JPH0228168A - Thiazole derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [R<1> and R<2> are H, alkyl, alkenyl, alkynyl, cycloalkyl, (substituted) aryl, (substituted) aralkyl, acyl, alkoxycarbonyl, etc., or R<1> and R<2> together with bonded N form heterocyclic group; R<3> is H, alkyl, aryl or halogen; R<4> is H, alkyl, (protected) carboxyl or (substituted) carbamoyl; R<5> is H, (protected) carboxyalkyl, etc.,; n is 0-2; X is O or S] and a salt thereof. EXAMPLE:5-[1-Ethoxycarbonyl-1-[2-(3-phenylureido]thiazol-4- yl]methylene]rhodanine-3-acetic acid. USE:Having inhibitory action on aldose reductase and useful as preventive and/or a remedy for diabetic complication. PREPARATION:A carbonyl group-containing thiazole compound shown by formula II is reacted with a thiazolidine compound shown by formula III to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to thiazole derivatives and salts thereof that have an aldose reductase inhibitory effect, and are used to treat diabetic complications such as retinopathy, cataracts, nephropathy, neuropathy, and arteriosclerosis. Provided are compounds useful as prophylactic and/or therapeutic agents.

2. Prior Art It has been known that the thiazolidine derivatives related to the present invention have an aldose reductase inhibitory effect as disclosed in Japanese Patent Application Laid-open No. 57-4.
It is described in JP-A No. 0478, JP-A-60-156387, and JP-A-61-56175.

Purpose of the Invention The present inventors have conducted extensive research on thiazole derivatives and their salts with the aim of developing highly safe drugs for treating diabetic complications, and have discovered that a novel compound having the general formula (1) below and its salts are highly potent. The present invention was completed by discovering that the compound has an aldose reductase inhibitory effect and that the toxicity of the compound is extremely low.

Constitution of the Invention The novel thiazole compound of the present invention is a compound represented by general formula (I) and a salt thereof.

In the above formula (1), R1 and R2 are the same or different and are a water X atom, a lower alkyl group, a lower alkenyl group, a lower alkyl group,
Acyl group, alkoxycarmenyl group, aryloxycargenyl group, aralkyloxycarbyl group, optionally substituted carbamoyl group, optionally substituted thiocarbamoyl group, lower alkylsulfonyl represents a halo-lower alkylsulfonyl group, an arylsulfonyl group which may have a substituent group, a lower alkylthio group, or an arylthio group.

Further, R1 and R2 may be taken together with a nitrogen atom to form a heterocyclic group.

R5 represents a hydrogen atom, a lower alkyl group, an aryl group, or a halo atom.

R4 represents a hydrogen atom, a lower alkyl group, an optionally protected carboxyl group, or a carbamoyl group that may have a substituent.

R5 represents a hydrogen atom, an optionally protected carboxyl group, or a tetrazolylmethyl group.

n represents an integer from 0 to 2.

X represents an oxygen atom or a sulfur atom.

In the general formula (I), specifically, the lower alkyl group represented by R or R2 is a linear or branched lower alkyl group having 1 to 12 carbon atoms, such as methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, t-butyl, S-butyl, pentyl, inpentyl, neopentyl, 2-methylnotyl, 1.1-tsumethylpropyl,
hexyl, isohexyl, neohexyl, 1-methylpentyl, 1.2.2-)limethylprobyl, 1.3-
dimethylbutyl, 2-ethylbutyl, l-ethyl-1-
Methylpropyl, heptyl, 1-methylhexyl, 3-
Methylhexyl, 1.3-dimethylpentyl, 1.4-
Dimethylpentyl, 1--7'ropyrubutyl, 1-ethylpentyl, 1-inpropyl-2-methylzorobyl,
Examples include octyl, 2,2,4.4-tetramethylbutyl, nonyl, decyl, undecyl, and dodecyl.

The lower alkenyl group represented by R1 or R is linear or branched and has 3 to 6 nitrogen atoms, such as allyl, 3-butenyl, 2-butenyl, 3-if-2-
Butenyl, R4-'ntazinyl, 2.3-2methyl-
2-butenyl, 2-methyl-2-propenyl, 2,4-
Hexagenyl is removed.

The lower furkynyl group represented by R or R2 is linear or branched and has 3 to 8 carbon atoms;
Propargyl, 1,1-dimethyl-2-derohy 0 + 1
．． /1, 1-diethyl-2-dero-121.

The cycloalkyl group represented by R1 or R has 3 to 8 carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclohexyl, 4-ethylcyclohexyl, cyclohebutyl, and cyclooctyl. .

The aryl group represented by R1 or R2 has 6 to 14 carbon atoms.
For example, phenyl, 1-naphthyl, 2
-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl.

Examples of the substituent of the aryl group having a substituent represented by R1 or R2 include a Cj-6 alkyl group, a C5-6 alkenyl group, a C5-8 cycloalkyl group, a C aryl group that may have a substituent, and a substituent. C7-4? Aralkyl group, acyl group, alkoxykrWnyl group, aryloxycarbonyl group, alkyloxycarbonyl group,
Carbamoyl group which may have a substituent, thiocarbamoyl group which may have a substituent, lower alkylsulfonyl group, arylsulfonyl group which may have an ffi conversion group, halogenoalkanesulfonyl group, lower alkylthio group, Arylthio group which may have a substituent, °amino group which may have a substituent, halogen atom, cyano group, nitro group, hydroxy group, C1-6 alkoxy group, aryloxy group, aralkyloxy group, Acyloxy group, cal? One or more groups selected from xyl group, alkyloxycarbonyl group, sulfo group, sulfamoyl group, and nitrogen-containing heterocyclic group.

For example; aminophenyl substituted in the o-, rn- or p-position, N,N-dimethylaminophenyl, nitrophenyl, fluorophenyl, chlorophenyl, bromophenyl, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, R-methyloxyphenyl, Fluorophenyl, formyloxyphenyl, acetoxyphenyl,
Carboxyphenyl, acetylaminophenyl, benzoylaminophenyl, benzoyloxyphenyl, acetylphenyl, carbamoylphenyl, sulfamoylphenyl, methylphenyl, ethylphenyl, isopropylphenyl, biphenyl, benzyloxyphenyl,
trifluoromethylphenyl, ethylaminophenyl,
Anilinophenyl, cyanophenyl, ethoxycarbonylphenyl, ethylcarbamoylphenyl, pensoylphenyl, 3.5-t-butyl-4-hydroxybenzoyloxyphenyl; 2-bromo4-methylphenyl, 2.4-dibromophenyl, 2,4.6-tribromophenyl, 4-iodophenyl, 2.3-dimethoxyphenyl, 2.4-dimethoxyphenyl, 3.4-
Dimethoxyphenyl, 3,4.5-)dimethoxyphenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 214*6-)') ri o o phenyl,
2-hydroxy-3,5-dibromophenyl, 2-hydroxy-3,5-di-t-butylphenyl, 4-hydroxy-3,5-di-t-butylphenyl, 2-hydroxy-5-(1, 1,3,3-tetramethylbutyl)phenyl, 2,4-nofluorophenyl, 2#4,6-1-
IJ fluorophenyl, 4-fluoro-2-chlorophenyl, 4-fluoro-2-)! J fluoromethylphenyl, 2,4-difluoro-6-promophenyl,
2-ethoxy-4-fluoro-6-nitrophenyl, 4
-10 rho 2-fluorophenyl, 2-acetamino-
5-trifluoromethylphenyl, 4-1J fluoromethyl-2-nitrophenyl, 4-hydroxy-3,5-
Dimethylphenyl, 4-fluoro-1-naphthyl, 3-
Examples include hydroxy-2-naphthyl and 4-sulfo-1-su7tyl.

The aralkyl group represented by R1 or R2 has 7 to 1 carbon atoms.
9, such as benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 3
-Phenylpropyl, 1-phenylbutyl, 4-phenylbutyl, 1-methyl-1-phenylethyl, 1-naphthylmethyl, 2-su7thylmethyl, 9-anthrylmethyl, nophenylmethyl, triphenylmethyl, etc. It will be done.

As a substituent for the aralkyl group having a substituent represented by R1 or R2, the aromatic ring may have a substituent listed as a substituent for the aryl group, for example; Olm-mano is substituted at the p-position. aminopenzyl, N,N-trimethylaminopenzyl, nitrobenzyl, fluoropenzyl, chlorobenzyl, bromobenzyl, hydroxypencyl, methoxypencyl, ethoxypennol, pentyloxypenzyl, phenoxybenzyl, formyloxypenzyl, acetoxy Benzil, Cal? Kishibenzuru, (
/ Soyloxypencyl, Acetylpencyl, Carbamoylpennol, Sul7-Amoylpenzyl, Methylbenzyl, Ethylpennol, Isopropyl Pencyl, Phenylbenzyl: 2,4-difluorobenzyl, 3.4-difluorobenzyl, 2.4.6-) Lifluoropencyl, 2,4-dichlorobenzyl, 3,5-t-butyl-4-hydroxybenzyl, di(4-fluorophenyl)methyl, α-phenyl-4-methoxybenzyl, α
-(4-fluoro7ethyl)-4-methylbenzyl, α
-phenyl-4-trifluoromethylbenzyl, /-(
4-t177,zoxycarbonyl)methyl,cy(3
,4,5-)rimethoxyphenyl)methyl, α-(1-
naphthyl)benzyl, di(2-f7thyl)methyl, α
-(2-su7tyl)-4-fluorobenzyl is erected.

The acyl group represented by R1 or R is a linear or branched aliphatic acyl group having 1 to 12 carbon atoms, such as formyl, acetyl, zolopionyl, butyryl, imbutyryl, valeryl, hexanoyl, nonanoyl, dodecanoyl, acryloyl. , methacryloyl, crotonoyl, incrotonoyl; alicyclic acyl group having 4 to 9 carbon atoms, such as Schiff 1 coderopylcar? Nyl, cyclobutyl carginyl, cyclopentyl car? Nil, cyclohexylcal? Nyl, cycloheptylcarbyl, cyclooctylcarbonyl; and aromatic acyl groups having 7 to 15 carbon atoms may have a substituent listed as a substituent for the aryl group on the aromatic ring, such as benzoyl, 1-naphthoyl, 2-su7
Toyl, 9-anthracenecarbyl, cinnamoyl;
o-, m-i ft-il: fluorobenzoyl, chlorobenzoyl, bromobenzoyl, methylbenzoyl, ethylpensoyl, nitropensoyl, cyanohendiyl, calgexipenzoyl, substituted with Kt at the p-position;
Ethoxycarbunylpendyl, hydroxybenzoyl, methoxybenzoyl, ethoxybenzoyl, formyloxybenzoyl, acetoxybenzoyl, phenoxybenzoyl, carbamoylpendzoyl, sulfamoylbenzoyl, trifluoromethylpendzoyl, benzoylbenzoyl, phenylbenzoyl, aminobenzoyl, Acetylaminoindiyl, benzoylaminobenzoyl; 2.4-dichlorobenzyl, 3.4-cycloabenzoyl, 2.5-#loropensoyl, pentafluorobenzoyl, 3,4.5-toIJmethoxybenzoyl, 4-hydroxy -3,5-not-butylbenzoyl, 2.3-, :/7'' lomobenzoyl, 3,5-dibromopenzoyl, 3,5-nonitrobenzoyl, 3-nitro-2-naphthoyl, 3-hydroxy -2-Anthracenecarbyl is chelalyl.

The alkoxycarbonyl group represented by R1 or R has 2 to 7 carbon atoms, and includes, for example, butoxycarbonyl, ethoxycarbonyl, zoropoxycarbonyl, inoderopoxycarbonyl, butoxycarbonyl, imbutoxycarbonyl, dibutoxycarbonyl, and dibutoxycarbonyl. Examples thereof include vinyl, -1-butoxycardenyl, pentyloxycarbonyl, iso-enthyloxycargonyl, neohentyloxycarbonyl, hexyloxycarbonyl, and isohexyloxycarbonyl.

The aryloxycarbunyl group represented by R1 or R has 7 to 15 carbon atoms, and includes, for example, phenoxycarbonyl, 1-naphthyloxycarbonyl, and 2-naphthyloxycarbonyl.

The aralkyloxycarbonyl group represented by R1 or R is,
The number of carbon atoms is 8 to 20, for example, pennoloxycar? nyl, 1-phenylethoxyrudenyl, 2-7
enylethoxycarponyl, 1-phenylpropoxycarbonyl, 4-phenylbutoxycarbonyl, ■-methyl-1-7enylethoxycarmenyl, 2-naphthyloxycarbonyl, 9-anthrylmethoxycarbinyl,
- Diphenylmethoxycarvinyl is mentioned.

1 of the carbamoyl group having a substituent represented by R1 or R
“4 substituents include Cj-6 alkyl group, C5-6 alkenyl group, C3-8 cycloalkyl group, C7-19 aralkyl group, C6-44 aryl group which may have a substituent, lower alkylsulfonyl group. group, an arylsulfonyl group which may have a substituent group, a no-lognoalkanesulfonyl group, an acyl group which may have a t4 substituent, such as methylcarbamoyl, ethylcarbamoyl, furoylcarbamoyl, isopropylcarbamoyl. ,
Butylcarno J moyl, inbutylcarbamoyl, 8-
Butylcarbamoyl, t-7'tylcarbamoyl, 1-
Ethylphenylcarbamoyl, inthylcarbamoyl,
Hexylcarbamoyl, zomethylcarpamoyl, N-butyl-N-methylcarbamoyl, N-ethyl-N-hexylcarbamoyl, allylcarbamoyl, 7-chlorohexylcarpamoyl, phenylcarbamoyl, 1-naphthylcarbamoyl, nophenylcarbamoyl, N- Methyl-
N-phenylcarbamoyl; 〇-position, m-position or p-position
aminophenylcarbamoyl substituted at position, N,N-dilfk aminophenylcarbamoyl, nitrophenylcarbamoyl, fluorophenylcarbamoyl, chlorophenylcarnormoyl, bromophenylcarbamoyl,
Trifluoromethylphenylcarbamoyl, hydroxyphenylcarbamoyl, methoxyphenylcarbamoyl, ethoxyphenylcarbamoyl, K/tyloxyphenylcarbamoyl, phenoxyphenylcarbamoyl, formyloxyphenylcarbamoyl, acetoxyphenylcarbamoyl, Cal? xyphenylcarbamoyl, acetylaminophenylcarbamoyl, benzoylaminophenylcarbamoyl, penzoyloxinphenylcarbamoyl, acetylphenylcarbamoyl, cart
4-moylphenylcarbamoyl, sulfamoylphenylcarbamoyl, methylphenylcarbamoyl, ethylphenylcarbamoyl, inpropylphenylcarbamoyl, biphenylcarbamoyl, pennoloxyphenylcarbamoyl; 2-bromo-4-methylphenylcarbamoyl, 2,4-difluorophenylcarbamoyl ,
2.4-dibromophenylcarbamoyl, 2.4.6-
) I7 fluorophenylcarbamoyl, 2.4.
6-tribromophenylcarbamoyl, 4-iodophenylcarbamoyl, 2,3-dimethoxyphenylcarbamoyl, 2,4-dimethoxyphenylcarbamoyl,
3,4-dimethoxyphenylcarbamoyl, 3,4.5
-trimethoxyphenylcarbamoyl, 2,4-dichlorophenylcarbamoyl, 3,4-dichlorophenylcarbamoyl, 2.6-/methylphenylcarbamoyl,
4-fluoro-3-nitrophenylcarbamoyl, 2,
4,6-Dolichlorophenylcarpamoyl, 2-hydroxy-3,5-dibromophenylcarbamoyl, 2-hydroxy-3,5-not-t-butylphenylcarbamoyl, 4-hydroxy-3,5-di-t-butyl Phenylcarbamoyl, 2-hydroxy-5-(1,1,3,3
-tetramethylbutyl)phenylcarbamoyl, 4-hydroxy-3,5-dichlorophenylcarbamoyl, 3
-Hydroxy-2-naphthylcarbamoyl, pen-solcarbamoyl, 4-phenylbutylcarbamoyl, 2-
Examples include phenylethylcarbamoyl, 1-+7thylmethylcarbamoyl, methanesulfonylcarbamoyl, trifluoromethanesulfonylcarbamoyl, benzenesulfonylcarbamoyl, 4-methylbenzenesulfonylcarbamoyl, benzoylcarbamoyl, and acetylcarbamoyl.

As a substituent of the thiocarbamoyl group having a substituent represented by R1 or R2, a Cl-15 alkyl group, a C alkenyl group, a C3-8 cycloalkyl group, a C7-19 aralkyl group, which may have a substituent C aryl group, lower alkylsulfonyl group, arylsulfonyl group which may have a substituent group, halo-alkanesulfonyl group, acyl group which may have a substituent, such as methylthiocarbamoyl, ethylthiocal/J Moyle, f.
Lopylthiocarbamoyl, isopropylthiocarbamoyl, butylthiocarbamoyl, isobutylthiocarbamoyl, S-butylthiocarbamoyl, t-butylthiocarbamoyl, 1-ethylpropylthiocarbamoyl, pentylthiocarbamoyl, hexylthiocarbamoyl,
Dimethylthiocarbamoyl, N-butyl-N-methylthiocarbamoyl, N-hexyl-N-ethylthiocarbamoyl, allylthiocarbamoyl, cyclohexylthiocarbamoyl, phenylthiocarbamoyl, 1-naphthylthiocarbamoyl, N,N -diphenylthiocarbamoyl, N-methyl-N-phenylthiocarbamoyl; aminophenylthiocarbamoyl substituted at 〇-, m- or p-position, N,N-nomethylaminobuenylthiolupamoyl, nitrophenylthio carbamoyl,
Fluorophenylthiocarpamoyl, chlorophenylthiocarbamoyl, bromophenylthiocarbamoyl, trifluorobamoyl, ethoxyphenylthiocarbamoyl, pentyloxyphenylthiocarbamoyl, phenoxyphenylthiocarbamoyl, formyloxyphenylthiocarbamoyl, acetoxyphenylthiocarbamoyl, cargoxy Phenylthiocarpamoyl, acetylaminophenylthiocarbamoyl, benzoylaminophenylthiocar/tetramoyl, pentyloxyphenylthiocarbamoyl, quecetylphenylthiocarpamoyl, carbamoylphenylthiocarbamoyl, sul7amoylphenylthiocarpamoyl, methylphenyl Thiocarbamoyl, ethylphenylthiocarbamoyl, isoderobilphenylthiocarpamoyl, biphenylthiocarpamoyl, pen-zoloxyphenylthiocarbamoyl; 2-bromo4-methylphenylthiocarbamoyl, 2,4-difluorophenylthio carbamoyl, 2,
4-dibromophenylthiocarbamoyl, 2,4.6-
) Lifluorophenylthiocarnormoyl, 2,4.
6-) dibromophenylthiocarbamoyl, 4-iodophenylthiocarbamoyl, 2,3-nomethoxyphenylthiocarpamoyl, 2,4-dimethoxyphenylthiocarbamoyl, 3,4-dimethoxyphenylthiocarbamoyl, 3,4.5- ) dimethoxyphenylthiocarbamoyl, 2.4-dichlorophenylthiocarbamoyl, 3.4-'#rolophenylthiocarbamoyl, 2
．． 4.6-IJ Chlorophenylthiocarbamoyl, 2-hydroquine-3,5-dibromophenylthiocarbamoyl, 2-hydroxy-3,5-di-t-7” tylphenylthiocarbamoyl, 4-hydroxy-3,5-
Not-7” tylphenylthiocarbamoyl, 2-hydroxy-5-(1,1,3,3-tetramethylbutyl)
Phenylthiocarbamoyl, 4-hydroxy-3,5-
Dichlorophenylthiocarbamoyl, 3-hydroxy-
2-naphthylthiocarbamoyl, pennorthiocarbamoyl, 4-7enylbutylthiocarpamoyl, 2-phenylethylthiocarbamoyl, 1-naphthylmethylthiocarbamoyl, methanesulfonylthiocarbamoyl, trifluoromethanesulfonylthiocarbamoyl, benzenesulfonylthiocarbamoyl, 4 -The lower alkylsulfonyl group, halogeno-lower alkylsulfonyl group, or optionally substituted arylsulfonyl group represented by methylbenzenesulfonylthiocarbamoyl, benzoylthiocarbamoyl, 4-fluorobenzoyl R1 or R2 has 1 to 6 carbon atoms. Alkylsulfonyl group, ＼
Indicates a Rodan-substituted alkylsulfonyl group having 1 to 4 carbon atoms or an arylsulfonyl group having 6 to 10 carbon atoms which may have a substituent group, such as 4, methanesulfonyl, trifluoromethanesulfonyl, benzenesulfonyl, p-)luene Examples include sulfonyl.

The lower alkylthio group or the alkylthio group which may have a substituent group represented by R1 or R2 has 1 to 6 carbon atoms.
represents an alkylthio group or an arylthio group having 6 to 10 carbon atoms which may have a substituent, such as methylthio, ethylthio, butylthio, hexylthio, phenylthio, and tolylthio.

The heterocyclic group formed by R1 and R2 together with the nitrogen atom represents a cyclic amine group, a cyclic amide group, or a cyclic imido group, such as 1-virolizonyl, py(lysine, hexamethyleneimino, heptamethyleneimino, Examples include morpholino, 4-thiomol-butylpibe2dino, 4-phenylpiperazino, 4-penzylpiperazino, 4-acetylpiperazino, 4-benzoylpiperazino, and ct ct ct .

The lower alkyl group represented by R3 is the same linear or branched alkyl group having 1 to 6 carbon atoms as exemplified as the lower alkyl group for R1 or R2.

The aryl group represented by R3 is the same aryl group having 6 to 14 carbon atoms as exemplified as al or R2 noaryl group.

The halodane atom represented by R3 is, for example, a chlorine atom or a bromine atom.

The lower alkyl group represented by R4 is the same linear or branched alkyl group having 1 to 6 carbon atoms as exemplified as the lower alkyl group for R1 or R2.

The protected carbonyl group represented by R4 is, for example,
Methoxycargenyl, ethoxycarvinyl, propoxycarbonyl, isopropoxycarbonyl, ptoxycardenyl, suspended ptoxycargonyl, isobutoxycargenyl?
Straight chain or branched alkoxycarbonyl group having 2 to 7 carbon atoms such as nyl, t-ptoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbinyl, hexyloxycarbonyl: allyloxycarbinyl , 3-methyl-2-putenyloxycardenyl, 2,
Straight-chain or branched alkenyloxycarbonyl group having 4 to 7 carbon atoms such as 4-hexagenyloxycarbunyl; cycloderobyloxycardenyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl group;
Cycloalkyloxycardenyl group having 4 to 9 carbon atoms such as Nyl, cyclooctyloxycarbonyl; phenoxycardenyl, 1-7tyloxycardenyl, 2-
Aryloxycarbonyl groups having 7 to 15 carbon atoms such as naphthyloxycarbonyl and 1-anthryloxycarbyl: p-chlorophenoxycarbonyl, p-promophenoxycargenyl, m-nitrophenoxycargenyl, o- Carboxyphenoxycarbonyl, p-carpamoylphenoxycardenyl, p-formyloxyphenoxycarbonyl, 2,4-dichlorophenoxycar? chlorophenoxycarbonyl, 3.4--)chlorophenoxycarbonyl,
2. Substituted aryloxycarbonyl group with an aryl group having a substituent such as 4-nogromophenoxy carbonyl; ? Nyl, 2-naphthylmethoxycarbonyl, 1-phenylbutoxycar? An aralkyloxygenyl group in which the alkylene 7 moiety, such as nyl, has a linear or branched aralkyl group having 7 to 19 carbon atoms has a 1s scale.

Substituents of the carbamoyl group having a substituent represented by R4 include an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 3 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, and a substituent having all substituents. It has an aryl group having 6 to 14 carbon atoms, an aralkyl group having 7 to 19 carbon atoms, which may optionally be Butylcarbamoyl, isobutylcarbamoyl, t-butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl, trimethylcarbamoyl, zoethylcarpamoyl, N-butyl-N-
Methylcarbamoyl, cyclohexylcarbamoyl, phenylcarbamoyl, 1-naphthylcarbamoyl, N,
N-diphenylcarbamoyl, allylcarbamoyl, m
-aminophenylcarbamoyl, m-nitrophenylcarbamoyl, p-fluorophenylcarbamoyl, p-
10 Lofenyllupamoyl, p-bromophenylcarbamoyl, 3,4-dichlorophenylcarbamoyl, 2
, 4.6-) Lichlorophenyl hamoyl, 3#4
15-)') Methoxyphenylcarbamoyl and pencilcarbamoyl.

The carboxyalkyl group represented by R5 is a linear or branched alkyl group having 1 to 5 carbon atoms and having a cargeoxy group, for example, carboxymethyl, 1-carboxyethyl, 2-carboxyethyl. , 3-carboxypropyl, 1-carboxy-1-methylethyl, 1-carboxyderovir, 2-carboxypropyl, 4-carboxybutyl, 3-carboxy-2-methylpropyl, 1-
Carboxyhentyl and 5-carboxypentyl are removed.

The protected carboxyalkyl group represented by R5 is a linear or branched alkyl group having 1 to 5 carbon atoms in which the protected carboxyl group has an xyl group, such as methoxycarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylmethyl, etc. nylmethyl, ingropoxycarponylmethyl, t-butoxycarginylmethyl, 2,2.2-1-lichloroethoxycar? Nylmethyl, 2-methylthioethoxycarbunylmethyl, 2-p
-Toluenesulfonyl ethoxycarbonylmethyl, penzyloxycarbonylmethyl, p-nitropenzyloxycarbonylmethyl, diphenylmethoxycarbonylmethyl, trityloxycarbonylmethyl, pendiylmethoxycarbonylmethyl, phthalimidomethoxycarmonylmethyl, piparoyloxymethoxycarmonylmethyl, 1-(piparoyloxy)ethoxycarbunylmethyl, 1-(inderopoxycarponyloxy)ethoxycarbunylmethyl, 1. -(Imbutyryloxy)butoxycarbonylmethyl, 1-(cyclohexyloxycar?nyloxy)ethoxycarbunylmethyl, 2-(ethoxycarbunyl)ethyl, 2-(t-ftoxycargonyl)ethyl, 2-(1-hiha Loyloxie)=? cicaldenyl)ethyl, 5-ethoxycarbylpentyl, 4-t-butoxycarbonylmethyl, 1-(,t-butoxycarbyl)ethyl, and 1-t-ptoxycargonyl-1-methylethyl.

The tetrazolylmethyl group represented by R5 is a 5-tetrazolylmethyl group.

Further, in the compound (I) of the present invention, a suitable compound is such that R and R are the same or different and are a linear or branched alkyl group having 1 to 8 carbon atoms, a linear Chained or branched alkenyl group having 3 to 6 carbon atoms, 7-chloroalkyl group having 3 to 8 carbon atoms, aryl group having 6 to 14 carbon atoms, substituted aryl group having 6 to 14 carbon atoms, linear or a branched aralkyl group having 7 to 19 carbon atoms, or a linear or branched aralkyl group having 7 to 1 carbon atoms;
9 is a substituted aralkyl group; or R1 and 82 together are a heterocyclic group such as a cyclic amino group or a cyclic imido group, such as 1-pyrrolidinyl, piperidino, hexamethyleneimino, morpholino, 4-thiomorpholinyl, 4-Methylbi(razono, 4-ethylbiyradino, 4
Examples include piperazino which may be substituted with an alkyl group having 1 to 4 carbon atoms such as -1-butylpiperazino, 4-acetylbiperazino, 4-benzoylpiperazino, and phthalimide, and R is an acyl group, carbamoyl group,
a substituted carbamoyl group, thiocarbamoyl group, substituted thiocarbamoyl group or sulfonyl group, R is a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 14 carbon atoms, Carbon number 6 to 14
or a linear or branched aralkyl group having 7 to 9 carbon atoms.

Regarding R3, R5 is a hydrogen atom, a linear or branched chain alkyl group having 1 to 6 carbon atoms, or an aryl group having 6 to 10 carbon atoms.

Regarding R4, R is a hydrogen atom, an IK chain or branched alkyl group having 1 to 6 carbon atoms, a carbamoyl group,
It is a substituted carbamoyl group, carboxyl group, or protected carboxyl group.

With respect to R5, R is a hydrogen atom, a cartzyl alkyl group, or a protected cal is a xyalkyl group.

Regarding n, n is an integer from O to 1.

Regarding X, X is an oxygen atom or a sulfur atom.

A further preferred compound is a compound in which, with respect to R and R, R and R are
Same or different linear or branched carbon number 1
-6 alkyl group, linear or branched, carbon number 3
It is an alkenyl group having 6 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, a substituted aryl group having 6 to 10 carbon atoms, or a pe/sol group which may have a substituent; or R and R are -
Together, they are a 1-pyrrolizonyl group, a piperidino group, or a veradino group, and R1 is a linear or branched aliphatic acyl group having 1 to 5 carbon atoms, or an aromatic acyl group having 7 to 11 carbon atoms. group, a substituted carbamoyl group, or a substituted thiocarbamoyl group, and 12 is a hydrogen atom.

Regarding R3, R is a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms.

Regarding R4, R is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched alkoxycarbonyl group having 2 to 6 carbon atoms.

Regarding R5, R has a hydrogen atom, a linear or branched carbon alkyl group having 2 to 5 carbon atoms, or a linear or branched alkoxycarbonyl group having 2 to 6 carbon atoms. It is a linear or branched alkyl group having 1 to 4 carbon atoms.

Regarding nK, n is an integer of O.

Regarding X, X is an oxygen atom or a sulfur atom.

In the compound (1) of the present invention, there are 1 to 3 double bonds between the thiazole ring and the thiazolidine ring,
Any stereoisomer based on these is included in the present invention, and furthermore, when R5 is a hydrogen atom in compound (1), tautomerism is established between the adjacent carbinyl group, but any tautomerism is included in the present invention. Variants are also encompassed by the invention.

The present invention will be specifically explained by further illustrating suitable compounds in Tables 1 to 5. In addition, in Table 2, R in -Sakatsu (1) indicates R''Co group,
In Table 3, RC3 group is shown.

Table 1 Table (continued) Table - (&) (continued) Table - (&) Table - (bl Table - (b) (continued) Table - (b) (continued) Table - ( b) (continued) Table - (c1 Table - (c) (continued) Table - (cl (continued) Table - (C) (continued) Table - (c) (continued) Table - (c) ) (Continued) Table 2 (d) Table 2 (c) (Continued) Table 2 (al) Table 2 (a) Table 2 (a) Table 2 (d) ) (Table 2 - (d) 0 Table 2 - (e) Table (continued) Table 2 (continued) Table (continued) Table - (a) Table (continued) Table - (a) (Continued) Table 4 - (1) (Continued) Celebrations (Table 4 - (1) (Continued) Shutoge Mu Nagide Banshichi "Ko M 剋ship ji LM Umatan handprint 1 hearing 1ml Table tb) Table (bl (Continued) Table (b) (Continued) Table +61 (Continued) Table (C) Table (dl Table (at) (Continued) Table (・) Table (d) (Continued) Table (・) (Continued) Table 1 (Continued) (Production method) The compound (1) of the present invention is a A thiazole compound in which Cal has a nyl group, represented by R4 and n have the same meanings as above; and a thiazolidine compound represented by -Sakatsu (wherein R and X have the same meanings as above). It is produced by reacting with.

This reaction is usually carried out in acetic acid, trifluoroacetic acid, or an alcoholic solvent such as methanol or ethanol, or a mixed solvent thereof, in the presence or absence of water, at room temperature or with heating.

In addition, to accelerate the reaction, amines such as ammonia, methylamine, ethylamine, diethylamine, propylamine, diisozolobylamine, piberison, pyrrolidine, and morpholine, and salts such as sodium acetate, ammonium acetate, and ammonium chloride are added. is preferable.

This compound (compounds in which R is a hydrogen atom)

Formula Z-D-Co□E [wherein 2 is a halogen atom such as a chlorine atom or a bromine atom, D is a linear or branched alkylene group having 1 to 5 carbon atoms, and E is the one described above. Indicates a carboxyl group protecting group having the same meaning as . ] in a normal solvent at room temperature or under heating, in the presence or absence of a base (wherein R', R2 R3, R4 n and X have the same meanings as above). can be converted into compounds.

Compounds (1) in which R1 or R2 is a hydrogen atom can be converted into corresponding compounds by alkylation, aralkylation, carbamoylation, acylation, thiocarbamoylation, sulfonylation, or sulfenylation, if desired. be changed.

In compound (1), when a carbonyl group or an alkoxylic acid group is present in R4 and/or R5, a diesterization reaction may be carried out if desired. It can also be converted into the corresponding amide compound by amidation reaction. Furthermore, ester and amide compounds can be converted to the corresponding carboxylic acids by hydrolysis reactions.

Compound (1) has geometric isomers based on the double bond between the thiazole ring and the thiazolidine ring, but by irradiating one isomer with light in the presence or absence of a solvent, the other isomer can be isolated. It can be transformed into a body.

The thiazole compound (1) obtained by the above reaction can be isolated and purified by known separation and purification means, such as concentration, vacuum concentration, solvent extraction, crystallization recrystallization, dissolution, and chromatography. be.

The thiazole compound (II) having a carbonyl group, which is a raw material compound of the thiazole derivative (1) of the present invention, and its synthetic intermediate are, for example, HetsrocycllcCo.
mpounds, Volume 34 (Nos. 1 to 3) J
ohnWllIy & 5ons, N@w Yor
It can be manufactured according to l< etc.

``Furthermore, the aldehyde compound represented by the general formula (wherein R+, R2 and R3 have the same meanings as above), which is a raw material for the thiazole derivative (I) of the present invention, is, for example.

A compound having a group represented by the corresponding formula -C-Coo -alkyl etc. is converted into a metal hydride χ such as sodium borohydride or lithium aluminum hydride.
It can be obtained by reduction and subsequent oxidation with a metal salt of metaperhalodic acid such as sodium metaperiodate.

In addition, the raw materials for the thiazole derivative (1) of the present invention (wherein +l or R is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group,
An aryl group that may have a substituent, an aralkyl group that may have a substituent, R3 has the same meaning as above, and 4/ represents the group shown for R4 above and a lower alkoxy group. may also be shown. The carbonyl compound represented by the above formula is a compound in which R1/ and R2' are hydrogen atoms, for example, by the Sandmsyer reaction. show. ) is produced by reacting with an amino compound shown in 1'.

In general formula (V), a compound in which 84' is an alkoxy group is reduced with a metal hydride such as sodium borohydride or lithium aluminum hydride.
It can be oxidized with an oxidizing agent such as 03-pyridine complex or Mn0z to form an aldehyde compound represented by general formula (IV).

In the compound represented by the general formula (1) of the present invention, when R5 is a hydrogen atom, when (1) has an acidic group such as a carboxylic acid, according to a conventional method, (1) is a pharmacologically acceptable Non-toxic salts may be used, such as salts of alkali metals such as sodium and potassium, salts of alkaline earth metals such as calcium, salts of trivalent metals such as aluminum, or morpholine. , piperidone, linone, arginine, ammonia, and other basic salts.

In addition, when the compound represented by the general formula (RI) is an organic base such as an amine, or has a basic group such as /''!, amino, mono-substituted amine or S-substituted amino, , may be non-toxic salts such as those mentioned above, e.g. inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates; acid salt, malate, glutamate,
As/'P diinate, no! Radruene sulfonate,
Examples include organic acid salts such as methanesulfonate.

Effects of the invention The target compound of the present invention represented by the general formula (1) is:
In a test of aldose reductase activity i1+11 using rat or bovine lens or kidney, or human red blood cells or fetus (11), it showed an enzyme inhibitory effect,
It also showed extremely excellent pharmacological effects, such as lowering the content of nrbitol in the nerve tissues of diabetic model animals. In addition, regarding its toxicity, it has been shown to have a suppressive effect on weight gain in experimental animals such as mice and rats, especially
Results showed that the hepatomegaly effect was extremely low.

From the results of the above tests, the thiazole derivative (1) of the present invention
is expected to be useful in treating complications of diabetes in humans, such as diabetic cataracts, diabetic neuropathy, and diabetic nephropathy. Administration methods include oral administration in the form of tablets, capsules, powders, granules, etc., as well as parenteral administration in the form of injections (intravenous, subcutaneous, intramuscular), suppositories, etc. For ocular mucosal administration, eye drops and ocular soft blue agents are preferred. The dosage varies depending on symptoms, age, etc., but for example, when used as a treatment for diabetic complications, it is usually 0.519 to 2 g per day for adults.
can be administered orally or parenterally.

EXAMPLES The present invention will be explained in further detail with reference to Examples and Reference Examples below.

Example 1 [Methyline]rhodanine-3-fft[t2-(3-phenylureido)thiazol-4-yl ethylclyoxylate 1 g, rhodanine-3-acetic acid 0.59F, ammonium chloride 0.4. F, 28 thiammonia water 0.4rnt
, and ethanol 4- was stirred at an external temperature of 80° C. for 1 hour. The reaction mixture was made acidic with dilute hydrochloric acid and extracted with ethyl acetate. After drying the extract over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica column chromatography [eluent: benzene: ethyl acetate: ethanol: acetic acid = 50:1:1:1] ]. The obtained crystals were recrystallized from acetic acid to obtain 0.741 of the target compound as a yellow powder.

Melting point: 246-250°C NMR exposure (δppm t DMS O-d, s
): 1.34 (3H, t, J=7Hz), 4.42
(2H, q, J=7Hz), 4.70 (2H, br, s
), 7.07 (IH.

br, t, J=7Hz), 7.35 (2H, br, t,
J=7Hz), 7.49 (2H,br,d,
J=7Hz), 7.70(IH,a),s,9
6 (xH, br, s), xl, o2 (IH.

brew )・Example 2 5-[1-ethoxycarbonyl-1-(2-(3-(1
-naphthyl)ureido]thiazole According to Example 1,
2-[:3-(1-su7tyl)ureidophthiazole-
Ethyl 4-ylglyoxylate 3.7! ! , rhodanine-
3-acetic acid 1.53. IJ negative ammonium 1.128%
The target compound in the form of a yellow powder produced from 1rnt of aqueous ammonia and 20ηl of ethanol has the following physical properties.

Melting point: 263-265°C NMR spectrum (δppm, DMSO-d6)
:1.34(3H,t,J=7I(z),4
．． 43 (2H, q.

J=711Z), 4.70 (2H, a), 7.49-7
．． 76 (4H.

m), 7.72 (IH, s), 7.95-8.13 (3
H, m).

9゜15 (IH, br, s), 11.36 (IH, br
, s).

Example 3 5-(1-(2-7cetylaminothiazol-4-yl)-1-ethoxycarbonylmethyline]rhodanine-3-
Vinegar i1F, 1/3 hydrate 2-aminothiazol-4-ylglyoxyl r quethyl 4.3510 danine-3-acetic acid 5g, sodium acetate 2.72 and acetic acid 50m! The mixture was heated under reflux for 2 days and then purified as in Example 1 to obtain the target compound as a yellow powder.

Melting point: 292-296°C NMR spectrum (δppm, DMSO-d6)
: 1.33 (3H, t, J=7Hz), 2.22 (3H
,s).

4.42 (2H,q, J =7I(z), 4.
68 (2H, s).

7.73 (IH, s), 12.47 (IH, br, s)
.

Example 4 5-(:1-(2-aminothiazol-4-yl)-1
-ethoxycarbonylmethyline] rhodanine 2-aminothiazol-4-ylglyoxylic acid ethyl ester according to Example 1 20. P, Rodan-3-Vinegar D22.9
,! 7. Ammonium chloride 11y, 28% ammonia water 15m/! , and ethanol 200- by reaction at room temperature for 15 minutes to produce fR, an orange target compound having the following physical properties.

Melting point +250-254°C NMI't spectrum (δppm, DMSO=d6):
1.31 (3H, t, J=7Hz), 4.37(2)i
,q.

J=7Hz), 4.66 (2H,s), 7.2
0(ll-1,s) 97.64(2H,br,s)
.

Example 5 5-[1-Ethoxylic 7vinyl-1-[2-("3-
(p-)toluenesulfonyl)ureido] 3-acetic acid monohydrate According to Example 1, 2-[:3-(p-toluenesulfonyl)ureidophthiazoate 2-4-ylglyoxylate ethyl ester 4F, rhodanine -3-acetic acid 2I, ammonium chloride 1.9, 28% ammonia water 1 tnl
The target compound, which is in the form of a yellow powder and is produced from 10% of ethanol and ethanol, has the following physical properties.

Melting point: 207-209°C NMR spectrum (δppm, DMSO-d6
): 1.31 (3II, t, J=7Hz), 2.
40 (3H, m ).

4.40(2I(,q,J=7Hz), 4.68(
2H,s).

7.43 (2) I, d, J = 8Hz), 7.70 (IH
,s).

7.87 (2H, d, J=8Hz), 11.32 (
IH.

br, s).

Example 6 5-[1-ethoxycal)genyl-1-(2-1yl]
Methyline] rhodanine-3-vinegar & 2 according to Example 1
-(3-Phenylthioureido)thiazol-4-ylglyoxylic acid dithyl ester 3.35.9. Loginol 3-acetic acid 1.71, ammonium chloride 1.9, 28%
The target compound in the form of a yellow powder produced from ammonia water 1-1 and ethanol 30WLt has the following physical properties.

Melting point: 240-248°C NMR spectral (δppm, DMSO-d6)
:1.34 (3H,t, J=7Hz), 4
．． 42 (2H,q.

J = 7Hz), 4.70 (2H, ++), 7.22 (I
H, br, t.

J=8Hz), 7.41 (2H,br,t,J=
8Hz).

7.63 (2H, br, d, J=8Hz), 7.6
5 (2H, s).

10.33 (IH, br, s), 11.8-12.2 (
IH.

br, s), 12.9-13.6 (IH, br, s).

Example 7 5-[1-[2-[3-(4-chlorophenyl)thioureidocthiazol-4-yl]-1-acetic acid 2-(:3-(4-chlorophenyl) Thiouridophthiate di-4-ylglyoxylic acid ethyl ester 0.93.l Rhodanine-3-acetic acid 0.4
8! The target compound in the form of a yellow powder prepared from 0.25 g of ammonium chloride, 0.25 ml of 28% aqueous ammonia, and 5-ethanol has the following physical properties.

Melting point: 225-235°C NMR spectrum (δppm, DMSO-d6)
: 1.34 (3H, t, J=7Hz), 4.42
(2H,q, J=7TIy,), 4.70(2)I,
s), 7.47 (2H, br, d).

7.65 (2H, br, d), 7.67 (IH, s),
10.38 (IH, br, s), 12.06 (LH, b
r, s), 13.0-13.7 (IH, br, s)
.

Example 8 5-(1-(2-benzamidothiazol-4-yl)
-1-Etquinecarbonylmethyline] rhodanine-3-acetic acid strength 10 Based on Example 1, 2-benzamidothiazol-4-ylglyoxylic acid ethyl ester 3.04g5
The target compound in the form of a yellow powder obtained from 7-3-vinegar 1'ff1.91 F, ammonium chloride IF, 1 ml of 28% aqueous ammonia, and 20 m of ethanol to 3M has the following physical properties.

Melting point: 278-281°C NMR spectrum (δppm, DMS<) -d6
): 1.35 (3H, t, J==7Hz), 4.44
(2H, q, J=-7Hz), 4.70 (2H, s),
7.57-7.72 (3H.

m), 7.83 (11-I, s), 8.12 (2H, b
r, d, J=7Hz), 12.91 (IH, br, s)
, 13.1-13.6 (IH, br, s).

Fruit 111! i Example 9 5-[1-Ethoxylic 7 vinyl-1-[:2-(3-
phenylureido)thiazol-4-yl]methyline]
Rhodanine/acetic acid adduct According to Example 1, 2-(3-phenylureido)thiazol-4-ylglyoxylic acid ethyl ester 3y1
0 ticks/1.259 s Ammonium chloride Ig, 28
The desired compound in the form of a 3'-colored powder prepared from 1-1% aqueous ammonia and 10 ml of ethanol has the following physical properties.

Melting point: approx. 257°C (decomposed) NMR spectrum (δppm, DMSO-d6)
: 1.32 (3H, t, J=711z), 1.91 (3
H-→.

4.39 (2H, q, J = 711z), 7.07 (IH
,br,t.

J = 7Hz), 7.34(2H, br, t,
J = 7f(z).

7.48 (2H, br, d, J = 7Hz), 7.58 (
IHy')y8.93(IH,br,a),10.94
(II-I, br, s).

11.7-12.2 (IH, br, s), 13.73
(IH, br, s).

Example 10 11.54 (IH, br, s, IJ water Reed disappeared upon addition of water.

Example 11 5-[1-(2-[:3-(3-methoxy7ediacetic acid)
Monohydrate production & according to Example 1 2-1:3-(2-methoxyphenyl)ureido]ethyl thiazol-4-ylglioformylate 1.75,9. rhodanine-3-acetic acid 0.95/,
Ammonium chloride 0.5 1.28 Polyammonium water 0.5
The objective compound in the form of a yellow powder was prepared using 25 m of ethanol and 25 m of ethanol, and had the following physical properties.

Melting point: Approximately 230°C (decomposition) NMR spectrum (δppm, DMSO-d6)
: 1.34 (3H, t, J=7Hz), 3.91 (3H
,s).

4.42 (2H,q, J=7Hz), 4.69 (2
H,B).

6.9-7.0 (IH, m), 7.0-71 (2H, m
).

7.69 (IH, s ), 8.1-8.15 (LH, m
).

8.76 (III, br, i, disappeared by addition of heavy water).

According to Example 1, 1.75 g of ethyl 2-(3-(3-methoxyphenyl)ureidocthiazole-4-,ylglyoxylate, 0.95 g of rhodanine-3-acetic acid, 0.5.9 g of ammonium chloride) .28 Thiammonia water 0.5
The target compound in the form of a yellow powder prepared from 20 g of ethanol and 20 g of ethanol has the following physical properties.

Melting point: 208-212°C (min?'#) NMR spectral (δppm, DMSO-d6): 1,. 34(
3H,t, J=7Hz), 3.76(3H,s).

” 2 (2Hp q, J = 7 Hz) t 4-6
9 (2Ht!+)? 6.65 (IH, dd, J
= 2 and 8 Hz).

6.98 (H(,ad,,y=2 and 8)Hz)
.

7.18 (IH, t, J = 2Hz), 7.24 (1, H
,t.

J-sHz), 7.7o(tHsgL 8.97 (IH, br, s, disappeared by addition of heavy water).

11.02 (IH, br, s, disappeared by addition of heavy water)
.

13.1-13.7 (LH, br, disappeared by addition of heavy water).

Example 12 6.91 (2H, d, J=9Hz), 7.39 (2H,
d.

J=9Hz), 7.67(IH,s), 8.79(
IH, br, s).

10.99 (IH, br, s), 13.1-13.7 (
IH,br,).

Example 13 Ethoxycarbonylmethyleneturodanine-3-acetic acid According to Example 1, 1.75 g of ethyl 2-(3-(4-methoxyphenyl)ureidophthiazol-4-ylglyoxylate), rhodanine-3-acetic acid 0.951 ammonium chloride 0.51!, 28 thiammonia water 0.5 ml
, and 20 ntt of ethanol, the target compound in the form of a yellow powder has the following physical properties.

Melting point: 230-235°C (decomposed) NMR spectrometer (δppm, DMSO-d4)
: 1.33 (3H, t, J=7Hz), 3.74 (3
H, a).

4.41 (2H, q, J=7Hz), 4.69 (2H,
s).

Acetic acid According to Example 1, 3.4 g of ethyl 2-[:3-(4-fluorophenyl)ureidophthiazol-4-ylglyoxylate, rhodanine-3-acetic acid i1, 911. The target compound in the form of a yellow powder prepared from 1.9 ammonium chloride, 28% ammonia water 1-1 and ethanol 50-1 has the following physical properties.

Melting point: 228-253°C (decomposed) NMR spectrum (δppm, DMSO-d6)
:1.34(3)(,t,J=7Hz)y4.42(2
H,q.

J = 7Hz), 4.70 (2H, s), 7.18 (2H
,t.

J=9Hz), 7.50 (2H, dd, J-5 and 9
Hz).

7.7o(xH,a)t 8.97 (IH, br, a, disappeared by addition of heavy water).

11.05 (IH, br, s, @disappearance due to water addition)
.

13.1-13.7 (IH, br, m disappears upon addition of water).

Example 14 Ureidophthiazol-4-yl]-1-eth Example 1
Ethyl 2-(3-(4-chlorophenyl)ureidophthiazol-4-ylglyoxylate 3.54
．． 9. The target compound in the form of a yellow powder, prepared from 1,9.9 of rhodanine-3-acetic acid, 1.9 of ammonium chloride, 1 ml of 28% aqueous ammonia, and 30 of ethanol, has the following physical properties.

Melting point: 238-242°C NMR spectrum (δppm, DMSO-d4)
:1, 34 (3Ht * J; 7 Hz)
t 4-42 (2H-q.

J=7Hz), 4.70(2H-→17.39(2)1
．． d.

J=9Hz), 7.52 (2H, d, J=9Hz).

7.71(xH,sL 9°08 (IH, br, a, disappeared by addition of heavy water).

11.08 (IH, br, m, disappeared by addition of heavy water)
.

Example 15 5-(1-[:2-(3-(4-bromophenyl)ureidophthiazol-4-yl]-1-ethoxycargonylmethyline]rhodanine-3-acetic acid According to Example 1, 2
-[:3-(4-7'romophenyl)ureidophthiazol-4-ylglyoxylate ethyl 4I, rhodanine-
The target compound in the form of a yellow powder prepared from 2 g of 3-acetic acid E, 1 ammonium chloride, 1-1 9.28% aqueous ammonia and 50 rnt of ethanol has the following physical properties.

Melting point: 251-258°C (decomposition) NMR spectrum (δppm, DMSO-d6)
: 1.33 (3H, t, J=7Hz), 4.42 (2H
, cljJ =7 Hz) e4. ．． 69 (2H
t s ) t 7-47 (2Ht d −J =9
Hz), 7.52 (2H, d, J = 9Hz
).

7.70 (IH, s).

9.11 (IH, br, s, disappeared by addition of heavy water).

11.11 (IH, br, s, disappeared by addition of heavy water).

13.1-13.7 (IH, br, disappeared by addition of heavy water).

Example 16 5-C1-C2-C3-(3,4-dichlorophenyl)ureidophthiazol-4-yl]-1-ethoxycarbonylmethyleneturodanine-3-acetic acid differential hydrate fruit was added to Example 1 Accordingly, 2-1: ethyl 3-(3,4-dichlorophenyl)ureido]thiazol-4-ylglyoxylate 3.9, F, rhodanine-3-acetic acid 1
, 9 g, ammonium tfA 1. P, 28% ammonia water 1m7! The target compound in the form of a yellow powder prepared from , and ethanol 60- has the following physical properties.

Melting point: 223-224°C NMR spectrum (δppm, DMSO-d6): 1
．． 34 (3H, t, J=7Hz), 4.42 (2HtQ
tJ-7Hz), 4.70 (2H, s), 7.40 (I
H, dd.

J = 2 and 9 Hz), 7°58 (I H,
d, J=9Hz).

7.73 (IH, I), 7.88 (IH, d, Jm2H
z).

9-22 (I Hy b r -m) p 11-
21 (I Ht b r * Dew) t13.0-1
3.8 (IH, br,).

Example 17 5-(2-)cutylaminothiazol-4-ylmethylene)rhodanine-3-acetic acid bilysine salt 2-tritylaminethiazol-4-aldehyde 2.5
, F, rhodanine-3-acetic acid 0.81. A mixture of P, piperidine 1.1.9 and 25 mg of ethanol was stirred at cold temperature for 7 hours. 2. Separate the precipitated crystals and wash with methanol to obtain the desired compound as a yellowish brown powder.
I got 71.

Melting point: 210-215°C (decomposed) NMR spectrum (J ppm, DMSO-d6)
: 1.521.61 (6H, m), 2.92 (4H,
br,t.

J = 5 Hz) * 4.24 (2H-→, 7.
16-7.42 (17II ym) t 8-97
(I Hr s ) Example 18 2.4-dioxo-5-(2-tritylaminothiazole-3-acetic acid piperidine/salt According to Example 17, 2-tritylaminothiazole-
The target compound in the form of a pale yellow powder prepared from 0.9.9% of 4-aldehyde 2,3.12,4-thiazolizonone-3-acetic acid, 0.911° of piperidine and 20% of ethanol has the following physical properties. .

Melting point: 205-210°C (decomposition) NMR spectral (δppm, DMSO-d6): L
, 53-1.62 (6H, m), 2.94 (4H, br
, t.

J=5Hz), 3.82 (2H,m), 7
．． 16-7.41 (17H, m), 8.91 (IH, i
).

Example 19 Azol-4-ylmethylene)thiazolidine-3-acetic acid t-butyl ester Contained from Example 17, 2-tritylaminothiazole-
4-aldehyde 2F, 2,4-thiazolidinedione-3
Acetic acid t-butyl ester 1.2.9゜diy 0
．． 88:! The target compound in the form of a yellow powder prepared from , and ethanol 20- has the following physical properties.

Melting point: 103-105°C (primary) NMR quictor (δppm, DMSO-d, )
: 1.40 (9H, @), 4.21 (2H, s), 7
．． 16-7.4 (17H, m), 8.96 (IH, s)
.

Mass suction # (m/e): 583 (M”) Example 20 5-(2-)ditylaminothiazole-4-i Example 1
2-tritylaminothiazole-4-aldehyde 2.9,2,4-thiazolidinedione 0.7 g
The desired compound in the form of a pale brown powder prepared from , piperidine 1y, and ethanol 20- has the following physical properties.

Melting point: 225-228℃ NMR exposure (δppm, DMSO-d, )
Near, 15-7.40 (17H, rn), 8.88 (
IH*5) pll, 99 (IH, br, s).

Mass spectrum (m/・): 469 (M+) Example 21 5-(2-aminothiazol-4-ylmethylene 5-(2
-) dithylaminothiazol-4-ylmethylene) rhodanine-3-acetic acid piperidine salt 2.2. A mixture of 30 ml of 4N hydrogen chloride dioxane solution was stirred at room temperature for 30 minutes, and then stirred overnight.

The precipitated crystals were collected and washed with nooxane to obtain the target compound in the form of an orange-brown powder.

Melting point: 244-246°C (decomposition) NMR exposure (δppm, DMSO-d6): 3
-4 (2H, br), 4.70 (2H, j), 7.50
(IH.

1') 17.51 (IH, s).

Example 22 Light brown color prepared from 5-(2-)ditylaminothiazol-4-ylmethylene)thiazolidine-2,4-dione 1.4,9,4N hydrogen chloride in dioxane solution 25- according to Example 21 The powdered target compound has the following physical properties.

Melting point: 280-288℃ (decomposition) NMR spectrum (δppm, DMSO-d4)
:4.8-6.9 (2H, br, disappeared by addition of heavy water).

7.28 (IH, s)? 7.41 (IH18)? 12.
2 (IH, br, s, disappeared by addition of heavy water).

Example 23 5-(2-aminothiazol-4-ylmethylene hydrochloride Q method 2.4-dioxo-5-(2-tritylaminothiazol-4-ylmethylene)thiazolidine-3-acetic acid t-butyl ester 2.9 , 4N hydrogen chloride dioxa/solution 30
A mixture of -1 and acetic acid 100- was heated at 80°C for 3 hours. The mixture was returned to room temperature and the precipitated crystals were counted to obtain the target compound in powder form.

(2) Method According to Example 21, 2,4-dioxo-5-(2-tritylaminothiazol-4-ylmethylene)thiazolidine-3-acetic acid/piperidine salt 2.7! i, 4N hydrogen chloride dioxane solution 301n1. The target compound produced in the form of a pale brown powder has the following physical properties.

Melting point: 295-298°C (decomposition) NMR spectrum (δppm, DMSO-d6)
: 3.7-5.7 (2H, br), 4.32 (2H-〇.

7.39 (IH, s), 7.60 (IH, s).

Example 24 5-[:2-(3-7enylureido)thiazo-2-(
3-7 enylureido) thiazole-4-aldehyde 1
y, rhodanine-3-acetic acid 0185I.

A mixture of 0.76 g of biridine and 15 g of ethanol was stirred at room temperature for 2 hours, and then heated overnight. The precipitated crystals were collected in a furnace and then dispersed in dilute hydrochloric acid for 30 minutes.
I washed it thoroughly. The obtained crystals were recrystallized from a mixed solvent of acetic acid and ethyl acetate to obtain the target compound in the form of an orange powder.

Melting point: 251-256°C (decomposed) NMR, 7, -! vector (δppm, DMSO-
d6): 4.72(2)(,s), 7.07(IH,t
, J-8Hz).

7.34 (2H, t, J+8Hz), 7.48 (2H,
d.

J=8Hz), 7.73 (IH, ++), 7.95 (I
H,s).

8.94 (IH, br, s ), 10.87 (IH, b
r, s).

13-13.7 (IH, br).

Example 25 Silidine-3-acetic acid ■ Method According to Example 24, 2-(3-7 enylureido)thiazole-4-aldehyde IF, 2,4-thiazolidinedione-3-acetic acid i'? 120.78, y, - with lysine 0.761. The target compound in the form of a yellow powder produced from 20 ml of ethanol has the following physical properties.

■According to Method Reference Example 1, 5-(2-aminothiazole-4-
ylmethylene) -2,4-dioxothiazolidine-3
-Acetic acid/hydrochloride 0.61! , phenyl isocyanate 0.
75 II, and hexamethylphosphoric triamide 20
The target compound in the form of a yellow powder prepared from - has the following physical properties.

Melting point: 230-235℃ (decomposed) NMR spectrometer (δppm, DMSO-d6)
: 4.35 (2H, s), 7.06 (IH, t, J=8
11Z).

7.34 (2H, t, J=8Hz), 7.48 (2H,
d.

J = 8Hz), 7.83 (IH, m), 7.87 (II
-I, s).

8.98 (IH, s), 10.76 (IH, s).

13-13.7 (I Ht br ) Example 2
6 According to Example 24, 2-(3-7enylureido)thiazole-4-aldehyde II, rhodanine 0.69, piperidine 0.75,! i', and ethanol 15
The target compound in the form of a yellowish brown powder produced from m1 has the following physical properties.

Melting point: 300℃ or higher NMR spectrum (δppm, DMSO-d6)
Near, 06 (IH, t, J=8Hz), 7.34 (2H
,,t.

J=8Hz), 7.48 (2H, d, J=8Hz), 7
．． 50 (IH, s), 7.5s (xu, s), s, c+
3(u■,s).

10.80 (IH, @, disappeared by addition of heavy water).

13.55 (IH, br, @, disappeared by addition of heavy water)
.

Example 27 5-(:1-(2-aminothiazol-4-yl)-1
-Ethoxycardenylmethyline]rhodanine-3-acetic acid pendyl ester 5-1:1-(2-aminothiazol-4-·yl)-
1-ethoxycarbonylmethyleneturodanine-3-vinegar
! A mixture of 1k-1 aquarium 2y, penyl bromide 3E, triethylamine 1.1 g, and hexamethylphosphoric acid triamide 10- was stirred at room temperature for 16 hours. The reaction mixture was made acidic with dilute hydrochloric acid and then extracted with ethyl acetate.

After drying the extract over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography [eluent: hexane: ethyl acetate: acetic acid = 8 =
2:1] to obtain yellow crystals.

Melting point: 177-179℃ NMR sample (δppm, DMSO-d4)
:1.30 (3H,t, J=7Hz), 4.3
7 (2H, q.

J=7Hz), 4.84(2H,s), 5.19(
2H, s-).

7.21 (IH, s), 7.36 (5H, s).

7.64 (IH, br, s, disappeared by addition of heavy water).

Example 28 5-[1-(2-acetylaminothiazole-Example 2
4, ethyl 2-(3-phenylureido)thiazol-4-ylglyoxylate 2.6/, 2.4-dioquinthiazolidine-3-acetic acid 1.2. Crude 5-[1-ethoxycarbanyl-1-hydroxy-1-[2-(3-7enylureido)thiazole-] prepared from F, 1.2 F of bi-4-linone, and 30 ml of ethanol.
4-ylcomethyl-2,4-dioquinthiazolidine-
A mixture of 0.69 g of 3-acetic acid, 0.5 g of anhydride e, and 4-pyridino was heated at 600 °C for 17 hours. The reaction solution was poured into water and extracted with ethyl acetate. After drying the extract over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained oil was subjected to silica gel column chromatography (eluent: benzene:ethyl acetate:acetic acid = 8:2:0.5 to 7:3:0.5) to obtain a yellow target compound.

Melting point: 288-290°C NMR spectrum (δppm, DMSO-d6)
: 1.32 (3H, t, J=7Hz), 2.22 (3H
,s).

4,31 (2Hy s ) p 4.39 (2Ht
q* J = 7 Hz) -7,63(IH-→,
12.38 (IH9br, s, m disappears upon addition of water).

Example 29 5-[:1-(2-(3-benzoylthioureido)thiazol-4-yl]-1-nitoxica 2-(3-benzoylthioureido)thiazole-
Ethyl 4-ylglyoxylate 1.51, rhodanine-3
- The target compound in the form of yellow powder, prepared from 0.79 g of acetic acid, 0.1128% ammonium chloride, 0.4-1 g of ammonia water and 20 g of ethanol, has the following physical properties.

Melting point: 233-235°C NMR spectrum (δppm, DMSO-d6): 1
．． 34 (3H, t, J=7Hz), 1.91 (1,5H
, I).

4.43 (2H, q, J=7Hz), 4.67 (2H,
s).

7.5a(2I(,t,,r=7Hz),y,6s(l
H,t.

J=7Hz), 7.69 (IH,s), 8°01 (2
H.a.

J=7Hz).

Example 30 5-[1-ethoxycarbonyl-1-[2-(3-7enylureido)thiazol-4-yl]methyline]rhodanine-3-vinegar? Methyl ester 5-[1-ethoxycarbζnyl-1-[2-(3-phenylureido)thiazol-4-yl]methyline]rhodanine-3-acetic acid i5.9. 10 g of methanol, and 4
A mixture of 75% N hydrogen chloride and dioxane was heated at room temperature for about 20%
I left it for a while. The reaction mixture was poured into water and extracted with ethyl acetate. After drying the extract over anhydrous sulfuric acid (IJum), the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica dull column chromatography [eluent=hexane:ethyl acetate=3=1 to 1:1] to obtain the target compound in the form of yellow crystals.

Melting point: 228-233°C NMR spectrum (δppm, DMS O-d6)
: 1.33 (3H, t, J=7Hz), 3.7
．． 0(3)(,s).

4.42 (2H, q, J=7Hz), 4.81 (2H,
s) *7.07 (IH, t, J=8Hz), 7.34 (
2H,t.

J = 8 Hz), 7.49 (2H, d, J = 8 Hz).

7.71 (IH, s).

8.95 (LH,s, disappeared by addition of heavy water).

11.03 (IH, br, s, disappeared by addition of heavy water).

Example 31 Chill monohydrate According to Example 30, 5-[1-ethoxycarbonyl-
1-[:2-(3-7enylclay)') thiazol-4-yl]methyline]rhodanine-3-acetic acid 211 ethanol 3I and 4N hydrogen chloride-dioxane solution 3
The target compound in the form of a yellow powder prepared from 0tRt has the following physical properties.

Melting point: 94-98°C NMR spectral (δppm, DMSO-d6): 1
．． 18 (3H, t, J=7Hz), 1.21 (3H, t
.

J=7Hz), 4.14 (2H, q, J=7Hz), 4
．． 29 (2H, q, J = 7Hz), 4.74 (2H, a
), 7.05 (IH, t, J=7Hz), 7.28 (I
Htl)y7.33 (2H, t, J-7Hz)
.

7.48 (2H, d, J=7Hz).

8.98 (IH, br, s, disappeared by addition of heavy water).

10.62 (IH, br, a, disappeared by addition of heavy water)
.

Example 32 5-[1-ethoxycarbonyl-1-(2-(3-phenylureido)thiazol-4-yl]methylin]rodani/-3-acetic acid inglovir ester hemipentahydrate Same as Example 27 5-[1-ethoxycarvinyl-
1-(2-(3-phenylureido)thiazole-4-
[Il]Methyline]Rhodanine-3-acetic acid 1! ! , 0.5.9 of isopropyl bromide, 0.251 of triethylamine, and 10-hexamethylphosphoric acid triamide The yellow crystalline target compound has the following physical properties.

Melting point: 113-116°C 1.21 (6H, d, J=6Hz), 1.33 (3H,
t.

J=7Hz), 4.42(2H,q, J=7I(z),
4.75(2H,s), 4.96(IH,s@pt
@t, J=6Hz).

7.07 (IH, t, J=8Hz), 7.34 (2H,
t.

J=8Hz), 7.49(2H,d, J=8
I-rz).

7.71 (IH, s).

8.95 (IH, br, a, M disappeared by water addition).

11.03 (IH, br, s, disappeared by addition of heavy water)
.

Example 33 (3-phenylureido)thiazole-4-ester 5-[1-ethoxycarbonyl-1-[2-(3-phenylureido)thiazol-4-yl]methyline]rhodanine-3-vinegar 21 g,) diethylamine 0 .25. P,
A mixture of 0.7 F of pencil bromide and 10-hexamethylphosphoric acid triamide was stirred overnight at room temperature.
The reaction solution was poured into water and extracted with ethyl acetate. After drying the extract over silicic anhydride, the solvent was distilled off under reduced pressure.

The obtained residue was subjected to silica dull column chromatography [
The mixture was subjected to eluent (hegizan:air acetate=2:1) to obtain the desired compound as a yellow powder.

Melting point: 209-216°C NMR7,-''kutor (δppm, DMSO-d6
): 1.33 (3H, t, J=7Hz), 4.42
(2H, q.

J = 7Hz), 4.87 (2H, s), 5.20 (2H
,s).

7.07 (IH, t, J=7Hz), 7.3-7.4 (
7H.

nd), 7.49 (2H, m), 7.72 (IH, m)
.

8.95 (IH, br, s, disappeared by addition of heavy water)
.

11.02 (IH, br, s, Ik heavy water addition j)
Disappearance) Example 34 5-[1-ethoxycarbonyl-1-(2-l]methyline]rodani/-3-acetic acid 1-isog 5-[1-ethoxycarbonyl-1-1:2-(3-7 enylureido)thiazol-4-yl]methyline]rhodanine-3-acetic acid 1
y and DBU (1,8-diazobicyclo(5,4,0
: l undes-7-ene) 0.651 was dissolved in 16 ml of trimethylacetamide, and then, while cooling with water and stirring, impropyl 1-iodoethyl 8-carbonate was added dropwise. After stirring under water cooling for 4 hours, the mixture was stirred at room temperature for 2 days.

The reaction mixture was poured into water and extracted with ethyl acetate.

After drying the extract over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica dull column chromatography [eluent: hexane: ethyl acetate = 3: 1]
]. The powder obtained by distilling off the solvent was washed with a small amount of the above eluent to obtain the target compound in the form of a yellow powder.

Melting point: 188-190°C NMR spectral (δppm, CDCl2):
1.30 (3H, d, J=6Hz), 1.31 (3
H,d.

J = 6Hz), 1.40 (3H,L, J = 7
Hz).

1.54 (3H, d, J = 5.5Hz), 4.48 (2
H,q.

J = 7Hz), 4.72 and 4.84 (2H
, AB type.

J=17Hz), 4.90(IH, 5eptet
, J=6Hz).

6.81(1)(,q,J-5,5Hz), 7.16(
IH,t.

J=7Hz), 7.19(IH,s), 7.36(
2H,t.

J=7Hz), 7.48 (2H, d, J=7Hz).

7.8-8.0 (IH, br, i disappeared by addition of water).

9,07 (I H * b r * s s M (disappears upon addition of water).

Example 35 5-[1-ethoxycarbonyl-1-C2-(3-phenylureido)thiazol-4-yl]methyline]rhodanine-3-acetic acid sodium salt tetrahydrate 5-[1-ethoxycarbonyl-1 -[2-(3-7enylureido)thiazol-4-yl]methylenerhodanine-3-acetic acid R2,461, tl-IJ A mixture of 0.549 ram methoxide and 3° of absolute ethanol was cooled with water for 1 hour. Stirring followed by sonication for 30 minutes at room temperature. The reaction mixture was poured into anhydrous ether and the precipitated crystals were separated to obtain the desired compound as a reddish brown powder.

Melting point: 300°C or higher NMR spectrum (δppm, DMSO-d6)
:L32 (3H, t, J=7Hz), 4.29 (2H,
s).

4.35 (2H, q, J=7Hz), 6.75 (IH,
t.

J=8Hz), 7.04(IH,s), 7.14(2H
,t.

J=8Hz), 7.59 (2H, d, J=8Hz).

8.79 (IH, br, s, disappeared by addition of heavy water).

Example 36 5-[:1-inbutoxycarcinyl-1-[2-(3
-Phenylureido ")thiazol-4-yl]methylin]rhodanine-3-vinegar fRAs in Example 1, 2-(3
-phenylureido) inbutyl thiazol-4-ylglyoxylate 160 m9, rhodanine-3-acetic acid 90
■, ammonium chloride 50η, 28% ani/monia water 0
．． The target compound in the form of a yellow powder produced from 05- and ethanol 2- has the following physical properties.

Melting point: 235-239°C (decomposed) NMR spectrum (δppm, DMSO-d6)
: 0.93 (6H, d, J=7Hz), 2.03 (IH
, 1 sptet.

J=7Hz), 4.15 (2H, d, J=7Hz), 4
．． 69 (2H, br, s ), 7.07 (IH, t
, Jz=8Hz).

7.34 (2H, t, J=8Hz), 7.49 (2H,
d.

J=8Hz), 7.66(IH,s).

8.96 (I H+ b r e s ? Disappeared by addition of heavy water).

11.03 (IH, br, s, disappeared by addition of heavy water).

13-13.7 (IH, br, disappeared by addition of heavy water).

Example 37 5-[1-carboxy-1-(2-(3-7enylureido)thiazol-4-yl]methylene/]rodani/-3
- Acetic acid quarter hydrate 5-(1-(
2-aminothiazol-4-yl)-1-carmeximethyline rhodanine-3-acetic acid 11. 3.9 g of phenyl isocyanate, and 10 g of hexamethylphosphoric triamide
The target compound in the form of a yellow powder prepared from m/ has the following physical properties.

Melting point: about 225°C (decomposed) NMR spectrum (δppm, DMSO-d6)
:4.63(2H,s), 7.04(II(,t
, J = 8Hz).

7.23 (IH, g), 7.32 (2H, t, J=8H
z).

7.48 (2H, d, J = 8Hz).

8.92 (IH,s, disappeared by addition of heavy water).

10.3-10.8 (IH, br, disappeared by addition of heavy water).

10.99 (LH,s, disappeared by addition of heavy water).

13.0-13.8 (LH, br, disappeared by addition of heavy water).

Example 38 5-[1-ethoxycarbonyl-1-(2-(3-(2
-fluorophenyl)ureido]thiazole-4-yl]methylene]rhodanine-3-acetic acid/215 acetic acid adduct Based on Example 1, 2-[:3-(2-fluorophenyl)ureidophthiazol-4-yl Ethyl glyoxylate 1.7.9, rhodanine-3-acetic acid idO,96, P
, ammonium chloride 0.5g, 28% aqueous ammonia 0.
The target compound in the form of a yellow powder prepared from 5d and ethanol 20- has the following physical properties.

Melting point: 220°C (decomposition) NMR spectrum (δppm, DMSO-d6): 1
．． 34 (3H, t, J=7Hz), 1.91 (1,2H
,s).

4.42 (2H, q, J=7Hz), 4.69 (2H,
br, s).

7.13 (H(, ddd, J=8.5. and 2Hz)
.

7.21 (IH, brat, J==8H$)
.

7.30 (Ii(, ddd, J=11, 8, and 1.5 Hz).

7.72 (LH, s).

8.12 (IH, at, J=2 and 8Hz)
.

8.93 (IH, br, a), 11.30 (IH, br
, i).

Example 39 5-[1-ethoxycarbonyl-1-[:2-[3-(
2-Fluorophenyl]ureido]Aζ in Example 30
Therefore, 5-[1-ethoxycarbonyl-1-(2-1:
3-(2-fluorophenyl)ureidocthiazole-
4-yl]methylene]rhodanine-3-acetic acid 5g, ethanol 1o! y, and 4N hydrogen chloride-dioxane solution 7
The mixture of 5 and 0 was left at room temperature for 5 days, and the reaction mixture was poured into water and extracted with ethyl acetate. After drying the extract over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from hexane-ethyl acetate (about 1:1). The obtained crystals were subjected to silica chromatography [
Eluent; hexane:ethyl acetate=3:1] to obtain target compound a in the form of an orange powder.

Melting point: 93-100°C Rf value in TLC! =; 0.29 [: developing solvent; hexane: ethyl acetate = 3: 1] NMR spectrum (δppm, DMSO-d6)
: 1.18 (3H, t, J=7Hz), 1.21 (3H
,t.

J=7Hz), 4.14 (2H, q, J=7Hz), 4
．． 29 (211,q, J=7Hz), 4. η4(2■
I,s).

7.05-7.3(31(,m), 7.31(IH,s
hmm.

8.08-8.16 (IH, rn), 8.93 (IH,
br, s).

10.84 (IH, br, g).

Then, the recrystallized mother liquor of a was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: hegisan: ethyl acetate = 5:1) to obtain the desired compound as a yellow powder.

Melting point: 230-235°C (decomposition) Rf value in TLC #0.53C Developing solvent: hexane: ethyl acetate = 3: 1) NMR spectral (δppm, DMSO-d6): 1
．． 20 (3H, L, J = 7Hz), 1.33 (3H, t
.

J=7Hz), 4.17 (2H, q, J=7Hz), 4
．． 42 (2H, q, J = 7Hz), 4.79 (2H, s
).

7.05-7.35 (3H, m), 7.73 (IH, s
).

8.08-8.16 (II (, m).

8.91 (IH, br, s, disappeared by addition of heavy water).

11.31 (IH, br, s, disappeared by addition of heavy water).

Example 40 5-[1-ethoxycarbonyl-1-(2-(:3-(
3-fluorophenyl) ureidophthiazol-4-ylglyoxylate ethyl 2-[:3-(3-fluorophenyl)ureidophthiazol-4-ylglyoxylate 1.7 g, rhodanine-3 Vinegar GO, 96, P, ammonium chloride 0.5g, 28-row ammonia water 0.5m/
The target compound in the form of an orange powder was produced using 20 ml of ethanol and ethanol, and had the following physical properties.

Melting point: 193-197°C NMR spectrum (δppm, DMSO-d6)
:1.34 (3H, t, J = 7Hz),
4.42 (2H, Q.

J-7Hz), 4.70 (2H, g), 6.90 (IH
,dt.

J = 2 and 8 Hz), 7.19 (IH, dt, J = 7
and IHz), 7.38 (IH, dt, J = 7 and 8 Hz).

7.48 (IH, dt, J-11 and 2Hz)
.

7.71 (IH, s) * 9.16 (IH, br, s, disappeared by addition of M water)
.

11.11 (IH, br, s, disappeared by addition of heavy water).

13.0-13.7 (IH, br, υ disappeared by addition of heavy water).

Example 41 5-[1-ethoxycarbonyl-1-(2-[3-(4
-Fluorophenyl) ureido edges Examples 30 and 3
9, 5-[1-ethoxycarbonyl-1-[2
-(3-(4-fluorophenyl)ureido]thiazol-4-yl]methylene]rhodanine-3-acetic acid 4.04
．． 9. The target compound A in the form of a yellow powder and the target compound S in the form of a reddish-brown powder prepared from ethanol 8 and 4N hydrogen chloride-dioxane solution 6O have the following physical properties.

Compound a Softening point: 115-125°C Rf value in TLC 0.70 [Developing solvent; hexane:ethyl acetate = 1:1:]] NMR solvent δPP”t acetone-d 6)
: 1.26 (3H,t, J=7IIz), 1.38
(3H, t.

J=7IIz), 4.21 (2H,q, J
-7Hz).

4.47 (2H,q, J=7Hz), 4.83 (2
H,s).

7.13 (2H, t, J=9Hz), 7.59 (IH,
s).

7.61 (2H, da, J=9 and 5Hz).

8.6.1(IH,br,s), 10.45(1)f
,br,s).

Compound Softening point: 110-115°C TLC 'Rf value gradient: 0.41 [: developing solvent; hexane: ethyl acetate = 1:1] NMR spectrum (δPpmyacetyl-a4):
1.23 (3H, t, J=7Hz), 1.26 (3H,
t.

J=7Hz), 4.18 (2H, q, J=7Hz), 4
．． 32 (2H, q, J=7Hz), 4,76
(2)(,s).

7.10 (2H,t, J=9Hz), 7.28 (I
H,s).

7.58 (2H, dd, J=9 and 5Hz).

8.75 (IH, br, s), 9.85 (IH, br,
s).

Example 42 5-[1-ethoxycarbonyl-1-[:2-azol-4-yl]methylene]rhodanine-3-acetic acid sodium salt According to Example 35, 5-[l-ethoxycarbonyl-
1-1: 2-(3-(4-fluorophenyl)ureido]thiazol-4-yl]methylene]rhodanine-3-acetic acid 1 g, 0.241 g of sodium methoxide and 20 ml of absolute ethanol A reddish brown powder object The compound has the following physical properties.

Melting point: 187-200°C (decomposed) NMR spectrum (δppm, DMSO-da)
: 1.31 (3H, t, J=7Hz), 4.25 (2H
, m).

4.35 (2H, q, J=7Hz), 6.96 (2H,
t.

, r=9nz), 7. o3(1■+, aL7.59 (
211, dd, J=9 and 5Hz).

8.86 (IH, br, s).

Example 43 Ethyl (orophenyl)ureidocthiazol-4-ylglyoxylate 1.8F, Rhodani:, y-3-acetic acid 0.
The target compound in the form of a yellow powder, prepared from 96.9 m/m of ammonium chloride, 0.5 m/m of thiammonium chloride, and 30 ml of ethanol, has the following physical properties.

Melting point: 235-243°C (decomposition) NMR spectrum (δppm, DMSO-d6)
: 1.34 (3H, t, J=7Hz), 4.42 (2H
,q.

J=7Hz), 4.69 (2H, br, s), 7.10
(IH.

br, t, J-9Hz), 7.37 (IH, ddd, J
= 3.9° and 11 Hz), 7.71 (IH, g).

8.06 (I H, dt, J=6 and 9 H
z).

8.87 (IH, br, d, J = IHz, i disappears due to water addition) + 11.30 (III, br, s, ff
(disappeared by adding water).

Example 44 Niethoxycarbonylmethyleneturodanine - Example 1
According to Example 1, 2-(3-(2,4-, Zoflu) according to Example 1, ethyl 2-(3-(4-fluoro-3-nitronenyl)ureido)thiazole-4-ylglyoxylate 2゜31 .Rhodanine-3-acetic acid 0.951 ammonium chloride 0.51.28% ammonia water 0.51 nt,
The target compound in the form of a yellow powder produced from 30 ml of ethanol has the following physical properties.

Melting point: approx. 250°C (decomposition)
) :1.34(3)1. t, J=7Hz), 1.9
1 (1,5H,a).

4.42 (2H, q, J=7Hz), 4.69 (2H,
br, s).

7.58 (IH, dd, J=9 and 11 Hz).

7.74 (LH, s), 7.75-7.80 (II (,
m).

s, 43 (IH, aa, r = 6 and 3 Hz))
9.40 (IH, br, s, disappeared by addition of heavy water)
.

11.35 (IH, br, 11. Disappears due to addition of heavy water)
.

Example 45 5-[1-ethoxycarbonyl-1-1:2-(3-(
2,4,6-)IJfluorophenyl)urenine-3-
Acetic acid dihydrate According to Example 1, ethyl 2-(3-(2,4,6-)lifluorophenyl)ureidocthiazol-4-ylglyoxylate 700 m9, rhodanine-3-acetic acid 35
(II9, ammonium chloride 190 m 9.28 thiammonium water 012-1 and ethanol 10 m) The target compound in the form of a yellow powder has the following physical properties.

Melting point: 183-187°C (decomposed) NMR spectrum (δppm, DMSO-d6)
: 1.33 (3H, t, J=7Hz), 4.41 (2H
,q.

J=7Hz), 4.69 (2H, br, s), 7.32
(2H.

dd, J=9 and 8Hz), 7.69(IH,s
).

8.38 (IH, br, s, disappeared by addition of heavy water).

11.60 (IH, br, g, disappeared by addition of heavy water).

13.0-13.7 (IH, br, M p disappeared by addition of water).

Example 46 5-[1-ethoxycarvinyl-1-(2-ene-3-
Acetic acid/1.5 hydrate According to Example 1, 1.1 g of ethyl 2-(3-(3,4,5-)rimethoxyphenyl)ureidophthiazol-4-ylglyoxylate, rhodanine-3- Acetic acid 0.4
8N, ammonium chloride 0.25. F.

28 thiammonia water 0.25d, and ethanol 20
The brown prismatic target compound produced from m1 has the following physical properties.

Melting point: 173-180°C NMR spectrum (δppm, DMSO-d6)
:1.34 (3H, t, J = 7 Hz) *
3.63 (3Hs ”) t3.78 (6H,s
), 4.42 (2H, q, J=7Hz).

4.69 (2H, br, s), 6.81 (2H, 1) p
7.70 (IH, s)? 8.92 (IH, br, a, M disappeared by addition of water)
.

11.04 (IH, br, s, disappeared by adding 77 g of water).

13.1-13.8 (IH, br, disappeared upon addition of ML heavy water).

Example 47 Xycardenylmethyline] rhodanine-3-vinegar ['ff.
Monohydrate According to Example 1, 2-(3-(2-chlorophenyl)
Ethyl ureidophthiazol-4-ylglyoxylate 1.771. Rodani: y-3-nR70.95g, ammonium chloride 0.5g, 28 thiammonia water 0.5d,
and 25 ml of ethanol The yellow powdered target compound thus produced has the following physical properties.

Melting point: 230-238°C (decomposition) NMR spectral (δppm, DMSO-d, s
): 1.34 (3H, t, J=7Hz), 4.42 (
2H,q.

J=7Hz), 4.69 (2H, br, a).

7.13 (IH, dt, J=8 and 1.5 Hz)
t7.36 (IH, dt, J=8 and 1.5 Hz
).

7.52 (IH, dd, J=8 and 1.5 Hz)
p7.72 (IH, g).

8.17 (IH, dd, J=s and 1.5 Hz)
t8.78 (IH, br, s, disappeared due to addition of heavy water)
jll, 64 (I H, br, s, disappeared by addition of heavy water).

13-14 (disappeared upon addition of IH, br, fc heavy water).

Example 48 (3-(p-)lyl)ureidocthiazol-4-yl]methylene]rhodanine-3-vinegar 1! According to Example 1,
2-C3-(P-)lyl)ureidophthiazole-4-
Ethyl ylglyoxylate 4.81. The target compound in the form of a yellow powder prepared from 2.5 g of rhodanine-3-acetic acid, 1.5 N of ammonium chloride, 1.5-1 of 28 thiammonium water and 50- of ethanol has the following physical properties.

Melting point: 240-245°C (decomposed) NMR spectrum (δppm, DhiSO-d6)
:134 (3H, t, J=7Hz), 2.27 (3H
−→.

4.42(2H, q, J=7i(z), 4.69(2H
,br,i).

7.15 (2H, d, J = 8F [z), 7.37 (2H
,d.

J=8Hz), 7.69 (IH, 8).

8, 86 (6 disappears by adding heavy water to I H! b r * s ).

10.99 (IH, br, s, disappearance of heavy water addition)
.

13.0-13.8 (IH, br, disappeared by addition of heavy water).

Example 49 5-[1-ethoxycarbunyl-1= (2-(3-(
2,6-xylyl)ureidophthiazol-according to Example 1, ethyl 2-(: 3-(2,6-xylyl)ureidophthiazol-4-ylglyoxylate 1.74
1. Rhodanine-3-acetic acid 0.961 Ammonium chloride 0
．． 5. ? , 0.5Mt of 28% aqueous ammonia, and 20Mt of ethanol.The target compound is in the form of a yellow powder and has the following physical properties.

Melting point: 240-245°C (decomposed) NMR spectrum (δppm r DMSO-d6)
: 1.33 (3H, t, J=7kh), 2.21 (6H
,s).

4.41 (2H,q, J=7Hz), 4.
69 (2H, br, s).

7.12 (3H-→, 7.65 (IH, s).

8.14 (IH, br, s, disappeared by addition of heavy water)
.

11.24 (I H, br, s, disappeared by addition of heavy water).

12.9-13.9(1)1. br, m disappears upon addition of water).

Example 50 [:3-(4-nitrophenyl)ureido]thiazole-41l]methylene]rhodanine-3-acetic acid/2(dimethylformamide) adduct According to Example 1, 2-(3-
Ethyl (4-nitrophenyl)ureidophthiazol-4-ylglyoxylate 3.7 g, Rhodanine-3-Vinegar 91.9.9. The objective compound in the form of a yellow powder prepared from 1 g of heptammonium chloride, 1 g of 28'% aqueous ammonia, and 40 m of ethanol has the following physical properties.

Melting point: 285-290°C (decomposition) NMR spectrum (δppm, DMSO-d6): 1.
34 (3H, t, J=7Hz), 2.73 (6H, s)
.

2.89 (6H, m), 4.42 (2H, q
, J = 7Hz).

4.70 (2H, br, a), 7.75 (2H, d, J
=9Hz).

7.75 (IH, drop), 7.95 (2H, s).

8.25 (2H, d, J=9Hz).

9.64 (IH, br, i, g disappeared by addition of water).

11.30 (IH, br*s, 1f1 disappeared by addition of water).

13.0-13.8 (IH, br, M disappeared by addition of water).

Example 51 5-[1-ethoxycarbonyl-1-[:2-(3-(
2-)Lifluoromethylphenyl)ureido]thiazol-4-yl]methylene]rhodanine-3-acetic acid According to Example 1, 2-[:3-(2-)lifluoromethylphenyl)ureidofuthiazole-4- 3.9 g of ethyl ylglyoxylate, 1.9 g of rhodanine-3-acetic acid
The target compound in the form of a yellow powder prepared from 1 g of ammonium chloride, 1-1 of 28 thiammonia water and 50- of ethanol has the following physical properties.

Melting point: 245-250°C (min M) NMR spectrum (δppm, DMSO-d6): 1.
34 (3H, t, J=7Hz), 4.42 (2H, q.

J=7Hz), 4.70(2)I,br,s)
, 7.39 (LH.

t, J=8Hz), 7.65-7.75 (IH, nd)
*7.72 (IH, a ), 7.75 (IH, d , J
=8Hz).

7.96 (IH, d, J=8Hz).

8.54 (IH, br, s, disappeared by addition of heavy water).

11.59 (IH, br, s, disappeared by addition of heavy water)
.

12.9-13.9 (IH, br, υ disappeared by addition of heavy water).

Example 52 5-[1-ethoxycarbonyl-1-[2-(:3-(
4-)lifluoromethylphenyl)ureidophthiazol-4-yl]methylef 3 mouthfuls Example 1
Ethyl 3-(4-)lifluoromethylphenyl)ureidophthiazol-4-ylglyoxylate 3.9 F
, rhodanine-3-acetic acid 1.9I% ammonium chloride 11
The target compound in the form of a yellow powder prepared from 28% ammonia water 1-1 and ethanol 30-1 has the following physical properties.

Melting point: 160-170°C (decomposition) NMR2dli-# (δppm, DMSO-
d6): 11.34 (3H, t, J=7Hz), 4.
42 (2H, q.

J=7Hz), 4.70(2)I, br, i), 7.7
0(4H,5)t7.73 (II(,s).

9.34 (IH, br, s, Q disappeared by addition of water).

11.17 (IH, br, s, disappears due to addition of heavy water)
.

Example 53 2-(3,3 -Diphenylureido) ethyl thiazol-4-ylglyoxylate 130
m9, rhodanine-3-acetic acid 60■, ammonium chloride 3
The objective compound in the form of a yellow powder prepared from 0.03-1.0%, 28% aqueous ammonia and 5-1.0% ethanol has the following physical properties.

Melting point: 205-230°C (decomposition) NMR spectrum (δppm, DMSO-d6)
: 1.32 (3H, t, J=7Hz), 4.40 (2H
,q.

J=7Hz), 4.66 (2H,br,s)
, 7.27-7.34 (6I(,m), 7.44(
4H, t, J=8) (Z).

7.69 (IH, s).

11.18 (H(, br, m, disappeared by addition of heavy water)
.

12.5-14.0 (IH, br, disappeared by addition of heavy water).

Example 54 5-[1-Ethoxycarbonyl-1-[:2-Jitakata] Following Example 1, ethyl 2-(3-methylureido)thiazol-4-ylglyoxylate 3.17I, rhodanine- 3-Vinegar r112.2g, chloride 77 mo:um 1.2.
P, 1.2 m of 28% ammonia water, and 5 ml of ethanol.
The target compound in the form of yellow powder prepared from 0m has the following physical properties.

Melting point: 241-245°C (decomposed) NMR spectral (δppm, DMSO-d6): 1.
32 (3H, t, J=7Hz), 2.73 (3H, d.

J=5Hz, by adding heavy water #)3H,l), 4.40(
2H.

q, J=7Hz), 4.68 (2H, br, s).

6.47 (LH, br, d, J=5Hz, ff
Disappearance due to addition of water) + 7-60CIHts)
tl 1.03 (I H* b r * m +disappeared by addition of heavy water).

13.0-13.7 (IH, br, disappeared by addition of heavy water).

Example 55 5-[1-[2-(3-benzylureido)thiazol-4-ylcy-1-ethoxycarbonylmethylene]rhodanine-3-acetic acid dihydrate According to Example 1, 2-(3
-pennorureido) ethyl thiazol-4-ylglyoxylate 1,67 g, rhodanine-3-acetic acid 0.95
The target compound in the form of a yellow powder prepared from 0.5 g of ammonium chloride, 0.5 g of 28 thiammonia water and 25 g of ethanol has the following physical properties.

Melting point: 220-225°C NMR spectrum (δppm, DMSO-d6
): 1.32 (3H, t, J=7Hz), 4.35-
4.45 (2H.

nd), 4.39 (2H, br, s), 4.68 (2H
,br,s).

7.08 (IH, br, t, J=w6Hz, M disappeared by addition of water).

7.2-7.4 (5H, m), 7.62 (IH, s).

11.06 (IH, br, s, disappeared by addition of heavy water)
.

13.0-13.8 (IH, br, disappeared by addition of heavy water).

Example 56 5-(1-(:2-(3-cyclohexylureido)thiazol-4-yl2-1-ethoxycarbonyl]methylene]logino-3-acetic acid According to Example 1, 2-(3
-cyclohexylureido) ethyl thiazol-4-ylglyoxylate 1y, rhodanine-3-acetic acid 0.58.
5', ammonium chloride 0.3! The target compound in the form of a yellow powder prepared from 0.3-1 of 28% aqueous ammonia and 10-1 of ethanol has the following physical properties.

Melting point: 245-248°C (decomposition) NMR Nuvector (δppm, DMSO-d6)
:1.15-1.45 (5H, m), 1.32 (3H,
t, J-7)-1z), 1.45-1.6 (IH, m)
, 1.6-1.75 (2H.

m), 1.75-1.9 (2H, m), 3.42-3°62 (IH.

m), 4.40 (2H, q, J=7Hz), 4.68 (
2H.

m ) -6-56(I H, b r -d * J
=8 Hz) * 7-60 (IJm) + 1
0-65 (I H, b r -s) s 12.9
-13-9 (I Hsbr, ).

Example 57 Allylidene] rhodanine-3-acetic acid A hydrate (E) -3-(2-(3-(4-bromophenyl)ureidophthiazol-4-yl)acrylicaldehyde 0 .4 g, rhodanine-3-acetic acid 0.2F, ammonium chloride 0.159.28 thiammonia water 0.15
The target compound in the form of an orange-brown powder prepared from tnt and ethanol 10- has the following physical properties.

Melting point: 215-220°C (decomposition) NMRy, vector (δppm, DMSO-d6): 4
．． 70 (2H, br, s+), 6.89 (IH, dd,
J = 15 and 12 Hz), 7.34 (IH, d, J =
15Hz).

7.47 and 7.50 (4H, A2B2 type, J=9
Hz).

7.55 (1) 1.1), 7.64 (IH, d, J =
= +12Hz).

9.06 (I Hv br*s 1 υ disappears by addition of heavy water).

10.8-11.2 (IH, br, disappeared by addition of heavy water).

13.0-13.8 (IH, br, disappeared by addition of heavy water).

Example 58 5-(2-(3-phenylureido)thiazodione.
1/3 hydrate According to Example 1, 2-(3-phenylureido)thiazole-4-aldehyde 1.11I, 2.4-thiazolidinedione 0.52. ! il', ammonium chloride 0.
The target compound in the form of a yellow powder prepared from 6N, 28% aqueous ammonia 0.6, d, and ethanol 20 has the following physical properties.

Melting point: 300℃ or higher NMR exposure (δppm, DMSO-d6) near,
06 (IH, t, J=8Hz), 7.33 (2H, t.

J-8 Hz), 7.48 (2H, dd, J=8 and I Hz).

7-63 (I H-m) * 7-78 (I H
s s) t8.96 (IT(, br, ++, disappeared by addition of heavy water).

10.70 (IH, br, s, disappeared by addition of heavy water)
.

12.32 (IH, br, s, disappeared by adding 1 fl water).

Example 59 5-(1-(2-dimethylaminothiazole-rhodanine-3-acetic acid) 2-dimethylaminothiazole-4
-ethylglyoxylate 0.5g, rhodanine-3-
Vinegar GO, 35F, J, Ammonium U chloride 0.26#,
The target compound in the form of orange needles prepared from 0.3-1 of 28 thiammonia water and 5-1 of ethanol has the following physical properties.

Melting point: 275-278°C (decomposed) NMR spectrum (δppm, DMSO-d6)
: 1.32 (3H, t, J=7Hz), 3.15 (6I
-1, s).

4.39 (2) I, q, J = 7Hz), 4.67 (2H
9ri *7.34 (IH, s), 13.2-13.6 (I
FI, br, ).

Example 60 5-(2-diethylaminothiazole-4-yreal azo 1
According to 2-diethylaminothiazole-4-aldehyde 1.21! , rhodanine-3-acetic acid if ammonium chloride 0.8 g, 28% aqueous ammonia 0.8 ml, and ethanol 25 nLt The yellow-brown needle-like target compound has the following physical properties.

Melting point: 257-260°C (decomposition) NMR spectrum (a ppm, DMSO-d6)
:1.23(6T(,t,J=7Hz),3.52(
4H,q.

J=7J(z), 4.70(2H,s), 7.56
(IH,s).

7.59 (IH, s), 13.2-13.5 (LH, b
r,).

Example 61 5-[1-ethoxycarbonyl-1-(2-(3-phenylthioureido)thiazol-4-yl]methylin)
Rhodanine-3-acetic acid ff ethyl ester 5-[niethoxycarbonyl-1-(2-(3-phenylthioureido)thiazol-4-yl]methylin)
Rhodanine-3-11ThfflO,! A mixture of i+, 20 g of ethanol, and 150 g of 4N hydrogen chloride-dioxa/solution was left at room temperature for 4-5 days.

The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with an aqueous potassium carbonate solution, then with brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to silica duplex column chromatography [eluent: hexane: ethyl acetate = 1:1], and the crystals obtained were subjected to hexane-ethyl acetate mixed solvent (approximately 1:1). Recrystallization from 5) yielded the target compound as a yellow powder.

Melting point: 195-200°C NMR spectrum (δppm, DMSO-46): 1.
17 (3H, t, J=7Hz), 1.21 (3H, t.

J = 7 Hz) t 4-13 (2Hy q s
J = 7 Hz) + 4-29(2H,q,
J=7Hz), 4.75 (2H,br,s)
.

6.8-7.9 (6H, m).

Example 62 5-[:1-(:2-(3-(4-chlorophenyl)thiourido]thiazol-4-yl]-1-ethoxycarbonylmethyline]rhodanine-3-acetic acid ethyl ester 5-(1-(2 -(3-(4-chlorophenyl)thioureido]thiazol-4-yl]-1-ethoxycarbonylmethyline]rhodanine-3-acetic acid u4.8g, ethanol 10I, and 4N hydrogen chloride-dioxa/solution 50ml
/! The mixture was left at room temperature for 4.5 days, the reaction solution was poured into water, and extracted with ethyl acetate. Wash the extract with salt water,
Anhydrous sulfuric acid (sulfuric acid anhydride) was used. The solvent was distilled off under reduced pressure, and the residue obtained was mixed with a hexane-ethyl acetate mixture (approximately 1
=1) to obtain the target compound in the form of an orange powder.

Melting point: 175-177°C NMR spectrum (δppm, DMSO-d6)
: 1.17 (6H, t, J=7Hz), 4°13 (2H
,q.

J=7Hz), 4.30 (2H, q, J=7Hz).

4.76 (2H, br, s), 7.0-7.9 (5H
, m).

Example 63 5-[1-Ethoxycargamma vinyl-1-(2-(3-(
2-Fluorophenyl)thiouraid]thiasole 4
-yl]methylene]rhodanine-3-acetic acid quarter hydrate According to Example 1, ethyl 2-1:3-(2-fluorophenyl)thiouridophthiazol-4-ylglyoxylate 7I! , Rodani y-3-fflEE3, 8.9
, F, 7 ammonium A 2.9, 28% aqueous ammonia 2-1 and ethanol 100- The objective compound in the form of a yellow powder has the following physical properties.

Melting point: 187-200°C (decomposition) NMR spectrum (δppm, DMSO-d6): 1.
34 (3H,t, J=7Hz), 4.42 (2
H,q.

J=7Hz), 4.69 (2■(,br,s),
7.2-7.37 (3H, m), 7.67 (IH, g)
, 7.87 (IH.

br, t, J=8Hz).

10.05 (IH, br, s, disappeared by addition of heavy water)
.

12.1-12.5 (IFI, br, 'Q disappeared after addition of heavy water).

Example 64 5-[1-ethoxycarbonyl-1-[2-thiazol-4-yl]methyline]rhodanine-3-acetic acid 2-(:3-(4-fluorophenyl)thiouridoph) Ethyl thiazol-4-ylglyoxylate 550rn9. Rhodanine-3-acetic acid 290 m
9. The yellow needle-like target compound prepared from 150 m of ammonium chloride, 0.15 m of 28 thiammonia water, and 10 - of ethanol has the following physical properties.

Melting point: 220-225°C (decomposition) NMR spectrum (δppm, DMSO-d6): 1.
34(3T(,t, J=7TIz), 4.42(2
H,q.

J-7Hz), 4.70 (2H, br, s), 7.25
(2H.

t, J=9Hz), 7.61 (2H, dd
, J = 5 and 9 Hz), 7.66 (IH, s) + 10.29 (IH, br, s, '4 disappeared due to water addition)
.

11.9-12.2 (H(, br, disappeared by addition of heavy water).

13゜15-13.7 (IH, br, M by adding water
disappearance).

Practical Example 65 5-(2-anilinothiazol-4-ylmethylene)rhodanine-3-acetic acid According to Fuazo 24, 440 m9 of 2-anilinothiazol-4-aldehyde, 412 m9 of rhodanine-3-acetic acid, The desired compound in the form of a tan powder prepared from 0.5 ml of Zerinone and 10 g of ethanol has the following physical properties.

Melting point: 242-246°C NMR spectrum (δppm, a7ton-d6): 4.
87 (2H, br, s), 7.10 (IH
, t, J=8Hz).

7,42 (2H, t, J = 8)Iz) *
7-59 (IH+g) +7.63(IH,s
), 7.78 (2H, d, J-8Hz).

9.63 (IH, br, a).

Example 66 5-(2-anilinothiazol-4-ylmethy) Example 3
0, 5-(2-anilinothiazol-4-ylmethylene)rhodanine-3-acetic acid G1y, ethanol 2y,
The target compound in the form of a yellow powder prepared from 4N hydrogen chloride-soxane solution 10- has the following physical properties.

Melting point: 212-215°C NMR spectrum (δppm, DMSO-d6)
:1.21 (3H,t, J==7Hz), 4
．． 17 (2H, q.

J = 7Hz), 4.81 (2H, s), 7.05 (IH
,t.

J = 8Hz), 7.37 (2H, t, J = 8Hz),
7.68 (IH, s), 7.71 (2II, d, J==
8Hz).

7.80 (IH, s).

10.54 (IH,s, disappeared by addition of heavy water).

Example 67 Phosphorus) Rhodanine-3-fiHi2 1-Ingro7+?
5-(2-anilinothiazole-
4-ylmethylene) rhodanine-3-acetic acid 1g, DBUo
, 5g, isopropyl carbonate 1-iodoethyl 4.5g
, and dimethylacetamide 16 The objective compound in the form of a yellow-green powder prepared from green onions has the following physical properties.

! , unique point: 1 (i6-169'C NMR spectrum (δppm, DMSO-d6): 1.
24 (6H, d, J=6Hz), 1.46 (3H, d.

J=5Hz), 4.79(IH,5eptet, J=6
Hz).

4.8-4.95 (2H, nd), 6.67 (IH, q
, J=5Hz), 7.05(LH,t, J=8Hz),
7.36 (2H.

t, J=8Hz), 7.68 (IH, s), 7.71 (
2H.

d, J=8Hz), 7.81 (IH,s).

10.55 (IH, br, a, g disappeared by adding water)
.

Actual JJ℃ Example 68 5-(2-anilinothiazol-4-ylmethylene)rhodanine-3-acetic acid sodium salt According to Example 35, 5
-(2-anilinothiazol-4-ylmethylene)rhodanin-3-acid 21y, sodium methoxide 280~,
The target compound in the form of a yellow powder produced from 20rnt of ethanol has the following physical properties.

Melting point: 280-295°C (decomposed) NMR spectrum (δppm, DMSO-d6)
:4.31(2Hts), 7.03(IH,t,J=8
H1).

7.35 (2H, t, J=8Hz), 7.51 (IH,
s).

7.69(If(,8), 7.74(2H,d, J=8
H1).

10.70 (IH, br, s, ffjl disappeared by adding water).

Example 69 5-(:2-(o-toluidino)thiazol-4-ylmethyleneturodanine-3-vinegar 112 According to Example 1,
2-(o-)luidino)thiazole-4-aldehyde 1
．． 12.7. Rhodanine-3-acetic acid 0.87 g, ammonium chloride 0.5 g, 28% ammonia water 0.5 w1t
The target compound in the form of an orange powder prepared from , and ethanol 15- has the following physical properties.

Melting point: 247-249.5°C (decomposed) NMR spectrum (δppm, DMSO-d6)
: 2.30 (3H, s), 4.70 (2H, s), 7.
08 (IH.

br, t, J=8Hz), 7.24(2H, br, t
, J=8Hz), 7.62 (IH, s+), 7.72
(IH, S).

7.95 (IH, br, d, J=8Hz), 9.67 (
IH.

br, a), 13.1-13.6 (IH, br,).

Example 70 5-[: (2E)-3-(2-7nilinothiazol) According to practical example 1, (2E)-3-[2-anilinothiazol-4-yl]acryaldehyde 0,4 ,!7
, rhodanine-3-acetic acid 0.29.9. Ammonium chloride 0.22 & 28% ammonia water 0.2W1t.

The target compound in the form of a reddish-brown powder produced from 10 m/g of ethanol has the following physical properties.

Melting point: 244-248°C (decomposition) NMR,'-vector (δppm, DMSO-d6
) :4.70(2J(,br,s),6.91(
IH, dd , J = 15 and 12 Hz), 7.00 (
IH, t, J = 7Hz).

7.2s(IH,a,,y=xsHz), 7.37(x
H*sL7.37 (2H, t, J=7Hz), 7.64
(1) j, d.

J=12Hz), 7.67(2H,d, J=7Hz
).

10.38 (IH, br, s *ffi disappeared by addition of water).

Example 71 5-(2-diphenylmethylaminothiazol-4-ylmethylene)rhodanine-3-acetic acidffiAccording to Example 1, 2-nobueremethylaminothiazole-4-aldehyde 1.95, P, rhodani;/ -3-acetic acid 1.32
g, ammonium chloride 0.4. ! The desired compound in the form of a reddish-brown powder produced from 0.4% of aqueous ammonia and 20% of ethanol has the following physical properties.

Melting point: 227-230°C NMR spectrum (δppm, DMSO-d6):
4.66 (2H, s), 6.13 (IH, d, J=7H
z).

By adding heavy water, it changes to 6.13 (IH, a). 7.2-
7.4 (IOH, m), 7.48 (IH, s), 7.5
4 (IH.

8).

8.99 (IH, d, J=7Hz, If disappeared by addition of heavy water).

13.0-13.7 (IH, br, disappeared by addition of heavy water).

Example 72 Example 73 5-(2-diphenylmethylaminothiazole-4-1
lumethylene) rhodanine-3-acetic acid! 5-(2-diphenylmethylaminothiazol-4-ylmethylene)rhodanine-3-acetic acid 0.6, F, ethanol 7, 7.9, and 4N
The objective compound in the form of a green-yellow powder prepared from hydrogen chloride-dioxane solution 15- has the following physical properties.

Melting point: 196-199°C NMn spectrum (δppm, DMSO-d6)
:1-19 (3H*txJ=7Hz)
-4-15 (2Hy qtJ=7Hz), 4.7
6 (2H, s).

6.13 (IH, d, J = 7 Hz, p6.12 (IH.) by addition of heavy water.

s)), 7.22-7.43 (IOH, m), 7.50
(IH.

s) *7-55 (IH*”) v8.9
9 (IH, d, J = 7 Hz, disappeared by addition of heavy water).

Yellow salt monohydrate prepared from 200m9 of 5-(2-diphenylmethylaminothiazol-4-ylmethylene)rhodanine-3-acetic acid, 24.5rn9 of sodium methoxide, and 6-ethanol according to Example 35. The powdered target compound has the following physical properties.

Melting point: 181-194°C (decomposition) NMR spectrum (δppm, DMSO-d6): 4.
20 (2H-→, 6.15 (IH, d, J=8Hz).

7.22-7.45 (12H, m), 8.95 (IH,
d.

J=8I(z).

Example 74 5-[1-(2-(bis(4-fluorophenyl)methylaminocothiazol-4-yl)-1-ethoxycarzenylmethylene/]rhodanine-3-acetic acid According to Example 1, 2 -(bis(4-fluorophenyl)methylaminocothiazol-4-ylglyoxylate ethyl 342m9.Rhodanine-3-acetic acid 164119,
Ammonium chloride 0.11g, 28 thiammonia water 0.
The target compound of red prism crystals produced from 2- and ethanol 2- has the following physical properties.

Melting point: 245-247°C NMn spectrum (δppm, DMSO=44)
: 1.29 (3H, t, J=7Hz), 4.35 (2
H,q.

J = 7Hz), 4.63 (2H, s), 6.08 (IH
,d.

J=6Hz), 7.14-7.23 (4H, m), 7.
26 (IH, s), 7.37-7.45 (4H, m),
9.03 (IH, d, J=6Hz).

Example 75 Then, 0.7 g of phthaloyl dichloride was added dropwise while cooling with water.

After stirring with water cooling for 6 hours, the mixture was heated at 60° C. for 4 hours. The precipitated crystals were then collected and recrystallized from ethanol to obtain the target compound as a yellow powder. Melting point: approx. 300°C (decomposed) NMn spectrum (δppm, DMSO-d6): 1
．． 36(3I(,t, J=7Hz), 4.46(
2H,q.

J=7Hz), 4.71 (2H, br, s), 7.98
(2H.

dd, J=5 and 3Hz), 8.05-8.15
(2H.

nd), s, 1o(xHr')r 12.9-13.8 (LH, br, p disappeared upon addition of water).

Example 76 5-(2-(4-fluoroanilino)thiazolhodanine-3-acetic acid hydrate 5-(1-(2-aminothiazol-4-yl)-1-
Ethoxycarbonyl methylene colodani 7-3-acetic acid 1.
Dissolve 19 g in tetrahydro 7rane 8-according to Azo 1, 2-(4-fluoroanilino)thiazole-4-aldehyde Ig, rhodanine-3-acetic acid 0.85N, ammonium chloride 0.5.9128% ammonia water 0.5 m
The target compound in the form of an orange powder prepared from 10rnt of ethanol and 10rnt of ethanol has the following physical properties.

Melting point: 263.5-266°C (min M) NMR spectrum (δppm, DMSO-d6): 4.71 (2H, s
), 7.19 (2H, t, J=9Hz).

7.65 (IH, s), 7.71 (2H, dd, J=9
and 5Hz), 7.78 (IH,s).

10.54 (IH, br, s, fi disappeared upon addition of heavy water).

13.0-13.8 (LH, br, disappeared by addition of water).

Example 77 5-(2-(p-anisidine)thiazol-4-ylmethylene]rhodanine-34'1=41 According to Example 1,
2-(p-anisidine)thiazole-4-aldehyde 1
g, rhodanine-3-acetic acid 0.8, @, J, ammonium chloride 0.5. P, 28 thiammonia water 0.5mA
, and 10 ml of ethanol, the target compound in the form of an orange powder has the following physical properties.

Melting point: 197-202°C NMR spectrum (δppm, DMSO-d6)
: 3.76 (3H, torture), 4.72 (2
H, m), 6.93 (2H.

d, J=9Hz), 7.60(2H,d, J=9
Hz).

7.63 (IH, s), 7.72 (IH, ++).

10.32 (IH, br, s, disappeared by addition of heavy water)
.

13.1-13.7 (IH, br, disappeared by addition of heavy water).

Example 78 s-[2-(3-)lifluoromethylanilino)thiazol-4-ylmethyline]rhodanine-3-acetic acid 2-(3-)lifluoromethylanilino)thiazole-4 -Aldehyde 1y.

The orange-yellow prismatic target compound prepared from rhodanine-3-acetic acid ff<0.7.9, ammonium chloride 0.51.28 thiammonium water 0.5 m, and ethanol 10-h has the following physical properties.

Melting point: 249-252°C (decomposition) NMR spectrum (δppm, DMSO-d6): 4.
72 (2H, s), 7.37 (IH, br, d, J=8
Hz).

7.58(IH, br-t, J=8Hz)*7.65(
IHtbr, d, J=8Hz), 7.69 (IH, s)
, 7.88 (IH.

s), 8.43 (IH, br, s).

10.90 (IH, br, s, disappeared by addition of heavy water)
.

13.2-13.6 (IH, br, disappeared by addition of heavy water).

Example 79 5-(2-ethylaminothiazol-4-ylmethylene)rhodanine-3-acetic acid 2-ethylaminothiazole-4-
Aldehyde 1.27g, rhodanine-3-acetic acid 1.3,9
．． Ammonium chloride 1. F, 28% ammonia water 1 green onion,
The yellow needle-shaped target compound produced from ethanol 30- and ethanol 30- has the following physical properties.

Melting point: 248-250°C (decomposition) NMR spectrum (δppm, DMSO-d6)
:1.23 (38,t, J=7Hr,), 3.3-3.
45 (2H.

m), 4.70 (2H, s), 7.52 (IH, s),
7.54 (IH+s), 8.05 (IH, br, t, J
=5Hz).

13.33 (IH, br, s).

Example 80 5-(2-allylaminothiazol-4-ylmethylene)rhodanine-3-acetic acid Added to Example 1, 2-allylaminothiazole-4-
Aldehyde 3.0g, rhodanine-3-acetic acid 2.8g, ammonium chloride 2.1g, 28 thiammonia water 2.1r
The brown needle-like target compound prepared from ILt and 70 ml of ethanol has the following physical properties.

Melting point: 234-236°C (decomposed) NMR spectrum (δppm, DMSO-d6): 3.
98-4.03 (2H, m), 4.70 (2H, s).

5.16 (IH, ddd, J=10, 3, and 1.5 Hz).

5.29 (IH, ddd, J=17, 3, and 1
．． 5Hz).

5.90-6.05 (IH, m), 7.537 (IH,
s).

7.540(IH,tI), 8.23(II(, br
, t, J=5Hz), 13.1-13.6(IH,b
r).

Example 81 5-(2-cyclohexylaminothiazole-Example 1
2-cyclohexylaminothiazole-4-
Aldehyde 3.0 & Rhodani/-3-acetic acid 2.27
! The yellowish brown needle-like target compound prepared from 1.7.9°28 ammonium chloride, 1.7 ml of ammonia water, and 60% of ethanol has the following physical properties.

Melting point: 220-222°C (min M) NMR spectrum (δppm, DMSO-d6)
: 1.15-1.5 (5Tr, m), 1.55-1.
85(:3I(,m).

2.0-2.1 (2H, m), 3.55-3.7 (IH
,rn).

4.70 (2H, I), 7.49 (IH, s), 7.5
2 (IH.

8).

8.02 (IH, d, J=7Hz, disappeared by addition of heavy water).

13.2-13.45 (HI, br, disappeared by addition of heavy water).

Example 82 5-(2-diphenylaminothiazol-4-ylmethylene)rhodanine-3-acetic acide Leading from Example 1, 2-diphenylaminothiazol-4-ylmethylene:,'-
Ru 4-alamide 3! i, rhodanine-3-acetic acid 1.7
．． 9, ammonium chloride 1.3, 9.28% ammonia water 1.3 m, and ethanol 6o- The orange needle-shaped target compound has the following physical properties.

Melting point: (approx.) 305-310°C (decomposed) NMR spectrum (δppm, DMso-d6): 4.69 (
2H,s), 7.3-7.48(2H,m).

7.49 (4H, br, s), 7.51 (4H, br,
s).

7゜64 (I H, s ), 7.75 (I H, s
).

13.1-13.5 (IH, br,).

Example 83 5-(2-morpholinothiazol-4-ylmethylene)
Rhodanine-3-acetic acid According to Example 1, 2-morpholinothiazole-4-aldehyde 1.6FM, rhodanine-3-acetic acid 1.3. F,
Ammonium chloride 1.9, 28% ammonia water 1tRt
The yellow needle-like target compound produced from , and ethanol 35trLt has the following physical properties.

Melting point: 287-290°C (decomposition) NMR7,-ector (δppm, DMSO-d6
): 3.50 (4H, br, t, J=5Hz), 3.
76 (4H.

br, t, J=5Hz), 4.70 (2H, s), 7.
61 (IH, i), 7.72 (IH, B)
, 13.1-13.6 (IH.

br@).

Example 84 5-(2-B?Ritzthiazo-/l/-4-iA,
methylene) rhodanine-3-acetic acid According to Example 1, 1.8 g of 2-piperidinothiazole-4-aldehyde, 1.4 g of rhodanine-3-acetic acid, and 1.01 g of 7y monofy chloride! , 28% 7 ammonia water 1-
1 and ethanol 40-, the target compound has the following properties as bright yellow needles.

Melting point: 277-280°C (decomposed) NMR spectroscopy (δppm, DMSO-d6): 1.
64 (6H, br, s), 3.52 (4H, br, a)
.

4.70 (2H, s), 7.57 (IH, s), 7.6
5 (IH.

s), 13.0-13.7(1)(,br,).

Example 85 5-(2-(thiomorpholin-4-yl)thiazole-
4-ylmethyline] rhodanine-3-acetic acid 2-(thiomorpholin-4-yl) according to Example 1
Thiazole-4-aldehyde 0.84M1゜rhodanine-
3-acetic acid o, r 6 g, ammonium chloride 0.4,
9.28% ammonia water 0.4-1 and ethanol 3
The target compound in the form of yellow crystals prepared from 0WLt has the following physical properties.

Melting point: 267-270°C (decomposition) NMR spectrum (δppm, DMSO-d6)
:2.7. -2.8 (4H, m), 3.8-3.9 (4
H, m).

4.71 (2H, s), 7.59 (IH, s), 7.7
0 (IH.

s), 13.0-13.6 (IH, br,).

Example 86 5-(2-aminothiazol-4-ylmethylene) rhodanine-3-acetic acid 4y was dissolved in 70 g of dimethylformamide, 2.61 g of benzoyl isothiocyanate was added dropwise thereto at room temperature, and the mixture was incubated at room temperature for 6 hours. Ethyl acetate was added to the stirred reaction mixture, and the precipitated crystals were filtered off. The ethyl acetate solution was washed with water, concentrated under reduced pressure, and the precipitated crystals were recrystallized from acetic acid to obtain the target compound as a yellow powder.

Melting point: 248-250°C (decomposed) NMR spectrometer (δppm, DMSO-d6): 4.
73 (2H, s), 7.57 (2H, br, t, J=8
Hz), 7.71 (IH, br, t, J=8Hz), 7
．． 84 (IH, s), 8.06 (2H, br, d, J=
8Hz).

8.09 (IH, s).

12.27 (II (, g, disappeared by addition of heavy water).

13.0-13.7 (IH, br, disappeared by addition of heavy water).

14.30 (LH,s, disappeared by addition of heavy water).

Example 87 Thiazole-4-ylmethyleneturodanine-3-acetic acid According to Example 1, 2-(4-methyl-1-piperazinyl)thiazole-4-aldehyde i,sy.

Rhodanine-3-vinegar ff<1.21! , 0.9 g of ammonium chloride, 0.9 ml of 28% aqueous ammonia, and 40 ml of ethanol. The target compound has the following physical properties as dark yellow needles.

Melting point: 300℃ or higher NMR quictor (δppm, CF, GOOD)
: 3.24 (3H, s), 3.63 (2H, br, d
t, J=13 and 3Hz), 4.04 (2H,
br, d, J=13T(z).

4.22 (2H, br, t, J = 13Hz)
, 4.39 (2I-I.

br-d, J=13Hz), 5.11 (2
Hy ”) p7.6=O(I H,s ).

Example 88 5-(2-octylaminothiazol-4-ylmethylene)rhodanine-3-fl12.1/3 ethanol 1 adduct According to Example 1, 2-octylaminothiazole-4
-Aldehyde 1.1.9. Rhodanine-3-acetic acid 0.66
g, ammonium chloride 0.5 g, 28% ammonia water 0
．． The yellow-brown needle-shaped target compound prepared from 5rnt and ethanol 30- has the following physical properties.

Melting point: 147-149°C NMR spectrum (δppm, DMSO-d6): 0.
85 (3H, br, t, J=7Hz), 1.06 (IH
.

t, J=7Hz), 1.15-1.45 (IOH, m)
.

L 55-1-7 (2Ht m) s 3-2-3
-5 (2-67Hand) *4.25-4.
4 (0,33H, m), 4.70 (2H, s).

7.50 (IH, s), 7.53 (IH, s), 8.0
6 (IH.

t, J-5Hz), 13.0-13.6 (IH,
br,).

Example 89 5-(2-isoglopylaminothiazol-4-ylmethylene) rhodanine-3-acetic acid 9 According to Example 1, 2-isoglopylaminothiazole-4-aldehyde 2.7 , P , rhodanine- 2.3 g of 3-acetic acid, 1.7 g of ammonium chloride. The dark red acicular target compound produced from F, 1.7 d of 28 thiammonia water, and 50 Wt of ethanol has the following physical properties.

Melting point: 227-229°C (decomposition) NMR spectrum (δppm, DMSO-d6)
: 1.25 (6H, d, J=7H2), 3.85-4.
0 (IH.

m), 4.70 (2H, s), 7.51 (IH, s),
7.53 (IH-→, 7.98 (IH, d, J=7Hz
).

13.0-13.8 (IH, br,).

Example 90 According to Example 1, 2-pennolaminothiazole-4
-aldehyde 0.58 F, rhodanine-3 acetic acid o, s
The yellow needle-like target compound prepared from II, 0.3 g of ammonium chloride, 0.3 m of 28 thiammonia water, and 40-mL of ethanol has the following physical properties.

Melting point: 207-210°C NMR spectrum (δppm t DMSO-d6)
:4.58 (2H, d, J=6Hz), 4.69 (2H
, a).

7.2-7.45 (5H, m), 7.53 (2H-→.

8.57 (IH, t, J=6.Hz, disappeared by addition of heavy water).

13.0-13.6 (IH, br, disappeared by addition of heavy water).

Example 91 5-[:1-(2-(3-penzoylthioureido) Crude 2-(3-benzoylthioureido)thiazol-4-ylglyoxylic acid sodium salt 1 according to Example 1
．． 0:! , rhodanine-3-acetic acid 0.75 , P , ammonium chloride 0.2.9, 28% aqueous ammonia 0.5
The target compound in the form of a yellow powder prepared from 20 ml of ethanol and 20 ml of ethanol has the following physical properties.

Melting point: 255-265°C (decomposition) NMR spec) # (a ppm, DMSO-d
6) :4-71 (2Hea) *7-58
(21(t b r -t p J-8Hz ) e
7-71 (I H) b r −t t J =8
Hz) $7-77 (I Hta), 8.06 (
2H,br,d,J=8Hz).

12.30 (IH, br, a, M disappeared by adding water)
.

13.0-13.9 (IH, br, , disappeared upon addition of water).

13.9-14.7 (2H, br, disappeared by addition of normal water).

Example 92 According to Example 1, 0.53 g of 2-cyclopropylaminothiazole-4-aldehyde, 0.0 g of rhodanine-3-acetic acid
．． The target compound in the form of an orange powder prepared from 0.3 g of 461 ammonium chloride, 0.3 m of 28 thiammonia water, and 20-mL of ethanol has the following physical properties.

Melting point: 255-257°C NMR spectral (δppm, DMSO-d6): 0.
54-0.6 (2H, m), 0.74-0.81 (2H
.

m), 2.6-2.7 (IH, m), 4.69 (211
,s).

7.56 (IH, m ), 7.58 (IH, s ), 8
．． 38 (IH, d, J=IHz), 13.1-13
．． 6 (IH, br-).

Reference Example 1 10 g of ethyl 2-aminothiazol-4-ylglyoxylate was dissolved in 100 ν of methylformamide, and 7,14 # of phenyl incyanate was added dropwise thereto under water cooling, and the mixture was heated overnight. The crystals obtained by distilling off dimethylformamide under reduced pressure were washed with water, dried, and recrystallized from ethyl acetate to obtain a yellow target compound.

Melting point: 217-220°C NMR spectral (δppm, DMSO-d6): 1.
34(3H,t, J-7Hri, 4.38(2Ht(it)
J=7Hz), 6.95-7.6 (5H-m)18.
41 (IH.

s), 8.93 (IH, br-s), 10.8-11.
3 (IH.

brew) Reference Example 2 According to Stell Reference Example 1, ethyl 2-aminothiazol-4-ylglyoxylate 5Ij, incyan r and 2-methoxyphenyl 4.5F, and trimethylformamide 40
The target compound in the form of a pale yellow powder prepared from No. 16 has the following physical properties.

Melting point: 223-227°C NMR spectrum (δp p m r DMS O-d
6): 1.34 (3H, t, J=7Hz), 3.8
8 (3H, s).

4.38 (2H,q, J = 7Hz), 6.
9-7.0 (IH, m) -7,0-7,1 (2H, m)
-8,05-8,15 (IH, m).

8.39 (IH, s).

8.65 (IH, br, s, disappeared by addition of heavy water).

11.46 (IH, br, s, disappeared by addition of heavy water)
.

Reference Example 3 According to Stell Reference Example IH, 5 g of ethyl 2-aminothiazol-4-ylglyoxylate, 4.5.9 g of 3-methoxyphenyl isocyanate, and 40 m of nomethylformamide
The yellow crystal target compound prepared from 1 has the following physical properties.

Melting point: 182-185°C NMR spectrum (δp p m t DMSO
-d 6): 1.33 (3H, L, J = 7Hz
), 3.75 (3H,s) -4,37(2H,
q, J=7Hz), 6.64 (IH, dd.

J=2 and 8Hz), 6.95-7.0 (IH, m)
.

7.16 (IH, t, J=2Hz), 7.23 (IH,
t.

J=8Hz), 8.41 (IH, 8).

8.90 (IH, br, s, disappeared by addition of heavy water).

10.99 (IH, br, s, disappeared by addition of heavy water).

Reference Example 4 According to Stell Reference Example 1, ethyl 2-aminothiazol-4-ylglyoxylate 10,9. 4-methoxy7phenyl isocyanate 911 and dimethylformamide 80ml
The target compound in the form of a yellow powder prepared from has the following physical properties.

Melting point: 193-196°C NMR spectrum (δppm, DMSO-d6): 1.
33 (3H*t, J=7Hz) t3.73 (3Hps)
.

4.37 (2Hv q e J = 7 T(z)
-6-90 (2H, d-J=9Hz), 7.3
8 (2H, d, J=9Hz).

8.39 (IH, s).

8.72 (I H, br, s, disappearance of heavy water addition)
.

10.96 (IH, br, s, disappeared by addition of heavy water).

Reference Example 5 According to Stell Reference Example 1, ethyl 2-aminothiazol-4-ylglyoxylate 59, 4-fluorophenyl isocyanate 5.1.9. and somethylphonamide 30
The target compound in the form of a yellow powder prepared from m7 has the following physical properties: Melting point: 220-223°C NMR spectrum (δp p m = DMS O-d
6) :1=34 (3Hlt e J =7H
z) #4-39 (2Hlq -J=7Hz)#
7.17 (2H,t, J=9Hz)t7.53 (
2H, dd, J=5 and 9 Hz).

8.43 (IH, s), 8.96 (IH, br, s
).

11.09 (IH, br, s).

Reference Example 6 According to Stell Reference Example 1, 10 g of ethyl 2-aminothiazol-4-ylglyoxylate, 8.6 g of 4-chlorophenyl isocyanate. ? , and dimethylformamide lQQ
The target compound in the form of a yellow powder prepared from +nl has the following physical properties.

Melting point: 230-234°C NMR spectrum (δppm, DMSO-d6): 1.
34 (3H, t, J=7Hz) 4.39 (2H, q.

J=7Hz), 7.38 (2H,d, J
=9Hz).

7.55 (2H, d, J=9Hz), 8.43 (IH,
s).

9.06 (IH, br, s), 11.14 (LH, by
,+).

Reference Example 7 According to Stell Reference Example 1, 10 g of ethyl 2-7 minothiazol-4-ylglyoxylate, 8.7 g, 9 g of 4-bromophenyl isocyanate. and dimethylformamide 80m
The yellow crystal target compound produced from has the following physical properties.

Melting point: 235-241°C NMR spectrum (δppm, DMSO-d6): 1
．． 33 (3H, L, J = 7Hz), 4.37 (
2H,q.

J=7Hz), 7.44-7.53 (4H, m), 8.
42 (IH, s) = 9.05 (IH, br, s), 1
1.10 (IH,br,s).

Reference Example 8 According to Reference Example 1, ethyl 2-aminothiazol-4-ylglyoxylate 1011 3.4-dichlorophenyl isocyanate 10FS and dimethylformamide 1
The target compound in the form of a pale yellow powder prepared from 00 mJ has the following physical properties.

Melting point: about 250°C (decomposed) NMR spectral (δppm, DMSO-d,): 1.
34(3)1. t, J=7Hz), 4.39(2
H,q.

J=7Hz), 7.43 (LH, dd, J
= 2 and 9Hz).

7.59 (LH, d, J=9Hz), 7.89 (IH,
d.

J=2Hz), 8.46 (LH, g), 9.22 (IH
, br, lt).

11.29 (IH, br, s).

Reference Example 9 According to Reference Example 1, ethyl 2-aminothiazol-4-ylglyoxylate 10y1 1-naphthyl incyanate 10.1.9. and 100ml of trimethylformamide
The target compound in the form of an off-white powder produced from the above has the following physical properties.

Melting point: 209-211°C NMR spectrum (δPpm, DMF-d, ): 1
, 37 (3Hlt, J==7Hz) a 4-4
4 (2H-Q IJ=7Hz), 7.45-8.4
(7H, m), 8.47 (IH.

s ), 9.44 (LH, br, s ), 10.81
1.7 (LH.

br, s).

Reference Example 10 According to Reference Example 1, ethyl 2-aminothiazol-4-ylglyoxylate 65'Sp-toluenesulfonyl isocyanate 6F and trimethylformamide 4Qm
The pale yellow target compound prepared from 1 has the following physical properties.

Melting point: 200-207°C (decomposed) NMFL spectrum (δppm, DMSO-d6):
1.31 (3H, t, J = 7Hz), 2.
40 (3H,s)4.35 (2H,q, J=
7Hz), 7.44 (2H,d.

J=8.3Hz), 7.86 (2H,d,
J = 8Hz).

8.44 (IH, s), 11.10-11.65 (IH
,br,s).

Reference Example 11 Ethyl 2-aminothiazol-4-ylglyoxylate 51 was dissolved in 30 ml of hexamethylphosphoric acid triamide, 5.21 phenyl inthiocyanate was added thereto under water cooling, and the mixture was stirred at an external temperature of 60°C for 8 hours. did. The reaction mixture was made acidic with dilute hydrochloric acid and extracted with ethyl acetate. After drying the extract over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure and the precipitated crystals were filtered to obtain a pale yellow target compound.

Melting point: 190-192°C NMR spectrum (δppm, DMSO-d6): 1.
33 (3Hat, J=7Hz)-4-41(2
H-q-J = 7 Hz) + 7.10-7-7
7 (5He m ) -8-40 (I H.

s), 10.52 (IH, br, s), 11.8-12
．． 6 (IH.

br, s).

Reference Example 12 2-(3-(4-10 Lofenyl)thiouridophthiazol-4-ylglyoxylic acid ethyl ester According to Reference Example 1, ethyl 2-aminothiazol-4-ylglyoxylate 511-thiocyanate r- The objective compound in the form of a yellow powder prepared from 6.35 g of chlorophenyl and 30 m of hexamethylphosphoric acid triamide has the following physical properties.

Melting point: 176-178°C NMR spectrum (δppm, DMF-d,): 1.3
5 (3H,t, J=7Hz), 4.43
(21-1, q.

J=7Hz) t 7.45 (2H1br-d,
J==9Hz) 17.80(2H,br,d,J
=9Hz), 8.43(IH,s).

10.7-11.2 (IH, br,).

Reference Example 13 Ethyl 2-aminothiazol-4-ylglyoxylate 5y was dissolved in 50d of tetrahydrofuran, 5.55.9% of benzoyl bromide was added dropwise under water cooling, and the mixture was further stirred for 1 hour. Water was added to the reaction mixture, and the precipitated crystals were separated and subjected to silica column chromatography (eluent: hexane:ethyl acetate = 2:1) to obtain a white target compound.

Melting point: 152-153°C NMR spectrum (δppm, acetate: y-a6)
:1.40 (3H, t, J=7Hz)+4.4
4 (2H1q, J=7Hz), 7.43-7.73
(2H, m), 8.10-8.36 (2H, m), 8.
37 (IH, s).

Reference Example 14 Ethyl 2-aminothiazole-4-carboxylate 3,1.
A mixture of 5 g of triphenylchloromethane and 15 ml of dichloromethane was added dropwise to a mixture of F, 25 rnl of trimethylformamide, and 1.811 ml of triethylamine. After 10 minutes at -30°C, the mixture was stirred at room temperature for 2 hours, and the reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with 0.1N acid and then with saline,
It was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica dal chromatography (eluent; benzene:ethyl acetate = 102 I). The resulting crystals were washed with n-hexane to obtain the target compound in the form of a white powder. I got it.

Melting point: 140-141°C Reference Example 15 2-Tritylaminothiazole-4-methanol In a mixture of 0.24F lithium aluminum hydride and 30ml of tetrahydrofuran, 2.6. 9,
A mixture of 10 m4 of tetrahydrofuran was added dropwise under water cooling. After the addition, the mixture was stirred at room temperature for 3 hours, and then heated under reflux for 1 hour. Ethyl acetate and then water were added to the reaction mixture under water cooling, the organic layer was separated, and the aqueous layer was further extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sulfuric acid.

The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica dal chromatography (eluent; benzene:ethyl acetate = 1+1
) The crystals obtained were recrystallized from a mixed solvent of ethyl acetate, acetone, and n-hexane to obtain the target compound as a pale yellow powder.

Melting point: 186-187°C Reference example 16 Do-2-tritylaminothiazole-4-methanol 0.5
,9. A mixture of 51 ml of manganese dioxide and 20 ml of acetone was stirred at room temperature for 60 hours.

Mandioxide-N7ffp was removed, the P solution was distilled off under reduced pressure, and the resulting residue was subjected to silica dal chromatography (eluent;
Benzene:ethyl acetate=10:1) to obtain the target compound as an orange-brown powder.

NMRy, vector (δppm, DMSO-d6) near, 19-7.36 (15H, m), 7.70 (LH,
br, s).

8.93 (IH, br, s, disappeared by addition of heavy water).

9.40 (IH, s).

Mass 4ri) Le (m/e): 370 (M
”) Reference Example 17 Ethyl 2-(3-7enyl ureto)thiazol-4-ylglyoxylate II!, Sodium borohydride 0
．． 6 g of methanol and 20 g of tetrahydrofuran were added dropwise over 1 hour while heating under reflux. After cooling to room temperature and acidifying with 3N hydrochloric acid, the solvent was distilled off under reduced pressure. The resulting residue was washed with water,
The target compound in the form of a white powder was obtained.

Melting point: 175-178°C Reference Example 18 Meta-periodic acid is added to a mixture of 4-(1,2-dihydroxyethyl)-2-(3-phenylureido)thiazo-/l/0.51 and methanol (15 m/l). IJum was dissolved in 15ml of 0.76Fk water and added dropwise at room temperature.

After the dropwise addition, the mixture was stirred for 2 hours, the solvent was distilled off under reduced pressure, and the resulting residue was washed with water to obtain the target compound in the form of a white powder.

Melting point: 216-220°C (decomposed) NMR Quick # (Jpprn, DMSO-d6)
:6.9-7.7 (5H, m), 8.26 (
LH,a).

9.03 (LH, br, ), 9.83 (LH, s )
, 10.5-11.2 (IH, br,).

Reference Example 19 Pale yellow powder prepared according to Reference Example 1 from 20 g of ethyl 2-aminothiazol-4-ylglyoxylate, pensoy, I+/intiocyanate) 16.5:i, and 100 m/of trimethylformamide. The target compound has the following physical properties.

Melting point: 155-157°C NMR exposure (δppm, DMso-d6): L3
4 (3H, L, J = 7Hz), 4.40 (21 (, q.

J=7Hz), 7.57 (2H,t, J
=8Hz), 7.70 (IH, t, J=gHz)
, 8.01 (2H, d, J=8Hz).

8.53 (IH, m).

12.1-12.5 (IH, br, disappeared by addition of heavy water).

14.0-14.4 (IH, br, disappeared by addition of heavy water 6).

Reference Example 20 2-7 minothiazol-4-ylglyoxylic acid potassium salt 10J1 inbutyl alcohol 15y1 and 4N
5 Q ml of hydrogen chloride-sooxane solution was stirred at room temperature for 2 days. The reaction mixture was poured into water, neutralized with potassium carbonate, extracted with ethyl acetate, and the extract was dried under anhydrous magnesium sulfate. Ethyl acetate was distilled off to obtain the target compound as a pale yellow powder.

Melting point: 105-108°C NMR spectrum (δp pm -DMS O-d 6
): 0.93 (6H, d, J=7Hz), 1.98
(IH, teptet.

J=7Hz, ), 4.08 (2H,d, J
=7H2), 7.40(2H+br,a)*7.8
9 (IH, i).

Reference Example 2 According to Reference Example 1, 1 g of isobutyl 2-aminothiazol-4-ylglyoxylate 6 phenyl isocyanate
The desired compound in the form of a pale yellow powder, prepared from 20m9 and 10m9 of tetrahydrofuran, has the following physical properties.

Melting point +190-200℃ (decomposition) NMR spectral (δp p m e DMS O-d
6) :0.96 (6H* d a J = 7
Hz) + 2.02 (L Hh s@ptst
+J =711z), 4.14(2H,d, J=7
Hz), 7.06 (IH, t, J=7Hz), 7.33
(2H, t, J=8Hz).

7.48 (2H, d, J=7Hz), 8.40 (IH,
5) 18.92 (IH, br, s), 10.98 (IH
,br,s).

Reference Example 22 According to Stell Reference Example 1, ethyl 2-aminothiazol-4-ylglyoxylate 51. 2-fluorophenyl incyanate 4.879, and trimethylformamide 30M
The target compound in the form of a pale yellow powder produced from the above has the following physical properties.

Melting point: 219-225°C NMR spectrum (δppm, DMSO-d6): 1
．． 34 (3H, t, J=7Hz), 4.38 (2
H.

q, J-7Hz), 7.1-7.15 (IH, m).

7.20 (IH, t, J==8Hz), 7.29 (IH
.

dd, J = 11 and 8 Hz), 8.08 (IH, t
.

J=8Hz), 8.43 (LH, g).

8.85 (I H# k)r*1+disappeared by addition of heavy water), 11.22 (IH, br, +s, disappeared by addition of heavy water).

Reference Example 23 According to Stell Reference Example 1, 5 g of ethyl 2-aminothiazol-4-ylglyoxylate, 4.9 g of 3-fluorophenyl isocyanate, and 30 ml of nomethylformamide
The target compound in the form of a pale yellow powder prepared from has the following physical properties.

Melting point: 215-216°C NMR spectrum (δppm, DMSO-d6)'1.
33 (3) (, t, J = 7 Hz), 4.38 (2B, q
.

J=7Hz), 6.89(IH, dt, J=2 and 8
Hz).

7.20 (LH, dt, J-8 and IHz),
7.36 (IH.

dt, J-7 and 8Hz), 7.47 (IH, dt,
J = 12 and 2 Hz), 8.43 (IH, s), 9
．． 13 (IH.

br,! *11.13 (IH+br-m).

Reference Example 24 According to Reference Example 1, ethyl 2-aminothiazol-4-ylglyoxylate 511 2,4-difluorophenyl isocyanate 5.8F, and dimethylformamide'
The target compound in the form of a white powder produced from 30ml has the following physical properties.

Melting point +245-263℃ (decomposition) NMR spectrum (δppm, DMSO-d6): 1
．． 33 (3H, t, J = 7Hz), 4.38 (2H, q
.

J = 7Hz), 7.05-7.15 (IH, m)
, 7.35 (IH, ddd, J=11.9. and 3
Hz), 8.00 (IH, dt, y = 6 and 9 Hz), 8.42 (IH, a).

8.79 (IH, br, s), 11.22 (IH, br
, s).

Reference Example 25 According to Reference Example 1, ethyl 2-aminothiazol-4-ylglyoxylate 5y1 isocyanate 4-fluoro-
3-Nitrophenyl 5.51iS: h-dimethylformamide 30! The target compound in the form of a yellow powder prepared from nl has the following physical properties.

Melting point: 230-240°C (decomposed) NMR, t, vector (δp p m lDMSO-
d b ): 1.33 (3H, t, J=7Hz), 4
．． 38 (2H, (1.

J=7Hz) *7-56 (IH, dd, J
-11 and 9 Hz).

7.76-7.85 (IH, m), 8.42 (IH, d
d, J-6 and 3 Hz), 8.46 (1, H, s).

9-40 (I He b r -8 + υ by adding heavy water
(disappeared), 11.42 (IH, br, s, disappeared by addition of heavy water).

Reference Example 26 2M trimethylamine-benzene solution 10rnl, ethyl 2-chlorothiazol-4-ylglyoxylate 1.3
g, and tetrahydrofuran 5- at room temperature.
I stirred the time. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water and drying over anhydrous magnesium sulfate, the interrogation solvent was distilled off under reduced pressure. The obtained residue was chromatographed with silica powder; benzene:ethyl acetate=9:1. ) to obtain the target compound in the form of a pale yellow oil.

NMR spectrum (δppm, CDCt, ): 1
．． 40 (3H, t, J=7Hz), 2.16 (6H, s
).

4.41(2)(, q-J=7Hz), 7.83(LH
,s).

Reference Example 27 According to Reference Example 1, ethyl 2-aminothiazol-4-ylglyoxylate 4.3/, incyanic acid 3.4.5
-) The target compound in the form of a yellow powder prepared from 5J1 rimethoxyphenyl and 30rnl dimethylformamide has the following physical properties.

Melting point: 185-186°C NMR spectrum (δppm, DMSO-d6)
: 1.33 (3H, t, J=7Hz), 3.62 (3H
,s).

3.77 (6H, s), 4.37 (2H, q, J=7H
1).

6.82 (2H, s), 8.41 (LH, s)'.

8.88 (IH, br, a, disappeared by addition of heavy water).

10.9-11.3 (IH, br, disappeared by addition of heavy water).

Reference Example 28 Stell According to Reference Example 1, ethyl 2-aminothiazol-4-ylglyoxylate 26.71! , 23 g of 2-chlorophenyl isocyanate, and 30 g of dimethylformamide
The target compound in the form of a white powder produced from 0ml has the following physical properties.

Melting point: 246-248℃ (decomposed) NMR Sue? vector (δppm, DMSO-d6)'1
．． 33 (3H, t, J = 7Hz), 4.38 (2H, q
.

J = 7Hz), 7.13 (IH, d, t,
J = 1.5 and 8 Hz), 7.35 (IH, dt
, J=1.5 and 8Hz).

7.51 (IH, dd, J=8 and 1.5 Hz)
, 8.13 (IH, dd, J=3 and 1.5Hz
), 8.44 (IH.

s), 8.66 (IH, br, s), 1
1.66 (IH, br, s).

Reference Example 29 According to Reference Example 1, ethyl 2-aminothiazol-4-ylglyoxylate 129. Iacyanate p-tolyl 1
The target compound in the form of a yellow powder prepared from (1' and dimethylformamide 801d) has the following physical properties.

Melting point: 210-212°C NMR spectrum (δppm, DMSO-d6): 1
．． 33 (3H, t, J = 7Hz), 2.26 (3H, s
).

4.37 (2H, q, J=7Hz), 7.13 (2H,
d.

J=9Hz), 7.36 (2H,d, J=
9Hz), 8.40(IH,s), 8.79(I
H, br, s), 10.97 (IH.

br, s).

Reference Example 30 According to Reference Example 1, ethyl 2-aminothiazol-4-ylglyoxyfurate 5II, 2,6-xylyl incyanate 5.5, 9. The target compound in the form of a pale yellow powder prepared from dimethylformamide 3Qm has the following physical properties.

Melting point: 172-174°C NMR spectrum (δppm, DMSO-d6): 1
．． 33 (3H, t, J-7Hz), 2.19 (6H, s
).

4.37 (2H,q, J=7Hz), 7.10 (3H
,s).

8.09 (IH, br, s), 8.35 (IH, i),
11.21 (IHebr-m).

Reference Example 31 According to Stell Reference Example 1, 4.88 g of ethyl 2-aminothiazol-4-ylglyoxylate, 4-nitrophenyl isocyanate 5I, and dimethylformamide 3Q+a
The target compound in the form of a pale yellow powder produced from / has the following physical properties.

Melting point: 243-265°C (decomposition) NMR spectrum (δppm, DMSO-d6): 1.
33 (3H,t, J=7Hz), 4.38
(2H, q.

J=7Hz), 7.75 (2H,d, J=
9Hz), 8.23 (2H, d, J = 9Hz
), 8.47(LH,s), 9°61(IH,
br, s), 11.33 (IH, br, s).

Reference Example 32 Ureido Thiazol-4-ylglyoxyl Reference Example 1
Ethyl 2-aminothiazol-4-ylgerioxylate 4.281. 2-trifluoromethylphenyl isocyanate 511 and dimethylformamide 40
The target compound in the form of a white powder produced from 11LI has the following physical properties.

Melting point: about 260°C (decomposition) NMR spectrum (δppm, DMSO-d6): 1.
33 (3H, t, J=7Hz), 4.37 (2H, q.

J=7Hz), 7.38(IH, br, t, J
=8Hz).

7.69-7.75 (2H, nd), 7.94 (IH,
br, d.

J-8Hz), 8.41 (LH, br, s), 8.42
(IH.

’) + 11-65 (IH*br*s).

Reference Example 33 According to Reference Example 1, ethyl 2-aminothiazol-4-ylglyoxylate 4.281. The target compound in the form of a pale yellow powder prepared from 511 ml of 4-trifluoromethylphenyl isocyanate and 40 ml of dimethylformamide has the following physical properties.

Melting point: 240-245°C (decomposition) NMR spectrum (δppm, DMSO-d6): 1
．． 33 (3H, t, J = 7Hz) * 4.38 (2H, q
.

J=7Hz), 7.69 and 7.70(4)(, A2
B2 type.

J=10Hz), 8.45(IH,s), 9.31(I
H.

br-m) pH, 20 (fHobr-a).

Reference Example 34 According to Reference Example 13, ethyl 2-aminothiazol-4-ylglyoxylate 511 sobuenylcarpamoyl chloride 71. The desired compound as a brown oil prepared from triethylamine 30R1° and trimethylformamide 20m has the following physical properties.

NMR, x, d vector (δppm, CDC65) ”1
．． 38 (3H, t, J=e7Hz), 4.39 (2H,
q.

, y-=tHx), 7.2-7.5 (IOH, m), 8
．． 27 (IH, s).

Reference Example 35 According to Reference Example 1, 10 g of ethyl 2-aminothiazol-4-ylglyoxylate, 7 g of methyl isocyanate,
The target compound, which is a pale yellow powder produced from 200 ml of ethyl acetate, has the following physical properties.

Melting point: 210-213°C NMR spectral (δppm, DMso-d6): 1.
32 (3H, t, J = 7) (z), 2.71
(3)(,d.

J = 4Hz), 4.37 (2H, q, J = 7Hz), 6
．． 41 (IH, br, q, J=4Hz, disappeared by addition of heavy water).

8.31 (IH-→lt1.os (iHlbr, I, disappeared by addition of heavy water).

Reference Example 36 According to Reference Example IK, ethyl 2-aminothiazol-4-ylglyoxylate 4.71. Benzyl isocyanate 4
．． The target compound in the form of a yellow powder prepared from 5 g and 30 M of trimethylformamide has the following physical properties.

Melting point: approx. 218°C (decomposed) NMR spectrum k (Jppm, DMSO-d6):
1.32 (3H, t, J=7Hz) e4.36 (2H-
q.

J=7Hz), 4.37 (2H, m), 7.0
3 (IH, br.

t, J=6Hz), 7.2-7.4 (5H, m), 8.
33 (IH.

s), 11.08 (IH, br, s, i disappeared by addition of water).

Reference Example 37 According to Reference Example 1, 5 g of ethyl 2-aminothiazol-4-ylglyoxylate, 4.7 J of cyclohexyl isocyanate, and 30. The target compound in the form of a yellow powder prepared from d has the following physical properties.

Melting point: 212-215°C NMR spectral (δppm, DMSO-d6):
1.1-1.4 (5H, nd), 1.32 (3H, t
, J-=7Hz).

1.5-1.6(IH,m)el, 6-1.75(2H
+m) el, 75-1.9 (2H, m), 3.45-3
．． 6 (LH, m).

4.35 (2H, q, J=7Hz) e6.44 (IH
*br-d.

J=8Hz), 8.31(IH,s), 10.64
(IH.

br-s).

Reference Example 38 Carbunyldiimidazole 25,9,2-aminothiazol-4-ylglyoxylate ethyl 30.87,!
A mixture of 730 Qml of Tetrahydro7 and I' was stirred at room temperature for 1 day. After completion of the reaction, the precipitated crystals were collected in a furnace and washed with ethyl acetate to obtain crude ethyl 2-(1-imidazolylcarbonylamino)thiazol-4-ylglyoxylate. Then the intermediate 7.92 N
, 2, 4. A mixture of 5 g of rottrifluoroaniline and 100 +++j of dimethylformamide was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and ethyl acetate was added.

Separate insoluble matter from 05+, rO, and silica dalkacum r1
The mixture was subjected to mudgraphy (eluent; hexane:ethyl acetate:acetic acid=8:2:1 to 6:2:1) to obtain the target compound in the form of a white powder. The target compound has the following physical properties.

Melting point: 242-248°C (decomposed) NMR spectrum (δppm, DMSO-d6): 1
．． 32 (31■, t, J = 7Hz), 4.
37 (2H.

q, J = 7 Hz), 7.31 (2H, dd, J = 9 and 8 Hz), 8.41 (LH, s).

8.42 (IH, s, i disappeared by adding water) 11.60
(IH, br, s, disappeared by addition of heavy water).

Reference example 39 2-diethylaminothiazole-4-aldehyde According to Reference Example 26, diethylamine 2.3! i.

Ethyl 2-chlorothiazole-4-carboxylate 411
Triethylamine 4.21! , and dimethylformamide 15! From this, ethyl 2-diethylaminothiazole-4-carboxylate was obtained as a pale yellow oil.

NMR spectral (δppm, CDCt3): L24
(6Hlt, J=7Hz), 1.37(3)(,t,
J=7Hz), 3.53 (4H,q, J=7Hz)
, 4.34 (2H, +1, J=7Hz).

7.36 (LH, s). Then, according to Reference Example J5, the ethyl ester 1.9. Colorless prismatic 2-diethylaminothiazole-4- was obtained from P, 0.31 g of lithium aluminum hydride, and 40 ml of tetrahydrofuran.
Ilmethanol was obtained. Melting point: 67-69°C. Then,
The methanol compound 1.3.9. ) IJ ethylamine 2.1
g, and dimethyl sulfoxide 1Qrnl, sulfur trioxide bilino/'J/plex 3.3
A dimethyl sulfoxide (lQ+++t) solution of y was added dropwise while stirring at room temperature. After stirring at the same temperature for 30 minutes, the reaction mixture was poured into water and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica dull column chromatography [eluent: penze/:ethyl acetate = 5:1] to obtain the target compound as a pale brown oil.

NMR spectrum (δp p m -CD Ct 5)
:1.26 (6H*t-J-7Hz) e
3,54 (4H# q - J = 7Hz), 7゜39 (
IH,s), 9.74 (IH,m).

Reference Example 40 According to Reference Example 1, ethyl 2-aminothiazol-4-ylglyoxylate 15I, 2-fluorophenyl isothiocyanate 171. The target compound in the form of a pale yellow powder prepared from hexamethylphosphoric acid triamide 30d has the following physical properties.

Melting point: 192-193°C NMR spectral (δppm, DMSO-d6): 1.
32 (3H, t, J=7Hz), 4.37 (2H, q.

J=7Hz), 7.2-7.35 (3H, m), 7.7
9 (IH.

t t J = 8 )lx ) -8-39(
I H#') elo, 12(11(, br
, s, disappeared by addition of heavy water).

12.45 (IH, br, m, heavy water addition K j, D
disappearance).

Reference Example 41 2-3-4-Fluorophenyl Thiouridophthiazol-4-ylglyoxylic Acid Process According to Reference Example 1, 5 g of ethyl 2-aminothiazol-4-ylglyoxylate, 4.0 g of 4-fluorophenyl isothiocyanate. 6
The target compound in the form of a pale yellow powder prepared from 100 g and trimethyl sulfoxide has the following physical properties.

Melting point 2 170-172°C NMR spectral (δppro, DMSO-d6):
1.32 (3H, t, J=7Hz), 4.37 (2H,
q.

J==7Hz), 7.23 (2H,t, J
=9Hz), 7.5-7.8 (2H, m), 8.
37 (IH, s), 10.34 (IH.

br, a), 11.9-12.4 (IH, br,).

Reference Example 42 2-anilinothiazo-4-cargenic acid ethyl ester phenylthiourine 8.61 ethyl bromopyruvate 10
A mixture of y1 and 100H of ethanol was heated under reflux for 3 hours. The reaction solution was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. After drying the extract with anhydrous sulfuric acid (IJ), the solvent was distilled off and the obtained crystals were washed with benzene. Then, recrystallization from ethanol gave the target compound in the form of pale yellow prisms.

Melting point: ], 40.5-142°C NMR spectrum (δppm, acetate/-d6): 1.
33 (3He t = J = 7 Hz) + 4
-29 (2H-q -J=7Hz), 6.98 (IH
, t, J=8Hz), 7.32(2H,t, J=8Hz
), 7.60 (IH, s), 7.72 (2H, d, J=
8Hz), 9.33 (IH, br, s).

Reference Example 43 2-anilinothiazol-4-ylmethanol Reference Example 1
5, ethyl 2-anilinothiazole-4-carboxylate 8.511. The target compound in the form of colorless scales prepared from lithium aluminum hydride 211 and tetrahydrofuran 150d has the following physical properties.

Melting point: 115-118°C NMR spectrum (δppmt acetone-d6): 3.
8-4.4 (IH, br, ), 4.58 (2) I, l)
.

6.59 (IH, 11), 6.94 (IH, t,
J=8Hz).

7, 30 (2H = t, J = 8 Hz) *
7-68 (2H, d.

J=8Hz), 8.8-9.4 (IH, br,
).

Reference Example 44 2-anilinothiazol-4-aldehyde 8.3 g of 2-anilinothiazol-4-ylmethanol, 1 G of triethylamine, 5 rnl, and 1 dimethyl sulfoxide
A dimethyl sulfoxide solution (1201 nl) of sulfur trioxide/pyridine complex 201 was added to the mixed solution of 20d.
) was added dropwise. After stirring at room temperature for 10 minutes, the mixture was poured into water and extracted with ethyl acetate. The extract was washed with acetic acid aqueous solution, table water, hydrogen carbonate, IJum aqueous solution, and dried over anhydrous sulfuric acid. The solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from 7 tons of benzene to give the target compound as a brown powder.

Melting point: 145-147°C NMR spectral (δppm t acetone-d6) near, 03 (IH, to, J=8Hz), 7.36 (2H,
t.

J = 8Hz), 7.77 (2H,d, J
=8Hz).

7.83 (IH, ■), 9.2-9.6 (IH, br,
).

9.80 (IH, s).

Reference Example 45 According to Reference Example 42, O-)! J Ruthiourea 2011 Ethyl Bromopyruvate 23I, and Ethanol 200
The pale yellow prismatic target compound prepared from Gogo has the following physical properties.

Melting point: 130-132.5°C NMR spectrum (δPI)me acetone-d6): 1
．． 30 (3H, t, J-7Ht), 2.34 (3
H.

s), 4.24 (2H, q, J=7)Iz
), 7.0-7.4 (3H, rn), 7.58 (IH,
s), 7.89 (IH.

d, J=8Hz), 8.77 (IH, br, g).

Reference Example 46 2-(o-)luidino)thiazol-4-ylmethanol According to Reference Example 15, ethyl 2-(o-)luidino)thiazole-4-carboxylate ION, lithium aluminum hydride 2.9 #, and Tetrahydro 7 Run 200
The target compound in the form of a brown oil produced from 1R1 has the following physical properties.

NMR spectrum (δpPm#acetone-d6): 2.
34. (3H, s), 4.56 (2H, s), 6.57
(IH.

s), 6.9-7.4 (3H, +n), 7.92 (IH
, d, J=8Hz).

Reference Example 47 2-(〇-Toluidino)thiazole-4-aldehyde According to Reference Example 44, 2-(o-)luidino)thiazol-4-ylmethanol-#6.121, sulfur trioxide.
Pyridine complex 13.2g, triethyl aiy
The light brown prismatic target compound prepared from 12 ml and 210 ml of dimethyl sulfoxide has the following physical properties.

Melting point: 104-111°C NMR spectrum (δpl+ml acetate/-d6): 2
．． 36 (3H, m), 6.95-7.4 (3H,
m).

7.76 (IH, *), 7.97 (IH, d, J
=8Hz).

8.5-8.9 (IH, br, ), 9.78 (IH, s
).

Reference example 48 2-anilinothiazole-4-aldehyde 3.521
A mixture of 6.5 g of (ethoxycarbonylmethylene)11 phenylphosfluoran and 35 ml of tetrahydro7 was heated at 60° C. for 2 hours.

The reaction solution was poured into water, extracted with benzene, and dried over anhydrous sodium sulfate. The oil obtained by distilling off the solvent was subjected to silica column chromatography [eluent: benzene:ethyl acetate = 9:1] to obtain the target compound in the form of yellow crystals.

Melting point: 113-118°C NMR, x, vector (δppm, DMSO-d4)
: E body vagina equivalent 1.27 (3H, t, J = 7Hz).

4.19 (2H, q, Jw7Hz).

6.46 (IH, d, J=16Hz).

6.97 (IH, t, J=7Hz).

7.35 (2H, t, J = 7Hz).

7.40 (IH, s).

7.46 (IH, d, J=16Hz).

7.69 (2H, d, J=7Hz).

10.33 (LH, br, s).

2 bodies corresponding 1.18 (3H, t, J = 7Hz), 4.17
(2H, q, J = 7Hz).

5.97 (IH, d, J=13Hz).

6.70 (IH, d, J=13Hz).

6.9-6.96 (IH, n.d.).

7.28 (2H, t, J = 7Hz).

7.44 (IH, s).

7.61 (2H, d, J-7Hz).

10.17 (IH, br, i).

Reference Example 49 4J of the crude ethyl 3-(2-a=IJnotiazol-4-yl)acrylate produced in Reference Example 48 was dissolved in 40% tetrahydrochloride, and IM hydrogenated neuisoptylalumina mohexane was added at -60°C. Solution 58d was added dropwise.

After stirring at −50° C. for 2 hours, excess reducing reagent was decomposed with 90-timethanol water. The mixture was then neutralized with 3N hydrochloric acid and extracted with ethyl acetate. After drying the extract over anhydrous sulfuric acid (IJum), the solvent was distilled off to obtain crude 3-(2-anilinothiazol-4-yl)allyl alcohol. Next, the alcohol compound 2.61 was dissolved in 201 Ll of dimethyl sulfoxide without isolation and purification, and triethylamine 3.4. ? i added. Furthermore, a solution of 5.3 g of sulfur trioxide/pyricine complex in trimethyl sulfoxide (lQytj) was added dropwise at room temperature. After stirring at the same temperature for 30 minutes, the reaction solution was poured into water, acidified with 3N hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off.The resulting residue was subjected to silica column chromatography [eluent: benzene/:ethyl acetate = 10:1].
1 to obtain the target compound in the form of pale yellow crystals.

Melting point: 142-143°C NMR spectrum (δppm, DMso-d6): 6
．． 67 (IH, dd, J=15 and 8 Hz).

6.98 (IH,t, J=8Hz), 7.35
(2H,t.

Jm8Hz), 7.53 (IH, s), 7.54 (IH
,d.

J=15Hz), 7.69 (2H,d, J=8H
z), 9.67 (IH, d, J-8Hz).

10.38 (IH, br, @, disappeared by addition of heavy water).

Reference Example 50 Ethyl 2-[3-(4-7''romophenyl)ureidophthiazol-4-ylglyoxylate 51 was suspended in 60 ml of tetrahydrofuran, and sodium borohydride 2.
4I! added. Next, methanol 201/ml was added dropwise over 1 hour while the reaction solution was refluxed, and then heated under reflux for an additional 1 hour. The reaction mixture was poured into water and neutralized with 3N hydrochloric acid. After precipitation, the crystals are separated, washed with water, and dried to obtain crude 1-[2-(3-(4-promophenylncleide)].
Thiazol-4-yl]ethane-1,2-diol was obtained. Melting point: 182-187°C (decomposed). Next, 4.31 of this nol was suspended in 200H of tetrahydrofuran, and under water cooling, an aqueous solution of 5.11 sodium metaperiodate (301
R1) was added dropwise. After stirring at the same temperature for 1 hour, the mixture was further stirred at room temperature for 1 hour.

The reaction mixture was poured into ice water, and the precipitated crystals were collected, washed with water, and dried to obtain the target compound in the form of a white powder.

Decomposition point: about 250°C NMR spectrum (δppm, DMSO-d6)
'7.47 and 7.50 (4H, A2B2 type,
J=9H1).

8.24 (IH, s).

9.16 (IH, br, s) 9.75 (IH, s).

10.93 (IH, br, s) q Reference side 51 -le According to Reference Example 48, 1 g of 2-(3-(4-bromophenyl)ureidophthiazole-4-aldehyde, ethoxycarbonylmethylenetriphenylphosph) Oran 1.
2# and tetrahydro 7 run 20WLt to obtain crude ethyl 3-(2-[3-(4-bromophenyl)ureidophthiazol-4-yl]acrylate. Then, according to Reference Example 49, the ethyl Ester 1.1JF,I
M hydrogenated diisobutylalumium hexane solution 14m
The target compound in the form of a white powder obtained from , and tetrahydrofuran 301j has the following physical properties.

Decomposition point: about 220°C NMR spectrum (δppm, DMSO-d4)
:4.10 (2H, dd, J-5 and 3Hz),
By adding heavy water') 4-10 (2Ht d F J-
3Hz) 4.84 (IHtt, J=5Hz, disappeared by addition of heavy water).

6, 40 (IH, dd, J-16 and 3Hz), 6
．． 47 (IH, d, J=16Hz), 6.94 (
IH, s), 7.46 and 7.48 (4H, 2B2 type, J I
:29 Hz), 9.1 5 (IH, brl11
Disappeared by adding heavy water, 10.66 (IH, br,
s, disappeared by addition of heavy water).

Reference Example 52 4-yl]allylic alcohol 0.84. F, sulfur trioxide-pyridine complex 1.131 IJ ethylamine 0.72Ii, and dimethyl sulfoxide 2
The target compound in the form of a light brown powder obtained from 017 has the following physical properties.

Decomposition point: about 260°C NMR spectrum (δppm, DMSO-d6)
:6.61 (IH, dd, J-15 and 8l-
Is), 7, 4-7.55 (4H, m), 7, 61 (IH, d, J=15Hz).

7.73 (IH, s).

9.13 (IH, song, disappeared by addition of heavy water), 9.6
6 (IH, d, J-8Hz, 10.6
-11.2 (IH, br, disappeared by addition of heavy water).

Reference Example 53 According to Lugahid Reference Example 49, (E)-3″″(2-C3-
2-aminothiazol-4-ylglyoxyl (4-7
"Romophenyl) ureidophthiazole-ethyl acid 1.
01F, [bis(4-fluoro7enyl)methyl]1.
48 g, triethylamine 0.751, trimethylformamide tertiary and ground potassium iodide 0.355'
The mixture was stirred at 85-90°C for 7.5 hours. After cooling the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with ethyl acetate. After drying the extract over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica column chromatography (eluent: benzene:ethyl acetate = 10:1).

The obtained crude product was recrystallized from benzene to obtain the target compound in the form of yellow crystals.

Melting point: 122-124℃ ■Spectrum (δppplL, DMSO-d4):
1, 25 (3H,t, J=7Hz), 4.29
(2H,q, J~7Hz), 6.05 (IH
, d, J-8H1), 7.12-7.21 (4H, r
n), 7.33-7.42 (4H, m), 8.01 (IH, s), 8-92 (IHId + J-8Hz).

Reference Example 54 According to Reference Example 53, ethyl 2-aminothiazol-4-ylglyoxylate 10.1i diphenylmethyl chloride 10.01 triethylamine 10ml. Dimethylformamide 10117 and potassium iodide 1. The target compound in the form of a yellow powder prepared from Oy has the following physical properties.

Melting point +82-85°C Shimansu hector (δppm, heavy chloroform): 1.3
8 (3H, t, J=7Hz), 4.38 (2H,
q, J=7Hz), 5, 64 (IH* d, J
-6Hz), 6,04 (IH, br, d, J=
6Hz), 7, 3-7.4 (10) (, m), 7.86 (IH, s).

Reference Example 55 According to Reference Example 50, ethyl phthiazol-4-ylglyoxylate was added to 2-nophenylmethyla 1.6811.
Sodium borohydride 0.35.9. methanol 3d
The target compound in the form of a white powder prepared from Tetrahydro7ran8d has the following physical properties.

Softening point: 143-148°C NMR spectrum (Jppm, M chloroform) ~
3.73 (IH, dd, J=11 and 4 Hz
).

3.81 (1)(, dd, J=11 and 4Hz
), 3.8-4.3 (2H, br, disappeared by addition of heavy water), 4.58 (IH, t, J = 4Hz), 5.5
7 (IH, a), 6.33 (IH, s), 7, 2-7.35 (IOH, m).

Reference Example 56 2-Sophenylmethylaminothiazole-4-aldehyde According to Reference Example 50, 1-(2-diphenylaminothiazol-4-yl)ethane-1,2-fol 2.11
JF, sodium metaperiodate 3.15I, water 4Qd
The desired compound in the form of a pale brown foamy powder obtained using methanol 20d has the following physical properties.

NMR spectrum (δppm, deuterochloroform): 5.
68 (11, s), 7.3-7.4 (IIH, nd), 9.65 (IH
, Hatake), mass spectrum # (m/e): 294 (M”)
.

Reference Example 57 According to Reference Example 42, 4-fluorophenylthiourea 1
21. ';I The pale yellow prismatic target compound prepared from 14.8 ethyl lomobilubate and 120 itl of ethanol has the following physical properties.

Melting point: 133-136°C NMR spectrum (δppm, acetone-d6): 1.
34 (3H, t, J=7Hz), 4, 31 (2H
, q', J=7Hz), 7, 10 (2H,t,
J=9Hz), 7.65 (IH, s), 7.78 (2H, dd, J-9 and 5Hz), 9
．． 2-9.6 (IH,br).

Reference Example 58 According to Reference Example 50, 2-(4-fluoroanilino)thiazole-4-power/l/l/pontyl 12.04I, sodium borohydride 6J, anhydrous tetrahydrofuran 1
20m7. The colorless prismatic target compound prepared from 70 ml of anhydrous methanol has the following physical properties: Melting point: 156-161°C NMR spectrum (δPPml acetone-dd): 4
, 05 (IH, br - L e J 5Hz), 4.
56 (2H, br, d, J-5Hz), 6.60 (
IH,l), 7,07 (2H,t, J-9Hz), 7.74
(2H, dd, J==9 and 5Hz), 8.9-9
．． 4 (IH, br, ).

Reference Example 59 According to Reference Example 44, 3.03 g of 2-(4-fluoroanilino)thiazol-4-ylmethanol, 8.5 g of sulfur trioxide/gylysine conglenox, 7.5 ml of triethylamine, and trimethyl sulfoxide 140
The light brown prismatic target compound prepared from d has the following physical properties.

Melting point: 152-155°C NMR spectrum (δppm, acetone-d6) near,
12 (2H,t, J=9Hz), 7.7-7.
9 (2H, nd), 7.86 (1) (, i), 9.3-9.7 (IH, br,), 9.83 (IH, s).

Reference Example 60 According to Reference Example 42, 4-methoxyphenylthiourea 1
0.03g, ethyl bromopyruvate 10g.

The pale yellow grism-like target compound produced from 100 m of ethanol has the following physical properties.

Melting point: 119-120.5°C NMR spectra (appm, 7 sets y-dd): 1
, 33 (3H,t, J=7Hz).

3.80 (3H, l).

4, 29 (2H, q, J=7Hz), 6, 94
(2H, d, J=9Hz).

7.55-7.7 (3H, nd), 9.13 (IH, br, s).

Reference Example 61 2-(p-anisidine)thiazol-4-ylmethanol According to Reference Example 15, ethyl 2-(p-anisidine)thiazole-4-cargenate 5.0. ! ? , 1.5 g of lithium aluminum hydride, and anhydrous tetrahedron. The target compound in the form of a slightly red powder produced from 7 runs at 1 oom has the following physical properties.

Melting point: 104-105°C NMR spectrum (δ11m, acetone-dd): 3.
80 (3H'+s), 3.8-4.3 (IH, br,).

4, 56 (2H, br, s).

6.53 (IH, s), 6°91 (2H, d, J=9Hz).

7, 59 (2H, d, J=9Hz).

8, 7-9.1 (IH, br,).

Reference Example 62 Dehyde Produced according to Reference Example 44 from 3 g of 2-(p-anisidine)thiazol-4-ylmethanol, 6.1 g of sulfur trioxide/pyridine complex, 5.3 J of triethylamine, and 9Qd of trimethyl sulfoxide. The target compound in the form of light brown crystals has the following physical properties.

Melting point: 108-110℃ NMR spectrum (δ, acetone-dd) 2 pm 3.80 (3H, s), f5.9 4 (2H, d, J = 9Hz).

7, 6 5 (2H, d, J = 9Hz), 7
．． 76 (IH, s), 9.0- 9.4 (IH, br, ), 9.79 (
IH,s).

Example 63 According to Reference Example 42, 3-trifluoromethylphenylthiourine $10.02. ji! , 88 g of ethyl bromopyruvate, and ethanol 10017. The target compound in the form of pale yellow crystals has the following physical properties.

Melting point: 124.5-127°C NMR spectrum (δppm'acetone-d6): 1,
36 (3H, t, J = 7Hz), 4, 31
(21(,q, J=7Hz), 7.25-7.7
(2H, nd), 7.75 (IH, i), 7,97 (I H, br, d, J=8Hz)
, 8.3 5 (IH, br, s), 9.6- 9.9 (IH, br, ).

Reference Example 64 According to Reference Example 15, ethyl 2-(3-)lifluoromethylanilino)thiazole-4-cargenate 3.92p
, water-accumulated lithium aluminum II.

The desired compound in the form of a colorless powder prepared with 80 ml of anhydrous tetrahydrofuran has the following physical properties.

Melting point: 126.5-128°C NMR spectral (δI) Pml acetone-d6): 4
, 16 (IH, br, t, J=5Hz).

4, 61 (2H, br, d, J=5Hz),
a70 (LH, S), 7, 26 (IH, br, d, J=8Hz),
7, 53 (IH, t, J=8Hz), 7, 99
(IH, br, d, J = 8Hz), 8.1
7 (IH, br, s).

9.1-9.9 (IH, br,).

Reference Example 65 Reference Example 66 According to Reference Example 44, 2-(3-trifluoromethylanilino)thiazol-4-ylmethanol 2.6FM'
, 4.8 g of sulfur trioxide/pyridine complex, 4.21 g of triethylamine, sulfur and dimethyl sulfoxide 9Qx/.

Melting point: 151-153°C Source spectrum (L3ppm, acetone-d6) Near,
34 (IH, br, d, J-8Hz).

7.58 (IH, t, J=8Hz).

7, 94 (IH, s).

8, 06 (IH, br, d, J=8HX).

8.26 (J, H, br, @).

9.6-10.0 (IH, br,).

9-87 (IH,s)s According to Reference Example 42, ethylthiourea 10. li+.

Ethyl bromopyruvate 20y, and ethanol I
The target compound in the form of a pale yellow powder prepared from 00d has the following physical properties: Melting point: 93-95°C ■Spectrum (δppm, DMSO-d4): 1.
17 (3H, t, J=7Hz).

1.28 (3I(,t, J=7Hz).

3.1-3.4 (2H, nd).

4.23 (2H, q, J=7Hz).

7.51 (IH, glue).

7, 76 (IH, br, t, J = 5 Hz) s Reference side 67-le Based on Reference Example 17, 2-ethylaminothiazole-4
-Ethyl carboxylate 109. Sodium borohydride 3
．． 8.9. The yellow oily target compound produced from 70m of methanol and 1501d of tetrahydrofuran has the following physical properties.

NMR spectral (δppm + CDC65): 1.
30 (3H, t, J = 7Hz).

3.24 (2H, q, J=7Hz).

4.51 (2H, s) + 6.2-6.5 (3H, nd, 6.
34 (IH, s)).

Reference Example 68 According to Reference Example 44, 2-ethylaminothiazole-4
-ylmethanol 4.4#, sulfur trioxide/pyrinone complex 13.3g, 17-ethylamine 8.4,
9. The light brown prismatic target compound produced from 60 ytl of dimethyl sulfoxide has the following physical properties.

Melting point: 84-85℃ Consistent spectrum (δppm, CDCLg) '1
, 32 (3H,t, J=7Hz).

3.2-3.6 (2H, rn).

6.3-6.7 (IH, br,).

7.40 (IH, @).

9.70 (IH, s).

Reference Example 69 According to Reference Example 42, 20.9 g of allylthiourea, 37 g of ethyl bromopyruvate, and 200 m of ethanol were added.
The target compound in the form of a pale yellow powder prepared from t has the following physical properties.

Melting point: 85-86℃ Audio spectrum (δppm, DMSO-d6):
1.26 (3H, t, J-7HS).

3.84-3.90 (2H, m).

4.21 (2H, q, J = 7Hz).

5.13 (IH, ddd, J=10.3. and 1.5 Hz).

5.24 (IH, ddd, J=17.3. and 1.5
Hz).

5.8-5.97 (IH, m)* 7.51 (IH, s).

7, 9 6 (L H, br, t, J-5Hz
L reference side 70 2-allylaminothiazole-4 according to Reference Example 15
-Ethyl Carzenate 101 Hydrogenation! J + Umu Aluminum 2.71. The target compound, which has the shape of light brown needles and was produced from tetrahydrofuran 15QiA', has the following physical properties.

Melting point: 74-75°C NMR (δppm, CDC45): 3.
1-3.9 (IH, br, ).

3, 86 (2H, br, a, J=5Hz).

4.51 (2H, a).

5.1-5.45 (2H, m).

5.5-6.2 (2H*m).

6.37 (IH-→.

Reference Example 71 According to Reference Example 44, 2-allylaminothiazole-4
-ylmethanol 111, sulfur trioxide/pyrinone complex 31 g, ) ethylamine 20 g, and dimethyl sulfoxide 100. ...The light brown needle-shaped target compound prepared from 2 has the following physical properties.

Melting point: 106-107°C NMR spectrum (δppm, CDC1x, )
:4.05 (2H, br, s).

5.1-5.5 (2H, rr+).

5.7-6.15 (IH, m).

7.3-7.7 (IH, br,).

7, 40 (IH, s).

9.6c+(xH+s)e Reference Example 72 According to Reference Example 42, cyclohexylthiourea 17, V
, ethyl bromopyruvate 22y, and ethanol 2
The yellow oily target compound produced from 00ml has the following physical properties.

NMR, x, - (cuttle (δppm, CT)CJ!
, 5): 1.0-2.3 (10H, m).

1.37 (3H, t, J=7Hz).

3.0-3.5 (IH, tn).

4.34 (2) T, q, J = 7H t).

5.1-5.6 (IH, m)1 7.41 (IH, s).

Reference Example 73 According to Reference Example 15, ethyl 2-cyclohexylaminothiazole-4-carzenate 19II, lithium aluminum hydride 4.211, and tetrahydrofuran 2
The pale yellow needle-like target compound prepared from 504 has the following physical properties.

Melting point: 118-120℃ Instant temperature (δppm, CDCt,): 1.0-
2.2 (IOH, rn).

2.9-3.5 (2H, nd).

4-50 (2Hls).

5.0-5.5 (I H, br,) +6.33 (I
H,s).

Reference Example 74 Rudehyde According to Reference Example 44, 2-cyclohexylaminothiazol-4-ylmethanol 101. Sulfur trioxide/pyridine complex 22.4F, triethylamine 14
．． 3. The target compound in the form of a light brown oil produced from F and trimethyl sulfoxide 1001j has the following physical properties.

NMR spectroscopy (δppm, CDCl2): 1.
0-2.2 (10H, m).

3.2-3.8 (IH, m).

5,! -5,4 (IH, m).

7.40 (IH, @).

9.72 (IH, s).

Reference Example 75 According to Reference Example 42, 1,1-diphenylthiourea 20
I, ethyl bromopyruvate 191 and ethanol 2
From 00-! ! The remaining orange oily target compound has the following physical properties.

NMR spectrum (δppm, CDCts): 1.
36 (3H, t, J=7Hz).

4.35 (2H, q, J=7Hz) +7.1-
7.5 (IOH, m).

7.54 (IH, s).

Reference Example 76 Tanol A pale yellow prismatic target compound produced from ethyl 2-diphenylaminothiazole-4-cargenate 271 lithium aluminum hydride 4.7 g and tetrahydrofuran 4001d according to Reference Example 15 has the following physical properties. .

Melting point: 136-i38°C NMR spectrum (δppm, CDCt5): 2.
33 (LH,br,t,J=6)1z).

4.56 (2H, br, d, J=6Hz).

6.52 (IH, s).

7.1-7.5 (IOH, rn).

Reference Example 77 According to Reference Example 44, 10 g of 2-diphenylaminothiazol-4-ylmethanol, 16.8 g of sulfur trioxide/pyridine complex. F, triethylamine 10.
The pale yellow prismatic target compound prepared from 71 and dimethyl sulfoxide 100d has the following physical properties.

Melting point: 160-161°C NMR spectrum (δppm, DMSO-d6)
Near, 2-7.6 (IOH, m).

8.06 (IH, s).

9.70 (IH, Karasu).

Reference example 78: Morpholine 1.41 on the μ blade side 26! , 3 g of ethyl 2-chlorothiazole-4-carmenate, 3 F of triethylamine, and 12 ml of dimethylformamide.

Melting point: 84-86°C NMR spectrum (δppm, CDCLB);
1.37 (3H, t, J=7Hz).

3.45-3.6 (4H, m).

3.75-3.9 (4H, m).

4.36 (2H, q, J=7Hz).

7.50 (IH, g).

Reference Example 79 According to Reference Example 15, 2-morpholinothiazole-4-
A white needle-like target compound prepared from 3.7 y of ethyl carboxylate, 0.6.9 y of lithium aluminum hydride, and 50 y of tetrahydrofuran has the following physical properties.

Melting point: 120-121°C NMR, X, -ector (δppm, CDC63):
2.40(II(,t, J=6Hz).

3.35-3.55 (4H, m).

3.7-3.9 (4H, m).

4.59 (2H, d, J=6Hz).

6.47 (IH, s).

Reference Example 80 According to Reference Example 44, 2-morpholinothiazole-4-
Ilmethanol 2.4,9. Sulfur trioxide/pyridine complex 5.711, triethylamine 3.6N,
The pale yellow needle-shaped target compound prepared from dimethyl sulfoxide and dimethyl sulfoxide 3Qrnl has the following physical properties.

Melting point: 107-108°C NMR spectroscopy (δppm, CDC23): 3.4
5-3.65 (4H, m).

3.75-3.9 (4H, m).

7.51 (IHli) * 9°77(1)I, Error).

Reference Example 81 Pi(lysine 2.11i', 2-chlorothiazole-4-
A mixture of ethyl carzenate 41, triethylamine 4.2y, and benzene ZOrLt was heated under reflux for 12 hours, and the reaction mixture was poured into water and extracted with benzene. The extract was washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica column chromatography [eluent: benzene: ethyl acetate = 10:1
1 to obtain the target compound as a pale yellow oil.

Consolidation (δppm l CDC45): 1-36
(3H, t, J = 7 Hz) +1.5-1.
9 (6H, m).

3.3-3.7 (4H, m).

4.35(2)(,q,J==7Hz).

7.1(xH,s).

Reference Example 82 According to Reference Example 15, 2-Biyritzthiazole-4-
3.0 g of ethyl cargenate, lithium aluminum hydride o, sll, and tetrahydrofuran 50111j
The pale yellow prismatic target compound prepared from has the following physical properties.

Melting point: 289-90°C NMR spectrum (δppm, CDCl3): 1
．． 51.9 (6H, m).

2.50 (LH, br) + 3.3-3.6 (4H, m).

4.45-4.65(2H,br,d)+6.37(I
I (, easy).

Reference Example 83 In Reference Example 44, 2-piperidinothiazole-4-
ilmethanol 2.4.9, sulfur trioxide-pyridine complex 5.8.9. Triethylamide 73.7g
, and 30 rnl of trimethyl sulfoxide, the pale orange prismatic target compound has the following physical properties.

Melting point: 68-69°C NMR spectrum (δppm, CDC45): 1
．． 55-1.85 (6H, m).

3.4-3.7 (4H, m).

7-44 (IH, s).

9.75 (LH, s).

Reference example 84 2-thiomorpholin-4-ylthiazole-42,7-
2,75 (4H, m).

3.85-3.9 (4H, m).

4.35 (2H, q, J-7Hz).

7.44 (IH, s).

According to Reference Example 26, thiomorphorin 1.53. P.

Ethyl 2-bromothiazole-4-carboxylate 2.36
g, triethylamine 2.025', and dimethylformamide 4 (It/), the target compound in the form of a pale yellow powder has the following physical properties.

Melting point: 99-100°C NMR spectrum (δppm, CDC1,5):
1.37 (3)1, t, J=7Hz).

Reference Example 85 The target compound in the form of a white powder was produced from 1.5y of ethyl 2-(thiomorpholin-4-yl)thiazole-4-carmenate, 0.261y of lithium aluminum hydride, and 15m of tetrahydrofuran according to Reference Example 15. has the following physical properties.

Melting point: 83-84°C NMR, spectrum (m, □, cpcz,): 2.51
(H(,br, d, J=5Hr, ,')f(
disappears by adding water).

2.68-2.73 (4H, m).

3.8-3.85 (4H, m).

4. 53 (2H, d, J=5Hz, 4.51 (2H.

s)).

6゜4　L　(I　Hlt, J-IHz).

Reference Example 86 According to Reference Example 44, 2-(thiomorpholin-4-yl)thiazol-4-ylmethanol 1,21, sulfur trioxide birinone congresox 2.65y, triethylamine 1.68i and dimethyl sulfoxide 3Qi
The target compound in the form of white powder prepared from u has the following physical properties.

Melting point: 69-71°C NMR spectrum (Jppm, CDCl3): 2
．． 7-2.76 (4H, m).

3.85-3.93 (4H, rn).

7.47 (IH, +s).

9.69 (11, m).

Reference Example 87 According to Reference Example 26, N-methylviperacin 2.5fi
ethyl 12-3'lolothiazole-4-carboxylate 4,
OI, triethylamine 4.2N, and toluene 30
The pale yellow oily target compound prepared from No. 4 has the following physical properties.

NMR spectrum/+ノ (δpprn, CDC43)
: 1.37 (3H, t, J=7H Atsushi).

2.34 (3, fog).

2.51 (4H, br, t, J=6Hz)
.

3.56 (4H, t+r,, L, J-6Hz
).

4.35 (2H, q, J = 7H Atsushi).

7.46 (IH, s).

Reference Example 88 According to Reference Example 15, ethyl 2-(4-methy)v-1-hiherazonyl)thiazo-/I/-4-carpinate 4.
0g, lithium aluminum hydride 0.6. The white grism-like target compound produced from F and tetrahydrofuran 504 has the following physical properties.

Melting point: 103-105°C NMR spectrum (δppm, CDCt,): 2.
26 (3H,s).

2.43 (4H, br, t, J=5Hz)
.

2.6-2.8 (IH, br).

3.41 (4H, br・, t + J = 5 Hz
) *4.47 (2H, 纒).

6.34 (IH, t, J=IHz).

Reference Example 89 According to Reference Example 44, 2-(4-methylbiverazonyl)
The target compound as a light brown oil prepared from 2.4y of thiazol-4-ylmethanol, 5,4y of sulfur trioxide/pyridine complex, 3.4y of triethylamine, and 30d of trimethyl sulfoxide has the following physical properties.

NMR spectrum (δppm, CDCLs)
:2.35 (3H, s).

2.53 (4H, br, t, J=5Hz)
.

3.59 (4H, br, t, J=5Hz).

7.47 (IH, g).

9.70 (LH, s).

Reference Example 90 According to Fuki Example 26, n-octylamine 2.7I, 2
-chlorothiazole-4-force/I/ethyl bonate 4.0
J11 A light yellow oily target compound prepared from triethylamine 4.2.1 and dimethylformamide 15M has the following physical properties.

Traction spectrum (δppm, CDCtρ: 0.7-1.
9 (18H, n.d.).

3.0-3.4 (2H, m).

4.36 (2H, q, J=7Hz).

5.5-6.0 (IH, br,).

7.41 (IH, easy), Reference Example 91 According to Nor Reference Example 15, 2-octylaminothiazole-
1.5y of ethyl 4-carbate, 0.2N of lithium aluminum hydride, and 3Qmi of tetrahydrofuran
The pale yellow oily target compound prepared from has the following physical properties: NMR,', vector (δppm, CDCA3):
0.88 (3H, br, t, J=7Hz).

1.2-1.45 (IOH, m).

1.55-1.75 (2H, m).

3.15-3.3 (2H, m).

4.51 (2H, d, J=IHz).

5.26 (IH, hr, s).

6.34 (IH, s).

Reference Example 92 According to Reference Example 44, 2-octylaminothiazole-
4-ylmethanol 1.31! , sulfur dioxide bilicin complex 2.6I, triethylamine 1.6g
, and trimethyl sulfoxide 20d has the following physical properties.

Melting point: 60-62℃ Absolute spectrum (δppm, CDC4,): 0.7
1.9(15)i,m).

3.1-3.6 (2H, m).

5.9-6.3 (IJ(,br,).

7.41 (IH, g).

9.72 (IH, s).

Reference Example 93 According to Reference Example 42, isopropylthiourea 3.7y,
The target compound 9, which was prepared from ethyl bromopyruvate 7,41 and 50 ml of ethanol, was a pale yellow oil and had the following physical properties.

NMR spectrum (δppm, CDC65): 1.
29 (6H, d, J=7Hz).

1.37 (3H, t, J=7Hz).

3.35-3.85 (1H1m).

4.35 (2H, q, J-7Hz).

5.0-5.7 (IH, br,).

7.42 (IH, +).

Reference Example 94 2-inpropylaminothiazol-4-ylmethanol 2-inpropylaminothiazol-4-ylmethanol According to Reference Example 15, 2-inpropylaminothiazol-4-ylmethanol
6.8 I of ethyl 4-carboxylate, 1.2 F of lithium aluminum hydride, and 10 I of tetrahydrofuran.
The pale yellow oily target compound prepared from 01d has the following physical properties.

Abuse spectrum (δppm, CDCl3): 2.2
7 (6H, d, J=7Hz).

3.4-3.9 (1) I, m).

4.51 (2H, s).

4.8-5.3 (IH, br,).

6.34 (IH, g).

Reference Example 95 2-isopropylaminothiazole-4-aldehyde According to Reference Example 44, 2-isopropylaminothiazol-4-ylmethanol 4.41, sulfur trioxide/pyridine complex 12.2N, triethylamine 7,
The target compound in the form of a light brown oil prepared from 7, F and dimethyl sulfoxide 60d has the following physical properties.

NMR spectrum (δppm, CDC23): 2.
31 (6H, d, J=7Hz).

3.55-4.0 (IH, m).

5.1-5.5 (IH, br,).

7.41 (IH, s).

9.74 (IH, s).

Reference Example 96 According to Reference Example 42, pennorthiourea 5.02y, ethyl bromopyruvate 5.871y. Oyohi ethanol 5
The pale yellow needle-like target compound prepared from 0d has the following physical properties.

Melting point: 132-136°C NMR spectral (δppm, DMSO-d6):
1.27 (3H, t, J=7Hz).

4.22 (2H, q, J=7Hz).

4.47 (2H, d, J=6Hz).

7-1-7.6 (5H*m).

7.53 (IH, s).

8.30 (IH, br, t, J=6Hz).

Reference Example 97 2-Benzylaminothiazol-4-ylmethanol According to Reference Example 15, 2-benzylaminothiazole-4-ylmethanol
Ethyl 4-carboxylate 5.9, lithium aluminum hydride 1.4. The white needle-like target compound prepared from 100d and tetrahydrofuran has the following physical properties.

Melting point: 85-86.5℃)
o-d6): 3.7-4.1 (IH, br,).

4.44 (2H, br, *).

4.54 (2H, br, m).

6.38 (IH, s).

6.9-7.3 (LH, br,).

7.2-7.4 (5H, m).

Reference Example 98 2-Pendylaminothiazole-4-aldehyde Reference Example 44 simply contains 2-pendylaminothiacyi/I/-
4-ylmethanol 1.21J! , Sulfur Trioxide Virison Consolex 2.6L, iJ Ethylamine 3ml
, and dimethyl sulfoxide 30d, the target compound in the form of light brown crystals has the following physical properties.

Melting point: 162-165°C NMR spectrum (δppm+acetone-d6): 4.
44 (2H, br, d, J=5Hz).

7.2-7.5 (5H, m).

7.5-7.9 (IH, br-).

7.65 (IH, s).

9.71 (IH, I).

Reference Example 99 2-(3-benzoylthioureido)thiazole-4-
Ilglyoxyl ethyl 2.0 & Potassium carbonate 2.
A mixture of 3 g, 100 ml of acetone, 100 d of methanol, and 20 mj of water was stirred outside at 60° C. for 50 minutes. The solvent was distilled off under reduced pressure, and ethyl acetate and brine were added to the residue, and the precipitated crystals were collected. In the presence of phosphorus pentoxide,
Drying under reduced pressure gave the crude target compound as a yellow powder.

Melting point: 223-226°C. Violence spectrum (δppm, DMSO-d6) near, 35-7.6 (3H, m).

7.70 (IH, s).

7.92 (2H, br, d, J=7Hz).

9.410.0 (IH, br, ii disappeared by addition of water).

Reference Example 100 Reference Example 26 only contains ethyl 2-bromothiazole-4-carboxylate/I15,! A mixture of 2.28N of cyclopropylamine, and 20% of toluene was heated in a sealed tube at 100-110°C for 16 hours to obtain the target compound as a pale yellow oil having the following physical properties.

High (g) spectrum (δppm, cDct,): 0
．． 5-0.9 (4H, m).

1.37 (3H, t, J = 7Hz).

2.45-2.75 (LH,, m).

4.36 (2H, q, J=7Hz).

5.8-6.1 (IH, br,).

7.48 (IH, m).

Reference Example 101 According to Reference Example 15, the target compound in the form of a pale yellow oil was produced from 1.21 parts of ethyl 2-cyclopropylaminothiazole-4-cargenate, 0.2.9 parts of lithium aluminum hydride, and 2 Qmt of tetrahydrofuran. It has the physical properties of

NMR spectrum (δppm, CDC4,): 0.
5-1.0 (4H, m).

2.45-2.7 (iH, m).

3.1-4.0 (IH, br,).

4.53 (2H, s).

5.9-6.7 (LH, br,).

6.42 (IH, s).

Reference Example 102 Rudehyde According to Reference Example 44, 2-cyclopropylaminothiazol-4-ylmethanol 1.1F, sulfur trioxide bilysin complex 3.1y, triethylamine 21
The yellow prism-shaped target compound prepared from dimethyl sulfoxide 15d has the following physical properties.

Melting point: 124-127°C NMR spectrum (δppm, CDCLs) 0°6-1.0 (4H, m).

1. 55-1.8 (IH, rn).

6.7-7.3 (IH, br,).

7.48 (IH, s).

9.76 (IH, s).

Patent Applicant: Sankyo Co., Ltd. Representative Patent Attorney Akio Ohno Procedural Amendment-F 1. Indication of the matter 4 patent application No. 03 (i40 No. 2, name of invention thiazole derivative) of 1999 (spontaneous) 311 July 1997 711 X3. Person making the amendment JIG4TI Relationship Patent applicant address 3-115 Nihonbashiki-cho, Chuo-ku, Tokyo 10;3
Number 1 Name (185) Sankyo Co., Ltd. Representative
I & President Pf Mura V (Central 4, Use of agent 1-2-58 Hiromachi, Honbunagawa-ku, Tokyo, Sankyo Co., Ltd. 1, specification drawing page 180, line 6 r 13.1-'13 .6 Insert the following words on the line following "(IH, br, )."

"Example 93 5-(2-7 cloptylaminothiazol-4-ylmethylene) rhodanine-3-acetic acid! Example IKm, 2-cyclobutylaminothiazole-4-aldehyde 0.85F, rhodanine-3-acetic acid 0.
The target compound in the form of a yellow powder prepared from 89P, 0.475' ammonium mide, 05 rnl of 28% aqueous ammonia, and 20 ml of ethanol has the following physical properties.

Melting point: 241-243°C (decomposed) NMR spectrum (δppm, DMSOd6)
: 1.69-1.81 (2H, m), 1.96-2.11 (2H, m), 2.31-2.42 (2H, m), 4.10-4.25 (IH, m), 4.70 (2H, s), 7.53 (2H, s).

8.35 (IH, d, J = 8 to 1 disappeared by addition of heavy water)
.

ylmethylene) rhodanine-3-acid 2 4-ylmethylene) rhodanine-3-acetic acid According to Example 1, 2-cyclopentylaminothiazole-4-aldehyde IP, rhodanine-3-acetic acid 0.97y, ammonium chloride 0.52.28e4 Ammonia water 0.5 at,
The target compound in the form of a yellow powder produced from 20 ml of ethanol has the following physical properties.

Melting point: 239-240°C NMR spectrum (δppm, DMso-a6)
"1.51-1.72 (6H, m), 1.95-2.06 (2H, m), 4.01-4.12 (LH, m), 4.70 (2H, s), 7 .51 (IH,s), 7.53 (IH,s), 8.07 (LH,d, J=6Hz, disappeared by addition of heavy water).

Example 95 5- (2-N-methylanilinothiazole-4-azole-4-aldehyl'x, sr, rhodanine-3-acetic acid 1.1?, ammonium chloride 0.8F, 28-width aqueous ammonia Q, The yellowish brown needle-shaped target compound prepared from 3 ml of ethanol and 30 ml of ethanol has the following physical properties.

Melting point: 245-248°C (decomposition) NMR spectrum (δppIn, DMSO-d6)
: 3.59 (3H, s), 4.72 (2H, s), 7.3-7.5 (5H, m), 7.61 (IH, s), 7.62 (IH, s), 13.1-13.6 (IH, br). ”2, same No. 2
r9.76 (IH, 8) on page 66, line 16. Insert the following words on the line after ``.

``S blade side 103 Ethyl 2-cyclobutylaminothiazole-4-carboxylate According to Reference Example 42, 11 cyclobutylthiourea, 1.5?
) The target compound in the form of a pale yellow oil has the following physical properties.

NMR spectrum (δppm, DMSO-d, S
): 1.26 (3H, t, J=7Hz), 1.60-1.72 (2H, m), 1.82-1.97 (2H, m), 2.24-2.35 (2H , m), 3.99-4.08 (IH, m), 4.20 (2H, q, J=7Hz), 7.4s (xH, s), 8.12 (IH, d, J=7Hz) , i disappears upon addition of water).

Reference Example 104 2-Cyclobutylaminothiazol-4-ylmethanol According to Reference Example 15, ethyl 2-cyclobutylaminothiazole-4-carboxylate 1.1? , lithium aluminum hydride 0.25f, and tetrahydrofuran 20
The brown oily target compound produced from rnl has the following physical properties.

NMR spectrum (δppm, DMSO-d6)
: 1.56-1.72 (2H, m), 1.81-1.96 (2H, m), 2.21-2.32 (2H, +n), 3.93-4.07 (IH, m), 4.27 (2H, br, d, J=5Hz, singlet by adding heavy water), 4.99 (IH, b
r, t, J=5Hz, disappeared by addition of heavy water), 6.30
(LH,S), 7.70 (I H,d, J=7Hz, disappeared by addition of heavy water).

Reference Example 105 2-Cyclobutylaminothiazole-4-aldehyde According to Reference Example 44, 2-cyclobutylaminothiazol-4-ylmethanol 1.1F, sulfur trioxide/pyridine complex 2,9? , triethylamine 1.8
The target compound in the form of a brown powder prepared from 2 and dimethyl sulfoxide 201 has the following physical properties.

Melting point: 89-99°C.

N), IR spectrum (δppm, pMso-a6
): 1.63-1.73 (2H, m), 1.87-1.95 (2H, rn), 2.25-2.
33 (2H, m), 4.07-4.16 (IH, m), 7.80 (IH, s), 8.19 (IH, d, J=7Hz, rainbow disappears due to addition of heavy water), 9. 54 (I H, s ) * Reference Example 106 Ethyl 2-cyclopentylaminothiazole-4-carboxylate According to Reference Example 42, cyclopentylthiourea 1.5S
F. Bromopyruvin completed Chill 2.1? The target compound in the form of a pale yellow oil produced from , and ethanol 501R1 has the following physical properties.

NMR, < vector (δppm, DMSO-d6
): 1.26 (3H, t, J=7Hz), 1.40-1.69 (6H, m), 1.85-1.93 (2H, m), 3.87-3.94 (IH , m), 4.21 (2H,q, J=7Hz), 7.47 (I
H,s).

7.84 (LH, d, J=7Hz, disappeared by addition of heavy water).

Reference Example 107 2-Cyclopentylaminothiazol-4-ylmethanol Manufactured according to Reference Example 15 from 2.31 ethyl 2-cyclopentylaminothiazole-4-carboxylate, 0.4 t of lithium aluminum hydride, and 50% of tetrahydrofuran. The target compound in the form of a pale yellow powder has the following physical properties.

Melting point: 90-92°C.

NMR spectrum (δppm, D+aso-a6)
: 1.41-1.68 (6H, m), 1.83-1.91 (2H, m), 3.80-3.92 (IH, m), 4.28 (2H, d, J= 6Hz, singlet for heavy water addition), 4.98 (IH, t, J=
6Hz, disappeared by addition of heavy water), 6.28 (LH, s)
, 7.42 (1) J, d, J = 7 Hz, 7F' disappears upon addition of water).

Reference Example 108 Aldehyde According to Reference Example 44, 2-cyclobutylaminothiazole-1-ylmethanol 1. FM, sulfur trioxide/pyrinone complex 3.6? , triethylamine2.
The target compound in the form of a light brown powder prepared from 3f and trimethyl sulfoxide IQml has the following physical properties.

Melting point: 110-118°C NMR spectrum (δppm, DMSO-66)
: 1.45-1.70 (6H, m), 1.86-1.95 (2H, m), 3, H-4, oz (xH, m), 7.78 (IH, s), 7 .92 (IH, d, J = 7 Hz, @disappeared by water addition), 9.54 (IH, S).

Reference Example 109 Ethyl 2-N-methylanilinothiazole-4-cardianoate According to Reference Example 42, N~methylphenylthiourea 1.
7v, 2.29 ml of ethyl bromopyruvate, and 25 rnl of ethanol. The target compound is a pale yellow oil and has the following physical properties.

NMR spectrum) (δppm, CDCl5):
1.40 (3H, t, J = 7Hz), 3.63 (3H, s), 4.38 (2H, q, J = 7Hz), 7.2
-7.6 (6H, m).

Reference Example 110 Methanol According to Reference Example 15, ethyl 2-N-methylanilinothiazole-4-cardianoate 2.7M, lithium aluminum hydride 0.4? , and tetrahydrofuran 30R
The pale yellow oily target compound prepared from 1 has the following physical properties.

NMR spectrum (δppm, CDcl, ):
3.54 (3H, S), 4.56 (2H, s), 6.33 (IH, s), 7.1-7.5 (6H, m).

Reference Example 111 2-N-methylanilinothiazol-4-aldehyde According to groove side 44, 2-N-methylanilinothiazol-4-ylmethanol 2.12, triethylamine 3
2. Sulfur trioxide/pyridine complex 4.52,
The target compound in the form of a yellow oil prepared from 20m and trimethyl sulfoxide has the following physical properties.

NMR spectrum (δppm, CDCl, ):
3.60 (3H, s), 7.2-7.6 (6H, m), 9.78 (IH, s). "that's all

Claims (1)

[Claims] General formula▲ Numerical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 and R^2 are the same or different and are hydrogen atoms, lower alkyl groups, lower alkenyl groups, lower alkynyl groups, Cycloalkyl group, aryl group which may have a substituent, aralkyl group which may have a substituent, acyl group, alkoxycarbonyl group, aryloxycarbonyl group, aralkyloxycarbonyl group, having a substituent a carbamoyl group which may have a substituent, a thiocarbamoyl group which may have a substituent, a lower alkylsulfonyl group, a halogeno-lower alkylsulfonyl group, an arylsulfonyl group which may have a substituent, a lower alkylthio group or an arylthio group shows. Further, R^1 and R^2 may be combined together with a nitrogen atom to form a heterocyclic group. R^3 represents a hydrogen atom, a lower alkyl group, an aryl group, or a halogen atom. R^4 represents a hydrogen atom, a lower alkyl group, an optionally protected carboxyl group, or a carbamoyl group that may have a substituent. R^5 represents a hydrogen atom, an optionally protected carboxyalkyl group, or a tetrazolylmethyl group. n represents an integer from 0 to 2. X represents an oxygen atom or a sulfur atom. ] Thiazole derivatives and salts thereof.