : 1785, 1730, 1610, 1590 cm-1
NMR (DMSO-d6, δ) : 1.23 (3H, t, J=7.3Hz), 2.99 (2H, q, J=7.3Hz), 3.45 (3H, s), 7.41 (1H, d,
J=9.0Hz), 7.7-7.9 (2H, m)
Mass (m/z) : 237 (M+)
( 2 ) 1-Methyl-6-(neopentylthio)-2H-3,1-benzoxazine- 2,4(1H)-dione
mp : 128-131°C
IR (Nujol) : 1780, 1765, 1735, 1610, 1580 cm-1
NMR (DMSO-d6, δ) : 1.00 (9H, s), 2.98 (2H, s), 3.45
(3H, s), 7.3-7.9 (3H, m)
Mass (m/z) : 279 (M+)
(3) 1-Ethyl-6-methylthio-2H-3,1-benzoxazine-2,4(1H)-dione mp : 135-145°C
IR (Nujol) : 1780, 1720, 1605, 1580 cm1
NMR (DMSO-d6, δ) : 1.22 (3H, t, J=7.1Hz), 2.54 (3H, s), 4.08 (2H, q, J=7.1Hz), 7.4-7.8 (3H, m) (4) 1-Benzyl-6-methylthio-2H-3,1-benzoxazine-2,4(1H)- dione
mp : 169-171°C
IR (Nujol) : 1780, 1720, 1620, 1580 cm-1
NMR (DMSO-d6, δ) : 2.51 (3H, s), 5.28 (2H, s),
7.1-7.8 (8H, m) Mass (m/z) : 299 (M+)
( 5) 1-Methoxymethyl-6-methylthio-2H-3,1-benzoxazine- 2,4(1H)-dione
mp : 122-126°C
IR (Nujol) : 1780, 1760, 1725, 1605, 1585 cm-1 NMR (DMSO-d6, δ) : 2.54 (3H, s), 3.36 (3H, s), 5.43
(2H, s), 7.3-7.8 (3H, m) (6) 6-Methylthio-1-propyl-2H-3,1-benzoxazine-2,4(1H)- dione
mp : 126-131°C
IR (Nujol) : 1775, 1730, 1605, 1580 cm-1
NMR (DMSO-d6, δ) : 0.95 (3H, t, J=7.3Hz), 1.64 (2H, sextet, J=7.3Hz), 2.54 (3H, s), 3.95 (2H, t,
J=7.3Hz), 7.46 (1H, d, J=8.9Hz), 7.7-7.8 (2H, m)
(7) 1-Methyl-6-phenylthio-2H-3,1-benzoxazine-2,4(1H)- dione
mp : 118-121°C
IR (Nujol) : 1790, 1770, 1735, 1610 cm-1
NMR (DMSO-d6, δ) : 3.45 (3H, s), 7.3-7.5 (6H, m),
7.7-7.9 (2H, m)
Mass (m/z) : 285 (M+)
( 8) 6-(4-Fluorophenylthio)-1-methyl-2H-3,1-benzoxazine- 2,4-(1H)-dione
mp : 131-133°C
IR (Nujol) : 1780, 1745, 1715, 1610, 1585 cm-1
NMR (DMSO-d6, δ) : 3.45 (3H, s), 7.2-7.9 (7H, m) Mass (m/z) : 303 (M )
Preparation 4
A mixture of 5-mercapto-2-nitrobenzoic acid (4 g) and potassium carbonate (2.76 g) in 2-methoxyethanol (40 ml) was stirred for 10 minutes. Neopentyl tosylate (6.3 g) was added and the mixture was refluxed for 1.5 hours. The solvent was evaporated, and the residue was dissolved in water, washed with isopropyl ether, acidified with
hydrochloric acid, and extracted with dichloromethane. The extract was evaporated to give 5-(neopentylthio)- 2-nitrobenzoic acid (yellow solid, 5.2 g).
mp : 145-198°C
IR (Nujol) : 1715, 1605, 1570, 1515 cm-1
NMR (DMSO-d6, δ) : 1.03 (9H, s), 3.10 (2H, s),
7.5-8.1 (3H, m)
Mass (m/z) : 269 (M+)
Preparation 5
(1) To a mixture of 5-(neopentylthio)-2-nitrobenzoic acid (4.8 g), sodium hydroxide (0.86 g), ferric chloride (0.29 g), activated carbon (0.2 g), and isopropyl alcohol (2 ml) in water (34 ml) was added hydrazine hydrate (2.1 ml) at 75°C. The mixture was stirred at 75-80°C for 90 minutes and filtered through celite. The filtrate was cooled and acidified to pH=4.6. The precipitates were collected by filtration, washed with water, and dried to give a yellow solid of 5-(neopentylthio)anthranilic acid (2.7 g).
mp : 115-122°C
IR (Nujol) : 3550, 3430, 1680, 1620, 1580, 1560 cm-1 NMR (DMSO-d6, δ) : 0.95 (9H, s), 2.73 (2H, s), 6.72 (1H, d, J=8.6Hz), 7.30 (1H, dd, J=8.6, 2.1Hz), 7.75 (1H, d, J=2.1Hz), 8.71 (2H, broad s)
Mass (m/z) : 239 (M+)
The following compound was obtained according to a similar manner to that of Preparation 5-(1).
(2) 5-(4-Fluorophenylthio) anthranilic acid
mp : 184-186°C IR (Nujol) : 3520, 3400, 1680, 1610, 1580, 1550 cm-1 NMR (DMSO-d6 δ) : 6.8-7.4 (6H, m), 7.86 (1H, d,
J=2.2Hz), 8.88 (1H, broad s)
Mass (m/z) 263 (M+)
Preparation 6
Into a solution of 5-(ethylthio)anthranilie acid (3.5 g), sodium hydroxide (1.42 g) and dry-ice (8.9 g) in water (89 ml) was bubbled phosgene prepared from trichloromethyl chloroformate (1.62 ml) and activated carbon (0.2 g) at room temperature for 10 minutes. The mixture was stirred for 2 hours, and the precipitates were collected by filtration, washed with water and dried in the air to give green-yellow crystals of 6-ethylthio-2H-3,1-benzoxazine- 2,4(1H)-dione (2.9 g).
mp : >300°C
IR (Nujol) : 3150, 3080, 1780, 1740, 1715, 1620 cm -1 NMR (DMSO-d6, δ) : 1.22 (3H, t, J=7.3Hz), 2.99 (2H, q, J=7.3Hz), 7.12 (1H, d, J=8.4Hz), 7.6-7.8 (2H, m), 11.8 (1H, s)
Mass (m/z) : 223 (M+)
Preparation 7
(1) A mixture of 5-(neopentylthio)anthranilic acid (5.8 g) and ethyl chloroformate (11.6 ml) in xylene (58 ml) was refluxed for 24 hours and cooled. The precipitates were collected by filtration and washed with ether to give a gray powder of 6-(neopentylthio)-2H-3,1-benzoxazine-2,4(1H)-dione (1.9 g).
mp : 221-225°C
IR (Nujol) : 3250, 1790, 1765, 1700, 1615 cm-1
NMR (DMSO-d 6, δ) 0.99 (9H, s), 2.95 (2H, s),
7.0-7.8 (3H, m), 11.7 (1H, s)
Mass (m/z) 265 (M+) The following compounds were obtained according to a similar- manner to that of Preparation 7-(l).
( 2 ) 6-Phenylthio-2H-3,1-benzoxazine-2,4(1H)-dione
mp : 135-138°C
IR (Nujol) : 3250, 1790, 1765, 1700, 1615 cm-1
NMR (DMSO-d6, δ) : 7.1-7.5 ( 6H, m), 7.7-7.8 (2H, m),
11.88 (1H, s)
Mass (m/z) : 271 (M+), 227
( 3 ) 6-(4-Fluorophenylthio)-2H-3,1-benzoxazine-2,4- (1H)-dione
mp : 237-240°C
IR (Nujol) : 3250, 3180, 1790, 1760, 1695, 1615,
1585 cm-1
NMR (DMSO-d6, δ) : 7.1-7.8 (7H, m), 11.85 (1H, s) Mass (m/z) : 289 (M+), 245
Preparation 8
(1) A mixture of ethyl 2-(methylamino)-5-(methylthio)-benzoate (2.25 g), benzoylacetic acid (1.9 g),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (2.7 g) and 4-dimethylaminopyridine (10 mg) in dichloromethane (50 ml) was stirred at room temperature overnight. The mixture was washed with brine, dried and concentrated in vacuo. The residue (4.2 g) was purified by column chromatography on silica gel (70 g) eluting with a mixture of ethyl acetate and n-hexane (1:3) to give a yellow oil of ethyl 2-{N-methyl-N-(2-benzoylacetyl)amino}-5-(methylthio)benzoate (2.9 g).
NMR (DMSO-d6, δ) : 1.17 (3H, t, J=7Hz), 2.58 (3H, s), 3.22 (3H, s), 4.24 (2H, g, J=7Hz), 5.18 (1H, s), 7.3-8.1 (8H, m), 15.1 (1H, s) The following compounds were obtained according to a similar manner to that of Preparation 8-(1).
( 2) Ethyl 2-[{2-(N-phenyl-N-methylcarbamoyl)acetyl}- amino]-5-(methylthio)benzoate
mp : 115-117°C
IR (Nujol) : 1705, 1680, 1660, 1595, 1495 cm-1 NMR (DMSO-d6, δ) : 1.32 (3H, t, J=7.1Hz), 2.49 (3H, s), 3.21 (3H, s), 3.27 (2H, s), 4.31 (2H, g, J=7.1Hz), 7.3-8.2 (8H, m), 10.6 (1H, s)
(3) Ethyl 2-[N-methyl-N-{3-oxo-3-(1-phenyl-1- cyclopropyl)propionyl}amino]-5-(methylthio)benzoate IR (Film) : 1725, 1705, 1660, 1615, 1490 cm-1
NMR (CDCl3, δ) : 1.1-1.2 (2H, m), 1.27 (3H, t,
J=7.1Hz), 1.5-1.6 (2H, m), 2.55 (3H, s), 3.10
(3H, s), 4.26 (2H, q, J=7.1Hz), 6.73 (1H, d, J=8.3Hz), 7.1-7.4 (6H, m), 7.74 (1H, d, J=2.3Hz) Mass (m/z) : 411 (M+) Preparation 9
A solution of potassium hydroxide (7.3 g) in methanol (40 ml) and water (3 ml) was added to a mixture of
4-fluorobenzenethiol (6.5 g) and 5-chloro-2-nitrobenzoic acid (10.1 g) in methanol (30 ml) under a nitrogen
atmosphere. The mixture was refluxed for 6 hours, cooled, and poured into water (350 ml). The solution obtained was acidified, and the precipitates were collected by
filtration and washed with water. The product was
recrystallized twice from a mixture of ethanol and water to give a white powder of 5-(4-fluorophenylthio)-2-nitrobenzoic acid (10 g).
mp : 150-153°C
IR (Nujol) : 1710, 1590, 1570, 1535 cm-1
NMR (DMSO-d6, δ) : 7.3-7.8 (6H, m), 7.95 (1H, d,
J=8.6Hz), 14.0 (1H, broad s) Mass (m/z ) : 293 ( M+)
Preparation 10
Sodium hydride (1.5 g) was added to a solution of 1-acetyl-1-phenylcyclopropane (5 g) and diethyl carbonate (18.8 ml) in tetrahydrofuran (62 ml). The mixture was refluxed for 1 hour, cooled, diluted with an saturated aqueous ammonium chloride solution, and extracted with ether. The extract was washed with brine, dried, and concentrated. The residue (7.7 g) was purified by column chromatography on silica gel (230 g) eluting with a mixture of ether and hexane (3:20) to give a light orange oil of ethyl 3-oxo-3-(1-phenyl-1-cyclopropyl)propionate (5 g).
IR (Film) : 1745, 1700, 1605, 1500 cm-1
NMR (CDCl3, δ) : 1.1-1.3 (5H, m), 1.6-1.8 (2H, m), 3.34 (2H, s), 4.10 (2H, q, J=7.1Hz), 7.3-7.5 (5H, m)
Mass (m/z) : 232 (M+)
Preparation 11
A mixture of ethyl 3-oxo-3-(1-phenyl-1-cyclopropyl)-propionate (4.9 g) in 1N agueous sodium hydroxide (21 ml) was stirred at room temperature overnight. The solution obtained was washed with ether, acidified with
hydrochloric acid, and extracted with dichloromethane.
The extract was dried and concentrated. The residue was kept in a freezer to give a white powder of
3-oxo-3-(l-phenyl-1-cyclopropyl)propionic acid (3.9 g). mp : 50-55°C
IR (Film) : 1745, 1710, 1605, 1500 cm-1
NMR (CDCl3, δ) : 1.3-1.4 (2H, m), 1.7-1.8 (2H, m),
3.39 (2H, s), 7.37 (5H, s)
Mass (m/z)) : 204 Example 1
(1) To a solution of ethyl 3-(N-methyl-N-phenylamino)-3- oxopropionate (16.8 g) in N,N-dimethylacetamide (48 ml), sodium hydride (3.03 g, 60%) was slowly added and the mixture was stirred for 30 minutes at room temperature. To the mixture was added dropwise a solution of
1-methyl-6-methylthio-2H-3,1-benzoxazine-2,4(1H)-dione ( 16 g) in N,N-dimethylacetamide (160 ml) at 80°C. Then the mixture was stirred at 120°C for 5 hours. The mixture was poured into ice-water (1 ℓ) and neutralized with
concentrated hydrochloric acid (7 ml). The precipitates were collected, washed with water, and dissolved in chloroform (250 ml). The solution was filtered and the filtrate was concentrated. The residue was heated in ethanol and cooled to give pale brown crystals of
1-methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4-hydroxy-6-methylthio-1,2-dihydroguinσline (13.4 g).
mp : 200-202°C (dec.)
IR (Nujol) : 1650, 1635, 1615, 1590, 1565, 1500 cm-1 NMR (DMSO-d6, δ) : 2.49 (3H, s), 3.29 (3H, s),
3.42 (3H, s), 7.0-7.8 ( 8H, m), 11.3 (1H, s) Mass (m/z) : 354 (M+)
Elemental Analysis Calcd. for C19H18N2O3S :
C 64.39, H 5.12, N 7.91 Found : C 64.54, H 5.07, N 7.69
The following compounds were obtained according to a similar manner to that of Example 1-(1). (2) 1-Methyl-2-oxo-3-(N-methyl-N-phenylaminosulfonyl)-4- hydroxy-6-methylthio-1,2-dihydroguinoline
mp : 154-156°C
IR (Nujol) : 1635, 1560 cm-1
NMR (DMSO-d6, δ) : 2.51 (3H, s), 3.51 (3H, s),
3.60 (3H, s), 7.2-7.8 (8H, m) Mass (m/z ) : 390 (M+)
Elemental Analysis Calcd. for C18H18N2O4S2 :
C 55.37, H 4.65, N 7.18 Found : C 55.08, H 4.59, N 7.11
(3) 1-Methyl-2-oxo-3-ethoxycarbonyl-4-hydroxy-6- methylthio-1,2-dihydroguinoline
mp : 114-115°C
IR (Nujol) : 1660, 1630, 1565, 1490 cm-1
NMR (DMSO-d6, δ) : 1.30 (3H, t, J=7.1Hz), 2.54 (3H, s), 3.51 (3H, s), 4.32 (2H, q, J=7.1Hz),
7.4-7.9 (3H, m)
Mass (m/z) : 293 (M+) (4) 1-Methyl-2-oxo-3-benzylsulfonyl-4-hydroxy-6- methylthio-1,2-dihydroquinoline
mp : 157-159°C
IR (Nujol) : 1645, 1575 cm-1
NMR (DSMO-d6, δ) : 2.51 (3H, s), 3.63 (3H, s),
5.00 (2H, s), 7.32 (5H, s), 7.5-7.8 (3H, m)
Mass (m/z) : 375 (M+)
Elemental Analysis Calcd. for C18H17NO4S2 :
C 57.58, H 4.56, N 3.73, S 17.08 Found : C 57.40, H 4.50, N 3.69, S 17.09
Example 2
To an ice-cooled solution of 1-methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4-hydroxy-6-methylthio-1,2-dihydroquinoline (1.45 g) in dichloromethane (40 ml) was added portionwise 80%-m-chloroperbenzoic acid (0.883 g). The mixture was stirred at 5°C for 1 hour, washed with water, dried over anhydrous magnesium sulfate, and
concentrated in vacuo. The residue was crystallized from acetone- to give colorless crystals of
1-methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4-hydroxy 6-methylsulfinyl-1,2-dihydroguinoline (1.5 g).
mp : 218-219°C (dec.)
IR (Nujol) : 1635, 1595, 1500 cm-1
NMR (DMSO-d6, δ) : 2.75 (3H, s), 3.30 (3H, s),
3.48 ( 3H, s) , 7. 0-8.2 ( 8H, m) , 11.7 ( 1H, s) Mass (m/z) : 370 (M+)
Elemental Analysis Calcd. for C19H18N2O4S·1/7H2O :
C 61.18, H 4.94, N 7.51 Found : C 60.95, H 5.00, N 7.24
Example 3
A mixture of 1-methyl-2-oxo-3-ethoxycarbonyl-4- hydroxy-6-methylthio-1,2-dihydroquinoline (2 g) and indoline (0.94 ml) in pyridine (10 ml) was stirred at 100°C for 4 hours. The solvent was evaporated and the residue was dissolved in chloroform. The solution was filtered and the filtrate was concentrated in vacuo. The residue was crystallized from ethanol to give pale brown crystals of 1-methyl-2-oxo-3-(1-indolinylcarbonyl)-4- hydroxy-6-methylthio-1,2-dihydroguinoline (2.1 g).
mp : 220-222°C (dec.)
IR (Nujol) : 1655, 1625, 1605, 1580, 1560 cm-1
NMR (DMSO-d6, δ) : 2.55 (3H, s), 3.08 (2H, t,
J=8.3Hz), 3.59 (3H, s), 3.88 (2H, t, J=8.3Hz), 7.0-8.3 (7H, m), 11.5 (1H, s)
Mass (m/z) : 366 (M+)
Elemental Analysis Calcd. for C20H18N2O3S·0.28H2O :
C 64.66, H 5.04, N 7.54 Found : C 64.47, H 4.92, N 7.42
Example 4
A mixture of 1-methyl-2-oxo-3-ethoxycarbonyl-4-hydroxy-6-methylthio-1,2-dihydroquinoline (2.2 g) and hydrobromic acid (1.7 ml) in acetic acid (6 ml) was
stirred at 70°C for 4 hours. The mixture was cooled to 5°C, and the precipitates were collected, washed with water and dried in vacuo at 60°C to give pale yellow crystals of 1-methyl-2-oxo-3-carboxy-4-hydroxy-6-methylthio-1,2-dihydroquinoline (1.8 g).
mp : 162-163°C
IR (Nujol) : 1690, 1630, 1600, 1490 cm-1
NMR (DMSO-d6, δ) : 2.5.7 (3H, s), 3.67 (3H, s),
7.6-7.9 (3H, m)
Mass (m/z) : 265 (M+)
Example 5
Phosphorus trichloride (0.347 ml) was added dropwise to a solution of N-methyl-4-fluoroaniline (2.99 g) in toluene (18 ml) under stirring. After stirring was continued at room temperature for 30 minutes, to the resultant solution 1-methyl-2-oxo-3-carboxy-4-hydroxy-6-methylthio-1,2-dihydroquinoline (2.11 g) was added. The mixture was heated at 100°C for 2 hours arid then cooled down. The reaction mixture was extracted with 2N sodium hydroxide solution. The extract was acidified with hydrochloric acid and extracted with chloroform. The extract obtained above was dried over magnesium sulfate, filtered and evaporated to dryness. The residue was washed with acetone and dried in vacuo to give pale brown crystals of 1-methyl-2-oxo-3-{N-(4-fluorophenyl)-N-methylcarbamoyl}-4-hydroxy-6-methylthio-1,2-dihydroguinoline (2.1 g).
mp : 201-203°c
IR (Nujol) : 1650, 1635, 1615, 1595, 1570, 1510 cm-1 NMR (DMSO-d6, δ) : 2.50 (3H, s), 3.28 (3H, s),
3.43 (3H, s), 7.0-7.8 (7H, m), 11.4 (1H, s) Mass (m/z) : 372 (M+)
Elemental Analysis Calcd. for C19H17FN2O3S :
C 61.27, H 4.60, N 7.52 Found : C 61.29, H 4.50, N 7.45 Example 6
The following compounds were obtained according to a similar manner to that of Example 1-(1). (1) 1-Methyl-2-oxo-3-cyano-4-hydroxy-6-methylthio-1,2- dihydroquinoline
mp : 258-260°C
IR (Nujol) : 2240, 1620, 1585, 1550 cm-1
NMR (DMSO-d6, δ) : 2.53 (3H, s), 3.53 (3H, s),
7.4-8.0 (3H, m)
Mass (m/z) : 246 (M+)
(2) 1-Methyl-2-oxo-3-[N-methyl-N-phenylamino-
(thiocarbonyl)]-4-hydroxy-6-methylthio-1,2- dihydroquinoline
mp : 174-176°C
IR (Nujol) : 1620, 1570 cm-1
NMR (DMSO-d6, δ) : 2.48 (3H, s), 3.41 (3H, s), 3.74 (3H, s), 7.1-7.7 (8H, m), 10.9 (1H, s) Mass (m/z) : 370 (M+), 263
Elemental Analysis Calcd. for C19H18N2O2S2 :
C 61.60, H 4.90, N 7.56, S 17.31 Found : C 61.29, H 4.87, N 7.42, S 17.09 (3) 1-Methyl-2-oxo-3-(1-phenyl-5-tetrazolyl)-4-hydroxy-6- methylthio-1,2-dihydroquinoline
mp : 263-265°C (dec.)
IR (Nujol) : 1630, 1605, 1590, 1560, 1515 cm-1
NMR (DMSO-d6, δ) : 2.53 (3H, s), 3.51 ( 3H, s), 7.52
(5H, s), 7.4-7.9 (3H, m)
Mass (m/z) : 365 (M+), 337
(4) 1-Methyl-2-oxo-3-(5-phenyl-l,3,4-oxadiazol-2-yl)-4- hydroxy-6-methylthio-1,2-dihydroquinoline
mp : 240-242°C IR (Nujol) : 1660, 1640, 1580, 1535 cm-1
NMR (DMSO-d6, δ) : 2.57 (3H, s), 3.79 (3H, s),
7.2-8.3 (8H, m)
Mass (m/z) : 365 (M+)
(5) 1-Methyl-2-oxo-3-(1-methyl-1H-benzimidazol-2-yl)-4- hydroxy-6-methylthio-1,2-dihydroquinoline
mp : 198-204°C
IR (Nujol) : 1605, 1575, 1530 cm-1
NMR (DMSO-d6, δ) : 2.51 (3H, s), 3.53 (3H, s), 3.79
(3H, s), 7.3-8.0 (7H, m)
Mass (m/z) : 351 (M+)
( 6 ) 1-Methyl-2-oxo-3-(1-phenylimidazolin-2-yl)-4-hydroxy- 6-methylthio-1,2-dihydroquinoline
mp : 120-130°C
IR (Nujol) : 1590, 1560, 1525 cm-1
NMR (DMSO-d6, δ) : 2.45 (3H, s), 3.27 (3H, s), 3.88 (2H, t, J=8.9Hz), 4.25 (2H, t, J=8.9Hz),
7.0-7.8 (8H, m), 10.4 (1H, s)
Mass (m/z) : 365 (M+)
(7) 1-Methyl-2-oxo-3-(1-isoquinolyl)-4-hydroxy-6- methylthio-1,2-dihydroguinoline
mp : 136-140°C
IR (Nujol) : 1645, 1620, 1610, 1585, 1565, 1515 cm-1 NMR (DMSO-d6, δ) : 2.53 (3H, s), 3.56 (3H, s),
7.4-8.5 (9H, m)
Mass (m/z) : 347
(8) 1-Methyl-2-oxo-3-(2-guinolyl)-4-hydroxy-6-methylthio- 1,2-dihydroquinoline
mp : 225-227°C
IR (Nujol) : 1640, 1610, 1570, 1505 cm-1
NMR (DMSO-d6, δ) : 2.55 (3H, s), 3.60 (3H, s), 7.4-8.1 (7H, m) , 8.63 (1H, d, J=9.4Hz), 9.49 (1H, d, J=9.4Hz)
Mass (m/z) : 348 (M+) (9) 1-Methyl-2-oxo-3-{N-(2-methoxyphenyl)-N-methylcarbamoyl}-4-hydroxy-6-methylthio-1,2-dihydroquinoline
mp : 178-180°C
IR (Nujol) : 1610, 1570, 1490 cm-1
NMR (DMSO-d6, δ) : 2.49 (3H, s), 3.21 (3H, s), 3.36
(3H, s), 3.71 (3H, s), 6.6-7.8 (7H, m), 11.0 (1H, s)
Mass (m/z) : 384 (M+), 247
Elemental Analysis Calcd. for C90H20N2O4S :
C 62.48, H 5.24, N 7.29
Found : C 62.17, H 5.29, N 7.15
(10) 1-Methyl-2-oxo-3-{N-(2-chlorophenyl)-N- methylcarbamoyl}-4-hydroxy-6-methylthio-l,2-dihydroquinoline
mp : 175-183°C
IR (Nujol) : 1630, 1620, 1585, 1570 cm-1
NMR (DMSO-d6, δ) : 2.50 (3H, s), 3.27 (3H, s), 3.38 (3H, s), 7.1-8.0 (7H, m), 11.3 (1H, broad s) Mass (m/z) : 388 (M+), 247
( 11) 1-Methyl-2-oXo-3-{N-methyl-N-(2-methylphenyl)- carbamoyl}-4-hydroxy-6-methylthio-l,2-dihydroquinoline mp : 188-194°C
IR (Nujol) : 1635, 1620, 1595, 1575, 1495 cm-1
NMR (DMSO-d6, δ) : 2.34 (3H, s), 2.49 (3H, s), 3.20
(3H, s), 3.38 (3H, s), 6.9-8.0 (7H, m) Mass (m/z) : 368 (M+), 247
Elemental Analysis Calcd. for C20H20N2O3S :
C 65.20, H 5.47, N 7.60
Found : C 65.75, H 5.79, N 7.30 (12) 1-Methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4- hydroxy-6-ethylthio-1,2-dihydroquinoline
mp : 140-148°C
IR (Nujol) : 1650, 1610, 1585, 1560 cm-1
NMR (DMSO-d6, δ) : 1.19 (3H, t, J=7.3Hz), 2.93 (2H, q, J=7.3Hz), 3.30 (3H, s), 3.43 (3H, s), 7.1-7.8 (8H, m), 11.3 (1H, s)
Mass (m/z) : 368 (M+), 261 (13) 1-Methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4- hydroxy-6-(neopentylthio)-1,2-dihydroquinoline mp : 121-123°C
IR (Nujol) : 1655, 1630, 1610, 1585 cm-1
NMR (DMSO-d6, δ) : 0.98 (9H, s), 2.92 (2H, s), 3.29 (3H, s), 3.42 (3H, s), 7.1-7.9 (8H, m), 11.3
(1H, broad s)
Mass (m/z) : 410 (M+)
( 14 ) 1-Ethyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4- hydroxy-6-methylthio-1,2-dihydroquinoline
mp : 174-180°C
IR (Nujol) : 1640, 1620, 1580 cm-1
NMR (DMSO-d6, δ) : 1.23 (3H, t, J=7Hz), 2.49 (3H, s), 3.29 (3H, s), 4.10 (2H, q, J=7Hz), 7.0-7.8 (8H, m), 11.3 (1H, s)
Mass (m/z) : 368 (M+)
Elemental Analysis Calcd. for C20H20N2O3S :
C 65.20, H 5.47, N 7.60, S 8.70 Found : C 65.52, H 5.59, N 7.34, S 8.74
( 15 ) 1-Benzyl-2-oxo-3- (N-methyl-N-phenylcarbaraoyl) -4- hydroxy-6-raethylthio-1 , 2-dihydroquinoline
mp : 185-195°C
IR (Nujol) : 1640, 1620, 1590, 1500 cm-1
NMR (DMSO-d6, δ) : 2.45 (3H, s), 3.33 (3H, s), 6.7-7.8 (13H, m), 11.5 (1H, s) Mass (m/z) : 430 (M+)
Elemental Analysis Calcd. for C25H22N2O3S :
C 65.20, H 5.47, N 7.60, S 8.70 Found : C 65.52, H 5.59, N 7.34, S 8.74
(16) 1-Methoxymethyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)- 4-hydroxy-6-methylthio-1,2-dihydroquinoline
mp : 152-156°C
IR (Nujol) : 1645, 1605, 1580, 1560 cm-1
NMR (DMSO-d6, δ) : 2.49 (3H, s), 2.95 (3H, s), 3.30 (3H, s), 5.49 (2H, s), 7.0-7.8 (8H, m), 11.6 (1H, broad s)
Mass (m/z) : 384 (M+)
(17) 1-Propyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4- hydroxy-6-methylthio-1,2-dihydroquinoline
mp : 142-152°C
IR (Nujol) : 1640, 1630, 1605, 1580 cm-1
NMR (DMSO-d6, δ) : 0.76 (3H, t, J=7.1Hz), 1.3-1.6 (2H, m), 2.48 (3H, s), 3.29 (3H, s), 3.9-4.1 (2H, m), 7.0-7.8 (8H, m), 11.3 (1H, s) Mass (m/z) : 382 (M+)
Elemental Analysis Calcd. for C21H22N2O3S :
C 65.95, H 5.80, N 7.32, S 8.38
Found : C 66.07, H 6.22, N 7.08, S 8.38
(18) 1-Methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4- hydroxy-6-phenylthio-l,2-dihydroquinoline
mp : 110-115°C
NMR (DMSO-d6, δ) : 3.28 (3H, s), 3.44 (3H, s),
7.0-8.0 (13H, m)
(19) 1-Methyl-2-thioxo-3-ethoxycarbonyl-4-hydroxy-6- methylthio-1,2-dihydroquinoline mp : 135-137°C
IR (Nujol) : 1690, 1610, 1530 cm-1
NMR (DMSO-d6, δ) : 1.28 (3H, t, J=7.1Hz), 2.57 (3H, s), 4.17 (3H, s), 4.26 (2H, q, J=7.1Hz), 7.6-8.0
(3H, m)
(20) 1-Methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4- hydroxy-6-(4-fluorophenylthio)-1,2-dihydroquinoline IR (Nujol) : 1640, 1615, 1585, 1550, 1510 cm-1
NMR (DMSO-d6, δ) : 3.26 (3H, s), 3.37 (3H, s),
7.0-7.6 (11H, m), 8.02 (1H, broad s)
Mass (m/z) : 327
Example 7
The following compounds were obtained according to a similar manner to that of Example 2.
(1) 1-Methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4- methoxy-6-methylsulfinyl-1,2-dihydroquinoline
mp : 322-325°C (dec.)
IR (Nujol) : 1640, 1630, 1595, 1495 cm-1
NMR (DMSO-d6, δ) : 2.74 (3H, s), 3.36 (3H, s), 3.53
(3H, s), 4.15 (3H, s), 7.1-8.4 (8H, m) Mass (m/z) : 384 (M+)
(2) 1-Methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4- hydroxy-6-phenylsulfinyl-1,2-dihydroquinoline
mp : 216-223°C
IR (Nujol) : 1640, 1600, 1590, 1495 cm-1
NMR (DMSO-d6, δ) : 3.29 ( 3H, s), 3.42 (3H, s),
7.0-8.3 (13H, m), 11.7 (1H, s) Mass (m/z) : 432 (M+)
Elemental Analysis Calcd. for C24H20N2O4S :
C 66.65, H 4.66, N 6.48 Found : C 66.55, H 4.67, N 6.37 Example 8
The following compounds were obtained according to a similar manner to that of Example 3. (1) 1-Methyl-2-oxo-3-(N-benzyl-N-methylcarbamoyl)-4- hydroxy-6-methylthio-1,2-dihydroquinoline
mp : 186-188°C
IR (Nujol) : 1645, 1635, 1605, 1575, 1500 cm-1 NMR (DMSO-d6, δ) : 2.54 (3H, s), 2.79 (3H, s), 3.58 (3H, s), 4.3-4.8 (2H, m), 7.2-8.0 (8H, m)
Mass (m/z) : 368 (M+), 247
Elemental Analysis Calcd. for C20H20N2O3S :
C 65.19, H 5.47, N 7.60 Found : C 65.52, H 5.46, N 7.52
(2) 1-Methyl-2-oxo-3-{N-(2-thiazolyl)carbamoyl}-4- hydroxy-6-methylthio-1,2-dihydroquinoline
mp : 264-267°C
IR (Nujol) : 1630, 1600, 1540 cm-1
NMR (DMSO-d6, δ) : 2.58 (3H, s), 3.69 (3H, s),
7.4-8.0 (5H, m)
Mass (m/z) : 347 (M+), 247
Elemental Analysis Calcd. for C15H13N3O3S2 :
C 51.86, H 3.77, N 12.10 Found : C 51.39, H 3.56, N 11.85
(3 ) 1-Methyl-2-oxo-3-(N-cyclohexyl-N-methylcarbamoyl)-4- hydroxy-6-methylthio-1,2-dihydroquinoline
mp : 144-147°C
IR (Nujol) : 1645, 1635, 1590, 1570, 1500 cm-1
NMR (DMSO-d6, δ) : 1.0-1.8 (10H, m), 2.52 (3H, s), 2.78 (3H, s), 3.3-3.6 (1H, m), 3.54 (3H, s), 7.4-7.9 (3H, m)
Mass (m/z) : 360 (M+), 247 Elemental Analysis Calcd. for C19H24N2O3S :
C 63.30, H 6.71, N 7.77 Found : C 63.01, H 6.85, N 7.48 (4) 1-Methyl-2-oxo-3-{N-(2-pyridyl)carbamoyl}-4-hydroxy- 6-methylthio-1,2-dihydroguinoline
mp : 212-213°C
IR (Nujol) : 1640, 1630, 1600, 1570, 1550, 1530 cm-1 NMR (DMSO-d6, δ) : 2.57 (3H, s), 3.67 (3H, s),
7.1-8.5 (7H, m), 13.0 (1H, broad s)
Mass (m/z) : 341 (M+), 247
Elemental Analysis Calcd. for C17H15N O3S :
C 59.81, H 4.43, N 12.31 Found : C 59.90, H 4.34, N 12.23
(5) 1-Methyl-2-oxo-3-(N-phenylσarbamoyl)-4-hydroxy-6- methylthio-1,2-dihydroguinoline
mp : 176-178°C
IR (Nujol) : 1650, 1600, 1590, 1565 cm-1
NMR (DMSO-d6, δ) : 2.57 (3H, s), 3.67 (3H, s),
7.1-8.0 (8H, m), 12.7 (1H, s)
Mass (m/z) : 340 (M+) , 247
Elemental Analysis Calcd. for C18H16N2O3S :
C 63.51, H 4.74, N 8.23 Found : C 63.52, H 4.57, N 8.14
(6) 1-Methyl-2-oxo-3-{N-(2-methylphenyl)carbamσyl}-4- hydroxy-6-methylthio-1,2-dihydroquinoline
mp : 159-160°C
IR (Nujol) : 1640, 1625, 1590, 1565 cm-1
NMR (DMSO-d6, δ) : 2.37 (3H, s), 2.57 (3H, s),
3.67 (3H, s), 7.1-8.2 (7H, m), 12.6 (1H, s) Mass (m/z) : 354 (M+), 247
Elemental Analysis Calcd. for C19H18N2O3S :
C 64.39, H 5.12, N 7.91
Found : C 64.06, H 4.97, N 7.83 (7) 1-Methyl-2-oxo-3-{N-(2-chlorophenyl)carbamoyl}-4- hydroxy-6-methylthio-1,2-dihydroquinoline
mp : 189-190°C
IR (Nujol) : 1660, 1640, 1590, 1580, 1555 cm-1 NMR (DMSO-d6, δ) : 2.57 (3H, s), 3.67 (3H, s),
7.1-8.4 (7H, m), 13.1 (1H, s) Mass (m/z) : 374 (M+), 247
Elemental Analysis Calcd. for C18H15N2ClO3S :
C 57.67, H 4.03, N 7.48 Found : C 57.68, H 3.76, N 7.38
(8) 1-Methyl-2-oxo-3-{N-(2,6-dichlorophenyl)carbamoyl}-4- hydroxy-6-methylthio-1,2-dihydroquinoline
mp : 198-200°C
IR (Nujol) : 1645, 1635, 1600, 1565, 1520 cm-1
NMR (DMSO-d6, δ) : 2.57 (3H, s), 3.69 (3H, s),
7.4-8.0 (6H, m), 12.2 (1H, s) Mass (m/z) : 408 (M+), 247 (9) 1-Methyl-2-oxo-3-{N-(2,6-dimethylphenyl)carbamoyl}- 4-hydroxy-6-methylthio-l,2-dihydroquinoline
mp : 215-216°C
IR (Nujol) : 1640, 1600, 1580, 1555 cm-1
NMR (DMSO-d6, δ) : 2.21 (6H, s), 2.57 (3H, s), 3.68 (3H, s), 7.16 (3H, s), 7.6-7.9 (3H, m), 11.9
(1H, s)
Mass (m/z) : 368 (M+), 247
(10) 4-Oxo-5-(1-indolinylcarbonyl)-6-hydroxy-8-methylthio- 1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinoline
mp : 246-249°C (dec.)
IR (Nujol) : 1655, 1610, 1550, 1495 cm-1
NMR (DMSO-d6, δ) : 2.52 (3H, s), 3.08 (2H, t,
J=8Hz), 3.37 (2H, t, J=8Hz), 3.89 (2H, t, J=8Hz), 4.27 (2H, t, J=8Hz), 6.9-8.2 (6H, m), 11.3 (1H, broad s)
Mass (m/z) : 378 (M+)
Example 9
The following compounds were obtained according to a similar manner to that of Example 4.
( 1) 4-Oxo-5-carboxy-6-hydroxy-8-methylthio-1,2-dihydro- 4H-pyrrolo[3,2,1-ij]guinoline
mp : 270-278°C (dec.)
IR (Nujol) : 1680, 1630, 1600 cm-1
Mass (m/z) : 277 (M+), 259
(2) 1-Methyl-2-thioxo-3-carboxy-4-hydroxy-6-methylthio- 1,2-dihydroguinoline
mp : 139-148°C (dec.)
IR (Nujol) : 1680, 1610, 1550 cm-1
NMR (DMSO-d6, δ) : 2.60 (3H, s), 4.19 (3S, s),
7.6-8.0 (3H, m)
Mass (m/z) : 281 (M+)
Example 10
The following compounds were obtained according to a similar manner to that of Example 5.
(1) 1-Methyl-2-oxo-3-{N-(4-methoxyphenyl)-N- methylcarbamoyl}-4-hydroxy-6-methylthio-1,2-dihydroquinoline
mp : 171-173°C (dec.)
IR (Nujol) : 1640, 1620, 1590, 1560, 1510 cm-1
NMR (DMSO-d6, δ) : 2.49 (3H, s), 3.25 (3H, s), 3.43 (3H, s), 3.62 (3H, s), 6.75 (2H, d, J=8.8Hz), 7.21 (2H, d, J=8.8Hz), 7.3-7.8 (3H, m), 11.2 (1H, s)
Mass (m/z) : 247 Elemental Analysis Calcd. for C20H20N2O4S :
C 62. 48 , H 5.24, N 7.29 Found : C 62.54, H 5.31, N 7.20 (2) 1-Methyl-2-oxo-3-(N-ethyl-N-phenylcarbamoyl)-4- hydroxy-6-methylthio-1,2-dihydroquinoline
mp : 204-205°C (dec.)
IR (Nujol) : 1645, 1605, 1580, 1560 cm-1
NMR (DMSO-d6, δ) : 1.07 (3H, t, J=7.0Hz), 2.49 (3H, s), 3.41 (3H, s), 3.80 (2H, q, J=7.0Hz), 7.1-7.8
(8H, m), 11.2 (1H, s)
Mass (m/z) : 247
Elemental Analysis Calcd. for C20H20N2O3S :
C 65.19, H 5.47, N 7.60 Found : C 65.26, H 5.59, N 7.62
(3) 1-Methyl-2-oxo-3-{N-(5-indanyl)-N-methylcarbamoyl}-4- hydroxy-6-methylthio-l,2-dihydroquinoline
mp : 136-140°C (dec.)
IR (Nujol) : 1650, 1630, 1595, 1565 cm-1
NMR (CDCl3, δ) : 2.04 (2H, quin, J=7.3Hz), 2.55 (3H, s), 2.84 (4H, t, J=7.3Hz), 3.36 (3H, s), 3.46 (3H, s), 6.9-8.0 (6H, m)
Mass (m/z) : 247
Elemental Analysis Calcd. for C22H22N2O3S :
C 66.98, H 5.62, N 7.10 Found : C 66.56, H 5.70, N 6.81
(4) 1-Methyl-2-oxo-3-{(3,4-dihydro-2H-1,4-benzothiazin- 4-yl)carbonyl}-4-hydroxy-6-methylthio-1,2-dihydroguinoline
mp : 191-194°C
IR (Nujol) : 3300, 1640, 1620, 1585 cm-1
NMR (DMSO-d6, δ) : 2.52 (3H, s), 3.29 (2H, broad s), 3.49 (3H, s), 3.92 (2H, broad s), 6.7-8.0 (7H, m), 11.5 (1H, broad s)
Mass (m/z) : 398 (M+), 247
Elemental Analysis Calcd. for C20H18N2O3S2 :
C 60.28, H 4.55, N 7.03 Found : C 60.02, H 4.53, N 6.88
(5) 1-Methyl-2-oxo-3-{(3,4-dihydro-2H-1,4-benzoxazin-4- yl)carbonyl}-4-hydroxy-6-methylthio-1,2- dihydroquinoline
mp : 202-204°C
IR (Nujol) : 1640, 1600, 1585, 1560, 1495 cm-1
NMR (DMSO-d6, δ) : 2.54 (3H, s), 3.54 (3H, s), 3.72 (2H, s), 4.30 (2H, s), 6.5-8.4 (7H, m), 11.6 (1H, s)
Mass (m/z) : 382 (M+), 247
Elemental Analysis Calcd. for C20H18N2O4S :
C 62.81, H 4.74, N 7.33 Found : C 62.47, H 4.58, N 7.20 (6) l-Methyl-2-oxo-3-{N-methyl-N-(4-methylthiophenyl)- carbamoyl}-4-hydroxy-6-methylthio-l , 2-dihydroguinoline mp : 168-169°C (dec . )
IR (Nujol) : 1645, 1625, 1565, 1495 cm-1
NMR (DMSO-d6, δ) : 2.36 (3H, s), 2.49 (3H, s), 3.27 (3H, s), 3.44 (3H, s), 7.0-7.8 (7H, m), 11.3
(1H, s)
Mass (m/z) : 400 (M+) , 247
Elemental Analysis Calcd. for C20H20N2O3S2 :
C 59.98, H 5.03, N 7.00 Found : C 60.08, H 5.25, N 6.75
(7) 1-Methyl-2-oxo-3-{N-(l,3-benzodioxol-5-yl)-N-methyl- carbamoyl}-4-hydroxy-6-methylthio-l,2-dihydroguinoline mp : 141-144°C (dec.)
IR (Nujol) : 1640, 1620, 1600, 1565, 1500 cm-1 NMR (DMSO-d6, δ) : 2.50 (3H, s), 3.24 (3H, s), 3.45 (3H, s), 5.93 (2H, s), 6.6-7.8 (6H, m), 11.2 (1H, s)
Mass (m/z) : 398 (M+), 247
Elemental Analysis Calcd. for C20H18N2O5S :
C 60.29, H 4.55, N 7.03 Found : C 60.08, H 4.93, N 6.72
(8) 1-Methyl-2-oxo-3-{N-methyl-N-(4-methylphenyl)- carbamoyl}-4-hydroxy-6-methylthio-1,2-dihydroquinoline mp : 192-193°C (dec.)
IR (Nujol) : 1650, 1630, 1590, 1565, 1515 cm-1
NMR (DMSO-d6, δ) : 2.14 (3H, s), 2.49 (3H, s), 3.26 (3H, s), 3.43 (3H, s), 6.9-7.8 (7H, m), 11.3 (1H, s)
Mass (m/z) : 368 (M+) , 247
Elemental Analysis Calcd. for C20H20N2O3S :
C 65.19, H 5.47, N 7.60 Found : C 65.14, H 5.55, N 7.49
( 9 ) 1-Methyl-2-oxo-3-{N-(2,4-difluorophenyl)-N- methylcarbamoyl}-4-hydroxy-6-methylthio-1,2- dihydroquinoline
mp : 129-131°C
IR (Nujol) : 1650, 1600, 1565, 1515 cm-1
NMR (DMSO-d6, δ) : 2.51 (3H, s), 3.27 (3H, s), 3.40
(3H, s), 6.8-8.0 (6H, m) , 11.5 (1H, broad s) Mass (m/z) : 390 (M+), 274
Elemental Analysis Calcd. for C19H1gN2F2O3S :
C 58.45, H 4.13, N 7.18
Found : C 58.56, H 3.88, N 7.08
(10) 4-OXo-5-(N-methyl-N-phenylcarbamoyl)-6-hydroxy-8- methylthio-l,2-dihydro-4H-pyrrolo[3,2,1-ij]quinoline mp : 120-121°C (dec.) IR (Nujol) : 3400, 1640, 1630, 1590, 1495 cm-1 NMR (DMSO-d6, δ) : 2.46 (3H, s), 3.29 (3H, s),
3.2-3.4 (2H, m), 4.0-4.2 (2H, m), 7.0-7.5 (7H, m), 11.1 (1H, broad s)
Mass (m/z) : 259
(11) 1-Methyl-2-thioxo-3-(N-methyl-N-phenylcarbamoyl)-4- hydroxy-6-methylthio-1,2-dihydroquinoline
mp : 130-150°C
IR (Nujol) : 1620, 1595, 1565, 1500 cm-1
NMR (DMSO-d6, δ) : 2.53 (3H, s), 3.30 (3H, s), 4.06
(3H, s), 7.0-8.0 (8H, m)
Mass (m/z) : 370 (M+), 263 (12) 1-Methyl-2-oxo-3-[N-methyl-N-{4-(trifluoromethoxy)- phenyl}carbamoyl]-4-hydroxy-6-methylthio-1,2- dihydroquinoline
IR (Nujol) : 1640, 1620, 1565, 1510 cm-1
NMR (CDCl3, δ) : 2.55 (3H, s), 3.28 (3H, s), 3.49
(3H, s), 7.0-8.0 (7H, m)
Mass (m/z) : 438 (M+) , 247
( 13 ) 1-Methyl-2-oxo-3-[N-methyl-N-{3-(trifluoromethyl)- phenyl}carbamoyl]-4-hydroxy-6-methylthio-1,2- dihydroguinoline
IR (Nujol) : 1640, 1625, 1610, 1570, 1495 cm-1
NMR (CDCl3, δ) : 2.56 (3H, s), 3.28 (3H, s), 3.52
(3H, s), 7.1-7.6 (6H, m) , 7.97 (1H, d, J=2.2Hz), 12.5 (1H, broad s)
Mass (m/z) : 422 (M+), 247
Example 11
(1) A mixture of 1-methyl-2-oxo-3-carboxy-4-hydroxy-6-methylthio-1,2-dihydroguinoline (1 g),
2-methylamino-1,3,4-thiadiazole (451 mg) and 1,3-dicyclohexylcarbodiimide (986 mg) in toluene (10 ml) was stirred at 90°C for 1 hour. The mixture was cooled, and the insoluble material was collected by filtration washed with toluene, and suspended in 2N-sodium hydroxide aqueous solution (12 ml). The suspension was filtered. The filtrate was acidified with hydrochloric acid and extracted with chloroform. The extract was dried and concentrated. The residue was recrystallized from acetone to give pale yellow crystals of 1-methyl-2-oxo-3- {N-methyl-N-(1,3,4-thiadiazol-2-yl)carbamoyl}-4-hydroxy- 6-methylthio-l,2-dihydroguinoline (0.47 g).
mp : 187-189°C (dec.)
IR (Nujol) : 1660, 1610, 1580 cm-1
NMR (DMSO-d6, δ) : 2.55 (3H, s), 3.60 (6H, s),
7.5-8.0 (3H, m), 9.30 (1H, s), 11.9 (1H, broad s)
Mass (m/z) : 247
Elemental Analysis Calcd. for C15H14N4O3S2 :
C 49.71, H 3.89, N 15.46 Found : C 49.55, H 3.84, N 15.15
The following compounds were obtained according to a similar manner to that of Example 11- (1). (2) 1-Methyl-2-oxo-3-{N-methyl-N-(2-pyridyl)carbamoyl}-4- hydroxy-6-methylthio-1,2-dihydroquinoline
mp : 151-154°C
IR (Nujol) : 1655, 1620, 1605, 1575 cm-1
NMR (DMSO-d6, δ) : 2.52 (3H, s), 3.37 (3H, s), 3.50
(3H, s), 7.1-8.4 (7H, m)
Mass (m/z) : 247
( 3 ) 1-Methyl-2-oxo-3- {N-methyl-N- ( 1-methyl-5-pyrazolyl) - carbamoyl}-4-hydroxy-6-methylthio-1 , 2-dihydroquinoline mp : 114-118 °C (dec . ) IR (Nujol ) : 3380 , 1665 , 1600 , 1570 , 1550 cm-1 NMR (DMSO-d6, δ) : 2.51 (3H, s), 3.22 (3H, s), 3.45 (3H, s), 3.72 (3H, s), 6.0-8.0 (5H, m) , 11.5 (1H, broad s)
Mass (m/z) : 247
Elemental Analysis Calcd. for C17H18N4O3S :
C 54.24, H 5.35, N 14.89 Found : C 54.04, H 5.45, N 14.69 (4) 1-Methyl-2-oxo-3-{N-(4-acetylphenyl)-N- methylcarbamoyl}-4-hydroxy-6-methylthio-1,2- dihydroquinoline
mp : 110-112°C
IR (Nujol) : 1690, 1645, 1600, 1565, 1500 cm-1
NMR (DMSO-d6, δ) : 2.50 (6H, s), 3.34 (3H, s), 3.47
(3H, s), 7.3-7.9 (7H, m), 11.5 (1H, broad s)
Mass (m/z) : 396 (M+), 247
Elemental Analysis Calcd. for C21H20N2O4S·1/6H2O :
C 63.14, H 5.13, N 7.01 Found : C 63.10, H 5.35, N 6.79
(5) 1-Methyl-2-oxo-3-[N-{4-(dimethylamino)phenyl}-N- methylcarbamoyl]-4-hydroxy-6-methylthio-1,2- dihydroguinoline
mp : 165-168°C
IR (Nujol) : 1640, 1615, 1565, 1525 cm-1
NMR (DMSO-d6, δ) : 2.49 (3H, s), 2.77 (6H, s),
3.21 (3H, s), 3.43 (3H, s)., 6.49 (2H, d, J=8.7Hz), 7.10 (2H, d, J=8.7Hz), 7.3-7.7 (3H, m) Mass (m/z) : 397 (M+), 247
(6) 1-Methyl-2-oxo-3-[N-{4-(methoxycarbonyl)phenyl}-N- methylcarbamoyl]-4-hydroxy-6-methylthio-1,2-dihydroguinoline
mp : 149-151°C IR (Nujol) : 1725, 1645, 1630, 1605, 1565, 1500 cm-1 NMR (DMSO-d6, δ) : 2.50 (3H, s) , 3.34 (3H, s), 3.46 (3H, s), 3.77 (3H, s), 7.3-7.9 (7H, m), 11.5 (1H, broad s)
Mass (m/z) : 412 (m+) , 247
Elemental Analysis Calcd. for C21H20N2O5S :
C 61.15, H 4.89, N 6.79 Found : C 60.91, H 5.00, N 6.53 (7) 1-Methyl-2-oxo-3-[N-methyl-N-(1-pyrrolyl)carbamoyl]- 4-hydroxy-6-methyIthio-1,2-dihydroguinoline
mp : 116-118°C (dec.)
IR (Nujol) : 3030, 1680, 1620, 1600, 1575, 1500 cm-1 NMR (DMSO-d6, δ) : 2.50 (3H, s), 3.39 (3H, s), 3.45 (3H, s), 5.83 (2H, broad s), 6.77 (2H, broad s),
7.3-7.8 (3H,m ), 11.5 (1H, s)
Mass (m/z) : 343 (M+)
Elemental Analysis Calcd. for C17H17N3O3S·EtOH :
C 58.59, H 5.95, N 10.79 Found : C 58.77, H 6.22, N 10.77
(8) 1-Methyl-2-oxo-3-[N-(4-cyanophenyl)-N- methylcarbamoyl]-4-hydroxy-6-methylthio-l,2-dihydroquinoline
mp : 171-181°C
IR (Nujol) : 2230, 1645, 1630, 1590, 1565, 1510 cm-1 NMR (DMSO-d6, δ) : 2.51 (3H, s), 3.34 ( 3H, s), 3.47 (3H, s), 7.3-7.9 (7H, m), 11.6 (1H, broad s)
Mass (m/z) : 379 (M+), 247
(9) 1-Methyl-2-oxo-3-[N-methyl-N-(4-nitorophenyl)- carbamoyl]-4-hydroxy-6-methylthio-l,2- dihydroguinoline
mp : 112-116°C
IR (Nujol) : 1640, 1630, 1610, 1580, 1525, 1495 cm-1 NMR (DMSO-d6, δ) : 2.51 (3H, s), 3.37 ( 3H, s), 3.48
(3H, s), 7.3-8.2 (7H, m), 11.6 (1H, broad s) Mass (m/z) : 399 (M+), 247 Example 12
A mixture of 1-methyl-2-oxo-3-[N-{4-(methoxycarbonyl)phenyl}-N-methylcarbamoyl]-4-hydroxy-6- methylthio-1,2-dihydroguinoline (0.55 g) and sodium hydroxide (0.21 g) in water (6 ml) was stirred at room temperature for 2 hours. The mixture was filtered and the filtrate was acidified with hydrochloric acid. The precipitates were collected and washed with water to give pale yellow crystals o1 1-methyl-2-oxo-3-{N-(4- carboxyphenyl)-N-methylcarbamoyl}-4-hydroxy-6-methylthio- 1,2-dihydroguinoline (0.5 g).
mp : 123-137°C
IR (Nujol) : 1710, 1630, 1600, 1570, 1500 cm-1
NMR (DMSO-d6, δ) : 2.50 (3H, s), 3.33 (3H, s), 3.47 (3H, s), 7.3-7.9 (7H, m), 11.5 (1H, broad s), 12.9 (1H, broad s)
Mass (m/z) : 399 (M+), 354
Example 13
A mixture of 1-methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4-hydroxy-6-methylthio-1,2-dihydroquinoline (2.5 g) and m-chloroperbenzoic acid (3.8 g) in
dichloromethane (70 ml) was stirred at room temperature for 7 hours. The mixture was extracted with an agueous solution of sodium bicarbonate and the extract was
acidified with hydrochloric acid. The precipitates were collected by filtration and purified by column
chromatography on silica gel (150 g) eluting with a mixture of chloroform and ethanol (20:1) and a mixture of chloroform, ethanol and acetic acid (100:10:1),
successively. The purified product was washed with ethanol to give pale brown crystals of 1-methyl-2-oxo-3- (N-methyl-N-phenylcarbamoyl)-4-hydroxy-6-methylsulfonyl- 1,2-dihydroquinoline (1.2 g).
mp : 221-223°C (dec.)
IR (Nujol) : 1640, 1620, 1590, 1550, 1495 cm-1
NMR (DMSO-d6, δ) : 3.23 (3H, s), 3.31 (3H, s), 3.49
(3H, s), 7.0-8.4 (8H, m), 11.9 (1H, broad s) Mass (m/z) : 386 (M+) Example 14
A mixture of 5-(methylthio)indoline (2 g) and tri(ethoxycarbonyl)methane (3.1 ml) was stirred at 150°C for 1 hour, at 200°C for 1 hour, and at 220°C for 1.5 hours. The product was purified by column chromatography on silica gel (60 g) eluting with a mixture of ethyl acetate and ethanol (10:1) to give a brown solid of
4-oxo-5-ethoxycarbonyl-6-hydroxy-8-methylthio-1,2-dihydro- 4H-pyrrolo[3,2,1-ij]guinoline (1.3 g).
IR (CHCl3) : 1655, 1620, 1560, 1490 cm-1
NMR (DMSO-d6, δ) : 1.29 (3H, t, J=7.1Hz), 2.51 (3H, s), 3.32 (2H, t, J=7.8Hz), 4.1-4.4 (4H, m), 7.47 (1H, s), 7.51 (1H, s)
Mass (m/z) : 305 (M+), 259 Example 15
To a stirred mixture of ethyl benzylsulfinylacetate (0.5 g) and l-methyl-6-methylthio-2H-3,1-benzoxazine-2,4 (1H)-dione (0.49 g) in tetrahydrofuran (11 ml) was added sodium hydride (0.18 g) at 3°C. After 30 minutes, the reaction mixture was quenched with water, acidified with 1N hydrochloric acid (5 ml) and extracted with dichloromethane. The extract was dried and concentrated. The residue was dissolved in toluene (15 ml) and the solution was allowed to stand at room temperature
overnight. The precipitates were collected and washed with toluene to give colorless crystals of
1-methyl-2-oxo-3-benzylsulfinyl-4-hydroxy-6-methylthio-1,2-dihydroquinoline (0.39 g).
mp : 158-160°C (dec.)
IR (Nujol) : 1615, 1565 cm-1
NMR (DMSO-d6, δ) : 2.49 (3H, s), 3.59 (3H, s), 4.33 (1H, d, J=13Hz), 4.60 (1H, d, J=13Hz), 7.1-7.8 (8H, m)
Mass (m/z) : 359 (M+)
Example 16
A mixture of diisopropylamine (2.8 ml) and 1.6 M n-butyl lithium in hexane (12.5 ml) in tetrahydrofuran (75 ml) was stirred at 5°C for 10 minutes. Ethyl
(benzylthio)acetate (2.1 g) was added at -78°C and the mixture was stirred for 1 hour. To the mixture was added 1-methyl-6-methylthio-2H-3,1-benzoxazine-2,4(1H)-dione (2.2 g). The resulting mixture was slowly warmed to room temperature, stirred for 2 hours, guenched with an aqueous solution of ammonium chloride, and extracted with
dichloromethane. The extract was dried and concentrated, and the residue was dissolved in toluene (25 ml) and refluxed for 90 minutes. The residue obtained by
evaporation of the solvent was purified by column
chromatography on silica gel (150 g) eluting with
dichloromethane-isopropanol (20:1), followed by
recrystallization from acetone to give colorless crystals of 1-methyl-2-oxo-3-benzylthio-4-hydroxy-6-methylthio-1,2-dihydroquinoline (0.86 g).
mp : 110-112°C
IR (Nujol) : 1635, 1610, 1585, 1560 cm-1
NMR (DMSO-d6, δ) : 2.51 (3H, s), 3.61 (3H, s), 4.06 (2H, s), 7.0-7.7 (8H, m), 10.45 (1H, s)
Mass (m/z) 343 (M+) Elemental Analysis Calcd. for C18H17NO2S2 :
C 62.95, H 4.99, N 4.08, S 18.67 Found : C 62.91, H 4.92, N 4.00, S 18.54 Example 17
(1) A mixture of ethyl 2-{N-methyl-N-(2-benzoylacetyl)- amino}-5-(methylthio)benzoate (2.9 g) and sodium ethoxide (1.1 g) in ethanol (39 ml) was stirred at room temperature for 2 hours. 3N Hydrochloric acid (6 ml) was added thereto, and the precipitates were collected by filtration and. washed with ethanol to give a yellow solid of
l-methyl-2-oxo-3-benzoyl-4-hydroxy-6-methylthio-1,2- dihydroguinoline (2 g).
mp : 170-171°C
IR (Nujol) : 1650, 1625, 1595, 1565 cm-1
NMR (DMSO-d6, δ) : 2.55 (3H, s), 3.54 (3H, s),
7.4-8.0 (8H, m), 11.8 (1H, s) Mass (m/z) : 324
Elemental Analysis Calcd. for C18H15NO3S :
C 66.44, H 4.65, N 4.30, S 9.85
Found : C 66.31, H 4.60, N 4.31, S 9.84
The following compounds were obtained according to a similar manner to that of Example 17-(1).
(2) 2-Oxo-3-(N-methyl-N-phenylcarbamoyl)-4-hydroxy-6- methylthio-1,2-dihydroguinoline
mp : 259°C (dec.)
IR (Nujol) : 1650, 1625, 1595, 1500 cm-1
NMR (DMSO-d6, δ) : 2.46 (3H, s), 3.29 (3H, s),
7.0-7.7 (8H, m), 11.25 (1H, s) Mass (m/z) : 340 (M+), 233
(3) 1-Methyl-2-oxo-3-(1-phenyl-1-cyclopropylcarbonyl)-4- hydroxy-6-methylthio-1,2-dihydroquinoline mp : 170-173°C
IR (Nujol) : 1665, 1590, 1565 cm-1
NMR (DMSO-d6, δ) : 1.3-1.4 ( 2H, m), 1.5-1.6 (2H, m), 2.51 (3H, s), 3.43 (3H, s), 7.1-7.6 (7H, m), 7.82 (1H, d, J=2.1Hz), 11.86 (1H, s) Mass (m/z) : 365 (M+), 337
Elemental Analysis Calcd. for C21H19NO3S·1/4H2O :
C 68.18, H 5.31, N 3.79 Found : C 68.27, H 5.12, N 3.79
Example 18
A mixture of 1-methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4-hydroxy-6-methylthio-1,2-dihydroquinoline (2.35 g) and phosphorus oxychloride (7.05 ml) was stirred at 80°C for 1 hour. Ice-water was added thereto and the preceipitates were collected to give pale yellow crystals of 1-methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4- chloro-6-methylthio-l,2-dihydroguinoline (2 g).
mp : 209-210°C
IR (Nujol) : 1645, 1630, 1590, 1560 cm-1
NMR (DMSO-d6, δ) : 2.51 (3H, s), 3.36 (3H, s), 3.56
(3H, s), 7.1-7.9 (8H, m)
Mass (m/z) : 372 (M+), 337, 266 Example 19
(1) A mixture of 1-methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4-chloro-6-methylthio-1,2-dihydroquinoline (2.4 g) and ammonia solution (28%; 10 ml) in methanol (20 ml) was heated at 100°C for 48 hours in a sealed tube. The solvent was evaporated and the residue was purified by column chromatography on silica gel
eluting with a mixture of chloroform and methanol (20:1) to give colorless crystals of l-methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4-amino-6-methylthio-l,2-dihydroguinoline (1.1 g). mp : 138-140°C
IR. (Nujol) : 3370, 3200, 1620, 1590, 1560, 1495 cm-1
NMR (DMSO-d6, δ) : 2.51 (3H, s), 3.29 (3H, s), 3.37
(3H, s), 6.55 (2H, s), 7.0-7.5 (7H, m), 7.84
(1H, s)
Mass (m/z) : 353 (M+)
The following compound was obtained according to a similar manner to that of Example 19-(1).
(2) 1-Methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4- methylamino-6-methylthio-1,2-dihydroquinoline
mp : 244-246°C
IR (Nujol) : 3350, 1620, 1585, 1550 cm-1
Mass (m/z) : 367 (M+), 261
Example 20
A mixture of 1-methyl-2-oxo-3-(N-methyl-N-phenyl¬carbamoyl)-4-chloro-6-methylthio-1,2-dihydroquinoline (1.5 g), S-potassium thioacetate (1.8 g) and sodium iodide (10 mg) in acetone (30 ml) was refluxed for 48 hours. The solvent was evaporated, and the residue was dissolved in chloroform and washed with water. The organic layer was extracted with an aqueous sodium bicarbonate solution.
The extract was acidified with hydrochloric acid and extracted with chloroform. The residue obtained from the extract was crystallized from acetone to give yellow crystals of 1-methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4-mercapto-6-methylthio-1,2-dihydroquinoline (0.5 g) .
mp : 210-212°C
IR (Nujol) : 1610, 1580, 1540, 1480 cm-1
NMR (DMSO-d6, δ) : 2.49 (3H, s), 3.37 (3H, s), 3.53
(3H, s), 7.1-7.7 (8H, m)
Mass (m/z) : 370 (M+) Elemental Analysis Calcd. for C19H18N2O2S2 :
C 61.60, H 4.90, N 7.56 Found : C 61.60, H 4.78, N 7.45 Example 21
A mixture of 1-methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4-chloro-6-methylthio-1,2-dihydroguinoline (0.3 g) and sodium methoxide (0.11 g) in methanol (5 ml) was stirred at 40°C for 3.5 hours. The mixture was filtered, and the filtrate was evaporated. The residue was washed with water to give colorless crystals of 1-methyl-2-oxo- 3-(N-methyl-N-phenylcarbamoyl)-4-methoxy-6-methylthio- 1,2-dihydroquinoline (0.28 g).
mp : 148-151°C
IR (Nujol) : 1640, 1620, 1590, 1575, 1495 cm-1
NMR (DMSO-d6, δ) : 2.48 (3H, s), 3.35 (3H, s),
3.47 (3H, s), 4.10 (3H, s), 7.1-7.9 (8H, m) Mass (m/z) : 368 (M+), 262 Example 22
A mixture of 1-methyl-2-oxo-3-[N-methyl-N-(4-nitrophenyl)carbamoyl]-4-hydroxy-6-methylthio-1,2-dihydroquinoline (0.28 g), iron powder (0.28 g) , and ammonium chloride (30 mg) in ethanol (8 ml) and water (3 ml) was refluxed and stirred for 2 hours. The solvent was
evaporated, and the residue was suspended in a mixture of chloroform and water, followed by filtration. The organic layer was separated, dried, and evaporated. The residue (0.26 g) was washed with ethanol to give a brown powder of 1-methyl-2-oxo-3-[N-(4-aminophenyl)-N-methylcarbamoyl]-4-hydroxy-6-methylthio-l,2-dihydroquinoline (0.1 g).
IR (Nujol) : 3450, 3350, 3250, 1630, 1610, 1570,
1540, 1515 cm-1
Mass (m/z) 369 (M+) Example 23
A mixture of formic acid (51 μl) and acetic anhydride (128 μl) was stirred at 50°C for 30 minutes, and then cooled. 1-Methyl-2-oxo-3-[N-(4-aminophenyl)-N-methyl- carbamoyl]-4-hydroxy-6-methylthio-1,2-dihydroquinoline (0.1 g) was added and the mixture was stirred for 40 minutes at room temperature. Then, acetic anhydride (0.5 ml) was added and the resulting mixture was stirred for 3 hours. The reaction mixture was poured into ice-water, and the precipitates were collected and washed with water. The product was dissolved in 0.4N sodium hydroxide (1 ml) and the solution was filtered. The filtrate was acidified with hydrochloric acid and the precipitates were collected to give a brown powder of 1-methyl-2-oxo-3-[N-[4-(formylamino)phenyl]-N-methylcarbamoyl]-4-hydroxy-6-methylthio-1,2-dihydroguinoline (58 mg).
IR (Nujol) : 3450 , 3250, 1630, 1565, 1510 cm-1
Mass (m/z) : 397 (M+), 247

Claims

C L A I M S
A compound of the formula :
Figure imgf000099_0001
wherein R2 is lower alkyl or aryl which may have
suitable substituent(s),
R2 is hydroxy, protected hydroxy, lower
alkoxy, halogen, amino, substituted amino, mercapto or protected mercapto,
R2 is hydrogen, lower alkyl, lower
alkoxy(lower)alkyl or ar( lower)alkyl and
R2 is hydrogen, or
R2 and R2 are linked together to form lower alkylene,
R 4 is an organic group,
2 is O or S, and
n is 0, 1 or 2,
and pharmaceutically acceptable salts thereof.
A compound of claim 1, wherein
R1 is lower alkyl, or phenyl which may have halogen,
R2 is hydroxy, acyloxy, lower alkoxy, halogen, amino, lower alkylamino, protected amino, mercapto or acylthio,
R3 is hydrogen, lower alkyl, lower
alkoxy( lower)alkyl, or phenyl(lower)alkyl and
R8 is hydrogen, or R3 and R8 are linked together to form lower alkylene, and
R4 is acyl, carboxy, ar(lower)alkylsulfinyl,
ar(lower)alkylthio, cyano, or heterocyclic group which may have suitable substituent(s).
3. A compound of claim 2, wherein
R1 is lower alkyl, phenyl or halophenyl,
R2 is hydroxy, acyloxy, lower alkoxy, halogen, amino, lower alkylamino, acylamino, mercapto or lower alkanoylthio, and
R4 is carbamoyl which may be substituted with one or two suitable substituent(s) selected from the group consisting of lower alkyl; phenyl which may have 1 to 3 suitable substituent(s)
selected from the group consisting of lower alkyl, halogen, lower alkoxy, lower alkylthio, acyl, di(lower)alkylamino, cyano, mono(or di or tri)halo(lower) alkyl, mono(or di or
tri)halo(lower) alkoxy, carboxy, protected carboxy, nitro, amino and acylamino;
heterocyclic group which may have lower alkyl; phenyl(lower)alkyl; lower cycloalkyl and a group of the formula :
Figure imgf000100_0001
(in which A is lower alkylene);
thiocarbamoyl which may be substituted with one or two suitable substituent(s) selected from the group consisting of lower alkyl and aryl; lower alkoxycarbonyl; aminosulfonyl which may be substituted with one or two suitable substituent(s) selected from the group consisting of lower alkyl and aryl; aroyl; ar( lower)cycloalkylcarbonyl;
ar( lower) alkylsulfonyl; heterocycliccarbonyl; carboxy;
ar( lower) alkylsulfinyl; ar ( lower) alkylthio;
cyano; or heterocyclic group which may have lower alkyl or aryl.
4. A compound of claim 3, wherein
R4 is carbamoyl which may be substituted with one or two suitable substituent(s) selected from the group consisting of lower alkyl, phenyl, mono(or di)( lower) alkylphenyl, mono(or di)halophenyl, ( lower) alkoxyphenyl, lower alkylthiophenyl, lower alkanoylphenyl,
N,N-di ( lower)alkylaminσphenyl, cyanophenyl, trihalo(lower)alkylphenyl,
trihalo(lower)alkoxyphenyl, carboxyphenyl, lower alkoxycarbonylphenyl, nitrophenyl, aminophenyl, lower alkanoylaminophenyl,
pyridyl, lower alkylpyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, benzodioxolyl,
phenyl( lower)alkyl, lower cycloalkyl and indanyl;
thiocarbamoyl which may be substituted with one or two suitable substituent (s) selected from the group consisting of lower alkyl and phenyl; lower alkoxycarbonyl;
aminosulfonyl which may be substituted with one or two suitable substituent(s) selected from the group consisting of lower alkyl and phenyl; benzoyl; phenyl(lower)cycloalkylcarbonyl;
phenyl (lower)alkylsulfonyl; indolinylcarbonyl; dihydrobenzoxazinylcarbonyl;
dihydrobenzothiazinylcarbonyl; carboxy;
phenyl(lower)alkylsulfinyl;
phenyl(lower)alkylthio; cyano;
imidazolinyl or tetrazolyl, each of which may have aryl;
oxadiazolyl which may have aryl; or benzimidazolyl, guinolyl or isoguinolyl, each of which may have lower alkyl.
5. A compound of claim 4, wherein
R4 is carbamoyl which may be substituted with one or two suitable substituent (s) selected from the group consisting of lower alkyl, phenyl, mono(or di) (lower) alkylphenyl, mono(or
di)halophenyl, ( lower) alkoxyphenyl, lower alkylthiophenyl, lower alkanoylphenyl,
N,N-di(lower) alkylaminophenyl, cyanophenyl, trihalo(lower)alkylphenyl,
trihalo(lower)alkoxyphenyl, carboxyphenyl, lower alkoxycarbonylphenyl, nitrophenyl, aminophenyl, lower alkanoylaminophenyl, pyridyl, lower alkylpyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, 1,3-benzodioxolyl, phenyl(lower) alkyl, lower cycloalkyl and indan-2-yl;
thiocarbamoyl which may be substituted with one or two suitable substituent(s) selected from the group consisting of lower alkyl and phenyl; lower alkoxycarbonyl;
aminosulfonyl which may be substituted with one or two suitable substituent(s) selected from the group consisting of lower alkyl and phenyl; benzoyl; phenyl(lower)cycloalkylcarbonyl;
phenyl(lower)alkylsulfonyl; indolinylcarbonyl; dihydrobenzoxazinylcarbonyl;
dihydrobenzothiazinylcarbonyl; carboxy;
phenyl(lower)alkylsulfinyl;
phenyl(lower)alkylthio; cyano; imidazolinyl; phenylimidazolinyl; tetrazolyl;
phenyltetrazolyl; oxadiazolyl;
phenyloxadiazolyl; benzimidazolyl; lower alkylbenzimidazolyl; quinolyl; or isoquinolyl.
6. A compound of claim 5, wherein
R1 is lower alkyl, phenyl or halophenyl
R 2 is hydroxy,
R3 is lower alkyl and
R8 is hydrogen, or
R 3 and R8 are linked together to form lower alkylene,
R 4 is carbamoyl which may have one or two suitable substituent(s) selected from the group
consisting of lower alkyl, phenyl, mono(or di)halophenyl, lower alkoxyphenyl, lower alkylphenyl, cyanophenyl, pyrrolyl, trihalo(lower)alkoxyphenyl,
trihalo(lower)alkylphenyl, nitrophenyl,
aminophenyl, 1,3-benzodioxolyl and lower alkanoylaminophenyl, or
phenyl(lower)cycloalkylcarbonyl,
Z is O or S, and
n is 0 or 1.
7. A compound of claim 6, which is selected from the
group consisting of
(1) 1-Methyl-2-oxo-3-{N-(4-fluorophenyl)-N- methylcarbamoyl}-4-hydroxy-6-methylthio-1,2- dihydroquinoline, (2) 1-Methyl-2-oxo-3-{N-(4-methoxyphenyl)-N- methylcarbamoyl}-4-hydroxy-6-methylthio-1,2- dihydroquinoline,
(3) 1-Methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4- hydroxy-6-methylsulfinyl-1,2-dihydroquinoline,
(4) 1-Methyl-2-oxo-3-[N-methyl-N-phenylamino(thiocarbonyl)]-4-hydroxy-6-methylthio-1,2-dihydroquinoline,
(5) 1-Methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4- hydroxy-6-ethylthio-1,2-dihydroquinoline,
( 6) 1-Methyl-2-oxo-3-[N-methyl-N-phenylcarbamoyl]-4- hydroxy-6-phenylthio-1,2-dihydroquinoline,
(7) 1-Methyl-2-oxo-3-{N-(2-methylphenyl)carbamoyl}- 4-hydroxy-6-methylthio-l,2-dihydroquinoline, ( 8) 1-Methyl-2-oxo-3-(N-ethyl-N-phenylcarbamoyl)- 4-hydroxy-6-methylthio-1,2-dihydroquinoline,
(9) 4-Oxo-5-(N-methyl-N-phenylcarbamoyl)-6-hydroxy- 8-methylthio-1,2-dihydro-4H-pyrrolo[3,2,1-ij]- quinoline,
(10) 1-Methyl-2-thioxo-3-(N-methyl-N-phenylcarbamoyl)-4-hydroxy-6-methylthio-1,2- dihydroguinoline,
(11) 1-Methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4- hydroxy-6-phenylsulfinyl-1,2-dihydroquinoline,
(12) 1-Methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)- 4-hydroxy-6-(4-fluorophenylthio)-1,2- dihydroquinoline,
( 13) 1-Methyl-2-oxo-3-(1-phenyl-1-cyclopropylcarbonyl)-4-hydroxy-6-methylthio-1,2-dihydroquinoline,
(14) 1-Methyl-2-oxo-3-[N-methyl-N-(1-pyrrolyl)- carbamoyl]-4-hydroxy-6-methylthio-1,2-dihydroquinoline,
(15) 1-Methyl-2-oxo-3-[N-(4-cyanophenyl)-N-methylcarbamoyl]-4-hydroxy-6-methylthio-1,2-dihydroguinoline, (16) 1-Methyl-2-oxo-3-[N-methyl-N-{4-(trifluoromethoxy)phenyl}carbamoyl]-4-hydroxy-6- methylthio-1,2-dihydroguinoline,
(17) 1-Methyl-2-oxo-3-[N-methyl-N-{3-(trifluoromethyl)phenyl}carbamoyl]-4-hydroxy-6-methylthio- 1,2-dihydroquinoline,
(18) 1-Methyl-2-oxo-3-[N-methyl-N-(4-nitrophenyl)- carbamoyl]-4-hydroxy-6-methylthio-1,2dihydroquinoline,
(19) 1-Methyl-2-oxo-3-[N-(4-aminophenyl)-4-methylcarbamoyl]-4-hydroxy-6-methylthio-1,2-dihydroquinoline,
(20) 1-Methyl-2-oxo-3-[N-[4-(formylamino)phenyl]- N-methylcarbamoyl]-4-hydroxy-6-methylthio-1,2- dihydroquinoline, (21) 1-Methyl-2-oxo-3-{N-(1,3-benzodioxol-5-yl)-N- methylcarbamoyl}-4-hydroxy-6-methylthio-1,2- dihydroquinoline,
(22) 1-Methyl-2-oxo-3-{N-(2,4-difluorophenyl)-N- methylcarbamoyl}-4-hydroxy-6-methylthio-1,2- dihydroquinoline and
(23) 1-Methyl-2-oxo-3-{N-methyl-N-(4-methylphenyl)- carbamoyl}-4-hydroxy-6-methylthio-1,2-dihydroquinoline.
8. A process for preparing a compound of the formula :
Figure imgf000106_0001
wherein R 1 is lower alkyl or aryl which may have
suitable substituent(s),
R 2 is hydroxy, protected hydroxy, lower
alkoxy, halogen, amino, substituted amino, mercapto or protected mercapto, R 3 is hydrogen, lower alkyl, lower
alkoxy(lower)alkyl or ar( lower) alkyl and
R 8 is hydrogen, or
R 3 and R8 are linked together to form lower alkylene,
R 4 is an organic group,
Z is O or S, and
n is 0, 1 or 2,
or a salt thereof, which comprises (1) reacting a compound of the formula
Figure imgf000107_0001
wherein R 1, R3, R8 and n are each as defined above, or a salt thereof with a compound of the formula :
Figure imgf000107_0002
wherein R 4 and Z are each as defined above, and
R 5 is a leaving group,
or a salt thereof to give a compound of the formula
Figure imgf000107_0003
wherein R 1, R 3, R 4, R 8, Z and n are each as defined above,
or a salt thereof, or
(2) subjecting a compound of the formula :
Figure imgf000108_0001
wherein R 1, R 2, R 3, R 4, R 8 and Z are each as defined above,
or a salt thereof to oxidation reaction to give a compound of the formula :
Figure imgf000108_0002
wherein R 1, R 2, R 3, R 4, R 8 and Z are each as defined above, and
m is 1 or 2,
or a salt thereof, or
(3) subjecting a compound of the formula
Figure imgf000108_0003
wherein R 1, R2, R3, R8, Z and n are each as defined above,
or its reactive derivative at the carboxy group or a salt thereof to amidation reaction to give a compound of the formula :
Figure imgf000109_0001
wherein R 1, R 2, R 3, R 8, Z and n are each as defined above, and
a group of the formula : -CO-R 6 is
amidated carboxy,
or a salt thereof, or
(4) subjecting a compound of the formula
Figure imgf000109_0002
wherein R 1, R 2, R 3, R 8, Z and n are each as defined above, and
Ra 4 is protected carboxy,
or a salt thereof to elimination reaction of the carboxy protective group in R 4 to give a compound of the formula
Figure imgf000109_0003
wherein R1, R2, R3, R8, Z and n are each as defined above,
or a salt thereof, or
(5) subjecting a compound of the formula
Figure imgf000110_0001
wherein R 1, R 2, R 3, R 8, Z and n are each as defined above, and
Rb 4 is acyl having protected carboxy, or a salt thereof to elimination reaction of the carboxy protective group to give a compound of the formula :
Figure imgf000110_0002
wherein R 1, R 2, R 3, R 8, Z and n are each as defined above, and
R4 c is acyl having carboxy.
or a salt thereof, or
(6) reacting a compound of the formula
Figure imgf000110_0003
wherein R1, and n are each as defined above, or a salt thereof with a compound of the formula
R4-CH(COX1)2 wherein R 4 is as defined above, and
X1 is a leaving group,
or a salt thereof to give a compound of the formula
Figure imgf000111_0001
wherein R 1, R4 and n are each as defined above, or a salt thereof, or
(7) subjecting a compound of the formula :
Figure imgf000111_0002
wherein R 1, R 2, R 3, R 8, Z and n are each as defined above, and
X 2 is a leaving group,
or a salt thereof to cyclization reaction to give a compound of the formula :
Figure imgf000112_0001
wherein R 1, R3, R4, R8, Z and n are each as defined above,
or a salt thereof, or
(8) subjecting a compound of the formula
Figure imgf000112_0002
wherein R1, R3, R4, R8, Z and n are each as defined above,
or a salt thereof to halogenation reaction to give a compound of the formula :
Figure imgf000112_0003
wherein R1, R3, R4, R8, Z and n are each as defined above, and
Ra 2 is halogen,
or a salt thereof, or (9) reacting a compound of the formula :
Figure imgf000113_0001
wherein R1, R3, R4, R8, Z and n are each as defined above, and
X3 is a leaving group,
or a salt thereof with a compound of the formula :
H - R2 b wherein R2 b is amino or substituted amino,
or a salt thereof to give a compound of the formula
Figure imgf000113_0002
wherein R1, R2 b, R3, R4, R8, Z and n are each as
defined above,
or a salt thereof, or
(10) reacting a compound of the formula
Figure imgf000114_0001
wherein R1 , R3, R4, R8, Z, n and X are each as defined above,
or a salt thereof with a compound of the formula Rc 2 - M1 wherein R2 c is protected mercapto, and
M1 is an alkali metal,
or a salt thereof to give a compound of the formula
Figure imgf000114_0002
wherein R1, R2 c, R3, R4, R8, Z and n are each as
defined above,
or a salt thereof, or subjecting a compound of the formula
Figure imgf000114_0003
wherein R1 , R2, R3, R4, R8, Z and n are each as defined above,
or a salt thereof to elimination reaction of the mercapto protective group to give a compound of the formula :
Figure imgf000115_0001
wherein R1, R3, R4 , R8, Z and n are each as defined above,
or a salt thereof, or
(12) reacting a compound of the formula
Figure imgf000115_0002
wherein R1, R3, R4, R8, Z, n and X are each as
defined above,
or a salt thereof with a compound of the formula Rd 2 - M2 wherein Rd 2 is lower alkoxy and
M2 is an alkali metal,
or a salt thereof to give a compound of the formula
Figure imgf000116_0001
wherein R1, R2 d, R3 , R4 , R8 , Z and n are each as defined above,
or a salt thereof, or
(13) subjecting a compound of the formula
Figure imgf000116_0002
wherein R 1, R2 , R3, R8, Z and n are each as defined above, and
Rd 4 is acyl having nitro,
or a salt thereof to reduction reaction
to give a compound of the formula :
Figure imgf000116_0003
wherein R1 , R2, R3 , R8 , Z and n are each as defined above, and
R4 e is acyl having ammo , or a salt thereof, or (14) subjecting a compound of the formula
Figure imgf000117_0001
wherein R1 , R2, R3, R4, R8, Z and n are each as
defined above,
or a salt thereof to acylation reaction to give a compound of the formula :
Figure imgf000117_0002
wherein R1, R2, R3, R4, R8, Z and n are each as
defined above, and
Rf 4 is acyl having acylamino,
or a salt thereof.
9. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a
pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers.
10. A use of a compound of claim 1 or a pharmaceutically acceptable salt thereof as immunomodulating agent, anti-inflammatory agent or anti-cancer agent.
11. A method for the prophylactic or therapeutic
treatment of inflammatory conditions, various pains, collagen diseases, autoimmune diseases, various immunity diseases or cancer which comprises
administering a compound of claim 1 or a
pharmaceutically acceptable salt thereof to human or animals.
12. A process for preparing a pharmaceutical composition which comprises admixing a compound of claim 1 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.
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Cited By (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994029295A1 (en) * 1993-06-04 1994-12-22 Fujisawa Pharmaceutical Co., Ltd. Heterocyclic derivatives with immunomodulating activity
WO1995024395A1 (en) * 1994-03-07 1995-09-14 Fujisawa Pharmaceutical Co., Ltd. Quinoline derivatives as immunomodulators
GB2290786A (en) * 1994-06-30 1996-01-10 Fujisawa Pharmaceutical Co Quinoline derivatives
WO1998026289A1 (en) * 1996-12-10 1998-06-18 Heska Corporation DETECTION OF ANTI-FcεR AUTOANTIBODIES IN ASTHMATICS
WO1999055678A1 (en) * 1998-04-27 1999-11-04 Active Biotech Ab Quinoline derivatives
WO2000003991A1 (en) * 1998-07-15 2000-01-27 Active Biotech Ab Quinoline derivatives
WO2000003992A1 (en) * 1998-07-15 2000-01-27 Active Biotech Ab Quinoline derivatives
WO2000006572A1 (en) * 1998-07-31 2000-02-10 Kyorin Pharmaceutical Co., Ltd. Bensoquinolizine derivatives and process for producing the same
WO2000006571A1 (en) * 1998-07-31 2000-02-10 Kyorin Pharmaceutical Co., Ltd. Pyrroloquinoline derivatives and process for producing the same
US6077851A (en) * 1998-04-27 2000-06-20 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
WO2001030758A1 (en) * 1999-10-25 2001-05-03 Active Biotech Ab Drugs for the treatment of malignant tumours
US6329525B1 (en) 1997-12-03 2001-12-11 Taisho Pharmaceutical Co., Ltd. 1,2-Dihydro-2-oxoquinoline derivatives
US6395750B1 (en) 1999-10-25 2002-05-28 Active Biotech Ab Drugs for the treatment of malignant tumors
US6509352B1 (en) 1999-01-08 2003-01-21 Japan Tobacco Inc. 2-oxoquinoline compounds and medicinal uses thereof
US6525049B2 (en) 2000-07-05 2003-02-25 Pharmacia & Upjohn Company Pyrroloquinolones as antiviral agents
US6605617B2 (en) 2000-09-11 2003-08-12 Chiron Corporation Quinolinone derivatives
US6756383B2 (en) 2000-09-01 2004-06-29 Chiron Corporation Heterocyclic derivatives of quinolinone benimidazoles
US6822097B1 (en) 2002-02-07 2004-11-23 Amgen, Inc. Compounds and methods of uses
WO2004087153A3 (en) * 2003-03-28 2005-03-17 Chiron Corp Use of organic compounds for immunopotentiation
WO2006081445A2 (en) 2005-01-27 2006-08-03 Novartis Vaccines And Diagnostics Inc. Treatment of metastasized tumors
WO2006093339A1 (en) 2005-03-02 2006-09-08 Sumitomo Chemical Company, Limited Use of cinnamoyl compound
US7317107B2 (en) 2002-02-15 2008-01-08 Astellas Pharma Inc. Imidazole 4-carboxamide compounds with adenosine deaminase inhibiting activity
US7470709B2 (en) 2002-08-23 2008-12-30 Novartis Vaccines And Diagnostics, Inc. Benzimidazole quinolinones and uses thereof
US7495103B2 (en) 2004-06-24 2009-02-24 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US7642278B2 (en) 2001-07-03 2010-01-05 Novartis Vaccines And Diagnostics, Inc. Indazole benzimidazole compounds
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US7838527B2 (en) 2002-11-13 2010-11-23 Novartis Vaccines And Diagnostics, Inc. Methods of treating cancer and related methods
US7875624B2 (en) 2004-02-20 2011-01-25 Novartis Vaccines And Diagnostics, Inc. Modulating and measuring cellular adhesion
US7989478B2 (en) 2003-09-17 2011-08-02 Sumitomo Chemical Company, Limited Cinnamoyl compound and use of the same
CN102146068A (en) * 2011-01-20 2011-08-10 南开大学 3-benzoyl-4-hydroxycoumarin derivatives and analogues thereof and application thereof in weeding aspect
WO2011150682A1 (en) * 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 4-hydroxyquinoline-3-amide derivatives and preparation methods and uses thereof
EP2465857A1 (en) 2005-05-17 2012-06-20 Novartis AG Methods for synthesizing heterocyclic compounds
US8299081B2 (en) 2005-05-13 2012-10-30 Novartis Ag Methods for treating drug resistant cancer
US8354427B2 (en) 2004-06-24 2013-01-15 Vertex Pharmaceutical Incorporated Modulators of ATP-binding cassette transporters
US8410274B2 (en) 2005-12-28 2013-04-02 Vertex Pharmaceuticals Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US20130203703A1 (en) * 2010-10-14 2013-08-08 Immunahr Ab 1,2-dihydro-4-hydroxy-2-oxo-quinoline-3-carboxanilides as ahr activators
US8524729B2 (en) 2003-09-17 2013-09-03 Sumitomo Chemical Company, Limited Cinnamoyl derivatives and use thereof
US8614216B2 (en) 2005-05-23 2013-12-24 Novartis Ag Crystalline and other forms of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one lactic acid salts
EP2762475A1 (en) 2003-11-07 2014-08-06 Novartis Vaccines and Diagnostics, Inc. Pharmaceutically acceptable salts of quinolinone compounds and their medical use
US8802700B2 (en) 2010-12-10 2014-08-12 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette transporters
EP2772257A1 (en) 2005-11-29 2014-09-03 Novartis AG Formulations of quinolinones
US20150051419A1 (en) * 2010-11-28 2015-02-19 Mapi Pharma Ltd. Intermediate compounds and processes for the preparation of quinoline derivatives such as laquinimod sodium
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US9751839B2 (en) 2009-03-20 2017-09-05 Vertex Pharmaceuticals Incorporated Process for making modulators of cystic fibrosis transmembrane conductance regulator
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US10646481B2 (en) 2008-08-13 2020-05-12 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
CN115836056A (en) * 2020-05-21 2023-03-21 Stemsynergy疗法有限责任公司 NOTCH inhibitors and uses thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2007110531A (en) * 2004-08-23 2008-09-27 Ф.Хоффманн-Ля Рош Аг (Ch) HETEROCYCLIC ANTIVIRAL COMPOUNDS

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3625969A (en) * 1966-10-20 1971-12-07 Ciba Geigy Corp 6-sulfamyl-4-hydroxy-3-carboxy-quinolines
EP0012639A2 (en) * 1978-12-08 1980-06-25 Roussel-Uclaf Quinolein-3-carboxylic acid derivatives, process for their preparation, their use in medicines and pharmaceutical compositions containing them
EP0059698A1 (en) * 1981-03-03 1982-09-08 Ab Leo Heterocyclic carboxamides, compositions containing such compounds, processes for their preparation and methods of treatment therewith
EP0214004A2 (en) * 1985-07-25 1987-03-11 Roussel-Uclaf 4-OH-quinoline-carboxylic-acid derivatives substituted in position 2 by a dihydroxy-substituted group, possibly etherified or esterified, process and intermediates for their preparation, their use as medicaments and compositions containing them
WO1990015052A1 (en) * 1989-06-09 1990-12-13 Pharmacia Ab Derivatives of quinoline-3-carboxanilide

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3625969A (en) * 1966-10-20 1971-12-07 Ciba Geigy Corp 6-sulfamyl-4-hydroxy-3-carboxy-quinolines
EP0012639A2 (en) * 1978-12-08 1980-06-25 Roussel-Uclaf Quinolein-3-carboxylic acid derivatives, process for their preparation, their use in medicines and pharmaceutical compositions containing them
EP0059698A1 (en) * 1981-03-03 1982-09-08 Ab Leo Heterocyclic carboxamides, compositions containing such compounds, processes for their preparation and methods of treatment therewith
EP0214004A2 (en) * 1985-07-25 1987-03-11 Roussel-Uclaf 4-OH-quinoline-carboxylic-acid derivatives substituted in position 2 by a dihydroxy-substituted group, possibly etherified or esterified, process and intermediates for their preparation, their use as medicaments and compositions containing them
WO1990015052A1 (en) * 1989-06-09 1990-12-13 Pharmacia Ab Derivatives of quinoline-3-carboxanilide

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994029295A1 (en) * 1993-06-04 1994-12-22 Fujisawa Pharmaceutical Co., Ltd. Heterocyclic derivatives with immunomodulating activity
WO1995024395A1 (en) * 1994-03-07 1995-09-14 Fujisawa Pharmaceutical Co., Ltd. Quinoline derivatives as immunomodulators
GB2290786A (en) * 1994-06-30 1996-01-10 Fujisawa Pharmaceutical Co Quinoline derivatives
US6165799A (en) * 1996-12-10 2000-12-26 Heska Corporation Detection of anti-Fc.sub.ε R autoantibodies in asthmatics
WO1998026289A1 (en) * 1996-12-10 1998-06-18 Heska Corporation DETECTION OF ANTI-FcεR AUTOANTIBODIES IN ASTHMATICS
US6380384B1 (en) 1997-12-03 2002-04-30 Taisho Pharmaceutical Co., Ltd. 1,2-dihydro-2-oxoquinoline derivatives
US6329525B1 (en) 1997-12-03 2001-12-11 Taisho Pharmaceutical Co., Ltd. 1,2-Dihydro-2-oxoquinoline derivatives
WO1999055678A1 (en) * 1998-04-27 1999-11-04 Active Biotech Ab Quinoline derivatives
AP1293A (en) * 1998-04-27 2004-08-30 Active Biotech Ab Quinoline derivatives.
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US6077851A (en) * 1998-04-27 2000-06-20 Active Biotech Ab Quinoline derivatives
WO2000003992A1 (en) * 1998-07-15 2000-01-27 Active Biotech Ab Quinoline derivatives
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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
AP1425A (en) * 1998-07-15 2005-06-06 Active Biotech Ab Quinoline derivatives.
HRP20010039B1 (en) * 1998-07-15 2009-04-30 Active Biotech Ab Quinoline derivatives
WO2000003991A1 (en) * 1998-07-15 2000-01-27 Active Biotech Ab Quinoline derivatives
US6593343B2 (en) 1998-07-15 2003-07-15 Active Biotech Ab Quinoline derivatives
CN1114597C (en) * 1998-07-15 2003-07-16 活跃生物技术有限公司 Quinoline derivs.
US6605616B1 (en) 1998-07-15 2003-08-12 Active Biotech Ab Quinoline derivatives
WO2000006571A1 (en) * 1998-07-31 2000-02-10 Kyorin Pharmaceutical Co., Ltd. Pyrroloquinoline derivatives and process for producing the same
WO2000006572A1 (en) * 1998-07-31 2000-02-10 Kyorin Pharmaceutical Co., Ltd. Bensoquinolizine derivatives and process for producing the same
US6806276B2 (en) 1999-01-08 2004-10-19 Japan Tobacco Inc. 2-oxoquinoline compounds and pharmaceutical uses thereof
US6509352B1 (en) 1999-01-08 2003-01-21 Japan Tobacco Inc. 2-oxoquinoline compounds and medicinal uses thereof
US6395750B1 (en) 1999-10-25 2002-05-28 Active Biotech Ab Drugs for the treatment of malignant tumors
WO2001030758A1 (en) * 1999-10-25 2001-05-03 Active Biotech Ab Drugs for the treatment of malignant tumours
US6683181B2 (en) 2000-07-05 2004-01-27 Pharmacia And Upjohn Comapny Pyrroloquinolones as antiviral agents
US6525049B2 (en) 2000-07-05 2003-02-25 Pharmacia & Upjohn Company Pyrroloquinolones as antiviral agents
US6759417B2 (en) 2000-09-01 2004-07-06 Chiron Corporation Heterocyclic compounds
US6756383B2 (en) 2000-09-01 2004-06-29 Chiron Corporation Heterocyclic derivatives of quinolinone benimidazoles
US7368459B2 (en) 2000-09-01 2008-05-06 Chiron Corporation Heterocyclic compounds
US7138409B2 (en) 2000-09-01 2006-11-21 Chiron Corporation Heterocyclic compounds
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US7335774B2 (en) 2000-09-11 2008-02-26 Novartis Vaccines And Diagnostics, Inc. Quinolinone derivatives
US6605617B2 (en) 2000-09-11 2003-08-12 Chiron Corporation Quinolinone derivatives
US6762194B2 (en) 2000-09-11 2004-07-13 Chiron Corporation Quinolinone derivatives
US6800760B2 (en) 2000-09-11 2004-10-05 Chiron Corporation Quinolinone derivatives
US7642278B2 (en) 2001-07-03 2010-01-05 Novartis Vaccines And Diagnostics, Inc. Indazole benzimidazole compounds
US6822097B1 (en) 2002-02-07 2004-11-23 Amgen, Inc. Compounds and methods of uses
US7317107B2 (en) 2002-02-15 2008-01-08 Astellas Pharma Inc. Imidazole 4-carboxamide compounds with adenosine deaminase inhibiting activity
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US7470709B2 (en) 2002-08-23 2008-12-30 Novartis Vaccines And Diagnostics, Inc. Benzimidazole quinolinones and uses thereof
US7825132B2 (en) 2002-08-23 2010-11-02 Novartis Vaccines And Diagnostics, Inc. Inhibition of FGFR3 and treatment of multiple myeloma
US7838527B2 (en) 2002-11-13 2010-11-23 Novartis Vaccines And Diagnostics, Inc. Methods of treating cancer and related methods
US7893096B2 (en) 2003-03-28 2011-02-22 Novartis Vaccines And Diagnostics, Inc. Use of small molecule compounds for immunopotentiation
WO2004087153A3 (en) * 2003-03-28 2005-03-17 Chiron Corp Use of organic compounds for immunopotentiation
US7989478B2 (en) 2003-09-17 2011-08-02 Sumitomo Chemical Company, Limited Cinnamoyl compound and use of the same
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US20130203703A1 (en) * 2010-10-14 2013-08-08 Immunahr Ab 1,2-dihydro-4-hydroxy-2-oxo-quinoline-3-carboxanilides as ahr activators
US9102592B2 (en) * 2010-11-28 2015-08-11 Mapi Pharma Ltd. Intermediate compounds and processes for the preparation of quinoline derivatives such as laquinimod sodium
US20150051419A1 (en) * 2010-11-28 2015-02-19 Mapi Pharma Ltd. Intermediate compounds and processes for the preparation of quinoline derivatives such as laquinimod sodium
US8802700B2 (en) 2010-12-10 2014-08-12 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette transporters
CN102146068A (en) * 2011-01-20 2011-08-10 南开大学 3-benzoyl-4-hydroxycoumarin derivatives and analogues thereof and application thereof in weeding aspect
US10272046B2 (en) 2012-02-27 2019-04-30 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US11147770B2 (en) 2012-02-27 2021-10-19 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US11752106B2 (en) 2012-02-27 2023-09-12 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US12214083B2 (en) 2012-02-27 2025-02-04 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US9701639B2 (en) 2014-10-07 2017-07-11 Vertex Pharmaceuticals Incorporated Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator
CN115836056A (en) * 2020-05-21 2023-03-21 Stemsynergy疗法有限责任公司 NOTCH inhibitors and uses thereof

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HUT67349A (en) 1995-03-28
JPH06506925A (en) 1994-08-04
GB9108547D0 (en) 1991-06-05
HU9302983D0 (en) 1994-01-28
MX9201823A (en) 1992-10-01
CA2108971A1 (en) 1992-10-23
AU1548792A (en) 1992-11-17
AU656576B2 (en) 1995-02-09
EP0639182A1 (en) 1995-02-22

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