EP0639182A1 - Derives de quinoleine - Google Patents

Derives de quinoleine

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Publication number
EP0639182A1
EP0639182A1 EP92908346A EP92908346A EP0639182A1 EP 0639182 A1 EP0639182 A1 EP 0639182A1 EP 92908346 A EP92908346 A EP 92908346A EP 92908346 A EP92908346 A EP 92908346A EP 0639182 A1 EP0639182 A1 EP 0639182A1
Authority
EP
European Patent Office
Prior art keywords
compound
methyl
salt
hydroxy
formula
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP92908346A
Other languages
German (de)
English (en)
Inventor
Masaaki Matsuo
Kiyoshi Tsuji
Katsuya Nakamura
Glen W. Spears
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fujisawa Pharmaceutical Co Ltd
Original Assignee
Fujisawa Pharmaceutical Co Ltd
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Filing date
Publication date
Application filed by Fujisawa Pharmaceutical Co Ltd filed Critical Fujisawa Pharmaceutical Co Ltd
Publication of EP0639182A1 publication Critical patent/EP0639182A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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 comprising the same and a use of the same.
  • 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.
  • the object guinoline derivatives of the present invention are novel and can be represented by the following general formula (I) :
  • R is lower alkyl or aryl which may have suitable substituent(s) ,
  • R is hydroxy, protected hydroxy, lower alkoxy, halogen, amino, substituted amino, mercapto or protected mercapto, 3 R is hydrogen, lower alkyl, lower alkoxy(lower)- alkyl or ar(lower)alkyl and
  • R is hydrogen, or
  • R 3 and R8 are linked together to form lower alkylene
  • R 4 i.s 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.
  • R , R , R , R , Z and n are each as defined above, R 2_ i.s halogen, , 2 is ammo or substituted amino, R 2 b i.s protected mercapto,
  • R 2 is lower alkoxy
  • R is protected carboxy
  • R, 4 is acyl having protected carboxy
  • R is acyl having carboxy, R 4, is acyl having nitro, R is acyl having amino, .
  • R f 4 is acyl having acylammo,
  • R is a leaving group, a group of the formula : -CO-R 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.
  • R , R , R , R , R , X , Z and n are each as defined above,
  • R C_J. is lloowweerr aallkkyyll,, 1l ⁇ ower alkoxy(lower)alkyl, or ar(lower)alkyl, '
  • R , R '., RR 10 ,, Xx 4 ,, X and X are each as a leaving group
  • 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.
  • 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 alkox (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--C-. alkyl.
  • Suitable "lower alkoxy” and “lower alkoxy moiety" in the term “lower alkoxy(lower)alkyl may include ethoxy, 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 C 1 -C 4 alkylene and - 20 -
  • 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, 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.
  • 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.
  • acyl may be illustrated as follows :-
  • Aliphatic acyl such as lower or higher alkanoyl (e.g. formyl, a ⁇ etyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexan ⁇ yl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.
  • alkanoyl e.g. formyl, a ⁇ etyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropano
  • 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.
  • aminosulf ⁇ nyl 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.
  • aroyl e.g. benzoyl, toluoyl, naphthoyl, etc.
  • ar(lower)alkanoyl e.g. phenyl(lower)alkanoyl (e.g. phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylis
  • ar(lower)alkenoyl e.g. phenyl(lower)alkenoyl (e.g. phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc. ) , naphthyl(lower)alkenoyl (e.g.
  • 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-l- cyclopropylcarbonyl, 1-phenyl-l-cyclopentylcarbonyl, etc.
  • aryloxycarbonyl e.g., phenoxycarbonyl, naphthyloxycarbonyl, etc.
  • aryloxy(lower) lkanoyl 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, - 23 -
  • heterocyclichexenoyl etc.
  • heterocyclicglyoxyloyl e.g. thiazolylglyoxyloyl, thienylglyoxyloyl, etc.
  • 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 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-l,2,4-triazolyl, lH-l,2,3-triazolyl, 2H-l,2,3-triazolyl, etc.), tetrazolyl (e.g.
  • 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.
  • 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 - 25 -
  • 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.
  • 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,
  • 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.
  • 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.
  • acyl e.g., lower alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, etc.), etc.]; nitro; amino; protected amino [e.g. acylamin ⁇ ⁇ e.g., lower alkanoylamino (e.g., formylamino, acetylamino, etc.), etc. ⁇ , etc.]; etc.]; a group of the formula :
  • 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.
  • 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. 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 : -CO-N J
  • 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.
  • aromatic(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,
  • 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.
  • 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- ⁇ ropen ⁇ l, allyl, 1-methylallyl, 1 or 2 or 3-butenyl, 1 or 2
  • halogen e.g., chlorine, bromine, fluorine and iodine
  • 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
  • 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)alky1 protected hydroxy(lower)alkyl
  • nitro acyl
  • cyano
  • 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. );.
  • 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, l-(or 2-)fluoroethyl, l-(or
  • 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.]
  • a group of the formula :
  • 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 substituent(s) e.g. lower alkyl; lower alkoxy; lower alkylthio; lower alkylamino; lower cycloalkyl, lower cycloalkenyl; halogen; amino; protected amino, etc.
  • 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 alkyl 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)
  • benzyl ester e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester,
  • aryl ester which may have one or more suitable substituent(s) such as substituted or unsubstituted phenyl ester (e.g., phenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, esityl ester, cumenyl ester,
  • suitable substituent(s) such as substituted or unsubstituted phenyl ester (e.g., phenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, esityl ester, cumenyl ester,
  • Suitable "heterocyclic group containing at least one nitrogen atom” may include unsaturated 3 to 8-membered (more preferably 5 or
  • 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.
  • 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.
  • 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
  • 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.
  • the 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 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.
  • 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.
  • 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.
  • a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, di
  • the 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'-dicyclohexyl ⁇ arbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodii ide; 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
  • the reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, or the like.
  • an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, or the like.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
  • the compound (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 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.
  • a 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, l,5-diazabicyclo[4.3.0]non-5-ene, l,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]- undec-7-ene, or the like.
  • an alkali metal e.g. sodium, potassium, etc.
  • an alkaline earth metal e.g. magnesium, calcium, etc.
  • trialkylamine e.g. trimethylamine, triethylamine, etc.
  • picoline
  • 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.].
  • metal e.g. tin, zinc, iron, etc.
  • metallic compound e.g. chromium chloride, chromium acetate, etc.
  • 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.
  • platinum catalysts e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.
  • palladium catalysts e.g. spongy
  • 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.
  • a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, di ⁇ xane, 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
  • 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.
  • 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.
  • the starting compound when in liquid, it can be also used as a solvent.
  • the compound (la) or a salt thereof can be prepared by subjecting the compound (VI) or a salt thereof to cyclization reaction.
  • This reaction is usually carried out 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,
  • 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 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.
  • 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 (la) 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.
  • 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.
  • 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 (I£) 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.
  • 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.
  • reaction temperature is not critical and the reaction is usually carried out under warming to heating.
  • the starting compound when it is 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, chloroform, 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, 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.
  • 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) , 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) .
  • 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.
  • 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.
  • 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.
  • 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 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.
  • platinum catalysts e.g., platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.
  • palladium catalysts e
  • 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.
  • a conventional solvent which does not adversely influence the reaction
  • tetrahydrofuran dioxane
  • N,N-dimethylformamide or a mixture thereof.
  • a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other - 44 -
  • 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 (Ig) 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
  • Suitable reactive derivative at the amino group of the compound (Ig) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (Ig) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (Ig) with a silyl compound such as N,0-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.
  • 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.
  • 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.
  • a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine
  • the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; N-cyclohexyl- '-morpholinoethylcarbodiimide;
  • 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.
  • 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.
  • the compound (lib) or a salt thereof can be prepared by reacting the compound (Ila) 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 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.
  • 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.
  • 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, benzene, hexane or any other organic solvent which does not adversely influence the reaction.
  • 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.
  • 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 (
  • 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 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, dimethyl
  • 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 hydrogencarbonate, potassium hydrogencarbonate, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.
  • 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.
  • the base and/or the starting compound and in liquid 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 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.
  • 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.
  • 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.
  • a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile,
  • the 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-
  • ethyl chloroformate isopropyl chloroforraate, etc.]; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt; l-(p-chlorobenzenesulfonyloxy)-6- chloro-lH-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.
  • 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 9 or similar manners thereto.
  • 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 - 53 -
  • 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.
  • a strong immunomodulating activity e.g. an inhibitory activity on the production of an autoantibody, etc.
  • an immunomodulating agent e.g. an inhibitor on the production of an autoantibody, etc.
  • anti-inflammatory agent e.g. an inhibitor on the production of an autoantibody, etc.
  • anti-inflammatory agent e.g. an inhibitor on the production of an autoantibody, etc.
  • anti-inflammatory agent e.g. an inhibitor on the production of an autoantibody, etc.
  • anti-inflammatory agent e.g. an inhibitor on the production of an autoantibody, 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.
  • heraolytic anemia pure red cell anemia, idiopathic thrombocytopenia, aplastic anemia, etc.
  • myasthenia gravis uveitis, contact dermatitis, psoriasis, Kawasaki disease, sarc ⁇ idosis, Wegner's granulomatosis, Hodgkin's disease, cancer [e.g. lung carcinoma, stomach carcinoma, colon cancer, renal carcinoma, hepatoma, etc.], and the like.
  • mice Six weeks old female (57BL/6 x DBA/2)F 1 and DBA/2 mice were used. Graft-varsus-host (GVH) disease was induced in (57BL/6 x DBA/2 ) F * mice with two injections of
  • 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)).
  • ELISA enzyme-linked immunosorbent assay
  • 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.
  • Mouse B16 melanoma cells (5x10 cells) were inoculated intravenously to 8 weeks old female (C57BL/6) mice on day 0.
  • the animals were sacrificed at day 16 and tumor - 56 -
  • test compound was administered orally once a day.
  • 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.
  • 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.
  • 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.
  • 1 R is lower alkyl or phenyl which may have suitable substituent(s) [more preferably phenyl which may have halogen; most preferably phenyl or halophenyl]
  • 2 R 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]
  • 3 R is hydrogen, lower alkyl, lower alkoxy(lower)alkyl, or ar(lower)alkyl [more preferably phenyl(lower)alkyl; most preferably benzyl]
  • R is hydrogen, or R 3 and R8 are linked together to form lower alkylene,
  • R 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 :
  • 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, cyanopheny
  • Preparation 8 (1) A mixture of ethyl 2-(methylamino)-5-(methylthio)- benzoate (2.25 g) , benzoylacetic acid (1.9 g) , l-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.
  • 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 l-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.
  • Example 7 The following compounds were obtained according to a similar manner to that of Example 2.
  • Example 9 The following compounds were obtained according to a similar manner to that of Example 4.
  • 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.

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Abstract

L'invention se rapporte à des dérivés de quinoléine représentés par la formule (I), où R1 représente alkyle inférieur ou aryle pouvant comporter un ou plusieurs substituants appropriés, R2 représente hydroxy, hydroxy protégé, alcoxy inférieur etc., R3 représente hydrogène, alkyle inférieur, alkyle (inférieur) d'alcoxy inférieur ou aralkyle (inférieur), et R8 représente hydrogène, ou alors R3 et R8 sont liés entre eux pour former alkylène inférieur, R4 représente un groupe organique, Z représente O ou S, et n est égal à 0, à 1 ou à 2; ainsi qu'à des sels pharmaceutiquement acceptables de ces dérivés, qui sont utiles comme médicament.
EP92908346A 1991-04-22 1992-04-21 Derives de quinoleine Withdrawn EP0639182A1 (fr)

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GB919108547A GB9108547D0 (en) 1991-04-22 1991-04-22 Quinoline derivatives
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PCT/JP1992/000510 WO1992018483A1 (fr) 1991-04-22 1992-04-21 Derives de quinoleine

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HUT67349A (en) 1995-03-28
GB9108547D0 (en) 1991-06-05
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AU656576B2 (en) 1995-02-09
HU9302983D0 (en) 1994-01-28

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