JPH10324629A - Age formation-inhibitory composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject that inhibits formation of AGE with reduced side-effect by using a combination of Maillard reaction inhibitor with vitamin B6 or its pharmaceutically acceptable salt. SOLUTION: The objective composition is obtained by formulating 100 pts.wt. of a Maillard reaction compound inhibitor as an aminoguanidine or a compound represented by the formula [R<1> is H, a lower alkoxycarbonyl-lower-alkyl, phenyl- lower-alkyl; R<2> is amino, phenylsulfonylamino; R<3> is H, a lower alkyl; X is S, N(R<10> ) (R<10> is H, a lower alkoxycarbonyl-lower-alkyl); the broken line means a single bond or a double bond; A is carbonyl or =C(R<11> )- (R<11> is a lower alkyl)] an preferably 2-50 pts.wt. of vitamin B6 or its salt.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to AGE which is a cause of diabetic complications such as cataract, nephropathy and retinopathy.
(Advanced Glycation End p
The present invention relates to a novel composition for inhibiting AGE production, which inhibits the production of

[0002]

It is well known that proteins are glycosylated non-enzymatically. It is known that the glycation stage of proteins includes an early stage that produces a product such as glycated hemoglobin that is clinically used as an index for controlling diabetes and a later stage that produces AGE.

In the above-mentioned AGE, a free amino group existing in the protein in the early stage and an aldehyde group of a reducing sugar such as glucose are non-enzymatically reacted (glycation), and transferred to Amadori via an aldimine Sciff base. After the product is formed, it is considered that the product is formed from the Amadori transition product through a late stage such as long-time complex cleavage and condensation (this series of reactions is called the Maillard reaction). ). However, the details of the generation process of AGE are unknown.

It is known that the AGE has features such as fluorescence, brown color, formation of molecular crosslinks, and recognition by receptors of endothelial cells and macrophages. However, the structure of AGE has not been elucidated. Recently, Neeper M, et al
(J. Biol. Chem., 267, 14998, 1
992), the cDNA of the AGE receptor has been cloned, and various studies have been conducted.

The biological activities of AGE include (1) enhanced permeability of endothelial cells, (2) enhanced coagulation ability of endothelial cells,
(3) enhancement of endothelial cell angiogenesis, (4) enhancement of endothelial cell chemotaxis, (5) inactivation of EDRF (endothelial cell relaxation factor), (6) enhancement of monocyte chemotaxis, ( 7) Reported to show various biological activities such as enhanced production and secretion of macrophage TNF (tumor necrosis factor), IL-1 (interleukin 1), PDGF (platelet-derived growth factor), and (8) reduced erythrocyte deformability. Has been done (Latest Medicine, Volume 49.
2, p78-83, 1994).

[0006]

However, the AGE-modified protein has a structure different from that of the original protein (cross-linked) and has an abnormal property and function. For example, the solubility may be reduced, the enzyme may be less likely to be metabolized by a degrading enzyme, and may be easily covalently bound to another protein. Therefore, AGE is considered to be involved in the formation of various lesions, particularly diseases associated with aging and diabetic complications (cataract, vascular disorder, nephropathy, retinopathy, neuropathy, arteriosclerosis, etc.).

As a so-called Maillard reaction inhibitor that inhibits AGE production, for example, aminoguanidine is known (Shinshin-gaku, Vol. 49, No. 2, p78-83, 1).
994), and is expected to prevent and treat the above diseases. However, although aminoguanidine and other Maillard reaction inhibitors are effective in inhibiting AGE production, there is a problem in that they cause various side effects.

That is, when the aminoguanidine was intraperitoneally administered to mice at a rate of 50 mg/kg of body weight, the mortality rate was increased as compared with the control group (Auto).
Immu 15:311 to 314, 1993), and the administration of streptozocin-induced diabetic rats for 8 months increased the incidence of renal tumors [Diabetes 43 (Suppll): 20].
4, 1994] and the like have been reported as examples of side effects.

Therefore, an object of the present invention is to provide a composition for inhibiting AGE production which has few side effects.

[0010]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that a Maillard inhibitor is used in combination with vitamin B ₆ or a pharmaceutically acceptable salt thereof. As a result, the new fact that the prevention of the occurrence of side effects and the reduction of side effects can be achieved was found, and the present invention was completed.

That is, the AGE production inhibitory composition of the present invention is characterized by containing a Maillard reaction inhibitor and vitamin B ₆ or a pharmaceutically acceptable salt thereof. The composition for inhibiting AGE production of the present invention is
Various diabetic complications caused by GE production, such as coronary artery disease, peripheral circulatory disorders, cerebrovascular disorders,
Useful for treating and/or preventing diabetic neuropathy, nephropathy, arteriosclerosis, arteriosclerosis, cataracts and retinopathy, and diseases caused by aging, such as atherosclerosis and senile cataract, Side effects such as vomiting, convulsions, death, abnormal serum biochemical test values, and abnormal hematological test values can be effectively prevented or reduced.

Examples of the Maillard reaction inhibitor used in the AGE production inhibiting composition of the present invention include, for example, JP-A-62-1.
42114, JP-A-64-56614, JP-A-64-83059, and the following general formula (1) disclosed in JP-A-7-133264:

[0013]

[Chemical 16]

[Wherein R ¹ is a hydrogen atom, a lower alkoxycarbonyl lower alkyl group, a halogen atom as a substituent on the phenyl ring, a hydroxyl group, a nitro group, a lower alkyl group,
A phenyl lower alkyl group which may have 1 to 3 groups selected from a lower alkoxy group and a lower alkylthio group or a substituent selected from a halogen atom, a hydroxyl group, a nitro group, a lower alkyl group, a lower alkoxy group and a lower alkylthio group. A phenyl group which may have 1 to 3 groups is shown. R ² is an amino group, a phenylsulfonylamino group or a group which may have a substituent selected from the group consisting of a halogen atom, a hydroxyl group, an amino group and a lower alkanoylamino group on the phenyl ring:-N=R
⁴ (R ⁴ represents a lower alkylidene group, a lower alkylidene group having 1 to 2 lower cycloalkyl groups, a lower cycloalkylidene group, a diphenyl lower alkylidene group or a phenyl lower alkylidene group). R ³ has a hydrogen atom; a lower alkyl group; a lower alkenyl group; a phenyl lower alkoxy lower alkyl group; a phenyl group which may have a hydroxyl group; and 1 or 2 hetero atoms selected from the group consisting of a nitrogen atom and a sulfur atom. 5-membered or 6-membered unsaturated heterocycle lower alkyl group (the heterocycle may be condensed with a benzene ring, and may have a hydroxyl group as a substituent on the heterocycle and the condensed benzene ring) ;
Group: -W- (NH) b-CO -OR 5; (W represents a lower alkylene group, R ⁵ represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, b is 0 or 1.) Group: -Z-CO-R ^a {wherein Z represents a lower alkylene group and R ^a represents a group: -Tyr(OR ^a1 )-OR.
^b1 , group: -Leu-OR ^b2 , group: -Trp-OR ^b3 ,
Group: -Asp(OR ^a2 )-OR ^b4 , Group: -Ph-Gly
-OR ^b5 (in each group, R ^a1 and R ^a2 are a hydrogen atom or a benzyl group, R ^b1 , R ^b2 , R ^b3 , R ^b4 and R ^b5 are a hydrogen atom or a lower alkyl group) or a group: -N
(R ⁶ )-R ⁷ (R ⁶ is a lower alkyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a phenyl lower alkyl group, a lower cycloalkyl group,
As a substituent, halogen atom, hydroxyl group, nitro group, lower alkyl group, lower alkoxy group, lower alkylthio group, carboxy group, lower alkoxycarbonyl group, phenyl lower alkoxy group, lower alkylenedioxy group, morpholino group, halogenated lower alkyl group , Carboxy lower alkyl group, lower alkoxycarbonyl lower alkyl group, 6
-Hydroxy-2,5,7,8-tetramethyl-2-chromanyl-methyloxy group and 6-lower alkanoyloxy-2,5,7,8-tetramethyl-2-chromanyl-methyloxy group 1 to 3 hetero atoms selected from the group consisting of a phenyl group, naphthyl group, 3,4-dihydrocarbostyryl group, morpholino group, nitrogen atom, oxygen atom and sulfur atom
A 5-membered or 6-membered unsaturated heterocyclic lower alkyl group having two, and R ⁷ represents a hydrogen atom or a lower alkyl group). }; Or group:

[0015]

[Chemical 17]

{B represents a lower alkylene group, and R ⁸ has a hydroxyl group, a nitro group, an amino group, a halogen atom, a lower alkyl group, a lower alkoxy group, a phenoxy group, a phenyl lower alkyl group, a lower alkylthio group and a halogen atom. An optionally present phenylthio group, a benzoylamino group which may have 1 to 3 halogen atoms or a group: -O-
D-R ⁹ (D represents a lower alkylene group, and R ⁹ is a substituent selected from a halogen atom, a hydroxyl group, a nitro group, a lower alkyl group, a lower alkoxy group and a lower alkylthio group on the phenyl ring. A 5-membered member having one hetero atom selected from the group consisting of a phenyl group (which may be condensed with a benzene ring or a cyclohexane ring), a nitrogen atom, a sulfur atom and an oxygen atom, 6-membered saturated or unsaturated heterocyclic group (the hetero ring may be condensed with a benzene ring, and a group consisting of a hydroxyl group and a lower alkyl group as a substituent on the hetero ring and the benzene ring condensed with the hetero ring) Which may have 1 to 5 groups selected from the group), a lower cycloalkyl group or a naphthoquinone group), and n is 0.
Or represents an integer of 1 to 3}. X is -S- or -N (R ¹⁰⁾ - shows the (R ¹⁰ represents a hydrogen atom or a lower alkoxycarbonyl lower alkyl group.).

[0017]

[Chemical 18]

Represents a single bond or a double bond. However,

[0019]

[Chemical 19]

When A represents a single bond, A represents a carbonyl group,

[0021]

[Chemical 20]

When is a double bond, A is =C(R ¹¹ )-
{R ¹¹ is a lower alkyl group which may have 1 to 3 halogen atoms, a lower alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group, a pyridyl group, a thienyl group, a thiazolyl group, and a lower alkoxy group on the phenyl ring. Phenylcarbamoyl lower alkyl groups or groups which may have two:

[0023]

[Chemical 21]

(R¹²Is a halogen atom, hydroxyl group, nitro
Group, lower alkyl group, lower alkoxy group, lower alkyl
Thio group, carboxy group, phenylthio group or phenyl
Pheny which may have 1 to 3 halogen atoms on the ring
Represents a lower alkoxy group, and m is 0 or an integer of 1 to 3.
Are shown). Also, the above R^FourIs
R ^TenAnd may combine with each other to form a 6- to 8-membered ring.
(However, when forming this ring, A is a carbonyl group
Indicates). However, R³Is a hydrogen atom, and A is cal
When a bonyl group is shown, R¹Is a hydrogen atom or
Lucoxycarbonyl must not represent a lower alkyl group
Yes. Also R³And R¹¹And are bonded to each other to form a 5- to 8-membered ring.
Or a pharmaceutically acceptable compound thereof.
Dissolved salt, disclosed in JP-A-5-201193
The following general formula (2):

[0025]

[Chemical formula 22]

[Wherein R ¹³ is a hydrogen atom, a lower alkyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a phenoxy lower alkanoyl group,
A phenoxy lower alkanoyl group or a lower cycloalkyl group having a lower alkoxycarbonyl group on the phenyl ring is shown, and R ¹⁴ is a group: -NHR ¹⁶ {R ¹⁶ is a hydrogen atom, a halogen atom on the phenyl ring, a nitro group, a lower alkoxy group. And a phenylsulfonyl group which may have 1 to 3 substituents selected from lower alkyl groups, a phenyl lower alkanoyl group or a group: —CO—NHR ¹⁷ (R ¹⁷ is a lower alkyl group, and has a halogen atom on the phenyl ring. An phenyl group, a phenyl lower alkyl group, or a naphthyl group, which may otherwise be present) or R ¹⁴ is a group: -N
=R ¹⁸ {R ¹⁸ is a lower alkylidene group, a lower alkylidene group having 1 to 2 lower cycloalkyl groups, a halogen atom, a carboxyl group, a lower alkoxycarbonyl group, a nitro group, a hydroxyl group, a lower alkoxy group and a halogen atom on the phenyl ring. A substituent selected from the following lower alkyl groups:
A phenyl lower alkylidene group that may have three, a phenyl lower alkenylidene group that may have a nitro group on the phenyl ring, a lower alkenylidene group, a lower cycloalkylidene group, or a phenoxy lower alkylidene that may have a carboxyl group on the phenyl ring. Indicates a group. }, R ¹⁵ represents 2 hydrogen atoms, a phenyl lower alkylidene group or a phenyl lower alkenylidene group which may have a substituent selected from a halogen atom and a halogenated lower alkyl group on the phenyl ring, and Y is-
S- or -N(R ¹⁹ )- (R ¹⁹ represents a hydrogen atom, a lower alkyl group, a carboxy lower alkyl group or a lower alkoxycarbonyl lower alkyl group), and R ¹³ and R ¹⁶ or R ¹⁶ and R ¹⁹ May combine to form an oxoethylene group. However, when R ¹³ is a hydrogen atom, R ¹⁵ is 2 hydrogen atoms and Y is —S—, R ¹⁴ is a group: —NHR.
¹⁶ (R ¹⁶ is a hydrogen atom or a phenylsulfonyl group which may have a lower alkoxy group on the phenyl ring), or R ¹⁴ is a group: —N═R ¹⁸ (R ¹⁸ is a lower alkylidene group,
A phenyl lower alkylidene group that may have a substituent selected from a halogen atom, a nitro group, a hydroxyl group and a lower alkoxy group on the phenyl ring, or a phenyl lower alkenylidene group that may have a nitro group on the phenyl ring) I won't. Further, R ¹³ is a hydrogen atom, R
¹⁴ groups: If -N = R ¹⁸ and Y is -S- or -NH-, R ¹⁵ and R ¹⁸ must not be phenyl-lower alkylidene group at the same time. Furthermore, R ¹⁴ is a group: —NHR
^16, if R ¹⁵ is a hydrogen atom two a and Y is -S- R ¹³
And R ¹⁶ must not combine to form an oxoethylene group. ] The compound or its pharmaceutically acceptable salt represented by these, and General formula (3) disclosed by Unexamined-Japanese-Patent No. 6-305964:

[0027]

[Chemical formula 23]

[Wherein R²⁰Is a hydrogen atom or lower alk
R group, R^{twenty one}Is a hydrogen atom, a lower alkyl group, a lower alkyl
Lucanoyl group or lower alkoxycarbonyl lower alkyl
R represents a kill group^{twenty two}Is a hydrogen atom, a lower alkyl group or
Represents a lower alkanoyl group, R ^{twenty three}Is a hydrogen atom, lower alcohol
Canoyl group, benzoyl group or group:

[0029]

[Chemical formula 24]

(R^{twenty four}Is a phenyl group or lower alkoxy
Group is shown). Also R^{twenty two}And R ^{twenty three}Are together
Lower alkylidene group, diphenylmethylene group or
It may also represent a lower alkylidene group. V is -S-
Or -N-(R^{twenty five})-Indicates. R^{twenty five}Is a hydrogen atom,
Alkyl group, lower alkoxycarbonyl lower alkyl group
Or having a halogen atom as a substituent on the phenyl ring
It represents a phenyl lower alkyl group which may be different. Furthermore R^{twenty three}
And R^{twenty five}May combine with each other to form a 6- to 8-membered ring. ]
Is a compound represented by or a pharmaceutically acceptable salt thereof.
You can

Among the above-mentioned Maillard reaction inhibitors, considering the compatibility with vitamin B ₆ or a pharmaceutically acceptable salt thereof, aminoguanidine and 2-isopropylidenehydrazono-5-(N-phenyl) are preferable. Carbamoylmethyl)thiazolidin-4-one, 5-[N-(2-
Carboxy-4-methylphenyl)carbamoylmethyl]-2-isopropylidenehydrazonothiazolidine-
4-one, 5-[N-(3,4-difluorophenyl)
Carbamoylmethyl]-2-isopropylidenehydrazonothiazolidin-4-one, 5-[N-(2-carboxy-4-chlorophenyl)carbamoylmethyl]-2-
Isopropylidene hydrazonothiazolidin-4-one,
5-[N-(2-carboxy-4,5-dimethoxyphenyl)carbamoylmethyl]-2-isopropylidenehydrazonothiazolidin-4-one and 5-[N-(2
-Carboxy-4-fluorophenyl)carbamoylmethyl]-2-isopropylidenehydrazonothiazolidin-4-one or a pharmaceutically acceptable salt thereof, more preferably 2-isopropylidenehydrazono-5. Examples include -(N-phenylcarbamoylmethyl)thiazolidin-4-one or a pharmaceutically acceptable salt thereof.

The AGE production inhibitory composition of the present invention may contain 0.1 to 200 parts by weight of vitamin B ₆ or a pharmaceutically acceptable salt thereof per 100 parts by weight of the Maillard reaction inhibitor.

[0033]

BEST MODE FOR CARRYING OUT THE INVENTION Each group of the above general formula (1) will be specifically described as follows. Examples of the lower alkoxycarbonyl lower alkyl group include methoxycarbonylmethyl, ethoxycarbonylmethyl, 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl,
6-propoxycarbonylhexyl, 5-isopropoxycarbonylpentyl, 1,1-dimethyl-2-butoxycarbonylethyl, 2-methyl-3-t-butoxycarbonylpropyl, 2-pentyloxycarbonylethyl, hexyloxycarbonylmethyl group, etc. And an alkoxycarbonylalkyl group having 1 to 6 carbon atoms in the alkoxy moiety and 1 to 6 carbon atoms in the alkyl moiety.

Halogen atoms include fluorine, chlorine, bromine and iodine atoms, whether present independently or in other groups. The lower alkyl group, whether present independently or in other groups, includes, for example, methyl, ethyl, propyl, isopropyl, butyl,
Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms such as t-butyl, pentyl and hexyl.

Lower alkoxy groups, whether independently present or in other groups, include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy,
Examples thereof include a straight-chain or branched alkoxy group having 1 to 6 carbon atoms such as hexyloxy. As the lower alkylthio group, an alkyl moiety such as methylthio, ethylthio, propylthio, butylthio, isopropylthio, t-butylthio, pentylthio, and hexylthio group has 1 to 6 carbon atoms.
And an alkylthio group which is a linear or branched alkyl group.

A group selected from a halogen atom, a hydroxyl group, a nitro group, a lower alkyl group, a lower alkoxy group and a lower alkylthio group as a substituent on the phenyl ring is 1-3.
As the phenyl lower alkyl group which may have,
Benzyl, 2-phenylethyl, 1-phenylethyl,
3-phenylpropyl, 4-phenylbutyl, 1,1-
Dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, 2-methyl-3-phenylpropyl, 2-phenylpropyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 4
-Chlorobenzyl, 4-bromobenzyl, 4-iodobenzyl, 2-(2-fluorophenyl)ethyl, 3-
(3-chlorophenyl)propyl, 4-(4-bromophenyl)butyl, 5-(4-iodophenyl)pentyl, 6-(3-fluorophenyl)hexyl, 1,1-
Dimethyl-2-(2-chlorophenyl)ethyl, 2-methyl-3-(4-chlorophenyl)propyl, 2-(4
-Fluorophenyl)propyl, 2,5-difluorobenzyl, 2,3-dichlorobenzyl, 2-(2,4-dibromophenyl)ethyl, 2-(2,6-difluorophenyl)ethyl, 3-(3,4 -Dichlorophenyl)propyl, 4-(3,5-dibromophenyl)butyl, 5
-(3,4-difluorophenyl)pentyl, 6-
(3,5-dichlorophenyl)hexyl, 2,4,5,
-Trifluorobenzyl, 2-(2,4,6-trichlorophenyl)ethyl, 3-(3,4,5-trifluorophenyl)propyl, 2-hydroxybenzyl, 3-hydroxybenzyl, 4-hydroxybenzyl, 2 -(2
-Hydroxyphenyl)ethyl, 3-(3-hydroxyphenyl)propyl, 4-(4-hydroxyphenyl)
Butyl, 5-(4-hydroxyphenyl)pentyl, 6
-(3-hydroxyphenyl)hexyl, 1,1-dimethyl-2-(2-hydroxyphenyl)ethyl, 2-methyl-3-(4-hydroxyphenyl)propyl, 2-
(4-hydroxyphenyl)propyl, 2,5-dihydroxybenzyl, 2,3-dihydroxybenzyl, 2-
(2,4-dihydroxyphenyl)ethyl, 2-(2,2
6-dihydroxyphenyl)ethyl, 3-(3,4-dihydroxyphenyl)propyl, 4-(3,5-dihydroxyphenyl)butyl, 5-(3,4-dihydroxyphenyl)pentyl, 6-(3,5- Dihydroxyphenyl)hexyl, 2,4,5,-trihydroxybenzyl, 2-(2,4,6-trihydroxyphenyl)ethyl, 3-(3,4,5-trihydroxyphenyl)propyl, 2-nitrobenzyl , 3-nitrobenzyl, 4-
Nitrobenzyl, 2-(2-nitrophenyl)ethyl,
3-(3-nitrophenyl)propyl, 4-(4-nitrophenyl)butyl, 5-(4-nitrophenyl)pentyl, 6-(3-nitrophenyl)hexyl, 1,1-
Dimethyl-2-(2-nitrophenyl)ethyl, 2-methyl-3-(4-nitrophenyl)propyl, 2-(4
-Nitrophenyl)propyl, 2,5-dinitrobenzyl, 2,3-dinitrobenzyl, 2-(2,4-dinitrophenyl)ethyl, 2-(2,6-dinitrophenyl)ethyl, 3-(3,4 -Dinitrophenyl)propyl, 4-(3,5-dinitrophenyl)butyl, 5-
(3,4-dinitrophenyl)pentyl, 6-(3,5
-Dinitrophenyl)hexyl, 2,4,5-trinitrobenzyl, 2-(2,4,6-trinitrophenyl)
Ethyl, 3-(3,4,5-trinitrophenyl)propyl, 2-methylbenzyl, 3-methylbenzyl, 4-
Methylbenzyl, 2-(2-methylphenyl)ethyl,
3-(3-methylphenyl)propyl, 4-(4-methylphenyl)butyl, 5-(4-methylphenyl)pentyl, 6-(3-methylphenyl)hexyl, 1,1-
Dimethyl-2-(2-methylphenyl)ethyl, 2-methyl-3-(4-methylphenyl)propyl, 2-(4
-Methylphenyl)propyl, 2,5-dimethylbenzyl, 2,3-dimethylbenzyl, 2-(2,4-dimethylphenyl)ethyl, 2-(2,6-dimethylphenyl)ethyl, 3-(3,4) -Dimethylphenyl)propyl, 4-(3,5-dimethylphenyl)butyl, 5-
(3,4-dimethylphenyl)pentyl, 6-(3,5
-Dimethylphenyl)hexyl, 2,4,5-trimethylbenzyl, 2-(2,4,5-trimethylphenyl)
Ethyl, 3-(2,4,6-trimethylphenyl)propyl, 2-methoxybenzyl, 3-methoxybenzyl,
4-methoxybenzyl, 4-ethoxybenzyl, 4-propoxybenzyl, 4-isopropoxybenzyl, 4-
Butoxybenzyl, 4-t-butoxybenzyl, 4-pentyloxybenzyl, 4-hexyloxybenzyl,
2,3-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,5-diethoxybenzyl, 2,6-diethoxybenzyl, 3,4-dimethoxybenzyl, 3,5-diethoxybenzyl, 2,3,4 -Trimethoxybenzyl, 2,3,5-trimethoxybenzyl, 2,3,6-
Triethoxybenzyl, 3,4,5-triethoxybenzyl, 2-(2-methoxyphenyl)ethyl, 3-(4
-Ethoxyphenyl)propyl, 3-(4-propoxyphenyl)butyl, 4-(4-butoxyphenyl)butyl, 1,1-dimethyl-2-(4-methoxyphenyl)
Ethyl, 5-(4 pentyloxyphenyl)hexyl,
3-(3,4-diethoxyphenyl)propyl, 2-
(2,4,5-Trimethoxyphenyl)ethyl, 3-
(3,4,5-triethoxyphenyl)propyl, 2-
Methylthiobenzyl, 3-(2-ethylthio)benzyl, 4-(3-propylthio)benzyl, 2-(2-methylthiophenyl)ethyl, 3-(3-methylthiophenyl)propyl, 4-(4-methylthiophenyl)butyl , 5-(4-methylthiophenyl)pentyl, 6-
(3-Methylthiophenyl)hexyl, 1,1-dimethyl-2-(2-methylthiophenyl)ethyl, 2-methyl-3-(4-methylthiophenyl)propyl, 2-
(4-methylphenyl)propyl, 2,5-di(4-butylthio)benzyl, 2,3-dimethylthiobenzyl,
2-(2,4-dimethylthiophenyl)ethyl, 2-
(2,6-Dimethylthiophenyl)ethyl, 4-(3,3
5-dimethylthiophenyl)butyl, 5-(3,4-dimethylthiophenyl)pentyl, 6-(3,5-dimethylthiophenyl)hexyl, 2,4,5-tri(6-hexylthio)benzyl, 2- A halogen atom, a hydroxyl group, a nitro group, or a carbon number of 1 to 6 as a substituent on a phenyl ring such as (2,4,6-trimethylthiophenyl)ethyl or 3-(3,4,5-trimethylthiophenyl)propyl group.
A straight-chain or branched alkyl group, a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, and a straight-chain or branched alkylthio group having 1 to 6 carbon atoms. Three
A phenyl lower alkyl group having an optionally present phenyl group and the alkyl moiety being a linear or branched alkyl group having 1 to 6 carbon atoms.

As the phenyl group which may have 1 to 3 groups selected from a halogen atom, a hydroxyl group, a nitro group, a lower alkyl group, a lower alkoxy group and a lower alkylthio group as a substituent, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2
-Chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl,
2,3-dichlorophenyl, 2,3-difluorophenyl, 2,5-dibromophenyl, 2,6-dichlorophenyl, 2,3,5-trifluorophenyl, 3,4,5
-Trichlorophenyl, 2-hydroxyphenyl, 3-
Hydroxyphenyl, 4-hydroxyphenyl, 2,5
-Dihydroxyphenyl, 2,3-dihydroxyphenyl, 2,4,5-trihydroxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl,
2,3-dinitrophenyl, 2,4,5-trinitrophenyl, 2-methylphenyl, 3-methylphenyl, 4
-Methylphenyl, 3-ethylphenyl, 4-ethylphenyl, 4-propylphenyl, 4-butylphenyl,
4-pentylphenyl, 4-hexylphenyl, 4-isopropylphenyl, 4-t-butylphenyl, 2,3
-Dimethylphenyl, 2,5-dimethylphenyl, 2,
6-dimethylphenyl, 3,4-dimethylphenyl,
3,5-diethylphenyl, 2,3,5-trimethylphenyl, 3,4,5-trimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl,
4-propoxyphenyl, 4-butoxyphenyl, 4-
Pentyloxyphenyl, 4-hexyloxyphenyl, 4-isopropoxyphenyl, 4-t-butoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-
Dimethoxyphenyl, 3,5-diethoxyphenyl,
2,3,5-trimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-methylthiophenyl, 3-ethylthiophenyl, 4-propylthiophenyl, 4-butylthiophenyl, 4-pentylthiophenyl, 4 -Hexylthiophenyl, 2,3-dimethylthiophenyl,
A halogen atom, a hydroxyl group, a nitro group, a straight or branched chain having 1 to 6 carbon atoms as a substituent such as 2,4-dimethylmethylthiophenyl, 3,4-dimethylthiophenyl, and 3,4,5-trimethylthiophenyl group. -Shaped alkyl group, carbon number 1
6 straight-chain or branched alkoxy groups and 1 carbon atom
A phenyl group which may have 1 to 3 groups selected from a straight-chain or branched alkylthio group of ~6.

As a lower alkanoylamino group, whether it is present independently or in another group, for example formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, penta Examples thereof include amino groups having a linear or branched alkanoyl group having 1 to 6 carbon atoms such as noylamino, t-butylcarbonylamino and hexanoylamino.

Examples of the phenylsulfonylamino group which may have a substituent selected from a halogen atom, a hydroxyl group, an amino group and an alkanoylamino group on the phenyl ring include, for example, phenylsulfonylamino and 2-
Fluorophenylsulfonylamino, 3-fluorophenylsulfonylamino, 4-fluorophenylsulfonylamino, 2-chlorophenylsulfonylamino, 3-
Chlorophenylsulfonylamino, 4-chlorophenylsulfonylamino, 4-bromophenylsulfonylamino, 4-iodophenylsulfonylamino, 2-hydroxyphenylsulfonylamino, 3-hydroxyphenylsulfonylamino, 4-hydroxyphenylsulfonylamino, 2-aminophenylsulfonyl Amino, 3-
Aminophenylsulfonylamino, 4-aminophenylsulfonylamino, 2-acetylaminophenylsulfonylamino, 3-acetylaminophenylsulfonylamino, 4-acetylaminophenylsulfonylamino,
Examples thereof include 2-butyrylaminophenylsulfonylamino and 4-butyrylaminophenylsulfonylamino groups.

Examples of the lower alkylidene group include methylene, ethylidene, propylidene, isopropylidene,
Examples thereof include linear or branched alkylidene groups having 1 to 6 carbon atoms such as butylidene, t-butylidene, pentylidene and hexylidene groups. 1 to 2 lower cycloalkyl groups
Examples of the lower alkylidene group having 2 are 2-cyclopropylethylidene, 1-cyclobutylethylidene,
3-cyclopentylpropylidene, 4-cyclohexylbutylidene, 1,1-dimethyl-cycloheptylethylidene, 5-cycloortylpentylidene, 6-cyclohexylhexylidene, 2-methyl-3-cyclohexylpropylidene, dicyclopropyl Examples thereof include a linear or branched alkylidene group having 1 to 2 carbon atoms and 1 to 2 cycloalkyl groups having 3 to 8 carbon atoms such as methylene and 2-dicyclopropylethylidene group.

Examples of the lower cycloalkylidene group are cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclohexylidene, cycloheptylidene,
Examples thereof include a cycloalkylidene group having 3 to 8 carbon atoms such as a cyclooctylidene group. Examples of the diphenyl lower alkylidene group include 1,1-diphenylethylidene,
2,2-diphenylethylidene, 3,3-diphenylpropylidene, 4,4-diphenylbutylidene, 5,5-
Examples thereof include a diphenylalkylidene group which is a linear or branched alkylidene group having 1 to 6 carbon atoms in the alkylidene moiety such as diphenylpentylidene and 6,6-diphenylhexylidene group.

Examples of the phenyl lower alkylidene group include benzylidene, 2-phenylethylidene, 1-phenylethylidene, 3-phenylpropylidene, 4-phenylbutylidene, 1,1-dimethyl-2-phenylethylidene and 5-phenylpentylidene. , 6-phenylhexylidene, 2-methyl-3-phenylpropylidene, 2
-A phenylalkylidene group which is a linear or branched alkylidene group having 1 to 6 carbon atoms in the alkylidene moiety such as a phenylpropylidene group.

Examples of the lower alkenyl group include linear or branched alkenyl having 2 to 6 carbon atoms such as vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl and 2-hexenyl. The group is raised. As the phenyl lower alkoxy lower alkyl group,
For example, benzyloxymethyl, 2-phenylethoxymethyl, 1-phenylethoxymethyl, 3-phenylpropoxymethyl, 4-phenylbutoxymethyl, 1,1-
A linear or branched alkoxy having 1 to 6 carbon atoms in the alkoxy moiety such as dimethyl-2-benzyloxypropyl, 5-benzyloxypentyl, 6-benzyloxyhexyl, and 2-methyl-3-benzyloxypropyl group. Examples thereof include a phenylalkoxyalkyl group which is a group and which is a linear or branched alkyl group having an alkyl moiety having 1 to 6 carbon atoms.

Examples of the phenyl group which may have a hydroxyl group include 2-hydroxyphenyl, 3-hydroxyphenyl and 4-hydroxyphenyl groups. 5-membered or 6-membered unsaturated heterocycle lower alkyl group having 1 to 2 heteroatoms selected from the group consisting of nitrogen atom and sulfur atom (the heterocycle may be condensed with a benzene ring, And optionally having a hydroxyl group on the condensed benzene ring), 2-pyridinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl, 2-(3-pyridinyl)ethyl, 3-(3-pyridinyl) ) Propyl, 4-(3-pyridinyl)butyl,
5-(3-pyridinyl)pentyl, 6-(3-pyridinyl)hexyl, 1-methyl-2-(3-pyridinyl)propyl, 2-hydroxy-3-pyridinylmethyl, 4-
Hydroxy-3-pyridinylmethyl, 6-hydroxy-
3-pyridinylmethyl, 2-thienylmethyl, 2-(2
-Thiethyl)ethyl, 3-(2-thienyl)propyl,
4-(2-thienyl)butyl, 5-(2-thienyl)pentyl, 6-(2-thienyl)hexyl, 1-methyl-
2-(2-thienyl)propyl, 3-hydroxy-2-
Thienylmethyl, 5-hydroxy-2-thienylmethyl, 1-imidazolylmethyl, 2-imidazolylmethyl, 4-imidazolylmethyl, 5-imidazolylmethyl, 2-(4-imidazolyl)ethyl, 3-(2-imidazolyl)propyl, 4-(4-imidazolyl)butyl, 5-(4-imidazolyl)pentyl, 6-(4-imidazolyl)hexyl, 1-methyl-2-(4-imidazolyl)propyl, 2-hydroxy-4-imidazolylmethyl, 1 -Indolylmethyl, 3-indolylmethyl, 2-(3-indolyl)ethyl, 3-(3-indolyl)propyl, 4-(3-indolyl)butyl, 5-
(3-Indolyl) Pentyl, 6-(3-Indolyl)
Hexyl, 4-hydroxy-3-indolylmethyl, 2
-Hydroxy-3-indolylmethyl, 6-hydroxy-3-indolylmethyl, 2-pyrrolylmethyl, 5-pyrazolylmethyl, 2-pyrimidinylmethyl, 2-pyrazinylmethyl, 2-thiazolylmethyl, 2-quinolylmethyl, 2-benzimidazolylmethyl, The alkyl moiety having a 5- or 6-membered unsaturated heterocycle having 1 to 2 heteroatoms selected from the group consisting of nitrogen atom and sulfur atom such as 3-benzothienylmethyl group has 1 to 6 carbon atoms.
And a straight-chain or branched alkyl group.

Examples of the lower alkylene group include methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene and hexamethylene. Examples thereof include linear or branched alkylene groups having 1 to 6 carbon atoms such as groups.

Examples of the phenyl lower alkyl group include benzyl, 2-phenylethyl, 1-phenylethyl,
3-phenylpropyl, 4-phenylbutyl, 1,1-
A linear or branched alkyl group having 1 to 6 carbon atoms such as dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, 2-methyl-3-phenylpropyl, 2-phenylpropyl group Examples thereof include a phenylalkyl group which is an alkyl group.

Examples of the carboxy lower alkyl group include carboxymethyl, 2-carboxyethyl, 1-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 1,1-dimethyl-2-carboxyethyl,
5-carboxypentyl, 6-carboxyhexyl, 2
Examples thereof include a carboxyalkyl group which is a linear or branched alkyl group having 1 to 6 carbon atoms in the alkyl moiety such as -methyl-3-carboxypropyl.

Examples of the lower cycloalkyl group include cycloalkyl groups having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups. The lower alkoxycarbonyl group is, for example, a straight chain or branched chain having 1 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl. The alkoxycarbonyl group of is mentioned.

Examples of the phenyl lower alkoxy group include benzyloxy, 2-phenylethoxy, 3-phenylpropoxy, 1-phenylisopropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, 6-phenylhexyloxy and 2-methyl. Examples thereof include a linear or branched phenylalkoxy group having 1 to 6 carbon atoms in the alkoxy moiety such as -3-phenylpropoxy group.

Examples of the halogenated lower alkyl group include chloromethyl, bromomethyl, iodomethyl, fluoromethyl, dichloromethyl, dibromomethyl, difluoromethyl, trichloromethyl, tribromomethyl, trifluoromethyl, 2-chloromethyl, 2-bromomethyl. , 2-fluoromethyl, 1,2-dichloroethyl,
2,2-difluoroethyl, 1-chloro-2-fluoroethyl, 3-fluoropropyl, 4-chlorobutyl, 5
Straight-chain or branched halogen having 1 to 3 halogen atoms such as -chloropentyl, 6-bromohexyl, and 3-fluoro-2-methylpropyl group, and having an alkyl moiety having 1 to 6 carbon atoms Alkyl group.

Examples of the lower alkylenedioxy group include alkylenedioxy groups having 1 to 3 carbon atoms such as methylenedioxy, ethylenedioxy and trimethylenedioxy groups. As a substituent, a halogen atom, a hydroxyl group,
Nitro group, lower alkyl group, lower alkoxy group, lower alkylthio group, carboxyl group, lower alkoxycarbonyl group, phenyl lower alkoxy group, lower alkylenedioxy group, morpholino group, halogenated lower alkyl group,
Carboxy lower alkyl group, lower alkoxycarbonyl lower alkyl group, 6-hydroxy-2,5,7,8-tetramethyl-2-chromanylmethyloxy group and 6-
The phenyl group which may have 1 to 3 groups selected from lower alkanoyloxy-2,5,7,8-tetramethyl-2-chromanyl-methyloxy group includes phenyl, 2-fluorophenyl and 3-fluoro. Phenyl, 4
-Fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-bromophenyl,
4-iodophenyl, 2,3-dichlorophenyl, 2,
3-difluorophenyl, 2,5-dibromophenyl,
2,6-dichlorophenyl, 2,3,5-trifluorophenyl, 3,4,5-trichlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2,5-dihydroxyphenyl, 2,3
-Dihydroxyphenyl, 2,4,5-trihydroxyphenyl, 2-nitrophenyl, 3-nitrophenyl,
4-nitrophenyl, 2,3-dinitrophenyl, 2,
4,5-trinitrophenyl, 2-methylphenyl, 3
-Methylphenyl, 4-methylphenyl, 3-ethylphenyl, 4-ethylphenyl, 4-propylphenyl,
4-butylphenyl, 4-pentylphenyl, 4-hexylphenyl, 4-isopropylphenyl, 4-t-butylphenyl, 2,3-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3, 4-
Dimethylphenyl, 3,5-diethylphenyl, 2,
3,5-trimethylphenyl, 3,4,5-trimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 4
-Ethoxyphenyl, 4-propoxyphenyl, 4-butoxyphenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl, 4-isopropoxyphenyl,
4-t-butoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,5-diethoxyphenyl, 2,3,5-tri Methoxyphenyl,
3,4,5-Trimethoxyphenyl, 2-methylthiophenyl, 3-ethylthiophenyl, 4-propylthiophenyl, 4-butylthiophenyl, 4-pentylthiophenyl, 4-hexylthiophenyl, 2,3-dimethyl Thiophenyl, 2,4-dimemethylthiophenyl, 3,
4-dimethylthiophenyl, 3,4,5-trimethylthiophenyl, 2-carboxyphenyl, 3-carboxyphenyl, 4-carboxyphenyl, 2,3-dicarboxyphenyl, 3,4-dicarboxyphenyl, 2,4
-Dicarboxyphenyl, 2-methoxycarbonylphenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 2-ethoxycarbonylphenyl, 3-ethoxycarbonylphenyl, 4-ethoxycarbonylphenyl, 4-isopropoxycarbonylphenyl, 4- Pentyloxycarbonylphenyl, 4-propoxycarbonylphenyl, 4-t-butoxycarbonylphenyl, 4-hexyloxycarbonylphenyl, 3,4-dimethoxycarbonylphenyl, 2,4-
Dimethoxycarbonylphenyl, 2,3-dimethoxycarbonylphenyl, 3-methoxycarbonyl-4-ethoxycarbonylphenyl, 3,4-diethoxycarbonylphenyl, 2,4-diethoxycarbonylphenyl,
2,3-diethoxycarbonylphenyl, 2-benzyloxyphenyl, 3-benzyloxyphenyl, 4-benzyloxyphenyl, 2,4-dibenzylphenyl,
4,6-dibenzylphenyl, 4-(2-phenylethoxy)phenyl, 4-(3-phenylpropoxy)phenyl, 4-(4-phenylbutoxy)phenyl, 4-
(5-Phenylpentyloxy)phenyl, 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-
Methylenedioxyphenyl, 2,3-propylenedioxyphenyl, 3,4-propylenedioxyphenyl, 2
-Morpholinophenyl, 3-morpholinophenyl, 4-
Morpholinophenyl, 2-chloromethylphenyl, 2-
Fluoromethylphenyl, 2-bromomethylphenyl,
4-iodomethylphenyl, 2-dichloromethylphenyl, 3-difluoromethylphenyl, 4-dibromomethylphenyl, 3-trichloromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-(1,2 -Dichloroethyl)phenyl, 2-
(3-Fluoropropyl)phenyl, 3-(4-chlorobutyl)phenyl, 4-(5-chloropentyl)phenyl, 4-(6-bromohexyl)phenyl, 2,3,4
-Trichloromethylphenyl, 2-carboxymethylphenyl, 3-carboxymethylphenyl, 4-carboxymethylphenyl, 3,5-dicarboxymethylphenyl, 4-(2-carboxyethyl)phenyl, 3-(4
-Carboxybutyl)phenyl, 4-(6-carboxyhexyl)phenyl, 2-methoxycarbonylmethylphenyl, 4-methoxycarbonylmethylphenyl, 2,
6-dimethoxycarbonylmethyl, 4-ethoxycarbonylmethylphenyl, 3-butoxycarbonylmethylphenyl, 4-(4-ethoxycarbonylbutyl)phenyl, 3-(6-hexyloxycarbonylhexyl)phenyl, 3-(6-hexyloxy Carbonylhexyl)phenyl, 3-(6-hydroxy-2,5,7,8
-Tetramethylchroman-2-yl)methoxyphenyl, 4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxyphenyl, 3-(6
-Propionyloxy-2,5,7,8-tetramethylchroman-2-yl)methoxyphenyl, 4-(6-hexanoyloxy-2,5,7,8-tetramethylchroman-2-yl)methoxyphenyl , 4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl)methoxyphenyl, 2-carboxy-4-methylphenyl, 2-carboxy-6-methylphenyl, 4-carboxy-6 -Methylphenyl, 2-carboxy-4-
Ethylphenyl, 2-carboxy-4-chlorophenyl, 3-carboxy-4-bromophenyl, 4-carboxy-6-chlorophenyl, 2-carboxy-4-bromophenyl, 2-methoxycarbonyl-5-methylphenyl, 3-methoxy. Carbonyl-6-methylphenyl,
Halogen as a substituent of 2-methoxycarbonyl-6-chlorophenyl, 3-methyl-5-fluorophenyl, 2-carboxy-3-fluoro-4-methylphenyl, 2-carboxy-4-methyl-6-methoxyphenyl group and the like. Atom, hydroxyl group, nitro group, straight-chain or branched alkyl group having 1 to 6 carbon atoms, straight-chain or branched alkoxy group having 1 to 6 carbon atoms, straight-chain having 1 to 6 carbon atoms Alternatively, a branched alkylthio group, a carboxyl group, an alkoxycarbonyl group which is a linear or branched alkoxy group having 1 to 6 carbon atoms in the alkoxy portion, and a linear or branched alkoxy group having 1 to 6 carbon atoms in the alkoxy portion. A branched alkoxy group having a phenylalkoxy group, an alkylenedioxy group, a morpholino group, 1 to 3 halogen atoms, and a linear or branched halogenated alkyl moiety having 1 to 6 carbon atoms Alkyl group, straight-chain or branched carboxyalkyl group having 1 to 6 carbon atoms in the alkyl portion, straight-chain or branched carboxyalkyl group having 1 to 6 carbon atoms in the alkoxy portion, and 1 to 6 carbon atoms in the alkyl portion 6 straight-chain or branched alkoxycarbonylalkyl group, 6-hydroxy-2,5,7,8-
6-alkanoyloxy-2,5,7, which is a tetramethyl-2-chromylmethyloxy group and an alkanoyloxy group having 1 to 6 carbon atoms in the alkanoyloxy moiety.
Examples thereof include a phenyl group which may have 1 to 3 groups selected from 8-tetramethyl-2-chromylmethyloxy group.

Examples of the 5- or 6-membered unsaturated heterocyclic lower alkyl group having 1 to 2 heteroatoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom include 2-pyridinylmethyl and 3-pyridinylmethyl. , 4-
Pyridinylmethyl, 2-(3-pyridinyl)ethyl, 3
-(3-pyridinyl)propyl, 4-(3-pyridinyl)butyl, 5-(3-pyridinyl)pentyl, 6-
(3-pyridinyl)hexyl, 1-methyl-2-(3-
Pyridinyl)propyl, 2-thienylmethyl, 3-thienylmethyl, 4-thienylmethyl, 2-(2-thienyl)ethyl, 3-(2-thienyl)propyl, 3-(2
-Thienyl)propyl, 4-(2-thienyl)butyl,
5-(2-thienyl)pentyl, 6-(2-thienyl)
Hexyl, 1-methyl-2-(2-thienyl)propyl, 2-imidazolylmethyl, 4-imidazolylmethyl, 5-imidazolylmethyl, 2-(1-imidazolyl)ethyl, 3-(4-imidazolyl)propyl, 4-
(4-imidazolyl)butyl, 5-(4-imidazolyl)pentyl, 6-(4-imidazolyl)hexyl, 1
-Methyl-2-(1-imidazolyl)propyl, 2-pyrrolylmethyl, 2-pyrimidinylmethyl, 2-pyrazinylmethyl, 2-thiazolylmethyl, 2-furylmethyl,
3-furylmethyl, 2-(2-furyl)methyl, 3-
(3-furyl)propyl, 4-(2-furyl)butyl,
Examples thereof include unsaturated heterocyclic alkyl groups having 1 to 6 carbon atoms in the alkyl moiety such as 5-(3-furyl)pentyl and 6-(2-furyl)hexyl groups.

Examples of the phenylthio group which may have a halogen atom include 2-chlorophenylthio and 3-
Examples thereof include chlorophenylthio, 4-chlorophenylthio, 2-bromophenylthio, 3-fluorophenylthio, 4-fluorophenylthio and 4-iodophenylthio groups. Examples of the phenylalkylthio group include benzylthio, 2-phenylethylthio, 1-phenylethylthio, 3-phenylpropylthio, 4-phenylbutylthio, 1,1-dimethyl-2-phenylethylthio, 5-phenylpentylthio, The number of carbon atoms in the alkyl moiety such as 6-phenylhexylthio, 2-methyl-3-phenylpropylthio and 2-phenylpropylthio groups is 1
A phenylalkylthio group, which is a straight-chain or branched alkyl group of 6 groups.

Examples of the benzoylamino group which may have 1 to 3 halogen atoms are, for example, benzoylamino, 2-fluorobenzoylamino, 3-fluorobenzoylamino, 4-fluorobenzoylamino, 2-chlorobenzoylamino and 3-chlorobenzoylamino. Chlorobenzoylamino,
4-chlorobenzoylamino, 4-bromobenzoylamino, 4-iodobenzoylamino, 2,3-dichlorobenzoylamino, 3,4-dichlorobenzoylamino, 2,4-dichlorobenzoylamino, 3,4,5-
1 halogen atom such as trichlorobenzoylamino group
Examples include benzoylamino groups which may have 3 to 3.

A phenyl group which may have 1 to 3 groups selected from a halogen atom, a hydroxyl group, a nitro group, a lower alkyl group, a lower alkoxy group and a lower alkylthio group as a substituent on the phenyl ring (wherein the phenyl ring is benzene. A ring or a cyclohexane ring may be fused),
For example, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 2,3-dichlorophenyl, 2,3- Difluorophenyl, 2,5-dibromophenyl, 2,6-dichlorophenyl, 2,3,5
-Trifluorophenyl, 3,4,5-trichlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2,5-dihydroxyphenyl, 2,3-dihydroxyphenyl, 2,4,5-
Trihydroxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2,3-dinitrophenyl, 2,4,5-trinitrophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl , 3-ethylphenyl, 4-ethylphenyl, 4-propylphenyl, 4-butylphenyl, 4-pentylphenyl, 4-hexylphenyl, 4-isopropylphenyl, 4-t-butylphenyl, 2,3-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl, 3,5-diethylphenyl, 2,3,5-trimethylphenyl, 3,4
5-trimethylphenyl, 2-methoxyphenyl, 3-
Methoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-butoxyphenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl, 4-isopropoxyphenyl, 4-t- Butoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,
5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,5-diethoxyphenyl, 2,3,5-trimethoxyphenyl, 3,4,5-trimethoxyphenyl,
2-methylthiophenyl, 3-ethylthiophenyl, 4
-Propylthiophenyl, 4-butylthiophenyl, 4
-Pentylthiophenyl, 4-hexylthiophenyl,
2,3-dimethylthiophenyl, 2,4-dimethylthiophenyl, 2,6-dimethylthiophenyl, 2,4,6
-Trimethylthiophenyl, 1-naphthyl, 2-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl group and the like can be mentioned.

5-membered or 6-membered having one hetero atom selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom
Membered saturated or unsaturated heterocyclic group (the heterocyclic ring may be condensed with a benzene ring, and a group selected from a hydroxyl group and a lower alkyl group as a substituent on the heterocyclic ring and the heterocyclic ring condensed with the benzene ring may be substituted). 1 to 5 may be), for example, 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 2-furanyl, 3-furanyl, 2-pyridinyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-tetrahydrothionyl, 2-tetrahydrofuranyl, 3-piperidinyl, 2-tetrahydrothiopyranyl, 2-tetrahydropyranyl, 3-indolyl, 2-dihydrobenzopyranyl, 3-dihydrobenzo Pyranyl, 5-methyl-2-
Pyrrolyl, 5-methyl-2-thienyl, 5-methyl-2
-Pyridinyl, 3,5-dimethyl-2-pyridinyl,
4,6-dihydroxy-2-pyridinyl, 6,8-dihydroxy-2-dihydrobenzopyranyl, 6-hydroxy-2,5,7-trimethyl-2-hydrobenzopyranyl group and the like can be mentioned.

1 to 2 lower alkoxy groups on the phenyl ring
Examples of the phenylcarbamoyl lower alkyl group which may be present include phenylcarbamoylmethyl, phenylcarbamoylethyl, phenylcarbamoylpropyl, phenylcarbamoylbutyl, phenylcarbamoylpentyl, phenylcarbamoylhexyl, 2-methoxyphenylcarbamoylmethyl, 3-methoxyphenylcarbamoyl. Methyl, 4-methoxyphenylcarbamoylmethyl, 4-ethoxyphenylcarbamoylmethyl, 4-butoxyphenylcarbamoylmethyl, 4-propoxyphenylcarbamoylmethyl, 2-ethoxy-
An alkoxy moiety such as 4-butoxyphenylcarbamoylmethyl, 4-pentyloxyphenylcarbamoylmethyl, 4-hexyloxyphenylcarbamoylmethyl, 2,6-dimethoxyphenylcarbamoylmethyl, 2-(2,4-dimethoxyphenylcarbamoyl)ethyl group 1 to 6 carbon atoms and 1 to 6 carbon atoms in the alkyl moiety
6 is a phenylcarbamoylalkyl group which may have 1 or 2 alkoxy groups on the phenyl ring.

In the present specification, regarding amino acid residues and the like, these are represented by abbreviations according to IUPAC and IUB or symbols conventionally used in the field, and examples thereof are given below. That is, Tyr is tyrosine, Leu is leucine, Trp is tryptophan,
Asp is aspartic acid, Gly is glycine, Ph-G
ly represents phenylglycine.

In the compound represented by the general formula (1), R
^In the case of a compound in which ¹ represents a hydrogen atom and A represents a carbonyl group, isomer structures represented by the following formulas (1-A) to (1-E) can be taken.

[0060]

[Chemical 25]

Each group of the above general formula (2) will be specifically described as follows. A lower alkyl group, a lower alkoxy group, a halogen atom, a carboxy lower alkyl group, a lower cycloalkyl group, a phenyl lower alkyl group, a lower alkylidene group having 1 to 2 lower cycloalkyl groups and a phenyl lower alkylidene group are represented by the above general formula ( 1)
A group similar to is mentioned.

As the lower alkoxycarbonyl lower alkyl group, for example, methoxycarbonylmethyl, ethoxycarbonylmethyl, 3-methoxycarbonylpropyl,
4-ethoxycarbonylbutyl, 6-propoxycarbonylhexyl, 5-isopropoxycarbonylpentyl, 1,1-dimethyl-2-butoxycarbonylethyl, 2-methyl-3-t-butoxycarbonylpropyl, 2-pentyloxycarbonylethyl, An alkoxycarbonylalkyl group having an alkoxy moiety having 1 to 6 carbon atoms and an alkyl moiety having 1 to 6 carbon atoms such as a hexyloxycarbonylmethyl group can be mentioned.

As the phenoxy lower alkanoyl group,
For example, 2-phenoxyacetyl, 3-phenoxypropionyl, 3-phenoxybutyryl, 4-phenoxybutyryl, 2-phenoxybutyryl, 6-phenoxyhexanoyl, 2-phenoxypropionyl, 3-methyl-4.
-Phenoxybutyryl, 5-phenoxypentanoyl,
Examples thereof include a linear or branched phenoxyalkanoyl group having 2 to 6 carbon atoms in the alkanoyl moiety such as a 2-methyl-4-phenoxypropionyl group.

Examples of the phenoxy lower alkanoyl group having a lower alkoxycarbonyl group on the phenyl ring include 2-(2-methoxycarbonylphenoxy)acetyl, 2-(3-methoxycarbonylphenoxy)acetyl and 2-(4-methoxycarbonyl). Phenoxy)acetyl, 2-(3,4-dimethoxycarbonylphenoxy)
Acetyl, 2-(3,4,5-trimethoxycarbonylphenoxy)acetyl, 3-(2-propoxycarbonylphenoxy)propionyl, 4-(4-pentyloxycarbonylphenoxy)butyryl, 5-(3-propoxycarbonylphenoxy) Pentanoyl, 6-(4-
Butoxycarbonylphenoxy)hexanoyl, 2-
2 to 7 carbon atoms having a phenoxy group having a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety as a substituent on a phenyl ring such as (4-hexyloxycarbonylphenoxy)acetyl A straight-chain or branched alkanoyl group.

Examples of the phenyl lower alkanoyl group include phenylacetyl, 3-phenylpropionyl, and 4
-Phenylbutyryl, 2,2-dimethyl-3-phenylpropionyl, 5-phenylpentanoyl, 6-phenylhexanoyl, 2-methyl-3-phenylpropionyl group and the like, the alkanoyl moiety having 1 to 6 carbon atoms. Examples thereof include a phenylalkanoyl group which is a chain or branched alkanoyl group.

Halogen atom, nitro group,
Examples of the phenylsulfonyl group which may have 1 to 3 groups selected from a lower alkoxy group and a lower alkyl group include, for example, phenylsulfonyl, 2-chlorophenylsulfonyl, 3-chlorophenylsulfonyl, 4-chlorophenylsulfonyl, 2-fluorophenylsulfonyl. , 3-bromophenylsulfonyl, 4-iodophenylsulfonyl, 2,3-dichlorophenylsulfonyl,
3,4-difluorophenylsulfonyl, 3,5-dibromophenylsulfonyl, 3,4,5-trichlorophenylsulfonyl, 3-methylphenylsulfonyl, 4-
Methylphenylsulfonyl, 3-ethylphenylsulfonyl, 3-isopropylphenylsulfonyl, 4-hexylphenylsulfonyl, 3,4-dimethylphenylsulfonyl, 2,5-dimethylphenylsulfonyl, 3,
4,5-Trimethylphenylsulfonyl, 2-methoxyphenylsulfonyl, 3-methoxyphenylsulfonyl, 2-ethoxyphenylsulfonyl, 4-hexylphenylsulfonyl, 3,4-dimethoxyphenylsulfonyl, 3,4,5-trimethoxyphenylsulfonyl ,
2-nitrophenylsulfonyl, 3-nitrophenylsulfonyl, 2,4-dinitrophenylsulfonyl, 2-
Chloro-6-methylphenylsulfonyl, 3-chloro-
A halogen atom, a nitro group, or a carbon number of 1 to 1 as a substituent on a phenyl ring such as a 2-methoxyphenylsulfonyl group.
6 straight-chain or branched alkoxy groups and 1 to 1 carbon atoms
1 is a group selected from 6 linear or branched alkyl groups.
A phenylsulfonyl group which may have 3 to 3.

As the phenyl group which may have a halogen atom on the phenyl ring, for example, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-bromophenyl, 4-
Iodophenyl, 2,3-dichlorophenyl, 2,4-
Dichlorophenyl, 3,4-dichlorophenyl, 3,
1 halogen atom such as 4,5-trichlorophenyl group
Up to 3 phenyl groups which may be present.

Examples of the lower alkylidene group include straight chain or branched alkylidene groups having 1 to 6 carbon atoms such as methylene, ethylene, propylidene, isopropylidene, butylidene, t-butylidene, pentylidene and hexylidene groups. Examples of the phenyl lower alkylidene group having 1 to 3 substituents selected from halogen atom, carboxyl group, lower alkoxycarbonyl group, nitro group, hydroxyl group, lower alkoxy group and halogenated lower alkyl group on the phenyl ring include 2- Chlorobenzylidene, 4-fluorobenzylidene, 3-iodobenzylidene, 2-(3-chlorophenyl)ethylidene, 1-(4
-Chlorophenyl)ethylidene, 3-(2-fluorophenyl)propylidene, 4-(3-fluorophenyl)
Butylidene, 1,1-dimethyl-2-(4-fluorophenyl)ethylidene, 5-(2-bromophenyl)pentylidene, 6-(3-bromophenyl)hexylidene,
2-Methyl-3-(4-bromophenyl)propylidene, trichloromethylbenzylidene, 2-(2-fluoromethylphenyl)ethylidene, 1-(3-chloromethylphenyl)ethylidene, 3-(3-bromomethylphenyl)propylidene , 4-[4-(2-fluoroethyl)phenyl]butylidene, 5-[4-(2-fluoroethyl)phenyl]butylidene, 4-[4-(2-fluoroethyl)phenyl]butylidene, 6-[3 -(3-
Chloropropyl)phenyl]hexylidene, 2-methyl-3-[3-(4-chlorohexyl)phenyl]propylidene, 2-(3,4-difluoromethylphenyl)ethylidene, 2-(3,4,5-trichloromethyl) Phenyl)ethylidene, 4-methoxybenzylidene, 3,4-
Dimethoxybenzylidene, 3,4,5-trimethoxybenzylidene, 1-(3-methoxyphenyl)ethylidene, 2-(2-methoxyphenyl)ethylidene, 3-
(2-ethoxyphenyl)propylidene, 4-(4-ethoxyphenyl)propylidene, 5-(3-ethoxyphenyl)pentylidene, 6-(4-isopropoxyphenyl)hexylidene, 4-butoxybenzylidene, 1,
1-dimethyl-2-(4-hexyloxyphenyl)ethylidene, 2-methyl-3-(3,4-dimethoxyphenyl)ethylidene, 2-(3,4-diethoxyphenyl)ethylidene, 2-carboxybenzylidene, 3 -Carboxybenzylidene, 4-carboxybenzylidene,
1-(2-carboxyphenyl)ethylidene, 3-
(2,4-dicarboxyphenyl)propylidene, 2-
Methoxycarbonylbenzylidene, 2-(2-ethoxycarbonyl)benzylidene, 2-nitrobenzylidene,
3,4,5-Trinitrobenzylidene, 1-(2-nitrophenyl)ethylidene, 3-(2,4-dinitrophenyl)propylidene, 4-(3-nitrophenyl)pentylidene, 6-(3-nitrophenyl) Hexylidene,
6-(3-nitrophenyl)hexylidene, 2-methoxy-3-chlorobenzylidene, 2-hydroxybenzylidene, 2-(3,4-dihydroxyphenyl)ethylidene, 2-(4-hydroxyphenyl)propylidene,
2,4-dihydroxybenzylidene, 3,4,5-trihydroxybenzylidene, 4-methoxycarbonylbenzylidene, 3,4-dimethoxycarbonylbenzylidene, 3-(2-ethoxycarbonylphenyl)propylidene, 6-(4-isopropoxycarbonyl) Phenyl)
A straight-chain or branched alkoxy group having 1 to 6 carbon atoms and a straight-chain or branched alkyl halide having 1 to 6 carbon atoms as a substituent on the phenyl ring such as hexylidene and 4-butoxycarbonylbenzylidene group. 1 to 6 carbon atoms having a phenyl group having 1 to 3 groups selected from a group, a halogen atom, a carboxyl group and an alkoxy moiety having 1 to 6 carbon atoms, an nitro group and a hydroxyl group.
And a straight-chain or branched alkylidene group.

As the phenyl lower alkenylidene group which may have a nitro group on the phenyl ring, for example, phenylvinylidene, 4-nitrophenylvinylidene, 3-
Phenylarylidene, 3-(4-nitrophenyl)arylidene, 4-phenyl-2-butenylidene, 1-methyl-3-phenylarylidene, 5-phenyl-2-pentenylidene, 6-phenyl-2-hexenylidene group, etc. Examples thereof include a phenylalkenylidene group having a linear or branched alkenylidene moiety having 2 to 6 carbon atoms in the alkenylidene moiety and optionally having 1 to 3 nitro groups on the phenyl ring.

Examples of the lower alkenylidene group include linear or branched alkenylidene groups having 2 to 6 carbon atoms such as vinylidene, arylidene, 2-butenylidene, 3-butenylidene, 2-pentenylidene and 2-hexenylidene groups. Be done. Examples of the lower cycloalkenylidene group include 2-cyclopropenylidene, 2-cyclobutenylidene, 2-cyclopentenylidene, 2-cyclohexenylidene, 2-cycloheptenylidene and 2-cyclooctenylidene groups. And a cycloalkenylidene group having 3 to 8 carbon atoms.

As the phenoxy lower alkylidene group which may have a carboxyl group on the phenyl ring, phenoxymethylene, 2-phenoxyethylidene, 1-phenoxyethylidene, 3-phenoxypropylidene and 4-
Phenoxybutylidene, 1,1-dimethyl-2-phenoxyethylidene, 5-phenoxypentylidene, 6-phenoxyhexylidene, 2-methyl-3-phenoxypropylidene, 2-carboxyphenoxymethylene, 1-
(3-carboxyphenoxy)ethylidene, 3-(2-
Carboxyphenoxy)propylidene, 4-(3-carboxyphenoxy)butylidene, 1,1-dimethyl-2
-(4-Carboxyphenoxy)ethylidene, 5-(2
-Carboxyphenoxy)pentylidene, 6-(3-carboxyphenoxy)hexylidene, 2-methyl-3-
Examples thereof include a phenoxyalkylidene group which may have a carboxyl group on the phenyl ring, which is a linear or branched alkylidene group having 1 to 6 carbon atoms in the alkylidene moiety such as (4-carboxyphenoxy)propylidene group.

As the phenyl lower alkylidene group which may have a substituent selected from a halogen atom and a halogenated lower alkyl group on the phenyl ring, for example, benzylidene, 2-phenylethylidene, 1-phenylethylidene, 3-phenylpropylidene, 4-phenylbutylidene, 1,1-dimethyl-2-phenylethylidene,
5-phenylpentylidene, 6-phenylhexylidene, 2-methyl-3-phenylpropylidene, 4-fluorobenzylidene, 4-chlorobenzylidene, 4-bromobenzylidene, 4-iodobenzylidene, 2-(2-
Fluorophenyl)ethylidene, 1-(3-chlorophenyl)ethylidene, 3-(3-bromophenyl)propylidene, 4-fluoromethylbenzylidene, 4-difluoromethylmethylbenzylidene, 4-trifluoromethylbenzylidene, 4-trichloromethylbenzylidene,
2-(2-fluoromethylphenyl)ethylidene, 1-
(3-chloromethylphenyl)ethylidene, 3-(3-
Bromomethylphenyl)propylidene, 4-[4-(2
-Fluoroethyl)phenyl]butylidene, 5-[4-
(2-chloroethyl)phenyl]propylidene, 6-
[3-(3-chloropropyl)phenyl]hexylidene, 2-methyl-3-[3-(4-chlorohexyl)phenyl]propylidene, 2-(3,4-difluoromethylphenyl)ethylidene, 2-(2,2 It has a linear or branched alkylidene moiety having 1 to 6 carbon atoms such as 5-dibromomethylphenyl)ethylidene and 2-(3,4,5-trichloromethylphenyl)ethylidene group, and a halogen atom on the phenyl ring. And a phenylalkylidene group which may have 1 to 3 substituents consisting of a linear or branched halogenated alkyl group having 1 to 6 carbon atoms.

In the general formula (2), when R ¹³ is a hydrogen atom, the following isomer structures (2-A) to (2-C) are possible.

[0074]

[Chemical formula 26]

Each group of the above general formula (3) will be specifically described as follows. Examples of the lower alkyl group, lower alkoxy group, lower alkylidene group, halogen atom, phenyl lower alkylidene group, and lower alkoxycarbonyl lower alkyl group include the same groups as in the above general formula (1). The lower alkanoyl group, regardless of whether it is present independently or in another group, includes, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, t-butylcarbonyl, hexanoyl and the like carbon atoms. Examples thereof include linear or branched alkanoyl groups of the numbers 1 to 6.

As the phenyl lower alkyl group which may have a halogen atom as a substituent on the phenyl ring,
For example, benzyl, 2-fluorobenzyl, 3-bromobenzyl, 4-chlorobenzyl, 4-iodobenzyl, 2
-Phenylethyl, 1-(4-chlorophenyl)ethyl, 3-(4-bromophenyl)propyl, 4-(2-
Fluorophenyl)butyl, 5-(3-bromophenyl)pentyl, 6-phenylhexyl, 2-methyl-3
A phenylalkyl group which may have a halogen atom as a substituent on a phenyl ring which is a linear or branched alkyl group having 1 to 6 carbon atoms in the alkyl moiety such as a -(3-chlorophenyl)propyl group. Be done.

Specific examples of the compound represented by the above general formula (1)
Examples include the following: (1-1): 5-(4-benzyloxybenzyl)-2-i
Sopropylidene hydrazono imidazolidin-4-one (1-2): 2-isopropylidene hydrazono-5-methyl
Imidazolidin-4-one (1-3): 5-benzyl-2-isopropylidenehydrazo
Neuimidazolidin-4-one (1-4): 5-(4-hydroxybenzyl)-2-isop
Ropylidene hydrazono imidazolidin-4-one (1-5): 5-[4-(2,6-dichlorobenzyloxy)
Si) benzyl]-2-isopropylidene hydrazonoimi
Dazolidin-4-one (1-6): 5-[4-(chlorobenzyloxy)benz
]]-2-Isopropylidene hydrazono imidazolidine
-4-one (1-7): 5-(4-hydroxyphenyl)-2-isop
Ropylidene hydrazono imidazolidin-4-one (1-8): 2-isopropylidene hydrazono-5-(4-
Phenylthiobenzyl)imidazolidin-4-one (1-9): 5-[N-(4-ethoxycarbonylpheny
) Carbamoylmethyl]-2-isopropylidene hydride
Razonothiazolidin-4-one (1-10): 2-isopropylidenehydrazono-5-(N-
Propylcarbamoylmethyl)thiazolidin-4-one (1-11): 2-isopropylidenehydrazono-5-[N-
(2-oxo-1,2,3,4-tetrahydroquinoline
-3-yl)carbamoylmethyl]-thiazolidine-4
-One (1-12): 5-(N-cyclohexylcarbamoylmethyi
)-2-Isopropylidene hydrazonothiazolidine-
4-one (1-13): 5-(N-ethoxycarbonylmethylcarbamo
Ilmethyl)-2-isopropylidene hydrazonothiazo
Lysin-4-one (1-14): 5-[N-(4-carboxyphenyl)carba
Moylmethyl]-2-isopropylidenehydrazonothia
Zolidine-4-one (1-15): 5-carboxymethyl-3-ethoxycarboni
Lumethyl-2-isopropylidene hydrazonothiazolide
N-4-one (1-16): 2-isopropylidenehydrazono-3-pheny
Luthiazolidin-4-one (1-17): 2-isopropylidenehydrazino-4-methyl
Thiazole (1-18): 2-isopropylidenehydrazino-4-phenyl
Luthiazole (1-19): 4-(4-chlorophenyl)-2-isopropyi
Liden hydrazino thiazole (1-20): 2-isopropylidene hydrazino-4-(4-
Phenylthiophenyl)thiazole (1-21): 4-(3,4-dihydroxyphenyl)-2-
Isopropylidene hydrazinothiazole (1-22): 4-[4-(4-chlorobenzyloxy)phene
Nyl]-2-isopropylidenehydrazinothiazole (1-23): 2-isopropylidenehydrazino-4,5,
6,7-Tetrahydrobenzothiazole (1-24): 3-benzyl-5-(4-hydroxybenzyl
)-2-Isopropylidene hydrazono imidazolidine
-4-one (1-25): 5-(4-hydroxybenzyl)-2-isop
Ropiridenhydrazono-3-(4-methoxybenzyl)
Imidazolidin-4-one (1-26): 5-(4-benzyloxybenzyl)-2-i
Sopropylidene hydrazonothiazolidin-4-one (1-27): 2-isopropylidene hydrazono-5-(4-
Methylthiobenzyl)thiazolidin-4-one (1-28):9-benzyloxymethyl-1,4,5,7-
Tetraazabicyclo-[4,3,0]nonane-5-ene
-3,8-dione (1-29): 2-isopropylidenehydrazono-5-(4-
Nitrobenzyl)imidazolidin-4-one (1-30): 5-(4-cyclohexylmethyloxybenzi
)-2-Isopropylidene hydrazono imidazolidine
-4-one (1-31): 5-(4-benzylbenzyl)-2-isopro
Pyridenehydrazonoimidazolidin-4-one (1-32): 5-[4-(4-chlorobenzoylamino)be
2-]-isopropylidenehydrazonoimidazole
Zin-4-one (1-33): 2-isopropylidenehydrazono-5-(N-
Phenylcarbamoylmethyl)thiazolidin-4-one (1-34):5-(N-isopropylcarbamoylmethyl)
-2-Isopropylidene hydrazonothiazolidine-4-
ON (1-35): 5-(N-benzylcarbamoylmethyl)-2
-Isopropylidene hydrazonothiazolidin-4-one (1-36): 5-[4-(4-chlorophenylthio)benzi
]]-2-Isopropylidene hydrazono imidazolidine
-4-one (1-37): 2-isopropylidenehydrazono-5-[N-
(2-Methoxycarbonyl-4-methylphenyl)calc
Vamoylmethyl]thiazolidin-4-one (1-38): 5-[N-(2-carboxy-4-methylphene
Nyl)carbamoylmethyl]-2-isopropylidene
Drazonothiazolidin-4-one (1-39): 5-(N-carboxymethylphenylcarbamo
Ilmethyl)-2-isopropylidene hydrazonothiazo
Lysin-4-one (1-40): 2-isopropylidenehydrazono-5-[N-
(4-Methylphenyl)carbamoylmethyl]thiazoli
Zin-4-one (1-41): 2-isopropylidenehydrazono-5-[4-
(3-Pyridylmethoxy)benzyl]thiazolidine-4
-One (1-42): 2-isopropylidenehydrazono-5-[4-
(2-Phenylethoxy)benzyl]imidazolidine-
4-one (1-43): 5-(3-indolylmethyl)-2-isopro
Pyridene hydrazono imidazolidin-4-one (1-44): 2-isopropylidene hydrazono-5-[4-
(2-thienylmethoxy)benzyl]imidazolidine-
4-one (1-45): 5-(5-hydroxy-3-indolylmethyi
)-2-Isopropylidene hydrazono imidazolidine
-4-one (1-46): 5-(3,4-dihydroxybenzyl)-2-
Isopropylidene hydrazono imidazolidin-4-one (1-47): 5-[N-(3,4-difluorophenyl)carb
Lubamoylmethyl]-2-isopropylidenehydrazono
Thiazolidin-4-one (1-48): 5-[N-(4-benzyloxyphenyl)carbox
Lubamoylmethyl]-2-isopropylidenehydrazono
Thiazolidin-4-one (1-49): 5-[N-(4-chlorophenyl)carbamoy
Lumethyl]-2-isopropylidene hydrazonothiazoli
Zin-4-one (1-50): 2-isopropylidenehydrazono-5-[N-
(4-Methoxyphenyl)carbamoylmethyl]thiazo
Lysin-4-one (1-51): 2-isopropylidenehydrazono-5-[N-
(4-Methylthiophenyl)carbamoylmethyl]thia
Zolidin-4-one (1-52): 5-[N-(4-bromophenyl)carbamoy
Lumethyl]-2-isopropylidene hydrazonothiazoli
Zin-4-one (1-53): 2-isopropylidenehydrazono-5-[N-
(3,4,5-Trichlorophenyl)carbamoylmethyi
Lu]thiazolidin-4-one (1-54): 2-isopropylidenehydrazono-5-[N-
(3,4-Methylenedioxyphenyl)carbamoylme
Cyl]thiazolidin-4-one (1-55):2-isopropylidenehydrazono-5-[N-
(1-Naphthyl)carbamoylmethyl]thiazolidine-
4-one (1-56): 5-[N-(3,5-dichlorophenyl)calc
Vamoylmethyl]-2-isopropylidene hydrazonoti
Azolidin-4-one (1-57): 2-isopropylidenehydrazono-5-(N-
Methyl-N-phenylcarbamoylmethyl)thiazolidi
N-4-one (1-58): 2-isopropylidenehydrazono-5-[N-
(3-Pyridylmethyl)carbamoylmethyl]thiazoli
Zin-4-one (1-59): 2-isopropylidenehydrazono-5-[N-
(3-Imidazol-1-yl)propylcarbamoyl
Methyl]thiazolidin-4-one (1-60): 2-isopropylidenehydrazono-5-(N-
Morpholinocarbamoylmethyl)thiazolidine-4-o
(1-61): 2-isopropylidenehydrazono-5-[N-
(2-thienylmethyl)carbamoylmethyl]thiazoli
Zin-4-one (1-62): 2-isopropylidenehydrazono-5-[N-
(4-morpholinophenyl)carbamoylmethyl]thia
Zolidin-4-one (1-63): 2-isopropylidenehydrazino-4-(3-
Pyridyl)thiazole (1-64): 4-(4-carboxyphenyl)-2-isop
Lopylidene hydrazinothiazole (1-65): 2-isopropylidene hydrazono-5-[N-
(1-Phenylethyl)carbamoylmethyl]thiazoli
Zin-4-one (1-66): 5-(4-benzyloxybenzyl)-2-hi
Drazonoimidazolidin-4-one hydrochloride (1-67): 2-hydrazono-5-(N-phenylcarbamo
Ilmethyl)thiazolidin-4-one (1-68):2-isopropylidenehydrazono-5-[N-
(2-methyl-5-methoxycarbonylphenyl)calc
Vamoylmethyl]thiazolidin-4-one (1-69): 2-isopropylidenehydrazino-4-trif
Luoromethylthiazole (1-70): 4-ethoxycarbonylmethyl-2-isopro
Pyridene hydrazinothiazole (1-71): 4-carboxymethyl-2-isopropylidene
Hydrazinothiazole (1-72): 2-cyclopentylidene hydrazono-5-(4
-Benzyloxybenzyl)imidazolidin-4-one (1-73): 2-dicyclopropylmethylenehydrazono-5
-(N-phenylcarbamoylmethyl)thiazolidine-
4-one (1-74): 2-cyclohexylmethylenehydrazono-5-
(N-phenylcarbamoylmethyl)thiazolidine-4
-One (1-75): 5-(4-benzyloxycarbonylaminobutane
Chill)-2-isopropylidene hydrazono imidazolidi
N-4-one (1-76): 2-isopropylidenehydrazono-5-(4-
Methoxycarbonylaminobutyl) imidazolidine-4
-One (1-77): 2-isopropylidenehydrazono-5-(2-
Methylpropyl)imidazolidin-4-one (1-78): 5-isopropyl-2-isopropylidene hydride
Razonoimidazolidin-4-one (1-79): 2-isopropylidenehydrazono-5-[2-
(N-Phenylcarbamoyl)ethyl]imidazolidine
-4-one (1-80): 5-benzyloxycarbonylmethyl-2-i
Sopropylidene hydrazono imidazolidin-4-one (1-81): 2-isopropylidene hydrazono-5-methoki
Cycarbonylmethylimidazolidin-4-one (1-82): 5-carboxymethyl-2-isopropylidene
Hydrazonoimidazolidin-4-one (1-83): 2-isopropylidenehydrazono-5-(N-
Phenylcarbamoylmethyl)imidazolidine-4-o
(1-84): 5-(N-cyclopropylcarbamoylmethyl)
)-2-Isopropylidene hydrazono imidazolidine
-4-one (1-85): 5-(4-benzyloxybenzyl)-2-
(4-Bromobenzenesulfonohydrazono) imidazole
Zin-4-one (1-86): 2-(4-acetamidobenzenesulfonohydride
Razono)-5-(4-benzyloxybenzyl)imida
Zolidine-4-one (1-87): 2-isopropylidenehydrazono-5-[N-
(1-Phenylethyl)carbamoylmethyl)]imida
Zolidine-4-one (1-88): 5-(4-imidazolylmethyl)-2-isop
Ropylidene hydrazono imidazolidin-4-one (1-89): 2-isopropylidene hydrazono-5-[N-
(2-Methoxycarbonylphenyl)carbamoylmethy
Lu]thiazolidin-4-one (1-90):5-[N-(2-carboxyphenyl)carba
Moylmethyl]-2-isopropylidenehydrazonothia
Zolidine-4-one (1-91): 5-[N-(5-carboxy-2-methylphen
Nyl)carbamoylmethyl]-2-isopropylidene
Drazonothiazolidin-4-one (1-92): 5-[N-(3,4-dimethoxyphenyl)carbox
Lubamoylmethyl]-2-isopropylidenehydrazono
Thiazolidine-4-one (1-93): 3-ethoxycarbonylmethyl-5-(N-phenyl)
(Phenylcarbamoylmethyl)-4-isopropylidene
Drazonothiazolidin-4-one (1-94): 2-isopropylidenehydrazino-4-(3-
Thienyl)thiazole (1-95): 4-[N-(3,4-dimethoxyphenyl)ca
Lubamoylmethyl]-2-isopropylidenehydrazino
Thiazole (1-96): 2-isopropylidenehydrazino-4-(2-
Thiazolyl)thiazole (1-97): 2-isopropylidenehydrazono-5-[N-
(2-Methoxycarbonyl-4-methylphenyl)calc
Vamoylmethyl]imidazolidin-4-one (1-98): 5-[N-(1-ethoxycarbonyl-3-me
Cylbutyl)carbamoylmethyl]-2-isopropylyl
Denhydrazonothiazolidin-4-one (1-99): 5-[N-(3-ethoxycarbonylpheny
) Carbamoylmethyl]-4-isopropylidene hydride
Razonothiazolidin-4-one (1-100): 5-{N-[1-ethoxycarbonyl-2-
(4-Benzyloxyphenyl)ethyl]carbamoyl
Methyl}-2-isopropylidene hydrazonothiazolide
N-4-one (1-101): 5-{N-[1-carboxy-2-(4-beta)
Benzyloxyphenyl)ethyl]carbamoylmethyl}
-2-Isopropylidene hydrazonothiazolidine-4-
On (1-102): 2-isopropylidenehydrazono-5-{N
-[1-methoxycarbonyl-2-(3-indolyl)
Ethyl]carbamoylmethyl}thiazolidin-4-one (1-103):5-[N-(1-carboxy-3-methylbutane
Cyl)carbamoylmethyl]-2-isopropylidene
Drazonothiazolidin-4-one (1-104): 5-{N-[1-carboxy-2-(3-i
And) carbamoylmethyl}-2-isop
Ropylidene hydrazonothiazolidin-4-one (1-105): 5-[N-(3-carboxyphenyl)calc
Vamoylmethyl]-2-isopropylidene hydrazonoti
Azolidin-4-one (1-106): 2-isopropylidenehydrazono-5-[N
-(2-Methoxycarbonylmethylphenyl)carbamo
Ilmethyl]thiazolidin-4-one (1-107): 5-[N-(2-carboxymethylphenyl
) Carbamoylmethyl]-2-isopropylidene hydride
Razonothiazolidin-4-one (1-108): 2-isopropylidenehydrazono-5(R)
-(N-phenylcarbamoylmethyl)thiazolidine-
4-one (1-109): 2-isopropylidenehydrazono-5(S)
-(N-phenylcarbamoylmethyl)thiazolidine-
4-one (1-110): 5-[N-(4-chloro-2-methoxycal
Bonylphenyl)carbamoylmethyl]-2-isopro
Pyridenehydrazonothiazolidin-4-one (1-111): 5-[N-(2-carboxy-4-chlorophenyl)
Phenyl)carbamoylmethyl]-2-isopropylidene
Hydrazonothiazolidin-4-one (1-112): 2-isopropylidenehydrazono-5-[N
-(2,3-Dimethylphenyl)carbamoylmethyl]
Thiazolidine-4-one (1-113): 5-[N-(2-furanylmethyl)carbamo
Ilmethyl]-2-isopropylidene hydrazonothiazo
Lysin-4-one (1-114): 5-[N-(2,6-dimethylphenyl)carbox
Lubamoylmethyl]-2-isopropylidenehydrazono
Thiazolidine-4-one (1-115): 2-isopropylidenehydrazono-5-[N
-(2-Methoxy-5-methoxycarbonylphenyl)
Carbamoylmethyl]thiazolidin-4-one (1-116): 5-[N-(5-carboxy-2-methoxy
Phenyl)carbamoylmethyl]-2-isopropylidene
Nhydrazonothiazolidin-4-one (1-117): 5-[N-(4,5-dimethoxy-2-eth
Xycarbonylphenyl)carbamoylmethyl]-2-
Isopropylidene hydrazonothiazolidin-4-one (1-118): 5-[N-(2-carboxy-4,5-dime
Toxyphenyl)carbamoylmethyl]-2-isopro
Pyridenehydrazonothiazolidin-4-one (1-119): 5-[N-(2-benzyloxycarbonyl
-1(S)-methoxyervonylethyl)carbamoyl
Methyl]-2-isopropylidene hydrazonothiazolide
N-4-one (1-120): 5-[N-(α-ethoxycarbonylbenzyl
) Carbamoylmethyl]-2-isopropylidene hydride
Razonothiazolidin-4-one (1-121): 5-[N-(α-carboxybenzyl)calc
Vamoylmethyl]-2-isopropylidene hydrazonoti
Azolidin-4-one (1-122): 5-[N-(2-hydroxy-5-methoxy
Carbonylphenyl)carbamoylmethyl]-2-iso
Propylidene hydrazonothiazolidin-4-one (1-123): 5-[N-(5-carboxy-2-hydroxy
Cyphenyl)carbamoylmethyl]-2-isopropylyl
Denhydrazonothiazolidin-4-one (1-124): 5-[N-(4-fluorophenyl)carba
Moylmethyl]-2-isopropylidenehydrazonothia
Zolidine-4-one (1-125): 5-[N-(2-carboxy-4-methylphenyl)
Phenyl)carbamoylmethyl]-2-isopropylidene
Hydrazonothiazolidin-4-one (1-126): 5-[N-(4-hydroxy-2-methoxy
Carbonylphenyl)carbamoylmethyl]-2-iso
Propylidene hydrazonothiazolidin-4-one (1-127): 5-[N-(2-carboxy-4-hydroxy
Cyphenyl)carbamoylmethyl]-2-isopropylyl
Denhydrazonothiazolidin-4-one (1-128): 5-[N-[4-[(6-acetoxy-2,
5,7,8-Tetramethylchroman-2-yl)methoxy
Cy]phenyl]carbamoylmethyl]-2-isopropyi
Rydenhydrazonothiazolidin-4-one (1-129): 5-[N-[4-[(6-hydroxy-2,
5,7,8-Tetramethylchroman-2-yl)methoxy
Cy]phenyl]carbamoylmethyl]-2-isopropyi
Ridenehydrazonothiazolidin-4-one (1-130): 2-isopropylidenehydrazono-5-[N
-[3-(trifluoromethyl)phenyl]carbamoy
Lumethyl]-thiazolidin-4-one (1-131): 2-isopropylidenehydrazono-5-[N
-(4-Methoxy-2-methylphenyl)carbamoyl
Methyl]-thiazolidin-4-one (1-132): 5-[N-(4-fluoro-2-methoxycaphyl
Rubonylphenyl)carbamoylmethyl]-2-isop
Ropylidene hydrazonothiazolidin-4-one (1-133): 5-[N-(2-carboxy-4-fluoro
Phenyl)carbamoylmethyl]-2-isopropylidene
Nhydrazonothiazolidin-4-one (1-134): 5-[N-(3-fluoro-2-methoxycarboxyl
Rubonylphenyl)carbamoylmethyl]-2-isop
Ropylidene hydrazonothiazolidin-4-one (1-135): 5-[N-(2-carboxy-3-fluoro
Phenyl)carbamoylmethyl]-2-isopropylidene
N-hydrazonothiazolidin-4-one (1-136): 2-isopropylidenehydrazono-5-[N
-(2-Methoxycarbonyl-5-methylphenyl)carb
Lubamoylmethyl]-thiazolidin-4-one (1-137): 5-[N-(2-carboxy-3-methylphenyl)
Phenyl)carbamoylmethyl]-2-isopropylidene
Hydrazonothiazolidin-4-one (1-138): 2-isopropylidenehydrazono-5-[N
-[3-methoxycarbonyl-5-(trifluoromethyl
Lu)phenyl]carbamoylmethyl]-thiazolidine-
4-one (1-139): 5-[N-[3-carboxy-5-(trif
Luoromethyl)phenyl]carbamoylmethyl]-2-
Isopropylidene hydrazonothiazolidin-4-one (1-140): 2-isopropylidene hydrazono-5-[N
-[4-(trifluoromethyl)phenyl]carbamoy
Lumethyl]-thiazolidin-4-one (1-141): 2-isopropylidenehydrazono-5-[N
-(4-Methoxy-2-methoxycarbonylphenyl)
Carbamoylmethyl]-thiazolidin-4-one (1-142): 5-[N-(2-carboxy-3-methoxy
Phenyl)carbamoylmethyl]-2-isopropylidene
Specific examples of the compound represented by the general formula (2) are as follows.
Here are the ones below. (2-1): 2-isopropylidenehydrazonoimidazolidi
N-4-one (2-2): 2-benzylidenehydrazonoimidazolidine-
4-one (2-3): 2-α-methylcinnamylidene hydrazonoimi
Dazolidin-4-one (2-4): 2-cyclopentylidene hydrazonoimidazol
Zin-4-one (2-5): 2-(1-cyclopropylethylidenehydrazo
No) imidazolidin-4-one (2-6): 2-cyclohexylmethylene hydrazono imidazole
Zolidine-4-one (2-7): 2-cyclohexylidene hydrazonoimidazoli
Zin-4-one (2-8): 2-n-butylidene hydrazonoimidazolidine
-4-one (2-9): 2-dicyclopropylmethylene hydrazonoimi
Dazolidin-4-one (2-10): 2-(1-trifluoromethylethylidene hydride
Razono)imidazolidin-4-one (2-11):2-hexafluoroisopropylidenehydrazo
Neuimidazolidin-4-one (2-12): 2-benzylidene hydrazono-1-methoxycarb
Rubonylmethylimidazolidin-4-one (2-13): 2-benzylidenehydrazono-1-carboxy
Methylimidazolidin-4-one (2-14): 2-isopropylidenehydrazono-1-methoxy
Cycarbonylmethylimidazolidin-4-one (2-15): 1-methoxycarbonylmethyl-2-α-methyl
Lucinnamylidene hydrazono imidazolidin-4-one (2-16): 2-(4-carboxybenzylidene hydrazo
No)-1-carboxymethylimidazolidin-4-one (2-17): 2-cinnamylidene hydrazono-5-cinnami
Ridene imidazolidin-4-one (2-18): 2-benzylidene hydrazono-5-benzylide
Nthiazolidin-4-one (2-19): 2-cinnamylidene hydrazono-5-cinnami
Redenthiazolidin-4-one (2-20): 2-(4-trifluoromethylbenzylidene den
Drazono)-5-(4-trifluoromethylbenzylidide
Thiazolidin-4-one (2-21): 2-cinnamylidene hydrazono-5-cinnami
Ridene-1-methoxycarbonylmethylimidazolidine
-4-one (2-22): 1-carboxymethyl-2-cinnamylidene
Drazono-5-cinnamylidene imidazolidine-4-o
(2-23): 2-(4-phenylsemicarbazono)thiazoli
Zin-4-one (2-24): 2-(4-naphthylsemicarbazono)thiazoli
Zin-4-one (2-25): 2-[4-(4-chlorophenyl)semicarba
Zono]thiazolidin-4-one (2-26): 2-(4-benzylsemicarbazono)thiazoli
Zin-4-one (2-27): 2-[4-(4-fluorophenyl)semical
Bazono]thiazolidin-4-one (2-28): 2-(4-butylsemicarbazono)thiazolidi
N-4-one (2-29): 1,4,5,7-tetraazabicyclo[4,4
3,0]Nonane-5-ene-3,8-dione (2-30): 2-benzylidenehydrazono-3-ethoxycarbox
Lubonylmethyl-1-methoxycarbonylmethyl imidazole
Zolidine-4-one (2-31): 2-benzylidene hydrazono-1,3-dical
Boxymethylimidazolidin-4-one (2-32): 7-ethoxycarbonylmethyl-1,4,5,
7-Tetraazabicyclo[4,3,0]nonane-5-e
-3,8-dione (2-33): 7-carboxymethyl-1,4,5,7-teto
Laazabicyclo[4,3,0]nonane-5-ene-3,
8-dione (2-34): 3-ethoxycarbonylmethyl-2-isopro
Pyridene hydrazonothiazolidin-4-one (2-35): 3-carboxymethyl-2-isopropylidene
Hydrazonothiazolidin-4-one (2-36): 5-benzylidene-2-benzylidene hydrazo
No-3-carboxymethylthiazolidin-4-one (2-37): 3-(5-carboxypentyl)-2-cinna
Millidene hydrazono-5-cinnamyri thiazolidine
-4-one (2-38): 3-(3-carboxypropyl)-2-cinna
Millidene hydrazono-5-cinnamyri thiazolidine
-4-one (2-39): 3-ethoxycarbonylmethyl-2-hydrazo
Notiazolidin-4-one (2-40): 2H-thiazolo[2,3-c][1,2,4]
Triazine-3,6(4H,7H)-dione (2-41):2-(2,4-dinitrobenzenesulfonohydr
Razono)-3-ethoxycarbonylmethylthiazolidine
-4-one (2-42): 3-Carboxymethyl-2-(2,4-dinito
Robenzenesulfonohydrazono) thiazolidine-4-o
(2-43): 3-Carboxymethyl-2-(2-nitroben
Zensulfonohydrazono) thiazolidin-4-one (2-44): 2-(4-bromobenzenesulfonohydrazo
No)-3-carboxymethylthiazolidin-4-one (2-45): 3-ethoxycarbonylmethyl-2-phenyl
Acetylhydrazonothiazolidin-4-one (2-46): 3-ethoxycarbonylmethyl-2-(4-me
Toxybenzenesulfonohydrazono) thiazolidine-4
-One (2-47): 3-ethoxycarbonylmethyl-2-cinnami
Redene hydrazono-5-cinnamylidene thiazolidine-
4-one (2-48): 3-carboxymethyl-2-cinnamyridenhi
Drazono-5-cinnamylidethiazolidin-4-one (2-49): 3-carboxymethyl-2-(4-fluorobe
Nylidene hydrazono)-5-(4-fluorobenzili
Den)thiazolidin-4-one (2-50): 2-(2,4-dinitrobenzenesulfonohydr
Razono)thiazolidin-4-one (2-51):2-(4-toluenesulfonohydrazono)thia
Zolidin-4-one (2-52): 2-(2,4-dinitrobenzenesulfonohydride
Razono)imidazolidin-4-one (2-53): 3-ethoxycarbonylmethyl-2-(4-me
Toxycarbonylbenzylidene hydrazono) thiazolidi
N-4-one (2-54): 2-(4-carboxybenzylidenehydrazo
No)-3-carboxymethylthiazolidin-4-one (2-55): 3-carboxymethyl-2-salicylidene hydride
Razonothiazolidin-4-one (2-56): 3-Cyclopentyl-2-isopropylidene
Drazonothiazolidin-4-one (2-57): 2-isopropylidenehydrazono-3-pheno
Xyacetylthiazolidin-4-one (2-58): 2-isopropylidenehydrazono-3-methoxy
Cycarbonylphenoxyacetyl thiazolidine-4-o
(2-59): 2-isopropylidenehydrazono-1-methoxy
Cycarbonylmethyl-3-methylimidazolidine-4-
On (2-60): 2-isopropylidenehydrazono-3-methyl
Imidazolidin-4-one (2-61): 2-isopropylidenehydrazono-1,3-di
Methyl imidazolidin-4-one (2-62): 2-(4-carboxybenzylidene hydrazo
No) thiazolidin-4-one (2-63): 2-(4-carboxyphenoxyethylidene den)
Drazono)thiazolidin-4-one (2-64): 2-(3,4,5-trimethoxybenzylidene
Hydrazono)thiazolidin-4-one (2-65): 2-phenylpropylidene hydrazonothiazoli
Zin-4-one (2-66): 2-(2-nitrocinnamylidene hydrazono)
Thiazolidine-4-one (2-67): 5-Cinnamylidene-2-(2,4-dinitro
Benzenesulfonohydrazono)-3-ethoxycarboni
Lumethylthiazolidin-4-one (2-68): 2-(2,4-dinitrobenzenesulfonohydr
Razono)-3-ethoxycarbonylmethyl-5-(2-
α-Methylcinnamylidene)thiazolidin-4-one Specific examples of the compound represented by the general formula (3) are as follows.
Here are the ones below. (3-1): 2-[2-(N-benzoylthiocarbamoy
Le) hydrazino]benzothiazole (3-2): 2-[2-(N-ethoxycarbonylthiocal
(Vamoyl)hydrazino]benzothiazole (3-3): 2-(2-benzoylhydrazino)benzothia
Zole (3-4): 2-isopropylidenehydrazinobenzimida
Zole (3-5): 2-diphenylmethylidene hydrazinobenzii
Midazole (3-6): 2-(2-methylhydrazino)benzimidazo
(3-7): 3-oxo-1,2,3,4-tetrahydro-
[1,2,4]triazino[4,3-a]benzimida
Zole (3-8): 2-isopropylidenehydrazino-1-methyl
Benzimidazole (3-9): 1-ethoxycarbonylmethyl-2-(1-d
Toxycarbonylmethyl-2-isopropylidene hydra
Dino)benzimidazole (3-10): 2-hydrazino-5-methylbenzimidazole
(3-11): 2-isopropylidenehydrazino-5-methyl
Benzimidazole (3-12): 1-benzyl-2-isopropylidenehydrazide
Nobenzimidazole (3-13): 1-benzyl-2-(1-ethoxycarbonyl)
Methyl-2-isopropylidenehydrazino)benzimi
Dazole (3-14): 1-(4-chlorobenzyl)-2-isopropyi
Lidenhydrazinobenzimidazole Compounds represented by the above general formulas (1), (2) and (3)
These isomers, other stereoisomers, optical
All the sexes and geometrical isomers are included.

The compounds represented by the above general formulas (1), (2) and (3) include addition salts of pharmaceutically acceptable acid or base compounds. The salt is easily formed by reacting the following acid or base. Examples of the acid used for salt formation include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, and in some cases, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid. Organic acids such as.

Examples of the base used for salt formation include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate and the like. Examples of vitamin B ₆ used in the AGE production inhibitory composition of the present invention include pyridoxine, pyridoxal, pyridoxamine, and vitamin B ₆ basic type _{6 of} each phosphoric acid ester form. Further, the above-mentioned vitamin B ₆ includes pharmaceutically acceptable acid addition salts.
Examples of the acid used for salt formation include the same inorganic acids or organic acids as described above.

In the composition for inhibiting AGE production of the present invention, the amount of vitamin B ₆ or a pharmaceutically acceptable salt thereof added is 0.1 with respect to 100 parts by weight of the Maillard reaction inhibitor.
To 200 parts by weight, preferably 1 to 100 parts by weight, more preferably 2 to 50 parts by weight. The AGE production inhibiting composition of the present invention is usually used in the form of a general pharmaceutical preparation. The preparation is prepared by using a diluent or an excipient such as a filler, a filler, a binder, a moisturizer, a disintegrant, a surface active agent and a lubricant which are usually used.

Various forms of this pharmaceutical preparation can be selected according to the purpose of treatment, and typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules,
Examples include suppositories, injections (solutions, suspensions, etc.), ointments and the like. In the case of molding into tablets, as a carrier, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, excipients such as silicic acid, water, ethanol, propanol, simple carrier, etc. Binders such as syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, calcium phosphate, polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan Disintegrants such as fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, etc., disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc.
Absorption agents such as high grade ammonium salts and sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, purified talc, stearates, boric acid powder, polyethylene A lubricant such as glycol can be used. Further, the tablet may be a tablet coated with a usual coating as necessary, for example, a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multi-layer tablet.

In the case of molding in the form of pills, as carriers, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, tragacanth powder, gelatin, ethyl alcohol, etc. Binders, disintegrating agents such as laminaran, agar and the like can be used. When molded into the form of suppositories, polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides, etc. can be used as carriers.

Preparation of capsules is carried out according to a conventional method, and usually the various carriers exemplified above and the compounds (1) to (3) of the present invention.
And vitamin B ₆ mixed, hard gelatin capsule,
It is performed by filling a hard capsule or the like. When prepared as an injection, solutions, emulsions and suspensions are preferably sterile and isotonic with blood. When molding into these forms, as a diluent, for example, water, lactic acid aqueous solution,
Ethyl alcohol, propylene glycol, ethoxylated isostearal alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used. In this case, a sufficient amount of salt, glucose or glycerin for preparing an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizing agent, buffer, soothing agent, etc. are added. You may. In addition, if necessary, colorants, preservatives,
Flavors, flavors, sweeteners and other pharmaceuticals may be included in the pharmaceutical preparation.

In formulating pastes, creams and gels, diluents such as white petrolatum,
Paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite, etc. can be used. The amounts of the Maillard reaction inhibitor and vitamin B ₆ or a pharmaceutically acceptable salt thereof to be contained in the AGE production inhibiting composition of the present invention are not particularly limited and are appropriately selected from a wide range. It is preferable to be 1 to 70% by weight in the preparation.

The administration method of the AGE production inhibitory composition of the present invention is not particularly limited and may be variously determined according to the patient's age, sex and other conditions, disease state, various formulation forms, etc. Orally or topically, orally or topically. For example, tablets, pills, solutions, suspensions,
Orally administered in the form of emulsions, granules and capsules,
In the form of injection, if necessary, mixed with normal replenisher solution and administered intravenously, intramuscularly, intracutaneously, subcutaneously or intraperitoneally,
It is administered rectally as a suppository or as an ointment.

In the composition for inhibiting AGE production of the present invention, the Maillard reaction inhibitor and vitamin B ₆ or a pharmaceutically acceptable salt thereof can be administered simultaneously or separately at a time. The dose of the AGE production inhibitor composition of the present invention to a person is appropriately selected depending on age, weight, symptoms, therapeutic effect, administration method, treatment time, etc. Is administered in 1 to several times.

[0087]

[Synthesis of 2-isopropylidenehydrazono-5-(N-phenylcarbamoylmethyl)thiazolidin-4-one (1-33)]

N,N-dimethyl of 5-carboxymethyl-2-isopropylidenehydrazonothiazolidin-4-one (0.37 g) and aniline (0.15 g) synthesized according to the method described in JP-A-46-15936. To a formamide (10 ml) solution, 1-hydroxybenztriazole hydrochloride (0.27 g), then 1-ethyl-3-
(3′-Dimethylaminopropyl)carbodiimide hydrochloride (0.34 g) was added, and the mixture was stirred at room temperature. After 16 hours, the reaction solution was added with 2N hydrochloric acid (100 ml)-ethyl acetate (1
(00 ml). The separated organic layer was taken, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.
The residue was separated and purified by silica gel chromatography (eluent; methylene chloride:methanol=9:1) to obtain the title compound.

¹ H-NMR (DMSO-d ₆ )δ;
93, 1.95 (2s, 6H), 2.87 (dd, 1
H, J _gem = 16.5 Hz, J = 9.57 Hz), 3.
16 (dd, 1H, J=3.95 Hz), 4.33 (d
d, 1H), 7.0-7.6 (m, 5H), 10.11.
(Brs, 1H), 11.70 ( brs, 1H) Formulation Example 2 isopropylidene hydrazono-5-(N-phenylcarbamoyl methyl) thiazolidin-4-one 5g Vitamin B ₆ (pyridoxine hydrochloride) 0.1 g lauryl sulfate Sodium 0.2 g Magnesium stearate 0.2 g Crystalline cellulose 4.6 g The above components were mixed by a conventional method and tableted to give tablets. Pharmacological test 1. AGE production inhibitory effect In vitro, the AGE production inhibitory effect of a sample consisting of the compound of Synthesis Example (hereinafter referred to as compound (1-33)) and vitamin B ₆ was determined by ELISA (Enzy).
me-linked immunosorbent a
It was confirmed by using an assay. The test method and analysis method are as follows. (I) Test method Bovine serum albumin (BSA) was dissolved in 0.25 M phosphate buffer (PBS) at a concentration of 0.1 g/ml, and fructose as a reducing sugar was dissolved so that the final concentration was 100 mM. Was produced.

Further, 0 mM, 0.3125 mM, 0.6
25 mM, 1.25 mM, 2.5 mM, 5 mM and 1
To the compound (1-33) prepared to have a concentration of 0 mM, 5 mM vitamin B ₆ (pyridoxine hydrochloride) was added to prepare a sample solution. The sample solution and the control solution were incubated at 37° C. for 4 days. (Ii) Analysis method 0.15 ml of each 100-fold diluted sample solution was added to each well of a 96-well microtiter plate and incubated. After 2 hours, 0.05% Tween 20 (polyoxyethylene (20) sorbitan monolaurate)
10 mM phosphate buffer solution (hereinafter referred to as buffer solution A) containing
Rinse three times with 0.3% 0.4% gelatin solution in each well.
ml was added and blocking was performed. Then 0.15 ml of anti-AGE antibody was added and incubated. After 2 hours, after washing with buffer A, peroxidase-conjugated anti-rabbit IgG antibody (0.1
5 ml) was added and incubated.

After 2 hours, the plate was washed with buffer solution A, and a color developing solution (0.4 mg/ml orthophenylenediamine, 0.
0.1 μl of 2 μl/ml 30% hydrogen peroxide solution) was added to develop color, and then 0.05 ml of 1M sulfuric acid was added,
The reaction was stopped. The absorbance at 492 nm of this color developing solution was measured using an ELISA plate reader. The result is shown in FIG. The absorbance of the control solution should be 1
The absorbance of each sample solution was quantified as 00%. 2. Development and suppression of side effects 1) Suppression of neuropsychiatric symptoms (suppressive effect on convulsions) and suppression of vitamin B ₆ reduction (i) Administration schedule After 6 hours, they were fed. (ii) Dose and administration period As Example 1, the compound (1-33) was added in an amount of 30 per kg of body weight.
After continuously administering an amount corresponding to 0 mg/day and an amount corresponding to 30 mg/day of pyridoxine hydrochloride for 1 kg of body weight for 20 consecutive days, each double dose was increased to 7 times.
It was administered daily.

As Comparative Example 1, the compound (1-33) was weighed 1 k.
An amount corresponding to 300 mg/day per g was continuously administered for 20 days, and then a double dose thereof was administered for 3 days. (iii) Measurement method References (Yoshiharu Yagi, Kenji Soda: Laboratory, Vol. 36,
No. 3, p. 244, 1992), the blood pyridoxal phosphate (PLP) and pyridoxal (PL) concentrations were measured during the administration period. Further, during the administration period, convulsions caused by vitamin B ₆ deficiency were observed. The results are shown in Tables 1 and 2. The measured values of PLP and PL in blood were digitized with the concentration before administration set to 100%.

[0092]

[Table 1]

[0093]

[Table 2]

As is clear from the results in Tables 1 and 2,
In Example 1 in which the compound (1-33) and vitamin B ₆ were used in combination, the decrease in blood PLP and PL concentrations was mild even on the 24th day of administration, and no convulsion was observed on the 27th day after administration. Was not done. In contrast, the compound (1-33)
In Comparative Example 1 in which blood was administered alone, PLP and PL in blood were
As the concentration decreased, convulsion was observed 3 times on the 22nd day after administration and 13 times on the 23rd day after administration. In Comparative Example 1, the convulsion of the sample was severe, and the observation was stopped 23 days after the administration. 2) Improvement of abnormal GPT value (improvement of abnormal value of serum biochemical test value) (i) Administration method Five SD male rats (5 weeks old) were used as a sample in each group. The compound (1-33) was made into a 0.5% carboxymethylcellulose suspension, and pyridoxine hydrochloride (PN) and aminoguanidine hydrochloride were made into aqueous solutions, and the following predetermined amounts were forcibly administered orally per kg of rat body weight. .

Example 2 was a group in which the compound (1-33) was administered in an amount corresponding to 1000 mg/day/kg body weight of rats and 100 mg/day/kg body weight of pyridoxine hydrochloride rats. Comparative Example 2 was a group in which only the compound (1-33) was administered in an amount corresponding to 1000 mg/day per 1 kg of rat body weight.

Comparative Example 3 was a group in which aminoguanidine was administered in an amount corresponding to 1000 mg/day per 1 kg of rat body weight. The drug-non-administered group was used as a control group. After administration for 1 week, blood was collected from rat aorta under mild ether anesthesia, and the obtained blood was centrifuged (3000 rpm,
After 15 minutes of treatment, serum was obtained. GPT in serum
The (glutamic acid-pyruvate transaminase) concentration was quantified by a modification of the Reitman-Franker (Ratemann-Franker) method. The results are shown in Table 3.

[0097]

[Table 3]

In Table 3, the body weight of rats and the concentration of GPT in serum are shown as the average value±standard deviation at n=5.
^* Is significantly different from the control group at p<0.05,
Significant difference was observed at ^** for p<0.01, and for ^*** at p<0.
A significant difference was observed at 001 (paired t-test). As is clear from Table 3, compared with the control group,
In Example 2 in which pyridoxine hydrochloride and the compound (1-33) were used in combination, the GPT value was hardly reduced.

On the other hand, in Comparative Example 2 in which only the compound (1-33) was administered and Comparative Example 3 in which only aminoguanidine was administered, the GPT value was significantly decreased as compared with the control group.

[0100]

INDUSTRIAL APPLICABILITY The composition for inhibiting AGE production of the present invention is effective in preventing or reducing side effects caused by administration of a Maillard reaction inhibitor. Therefore, it is suitable as a therapeutic agent for diabetic complications caused by AGE.

[Brief description of drawings]

FIG. 1 is a graph showing the results of measuring the AGE production inhibitory effect of an AGE production inhibitor composition according to the present invention with changes in concentration using an ELISA plate reader (Titer Tech (registered trademark), Multiscan MCC/340MKII). is there.

Claims (6)

[Claims] 1. An AGE production inhibitory composition comprising a Maillard reaction inhibitor and vitamin B ₆ or a pharmaceutically acceptable salt thereof. 2. The composition for inhibiting AGE production according to claim 1, wherein the Maillard reaction inhibitor is aminoguanidine. 3. The Maillard reaction inhibitor has the general formula
(1):[In the formula, R¹Is a hydrogen atom, lower alkoxycarbonyl
Primary alkyl group, halogen source as a substituent on the phenyl ring
Child, hydroxyl group, nitro group, lower alkyl group, lower alkoxy group
1 to 3 groups selected from Si group and lower alkylthio group.
Phenyl lower alkyl groups or substituents that may have
Halogen atom, hydroxyl group, nitro group, lower alkyl group
Group, lower alkoxy group and lower alkylthio group
Indicates a phenyl group which may have 1 to 3 selected groups
You R²Is an amino group, halo as a substituent on the phenyl ring
Gen atom, hydroxyl group, amino group and lower alkanoyl group
Phenylsul which may have a group selected from mino groups
Honylamino group or group: -N=R^Four(R^FourIs lower al
Low having 1 to 2 pyridene groups and lower cycloalkyl groups
Class alkylidene group, lower cycloalkylidene group, diphe
Nyl lower alkylidene group or phenyl lower alkylide
Group) is shown). R³Is a hydrogen atom; lower alkyl
Group; lower alkenyl group; phenyl lower alkoxy lower group
Alkyl group; phenyl group which may have a hydroxyl group; nitrogen
Heteroatoms selected from the group consisting of atoms and sulfur atoms
5- or 6-membered unsaturated heterocyclic ring having 1-2
Primary alkyl group (the hetero ring may be condensed with a benzene ring)
A substituent on the heterocycle and on the fused benzene ring.
May have a hydroxyl group); Group: -W-(N
H) b-CO-OR^Five(W represents a lower alkylene group,
R^FiveIs a hydrogen atom, lower alkyl group, phenyl lower alkyl
Group, and b represents 0 or 1. ); Group: -Z-C
OR^a{Wherein Z represents a lower alkylene group, R^a
Is a group: -Tyr(OR^a1)-OR^b1, Group: -Leu-O
R^b2, Group: -Trp-OR^b3, Group: -Asp(OR^a2)
-OR^b4, Group: -Ph-Gly-OR^b5(In each group, R^a1
And R^a2Is a hydrogen atom or a benzyl group, R^b1, R^b2,
R^b3, R^b4And R^b5Is a hydrogen atom or a lower alkyl group
Or the group: -N(R⁶)-R⁷(R⁶Is lower
Alkyl group, carboxy lower alkyl group, lower alkoxy
Carbonyl lower alkyl group, phenyl lower alkyl group,
Lower cycloalkyl group, halogen atom as a substituent, water
Acid group, nitro group, lower alkyl group, lower alkoxy group,
Lower alkylthio group, carboxyl group, lower alkoxy
Carbonyl group, phenyl lower alkoxy group, lower alk
Dioxy group, morpholino group, halogenated lower alkyl
Group, carboxy lower alkyl group, lower alkoxycal
Bonyl lower alkyl group, 6-hydroxy-2,5,7,
8-tetramethyl-2-chromanyl-methyloxy group
And 6-lower alkanoyloxy-2,5,7,8-te
Selected from tramethyl-2-chromanyl-methyloxy group
Phenyl group, which may have 1 to 3 groups, naphthi
Group, 3,4-dihydrocarbostyryl group, morpholino
From the group consisting of groups, nitrogen atoms, oxygen atoms and sulfur atoms
5-membered or 6-membered having 1-2 selected heteroatoms
An unsaturated heterocyclic lower alkyl group of R⁷Is hydrogen
Child or lower alkyl group). }; or
Group:{B represents a lower alkylene group, R⁸Is hydroxyl, nitro
Group, amino group, halogen atom, lower alkyl group, lower alkyl group
Lucoxy group, phenoxy group, phenyl lower alkyl group,
May have lower alkylthio groups and halogen atoms
Phenylthio group, having 1 to 3 halogen atoms
A benzoylamino group or group: -O-D-R⁹(D
Represents a lower alkylene group, R⁹Is substituted on the phenyl ring
Halogen atom, hydroxyl group, nitro group, lower alkyl group
Group, lower alkoxy group and lower alkylthio group
A phenyl group which may have 1 to 3 selected groups (
Phenyl ring fused with benzene ring or cyclohexane ring
You may. ), nitrogen atom, sulfur atom and oxygen atom
5 member having 1 heteroatom selected from the group consisting of
Is a 6-membered saturated or unsaturated heterocyclic group (wherein the heterocycle is
It may be fused with a benzene ring, on the heterocycle and on the heterocycle.
On the benzene ring fused with the telocycle, a hydroxyl group or
And a group selected from the group consisting of lower alkyl groups of 1 to 5
May have one), a lower cycloalkyl group or
Indicates a futoquinone group. ), n is 0 or 1 to 3
Indicates an integer}. X is -S- or -N(R^Ten) −
(R^TenIs a hydrogen atom or lower alkoxycarbonyl lower
Indicates an alkyl group. ) Is shown. [Chemical 3]Represents a single bond or a double bond. However,When represents a single bond, A represents a carbonyl group, andIs a double bond, A is =C(R¹¹)-{R¹¹Is halo
A lower alkyl group which may have 1 to 3 gen atoms,
Lower alkoxycarbonyl lower alkyl group, carboxy
Lower alkyl group, pyridyl group, thienyl group, thiazolyl
Group, having 1-2 lower alkoxy groups on the phenyl ring
Sometimes a phenylcarbamoyl lower alkyl group or
Group:(R¹²Is a halogen atom, hydroxyl group, nitro group, lower alkyl
Group, lower alkoxy group, lower alkylthio group, carbo
Halogen on xy, phenylthio or phenyl ring
Phenyl lower alkoxy, which may have 1 to 3 atoms
Si group, m represents 0 or an integer of 1 to 3)
}}. Also, the above R^FourIs R ^TenAnd each other
To form a 6- to 8-membered ring (provided that this ring
A represents a carbonyl group). However
And R³Represents a hydrogen atom, and A represents a carbonyl group.
In case of¹Is a hydrogen atom or lower alkoxycar
Do not represent a carbonyl lower alkyl group. Also R³When
R¹¹And may combine with each other to form a 5- to 8-membered ring]
A compound represented by or a pharmaceutically acceptable salt thereof,
General formula (2):[In the formula, R¹³Is a hydrogen atom, lower alkyl group, carboxy
Lower alkyl group, lower alkoxycarbonyl lower alk
Group, phenoxy lower alkanoyl group, on the phenyl ring
Phenoxy-lower alkyl having a lower alkoxycarbonyl group
Rucanoyl group or lower cycloalkyl group, R¹⁴
Is a group: -NHR¹⁶{R¹⁶Is a hydrogen atom,
Rogen atom, nitro group, lower alkoxy group and lower
Having 1 to 3 substituents selected from alkyl groups.
Phenylsulfonyl group, phenyl lower alkanoyl group
Or group: -CO-NHR¹⁷(R¹⁷Is a lower alkyl group,
Pheny, which may have halogen atoms on the phenyl ring
Group, phenyl lower alkyl group or naphthyl group
You )} or R¹⁴Is a group: -N=R¹⁸{R¹⁸
Is a lower alkylidene group or a lower cycloalkyl group of 1 to 2
Lower alkylidene groups, each having a halogen on the phenyl ring
Atom, carboxyl group, lower alkoxycarbonyl group,
Nitro group, hydroxyl group, lower alkoxy group and halogenated
It has 1 to 3 substituents selected from lower alkyl groups.
With a phenyl lower alkylidene group, on the phenyl ring
Phenyl lower alkenylide which may have nitro group
Group, lower alkenylidene group, lower cycloalkylidene group
Having a carboxyl group on the group or on the phenyl ring
A phenoxy lower alkylidene group is shown. } Is shown,
R¹⁵Has two hydrogen atoms, a halogen atom on the phenyl ring and
And a substituent selected from halogenated lower alkyl groups
Sometimes phenyl lower alkylidene group or phenyl
A lower alkenylidene group, Y is -S- or -N
(R¹⁹)-(R¹⁹Is a hydrogen atom, lower alkyl group, carbo
Xy lower alkyl group or lower alkoxycarbonyl low
Indicates a primary alkyl group. ), and R¹³And R¹⁶Or R¹⁶
And R¹⁹May combine to form an oxoethylene group.
Yes. However, R¹³Is a hydrogen atom, R¹⁵Is 2 hydrogen atoms and
When Y is -S-, R¹⁴Is a group: -NHR¹⁶(R¹⁶Is water
Having a lower alkoxy group on the elementary atom or on the phenyl ring
Sometimes a phenylsulfonyl group), or R¹⁴Is based on:
-N=R¹⁸(R¹⁸Is a lower alkylidene group, on the phenyl ring
Halogen atom, nitro group, hydroxyl group and lower alcohol
Phenyl low which may have a substituent selected from
Having a primary alkylidene group or a nitro group on the phenyl ring
A phenyl lower alkenylidene group)
Don't Furthermore, R¹³Is a hydrogen atom, R¹⁴Is based on: -N
=R¹⁸And when Y is -S- or -NH-, R¹⁵When
R¹⁸Are not simultaneously phenyl lower alkylidene groups
No Furthermore, R¹⁴Is a group: -NHR¹⁶, R¹⁵Water
R when two elementary atoms and Y is -S-¹³And R¹⁶Is a bond
To form an oxoethylene group. ]]
Compound or a pharmaceutically acceptable salt thereof, or
General formula (3):[In the formula, R²⁰Represents a hydrogen atom or a lower alkyl group,
R^{twenty one}Is a hydrogen atom, a lower alkyl group, a lower alkanoyl group
Or a lower alkoxycarbonyl lower alkyl group
And R^{twenty two}Is a hydrogen atom, a lower alkyl group or a lower
R represents a noyl group ^{twenty three}Is a hydrogen atom, lower alkanoyl
A group, a benzoyl group or a group:(R^{twenty four}Represents a phenyl group or a lower alkoxy group)
Show. Also R^{twenty two}And R ^{twenty three}Together is a lower archi
Den group, diphenylmethylene group or phenyl lower alkyl group
It may also represent a pyridene group. V is -S- or -N-
(R^{twenty five})-Indicates. R^{twenty five}Is a hydrogen atom, a lower alkyl group,
Lower alkoxycarbonyl lower alkyl group or phenyl
May have a halogen atom as a substituent on the ring.
A phenyl lower alkyl group is shown. Furthermore R^{twenty three}And R^{twenty five}
May combine with each other to form a 6- to 8-membered ring. ]
The compound or its pharmaceutically acceptable salt.
A composition for inhibiting AGE production as described. 4. General formula (1): [Wherein R ¹ represents a hydrogen atom, a lower alkoxycarbonyl lower alkyl group, a substituent on the phenyl ring selected from a halogen atom, a hydroxyl group, a nitro group, a lower alkyl group, a lower alkoxy group and a lower alkylthio group; Three
A phenyl lower alkyl group which may have 1 to 3 or a phenyl group which may have 1 to 3 groups selected from a halogen atom, a hydroxyl group, a nitro group, a lower alkyl group, a lower alkoxy group and a lower alkylthio group as a substituent. R ² is an amino group, a phenylsulfonylamino group which may have a group selected from a halogen atom, a hydroxyl group, an amino group and a lower alkanoylamino group as a substituent on the phenyl ring or a group: —N═R ⁴ (R ⁴ is A lower alkylidene group, a lower alkylidene group having 1 to 2 lower cycloalkyl groups, a lower cycloalkylidene group, a diphenyl lower alkylidene group or a phenyl lower alkylidene group). R ³ has a hydrogen atom; a lower alkyl group; a lower alkenyl group; a phenyl lower alkoxy lower alkyl group; a phenyl group which may have a hydroxyl group; and 1 or 2 hetero atoms selected from the group consisting of a nitrogen atom and a sulfur atom. 5-membered or 6-membered unsaturated heterocycle lower alkyl group (the heterocycle may be condensed with a benzene ring, and may have a hydroxyl group as a substituent on the heterocycle and the condensed benzene ring) Group: -W-(N
H) b-CO-OR ⁵ (W represents a lower alkylene group,
R ⁵ represents a hydrogen atom, a lower alkyl group or a phenyl lower alkyl group, and b represents 0 or 1. ); Group: -Z-C
O—R ^a {wherein Z represents a lower alkylene group, and R ^a
Is a group: -Tyr(OR ^a1 )-OR ^b1 , a group: -Leu-O
R ^b2, group: -Trp-OR ^b3, based on: -Asp (OR ^a2)
-OR ^b4 , group: -Ph-Gly-OR ^b5 (in each group, R ^a1
And R ^a2 is a hydrogen atom or a benzyl group, R ^b1 , R ^b2 ,
R ^b3 , R ^b4 and R ^b5 are a hydrogen atom or a lower alkyl group) or a group: —N(R ⁶ )—R ⁷ (R ⁶ is a lower alkyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, Phenyl lower alkyl group,
Lower cycloalkyl group, halogen atom as a substituent, hydroxyl group, nitro group, lower alkyl group, lower alkoxy group,
Lower alkylthio group, carboxyl group, lower alkoxycarbonyl group, phenyl lower alkoxy group, lower alkylenedioxy group, morpholino group, halogenated lower alkyl group, carboxy lower alkyl group, lower alkoxycarbonyl lower alkyl group, 6-hydroxy-2, 5, 7,
It may have 1 to 3 groups selected from an 8-tetramethyl-2-chromanyl-methyloxy group and a 6-lower alkanoyloxy-2,5,7,8-tetramethyl-2-chromanyl-methyloxy group. 5- or 6-membered unsaturated hetero having 1 to 2 heteroatoms selected from the group consisting of phenyl group, naphthyl group, 3,4-dihydrocarbostyryl group, morpholino group, nitrogen atom, oxygen atom and sulfur atom. A ring lower alkyl group, R ⁷ represents a hydrogen atom or a lower alkyl group. )} or a group: {B represents a lower alkylene group, R ⁸ represents a hydroxyl group, a nitro group, an amino group, a halogen atom, a lower alkyl group, a lower alkoxy group, a phenoxy group, a phenyl lower alkyl group,
A lower alkylthio group, a phenylthio group which may have a halogen atom, a benzoylamino group which may have 1 to 3 halogen atoms or a group: -O-D-R ⁹ (D
Represents a lower alkylene group, and R ⁹ represents phenyl which may have 1 to 3 groups selected from halogen atom, hydroxyl group, nitro group, lower alkyl group, lower alkoxy group and lower alkylthio group as a substituent on the phenyl ring. A 5-membered or 6-membered saturated or unsaturated group having one hetero atom selected from the group consisting of a group (the phenyl ring may be condensed with a benzene ring or a cyclohexane ring), a nitrogen atom, a sulfur atom and an oxygen atom. Saturated heterocyclic group (the heterocyclic ring may be condensed with a benzene ring, and a group selected from the group consisting of a hydroxyl group and a lower alkyl group as a substituent on the heterocyclic ring and the benzene ring condensed with the heterocyclic ring is 1 ~ 5
May have one), a lower cycloalkyl group or a naphthoquinone group. ), and n represents 0 or an integer of 1 to 3}. X is -S- or -N (R ¹⁰⁾ -
(R ¹⁰ represents a hydrogen atom or a lower alkoxycarbonyl lower alkyl group). [Chemical formula 12] Represents a single bond or a double bond. However, When is a single bond, A is a carbonyl group, and Is a double bond, A is ═C(R ¹¹ )-{R ¹¹ is a lower alkyl group which may have 1 to 3 halogen atoms,
Lower alkoxycarbonyl lower alkyl group, carboxy lower alkyl group, pyridyl group, thienyl group, thiazolyl group, phenylcarbamoyl lower alkyl group or group which may have 1 or 2 lower alkoxy groups on the phenyl ring: (R ¹² is a halogen atom, a hydroxyl group, a nitro group, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a carboxyl group, a phenylthio group or a phenyl lower alkoxy group which may have 1 to 3 halogen atoms on the phenyl ring. And m represents 0 or an integer of 1 to 3)}. R ^{4 and} R ¹⁰ may combine with each other to form a 6- to 8-membered ring (provided that when forming this ring, A represents a carbonyl group). However, when R ³ represents a hydrogen atom and A represents a carbonyl group, R ¹ must not represent a hydrogen atom or a lower alkoxycarbonyl lower alkyl group. R ³ and R ¹¹ may combine with each other to form a 5- to 8-membered ring.]
A compound represented by or a pharmaceutically acceptable salt thereof,
An AGE production inhibitor composition containing vitamin B ₆ or a pharmaceutically acceptable salt thereof. 5. 2-Isopropylidenehydrazono-5-
(N-phenylcarbamoylmethyl)thiazolidine-4
-One, 5-[N-(2-carboxy-4-methylphenyl)carbamoylmethyl]-2-isopropylidenehydrazonothiazolidin-4-one, 5-[N-(3,4
-Difluorophenyl)carbamoylmethyl]-2-isopropylidene hydrazonothiazolidin-4-one, 5
-[N-(2-carboxy-4-chlorophenyl)carbamoylmethyl]-2-isopropylidenehydrazonothiazolidin-4-one, 5-[N-(2-carboxy-
4,5-Dimethoxyphenyl)carbamoylmethyl]-
At least one selected from the group consisting of 2-isopropylidenehydrazonothiazolidin-4-one and 5-[N-(2-carboxy-4-fluorophenyl)carbamoylmethyl]-2-isopropylidenehydrazonothiazolidin-4-one A composition for inhibiting AGE production, which comprises a compound of any of the following, or a pharmaceutically acceptable salt thereof, and vitamin B ₆ or a pharmaceutically acceptable salt thereof. 6. The method according to claim 1, wherein the vitamin B ₆ or a pharmaceutically acceptable salt thereof is contained in an amount of 0.1 to 200 parts by weight based on 100 parts by weight of the Maillard reaction inhibitor. An AGE production inhibitory composition.