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CA2108971A1 - Quinoline derivatives - Google Patents

Quinoline derivatives

Info

Publication number
CA2108971A1
CA2108971A1 CA002108971A CA2108971A CA2108971A1 CA 2108971 A1 CA2108971 A1 CA 2108971A1 CA 002108971 A CA002108971 A CA 002108971A CA 2108971 A CA2108971 A CA 2108971A CA 2108971 A1 CA2108971 A1 CA 2108971A1
Authority
CA
Canada
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.)
Abandoned
Application number
CA002108971A
Other languages
French (fr)
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
Individual
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 Individual filed Critical Individual
Publication of CA2108971A1 publication Critical patent/CA2108971A1/en
Abandoned legal-status Critical Current

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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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Quinoline Compounds (AREA)

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 R8 are linked together to form lower alkylene, R4 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

wo g2/l8483 2 1 0 8 9 7 I PCr/JPg2/00510 'DESCRIPTION

~2UINOLINE DERIVATIVES

TECHNI CAL FIELD
This invention relates to new ~uinoline derivatives and pharmace~tically acceptable salts thereof which are useful as a medicament.

BACgGROUND ART
~ome quinoline derivatives have been known as described, for example, in U.S. Patent 4,547,511 and U.S.
Patent 4,127,574.
1~
DISCLOSURE OF INVE~ION
This invention relates to new quinoline derivatives.
More particularly, this invention relates to new quinoline derivatives and pharmaceutically acceptable salts thereof
2~ which have pharmacological activities, processes for preparation thereof, a pharmaceutical composition comprisin~ the same and a use of the same.
Accordingly, one object o~ this invention is to provide the new and useful quinoline 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 quinoline derivatives and salts thereof.
A further object of this invention is to provide a pharmaceutical composition comprising said quinoline derivatives or a pharmaceutically acceptable salt thereof.
Still further object of this invention is ~o provide WO g2/18483 PCI~/JPg2/00510 , 210~971 a use of said quinoline 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 quinoline derivatives of the present invention are novel and can be represented by the following general formula (I) :

1S Rl'S~ ~ J _ R4 (I) R

wherein Rl 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, R is hydrogen, lower alkyl, lower alkoxy(lower)-:
alkyl or ar(lower)alkyl and R8 is hydroqen, ox R3 and R8 are linked together to form lower alkylene, R4 is an organic group, . . .
Z is O or S, and n is 0, l or 2.

The ob;ect compound (I) of the present invention can be prepared by the following processes.

wo g2/18483 2 1 0 8 9 7 l PCr/JPg2/00510 Process (1) o Rl ( 5~0 N O

~II) or a salt thereof z (III~ :
or a salt thereof OH
20R1_5 ~ - R4 (Ia) 25or a salt thereof Process (2) R1 S ~ R4 R8 l3 (Ib) or a 5alt thereof --Wo92/1&~ PcT/Jps2/~lo ~I~8!~71 ~ oxidation 1( ~ ~ ~4 N Z

(Ic) or a salt thereof Process ~3) 1(~ COO~

(Id) or its reactive derivative at the carboxy group or a salt thereof 1 Amidation reaction 1 ( ~~ '~ 1 Co-R6 ~ (Ie) or a salt thereof ;

W092/l&W~ ~ 1 0 8 9 7 1 PCT/JPg2/~10 Process (4) .

5 1( ~ - R4 R

(If) or a salt thereof I Elimination reaction of the 1 carboxy protective group in R4 1~ R2 Rl~SO ~ ~ '`r co~

(Id) or a salt thereof Process l5) R1(SO ~ ~ r R~

R8 l3 (Ig)
3; or a salt thereof WO ~/1&~ PCT/JP92/~l0 ~1~8~
¦ Elimination reaction of the - 1 carboxy protective group ~1 ( (Ih) or a salt thereof Process (6) 1(O ~ N-H

(IV) or a salt thereof R4-CH(CoXl)2 (V) or a salt thereof OH

R~

N
~/
tIi) or a salt thereof WOs2/l&u~ PCT/JPs2/~10 ` 21~971 Process (7) Il x2 (O)n ~ ~

Rl _S~ ,!1 ~ N-C-CH2-R4 R8 ¦ 3 (VI) or a salt thereof ~ Cyclization 1~
OH

R~ R4 (Ia) or a salt thereof Process (8) OH
Rl S ~ ~ r R4 R8 l3 (Ia) or a salt thereof WO ~/1~#~ PCT/JP~ 10 . l Halogenation 1( ~ R4 ~ N'~z (I~) or a salt thereof Process (9) r N Z

(Ik) or a salt thereof 2~
H - Rb (VII) ~ or a salt thereof ``

3~

WO 92/18483 2 1 0 8 ~ 7 ~ P
:, g R1( R4 (IQ) or a salt thereof Process (10) Rl_5 ~ z R4 (Ik) or a salt thereof R2 Ml (VIII) . or a salt thereof - Rl_s ~ - R4 3j (Im) or a salt thereof WO ~/1&#~ PCT/JP92/~10 2 l O ~ o - :

¦ Elimination reaction of the mercapto protective group SH
R~ ~ f I r R4 (In) or a salt thereof lS Process (11) Rl( ~ - R4 (Ik) or a salt thereof ¦ Rd ~ M~
. ~IX) or a salt thereof WO92~1&U~ 21 ~ 8 9 71 PCT/JW2/~10 Rl(S~ R4 N Z
l8 l3 (Io) or a salt thereof Process (12) lS 1( ~ R4 R8 l3 (Ip) or a salt thereof.

¦ Reduction R2 .

Rl(S~ ~ ` Re . N Z

(Iq) or a salt thereof - `~

WO ~1&~ PCT/JP92/~lO
2 ~ 0;$~7 I - 12 -Process (13) R
R1~ ~ ~ R4 (Iq) or a salt thereof ¦ Acylation R1( ~ Rf ~ Z

(Ir) or a salt thereof ;
herein R , R , R , R , R8, Z and n are each as defined above, Ra is halogen, Rb is amino or substituted amino, Rc is protected mercapto, Rd is lower alkoxy, Ra is protected carboxy, Rb is acyl having protected carboxy, Rc is acyl having carboxy, Rd is acyl having nitro, WO92/1&~3 2 1 0 ~ 9 7 1 PCT/JPg2/~10 ~ 13 -Re is acyl having amino, Rf is acyl having acylamino, R is a leaving group, a group of the formula : -CO-R6 5- is amidated carboxy, Xl, x2 and X3 are each as a leaving group, M and M are each as an alkali metal and m is l or 2.

The starting compounds or salts thereof can be prepared by the following processes.

Process (A) O

Rl(S~--N O
H
(IIa) or a salt thereof ~5 (X) or a salt thereof Rl-S~ J~
N O

(IIb~
or a salt thereof WO9~/1*W~ PCT/JP92/~K10 210897i - 14 -Process (B) ~XI ) or a salt thereof . (XII) or a salt thereof R5-C-CH~-R

(III) or a salt thereof Process (C) ~ COOH
H-S~ 11 (XIII) or a salt thereof ` Rl _ X5 (XIV) or a salt thereof Rl_S ~ COOH

(XV) or a salt thereof Process (D) ~ COOH
Rl_s ~ ~

(X~) or a salt thereof `
Reduction l_5~COOH

(XVIb) `
or a salt thereof 2~ Process (E) O .
Rl _5~C-OH

.~ I NH
R8 l3 (XVIa) or a salt thereof WO ~/18#~ PCT/JPg2/~Kl0 210:8~7~1 - 16 -O

(XVII) ~ or a salt thereof (II) or a salt thereof Process (F) 1( ~ CO-X
N-H

(XVIc) or its reactive derivative, or a salt thereof tXVIII) or its reactive derivative, or a salt thereof WO92/1&#~ PCT/JPg2/~10 21089~

Rl -S~Co-x2 ~ N-C-CH -R4 R ~3z (VI) or a salt thereof Process (G) x6~ COOE~

`--' N02 (XIX) or a salt thereof (O)n (XX) or a salt thereof :
Rl_5~ COO~

(XV) ~ or a salt thereof WO92/18U~PCT/JP92/~lO
. .

Process (H) (XXII) or a salt thereof ¦ Elimination reaction of 101 the carboxy protective group R4-CH2-CooH

(XVIIIa) or a salt thereof h i R1 R3 R4 R5 R8, X2, Z and n are each as defined above, 20Ra is lower alkyl, lower alkoxy(lower)alkyl, or ar(lower)alkyl, R7, R9, R10, X4, X5 and x6 are each as a leaving group, and R12 is protected carboxy.
~5 Suitable phaxmaceutically 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 alka~i 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 . ~ ~ ... . . ... . .

WO92/1~#~ PCT/JP~2/~10 2las~7~

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.
ar~inine, 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 alk~l" and "lower alkyl moiety" in the terms "10~2r alkoxy(lower)alkyl and "ar(lower)alkyl"
may include straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, t-bu~yl, 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, hexylo~y 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, tetxamethylene, pentamethylene, hexamethylene, methylmethylene, ethylethylene, propylene, and the like, in which more preferable example may be C1-C4 alkylene and .. . .. , ... . .~ .. .

WO 92~18483 / ,~,~,, 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, neopentyloxy, tert-pentyloxy, hexylo~y, etc.), lower alkenyl (e.g., vinyl, l-propenyl, allyl, l-methylallyl, l or 2 or 3-butenyl, l or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl, etc.), lower alkynyl (e.g., ethynyl, l-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, l 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, 2~ difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, bromomethoxy, dibromomethoxy, tribromomethoxy, 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 WO~ #3 2 1 0 8 9 7 1 PCT/JPg2/ ~ 10 carboxy moiety can be referred to the ones as exemplified below, amino, protected amino, di(lower)alkylamino (e.g., dimethylamino, diethylamino, diisopropylamino, ethylmethylamino, isopropylmethylamino, S 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, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.);
2S lower or higher alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.);
lower or higher alkylsulfonyl (e.g. ~ethylsulfonyl, ethylsulfonyl, etc.);
lower or higher alkoxysulfonyl (e.g. methoxysulfonyl, ethoxysu~fonyl, etc.); aminosulfonyl; or the like.

Aroma~ic acyl such as aroyl (e.g. benzoyl, toluoyl, naphthoyl, etc.);
3i ar(lower)alkanoyl ~e.g. phenyl(lower)alkanoyl (e.g.

PCT/JPg2/~10 W092/1~

~10~71 - 22 -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 le.g.
phenyl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, etc.), etc.~;
ar(lower)cycloalkylcarbonyl le.g.
phenyl(lower)cycloalkylcarbonyl (e.g., 1-phenyl-1-cyclopropylcarbonyl, l-phenyl-1-cyclopentylcarbonyl, etc.~, etc.];
aryloxycarbonyl (e.g., phenoxycarbonyl, naphthyloxycarbonyl, etc.);
aryloxy(lower)alkanoyl ~e.g. phenoxyacetyl, ~0 phenoxypropionyl, etc.);
arylglyoxyloyl (e.g. phenylglyoxyloyl, naphthylglyoxyIoyl, etc.);
arenesulfonyl (e.g. benzenesulfonyl, p-toluenesulfonyl, etc.);
ar(lower)alkylsulfonyl le.g.
phenyltlower)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, WO g2/1~483 2 1 0 8 9 7 ~
- 2~ -heterocyclichexenoyl, etc.);
heterocyclicglyoxyloyl (e.g. thiazolylglyoxyloyl, thienylglyoxyloyl, etc.); or the like; in which suitable heterocyclic moiety in the terms "heterocycliccarbonyl'`, 5- "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 ~-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, lH-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g. lH-tetrazolyl, 2H-tetrazolyl, etc.), etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic qroup containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, 2~5 imidazolidinyl, piperidyl, piperazinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom(sj and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,S-oxadiazolyl, etc.) etc.;
3; saturated 3 to 8-membered (more preferably 5 or 6-WO 92~18483 , PCI~/JPg2/00510 - ?4 _ membered) heteromonocyclic group containing 1 to 2 oxy~en 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(sl, 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(-), for example, thienyl/ dihydrodithiinyl, dihydrodithionyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 ; ~.5 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, benzothiazinyl (e.g.
2~-1,4-benzothiazinyl, etc.), dihydrobenzothiazinyl (e.g.
2H-3,4-dihydrobenzothiazinyl, etc.), etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-memberedi heteromonocyclic group containing an oxygen atom, for example, furyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s), for example, benzo~ioxolyl (e.g.
1,3-benzodioxolyl, etc.), etc.;
3S unsaturated 3 to 8-membered (more preferably 5 or ' PCT/JP92/~K10 WO92/1&~ 21~8971 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
5- sulfur atom(s), for example, benzothienyl, benzodithiinyl, etc.;
unsaturated condensed hetero~yclic group containin~ 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,`
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; sulf o; 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 r e.g. phenyl(lower)alkyl (e.g., benzyl, 2~ 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, dipropyl~mino, etc.); cyano; mono(or di or ..
tri)halollower)alkyl (e.g., fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, l-(or 2- ) f luoroethyl, l-(or 2-)chloromethyl, l-tor 2-)bromomethyl, etc.);
mono(or di or tri)halo(lower)alkoxy (e.g., W0 92/18483 ~ /JP92/0051-fluoromethoxy, chloromethoxy, bromomethoxy, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, 1-(or 2-)fluoroethoxy, l-(or 2-)chloroethoxy, l-(or 2-)bromoethoxy, etc.);
carboxy; protected carboxy ~e.g., esterified carboxy {e.g.
lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), et~.}, 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 te.g., formylamino, acetylamino, etc.), etc.}, etc.~; etc.];
a group of the formula :

/

(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;
2S 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.
3~ Suitable "acyl moiety" in the terms "acyloxy", WO92/1&U~ 2 1 0 ~ ~ 7 ~ PCT/JY92/~10 , "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 : -CO-N 3 Iwherein a group of the formula : -N ~
is a heterocyclic group containing at least one nitrogen atom), and the like.
Suitable "organic group" may include lower alXyl, lower alkenyl, lower al~ynyl, 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 al~yl 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, l-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, l-propynyl, propargyl, l-methylpropargyl, 1 or 2 or 3 3~ butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or PCT/JP~2/~KI~
WO92/1&U~

211)~3971 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 tenm "heterocyclic group which may have suitable substituent~s)" may include lower alXyl (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-propenyl, allyl, l-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 r 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, 25 , dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, 1 or 2-fluQroethyl, 1 or 2-bromoethyl, 1 or 2-chloroethyl, l,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~lawer)alXyl wherein lower alkyl moiety can be referred to the ones as exemplified above and protecte~

WO~/I~U3 21~71 PCT/JPg2/~10 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 le.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, l-(or 2-)fluoroethyl, 1-(or 2-)chloromethyl, l-(or 2-)bromomethyl etc.);
mono(or di or tri)halo(lower)alkoxy (e.g., fluoromethoxy, chl~romethoxy, bromomethoxy, WOg2~1&u~ ~ PcT/Jps2/~lo 21089~
difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, l-(or 2-)fluoroethoxy, 1-(or 2-)chloroethoxy, 1-(or 2-)bxomoethoxy, etc.);
carboxy; protected carboxy [e.g. esterified carboxy {e.
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 :

~3 ~ .

( ) (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; a~ino; protected amino, etc.]; or the like.
~5 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 es~er, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, l-cyclopropylethyl ester, etc.);
lower alkenyl ester ~e.g., vinyl ester, allyl ester, etc.);
lower alkynyl ester (e.g., ethynyl ester, propynyl ester, W092/1~ 2 1 0 8 9 7 ~ Pcr/JPgn/~lo etc.);
- lower alkoxyalkyl ester (e.g., methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, l-methoxyethyl ester, l-ethoxyethyl ester, et~.);
lower alkylthioalkyl ester (e.g., methylthiomethyl 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, ~or example, phenyl(lower)alkyl ester which may have one or more suitable substituent(s) (e.g., benzyl ester, 4-methaxybenzyl 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 ~5 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, pyrrolinyl, WO ~/I&U~ PCT~JP92/~K10 imidazolyl, pyrazolyl, dihydropyridyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1,2,4-triazolyl, lH-1,2,3-triazolyl, 2H 1,2,3-triazolyl, etc.), tetrazolyl (e.g. lH-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-mem~ered (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 pre~erably 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 heterocycli~ 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.), ètc.; and the like.

The processes for preparin~ the object and starting compounds are explained in detail in the f~llowing~

W092/1~ 2 1 ~ ~ 9 ~ 1 PCT/JPg2/~10 Process (1) ~ The object compound (Ia) 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, tetrahy~rofuran, benzene, N,N-dimethylformamide, N,N-dimethylacetamide or any other organic solvent which does not adversely influence the reaction.
The reaction ~emperature 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., diisopropyla~ine, 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 (Ib) 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. pèroxybenzoic acid, m-chloroperoxybenzoic acid, etc.), an~ the like.
The reaction is usually carried out in a conventional solvent su~h as water, alcohol (e.g., methanol, ethanol, WO ~/1&~ PCT/JPs2/ ~ 10 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 ~ompound (Ie) or a salt thereof can be prepared by subjecting the compound (I~) 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 reactiva derivative of the compound (XXIII) may include Schiff's base type imino or its tautomeric ~25 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 xeaction of the compound (XXIII) with a silyl compound such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)-acetamide [e.g. N-(trimethylsilyl)acetamideJ, bis(~rimethylsilyl)urea or the like;
a derivàtive 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 WO9~1&~ PCT/JP92/~10 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 re.g. benzoic acid, etc.]; a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dLmethylpyrazole, triazole or tetrazole; or an activated ester ~e.g.
cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl ~ICH3~2~=CH-] ester, vinyl ester, ethyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioest~r, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, ~5 pyranyl ester, pyridyl ester, piperidyl ester, 8-quînolyl thioester, etc.], or an ester with a N-hydroxy compound [e.g. N,N-dimethyl hydroxylamine, l-hydroxy-2-(lH)-pyridone, N-hydroxysuccinimide~
N-hydroxyphthalimide, l-hydroxy-lH-benzotriazole, etc.~, and the like. These reactive derivatives can optionally be selected from them according to the kind of the compound (Idl to be used.
The reaction is usually carried QUt in a conventional solvent such as water, alcohol ~e~g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, . . -W092/1&~ ~ PCT/JPg2/~10 210837~ - 36 -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 liquid, 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'-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-cyclohexylLmine; ethoxyacetylene;
l-alkoxy-l-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride ~phosphoryl chloride); phosphorus trichloride;
thionyl chloride; oxalyl chloride; lower alkyl haloformate le.g. ethyl chloroformate, isopropyl chloroformate, etc.];
triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt;
~5 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,~-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc.; or the like.
Th~e reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, trillower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N-dillower)alkylbenzylamine, or the like.

WO 92/18483 2 1 0 8 g 7 1 ~

The reaction temperature is not cxitical, 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-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 te.g. magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonate thereof, trialkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, l,5-diazabicyclo~4.3.0Jnon-5-ene, 1,4-diazabicyclo~2.2.2]octane, 1,8-diazabicyclo E 5 . 4 . O ] -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 liquid base or acid can be also used as the WO ~/1~ PCT/JP92/~10 .. .

21089~1 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 te.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 te.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 le.g.
reduced copper, Raney copper, Ullman copper, etc.] and the ~25 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 liguid, 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, e~c., or a mix~ure thereof.

wo ~ U~ 2 1 0 8 9 7 1 PCT/JPg2/~10 The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to heating.

Process (S) The compound (Ih) or a salt thereo~ can be prepared by subjecting the compound (Ig) or a salt thereof to elimination reaction of the carboxy protective group in Rb- .
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 c,arried 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 ~5 adversely affect the reaction.
The reaction temperature is not critical and the reactîon 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 lVI) or a salt thereof to cyclization reaction.
3~ This reaction is usually carried out in a solvent WO ~/1~ PCT/JPg2/~K10 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 S 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 tIa) or a salt thereof to halogenation reaction.
I`his 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, WO 92/18483 PCI~/JPg2/00510 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 li~uid, it can be also used as a solvent.

Process ~9) The compound (IQ) 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.~., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, ,25 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 (10) - ~
The compound (Im) or a salt thereof can be prepared by reacting the compound (Ik) or a salt thereof wi~h the compound (VIII) or a salt thereof.

WOg2/l&U~ PCT/JP92/ ~ 10 , 2l~89~
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 tempera~ure is not critical and the reaction is usually carried out under cooling to heating.

Process (10) - ~
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).

Process (11) The c~mpound (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 ~S 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 (Ig~ or a salt thereof can be prepared 3; by subjecting the compound (Ip) ox a salt thereof to PCT/JP92/~lO
wo 92/18483 2 1 0 8 9 7 ~

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 h~dride, 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 cm organic acid or an inorganic acid ~e.g., formic acid, ac:etic 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 platinumr 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 ~ron, Raney iron, etc.), copper catalysts (e.g., xeduced copper, Raney copper, Ullman copper, etc.) and the li~e.
~ he reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, alcohol (e.g., methanol, ethano~, 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 PCT/JP~2/~10 WO g2/18483 .

conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc. or a mixture thereof.
The reaction temperature is not critical and the reaction is usuially carried out under c~oling to warming.
Process (13) Ths 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 acylati.on reaction.
Suitable acylating agent to be used in the! present acylation reaction may include the compound of the formula :
Rll _ 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 (~q) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (Igj) 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 phiosphorus trichloride or phosgene, and the like.

Sui~able 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, WO ~/l&U~ PCT/JPg21~10 210897~ ~
- 45 - ~.

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, dimethylpyrazole, triazole or tetrazole; or an activated ester (e.g.
cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl r ( CH3)2~=CH-] 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-quinolyl thioester, etc.), or an ester with a N-hydroxy compound (e.g. N,N-dimethylhydroxylamine, l-hydroxy-2-(lH)-pyridone, N-hydroxysuccinLmide, N-hydroxybenzotriazole, N-hydroxyphthalLmide, l-hydroxy-6-chloro-lH-benzotriazole, etc.);
substituted or unsubstituted aryl isocyanate;
2S 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, d'oxane, aceto~itrile, 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.

WO ~/18~ . ;` PCT/JP92/~10 21089~1 - 46 -When the compound (XXI) is used in free acid form or its salt form in the reaction, the reaction is pxeferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;
S N-cyclohexyl-N'-morpholinoethylcarbodiimide;
N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide;
N,N'-diethylcarbodiimide; N,N'-diisopropylcarbodiLmide;
N-ethyl-N'-(3-dLmethylaminopropyl)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; l-(p-chlorobenzenesulfonyloxy)-6-chloro-lH-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, ~25 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 PCT/JPg2l ~ 10 WO ~18U3 2108971 glycol, etc.), chloroform, ether, tetrahydrofuran, benzene, N,N-dimethylformamide, N,N-dimethylaeetamide or any other organic solvent which does not adversely influenee the reaetion.
The reaetion temperature is not critieal and the reaetion is usually carried out under cooling to heating.
The reaetion is usually earried out in the presenee of an inorganie or an organie base sueh as an alkali metal hydroxide, an alkali metal hydrogenearbonate, alkali metal earbonate, alkali metal hydride (e.g. sodium hydride, ete.), alkali metal aeetate, tri~lower)alkylamine, pyridîne base te.g. pyridine, lutidine, pieolîne, dimethylamînopyridine, ete.), N-(lower)alkylmorpholîne, N,N-dî~lower)alkylbehzylamine, N,N-di(lower)alkylanîline or the lîke. When the base and/or the startîng eompound are în liquid, they ean be used also as a solvent.

Proeess (B) The compound (III) or a salt thereof can be prepared by reaeting the eompound (XI) or a salt thereof with the eompound (XII) or a salt thereof.
The reaetion is usually earried QUt in a eonventional solvent sueh as aleohols (e.g. methanol, ethanol, ethylene glyeol, ete.), ehloroform, ether, tetrahydrofuran, S benzene, hexane or any other organic solvent which does not adversely influenee the reaetion.
The reaetion temperature is not eritieal and the reaetion is usually earried out under eooling to warming.
T~e reaetion is usually earried out in the presenee of an inorganie or an organie base sueh as an alkali metal ~ hydroxide, an alkali metal hydrogencarbonate, alkali metal ;~ earbonate, alkali metal aeetate, tri(lower)alkylamine, lower alkyl alkali metal (e.g. n-butyl lithium, ete.), pyridine base (e.g. pyridine, lutidine, picoline, dimethylaminopyridine, ete.), N-(lower)alkylmorpholine, : :
:

wo n/l&U~ PC~/JPg2/~K10 . .

zlo89ll 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.

S Process (C) The compound (XV~ or a salt thereof can be prepared by reacting the compound (XIII) or a salt thereof with ~he 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, potassi~m hydroxide, etc.), an alkali metal hydrogencarbonate (e.g. f sodium hydrogencarbonate, potassium hydrogencarbonate, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium ~5 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 c~mpound are in liquid, they can be used also as a solvent.

WOg~l&~ PCTJJP~ lO
~ ` 21Q8971 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-dimethylfonmamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chlorofonm, 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 èthoxide, 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.

WO9~/1&~ PcT/Jps2/ ~ 10 2 10~9~ 1 _ 50 _ When the base and/or the starting compound and in li~uid, 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 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 cQmpound (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, halogena~ted 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 PCT/JP9~ ~ IO
WO g2/184~3 ,,," 210~971 acid, etc.]; a symmetrical acid anhydride; an activated amide with imidazole, 1-hydroxy-lH-benzotriazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester ~e.~. cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH3)2~=CH-]
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, benzothiaz~lyl 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, l-hydroxy-2-(lH)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, l-hydroxy-lH-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 le.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 ~5 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 o~ a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;
N-cyclohexyl-N`-morpholinoethylcarbodiimide;
N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide;
N,N'-diethylcarbodiimide; N,N'-diisopropylcaxbodiimide;
N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;
3; N,N'-carbonyl-bis(2-methylimidazole);

WO ~/1&~ PCT~JPg2/~10 pentamethyleneketene-N-cyclohexylimine;
diphenylketene-N-cyclohexylimine; ethoxyacetylene;
l-alkoxy-l-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-chlorobenzenesul~onyloxy)-6-chloro-lH-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosyene, trichloromethyl chloro~ormate, 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 ~5 by reacting the compound 5XIX) or a salt thereo~ 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.
miS reaction can be carried out in the manner wo ~/1&~ 2 1 0 8 ~ 7 1 PCT/JP92/~lO

- ~3 -disclosed in Preparation 11 or similar manners thereto.
Suitable salts of the object and starting compounds and their reactive derivatives in Processes ~ (13) and (A)-(H) can be referred to the ones as exemplified for the compound (I).
The new quinoline derivatives (I) and a pharmaceutically acceptable salt thereof of the present invention possess a strong immunomodulating actîvity (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 le.~ an inhibitor on the production of an autoantibody, etc.), anti-inflhmmatory 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.], i~flammatory 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 ~ancier's disease, farmer's lung, etc.], condition of the gastrointestinal tract associated with inflammation re.g. aphthous ulcer, Crohn's disease, atrophic gastritis, gastritis varialofonme, ulcerative colitis, coeliac disease, regional ileitis, irritable bowel syndrome, etc.], gingivitis, linflammation, pain and tumescence after operation or injury), pyrexia, pain and other .;, - ~4 -21089~1 conditions associated with inflammation, rejection by transplantation, systemic lupus erythematosus, scleroderma, po~ymyositis, polychondritis, periarteritis nodosa, ankylosing spondytis, inflammatory chronic renal condition le.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 cirrhori~, 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, sarcoidosis, Wegner's lS 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 quinoline `~-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-antibodv and on the leakage of a Proteinuria.

~` 1. Test method Six weeks old female (57BL/6 x DBA/2)F1 and DBAl2 mice wer~e used. Graft-varsus-host (GVH) disease was induced in (S7BL/6 x DBA/2)Fl mice with two injections of DBA/2 spleen cells given S days apart. Each`injection contained S x 107 cells. From 3 days after the second cell injection, drug was administered orally once a day for 8 weeks.
As an indication of autQimmune disease, 4 weeks after WO ~/I&U~ PCT/JP92/ ~ 10 21Q897~

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)-4-15 hydroxy-6-methylsulfinyl-1,2-dihydroquinoline 3. Test result Inhibition (%) Dose 20 (mgJkg~ anti-DNA antibody proteinuria 100 68* 100*
. .__ * : Significantly different from control group at P<O.O1 InhibitorY activit~ on B16 melanoma metastases 1. Test Method According to the experimental schedule as exemplified below, the experiment was carried out.
Mouse B16 melanoma cells (5x105 cells) were inoculated intravenously to 8 weeks old f~male (C57BL/6) mice on day 0.
3 The animals were sacrificed at day 16 and tumor O ~/1~ PCT/JW2/~K10 , i, 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 - -6 0 1 2 3 4 5 6 7 8 9 lO 11 12 13 14 ( day) 1 0 ~ L.~
( adminis-- . I tration ~ of test inoculation of B16 melanoma removal of lung 2. Test compound l-methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)~4-hydroxy-6-methylthio-1,2-dihydroquinoline 3. Test result kg) ¦ inhibition (96) 34*
~5 100 ~ 63 * Significantly different from control group at P<O.Ol ` :
.. .
For therapeutic administration, the object compounds (I) of the present invention and pharmaceutically acceptable salts thereof are used i~ a form of the conventional pharmaceutical preparation in admixture with a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liguid excipient which is W092/l&~ PCT/JP~ lO
~Q~971 suitable for oral, paren~eral 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 O.01 mg/kg to lO mg/kg, 1 to 4 tLmes a day. However, the above dosage may be increased or decreased according..to age, weight and conditions of the patient or the 15 administering method. :

Pre~erred embodiments of the object compound (I) are as follows.

R1 is lower alkyl or phenyl which may have suitable substituent~s) [more preferably phenyl which may have halogen; most preferably phenyl or halophenyl], R is hydroxy, protected hydro~y ~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], R3 is hydrogen, lower alkyl, lower alkoxytlower)alkyl, or ar(.lower)alkyl ~more preferably phenyl(lower)alkyl;
most preferably benzyl~, R8 is hydrogen, or R3 and R8 are li~ked together to form lower alkylene, R4 is acyl ~more preferably carbamoyl which may be substituted with one or two suitable substituent(s) WO g2/l&~B3 ' '' ' `' Pcr/Jm/ooslo selected fxom the group onsisting 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 alk~l, 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 -~) (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)cycloalkylcarbon~l;
ar(lower)alkylsulfonyl; or heterocycliccarbonyl;
2S most preferably carbamoyl which may be substituted wi~h one or two suitable substituent(s) selected fr~m the group consisting of lower alkyl, phe~yl, 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 wo 92/18483 2 I 0 8 9 71 ...... 5 9 indanyl; thiocarbamoyl which may be substituted with one or two suitable substituent(s) sel~cted from the ~roup consisting o~ lower alkyl and phenyl;
lower alkoxycarbonyl;
5- aminosul~onyl which may be subst~tuted with one or two suitable s~bstituent(s3 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 lmore preferably phenyl(lower)-alkylsulfinyl; most preferably benzylsulfi~yl];.
ar(lower)alkylthio ~more preferably phe~yl(lower)-alk~lthio; most preferably benzylthio]; cyano;
heterocyclic group which may have suitable substituent(s) lmore preferably unsaturated 3 to 8-membered (more preferably ~ or 6-membered) heteromonocy~lic group containin~ 1 to 4 nitrogen atom(s) which may have aryl, unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic ~roup 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 at~m(s) which may have lower alkyl;
most preferably imidazolinyl, phenylimidazolinyl, tetrazolyl, phenyltetrazolyl, oxadiazolyl, phenyloxadiazolyl, benzimidazolyl, lower alkylbenzimidazolyl, ~uinolyl or iso~uinolyl~, Z is O or S and n is 0, 1 or 2.

The following Preparations and Examples are given for 3~ the purpose of illustrating the present in~ention in more detail.

WO 92/18483 j . . pcr/Jm/ooslo Pre~aration l To a solution of 6-methylthio-2H-3,1-~enzoxazine-2,4(1H)-dione (13 g) in N,N-dimethylacetamide ~130 ml), sodium hydride (2.74 g, 60% in mineral oil) was slowly added S 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 l-methyl-6-methylthio-2H-3,1-benzoxazine-2,4(lH)-dione (12.8 g). ~`
mp : 183-191C
IR (Nujol) : 1770, 1720, 1610, 1590 cm lS NMR (DMSO-d6, ~) : 2.54 (3H, s), 3.45 (3H, s),
7.3-7.8 (3H, m) Pre~aration 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 20C. Then a solution of diethyl carbonate (8~2 ml) in tetrahydrofuran (40 ml) was added dropwise, keeping the temperature of the reaction below -30C. 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 chlorofonm. 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)-sulfonyIacetate (12.5 g).
IR (Film) : 1740, 1600, 1495, 1355 cm 1 NMR ~CDC13, ~) : 1.31 (3H, t, J=7.1Hz), 3.41 (3H, s), 3.94 (2H, s), 4.25 (2H, q, J=7.tHz), WOg2/1&#~ 2 1 D 8 9 71 PCT/JP~ lO
, ~ , 7.1-7.6 (5H, m) Nass (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(lH)-dione mp : 143-150C
IR (Nujol) : 1785, 1730, 1610, 1590 cm 1 NMR (DMSO-d6, ~1 1.23 (3H, t, J=7.3Hz~, 2.99 (2H, q, J-7.3Hz), 3.45 (3H, s), 7.41 (lH, d, J=9.OHz), 7.7-7.9 (2H, m) Mass (m/z) : 237 (M ) (2) 1-Methyl-6-(neopentylthio)-2H-3,1-benzoxazine-2,4(lH)-dione mp : 128-181C
IR (Nujol) : 1780, 1765, 1735, 1610, 1580 ~m 1 NMR (DMSO-d6, ~) : 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(lH)-dione 2S mp : 135-145C
IR (Nujol) : 1780, 1720, 1605, 1580 cm1 NMR (DMSO-d6, ~) : 1.22 (3H, t, J=7.1Hz), 2.54 (3~, `
s), 4.08 (2H, q, J=7.1Hz), 7.4-7.8 (3H, m) ~
... ;;
(41 1-Benzyl-6-methylthio-2H-3,1-benzoxazine-2,4(lH)-dione mp : 169-171C
IR (Nujol) : 1780, 1720, 1620, 1580 cm 1 NMR (DMSO-d6, ~) : 2.51 (3H, s), 5.28 (2H, s), 3; 7.1-7.8 (8H, ml WOg~/l~U~ P~T/JPg2/~10 ' 2108~71 Mass (mJz) : 299 (M ) (S~ 1-Methoxymethyl-6-methylthio-2H-3,1-benzoxazine-2,4(lH)-dione mp : 122-126C
IR (Nujol) : 1780, 1760, 1725, 1605, 1585 cm 1 NMR (DMSO~d6, ~) : 2.54 (3H, s), 3.36 (3H, s), 5.43 (2~, s), 7.3-7.8 (3H, m) (6) 6-Methylthio-1-propyl-2H-3,1-benzoxazine-2,4(lH)-. dione mp : 1~6-131C
IR (Nujol) : 1775, 1730, 1605, 1580 cm 1 NMR (DMSO-d6, ~) : 0.95 (3H, t, J-~.3Hz), 1.64 ~2H, sextet, J=7.3Hz), 2.54 (3H, s), 3.95 (2H, t, J=7.3Hz), 7.46 (lH, d, J-8.9Hz), 7.7-7.8 ~2H, m) (7) 1-Methyl-6-phenylthio-2H-3,1-benzoxazine-2,4(1H)-dione mp : 118-121C
IR (Nujol) : 1790, 1770, 1i35, 1610 cm 1 NMR (DMSO-d6, ~) : 3.45 (3H, s), 7.3-7.5 (6H, m), 7.7-7.9 (2H, m) Mass (m/z) : 285 (M ) 2~ :
(8) 6-(4-Fluorophenylthio)-1-methyl-2H-3,1-benzoxazine-2,4-(lH~-dione mp : 131-133C
IR (Nujol) : 1780, 1745, 1715, 1610, 1585 cm 1 NM~ (DMSO-d6, ~) : 3.45 (3H, s), 7.2-7.9 (7H, m) Mass (m/z) : 303 (M ) reeara~
A mixture of 5-mercapto-2-~itrobenzoic acîd (4 g) and potassium carbonate (2.76 g) in 2-methoxyethanol.(40 ml) WO92/18~ PCT/JP92/ ~ lO
` ~ 210~971 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 : 145-198C
IR (Nujol) : 1715, 1605, 1570, 1515 cm 1 NMR (DMSO-d6, 6) : 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 75C. The mixture was stirred at 75-80C for 90 minutes and filtered through ceiite. 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-lneoPentylthio)anthranilic acid (2.7 g).
mp : I15-122C
IR ~Nujol) : 3550, 3430, 1680, 1620, 1580, 1560 cm 1 NMR (DMSO-d6, ~) : 0.95 (9H, s), 2.?3 (2H, s), 6.72 llH, d, J=8.6Hz), 7.30 (lH, dd, J=8.6, 2.1Hz), 7.75 (lHj 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 : 184-186C
:

WO92/1&~ PCT/JPg2/~KlO

2108~71 64 - ~

IR (Nujol) : 3520, 3400, 1680, 1610, 1580, 1550 cm 1 NMR (DMSO-d6, ~) : 6.8-7.4 (6H, m), 7.86 ~lH, d, J=2.2Hz), 8.88 (lH, broad s) Mass (m~z) : 263 (M ) PreParation 6 Into a solution of 5-(ethylthio)anthranilic acid (3.5 g), sodium hydroxide (1.42 g) and dry-ice ~8.9 g) in water (89 ml3 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 ~y filtration, washed with water and dried in the air to give green-yellow crystals of 6-ethylthio-2~-3,1benzoxazine-lS 2,4(1H)-dione (2.9 g).
mp : >300C
IR (Nujol) : 31S0, 3080, 1780, 1740, 1715, 1620 cm 1 NMR tDMSO-d6, ~) : 1.22 (3H, t, J=7.3Hz), 2.99 (2H, q, J=7.3Hz), 7.12 (lH, d, J=8.4~z), 7.6-7.8 (2H, m), 11.8 (lH, s) Nass (m/z) : 223 (M ) Pre~aration 7 (1) A mixture of S-(neopentylthio)anthranilic acid (5.8 g) and ethyl chloroformate ~11.6 ml) in xylene (58 ml) was refl~xed 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 : 221-225C
IR (Nujol) : 3250, 1790, 1765, 1700, 1615 cm l NMR (DMSO-d6, ~) : 0.99 (9H, s)`, 2.95 (2H, s), 7.0-7.8 (3H, m), 11.7 (lH, s~
Mass (m/z) : 265 (M ) 3~

WO92/1~#~ 21 D ~ 9 7 1 PCT/JP~ ~ 10 The following compounds were obtained according to a similar manner to that of Preparation 7-(1).

(2) 6-Phenylthio-2H-3,1-benzoxazine-2,4(lH)-dione mp : 135-138C
IR ~Nujol) : 3250, 1790, 1765, 1700, 1615 c~ 1 NMR (DMSO-d6, ~) : 7.1-7.5 (6H, m), 7.7-7.8 (2H, m), 11.88 (lH, s) Mass (m/z) : 271 (M ), 227 (3) 6-(4-Fluorophenylthio)-2H-3,1-benzoxazine-2,4-(lH)-dione mp : 237-240C
IR (Nujol) : 3250, 3180, 1790, 1760, 1695, 1615, 1585 cm 1 NMR (DMSO-d6, ~) : 7.1-7.8 17H, m), 11.85 ~lH, s) Mass (m/z) : 289 (M ), 245 ;

Pre~aration 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 ~) 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, ~) : 1.17 (3H, t, J=7Hz), 2.58 (3H, s), 3.22 (3H, s), 4.24 (2H, q, J=7Hz), 5.18 (lH, s), 7.3-8.1 (8H, m), 15.1 (lH, s) 3S The following compounds were obtained according to a WO ~l~U~ ` PCT/JPs2/~10 21089~

similar manner to that of Preparation 8-(l).

(2) Ethyl 2-t{2-(N-phenyl-N-methylcarbamoyl)acetyl}-amino~-5-(methylthio)benzoate mp : 115-117C
IR (Nujol~ : 1705, 1680, 1660, 1595, 1495 cm 1 NMR (DMSO-d6, ~) : 1.32 (3~, t, J=7.1Hz), 2.49 (3H, sJ, 3.21 ~3H, s), 3.27 (2H, s), 4.31 (2H, q, J=7.1Hz), 7.3-8.2 (8H, m), 10.6 (lH, 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, 149Q cm 1 :
NMR (CDCl3, ~) : 1.1-1.2 (2H, m), 1.27 (3R, t, ::
J-7.1Hz), 1.5-1.6 (2H, m), 2.55 (3~, s~, 3.10 :`
(3H, s), 4.26 (2H, q, J=7.1Hz), 6.73 (lH, d, J=8.3Hz), 7.1-7.4 (6H, m), 7.74 (lH, d, J-2.3Hz) Macs (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 w~ter to give a white powder of 5-(4-fluorophenylthio)-2-nitrobenzoic acid ~10 g).
mp : 150-153C
IR (Nujol) : 1710, 1590, 1570, 1535 cm NMR ~DMSO-d6, ~) : 7.3-7.8 (6H, m), 7.95 (lH, d, J=8.6Hz), 14.0 (lH, broad s) ` 21 0 8 97 1 PCT/JP92/~K10 Mass (m/z) : 293 tM ) .
Pre~aration 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) wa~ 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 NMR (CDCl3, ~) : 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 (N ) PreRaration 11 A mixture of ethyl 3-oxo-3-(1-phenyl-1-cyclopropyl)-propionate (4.9 g) in lN aqueous sodium hydroxide (21 ml) was stirred at room temperature overnight. The solution ~5 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-(1-phenyl-l-cyclopropyl)propionic acid (3.9 g).
mp : 50-55C
IR (Film) : }745, 1710, 1605, 1500 cm 1 NMR (CDCl3, ~) : 1.3-1.4 (2H, m), 1.7-1~8 (2H, m), 3.39 (2H, s), 7.37 (SH, s) Mass (m/z) : 204 WO ~/1&~3 PCT/JPg2/ ~ lO

210897l 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 ~, 60%) was slowly added and the mixture was stirred for 30 minutes at room temperature.
To the mixture was added dropwise a solution of l-methyl-6-methylthio-2H-3,1-benzoxazine-2,4(lH)-dione (16 g) in N,N-dimethylaeetamide (160 ml) at 80C. Then the mixture was stirred at 120C for 5 hours. The mixture was poured into iee-water (1 Q) and neutralized with concentrated hydroehloric aeid (7 ml). The preeipitates were eollected, washed with water, and dissolved in ehloro~orm (250 ml). The solution was filtered and the filtrate was eoneentrated. The residue was heated in ethanol and eooled to give pale brown erystals of l-methyl-2-oxo-3-(N-methyl-N-phenylearbamoyl)-4-hydroxy-6-methylthio-1,2-dihydroquinoline (13.4 g).
mp : 200-202C (dec.) IR ~Nujol) : 1650, 1635, 1615, 1590, 1565, lS00 em 1 NMR (DMSO-d6, ~) : 2.49 (3H, s), 3.29 (3H, s), 3.42 (3H, s), 7.0-7;8 (8H, m), 11.3 (lH, s) Mass tm/z) : 354 (M ) Elemental Analysis Calcd. for ClgH18N203S :
C 64.39, H 5.12, N 7.91 Found : C 64.54, H 5.07, N 7.69 .
The following eompounds were obtained according to a similar manner to that of Example 1-(1).

(2) l-Methyl-2-oxo-3-(N-methy7-N-phenylaminosulfonyl~-4-hydroxy-6-methylthio-1,2-dihydroquinoline mp : 154-156C
IR ~Nujol) : 1635, lS60 cm 1 NMR (DMSO-d6, ~) : 2.51 (3H, s), 3.51 (3H, s), 3.60 (3H, s), 7.2--7.8 (8H, m) Wo~/l&U~ 2 1 ~ 8 9 7 ~ PCT/JP92/ ~ 10 ., 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-dihydroquinoline mp : 114-115C
IR (Nujol) : 1660, 1630, 1565, 1490 cm 1 NMR (DMSO-d6, ~) : 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 : 157-159C
IR ~Nujol) : 1645, 1575 cm 1 NMR (DSMO-d6, ~) : 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 (N ) Elemental Analysis Calcd. for Cl8H17N04S2 :
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 Exam~le 2 To an ice-cooled solution of l-methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4-hydroxy-6-methylthio-1,2-dihydroq.uinoline (1.45 g) in dichloromethane (40 ml) was added portionwise 80%-m-chloroperbenzoic acid (0.883 g).
The mixture was stirred at 5C 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-WO9~1~U~ PCT/JPg2/~lO

2 iO~ 70 _ 6-methylsulfinyl-1,2-dihydroquinoline (1.5 g).
mp : 218-219C (dec.) IR (Nujol) : 1635, 1595, 1500 cm 1 NMR (DMSO-d~, ~) : 2.75 (3H, s), 3.30 (3H, s), 3.48 (3H, s), 7.0-8.2 (8H, m), 11.7 (1~, s) Mass (m/z) : 370 (M+) Elemental Analysis Calcd. for C1gH18N2O4S-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 l-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 100C 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 l-methyl-2-oxo-3-(1-indolinylcaxbonyl)-4-hydroxy-6-methylthio-1,2-dihydxoquinoline (2.1 g).
mp : 220-222C (dec.) IR (Nujol) : 1655, 1625, 1605, 1580, 1560 cm 1 NMR IDMSO-d6, ~) : 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 (lH, s) Mass (m/2) : 366 (M ) ~lemental Analysis Calcd. for C2oH18N2O3S-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 l-methyl-2-oxo-3-ethoxycarbonyl-4-hydrox-~-6-methylthio-1,2-dihydro~uinoline (2.2 g) and hydrobromic acid (1.7 ml) in acetic acid (6 ml) was stirred at 70C for 4 hours. The mixture was cooled to WOg2/1~ 21~8'~71 PCT/J ~ ~lO

5C, and the precipitates were collected, washed with water and dried in vacuo at 60C to give pale yellow crystals of l-methyl-2-oxo-3-carboxy-4-hydroxy-6-methylthio-1,2-dihydroquinoline ~1.8 g).
5- mp : 162-163C
IR tNujol) : 1690, 1630, 1600, 1490 cm 1 NMR (DMSO-d6, ~) : 2.57 (3H, s), 3.67 (3H, s), 7.6-7.9 (3H, m) Mass (m/z) : 265 ~N ) Exam~le 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 l-methyl-2-oxo-3-carboxy-4-hydroxy-6-methylthio-1,2-dihydroquinoline (2.11 g) was added. The mixture was heated at 100C for 2 hours and 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 2~5 crystals of 1-methyl-2-oxo-3-{N-(4-fluorophenyl)-N-methylcarbamoyl}-4-hydroxy-6-methylthio-1,2-dihydroquinoline (2.1 g).
mp : 201-203c IR (Nujol) : 1650, 1635, 1615, 1595, 1570, 1510 cm 1 NMR (DMSO-d6, ~) : 2.50 (3H, s), 3.28 (3H, s), 3.43 (3H, s), 7.0-7.8 (7H, m), 11.4 (lH, s) Mass (m~z) : 372 (M ) Elemental Analysis Calcd. for C1gH17FN2~3S :
C 61.27, H 4.60, N 7.52 Found : C 61.29, H 4.50, N 7.45 PCT/JP~ 10 21083~

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 : 258-260C
IR (Nujol) : 2240, 1620, 1585, 1550 cm 1 NMR (DMSO-d6, ~) : 2.53 (3H, s~, 3.53 (3H, s), 7~4-8.0 (3H, m) . Mass (m/z) : 246 (M ) (2) 1-Nethyl-2-oxo-3-~N-methyl-N-phenylamino-(thiocarbonyl)]-4-hydroxy-6-methylthio-1,2-dihydroquinoline mp : 174-176C
IR (Nu~ol) : 1620, 1570 cm 1 NMR (DMSO-d6, ~) : 2.48 (3H, s), 3.41 (3H, s), 3.74 (3H, s), 7.1-7.7 (8H, m), 10.9 (lH, s) Mass (m/z) : 370 (M ), 263 Elemental Analysis Calcd. for C1gH18N2O2S2 :
C 61.60, H 4.~0, N 7.56, S 17.31 Found : C 61.29, H 4.87, N 7.42, S 17.09 2~ (3) 1-Methyl-2-oxo-3-(1-phenyl-~-tetrazolyl)-4-hydroxy-6-methylthio-1,2-dihydroguinoline mp : 263-265C (dec.) IR (Nujol) : 1630, 1605, 1590, 1560, 1515 cm 1 NMR (DMSO-d6, ~) : 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-1,3,4-oxadiazol-2-yl)-4-hydroxy-6-methylthio-1,2-dihydroquinoline mp : 240-242C

WO92/l~#~ 21 0 ~ 9 7 ~ PCT/JPg2~ ~ 10 IR (Nujol) : 1660, 1640, 1580, 1535 cm 1 NMR (DMSO-d6, ~) : 2.57 (3H, s), 3.79 t3H, s), 7.2-8.3 (8~, m) Mass (m/z) : 365 (M+) 5- :
(5) 1-Methyl-2-oxo-3-(1-methyl-lH-benzimidazol-2-yl)-4-hydroxy-6-methylthio-1,2-dihydroquinoline mp : 198-204C
IR (Nujol) : 1605, lS75, 1530 cm l NMR (DMSO-d6, ~) : 2.51 (3H, s), 3.53 (3H, s), 3.79 (3~, s), 7.3-8.0 (7H, m) Mass ~m/z) : 351 (~+) (6) 1-Methyl-2-oxo-3-(}-phenylimidazolin-2-yl)-4-hydro~y-6-methylthio-1,2-dihydro~uinoline mp : 120-130C
IR (Nujol) : 1590, 1560, 1525 cm 1 NMR (DMSO-d6, ~) : 2~45 (3H, s), 3.27 (3H, s), 3.88 (2H, t, J=8.9Hz), 4.25 (2H, t, Ji8.9Hz), 7.0-7.8 (8H, m), 10.4 (lH, s) Mass (m/z) : 365 ~M ) (7) 1-Methyl-2-oxo-3-(1-isoquinolyl)-4-hydroxy-6-methylthio-1,2-dihydroquinoline 2S mp : 136-140C
IR (Nujol) : 1645, 1620, 1610, 1585, 1565, 1515 cm l NMR (DMSO-d6, ~) : 2.53 (3~, s), 3.56 (3H, s), 7.4-8.5 (9H, m) ~ass (m/z) : 347 (8) 1-Methyl-2-oxo-3-(2-quinolyl)-4-hydroxy-6-methylthio-1,2-dihydroquinoline mp : 225-227C
IR tNUjol) : 1640, 1610, 1570, 1505 cm 1 NMR (~MSO-d6, ~) : 2.55 (3H, s), ~.60 (3~, s), WO ~I~U~ PCT/JPg2/~10 210897~ - ~4 -7.4-B.1 ~7~, m), 8.63 (lH, d, J=9.4Hz), 9.49 (lH, d, J=9.4Hz) Mass ~m/z) : 348 ~M ) . ~:
.
(9) 1-Methyl-2-oxo-3-tN-l2-methoxyphenyl)-N-methyl-carbamoyl}-4-hydroxy-6-methylthio-1,2-dihydro-quinoline mp : 178-180C
IR (Nujol) : 1610, 1570, 1490 cm 1 NMR ~DMSO-d6, ~) : 2.49 (3H, s), 3.21 (3H, s), 3.36 . ~3H, s), 3.71 (3H, s), 6.6-7.8 (7H, m), 11.0 (1~, s) Mass (m/z) : 384 (M ), 247 Elemental Analysis Calcd. for C20H20N2O4S :
C 62.48, H ~.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-1,2-dihydro-quinoline mp : 175-183C
IR (Nujol) : 1630, 1620, 1585, 1570 cm 1 NMR ~DMSO-d6, ~) : 2.50 (3H, s), 3.27 (3H, s), 3.38 ~3~, s), 7.1-8.0 t7H, m), 11.3 (lH, broad s) 2S Mass (m/z) : 388 (M+~, 247
(11) 1-Methyl-2-oxo-3-{N-methyl-N-(2-methylphenyl)-carbamoyl}-4-hydroxy-6Omethylthio-1,2-dihydroquinoline mp : 188-194C
IR (Nujol) : 1635, 1620, 1595, 1575, 1495 cm 1 NMR (DMSO-d6, ~) : 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 ~.79, N 7.30 W092/~&U~ 2 1 0 8 ~ 7 1 PCT/JP92/~10 .
(12) 1-Methyl-2-oxo-3-(N-methyl-N-phenylcarbamOyl)-4-hydroxy-6-ethylthio-1,2-dihydroquinoline mp : 140-}48C
IR (Nujol) : 1650, 1610, 1585, 1560 cm 1 5- NMR ~DMSO-d6, ~) : 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 (lH, s) Mass (m/z) : 368 (M+), 261
(13) 1-Methyl-2-oxo-3-(N-met~yl-N-phenylcarbamoyl)~4-hydroxy-6-(neopentylthio~-1,2-dihydr~quinoline mp : 121-123C
IR tNUjol) : 1655, 1630, 1610, 1585 cm 1 NMR (DMSO-d6, ~) : 0.98 (9H, s), 2.92 (2H, s), 3.29 (3H, s), 3.42 (3H, s), 7.1-7.9 (8H, m), 11.3 (lH, broad s) Mass ~m/z3 : 410 (M ~
(14) 1-Ethyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4-hydroxy-6-methylthio-1,2-dihydroquinoline mp : 174-180C
IR (Nujol) : 1640, 1620, 1580 cm 1 NNR ~DNSO-d6, ~) : 1.23 (3H, t, J=7Hz), 2.49 (3H, s), 3.29 ~3H, s), 4.~0 (2H, q, J=7~z), 7.0-7.8 t8H~ m), 11.3 (lH, s) Mass (m/z) : 368 (M ) Elemental Analysis Calcd. ~or C20H20N2O3S :
C 65.20, H 5.47, N 7.60, S 8.~0 Found : C 65.52, H 5.59, N 7.34, S 8.74 (15~ 1-Benzyl-2-oxo-3-~N-methyl-N-phenylcarbamoyl~-4-hydroxy-6-methylthio-1,2-dihydroquinoline mp : 185-195C
IR (Nujol) : 1640, 1620, 1590, 1500 cm 1 NMR (DMSO-d6, ~) : 2.45 (3H, s), 3.33 (3H, s), WO92/l&U~ PCT~JP92/~lO
089~ ~ - 76 -6.7-7.8 (13H, m), 11.5 (lH, s) Mass (m/z) : 430 (N ) 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 : 152-156C
IR (Nujol) : 1645, 1605, 1580, 1560 cm 1 NMR IDMSO-d6, ~) : 2.49 (3H, s), 2.95 (3H, ~), 3.30 (3~, s), 5.49 (2H, s), 7.0-7.8 18H, m), 11.6 (lH, 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 : 142-152C
IR (Nujol) : 1640, 1630, 1605, 1580 cm 1 NMR (~MSO-d6, ~) : 0~76 (3H, t, ~=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 (lH, s) Mass ~mtz ) : 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-hydro~y-6-phenylthio-1,2-dihydroquinoline mp : 110-115C
NMR (DMSO-d6, ~) : 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-dihydroquinoli~e WO92/1&~ 0 8 9 7 ~ P~T/JP92/ ~ 10 ) - 77 -mp : l35-137C
IR (Nujol) ~ 1690, 1610, 1530 cm 1 NMR (DMSO-d6, ~ 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 5 - (3H, m) (20) 1-Methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4-hydroxy-6-(4-fluorophen~lthio)-1,2-dihydroguinoline IR (Nujol) : 1640, 1615, 1585, 1550, 1510 cm 1 NMR (DMSO-d6, ~) : 3.26 (3H, s), 3.37 (3H, s), 7.0-7.6 (llH, m), 8.02 (lH, 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-phenylcar~amoyl)-4-methoxy-6-methylsulfinyl-1,2-dihydroquinoline mp : 322-325C (dec.) IR (Nujol) : 1640, 1630, 1595, 1495 cm 1 NMR (DMSO-d6, ~) : 2.74 ~3H, s), 3.36 (3H, s), 3.53 (3H, s), 4.15 (3H, s), 7.1-8.4 (8H, m) Mass (mlz): 384 (M~) 25.
l2) 1-Methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4-hydroxy-6-phenylsulfinyl-1,2-dihydroquinoline mp : 216-223C
IR (Nujol) : 1640, 1600, 1590, 1495 cm 1 NMR (DMSO-d6, ~) : 3.29 (3H, s), 3.42 (3H, s), 7.0-8.3 (13H, m), 11.7 (lH, s) Mass (m/z) : 432 (M ) Elemental Analysis Calcd. for C24H20N2O4S : ;
C 66.65, H 4.66, N 6.48 ~5 Found : C 66.5~, H 4.67, N 6.37 WO ~/1&~ PCT/JP92/~10 210897~ - 78 -ExamPle 8 The following compounds were obtained according to a similar manner to th~t of Example 3.

(1) 1-Methyl-2-oxo-3-~N-benzyl-N-methylcarbamoyl)-4-hydroxy-6-methylthio-1,2-dihydroguinoline mp : 186-188C
IR (Nujol) : 1645, 1635, 1605, 1575, 1500 cm 1 NMR (DMSO-d6, ~) : 2~54 (3H, s~, 2.79 (3H, s), 3.58 (3H, s), 4.3-4.8 12H, m), 7.2-8.0 (8H, m) Mass (m/z) : 368 (M ), 247 Elemental Analysis Calcd. for C20H20N203S :
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-dihydro~uinoline mp : 264-267C
IR (Nujol) : 1630, 1600, 1540 cm 1 NMR (DMSO-d6, ~) : 2.58 (3H, s), 3.69 (3H, s), 7.4-8.0 (5H, m) Mass (m/z) : 347 (M+), 247 Elemental Analysis Calcd. for C15H13N303S2 :
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-dihydr~quinoline mp~; 144~147C
~0 IR (Nujol) : 1645, 1635, 1590, 1570, 1500 cm 1 NMR (DNSO-d~ 1.0-l.B (lOH, m), 2.52 (3H, s), 2.78 (3H, s), 3.3-3.6 (lH, m), 3.54 (3H, s), 7.4-7.9 (3H, m) Mass ~m/z) : 360 (M ), 247 wo 92/.8483 2 1 0 8 9 7 ~

Elemental Analysis Calcd. for ClgH24N2O3S :
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-tN-~2-pyridyl)carbamoyl}-4-hydroxy-6-methylthio-1,2-dihydroquinoline mp : 212-213C
IR (Nujol) : 1640, 1630, 1600, 1570, 15S0, 1530 cm 1 N~R (DMSO-d6, ~) : 2.57 t3H, s), 3.67 (3H, s), 7.1-8~5 (7H, m), 13.0 (lH, broad s) Mass ~m/z) : 341 (M ), 247 Elemental Analysis Calcd. for C17H15N3O3S :
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-phenylcarbamoyl)-4-hydroxy-6-methylthio-1,2-dihydroquinoline mp : 176-178C
IR (Nujol~ : 1650, 1600, 1590, 1565 cm 1 NMR (DMSO-d6, ~) : 2.57 (3H, s), 3.67 (3H, s), 7.1-B.0 ~8H, m), 12.7 (lH, s) Mass (m/z) : 340 (M ), 247 Elemental Analysis Calcd. for C1~H16N2O3S :
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)carbamoyl}-4-hydroxy-6-methylthio-1,2-dihydroquinoline mp ~. 159-160C
IR (Nujol) : 1640, 1625, 1590, 156~ cm 1 NMR (DMSO-d6, ~) : 2.37 (3H, s), 2.57 (3H, s), 3.67 (3H, s), 7.1-8.2 (7H, m), 12.6 (lH, s) Mass (m/z) : 3S4 ~M ), 247 Elemental Analysis Calcd. for ClgH18N2O3S : -C 64.39, H 5.12, N 7.91 Found : C 64.06, H 4.97, N 7.83 WO ~/1&U~ PCT/JP92/~K10 210~9~

(7) 1-Methyl-2-oxo-3-{N-(2-chlorophenyl)carbamoyl}-4-hydroxy-6-methylthio-1,2-dihydroquinoline mp : 189-190C
IR (Nujol) : 1660, 1640, 1590, 1580, 1555 cm 1 S NMR ~DMSO-d6, ~ : 2.57 (3H, s), 3.67 (3H, s), 7.1-8.4 (7H, m), 13.1 (lH, s) Mass (m/z) : 374 (M~, 247 Elemental Analysis Calcd. for C18H15N2C1O3S :
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-dihydroguinoline mp : 198-200C
IR (Nujol) : 1645, 1635, 1600, 1565, 1520 cm l NMR (DMSO-d6, ~) : 2.57 (3H, s), 3.69 (3H, s), 7.4-8.0 ~6H, m), 12.2 (lH, s~
Mass (m/z) : 408 (M ), 247 (9) 1-Methyl-2-oxo-3-{N-(2,6-dimethylphenyl)carbamoyl}-4-hydroxy-6-methylthio-1,2-dihydroquinoline mp : 215-216C
IR (Nujol) : 164Q, 1600, 1580, 1555 cm 1 NNR (DMSO-d6, ~) : 2.21 (6H, s), 2.57 (3H, s), 3.68 2~ (3H, s), 7.16 (3H, s), 7.6-7.9 (3H, m), 11.9 (lH, 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 : 246-249C (dec.) IR (Nujol) : 1655, 1610, 1550, 1495 cm 1 NMR (DMSO-d6, ~) : 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~g-8.2 (6H, m), ~092/1~#~ 2 1 0 ~ 9 7 1 PCT/JPg2/ ~ 10 11.3 (lH, broad s) Mass (mJz): 378 ~M ) Exam~le 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 r 3,2,1-ij]~uinoline mp : 270-278C (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-dihydroquinoline mp : 139-148~C (dec.) IR ~Nujol) : 1680, 1610, 1550 cm 1 NMR (DMSO-d6, ~) : 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.
2~5 (1) 1-Methyl-2-oxo-3-{N-(4-methoxyphenyl)-N-methylcarbamoyl}-4-hydroxy-6-methylthio-1,2-dihydro-quinoline mp :. 171-173C (dec.) IR (Nujol) : 1640, 1620, 1590, 1560, 1510 cm 1 NMR (DMSO-d6, ~) : 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 (lH, s) Mass (m/z) : 247 WOg2/1&~3 PCT/JPg2/~10 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-hydrox~-6-methylthio-1,2-dihydroquinoline mp : 204-205C (dec.) IR (Nujol) : 1645, 1605, 1580, 1560 cm 1 NMR (DMSO-d6, ~) : 1.07 l3H, t, J-7.0Hz), 2.49 (3H, s), 3.41 (3H, s), 3.80 (2H, q, J=7.0Hz), 7.1-7.8 18H, m), 11.2 (lH, 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-1,2-dihydroquinoline mp : 136-140C (dec.) IR (Nujol) : 1650, 1630, 159S, lS65 cm 1 NMR (CDC13, ~) : 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-dîhydro-quinoline mp : 191-194~C
IR (Nujol) : 3300, 1640, ~620, 1585 cm 1 NMR (DMSO-d6, ~) : 2.52 (3H, s), 3.29 (2H, broad s), 3.49 (3H, s), 3.92 (2H, broad s), 6.7-8.0 (7H, WO g2/18483 PCI/JPg2/00510 ^`` 2108!~74.

m), 11.5 tlH, broad s) Mass ~m/z) : 398 (M ), 247 Elemental Analysis Calcd. for C20~18N2O3S2 :
C 60.28, ~ 4.55, N ~.03 Found : C 60.02, H 4.53, N 6.88 (S) 1-Methyl-2-oxo-3-{~3,4-dihydro-2~-1,4-benzoxazin-4-yl)carbonyl}-4-hydroxy-6-methylthio-1,2-dihydroquinoline mp : 202-204C
IR (Nujol) : 1640, 1600, 1585, 1560, 1495 cm 1 NMR (DMSO-d6, ~) : 2.54 ~3H, s), 3.54 (3H, s), 3.72 (2H, s), 4.30 (2H, s), 6.5-8.4 (7H, m), 11.6 (lH, 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) 1-Methyl-2-oxo-3-{N-methyl-N-(4-methylthiophenyl)-carbamoyl}-4-hydroxy-6-methylthio-1,2-dihydroguinoline mp : 168-169C (dec.) IR ~Nujol) : 1645, 1625, 1565, 14~5 cm 1 NMR (DMSO-d6, ~) : 2.36 (3H, s), 2.49 (3H, s), 3~27 (3H, s), 3.44 (3H, s~, 7.0-7.8 (7H, m), 11.3 (lH, s) Mass (m/z) : 400 (M ), 247 Elemental Analysis Cal~d. for C20H20N2O3S2 :
C 59.98, H 5.03, N 7.00 Found : C 60.08, H 5.25, N 6.7S

t7) 1-Methyl-2-oxo-3-{N-~1,3-benzodioxol-5-yl)-N-methyl-carbamoyl}-4-hydroxy-6-methylthio-1,2-dihydroguinoline mp : 141-144C (dec.) IR ~Nujol) : 1640, 1620, 1600, 156S, 1500 cm 1 WO92/1&#~ PCT/JPg2/ ~ l0 8 ~ ~ ~

NMR IDMSO-d6, ~) : 2.50 (3H, s), 3.24 (3H, s), 3.45 (3H, s), 5.93 (2H, s), 6.6-7.8 (6H, m), 11.2 (lH, 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-dihydroguinoline mp : 192-1~3C ~dec.) IR (Nujol) : 1650, 1630, 1590, 1565, 1515 cm NMR (DMSO-d6, ~) : 2.14 (3~, s), 2.49 ~3H, s), 3.26 (3H, sl, 3.43 (3H, s), 6.9-7.8 (7H, m), 11.3 (lH, 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 t9) 1 Methyl-2-oxo-3-{N-(2,4-difluorophenyl)-N-methylc~rbamoyl}-4-hydroxy-6-methylthio-1,2-dihydroguinoline mp : 129-131C
IR (Nujol) : 1650, 1600, 1565, 1515 cm 1 NMR (DMSO-d6, ~) : 2.51 (3H, s), 3.27 (3H, s), 3.40 (3H, s), 6.8-8.0 t6H, m), 11.5 (1~, broad s) Mass (m/z) : 390 (M ), 274 Elemental Analysis Calcd. for C1gH16N2F2O3S :
C 58.45, H 4.13, N 7.18 Found : C 58.56, H 3.88, N 7.08 t10) 4-Oxo-5-(N-methyl-N-phenylcarbamoyl)-6-hydroxy-8-methylthio-1,2-dihydro-4H-pyrrolo~3,2,1-ij]quinoline mp : 120-121C (dec.) WO g2/18483 2 1 0 8 9 7 ~ PCr/J

IR (Nujol): 3400, 1640, 1630, 1590, 1495 cm N~ (DMSO-d6, ~): 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 ( lH, broad s ) S Mass (m/z 3 : 259 (11) 1-Methyl-2-thioxo-3-(N-methyl-N-phenylcarbamoyl)-4-hydroxy-6-methylthio-1,2-dihydroquinoline mp: 130-150C
IR (Nujol): 1620, 1595, 1565, 1500 cm 1 NMR (DMSO-d6, ~) : 2.53 (3H, s), 3.30 (3H, s), 4.06 (3H, s), 7.0-8.0 (8H, m) Mass (m/z) : 370 (M 3, 263 (12) 1-Methyl-2-oxo-3-~N-methyl-N-{4-~trifluoromethoxy)-phenyl}carbamoyl]-4-hydroxy-6-methylthio-1,2- :
dihydro~uinoline IR ~Nujol) : 1640, 1620, 156S, 1510 cm 1 NMR (CDCl3, ~) : 2.55 l3H, s), 3.28 (3H, s), 3.49 `~
(3H, s), 7.0-8.0 (7~, m) Mass (m~z) : 438 (M ), 247 (13) 1-Methyl-2-oxo-3-[N-me~hyl-N-{3-ttrifluoromethyl)-phenyl}c~rbamoyl~-4-hydroxy-6-methylthio-1,2-~5 dihydroquinoline IR (Nujol) : 1640, 1625, 1610, 1570, 149S cm 1 NMR (CDCl3, ~) : 2.56 (3H, s), 3.28 (3H, s), 3.52 (3H, s), 7.1-7.6 t6H, m), 7.97 (lH, d, J=2.2Hz), .12.5 (lH, broad s) Mass (m/z) : 422 ~M+), 247 Exam~
(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 PCl'tJm/00510 wo g2,~8483 1,3-dicyclohexylcarbodiimide (986 mg) in toluene (10 ml) was stirred at 90C 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 acidifiied 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-1,2-dihydroquinoline (O.47 g).
mp : 187-189C (dec.) IR (Nujol) : 1660, 1610, 1580 cm l NMR (DMSO-d6, ~) : 2.55 (3H, s), 3.60 (6~, s), 7.5-8.0 (3H, m)~ 9.30 (lH, s), 11.9 (lH, 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 : 151-154C
IR (Nujol) : 1655, 1620, 1605, 1575 cm 1 NMR (DMSO-d6, ~) : 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-(l-methyl-5-pyrazolyl)-earbamoyl}-4-hydroxy-6-methylthio-1,2-dihydroquinQline mp : 114-118C (dec.) WO 92/1&~83 PCI~/JPg2/00~10 8 !3 7 1 IR (Nujol) : 3380, 1665, 1600, 1570, 1550 cm 1 NMR ~DMSO-d6, ~) : 2.51 (3H, s), 3.22 (3H, s), 3.45 (3H, s), 3~72 (3H, s), 6.0-8.0 (5H, m), 11.5 (lH, broad s) Mass (m/z) : 247 Elemental Analysis Calcd. for C17~il8N4O3S :
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 "!-dihydroquinoline mp : 110-112C
IR (Nujol~ : 1690, 1645, 1600, 1565, 1500 cm 1 NMR (DMSO-d6, ~) : 2.50 (6H, s), 3~34 (3~, s), 3.47 13H, s), 7.3-7.9 (7H, m), 11.5 (lH, broad s) Mass ~m/z) : 396 (M ), 247 Elemental Analysis Calcd. for C~1~20~2o4S1/6H20 :
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-dihydroquinoline mp : 165-168C
IR (Nujol) : 1640, 1615, 1565, 1525 cm 1 NMR (DMSO-d6, ~) : 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 ) t 247 (6) 1-Methyl-2-oxo-3-[N-{4-~methoxycarbonyl)phenyl}-N-methylcarbamoyl]-4-hydroxy-6-methylthio-1,2-dihydro-quinoline mp : 149-151C

WO ~/1&~ PCT/JP92/~10 IR (Nujol) : 1725, 1645, 1630, 1605, 1565, lS00 cm 1 NMR (DMSO-d6, ~) : 2.50 (3H, s), 3.34 (3H, s), 3~46 (3H, s), 3.77 (3H, s), 7.3 7.9 (7H, m), 11.5 (lH, broad s) Mass (m/z) : 412 (m+~, 247 Elemental Analysis ~aicd. 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-methylthio-1,2-dihydroquinoline mp : 116-118C (dec.) -IR (Nujol) : 3030, 1680, 1620, 1600, 1575, 1500 cm 1 N~R ~DMSO-d6, ~) : 2.50 (3H, s), 3.39 (3H, s~, 3.45 ~
lS (3H, s), 5.83 (2H, broad s~, 6.77 (2H, broad s), ~--7.3-7.8 (3H,m ), 11.5 (lH, s) Mass (m~z) : 343 (M+) `
Elemental Analysis Calcd. for Cl7Hl7N3O3S-EtOH :
C S8.59, 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-1,2-dihydro-quinoline mp : 171-181C
IR (Nujol) : 2230, 1645, 1630, 1590, 1565r 1510 cm 1 NMR (DMSO-d6, ~) : 2.51 (3H, s), 3.34 (3H, s~, 3.47 (3H, s), 7.3-7.9 (7H, m), 11.6 tlH, broad s) Mass (m/z) : 379 ~M ), 247 :
(9) 1-Methyl-2-oxo-3-[N-methyl-N-(4-nitorophenyl)-carbamoyl]-4-hydroxy-6-methylthio-1,2-dihydroquinoline mp : 112-116C `
IR (Nujol) : 1640, 1630, 1610, 1580, 1525, 1495 cm 1 WO92/l~U~ 210 ~ 9 7 l NMR (DMSO-d6, ~) : 2.51 (3H, s), 3~37 (3H, s), 3.48 (3H, s), 7.3-8.2 (7H, m), 11.6 ~lH, broad s) Mass ~m/z) : 399 (M ), 247 ExamPle 12 A mixture of 1-methyl-2-oxo-3-~N-{4-(methoxy-carbonyl)phenyl}-N-methylcarbamoyl~-4-hydroxy-6-methylthio-1,2-dihydroquinoline (O.55 g) and sodium hydroxide (0.21 g) in water (~ ml) was stirred at room , 10 temperature for 2 hours. The mixture was filtered and the filtrate was acidified with hydrochloric acid. ~he precipitates were collected and washed with water to give pale yellow crystals of 1-methyl-2-oxo-3-{N-~4-carboxyphenyl)-N-methylcarbamoyl}-g-hydroxy-6-methylthio- j 1,2-dihydroquinoline (O.5 g). --mp : 123-137C
IR (Nujol) : 1710, 1630, 1600, 1570, 1500 cm 1 NNR (DMSO-d6, ~) : 2.50 (3H, s), 3.33 (3H, s), 3.47 (3H, s3, 7.3-7.9 (7H, m), 11.5 (lH, broad s), 12.9 (lH, broad s) Mass tm/z) : 399 (M ), 354 Exam~le 13 A mixture of 1-methyl-2-oxo-3-(N-methyl-N-phenyl-2~ carbamoyl)-4-hydroxy-6-methylthio-1,2-dihydroquinoline (2.5 ~) 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 aqueous solution of sodium bicarbonate and the extract was acidified with hydrochloric acid. The precipitates were collected by filtration and purifiea 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 WO ~1&U~ pcr/Jp92/ ~ lO

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 : 221-223C (dec.) IR (Nujol) : 1640, 1620, 1590, 1550, 1495 cm 1 NMR (DMSO-d6, ~) : 3.23 (3H, s), 3.31 (3H, s), 3.49 (3H, s), 7.0-8.4 (8H, m), 11.9 (lH, 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 150C
for 1 hour, at 200C for 1 hour, and at 220C 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-pyrrolol3,2,1-ij]quinoline (1.3 g).
IR (CHC13) : 1655, 1620, 1560, 1490 cm 1 NMR (DMSO-d6, ~) : 1.29 (3H, t, J-7.1Hz), 2.51 t3H, s), 3.32 (2H, t, J=7.8Hz), 4.1-4.4 14H, m), 7.47 ~lH, s), 7.51 (lH, s) Mass (m/z) : 305 (M+), 259 2S Exam~le 15 To a stirred mixture of ethyl benzylsulfinylacetate (0.5 g) and 1-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 3C. After 30 minutes, the reaction mixture was quenched with water, acidified with lN hydrochloric acid (5 ml) and extracted with dichloromethane. The extract was dried and concentrated.
The residue was dissolved in toluene (~5 ml) and the solution was allowed to stand at room temperature -overnight. The precipitates were collected and washed PCT/JP~ ~ 10 WO g2/18483 ~ ` 21~1897~

with toluene to give colorless crystals of l-meth~1-2-oxo-3-benzylsulfinyl-4-hydroxy-6-methylthio-1,2-dihydroquinoline (O.39 g).
mp : 158-160C (dec.) IR (Nujol) : 1615, 1565 cm 1 NMR (DMSO-d6, ~) : 2.49 (3H, s), 3.59 (3H, s), 4.33 (lH, d, J=13Hz), 4.60 (lH, d, J=13Hz), 7.1-7.8 (8H, m) Mass (m/z) : 359 (M ) Exam~le 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 5C for 10 minutes. Ethyl (benzylthio)acetate (2.1 g) was added at -78C and the mixture was stirred for 1 hour. To the mixture was added l-methyl-6-methylthio-2H-3,1-benzoxazine-2,4(lH)-dione (2.2 g). The resulting mixture was slowly warmed to room temperature, stirred for 2 hours, quenched 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 ~5 chromatography on silica gel (lS0 g) eluti~g with dichloromethane-isopropanol (20:1), followed by recrystallization from acetone to gi~e colorless crystals of 1-methyl-2-oxo-3-benzylthio-4-hydroxy-6-methylthio-1,2-dihydroquinoline (0.86 g).
....
mp : 110-112C
IR (Nujol) : 1635, 1610, 1585, 1560 cm 1 NMR ~DMSO-d6, ~ : 2.51 ~3H, s), 3.61 (3H, s), 4.06 (2H, s), 7.0-7.7 (8H, m), 10.45 (lH, s~
Mass (m/z) : 343 (M ) WOg2/l~U~ PCT/JPg2/~0 ~1~897~

Elemental Analysis Calcd. for C18H17NO2S2 :
C 52.95, H 4.9g, 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 eth~l 2-{N-methyl-N-(2-benzoylacetyl)-amino3-5-(methylthio)benzoate (2.9 g) and sodium ethoxide (1.1 g) in ethanol (39 ml) was stirred at room t~mperature 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 o 1-methyl-2-oxo-3-benzoyl-4-hydroxy-6-methylthio-1,2-dihydroquinoline (2 g).
mp : 170-171C
IR (Nujol) : 1650, 1625, 1595, 1565 cm 1 NMR IDMSO-d6, ~) : 2.55 (3H, s), 3.54 (3H, s~, 7.4-8.0 (8H, m), 11.8 (lH, 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).
25~
(2) 2-Oxo-3-(N-methyl-N-phenylcarbamoyl)-4-hydroxy-6-methylthio-1,2-dihydroquinoline mp : 259C (dec.) IR (Nujol) : 165Q, 1625, 1595, 1500 cm 1 NMR (DNSO-d6, ~) : 2.46 (3H, s), 3.29 (3H, s), 7.0-7.7 (8H, m), 11.25 (lH, s) Mass (m/z) : 340 IM ), 233 ~3) 1-Methyl-2-oxo-3-(1-phenyl-1-Cyclopropylcarbonyl)-4-hydroxy-6-methylthio-1,2-dihydroquinoline WO92/1&~ 2 1 0 8 9 7 ~ PCT/JP92/ ~ 1~

mp : 170-173C
- IR (Nujol) : 1665, 1590, 1565 cm 1 NMR (DMSO-d6, ~) : 1.3-1.4 (2H, m~, 1.5-1.6 ~2H, m), 2.51 (3H, s), 3.43 (3H, s), 7.1-7.6 (7~, m), 5- 7.82 (lH, d, J=2.1Hz), 11.86 ~lH, s) Mass (m/z) : 365 (M+), 337 Elemental Analysis Calcd. for C21H1~NO3S-1/4H2O :
C 68.18, H 5.31~ N 3.79 Found : C 68.27, H 5.12, N 3.79 Ex~
A mixture of 1-methyl-2-oxo-3-~N-methyl-N-phenyl-carbamoyl)-4-hydroxy-6-methylthio-1,2-dihydroquinoline (2.35 g) and phosphorus oxychloride (7.05 ml) was stirred at 80C 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-1,2-dihydroquinoline (2 g).
mp : 209-210C
IR (Nujol) : 1645, 1630, 1590, 1560 cm 1 NMR (DMSO-d6, ~) : 2.51 (3H, s), 3.36 ~3H, s), 3.56 (3H, s), 7.1-7.9 (8~, m) Mass (m/z) : 372 (M+?, 337, 266 2~ Exam~le 19 (1) A mixture of l-methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4-chloro-6-methylthio-1 r 2-dihydro-quinoline (2.4 g) and ammonia solution (28%; 10 ml) in methanol (20 ml) was heated at 100C 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 chloro~orm and methanol (20:1) to give colorless crystals of l-methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4-amino-6-methylthio-1,2-dihydroyuinoline (1.1 g).

WO92/1&~ PCT/JP92/~10 21D8!~7~

mp : 138-140C
IR (Nujol) : 3370, 3200, 1620, 1590, 1560, 1495 cm 1 NMR (DMSO-d6, ~) : 2.51 (3H, s), 3.29 (3H, s), 3.37 (3H, s), 6.55 (2H, s), 7.0-7.5 (7H, m), 7.84 (1~, s) Nass (m/z) : 353 (M+) .
The following compound was obtained according to a similar manner to that of Example 19-ll).
(2) 1-Methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl)-4-methylamino-6-methylthio-1,2-dihydroquinoline mp : 244-246C
IR (Nujol) : 3350, 1620, 1585, 1550 cm 1 Mass (m/~) : 367 (M ), 261 Exam~le 20 A mixture of l-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-me~hyl-N-phenylcarbamoyl)-4-mercapto-6-methylthio-1,2-dihydroquinoline (O~5 g).
m~ : 210-212C
IR (Nujol) : 1610, 1580, 1540, 1480 cm 1 NMR IDMSO-d6, ~) : 2.49 (3H, s), 3.37 ~3H, s), 3.53 (3H~ s), 7~1-7.7 (8H, m) Mass (m/z) : 370 (M ) WOg2/l&#~ 21 ~ ~ 9 7 1 pcT/Jm/~lo Elemental Analysis Calcd. for C1gH18N2O2S2 :
C 61.60, H 4.90, N 7.56 Found : C 61.60, H 4.78, N 7.45 Example 21 A mixture of l-methyl-2-oxo-3-(N-methyl-N-phenyl-carbamoyl)-4-chloro-6-methylthio-1,2-dihydroguinoline (O.3 g) and sodium methoxide (0.11 g) in methanol (5 ml) was stirred at 40C for 3.5 hours. The mixture was filtered, and the ~iltrate was evaporated. The residue was washed with water to give colorless crystals of l-methyl-2-oxo-3-(N-methyl-N-phenylcarbamoyl~-4-methoxy-6-me~hylthio-1,2-dihydroquinoline (O.28 g).
mp : 148-151C
IR (Nujol) : 1640, 1620, 1590, 1575, 1495 cm 1 NMR (DMSO-d6, ~ : 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 Exam~le 22 A mixture of 1-methyl-2-oxo-3-~N-methyl-N-(4-nitrophenyl)carbamoyl]-4-hydroxy-6-methylthio-1,2-dihydro-quinoline (0.28 g), iron powder (0.28 g), and ammonium chloride (30 m~) in ethanol (8 ml) and water (3 ml~ was 2,5 refluxed and stirred for 2 hours. The solvent was evaporated, and the residue was suspended in a mix~ure of chloroform and water, followed by filtration. The organic layer was separated, dried, and eYaporated. The residue ~0.26 g) was washed with ethanol to give a brown powder of 1-methyl-2-oxo-3-rN-(4-aminophenyl)-N-methylcarbamoyl]-4-hydroxy-6-methylthio-1,2-dihydroguinoline (O.1 g).
IR (Nujol) : 3450, 3350, 3250, 1630, 1610, 1570, 1540, 1515 cm~
Mass (m~z) : 369 ~M ) WO ~/l~U3 PCT/JP92/ ~ lO

210897 ~ 96 -ExamPle 23 A mixture of formic acid (51 yl) and acetic anhydride (128 ~l) was stirred at 50C for 30 minutes, and then cooled. 1-Methyl-2-oxo-3-LN-(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 (O.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 (l 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-dihydro~uinoline (58 mg).
IR (Nujol) : 3450 , 3250, 1630, 1565, 1510 cm 1 Mass (m/z) : 397 ~M ), 247 ~0 ...

Claims (12)

C L A I M S
1. A compound of the formula :

wherein R1 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, R3 is hydrogen, lower alkyl, lower alkoxy(lower)alkyl or ar(lower)alkyl and R8 is hydrogen, or R3 and R8 are linked together to form lower alkylene, R4 is an organic group, Z is O or S, and n is 0, 1 or 2, and pharmaceutically acceptable salts thereof.
2. 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 :

(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 alkoxycaxbonyl;

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)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;
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, quinolyl or isoquinolyl, 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)haiophenyl, (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 R2 is hydroxy, R3 is lower alkyl and R8 is hydrogen, or R3 and R8 are linked together to form lower alkylene, R4 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(thio-carbonyl)]-4-hydroxy-6-methylthio-1,2-dihydro-quinoline, (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-1,2-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-phenyl-carbamoyl)-4-hydroxy-6-methylthio-1,2-dihydroquinoline, (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-cyclopropyl-carbonyl)-4-hydroxy-6-methylthio-1,2-dihydro-quinoline, (14) 1-Methyl-2-oxo-3-[N-methyl-N-(1-pyrrolyl)-carbamoyl]-4-hydroxy-6-methylthio-1,2-dihydro-quinoline, (15) 1-Methyl-2-oxo-3-[N-(4-cyanophenyl)-N-methyl-carbamoyl]-4-hydroxy-6-methylthio-1,2-dihydro-quinoline, (16) 1-Methyl-2-oxo-3-[N-methyl-N-{4-(trifluoro-methoxy)phenyl}carbamoyl]-4-hydroxy-6-methylthio-1,2-dihydroquinoline, (17) 1-Methyl-2-oxo-3-[N-methyl-N-{3-(trifluoro-methyl)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-1,2-dihydroquinoline, (19) 1-Methyl-2-oxo-3-[N-(4-aminophenyl)-4-methyl-carbamoyl]-4-hydroxy-6-methylthio-1,2-dihydro-quinoline, (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-dihydro-quinoline.
8. A process for preparing a compound of the formula :
wherein R1 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, R3 is hydrogen, lower alkyl, lower alkoxy(lower)alkyl or ar(lower)alkyl and R8 is hydrogen, or R3 and R8 are linked together to form lower alkylene, R4 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 :
wherein R1, R3, R8 and n are each as defined above, or a salt thereof with a compound of the formula :
wherein R4 and Z are each as defined above, and R5 is a leaving group, or a salt thereof to give a compound of the formula :
wherein R1, R3, R4, R8, Z and n are each as defined above, or a salt thereof, or (2) subjecting a compound of the formula :

wherein R1, R2, R3, R4, R8 and Z are each as defined above, or a salt thereof to oxidation reaction to give a compound of the formula :
wherein R1, R2, R3, R4, R8 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 :
wherein R1, 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 :
wherein R1, R2, R3, R8, Z and n are each as defined above, and a group of the formula : -CO-R6 is amidated carboxy, or a salt thereof, or (4) subjecting a compound of the formula :
wherein R1, R2, R3, R8, Z and n are each as defined above, and R? is protected carboxy, or a salt thereof to elimination reaction of the carboxy protective group in R? to give a compound of the formula :
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 :
wherein R1, R2, R3, R8, Z and n are each as defined above, and R? is acyl having protected carboxy, or a salt thereof to elimination reaction of the carboxy protective group to give a compound of the formula :
wherein R1, R2, R3, R8, Z and n are each as defined above, and R? is acyl having carboxy, or a salt thereof, or (6) reacting a compound of the formula :
wherein R1, and n are each as defined above, or a salt thereof with a compound of the formula :
R4-CH(COX1)2 wherein R4 is as defined above, and X1 is a leaving group, or a salt thereof to give a compound of the formula :
wherein R1, R4 and n are each as defined above, or a salt thereof, or (7) subjecting a compound of the formula wherein R1, R3, R4, R8, Z and n are each as defined above, and X2 is a leaving group, or a salt thereof to cyclization reaction to give a compound of the formula :

wherein R1, R3, R4, R8, Z and n are each as defined above, or a salt thereof, or (8) subjecting a compound of the formula :
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 :
wherein R1, R3, R4, R8, Z and n are each as defined above, and R? is halogen, or a salt thereof, or (9) reacting a compound of the formula :
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 - R?
wherein R? is amino or substituted amino, or a salt thereof to give a compound of the formula :
wherein R1, R?, R3, R4, R8, Z and n are each as defined above, or a salt thereof, or (10) reacting a compound of the formula :

wherein R1, R3, R4, R8, Z, n and X3 are each as defined above, or a salt thereof with a compound of the formula :

wherein R? is protected mercapto, and M1 is an alkali metal, or a salt thereof to give a compound of the formula :
wherein R1, R?, R3, R4, R8, Z and n are each as defined above, or a salt thereof, or (11) subjecting a compound of the formula :
wherein R1, R?, 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 :
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 :
wherein R1, R3, R4, R8, Z, n and X3 are each as defined above, or a salt thereof with a compound of the formula :
R? - M2 wherein R? is lower alkoxy and M2 is an alkali metal, or a salt thereof to give a compound of the formula :

wherein R1, R?, R3, R4, R8, Z and n are each as defined above, or a salt thereof, or (13) subjecting a compound of the formula :

wherein R1, R2, R3, R8, Z and n are each as defined above, and R? is acyl having nitro, or a salt thereof to reduction reaction to give a compound of the formula :

wherein R1, R2, R3, R8, Z and n are each as defined above, and R? is acyl having amino, or a salt thereof, or (14) subjecting a compound of the formula :

wherein R1, R2, R3, R?, R8, Z and n are each as defined above, or a salt thereof to acylation reaction to give a compound of the formula :

wherein R1, R2, R3, R4, R8, Z and n are each as defined above, and R? 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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