JPS63243079A - Thiazole derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (M is 5-7-membered heterocyclic base containing two N atoms.; A is substituent group on one of the N atoms. of the group M and is H, aryl, aralkyl, heteroaryl, heteroaralkyl or cycloalkyl; M is a group bonded to the other N atom. of the group M and is single bond or lower alkylene; B is group of formula II; R<1> is amino, hydrazino, guanidino, isothioureido or thioureido) and its salt. EXAMPLE:1-( 4-Fluorophenyl )-4-( 2-guanidino-1,3-thiazol-4-yl )methylpiperazinehy drochloride. USE:It has excellent Gasping prolonging action and antagonistic action against lethal hypoxia. It is non-toxic and is useful as a cerebral function improver. PREPARATION:The compound of formula can be produced e.g. by reacting an amino compound of formula A-M-H with a compound of formula III (X is halogen, alkanesulfonyloxy, etc.).

Description

DETAILED DESCRIPTION OF THE INVENTION [Objective] (Field of Industrial Application) The present invention relates to a novel thiazole derivative that has an effect of improving brain metabolism.

(Problem to be solved by the present invention) As a result of extensive research over many years on the synthesis of derivatives having a thiazole skeleton and their pharmacological activities, the present inventors have discovered that the structure is completely different from known compounds. The present invention has been completed based on the discovery that a novel thiazole derivative has excellent Gaspjng prolongation action and hypoxia lethal antagonism, and is a useful brain metabolism improving agent.

[Constitution] The novel thiazole derivatives and pharmacologically acceptable salts thereof of the present invention have the general formula [wherein M is 1 to 2 aryl or 5 to 7
5 to 5 containing two nitrogen atoms -F, which may be fused with a cycloalkyl or/and which may be substituted with 1 to 4 lower alkyl, aryl or/and oxo on the carbon atom. Indicates a 7-shell heterocyclic group. A is a substituent on one nitrogen atom of the M group; hydrogen atom: an aryl group which may have a substituent on the ring - an aralgyl group which may have a substituent on the ring : Heteroaryl group which may have a substituent on the ring; Heteroaryl group which may have a substituent on the ring; Or a heteroaryl group which may be fused with aryl and have a substituent on the ring Indicates a cycloalkyl group which may have. 2 is a group bonded to the other nitrogen atom of the M group, and represents a straight chain or branched lower alkylene group which may be substituted with a single bond or a halogen atom.

(In the formula, R1 is an optionally substituted amino group, an optionally substituted hydrazino group, an optionally substituted guanidino group, an optionally substituted isothioureido group, or an optionally substituted thioureido group. (indicates the group)
Group having = 4 = In the above general formula (I), the "aryl group" defined by M is, for example, phenyl,
Examples include aromatic hydrocarbon groups having 5 to 1-2 carbon atoms such as naphthyl, and phenyl is preferred.

The "5- to 7-membered cycloalkyl group" defined by M is
Examples include 5- to 7-membered saturated cyclic hydrocarbon groups such as cyclopentyl, cyclohexyl, and cycloheptyl, with cyclohexyl being preferred.

The "lower alkyl group" defined by M refers to 1 such as methyl, ethyl, n-propyl, isopropyl, n-butyl,
Isobutyl, S-butyl, t-butyl, n-pentyl,
isopentyl, 2-methylbutyl, neopentyl, rhohexyl, 4-methylpentyl, 3-methylpentyl,
2-methylpentyl, 3.3-dimethylbutyl, 2.2
-dimethylbutyl, 1.1-dimethylbutyl, 1.2-
Examples include straight-chain or branched alkyl groups having 1 to 6 carbon atoms such as dimethylbutyl, 1,3-dimethylbutyl, and 2,3-dimethylbutyl, preferably straight-chain or branched alkyl groups having 1 to 4 carbon atoms. It is an alkyl group.

The "5- to 7-membered heterocyclic group containing two nitrogen atoms" defined by M means imidazolidinyl, hexahydropyridazinyl, hexahydropyrimidinyl, piperazinyl, 1,2
- 5- to 7-membered saturated heterocyclic groups containing two nitrogen atoms such as diazacycloheptyl, 1,3-diazacycloheptyl, and homopiperazinyl; preferably 6- to 7-membered heterocyclic groups containing two nitrogen atoms; to 7-membered saturated heterocyclic group, more preferably piperazinyl or homopiperazinyl.

"Optionally substituted amino group" in the definition of R1
, "Optionally substituted hydrazino group", "optionally substituted guanidino group", "optionally substituted thioureido group j" and "optionally substituted thioureido group" are the following: The substituent is "amino group",
Indicates a group that may have one or two substituents on a "hydrazino group,""guanidinogroup,""isothioureidogroup," or "thiourido group," and the substituent is one that is usually a substituent for an amino group. Preferably, for example, an alkylcarbonyl group such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, lauroyl, balmitoyl, stearoyl, although there is no limitation.
Halogenated aliphatic acyl groups such as taloloacetyl, dichloroacetyl, trichloroacetyl, and trifluoroacetyl, lower alkoxy aliphatic acyl groups such as methoxyacetyl, and unsaturated fatty acids such as (E)-2-methyl-2-butenoyl. Aliphatic acyl groups such as group acyl groups; arylcarbonyl groups such as benzoyl, α-naphthoyl, and β-naphthoyl; halogenated arylcarbonyl groups such as 2-bromobenzoyl and 4-chlorobenzoyl;
, 4.6-drimethylbenzoyl, lower alkylated arylcarbonyl groups such as 4-toluoyl, lower alkoxylated arylcarbonyl groups such as 4-anisoyl,
Nitrated arylcarbonyl groups such as 4-nitrobenzoyl and 2-nitrobenzoyl, lower alkoxycarbonylated arylcarbonyl groups such as 2-(methoxycarbonyl)benzoyl, arylated arylcarbonyl groups such as 4-phenylbenzoyl, etc. Aromatic acyl group; lower alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl, halogen or tri-lower alkyl group such as 2,2.2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl Alkoxycarbonyl groups such as lower alkoxycarbonyl groups substituted with silyl; alkenyloxycarbonyl groups such as vinyloxycarbonyl and allyloxycarbonyl; benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, Aralkyloxycarbonyl group whose aryl ring may be substituted with 1 or 2 lower alkoxy or nitro, such as 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t
- tri-lower alkylsilyl groups such as butyldimethylsilyl, methyldiisopropylsilyl, methyldi-butylsilyl, triisopropylsilyl, substituted with one or two aryl groups such as diphenylmethyl, diphenylbutyl, diphenylisopropyl, phenyldiisopropyl Silyl groups such as tri-lower alkylsilyl groups; benzyl, phenethyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl,
triphenylmethyl, α-naphthyldiphenylmethyl,
Lower alkyl group substituted with 1 to 3 aryl groups such as 9-anthrylmethyl, 4-methylbenzyl, 2
．． 4.6-Dolimethylbenzyl, 3,4.5-1-limethylbenzyl, 4-methoxybenzyl, 4-MeI-xyphenyldiphenylmethyl, 2-nitrobenzyl, 4
- lower alkyl, lower alkoxy, nitro, halogen, cyano such as nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis(2-nitrophenyl)methyl, piveronyl Aralkyl groups such as lower alkyl groups substituted with 1 to 3 aryl rings; N, N-dimethylaminomethylene, benzylidene,
4-methoxybenzylidene, 4-nitrobenzylidene,
a substituted methylene group forming a ship base such as salicylidene, 5-chlorosalicylidene, diphenylmethylene, (5-chloro-2-hydroxyphenyl)phenylmethylene; the lower alkyl group; the lower alkyl group is an oxygen atom; a lower alkoxy group substituted with , a lower alkoxylated lower alkoxy group such as 2-methoxyel 1hexy, an alkyloxy group such as a halogenated lower alkoxy group such as 2.2.2-trichloroethoxy; hydroxyl group; hydroxymethyl, 2 - hydroxy-substituted lower alkyl groups such as hydroxyethyl, 3-hydroxypropyl;
2-Aminoethyl.

Aryl optionally substituted with an amino-substituted alkyl group such as 3-aminopropyl, or lower alkyl, lower alkoxy, or halogen such as phenyl, 4-tolyl, 4-methoxyphenyl, 4-chlorophenyl, α- or β-naphthyl; Examples include aliphatic acyl groups, aromatic acyl groups, alkoxycarbonyl groups, alkenyloxycarbonyl groups, aralkyloxycarbonyl groups, aralkyl groups, lower alkyl groups, and allyl groups.

The "aryl group which may have a substituent on the ring" defined in A is an aryl group which may have one to four substituents selected from the following on the ring of the aryl group. The substituents on the ring -H include the above optionally substituted amino group; the nitro group; the cyano group; the above lower alkyl, the above halogenated lower alkyl, or the above a=
Carboxy group optionally substituted with 11-ralkyl; carbamoyl group; halogen atom such as fluorine atom, chlorine atom, bromine atom, iodine atom; lower alkyl group; lower alkoxy group; trifluoromethyl, trichloromethyl,
difluoromethyl, dibromomethyl, dibromomethyl,
Fluoromethyl, 2.2.2-trichloroethyl, 2.
2.2-trifluoroethyl, 2-bromoethyl, 2-
Halogenated lower alkyl groups such as chloroethyl, 2-fluoroethyl, and 2,2-dibromoethyl; the aforementioned aliphatic acyl groups and alkyl groups having 1 to 4 carbon atoms such as methylenedioxy, ethylenedioxy, and propylenedioxy; Examples include a dioxy group, preferably a halogen atom or a halogenated lower alkyl group.

The "aralkyl group which may have a substituent on the ring" defined in A means that the "aryl group which may have a substituent on the ring" is attached to the lower alkyl group from 1- to Indicates two bonded groups.

The "heteroaryl group that may have a substituent on the ring" defined in A is a heteroaryl group in which the substituent described in J above [Aryl group that may have a substituent on the ring] Indicates a heteroaryl group which may be substituted 1 to 4 times on the ring, and the heteroaryl group includes a 5- to 7-membered heterocyclic group containing 1- to 3 sulfur atoms, oxygen atoms, and/or nitrogen atoms. For example, furyl, chenyl, pyrrolyl, azepinyl, morpholinyl, thiomorpholinyl,
Pyrazolyl, imidazolyl, oxasilyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, acridyl and moieties corresponding to these groups. Alternatively, it can be a completely reduced group, preferably a 5- to 7-membered heteroaromatic ring group containing 1 to 3 sulfur atoms, oxygen atoms, and/or nitrogen atoms, More preferred are biridyl, pyrimidyl, and thiazolyl.

The "heteroaralkyl group which may have a substituent on the ring" defined in A means that the above-mentioned "heteroaryl group which may have a substituent on the ring" is attached to the lower alkyl group with 1
This represents a group in which 2 to 2 are bonded.

The "cycloalkyl group which may be fused with an aryl and may have a substituent on the ring" defined in A is,
A cycloalkyl group having 3 to 10 carbon atoms may be substituted with a substituent described in the above "Aryl group which may have a substituent on the ring", or/and the aryl group may be substituted with the above aryl group. Indicates a group that may be ring-fused, such as cyclopropyl, cyclobutyl, cyclopentyl,
The A group such as cyclohexyl, norbornyl, adamantyl, and 2-indanyl is preferably a hydrogen atom; an aryl group such as phenyl or naphthyl; 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, -chlorophenyl, 3-chlorophenyl, 4-
Chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3,5-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,5-dibromo Phenyl, 2,5-dibromophenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 2,3.
Lotrifluorophenyl, 2.3.4-trifluorophenyl, 3,4゜5-trifluorophenyl, 2,5
．． rottrifluorophenyl, 2,4. Lotrifluorophenyl, 2,3.6-tribromophenyl, 2.3
．． 4-tribromophenyl, 3,4.5-tribromophenyl, 2,5.6-trichlorophenyl, 2,4.6
-trichlorophenyl, 1-fluoro-2-naphthyl,
2-fluoro ■-naphthyl, 3-fluoro-1-naphthyl, ■-chloro-2-naphthyl, 2-chloro-1-naphthyl, 3-bromo-1-naphthyl, 3,8-difluoro-1-naphthyl, 2, 3-difluoro-1-naphthyl, 4,8-difluoro-1-naphthyl, 5,6-difluoro-1-naphthyl, 3,8-dichloro-1-naphthyl, 2,3-dichloro-1-naphthyl, 4, 8-dibromo-1-naphthyl, 5,6-dibromo-1-naphthyl, 2
,3. rottrifluoro-1-naphthyl, 2,3.4-
)-rifluoro-1-naphthyl, 3.4.5-trifluoro-1-naphthyl, 4°5, rhotrifluoro-1-
Aryl group substituted with a halogen atom such as naphthyl, 2,4゜8-trifluoro-1-naphthyl; 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trichloro Methylphenyl, 3-dichloromethylphenyl, 4-
Trichloromethylphenyl, 2-tribromomethylphenyl, 3-dibromomethylphenyl, 4-dibromomethylphenyl, 3,5-bistrifluoromethylphenyl, 2,5-bistrifluoromethylphenyl, 2.6-
Bistrifluoromethylphenyl, 2゜4-bistrifluoromethylphenyl, 3,5-bistribromomethylphenyl, 2,5-bisdibromomethylphenyl, 2,
6-pisdichloromethylmethylphenyl, 2,4-bisdichloromethylphenyl, 2,3.6-tristrifluoromethylphenyl, 2,3.4-)-tristrifluoromethylphenyl, 3,4.5- tristrifluoromethylphenyl, 2,5,6-tristrifluoromethylphenyl, 2,4゜rotristrifluoromethylphenyl, 2゜3.6-) tristribromomethylphenyl, 2゜3,4-trisdibromo Methylphenyl, 3°4
．． 5-tristribromomethylphenyl, 2゜5.6-
Trisdichloromethylmethylphenyl, 2.4,6-trisdichloromethylphenyl, 1-trifluoromethyl-2-naphthyl, 2-trifluoromethyl-1-naphthyl, 3-trifluoromethyl-1-naphthyl, 1 -trichloromethyl-2-naphthyl, 2-dichloromethyl-]
--naphthyl, 3-tribromomethyl-1-naphthyl,
3,8-bistrifluoromethyl-1-naphthyl, 2
, 3-bish-lifluoromethyl-1-naphthyl, 4,8
-bis1-lifluoromethyl-1-naphthyl, 5,6-
Pis-difluoromethyl-1-naphthyl, 3,8-bis-l-liglolomethyl-1-naphthyl, 2,3-bisdichloromethyl-1-naphthyl, 4,8-bisdibromomethyl-1-naphthyl, 5,6- Pisdribromomethyl-1-naphthyl, 2,3.6-1-trifluoromethyl-1-naphthyl, 2゜3.4-tristrifluoromethyl-1-naphthyl, 3,4,5-F-list Substituted with a halogenated lower alkyl group such as trifluoromethyl-1-naphthyl, 4,5.6-1-trifluoromethyl-1-naphthyl, 2,4.8-trifluoromethyl-1-naphthyl. Aryl group; 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methylphenyl
-ethylphenyl, 3-propylphenyl, 4-ethylphenyl, 2-butylphenyl, 3-pentylphenyl, 4-pentylphenyl, 3,5-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 2,4-dimethylphenyl, 3.5-dibutylphenyl, 2,5-dibutylphenyl, 2,6-dipylphenyl, 2,4-dipropylphenyl, 2,
3.6-trimethylphenyl, 2,3.4-trimethylphenyl, 3,4.5-trimethylphenyl, 2.5.
6-trimethylphenyl, 2,4.6-trimethylphenyl, 2,3.6-1-butylphenyl, 2,3.4
-tripentylphenyl, 3,4,5-ihelibutylphenyl, 2,5゜6-tribrobylmethylphenyl, 2
, 4.6-triprobylphenyl, 1-methyl-2-naphthyl, 2-methyl-1-naphthyl, 3-methyl-1-
naphthyl, 1-ethyl-2-naphthyl, 2-propyl-
1-naphthyl, 3-butyl-1-naphthyl, 3,8-
Dimethyl-]-naphthyl, 2,3-dimethyl-1-naphthyl, 4,8-dimethyl-1-naphthyl, 5,6-dimethyl-1-naphthyl, 3,8-diethyl-1-naphthyl, 2.3- Dipropyl-1-naphthyl, 4,8-dipentyl-1-naphthyl, 5,6-cyptyl-1-naphthyl, 2,3.6-drimethyl-1-naphthyl, 2,3.
4-trimethyl-1-naphthyl, 3,4.5-)-trimethyl-1-naphthyl, 4,5.6-trimethyl-
-Aryl groups substituted with lower alkyl groups such as naphthyl, 2.4.8-trimethyl-1-naphthyl: 2-methoxyphenyl-3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-propoxy phenyl, 4-ethoxyphenyl, 2-butoxyphenyl,
3-pentoxyphenyl, 4-pentoxyphenyl, 3
, 5-dume-1-xyphenyl, 2,5-dimethoxyphenyl, 2,6-ristooxyphenyl, 2,4-ristooxyphenyl, 3,5-dibutoxyphenyl, 2,5-dibutoxyphenyl, 2,6 -dipropoxymethoxyphenyl, 2,4-dipropoxyphenyl, 2,3.6-trimethoxyphenyl, 2,3.4-trimethoxyphenyl, 3゜4.5-trimethoxyphenyl, 2,5.6-
Trimethoxyphenyl, 2,4.6-trimethoxyphenyl, 2,3.6-tributoxyphenyl, 2,3,4
-tripentoxyphenyl, 3.4,5-tripentoxyphenyl, 2,5゜6-tripropoxyphenyl, 2
, 4.6-tripropoxyphenyl, 1-methoxy-2
-naphthyl, 2-methoxy-1-naphthyl, 3-methoxy-1-naphthyl, 1-ethoxy-2-naphthyl, 2
-Propoxy-1-naphthyl, 3-butoxy-1-naphthyl, 3,8-dimethoxy-1-naphthyl, 2,3-
Dimethoxy-1-naphthyl, 4,8-dimethoxy-1-
naphthyl, 5.6-dime-1hex-1-naphthyl, 3,
8-jethoxy-1-naphthyl, 2,3-dibroboxy-1-naphthyl, 4,8-dipentoxy-1-naphthyl, 5,6-diptoxy-1-naphthyl, 2,3,6-drimethoxy-1-naphthyl, 2,3. 4-trimethoxy-1-naphthyl, 3,4,5-trimethoxy-1-naphthyl, 4,5.6-trimethoxy-1-naphthyl, 2.
Aryl group substituted with a lower alkoxy group such as 4,8-1 to rimethoxy-1-naphthyl; 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 3,5
-diaminophenyl, 2,5-diaminophenyl, 2,
6-diaminophenyl, 2,4-diaminophenyl, 2
゜3.6-triaminophenyl, 2,3.4-triaminophenyl, 3,4.5-triaminophenyl, 2,5
．． 6-triaminophenyl, 2゜4.6-triaminophenyl, 1-amino-2-naphthyl, 2-amino-1-
Naphthyl, 3-amino-1-naphthyl, 3,8-diamino-1-naphthyl, 2,3-diamino-1-naphthyl,
4.8-Diamino-1-naphthyl, 5,6-diamino-1-naphthyl, 2,3.6-triamino-1-naphthyl, 2,3.4-triamino-1-naphthyl, 3,4.5
-Aryl groups substituted with amino groups such as triamino-1-naphthyl, 4,5.6-triamino-1-naphthyl, 2,4.8-triamino-1-naphthyl; 2-nitrophenyl, 3-nitro Phenyl, 4-nitrophenyl, 3,5-dinitrophenyl, 2,5-dinitrophenyl, 2,6-dinitrophenyl, 2,4-dinitrophenyl, 2,3°6-trinitrophenyl, 2,3.4 −
Trinitrophenyl, 3,4.5-trinitrophenyl, 2,5,6-trinitrophenyl, 2,4゜6-trinitrophenyl, 1-nitro-2-naphthyl, 2-nitro-1-naphthyl, 3-nitro-1-naphthyl, 3,8
-dinitro-1-naphthyl, 2,3-dinitro-1-naphthyl, 4゜8-dinitro-1-naphthyl, 5,6-sinitro-1-naphthyl, 2,3,6-dolinitro-1-
Naphthyl, 2,3,4-trinitro-1-1 23
- Naphthyl, 3,4,5-trinitro-1-naphthyl, 4
, 5.6-dolinitro-1-naphthyl, 2.4. ．． 8-
Aryl groups substituted with nitro groups such as trinitro-1-naphthyl; 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3,5-dicyanophenyl,
2,5-dicyanophenyl, 2,6-dicyanophenyl, 2,4-dicyanophenyl, 2,3.6-tricyanophenyl, 2,3.4-tricyanophenyl, 3,4,
5-tricyanophenyl, 2.5,6-tricyanophenyl, 2,4.6-tricyanophenyl, 1-cyano-
2-naphthyl, 2-cyano-1-naphthyl, 3-cyano-1-naphthyl, 3,8-dicyano-1-naphthyl, 2
, 3-dicyano-1-naphthyl, 4゜8-dicyano-1
-naphthyl, 5,6-dicyano-1-naphthyl, 2,3
．． 6-dolycyano-1-naphthyl, 2,3,4-tricyano-1-naphthyl, 3,4.5-tricyano-1-naphthyl, 4,5.6-dolycyano-1-naphthyl, 2,
Aryl groups substituted with cyano groups such as 4,8-tricyano-1-naphthyl; 2-acetylphenyl, 3-acetylphenyl, 4-acetylphenyl, 3,5-diacetylphenyl, 2.5-diacetylphenyl, 2,6
-Diacetylphenyl, 2,4-diacetylphenyl,
2.3.6-Tripropionylphenyl, 2゜3.4-
Tripropionylphenyl, 3,4゜5-tripropionylphenyl, 2,5.6-tributyrylphenyl, 2
, 4.6-tributyrylphenyl, 1-acetyl-2-
Naphthyl, 2-acetyl-1-naphthyl, 3-acetyl-1-naphthyl, 3,8-diacetyl-1-naphthyl,
2,3-dipropionyl-1-naphthyl, 4,8-dibutyryl-1-naphthyl, 5,6-diptyryl-1-naphthyl, 2,3.6-)-lyacetyl-1-naphthyl, 2
, 3,4-triacetyl-1-naphthyl, 3,4.5-
Tripropionyl-1-naphthyl, 4,5,6-tributyru-1-naphthyl, 2,4,8-tributyru-1
-Aryl group substituted with an aliphatic acyl group such as naphthyl; 2-carboxyphenyl, 3-carboxyphenyl, 4-carboxyphenyl, 3,5-dicarboxyphenyl, 2゜5-dicarboxyphenyl, 2,6 -Aryl group substituted with a carboxy group such as dicarboxyphenyl, 2,4-dicarboxyphenyl; 2-carbamoylphenyl, 3-carbamoylphenyl, 4-carbamoylphenyl, 3゜5-dicarbamoylphenyl,
Aryl group substituted with a carbamoyl group such as 2,5-dicarbamoylphenyl, 2,6-dicarbamoylphenyl, 2,4-dicarbamoylphenyl; alkylenedioxy such as 3゜4-methylenedioxyphenyl Aryl radicals substituted with groups; unsubstituted aralkyl groups such as diphenylmethyl, benzyl, phenethyl, phenylpropyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl,
3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl,
3,5-difluorobenthyl, 2,5-difluorophenethyl, 2,6-difluorobenzyl, 2,4-difluorophenethyl, 3,5-dibromobenzyl, 2,5-
Dibromophenethyl, 2,6-dichlorobenzyl, 2.
4-dichlorophenethyl, 2,3. Lotrifluorobenzyl, 2,3.4-trifluorophenethyl, 3,4
．． 5-trifluorobenzyl, 2,5. Lotrifluorophenethyl, 2.4. rottrifluorobenzyl, 2
, 3゜6-tribromophenethyl, 2,3.4-tribromobenzyl, 3,4.5-tribromophenethyl, 2
, 5.6-t-dichlorobenzyl, 2゜4.6-trichlorophenethyl, 1-fluoro-2-naphthylmethyl,
2-fluoro-1-naphthylethyl, 3-fluoro-1
-naphthylmethyl, ■-chloro-2-naphthylethyl,
2-chloro-1-naphthylmethyl, 3-bromo-1-naphthylethyl, 3,8-difluoro-1-naphthylmethyl, 2,3-difluoro-1-naphthylethyl, 4,8
-difluoro-]--naphthylmethyl, 5,6-difluoro-1-naphthylethyl, 3,8-dichloro-1-naphthylmethyl, 2,3-dichloro-1-naphthylethyl, 4,8-dibromo-1- Naphthylmethyl, 5゜6-dipromo-1-naphthylethyl, 2,3゜rotrifluoro-1-naphthylmethyl, 2゜3.4-trifluoro-
1-naphthylethyl, 3.4.5-trifluoro-1-
naphthylmethyl, 4,5. Lotrifluoro-1-naphthyl ethyl, 2,4,8-trifluoro-1-naphthylmethyl, bis(2-fluorophenyl)methyl, 3-fluorophenylphenylmethyl, bis(4-fluorophenyl)methyl, 4- Fluorophenylphenylmethyl, bis(2-chlorophenyl)methyl, bis(3-chlorophenyl)methyl, bis(4-chlorophenyl)methyl, 4-chlorophenylphenylmethyl, 2-bromophenylphenylmethyl, 3-bromophenylphenylmethyl, bis (4-bromophenyl)methyl, bis(3,
5-difluorophenyl)methyl, bis(2,5-difluorophenyl)methyl, bis(2,6-difluorophenyl)methyl, 2,4-difluorophenylphenylmethyl, bis(3,5-dibromophenyl)methyl, 2
, 5-dibromophenylphenylmethyl, 2,6-dichlorophenylphenylmethyl, bis(2,4-dichlorophenyl)methyl, bis(2,3, lotrifluorophenyl)methyl Aralkyl group; 2-trifluoromethylbenzyl, 3-trifluoromethylphenethyl, 4-trifluoromethylbenzyl, 2-trichloromethylphenethyl, 3-dichloromethylbenzyl, 4-trichloromethylphenethyl,
2-Tribromomethylbenzyl, 3-dibromomethylphenethyl, 4-dibromomethylbenzyl, 3,5-bistrifluoromethylphenethyl, 2,5-bistrifluoromethylbenzyl, 2,6-pistrifluoromethylphenethyl, 2 , 4-bistrifluoromethylbenzyl, 3,5-bistribromomethylphenethyl, 2,5-
Bisdibromomethylbenzyl, 2,6-bisdichloromethylmethylphenethyl, 2,4-bisdichloromethylbenzyl, 2,3.6-tristrifluoromethylphenethyl, 2,3.4-tristrifluoromethylbenzyl, 3, 4.5-tristrifluoromethylphenethyl,
2,5゜6-tristrifluoromethylbenzyl, 2゜4.6-tristrifluoromethylphenethyl, 2.3
．． 6-tristribromomethylbenzyl, 2,3,4-
Trisdibromo, methylphenethyl, 3.4.5-tristribromomethylbenzyl, 2.5.6-trisdichloromethylmethylphenethyl, 2,4.6-trisdichloromethylbenzyl, 1-trifluoromethyl-2 -Naphthylethyl, 2-trifluoromethyl-1-naphthylmethyl, 3-trifluoromethyl-1-naphthylethyl, 1-trichloromethyl-2-naphthylmethyl, 2-dichloromethyl-1-naphthylethyl, 3-tribromo Methyl-1-naphthylmethyl, 3,8-bistrifluoromethyl-1-naphthylethyl, 2,3-bistrifluoromethyl-1-naphthylmethyl, 4,8-bistrifluoromethyl-1-naphthylethyl, 5.6- Pis-difluoromethyl-1-naphthylmethyl, 3,8-bistrichloromethyl-1-naphthylethyl, 2,3-bisdichloromethyl-1-naphthylmethyl, 4,8-bisdibromomethyl-1-naphthylethyl, 5 , 6-pistribromomethyl-1-naphthylmethyl, 2゜3.6-pistrifluoromethyl-1-naphthylethyl, 2,3,4-
tristrifluoromethyl-1-naphthylmethyl, 3,
4.5-1-tristrifluoromethyl-1-naphthyl ethyl, 4.5-1-tristrifluoromethyl-1-naphthylmethyl, 2,4,8-tristrifluoromethyl-1-naphthylmethyl, bis(4 -trifluoromethylphenyl)methyl, 4-trifluoromethylphenylphenylmethyl, bis(2-trichloromethylphenyl)
Methyl, bis(3-trichloromethylphenyl)methyl, bis(4-trichloromethylphenyl)methyl, 2-
Tribromomethylphenylphenylmethyl, 3-tribromomethylphenylphenylmethyl, bis(4-tribromomethylphenyl)methyl, bis(3,5-bistrifluoromethylphenyl)methyl, bis(2,5-bistrifluoromethylphenyl) ) Methyl, bis(2,6-
bistrifluoromethylphenyl)methyl, 2,4-bistrifluoromethylphenylphenylmethyl, bis(
3,5-bistribromomethylphenyl)methyl, 2,
5-bistribromomethylphenylphenylmethyl, 2
, 6-pistrichloromethylphenyl phenylmethyl,
Aralkyl group substituted with a halogenated lower alkyl group such as bis(2゜4-bistrichloromethylphenyl)methyl, bis(2,3,6-tristrifluoromethylphenyl)methyl; 2-methylphenethyl, 3 -Methylbenzyl, 4-methylphenethyl, 2-ethylbenzyl, 3-propylphenethyl, 4-ethylbenzyl, 2-
Butylphenethyl, 3-pentylbenzyl, 4-pentylphenethyl, 3,5-dimethylbenzyl, 2,5-dimethylphenethyl, 2,6-dimethylbenzyl, 2,4
-dimethylphenethyl, 3゜5-dibutylbenzyl, 2
, 5-dimethylphenethyl, 2,6-dipropylbenthyl, 2,4-dipropylphenethyl, 2,3.6-trimethylbenzyl, 2,3,4-)-dimethylphenethyl, 3,4.5-trimethylbenzyl , 2゜5.6-trimethylphenethyl, 2,4.6-trimethylbenzyl,
2,3.6-tributylphenethyl, 2,3.4-tripentylbenzyl, 3,4,5-tributylphenethyl, 2゜5.6-tripropylphenethyl, 2,4,6-trippylphenethyl, Methyl-2-naphthylmethyl, 2-methyl-]--naphthylethyl, 3-methyl-1-naphthylmethyl, 1-1ethyl-2-naphthylethyl, 2-propyl-]-naphthylmethyl, 3-butyl-]- Naphthylethyl, 3,8-dimethyl-1-naphthylmethyl, 2,3-dimethyl-1-naphthylethyl,
4.8-dimethyl-1-naphthylmethyl, 5゜6-dimethyl-1-naphthylethyl, 3,8-diethyl-1-naphthylmethyl, 2,3-dipropyl-1-naphthylmethyl, 4,8-dipentyl-1- naphthylethyl, 5,6
-Cyptyl-1-naphthylmethyl, 2,3,6-drimethyl-1-naphthylmethyl, 2,3,4-trimethyl-
1-naphthylethyl, 3,4.5-trimethyl-1-naphthylmethyl, 4,5.6-trimethyl-1-naphthylmethyl, 2,4.8-trimethyl-1-naphthylmethyl, bis(2-methylphenyl) Methyl, 3-methylphenylphenylmethyl, bis(4-methylphenyl)methyl, 4-methylphenylphenylmethyl, bis(2-ethylphenyl)methyl, bis(3-ethylphenyl)methyl, bis(4-ethylphenyl) Methyl, 2-propylphenylphenylmethyl, 3-propylphenylphenylmethyl, bis(4-propylphenyl)methyl, bis(3,5-dimethylphenyl)methyl, bis(2,5
-dimethylphenyl)methyl, bis(2,6-dimethylphenyl)methyl, 2,4-dimethylphenylphenylmethyl, bis(3゜5-dipropylphenyl)methyl, 2,5'-dipropylphenylphenylmethyl , 2,6-dimethylphenylphenylmethyl, bis(2
,4-diethylphenyl)methyl, bis(2q 3 v
Aralkyl groups substituted with lower alkyl groups such as 6-1 (helimethylphenyl)methyl: 2-methoxybenzyl, 3-methoxyphenyl, 4-methoxybenzyl, 2-
1-hexyphenethyl, 3-propoxybenzyl, 4-
I-xyphenethyl, 2-butoxybenzyl, 3-pen-1-xyphenethyl, 4-pentoxybenzyl, 3,
5-dimethoxyphenethyl, 2,5-dimethoxybenzyl, 2,6-simethoxyphenethyl, 2゜4-dimethoxybenzyl, 3,5-dibutoxyphenethyl, 2,5-
Dipentoxybenzyl, 2,6-dipropoxyphenethyl, 2,4-dipropoxybenzyl, 2,3.6-trimethoxyphenethyl, 2,3,4-trimethoxybenzyl, 3,4.5-trimethoxyphenethyl , 2.5.6
-trimethoxybenzyl, 2,4゜6-trimethoxyphenethyl, 2,3.6-tributoxybenzyl, 2,3
．． 4-tripentoxyphenethyl, 3,4.5-tributoxybenzyl, 2,5.6-tripropoxyphenethyl, 2.4.6-tribropoxybenzyl, 1-methoxy-2-naphthylmethyl, 2 -Methoxy-1-naphthylmethyl, 3-methoxy-1-naphthylethyl, 1-1-2-naphthylmethyl, 2-propoxy-1-naphthylmethyl, 3-butoxy-1-naphthylethyl, 3
,8-1 36-dimethoxy-1-naphthylmethyl, 2,3-dimethoxy-1-naphthylmethyl, 4,8-dimethoxy-1-naphthylethyl, 5.6-dimethoxy-1-naphthylmethyl, 3,8-diethylmethyl I-xy-1-naphthylmethyl, 2,3
-dipropoxy-1-naphthyl ethyl, 4,8-dibenxy-1-naphthylmethyl, 5,6-dipropyl-xy-1-naphthylmethyl, 2,3,6-1-listoxy-
1-naphthylethyl, 2,3.4-1-listoxy-1
--Naphthylmethyl, 3 e 4 g J-trimethoxy-1-naphthylmethyl, 4,5゜6-dorimethoxy-1-naphthylethyl, 2゜4.8-trimethoxy-1-
Naphthylmethyl, bis(2-methoxyphenyl)methyl, 3-methoxyphenylphenylmethyl, bis(4-methoxyphenyl)methyl, 4-methoxyphenylphenylmethyl, bis(2-ethoxyphenyl)methyl, bis(3-ethoxyphenyl) ) methyl, bis(4-ethoxyphenyl)methyl, 2-propoxyphenylphenylmethyl, 3-propoxyphenylphenylmethyl, bis(
4-propoxyphenyl)methyl, bis(3,5-dimethoxyphenyl)methyl, bis(2,5-dimethoxyphenyl)methyl, bis(2,6-dimethoxyphenyl)
Methyl, 2,4-dimethoxyphenylphenylmethyl,
Bis(3,5-dipropoxyphenyl)methyl, 2,5
-substituted with lower alkoxy groups such as dipropoxyphenylphenylmethyl, 2,6-dinitrophenylphenylmethyl, bis(2°4-jethoxyphenyl)methyl, bis(2°3,6-trimethoxyphenyl)methyl Aralkyl group; 2-aminophenethyl, 3-aminobenzyl, 4-aminophenethyl, 3,5-diaminophenethyl, 2,5-diaminophenethyl, 2,6-diaminobenzyl, 2,4-diaminophenethyl, 2, 3.6-
Triaminobenzyl, 2,3゜4-triaminophenethyl, 3,4.5-triaminobenzyl, 2,5.6-1
~riaminophenethyl, 2,4.6-triaminobenzyl, 1-amino-2-naphthylmethyl, 2-amino-1
-naphthyl ethyl, 3-amino-1-naphthylmethyl,
3,8-diamino-1-naphthylmethyl, 2,3-diamino-1-naphthylethyl, 4,8-diamino-1-naphthylmethyl, 5゜6-diamino-1-naphthylmethyl, 2,3゜6-triamino -1-naphthylethyl, 2,
3゜4-triamino-1-naphthylmethyl, 3,4゜5
-triamino-1-naphthylmethyl, 4,5゜6-triamino-1-naphthylethyl, 2,4゜8-triamino-1-naphthylmethyl, bis(2-aminophenyl)methyl, 3-aminophenylphenylmethyl, Bis(4-
aminophenyl)methyl, 4-aminophenylphenylmethyl, bis(3,5-diaminophenyl)methyl, bis(2,5-diaminophenyl)methyl, bis(2,6
-diaminophenyl)methyl, 2゜4-diaminophenyl phenylmethyl, an aralkyl group substituted with an amino group such as bis(2,3,6-triaminophenyl)methyl; 2=39-mononitrophenethyl, 3- Nitrobenzyl, 4-nitrophenethyl, 3,5-dinitrobenzyl, 2,5-dinitrophenethyl, 2,6-dinitrobenzyl, 2,4-
Dinitrophenethyl, 2.3.6-trinitrobenzyl, 2,3.4-trinitrobenzyl, 3,4,5-trinitrobenzyl, 2,5.6-trinitrobenethyl, 2,4,6-trinitrobenethyl Nitrobenzyl, 1-nitro-2-
naphthylmethyl, 2-nitro-1-naphthylethyl, 3
-Nitro-1-naphthylmethyl, 3,8-dinitro-1
-naphthylmethyl, 2,3-dinitro-1-naphthyl ethyl, 4,8-dinitro-1-naphthylmethyl, 5゜6
-Sinitro 1-naphthylmethyl, 2,3゜6-dolinitro 1-naphthylethyl, 2,3゜4-trinitro-
1-naphthylmethyl, 3,4゜5-trinitro-1-naphthylmethyl, 4,5゜6-dolinitro-1-naphthylethyl, 2,4゜8-trinitro-ninaphthylmethyl, bis(2-nitrophenyl)methyl , 3-nitrophenylphenylmethyl, bis(4-nitrophenyl)methyl, 4-nitrophenylphenylmethyl, bis(3,5
-dinitrophenyl)methyl, bis(2,5-dinitrophenyl)methyl, bis(2,6-dinitrophenyl)
Aralkyl groups substituted with nitro groups such as methyl, 2゜4-dinitrophenylphenylmethyl, bis(2,3,6-trinitrophenyl)methyl; 2-cyanophenethyl, 3-cyanobenzyl, 4-cyanophenethyl ,3
, 5-dicyanobenzyl, 2,5-dicyanophenethyl, 2,6-dicyanobenzyl, 2,4-dicyanophenethyl, 2.3.6-tricyanobenzyl, 2,3,4-
Tricyanophenethyl, 3,4.5-tricyanobenzyl, 2,5,6-)-dicyanophenethyl, 2,4.6
-Tricyanobenzyl, 1-cyano-2-naphthylmethyl, 3-cyano-1-naphthylmethyl, 3,8-dicyano-1-naphthylmethyl, 2,3-dicyano-1-naphthylethyl, 4,8-dicyano -1-naphthylmethyl,
5,6-dicyano-1-naphthylmethyl, 2,3.6-
Doricyano-1-naphthylethyl-2,3,4-tricyano-1-naphthylmethyl-3,4,5-tricyano-
1-naphthylmethyl, 4-. 5.6-Doriciano 1-
naphthyl ethyl, 2.4.8-tricyano-]-naphthylmethyl, bis(2-cyanophenyl)methyl, 3-
Cyanophenylphenylmethyl, bis(4-cyanophenyl)methyl, 4-cyanophenylphenylmethyl, bis(3,5-dicyanophenyl)methyl, bis(2,5
Aralkyl substituted with a cyano group such as -dicyanophenyl)methyl, bis(2,6-dicyanophenyl)methyl, 2,4-dicyanophenyl phenylmethyl, bis(2,3,6-)-dicyanophenyl)methyl Group; 2-
Acetylphenethyl, 3-acetylbenzyl, 4-acetylphenethyl, 3,5-diacetylbenzyl, 2,5
-Diacetylphenethyl, 2,6-diacetylbenzyl, 2,4-diacetylphenethyl, 2,3.6-triplobionylbenzyl, 2,3.4-1-rifobionylphenethyl, 3t 49 J - Shout ~ Libropionylbenzyl, 2,5.6-)-LibuchijJ Ruf]-
Netyl, 2,4,6-tributyrylbenzyl, 1-acetyl-2-naphthylmethyl, 2-acetyl-]-naphthylethyl, 3-acetyl-1-naphthylmethyl, 3
, 8-diacetyl-1-naphthylethyl, 2,3-dibu[1-pionyl-1-naphthylethyl, 4,8-dibutyryl-1-naphthylmethyl, 5,6-diptyryl-1--
-naphthyl 7-methyl, 2,3,6-1 heliacetyl-naphthylethyl, 2,3,4-triacetyl-1-naphthylmethyl, 3,4,5-1-ribrobionyluco,
-naphthylmethyl, 4,5,6 h'J butyryl-1
-naphthylethyl, 2,4.8-tributyryl-1-naphthylmethyl, bis(2-acetylphenyl)methyl,
3-acetylphenylphenylmethyl, bis(4-acetylphenyl)methyl, 4-acetylphenylphenylmethyl, bis(2-propionylphenyl)methyl, bis(3-propionylphenyl)methyl, bis(4-propionylphenyl)methyl, 2-butyrylphenylphenylmethyl, 3-butyrylphenylphenylmethyl,
Bis(4-butyrylphenyl)methyl, bis(3,5-
diacetylphenyl)methyl, bis(2,5-diacetylphenyl)methyl, bis(2,6-diacetylphenyl)methyl, 2,4-diacetylphenylphenylmethyl, bis(3,5-dibu).

tyrylphenyl)methyl, 2,5-dibutyrylphenylphenylmethyl, 2,6-dipropionylphenylphenylmethyl, bis(2,4-dipropionylphenyl)
Aralkyl groups substituted with aliphatic acyl groups such as methyl, bis(2゜3.6-triacetylphenyl)methyl; 2-carboxyphenethyl, 3-carboxybenzyl, 4-carboxyphenethyl, 3,5-dicarboxy Benzyl, 2,5-dicarboxyphenethyl, 2,6-dicarboxybenzyl, 2,4-dicarboxyphenethyl, bis(2-carboxyphenylphenylphenylmethyl, bis(4-carboxyphenyl)methyl, 4-carboxyphenylphenyl) methyl,
Bis(3,5-dicarboxyphenyl)methyl, bis(
2,5-dicarboxyphenyl)methyl, bis(2,6
-dicarpoxyphenyl)methyl, 2,4-dicarboxyphenylphenylmethyl, aralkyl group substituted with bis(2,3.6-tricarboxyphenylboxy group); 2-carbamoylbenzyl, 3-carbamoylphenethyl, 4 -Carbamoylbenzyl, 3,5-dicarbamoylphenethyl, 2
, 5-dicarbamoylbenzyl, 2,6-dicarbamoylphenethyl, 2,4-dicarbamoylbenzyl, bis(2-carbamoylphenyl)methyl, 3-dicarbamoylphenylphenylmethyl, bis(4-carbamoylphenyl) Methyl, 4-carbamoylphenylphenylmethyl, bis(3,5-dicarbamoylphenyl)methyl, bis(2.

5-dicarbamoylphenyl)methyl, bis(2,6-
aralkyl group substituted with a carbamoyl group such as dicarbamoylphenyl)methyl, 2,4-dicarbamoylphenyl phenylmethyl, bis(2,3,6-tricarbamoylphenyl)methyl; 3,4-methylenedioxy Benzyl, 3,4-methylenedioxyphenethyl, bis(3,4-methylenedioxyphenyl)methyl, 3,4
- aralkyl group substituted with an alkylene dioxy group such as methylenedioxyphenylphenylmethyl; 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 2-thiazolyl,
4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 3-chloro-2-pyridyl, 4-methyl-2-pyridyl, 5-methoxy-2-pyridyl, 6-trifluoromethyl-2-pyridyl, 5-acetyl-3-pyridyl, 6-carboxy-3-pyridyl, 2-carbamoyl-
4-pyridyl, 6-amino-4-pyridyl, 4-nitro-2-pyrimidyl, 5-cyano-2-pyrimidyl, 2-
Methyl-4-pyrimidyl, 3-1-lifluoromethyl-
4-pyrimidyl, 2-amino-5-pyrimidyl, 5-carboxy-2-thiazolyl, 4-fluoro-2-thiazolyl, 2-trifluoromethyl-4-thiazolyl, 2-
Optionally substituted heteroaryl groups such as amino-5-thiazolyl, 3-carboxy-2-furyl, 2-cyano-3-furyl; 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethyl; -pyrimidylmethyl, 4-pyrimidylmethyl, 5-pyrimidylethyl, 2-
Thiazolylmethyl, 4-thiazolylethyl, 5-thiazolylmethyl, 2-furylmethyl, 3-furylethyl, 3
-chloro-2-pyridylmethyl, 4-methyl-2-pyridylmethyl, 5-methoxy-2-pyridylethyl, 6-
Trifluoromethyl-2-pyridylmethyl, 5-acetyl-3-pyridylethyl, 6-carboxy-3-pyridylmethyl, 2-carbamoyl-4-pyridylethyl, 6
-amino-4-pyridylmethyl, 4-nitro-2-pyrimidylethyl, 5-cyano-2-pyrimidylmethyl, 2
-Methyl-4-pyrimidylethyl, 3-trifluoromethyl-4-pyrimidylmethyl, 2-amino-5-pyrimidylethyl, 5-carboxy-2-thiazolylmethyl,
4-fluoro-2-thiazolylethyl, 2-trifluoromethyl-4-thiazolylethyl, 2-amino-5-thiazolylmethyl, 3-carboxy-2-furylmethyl,
Optionally substituted heteroaralkyl group such as 2-cyano-3-furylmethyl; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl, 2-indanyl 2. Examples of "good linear or branched lower alkylene groups" include methylene, methylmethylene, ethylene, propylene, trimethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene, and pentamethylene. , C1-C6 alkylene group such as hexamethylene; fluoromethylene, fluoroethylene, 1-fluoropropylene, 2-fluoropropylene, 1-methyl-2
-Fluoroethylene, 1-fluorobutylene, 1-methyl-3-fluoropropylene, 1-ethyl-1-fluoromethylene, 1-propyl-1-fluoromethylene, 1
-(3-fluoropropyl)-1-fluoromethylene,
1,1-dimethyl-2-fluoroethylene, 1-fluoromethyl-1-methyl-2-fluoroethylene, 1.1
,1. -tri(fluoromethyl)methylene, 1-fluoropentamethylene, 2-ethyl-3-fluorotrimethylene, 2-methyl-4-fluorotetramethylene, 3-
Methyl-4-fluorotetramethylene, 2,2-dimethyl-3-fluorotrimethylene, 2-fluoromethyl-
2-Methyl-3-fluorotrimethylene, 2.2.2-
Tri(fluoromethyl)ethylene, 1-fluorohexamethylene, chloromethylene, bromoethylene, 1-talolotrimethinone, 2-bromotrimethylene, 1-methyl-2-iodoethylene, 1-chlorotetramethylene,
1-Methyl-3-talolotitramethylene, ]-]1ethyl-1-bromomethylene]-]propyl-1-chloromethylene 1-(3-fluoropropyl)-1-chloromethylene, 1-91--dimethyl-2- Bromoethylene, 1
-fluoromethyl-1-methyl-2-bromoethylene,
1, 1, 1. -tri(bromomethyl)methylene, 1-talolopentamethynone, 2-ethyl-3-chlorotrimethylene, 2-methyl-4-talolotrimethylene, 3-
Methyl-4-bromotetramethylene, 2,2-dimethyl-3-bromotrimethylene, 2-bromomethyl-2-methyl-3-fluorotrimethylene, 2,2,2. Examples include alkylene groups having 1 to 6 carbon atoms substituted with halogen atoms, such as -tri(chloromethyl)ethylene, 1-tri(chloromethyl)ethylene, and xamethylene, preferably methylene, ethylene, trimethylene or tetra It is methylene.

Compound (I) of the present invention can be made into a pharmacologically acceptable non-toxic salt, but such salts preferably include alkali salts such as lithium salts, potassium salts or calcium salts. Salts of metals or alkaline earth metals; hydrohalides such as hydrofluorides, hydrochlorides, hydrobromides, hydroiodides, nitrates, perchlorates, sulfates, phosphates Inorganic acid salts such as methanesulfonates, 1-lyfluoromethanesulfonates, lower alkylsulfonates such as ethanesulfonates, benzenesulfonates, and arylsulfonic acids such as p-toluenesulfonates. Salts, organic acid salts such as fumarates, succinates, citrates, tartrates, oxalates, maleates, and amino acid salts such as glutamates, aspartates - 52 - Compounds of the present invention ( I) has asymmetric carbon atoms, each of which is S
There are stereoisomers that are in the configuration and the R configuration, and each of these stereoisomers or a mixture thereof is included in the present invention.

Among the compounds (■), suitable compounds include (1)
M may be fused with one aryl or 6- to 7-membered cycloalkyl, or/and one carbon atom
6 to 7 containing 2 nitrogen atoms, optionally substituted with 2 lower alkyl, aryl or/and oxo
Compound (2) M, which is a membered heterocyclic group, contains two nitrogen atoms and may be fused with one aryl or 6- to 7-membered cycloalkyl.
Compound (3) M, which is a 7-membered heterocyclic group, has 1 or 2 lower alkyl atoms on a carbon atom,
Aryl or/and oxo may be substituted,
Compound (4) M is a 6- to 7-membered heterocyclic group containing two nitrogen atoms; Compound (5) M is a 6- to 7-membered heterocyclic group containing two nitrogen atoms; A compound which is a piperazinyl group or a homopiperazinyl group, which may be fused with a 7-membered cycloalkyl group, or/and which may be substituted with 1 or 2 lower alkyl, aryl, or/and oxo on a carbon atom. (6) A compound in which M is a piperazinyl group or a homopiperazinyl group which may be fused with one aryl or 6- to 7-membered cycloalkyl (7) A compound in which M is a alkyl,
Aryl or/and oxo may be substituted,
Compound (8) where M is a piperazinyl group or homopiperazinyl group (9) Compound (10) where M is a homopiperazinyl group
? Compound (1,1) where vi is a piperazinyl group
A is fused with a hydrogen atom, an aryl group that may have a substituent on the ring, an aralkyl group that may have a substituent on the ring, a heteroaryl group, a heteroaralkyl group, or an aryl group; Compound (12) where A is a cycloalkyl group which may have a substituent on the ring Compound (13) where A is a hydrogen atom, an aryl group or heteroaryl group which may have a substituent on the ring Compound (14) which is an aryl group or heteroaryl group which may have a halogen atom, halogenated lower alkyl or lower alkoxy as a substituent on the ring (14) A is a hydrogen atom, and a halogen atom as a substituent on the ring , a compound (15) which is an aryl group or a heteroaryl group which may have trifluoromethyl or methoxy A may have a halogen atom, trifluoromethyl or methoxy as a substituent on the ring Compound (16) which is an aryl group Compound (17) where A is an aryl group which may have a halogen atom or trifluoromethyl as a substituent on the ring Even if Z is substituted with a halogen atom Compound (18) which is a straight chain or branched chain alkylene group having 1 to 4 carbon atoms Compound (19) where Z is a straight chain or branched chain alkylene group having 1 to 4 carbon atoms R' is an optionally substituted amino group or an optionally substituted guanidino group (20) A compound (2]) in which R'' is an optionally substituted guanidino group M is one Two nitrogen atoms, which may be fused with aryl or 6- to 7-membered cycloalkyl, or/and which may be substituted with 1 to 2 lower alkyl, aryl, or/and oxo on carbon atoms. A 6- to 7-membered heterocyclic group containing a hydrogen atom, an aryl group which may have a substituent on the ring,
An aralkyl group, a heteroaryl group, a heteroaralkyl group that may have a substituent on the ring, or a cycloalkyl group that may be fused with an aryl group, even if Z is substituted with a halogen atom. Compound (22) which is a straight-chain or branched-chain lower alkylene group, and R1 is an optionally substituted amino group or an optionally substituted guanidino group, M is one aryl or 6 to 7 A 6- to 7-membered heterocyclic group containing two nitrogen atoms which may be condensed with a member cycloalkyl, where A is a hydrogen atom, an aryl group or heteroaryl which may have a substituent on the ring 2 is a linear or branched lower alkylene group which may be substituted with a halogen atom, and R1 is an optionally substituted amino group or an optionally substituted guanidino group. Compound (23) M is a 6- to 7-membered heterocyclic group containing 2 nitrogen atoms, which may be substituted with 1- to 2 lower alkyl, aryl, or/and oxo on the carbon atom, and A is a hydrogen atom, an aryl group or a heteroaryl group which may have a substituent on the ring, and 2 is a linear or branched lower alkylene group which may be substituted with a halogen atom, Compound (24) in which R1 is an optionally substituted amino group or an optionally substituted guanidino group, M is a 6- to 7-membered heterocyclic group containing two nitrogen atoms, and A is a hydrogen atom. , is an aryl group or heteroaryl group which may have a halogen atom, halogenated lower alkyl or lower alkoxy as a substituent on the ring, and 2 is substituted with a halogen atom, and b
A compound which is a linear or branched alkylene group having 1 to 4 carbon atoms, and R' is an optionally substituted amino group or an unsubstituted anilino group. (25) M is Co aryls or 6 to 7
A piperazinyl group or homopiperazinyl group which may be fused with a member cycloalkyl or/and which may be substituted with J- to 2 lower alkyl, aryl or/and oxo on the carbon atom; is a hydrogen atom,
An aryl group or a heteroaryl group which may have a halogen atom, trifluoromethyl or methoxy as a substituent on the ring, and Z is a straight chain or branched chain which may be substituted with a halogen atom. carbon number 1- to 4
A compound (26) in which M is an aryl or a 6- to 7-membered cycloalkyl group, and R1 is an optionally substituted amino group or an optionally substituted guanidino group A is a piperazinyl group or a homopiperazinyl group which may have a halogen atom, trifluoromethyl or methoxy as a substituent on the ring, and 2 is a linear Compound (27) which is a branched alkylene group having 1 to 4 carbon atoms, and R1 is an optionally substituted amino group or an optionally substituted guanidino group. A piperazinyl group or homopiperazinyl group, which may be substituted with to two lower alkyl, aryl or/and oxo,
A is an aryl group which may have a halogen atom, trifluoromethyl or methoxy as a substituent on the ring, and 2 is a linear or branched chain having 1 to 4 carbon atoms;
compound (29), in which R1 is an optionally substituted amino group or an optionally substituted guanidino group, M is a piperazinyl group or a homopiperazinyl group, and A is An aryl group which may have a halogen atom or trifluoromethyl as a substituent, Z is a linear or branched alkylene group having 1 to 4 carbon atoms, and R1 is an unsubstituted Compound (30), which is a guanidino group, M is a homopiperazinyl group, and A is
It is an aryl group which may have a halogen atom or trifluoromethyl as a substituent on ring -H, Z is a linear or branched alkylene group having 1 to 4 carbon atoms, and R1 is , a compound (31) which is an optionally substituted guanidino group, M is a piperazinyl group, and A is an aryl group which may have a halogen atom or trifluoromethyl as a substituent on the ring. , 2 is a linear or branched alkylene group having 1 to 4 carbon atoms,
Compounds in which R1 is an optionally substituted guanidino group can be mentioned.

Representative compounds of the present invention include, for example, the compounds listed in Table 1, but the present invention is not limited to these compounds. 3-ayathylbenzyl, 4AB
is 4-acetylbenzyl, Ac is acetyl, IAD is 1
-Adamantyl, 2AD is 2-adamantyl, 2AP is 2-acetylphenyl, 3AP is 3-acetylphenyl, 4AP is 4-acetylphenyl, Bz is benzyl, B
zh is diphenylmethyl, 2CB is 2-chlorobenzyl, 3CB is 3-chlorobenzyl, 4CB is 4-chlorobenzyl, CH is cyclohexyl, 2CP is 2-chlorophenyl, 3CP is 3-chlorophenyl, 4CP is 4-chlorophenyl, 2GNP is 2-cyanophenyl, 3ON
P is 3-cyanophenyl, 4GNP is 4-cyanophenyl, DB is 1,1-dimethylbenzyl, 3.5DFP is 3,5-difluorophenyl, 2,5DFP is 2゜5-
Difluorophenyl, 2,6DFP is 2,6-difluorophenyl, DMP is 3,5-dimethoxyphenyl, 2
FBz is 2-fluorobenzyl, 3FBz is 3-fluorobenzyl, 4FBz is 4-fluorobenzyl, 44F
Bzh is bis(4-fluorophenyl)methyl, 2FM
is 2-furylmethyl, 2FP is 2-fluorophenyl,
3FP is 3-fluorophenyl, 4FP is 4-fluorophenyl, FR is 2-furyl, HQ is tetrahydroquinolino, ID is isoindolino, 2MB is 2-methoxybenzyl, 3MB is 3-methoxybenzyl, 4MB is 4-
Methoxybenzyl, 44MBzh is bis(4-methoxyphenyl)methyl, 34MDBz is 3,4-methylenedioxybenzyl, 34MDP is 3,4-methylenedioxyphenyl, 2MP is 2-methoxyphenyl, 3MP is 3-methoxyphenyl, 4MP is 4-methoxyphenyl, 2MTB is 2-methylbenzyl, 3MTB is 3-methylbenzyl, 4MTB is 4-methylbenzyl, NP is 1
- Naphthyl, 2NPh is 2-nitrophenyl, 3NPh
is 3-nitrophenyl, 4NPh is 4-nitorphenyl, ph is phenyl, 2PL is 2-pyrimidyl, 4PP is 4-propoxyphenyl, 2PYD is 2-pyridyl, T
AO is N-(1,3,3-trimethyl-6-azabisiglo[3,2,1]octyl) 2-TFBz is 2-trifluoromethylbenzyl, 3-TFBz is 3-trifluoromethylbenzyl, 4-TFBz is 4-trifluoromethylbenzyl, 2-TFP is 2-trifluoromethylphenyl, 3-TFP is 3-trifluoromethylphenyl, 4-TFP is 4-trifluoromethylphenyl, 2TL is 2-tolyl, 3TL is 3-tolyl, 4TL is 4-tolyl, TM is 2,4.6-trimethylphenyl,
TMBz is 2,3,4-trimethoxybenzyl, TMP
is 2,3,4-trimethoxyphenyl, TP is 2°4.
5-trimethoxyphenyl, 2TZ represents 2-thiazole, Am represents amino, Hd represents hydrazino, ITU represents isothioureido, Gu represents guanidino, and TU represents thioureido.

Among the above exemplary compounds, preferred compounds include 4,1
0, 12, 14, 1.5, 16, 17, 19, 20, 2
1,22,23,24゜25.26,31,38,39
,40,43,44,45,51,52,53,55,
56°57.58,59,62,63,64,65,6
6.67.68,71,72,74,76°81.82
,84,85,86,87,89,90,92,93,
94,95,96,97゜98.99400,101,
102,103j05,106,107,108,10
9゜110.111,113,126,127,128
,130,132,137,139440.141,1
51,166.167.168475,177.193
,203,205゜206.207,217.225,
226, 227, 228, 239, 240, 251, 2
52.253,263,270,278,279,28
0,287,291. ．． 305,306°317.31
Compounds 8,319,329,345,346 and 353 may be mentioned.

Furthermore, suitable compounds include 39,55,56,57
゜58a59,62,63,64. t4. cn, 93,
94,95,96. q9,1oo,1゜7.225,2
Compounds 26 and 291 can be mentioned.

The most preferred compounds include 39,57,58,59,
62°74.92,94,95,96,1.07,22
Compounds 5,226 and 291 may be mentioned.

The thiazole derivative of the present invention can be produced, for example, by the method described below.

[Manufacturing method 1] [■] In the formula, A, M, Z and R1 have the same meanings as above. X
is a halogen atom such as a chlorine atom, a bromine atom, or an iodine atom; a lower alkanesulfonyloxy group such as methanesulfonyloxy or ethanesulfonyloxy; Halogenated lower alkanesulfonyloxy group; represents a halogenated acetyloxy group such as trifluoroacetyloxy, chloroacetyloxy, trichloroacetyloxy, or an arylsulfonyloxy group such as toluenesulfonyloxy and benzenesulfonyloxy.

In the step ↓, the amino compound (II) and the alkylating or acylating agent (III) are reacted in a solvent, in the presence of a base, or in the presence or absence of an inorganic salt, and optionally,
An optionally substituted amino group, an optionally substituted hydrazino group, an optionally substituted guanidino group, an optionally substituted isothioureido group, or an optionally substituted thioureido group defined as R1 aliphatic acylation, aromatic acylation, alkoxycarbonylation, alkenyloxycarbonylation, aralkyloxycarbonylation, silylation, aralkylation, substituted methylenation to form a ship base, lower alkylation, alkyloxylation , hydroxylation, hydroxy-substituted lower alkylation,
By amino-substituted alkylation or arylation,
This is a process for producing compound (IV) of the present invention.

The solvent used is not particularly limited as long as it does not inhibit the reaction, but preferably benzene, toluene,
Aromatic hydrocarbons such as xylene; ketones such as acetone; ethers such as ether, dimethoxyethane, diethylene glycol dimethyl ether, and tetrahydrofuran; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoramide, dimethyl Sulfoxides such as sulfoxide and mixed solvents thereof can be used, and ethers or amides are more preferred.

The base to be used is not particularly limited as long as it is used as a base in normal reactions, but preferably alkali metal carbonates such as sodium carbonate and potassium carbonate; sodium hydrogen carbonate and potassium hydrogen carbonate. alkali metal bicarbonates such as; inorganic bases such as alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; triethylamine, diisopropylethylamine, pyridine, 1°5-diazabicyclo[4,
3,0] non-5-ene, 1,4-diazabicyclo[
2,2,2-cooctane, ■,8-diazabicyclo[5,
Organic bases such as undec-7-ene or organometallic bases such as butyllithium, lithium diisopropylamide can be used.

Inorganic salts used are preferably sodium iodide,
Examples include alkali metal iodide salts such as potassium iodide and cesium iodide.

The reaction temperature is usually 0°C to 240°C, preferably 10°C to 110°C.

The reaction time varies mainly depending on the reaction temperature, starting compounds, whether or not a solvent is used, the solvent used, whether or not a base is used, and the type of base, but is usually from 1 hour to 2 days.

The desired process can be carried out using, for example, a compound having the formula R''-X (wherein, X has the same meaning as Ichiki).

R'' is an aliphatic acyl group, aromatic acyl group, alkoxycarbonyl group, alkenyloxycarbonyl group, aralkyloxycarbonyl group, silyl group, aralkyl group, substituted methylene group forming a Schiff base, lower alkyl group, alkyl oxy group, hydroxyl group, hydroxy-substituted lower alkyl group, amino-substituted alkyl group, or aryl group) in a solvent in the presence of a base.

The solvent used is not particularly limited as long as it does not inhibit the reaction, but preferably halogenated hydrocarbons such as methylene chloride and chloroform; benzene;
Aromatic hydrocarbons such as toluene and xylene; Ketones such as acetone; Ethers such as ether, dimethoxyethane, diethylene glycol dimethyl ether, and tetrahydrofuran; Amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoramide and these mixed solvents can be boiled,
More preferred are ethers or amides.

The base to be used is not particularly limited as long as it is used as a base in normal reactions, but preferably alkali metal carbonates such as sodium carbonate and potassium carbonate; sodium hydrogen carbonate and potassium hydrogen carbonate. alkali metal hydrogen carbonates such as; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; inorganic bases such as alkali metal hydroxides such as sodium hydroxide, potassium hydroxide; nitriethylamine; Diisopropylethylamine, 4-dimethylaminopyridine, pyridine, 1,5-diazabicyclo[4,3,0]non-5-ene, 1,8-diazabicyclo[5,4゜0]
Organic bases such as undec-7-ene or organometallic bases such as butyllithium, lithium diisopropylamide can be used.

The reaction temperature is usually 0°C to 100°C, preferably 10°C to 40°C.

The reaction time mainly varies depending on the reaction temperature, the raw material compound, the presence or absence of a solvent, the presence or absence of a base, and the type of base. indicates the same meaning as above.

R'' represents a lower alkyl group or an aryl group, and RI
+ represents a lower alkyl group or an aralkyl group. R'' represents a lower alkyl group.

This is a method for producing U or thioureido derivatives, isothioureido derivatives, and N-methylguanidino derivatives.

The λ step is a step of producing an acyl thiouride compound (VI) by stirring the amino compound (V) and the acylisothiocyanate compound having RCON=C=S in a solvent. .

The solvent used is not particularly limited as long as it does not inhibit the reaction, but preferably benzene, toluene,
Aromatic hydrocarbons such as xylene; ketones such as acetone; ethers such as ether, dimethoxyethane, diethylene glycol dimethyl ether, and tetrahydrofuran; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoramide; A mixed solvent can be used, and more preferably ethers or ketones are used.

The reaction temperature is usually 10°C to 100°C, but
Preferably, the temperature is between 00°C and 40°C.

The reaction time varies mainly depending on the reaction temperature, raw material compounds and solvent used, but is usually 5 hours to 2 days.

z3IN is a process for producing thioureido compound (VII) by hydrolyzing compound (VI) in a solvent under dibasic or acidic conditions.

The solvent used is not particularly limited as long as it does not inhibit the reaction, but preferably water; aromatic hydrocarbons such as benzene, toluene, and xylene; ketones such as acetone; ether; Ethers such as dimethoxyethane, diethylene glycol dimethyl ether, and tetrahydrofuran; amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoramide; alcohols such as methanol and ethanol; and mixed solvents thereof; Water, ketones or alcohols are preferred.

The base to be used is not particularly limited as long as it is used as a base in normal reactions, but preferably alkali metal carbonates such as sodium carbonate and potassium carbonate; sodium hydrogen carbonate and potassium hydrogen carbonate. Inorganic bases such as alkali metal hydrogen carbonates such as; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide can also be used.

The acid used is not particularly limited as long as it is used as an acid in ordinary reactions, but inorganic acids such as hydrochloric acid and sulfuric acid can be preferably used.

The reaction temperature is usually 20"C to 150C, preferably 40C to 100C.The reaction time is
Although it mainly depends on the reaction temperature, raw material compounds and solvent used, it is usually 1 hour to 2 days.

In the L4L step, the thioureido compound (VII) is mixed with a compound having the formula R11X (wherein R'' and
indicates the same meaning as above. ) in the presence or absence of a base, the inthioureide compound (
VIII).

The solvent used is not particularly limited as long as it does not inhibit the reaction, but preferably aromatic hydrocarbons such as benzene, I-luene, and xylene; ketones such as acetone; ether, Ethers such as dimethoxyethane, diethylene glycol dimethyl ether, and tetrahydrofuran; amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoramide; alcohols such as methanol and ethanol; and mixed solvents thereof. , more preferably,
Ethers or alcohols.

The base used is not particularly limited as long as it is used as a base in normal reactions, but preferably alkali metal carbonates such as sodium carbonate and potassium carbonate; sulfur hydrogen carbonate to thulium hydrogen carbonate. Alkali metal bicarbonates such as potassium; alkali metal hydrides such as lithium hydride, sodium hydride, and potassium hydride; inorganic bases such as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; Triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, pyridine, 1,5-diazabicyclo[4,3,0]
Non-5-ene, 1,8-diazabicyclo [5,4°O
] Organic bases such as undec-7-ene or organometallic bases such as butyllithium, lithium diisopropylamide can be used.

The reaction temperature is usually 0°C to 100°C, preferably 50°C to 90°C.

The reaction time varies mainly depending on the reaction temperature, the raw material compound and the solvent used, but is usually from 2 hours to 2 days.

The strategy and process is to add the inthioureide compound (VIII),
This is a step of producing an alkylguanine compound (IX) by reacting it with an alkylamine compound having the formula R''-NH (wherein R12 has the same meaning as above) in a solvent.

The solvent used is not particularly limited as long as it does not inhibit the reaction, but preferably water; ketones such as acetone; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoramide. ;Alcohols such as methanol and ethanol, and mixed solvents thereof can be used; alcohols or ketones are more preferred.

The reaction temperature is usually room temperature to 100°C, preferably 60'C to 100°C.

The reaction time varies mainly depending on the reaction temperature, raw material compounds and solvent used, but is usually 6 hours to 1 day.

Among the thiazole derivatives that are the raw material compounds of the present invention, 2
-Amino-4-chloromethyl-1°3-thiazole is
The method of Ziegler et al. [J.

Am, Chem, SoC, 682155 (1946)
] Synthesized according to . 2-guanidino-1,3-thiazole, 2-(N-methylguanidino)-1,3-thiazole, 2-dimethylhydrazino-4-chloromethyl-1
゜3-thiazole and 2-guanidino-4-(4-globutyl)-1,3-thiazole were prepared by the method of Yanagisawa et al. [J
, Med, Chem, -27°849 (1984
)]. 2-guanidino-4-(3-talobutyl)-1,3-thiazole, 2-guanidino-
4-(2-chloroethyl)-1,3-thiazole]-2
3-thiazole is produced by combining amidinothiourea, 1,5-dichloro-2-pentanone and 1,4-dichloro-2- Synthesized from butanone. Commercially available products were used for other raw materials.

[Effect] The novel thiazole derivative of the present invention has excellent gas
It has a pin prolonging effect and an antihypoxia lethal antagonistic effect, and is not toxic, so it is useful as a brain function improving agent.

The administration form of the compound (I) of the present invention includes, for example, oral administration in the form of tablets, capsules, granules, powders, or syrups, or parenteral administration in the form of injections or suppositories. These preparations are manufactured by well-known methods using additives such as excipients, binders, disintegrants, lubricants, stabilizers, and flavoring agents. The amount of use depends on the symptoms,
Although it varies depending on age, etc., 1-100 mg/kg body weight per day can be administered to adults, usually once a day or in divided doses.

<Gasping prolongation effect> 40 mg/kg of the drug was intraperitoneally administered to 5-6 week old male mice, and 2 hours later, the mice were decapitated and the duration of gasping was measured. As shown in Table 2, the compound of the present invention prolonged the gasping duration in mice.

Table 2 <Hypoxic/oxygen lethal antagonism> The compound of the present invention was intraperitoneally administered to 5- to 6-week-old DDY male mice, and 1 hour later, the mice were placed in a plastic box.
The chamber was filled with 96% nitrogen-4% oxygen gas, and the time until the mouse died was measured. As shown in Table 3, the compound of the present invention prolonged the lethal time of mice.

Table 3 = 147 - The present invention will be explained in more detail by giving examples below.

Example 1 Acid Castle L 1-(4-fluorophenyl)piperazine hydrochloride 1.5
g and 1.62 g of 4-chloromethyl-2-guanidino-1,3-thiazole hydrochloride in tetrahydrofuran (TH
F) -N,N-dimethylformamide (DMF) (1
:1) Suspend in 10ml and add 3.6ml of triethylamine
added. The reaction mixture was stirred at 80°C for 5 hours. Ethyl acetate was added, washed with water three times, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, compound 1 was obtained by isolation and purification using silica gel thin layer chromatography (methylene chloride: ethanol: aqueous ammonia = 50:8:1).

Melting point: 93-97°C Dissolve this compound in ethanol, add dropwise an excess of hydrogen chloride in ethanol (4.92M), add ether and crystallize to obtain 1.48g of the target compound (56
%) was obtained.

Melting point: 238°C Elemental analysis value (as C,, H-, □NgC, bFS) Calculated value: C40,60, H4,99, N18.94 Actual value: C4], 32. H4.77, N18.73NM
R spectrum (270Mt(z) (020)δ pp
m3.2-3.5 (8H, m), 4.28 (2H, s
), 6.93 (2H, s), 6.95 (2H, s)
, 7.30 (It(,s) Example 2 ■-(3-trifluoromethylphenyl)piperazine hydrochloride 1.5 g and 4-chloromethyl-2-guanidino-
1.29 g of 1,3-thiazole hydrochloride was dissolved in tetrahydrofuran (THF)-N,N-dimethylformamide (DM
F) ('L:1) was suspended in 10 ml, and 2.9 ml of triethylamine was added. The reaction mixture was stirred at 80°C for 5 hours. Ethyl acetate was added, washed with water three times, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, silica gel thin layer chromatography (methylene chloride:
It was isolated and purified using ethanol: aqueous ammonia = 50:8:1).

This was dissolved in ethanol, an excess of an ethanol solution (4.92 M) of hydrogen chloride was added dropwise, and ether was added to crystallize to obtain 1.28 g (53%) of the target compound.

Melting point: 235-245°C Elemental analysis value (C16H=JeC13FgS-) 120) Calculated value: C37,55, H4,72, N16.
42 actual measurements: C37, 37, H4, 7], N16.
12NMR spectrum (270MHz) (D20)
δ ppm2,8-3,3(4H,m), 3.3-3
．． 9 (4H, m), 4.27 (2H, s).

7.1-7.25 (3H, m), 7.3-7.45 (
2H, m) Example 3 1.5 g of l-(3-trifluoromethylphenyl)piperazine hydrochloride and 4-chloromethyl-2-guanidino-
1.29 g of 1,3-thiazole hydrochloride was dissolved in tetrahydrofuran (THF)-N,N-dimethylformamide (D
The suspension was suspended in 10 ml of MF) (1:1), and 2.9 ml of triethylamine was added. The reaction mixture was stirred at 80°C for 5 hours. Ethyl acetate was added, washed with water three times, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was isolated and purified by silica gel thin layer chromatography (methylene chloride:ethanol:aqueous ammonia=50:8:1).

After dissolving this in ethanol and adding an equivalent amount of an acetone solution of maleic acid, the resulting maleate salt was crystallized by adding ether to obtain the target compound.

NMR spectrum (270MHz) (D20) δ p
pm3.1-3.6 (8H, m), 4.23 (2H,
s), 6.10 (3H, s), 7.05-7.2 (
3H,m), 7.25-7.40 (2H,m) Example 4 Acid) 1-(2-methoxyphenyl)piperazine 1g and 4-
1.2 g of chloromethyl-2-guanidino-1゜3-thiazole hydrochloride was added to tetrahydrofuran (THF)-N,N
-dimethylformamide (DMF) (1:1)2
The suspension was suspended in 0 ml, and 1.81 ml of triethylamine was added. The reaction mixture was stirred at 80°C for 4 hours. Ethyl acetate was added, washed with water three times, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was isolated and purified by silica gel thin layer chromatography (methylene chloride:ethanol:ammonia water = 50:8:1). Dissolve this in ethanol and add a solution of hydrogen chloride in ethanol (4,9
2M) was added dropwise and crystallized by adding ether to obtain 1 g (45%) of the target compound.

Example 5 330 mg of 1-phenylpiperazine and 46 mg of 4-chloromethyl-2-guanidino-1,3-thiazole hydrochloride
0 mg was dissolved in 10 ml of tetrahydrofuran (TI(F)-N,N-dimethylformamide (DMF) (1:1), and 2 g of potassium carbonate was added.
The mixture was stirred at ℃ for 1 hour. Add ethyl acetate and wash with water 3 times.
1. After distilling off the solvent under reduced pressure, silica gel thin layer chromatography (
Methylene chloride: Ethanol: Aqueous ammonia = 50:
8:1) (500 mg). This compound (400 mg) was dissolved in ethanol, an excess ethanol solution of hydrogen chloride (4.92 M) was added dropwise, and ether was added to crystallize, yielding 400 m, g of the target compound.
(58%).

Example 6 1.2,3.4-tetrahydroquinoxaline 200 mg
and 460 mg of 4-chloromethyl-2-guanidino-1-93-thiazole hydrochloride in tetrahydrofuran (TH
F)-N,N-dimethylformamide (DMF) (
1: ], ) 110m, and 2g of potassium carbonate was added. The reaction mixture was stirred at 70°C for 2 hours. Ethyl acetate was added, washed with water three times, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, it was isolated and purified by silica gel thin layer chromatography (methylene chloride: ethanol: aqueous ammonia = 50:8:1) (280
mg). This compound (180 mg) was dissolved in ethanol, an excess solution of hydrogen chloride in ethanol (4.92 M) was added dropwise, and ether was added to crystallize to obtain 180 mg (30%) of the target compound.

Example 7 1.2,3.4-tetrahydroquinoxaline 200 mg
and 460 mg of 4-chloromethyl-2-guanisino 1,3-thiazole hydrochloride in tetrahydrofuran (THF
)-N,N-dimethylformamide (DMF) (1:
1) Dissolved in 10 ml and added 2 g of potassium carbonate. The reaction mixture was stirred at 70°C for 2 hours. Ethyl acetate was added, washed with water three times, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was isolated and purified by silica gel thin layer chromatography (methylene chloride: ethanol: aqueous ammonia = 50:8:1) (280 mg).

This compound (70 mg) was dissolved in ethanol, an equivalent amount of an ethanol solution of maleic acid was added, and the resulting maleate salt was crystallized by adding ether to obtain 100 mg of the target compound.

Example 8 Hi°''-3-7 right filled linone salt @1 tray-,,,,,,, (
Kido hydrochloride 1,2,3.4-tetrahydro-2-quinoxalinone 1 of compound 56 of J-4-
48 mg and 4-chloromethyl-2-guanidino-1,
227 mg of 3-thiazole hydrochloride was dissolved in 8 ml of N,N-dimethylformamide (DMF), and 227 mg of 3-thiazole hydrochloride was dissolved in 8 ml of N,N-dimethylformamide (DMF).
g was added. The reaction mixture was stirred at 70-75°C for 5 hours. Ethyl acetate was added, washed with water three times, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was isolated and purified by silica gel thin layer chromatography (methylene chloride: ethanol: ammonia water = 50:8:1) (180 mg).

The compound (70 mg) was dissolved in ethanol, an equivalent amount of an ethanol solution of maleic acid was added, and the resulting maleate salt was crystallized by adding ether to obtain 100 mg of the target compound.

Melting point 225°C Example 9 [1-(4-fluorophenyl)piperazine hydrochloride 611
mg and 491.5 mg of 2-amino-4-chloromethyl-1,3-thiazole hydrochloride in tetrahydrofuran (T
HF)-N,N-dimethylformamide (DMF) (1
: 1) Suspended in 8 ml and added 1 ml of triethylamine. The reaction mixture was stirred at 80°C for 7 hours.

Ethyl acetate was added, washed with water three times, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, it was isolated and purified by silica gel thin layer chromatography (methylene chloride: ethanol: aqueous ammonia = 50:8:1).
280mg). This compound (180 mg) was dissolved in ethanol, an excess ethanol solution of hydrogen chloride (4.92 M) was added dropwise, and ether was added to crystallize to obtain 600 mg (62%) of the target compound.

Melting point 146-152℃ NMR spectrum (270MHz) (CHCL3) δ
ppm3.2-3.4 (8H, m), 4.18 (2H
,s), 6.96(2H,s), 6.99(2H,
s), 6.99 (LH, s) Example 10 Decahydro-2-quinoxalinone 571 mg and 4
-Chloromethyl-2-guanidino-1°3-thiazole hydrochloride (1.00 g) was added to N,N-dimethylformamide (D
MF), and 2 g of potassium carbonate was added. The reaction mixture was stirred at 100°C for 6 hours. Ethyl acetate was added, washed with water three times, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was isolated and purified by silica gel thin layer chromatography (methylene chloride: nitanol: aqueous ammonia = 50:8:1). This was dissolved in ethanol, and a solution of hydrogen chloride in ethanol (4.92M
) was added dropwise in excess, and ether was added for crystallization to obtain 210 mg (15%) of the target compound.

Example 11 1-(1,3-thiazol-2-yl)piperazine 20
0 mg and 4-chloromethyl-2=guanidino-1,3
- 500 mg of thiazole hydrochloride was added to tetrahydrofuran (
THF) -N,N-dimethylformamide (DMF)
(1:1) and 2 g of potassium carbonate was added.

The reaction mixture was stirred at 20°C for 15 hours. Ethyl acetate was added, washed with water three times, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, it was isolated and purified by silica gel thin layer chromatography (methylene chloride: ethanol: aqueous ammonia = 50:8:1) (340 mg
) - 300 mg of this compound was dissolved in ethanol, and an excess ethanol solution of hydrogen chloride (4.92M) was added dropwise.
By adding ether and crystallizing, the target compound 30
Obtained 0 mg (59%).

Example 12 217 mg of 1-(3-trifluoromethylphenyl)piperazine hydrochloride and 4-(3-chloropropyl)-2-
255 mg of guanidino-1,3-thiazole hydrochloride was suspended in 5 ml of tetrahydrofuran (TI-IF)-N,N-dimethylformamide (DMF) (]-: , 1), and 0.6 ml of triethylamine and 1 equivalent of sodium iodide were added. added. The reaction mixture was stirred at 80°C for 16 hours. Ethyl acetate was added, washed with water three times, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was isolated and purified using silica gel thin layer chromatography (methylene chloride:ethanol:ammonia water = 50:8:1).

This was dissolved in ethanol, an excess of an ethanol solution (4.92 M) of hydrogen chloride was added dropwise, and ether was added to crystallize to obtain 30 mg (8%) of the target compound.

Example 13 100 mg of 1-(3-1-lifluoromethylphenyl)piperazine hydrochloride and 4-chloromethyl-2(2,2-
Dimethylhydrazo)-1゜3-thiazole 72.1mg
was suspended in 3 ml of tetrahydrofuran (TI-IF)-N,N-dimethylformamide (DMF) (1:1), and 0.2 ml of triethylamine was added. The reaction mixture was stirred at 60-80°C for 5 hours. Ethyl acetate was added, washed with water three times, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was isolated and purified by silica gel thin layer chromatography (ethyl acetate). Dissolve this in ethanol and add a solution of hydrogen chloride in ethanol (4,92
M) was added dropwise in excess, and ether was added for crystallization to obtain 96.6 mg (62%) of the target compound.

Melting point 129-136°C Example]-4 110 mg of the compound obtained in Example 9 was dissolved in methylene chloride 3
ml of Q, Q5 ml of benzoyl chloride, 0.0
6m] of pyridine and a catalytic amount of 4-dimethylaminopyridine were added and stirred at room temperature for 18 hours. Methylene chloride was added, washed with water three times, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was isolated and purified using silica gel thin layer chromatography (methylene chloride:ethanol:ammonia water = 109:8:1). Dissolve this in ethanol and add a solution of hydrogen chloride in ethanol (
4.92M) was added dropwise and crystallized by adding ether to obtain 88.9 mg (50%) of the compound.

Example 15 100 mg of the guanidinothiazole compound obtained in Example 2
was dissolved in 3 ml of pyridine, 0.24 ml of acetic anhydride was added, and the mixture was stirred at room temperature for 18 hours. Add ethyl acetate, wash three times with water, extract the aqueous layer once with ethyl acetate, combine the organic layers, and wash with an aqueous copper sulfate solution. The organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure,
It was isolated and purified by silica gel thin layer chromatography (methylene chloride:ethanol:ammonia water=168:8:1). Dissolve this in ethanol, add dropwise an excess of hydrogen chloride in ethanol (4.92M), add ether and crystallize to obtain 62.4 mg of the target compound.
(48%).

Example 16 460.1 mg of aminothiazole compound obtained in Example 9
was dissolved in 5 ml of acetone, 0.23 ml of benzoyl isothiocyanate was added, and the mixture was stirred at room temperature for 27 hours.
The mixture was heated under reflux for 4 hours.

After distilling off the solvent under reduced pressure, the residue was recrystallized from ethanol-acetone to isolate and purify 270 mg'i of the compound (36%). This compound was dissolved in ethanol, an excess of an ethanol solution of hydrogen chloride (4,921vi) was added dropwise, and ether was added to crystallize to obtain the target compound.

Example 17 A methanol (0.6 ml)-acetone (3 ml) solution of 250.2 mg of the benzoyl compound obtained in Example 16 was added to a mixture of 0.6 ml of potassium carbonate (0.483 M) aqueous solution and 0.6 ml of water. Add. This mixture was heated to 50”C.
The mixture was stirred for 2 days. After distilling off the solvent under reduced pressure, ice water 4
ml, stirred for 24 hours, filtered the generated precipitate,
By drying, 145.6 mg of the compound was isolated and purified (76.5%). This compound was dissolved in ethanol, an excess ethanol solution of hydrogen chloride (4.92M) was added dropwise, and ether was added to crystallize to obtain the target compound.

Example 18 108 mg of the thioureido compound obtained in Example 17 was added to 5 m
1 of ethanol and add methyl iodide. This mixture was heated to reflux for 5 days. The solvent was distilled off under reduced pressure,
110 mg (73%) of the target compound was obtained.

-168 Example 19 100 m of isothioureido compound obtained in Example 18
5 ml of an ethanol solution (30%) of methylamine was added to the mixture, and the mixture was heated under reflux for 20 hours.

After distilling off the solvent under reduced pressure, ml of water was added, and the mixture was made basic with saturated potassium carbonate water. The resulting oil was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and isolated and purified using silica gel thin layer chromatography (methylene chloride: ethanol: aqueous ammonia = 5Q:8:1). This compound was dissolved in ethanol, an excess ethanol solution of hydrogen chloride (4.92M) was added dropwise, and ether was added to crystallize, yielding 28.0m of the target compound.
g (30%) was obtained.

Table 4 below shows the physical data of a compound that was synthesized in the same manner and did not form a salt.

Claims (1)

[Claims] General formula A-M-Z-B (I) [wherein M is 1 to 2 aryl or 5 to 7
The nitrogen atom may be fused with a member cycloalkyl or/and may be substituted with 1 to 4 lower alkyl, aryl or/and oxo on the carbon atom.
represents a 5- to 7-membered heterocyclic group containing A is a substituent on one nitrogen atom of the M group; a hydrogen atom; an aryl group that may have a substituent on the ring; an aralkyl group that may have a substituent on the ring; A heteroaryl group that may have a substituent on the ring; a heteroaralkyl group that may have a substituent on the ring; or a heteroaryl group that may be fused with an aryl and have a substituent on the ring. Indicates an optionally cycloalkyl group. Z is a group bonded to the other nitrogen atom of the M group, and represents a straight chain or branched lower alkylene group which may be substituted with a single bond or a halogen atom. B has the formula ▲ mathematical formula, chemical formula, table, etc. ▼ (wherein R^1 is an optionally substituted amino group, an optionally substituted hydrazino group, an optionally substituted guanidino group, Indicates an optionally substituted isothioureido group or an optionally substituted thiourido group. ] and its pharmacologically acceptable salts.