JPH07242666A - Heterocyclic compound - Google Patents

Abstract

PURPOSE:To provide the novel compound useful for preventing and treating allergy,. inflammation, autoimmune diseases, shock, ache, etc., as a bradykinin- antagonizing agent. CONSTITUTION:This compound is expressed by formula I [R<1> is H, lower alkyl, etc.; R<2> is H, acyl, etc., R<3> is H, halogenated lower alkyl, etc.; R<4> is aryl, heterocyclic group, etc.; the group of formula II is a group of formula III or IV (X<2>-X<4> are N, CH); Q is O, NH, etc.; X<1> is N, C-R<5> (R<5> is H, halogen); Y<1>, Y<2> are single bond, lower alkylene] and its salt, e.g. delta-(2,6-dichlorobenzyloxy)-2- phenylimidazo[1,2-a]pyridine hydrochloride. The compound is obtained e.g. by reacting 2-amino-2-(2,6-dichlorobenzyloxy) pyridine with 2-bromoacetophenone in ethanol under thermally refluxing.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a heterocyclic compound and a salt thereof which have activity as a bradykinin antagonist and are useful for treating various diseases, and are used in the medical field.

[0002]

BACKGROUND OF THE INVENTION Certain heterocyclic compounds are known, for example, from the Journal of Medicinal Chemistry (Jour.
nal of Medicinal Chemistr
y) Vol. 28, 876-892 (1985), but it is not known at all that the compound has activity as a bradykinin antagonist.

[0003]

The object of the present invention is to provide a heterocyclic compound having activity as a bradykinin antagonist and a salt thereof. Another object of the present invention is to provide a method for producing the heterocyclic compound and salts thereof. Another object of the present invention is to provide a pharmaceutical composition containing the heterocyclic compound and salts thereof as an active ingredient. Still another object of the present invention is to prevent diseases caused by bradykinin or its analogs, such as allergies, inflammations, autoimmune diseases, shocks and pains, which contain the heterocyclic compounds and salts thereof as active ingredients. /
Or to provide a therapeutic agent. The heterocyclic compounds aimed at by this invention are new and can be represented by the following general formula [I]:

[Chemical 4] [Wherein R ¹ is hydrogen, a lower alkyl group, a lower alkenyl group, a hydroxy lower alkyl group, a substituted hydroxy lower alkyl group, a lower alkylthio group, a hydroxy group,
A lower alkoxy group, a halo lower alkyl group, an acyl group or halogen, R ² represents hydrogen, a lower alkyl group, a halo lower alkyl group, an acyl group or an aryl group, or R ¹ and R ² are bonded to each other. To form a lower alkylene group, R ³ is hydrogen, a lower alkyl group, a halo lower alkyl group or an acyl group, R ⁴ is an aryl group which may have a suitable substituent, and a suitable substituent. Optionally lower alkyl group or an optionally substituted heterocyclic group, formula

[Chemical 5] Is

[Chemical 6] And Q is O, NH, S, SO, SO ₂ , CO
O or lower alkenylene group, X ¹ is N or C—R
⁵ , R ⁵ are hydrogen or halogen, X ² , X ³ , and X ⁴ are N or CH, and Y ¹ and Y ² are single bond or lower alkylene group. The target compound [I] or a salt thereof can be produced, for example, by the production method shown by the following reaction formula.

Manufacturing method 1

[Chemical 7]

Manufacturing method 2

[Chemical 8] [In the formula, R ⁶ is an amino group or a methyl group, Q _a Is O, N
H or S, X ¹ _a is N or CH, Z is a leaving group, and R ¹ , R ² , R ³ , R ⁴ ,

[Chemical 9] Q, X ¹ , X ² , X ³ , X ⁴ , Y ¹ and Y ² have the same meanings as above]

In the above and below description of the present specification, suitable examples of the various definitions to be included within the scope of the present invention will be explained in detail below. The term "lower" means a group having 1 to 6 carbon atoms unless otherwise specified. Suitable "halogen" includes fluorine, chlorine,
Examples include bromine and iodine. Suitable "aryl" includes phenyl, naphthyl, lower alkyl-substituted phenyl [eg tolyl, xylyl, mesityl, cumenyl, di (tertiary butyl) phenyl, etc.] and the like, among which preferred is phenyl. And Toril. Suitable "ar lower alkyl" includes benzyl, phenethyl, benzhydryl, trityl and the like. Suitable "lower alkyl" as well as "hydroxy lower alkyl"
And suitable lower alkyl moieties in "lower alkylthio" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl,
Examples include linear or branched ones such as hexyl,
Of these, preferred is C ₁ -C ₄ alkyl such as methyl, ethyl, propyl, isobutyl and tertiary butyl. Suitable "lower alkylene" includes linear or branched ones such as methylene, ethylene, trimethylene, methylmethylene, tetramethylene, ethylethylene, propylene, pentamethylene, hexamethylene, and the like. Most preferred is methylene. Suitable "halo lower alkyl" includes fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,
Examples thereof include dichloromethyl, bromomethyl, fluoroethyl, difluoroethyl, chloroethyl, dichloroethyl and the like.

Suitable "lower alkoxy" includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy,
Hexyloxy and the like can be mentioned. Suitable "lower alkenyl" includes vinyl, allyl, propenyl, isopropenyl, butenyl, pentenyl and the like. Suitable substituents in the expression "substituted hydroxy lower alkyl" include the above lower alkyl, the above lower alkenyl, the above halo lower alkyl, the above aryl, the following acyl and the like. Suitable "lower alkenylene"
As, vinylene, methylvinylene, propenylene,
Examples thereof include linear or branched ones such as 1,3-butadienylene, of which vinylene is most preferable. Suitable "acyl" includes, for example, alkanoyl [eg formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, 3,3-dimethylbutyryl, etc.], halo lower alkanoyl [eg chloroacetyl, Trifluoroacetyl, bromoacetyl, bromobutyryl, heptafluorobutyryl, etc.], hydroxy lower alkanoyl [eg glycoloyl, lactoyl, 3
-Hydroxypropionyl, glyceroyl, etc.], lower alkylsulfonyloxy lower alkanoyl [eg mesyloxyacetyl, ethylsulfonyloxyacetyl,
Mesyloxypropionyl etc.], lower alkoxy lower alkanoyl [eg methoxyacetyl, ethoxyacetyl, methoxypropionyl, ethoxypropionyl, bropropoxypropionyl, methoxybutyryl etc.], lower alkylthio lower alkanoyl [eg methylthioacetyl, ethylthioacetyl, methylthiopropionyl, Ethylthiopropionyl, propylthiopropionyl, methylthiobutyryl etc.], lower alkanoyloxy lower alkanoyl [eg acetyloxyacetyl, acetyloxypropionyl, propionyloxyacetyl etc.], aryloxy lower alkanoyl [eg phenyloxyacetyl, phenyloxypropionyl, tolyl Oxyacetyl, naphthyloxyacetyl, etc.], aroyl lower alkanoyl Such as phenyl oxalyl, benzoyl acetyl, benzoyl propionyl, etc.],

Carboxy lower alkanoyl [eg oxalo, carboxyacetyl, 3-carboxypropionyl, 3-carboxybutyryl, 4-carboxybutyryl, 4-carboxyvaleryl etc.], esterified carboxy lower alkanoyl, eg lower alkoxycarbonyl. Lower alkanoyl [eg methoxycarbonylacetyl, ethoxycarbonylacetyl, methoxycarbonylpropionyl, ethoxycarbonylpropionyl etc.], carbamoyl lower alkanoyl [eg carbamoylacetyl, carbamoylpropionyl etc.], lower alkylcarbamoyl lower alkanoyl [eg methylcarbamoylacetyl, methylcarbamoylpropionyl, Ethylcarbamoylpropionyl, dimethylcarbamoylpropionyl, N Methyl-N-ethylcarbamoylpropionyl etc.], lower alkanoyl [eg phenylacetyl, tolylacetyl, naphthylacetyl, 2-phenylpropionyl, 3-phenylpropionyl, 4-phenylbutyryl, tritylcarbonyl etc.], even if substituted Good heterocyclic lower alkanoyl [eg morpholinoacetyl, thiomorpholinoacetyl, morpholinopropionyl, thiomorpholinopropionyl, piperidinopropionyl, piperazinylpropionyl, pyridylacetyl, pyrrolidinylpropionyl,
Imidazolidinyl propionyl, piperidinoacetyl,
Pyrrolidinylacetyl, hexamethyleneiminoacetyl, hexamethyleneiminopropionyl, imidazolylacetyl, furylacetyl, thienylacetyl, methylpiperazinylacetyl, pyridylpiperazinylacetyl, etc., heterocyclic thio-lower alkanoyl [eg pyridylthioacetyl, pyrimidinyl] Substituted or unsubstituted alkanoyl such as thioacetyl, imidazolylthiopropionyl, etc., lower alkenoyl [eg, acryloyl, crotonoyl, isocrotonoyl, 3-butenoyl, 3-pentenoyl, 4-pentenoyl, methacryloyl, etc.], lower alkinoyl [eg, propioroyl, 2- Butynoyl, 3-butynoyl, etc.], cyclo-lower alkylcarbonyl [eg cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentene Ylcarbonyl, cyclohexylcarbonyl, etc.], cyclo lower alkenylcarbonyl [e.g. cyclopentenyl carbonyl, cyclohexenyl carbonyl, etc.],

Carboxy, eg lower alkoxycarbonyl [eg methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl,
Hexyloxycarbonyl etc.], lower alkenyloxycarbonyl [eg vinyloxycarbonyl, allyloxycarbonyl etc.], lower alkynyloxycarbonyl [eg ethynyloxycarbonyl, propynyloxycarbonyl etc.], aryloxycarbonyl [eg phenoxycarbonyl etc.] etc. Esterified carboxy, such as aroyl [eg benzoyl, toluoyl, xyloyl, naphthoyl etc.], lower alkoxy aroyl [eg methoxybenzoyl etc.], haloaroyl [eg chlorobenzoyl, fluorobenzoyl etc.],
A substituted or unsubstituted aroyl such as acylaroyl, eg, lower alkoxycarbonylaroyl [eg, methoxycarbonylbenzoyl, etc.], eg, al-lower alkenoyl [eg, cinnamoyl, arosinnamoyl, α-methylcinnamoyl, 4-methylcinnamoyl, etc.], lower alkoxyar Lower alkenoyl [eg methoxycinnamoyl, ethoxycinnamoyl, dimethoxycinnamoyl etc.], lower alkylenedioxyar lower alkenoyl [eg methylenedioxycinnamoyl, ethylenedioxycinnamoyl etc.], nitroal lower alkenoyl [eg nitrocinnamoyl Etc.], haloal lower alkenoyl [eg chlorocinnamoyl, fluorocinnamoyl etc.], hydroxyal lower alkenoyl [eg cidroxycinnamoyl Etc.], hydroxy lower alkoxy al lower alkenoyl [eg hydroxymethoxycinnamoyl, hydroxyethoxy cinnamoyl etc.], amino lower alkoxy al lower alkenoyl [eg aminoethoxy cinnamoyl etc.], lower alkylamino lower alkoxy al lower alkenoyl [eg methylamino Methoxycinnamoyl, dimethylaminomethoxycinnamoyl, etc.],

Heterocyclic lower alkoxyalkoxyl lower alkenoyl [eg pyridyl methoxycinnamoyl etc.], optionally substituted heterocyclic al lower alkenoyl [eg morpholinocinnamoyl, methylpiperazinylcinnamoyl, pyrrolidinylcinnamoyl, oxo] Pyrrolidinyl cinnamoyl, oxopiperidinocinnamoyl, dioxopyrrolidinyl cinnamoyl, oxooxazolidinyl cinnamoyl, pyrrolyl cinnamoyl, etc.], aminoar lower alkenoyl [eg aminocinnamoyl etc.], lower alkyl Aminoar lower alkenoyl [eg, methylaminocinnamoyl, dimethylaminocinnamoyl, etc.], acylaminoar lower alkenoyl, eg, lower alkanoylaminoar lower alkenoyl [eg, acetylaminocinnamoyl] , Propionylaminocinnamoyl, etc.], hydroxy lower alkanoylaminoal lower alkenoyl [eg hydroxyacetylaminocinnamoyl, hydroxypropionylaminocinnamoyl etc.], lower alkoxy lower alkanoylaminoal lower alkenoyl [eg methoxyacetylaminocinnamoyl, methoxypropionylamino Cinnamoile, etc.],
Halo lower alkanoylaminoar lower alkenoyl [eg chloroacetylaminocinnamoyl, bromobutyrylaminocinnamoyl etc.], amino lower alkanoylaminoar lower alkenoyl [eg aminoacetylaminocinnamoyl, aminopropionylaminocinnamoyl, etc.], lower alkyl Amino lower alkanoyl amino al lower alkenoyl [eg methylaminoacetylaminocinnamoyl, dimethylaminoacetylaminocinnamoyl, etc.], lower alkanoylamino lower alkanoylamino al lower alkenoyl [eg acetylaminoacetylaminocinnamoyl, acetylaminopropionylaminocinnamoyl , Etc.], carboxy lower alkanoylamino ar lower alkenoyl [eg carboxyacetylamino N'namoiru, carboxy-propionylamino cinnamoyl, etc.], lower alkoxycarbonyl-lower alkanoylamino ar (lower) alkenoyl [e.g. ethoxycarbonylacetyl aminocinnamoyl, ethoxycarbonyl propionylamino cinnamoyl,
Etc.], lower alkoxycarbonyl lower alkenoylaminoar lower alkenoyl [eg ethoxycarbonylacryloylaminocinnamoyl, etc.], halo lower alkoxycarbonylaminoar lower alkenoyl [eg chloroethoxycarbonylaminocinnamoyl, etc.],

Heterocycle lower alkanoylaminoar lower alkenoyl [eg pyridylacetylaminocinnamoyl etc.], aroylaminoar lower alkenoyl [eg benzoylaminocinnamoyl etc.], heterocycle carbonylaminoar lower alkenoyl [eg nicotinoylaminocinnamoyl] , Isonicotinoylaminocinnamoyl, morpholinocarbonylaminocinnamoyl, etc.], lower alkylsulfonylaminoar lower alkenoyl [eg, mesylaminocinnamoyl, ethylsulfonylaminocinnamoyl, etc.], N- (lower alkanoyl) -N
-(Lower alkyl) aminoar lower alkenoyl [eg N-acetyl-N-methylaminocinnamoyl, N-
Acetyl-N-ethylaminocinnamoyl, N-propionyl-N-methylaminocinnamoyl, etc.], N-
(Lower alkoxy lower alkanoyl) -N- (lower alkyl) aminoar lower alkenoyl [eg N-methoxyacetyl-N-methylaminocinnamoyl, N-methoxypropionyl-N-methylaminocinnamoyl,
Etc.], N- (lower alkanoyl) -N- (heterocyclic lower alkyl) aminoar lower alkenoyl [eg N-acetyl-N-pyridylmethylaminocinnamoyl, etc.],
Ureido al lower alkenoyl [eg ureido cinnamoyl etc.], lower alkyl ureido al lower alkenoyl [eg methyl ureido cinnamoyl, ethyl ureido cinnamoyl, dimethyl ureido cinnamoyl etc.],
Heterocyclic ureido ar lower alkenoyl [eg pyridyl ureido cinnamoyl, pyrimidinyl ureido cinnamoyl, thienyl ureido cinnamoyl, etc.], acyl ar lower alkenoyl, eg lower alkanoyl ar lower alkenoyl [eg formyl cinnamoyl, acetyl cinnamoyl, propionyl cinnamoyl etc.] , Carboxyar lower alkenoyl [eg carboxycinnamoyl, etc.], lower alkoxycarbonylar lower alkenoyl [eg methoxycarbonylcinnamoyl, ethoxycarbonylcinnamoyl, etc.], carbamoyl al lower alkenoyl [eg carbamoylcinnamoyl etc.], lower alkylcarbamoyl Al-lower alkenoyl [eg methylcarbamoylcinnamoyl, ethylcarbamoylcinnamoyl , Dimethylcarbamoylcinnamoyl, propylcarbamoylcinnamoyl, isopropylcarbamoylcinnamoyl, diethylcarbamoylcinnamoyl, N-methyl-N-ethylcarbamoylcinnamoyl and the like], hydroxy lower alkylcarbamoyl al lower alkenoyl [eg hydroxyethylcarbamoylcinnamoyl, bis (Hydroxyethyl) carbamoylcinnamoyl etc.], N- (hydroxylower alkyl) -N- (lower alkyl) carbamoylar lower alkenoyl [eg N-hydroxyethyl-N-methylcarbamoylcinnamoyl, etc.], lower alkoxy lower alkylcarbamoyl Al-lower alkenoyl [eg methoxymethylcarbamoylcinnamoyl, methoxyethylcarbamoylcinnamoyl, bis (meth) Shiechiru) carbamoyl cinnamoyl, ethoxy ethylcarbamoyl cinnamoyl, methoxy propylcarbamoyl cinnamoyl, bis (ethoxyethyl) carbamoyl cinnamoyl, etc.],

N- (lower alkoxy lower alkyl) -N
-(Lower alkyl) carbamoyl ar lower alkenoyl [eg N-methoxyethyl-N-methylcarbamoylcinnamoyl, etc.], heterocyclic carbamoyl al lower alkenoyl [eg morpholinylcarbamoylcinnamoyl, thienylcarbamoylcinnamoyl, pyridylcarbamoylcinnamoyl] , Pyrimidinylcarbamoylcinnamoyl, etc.], heterocyclic carbonylar lower alkenoyl [eg morpholinocarbonylcinnamoyl, pyrrolidinylcarbonylcinnamoyl, piperidinocarbonylcinnamoyl, etc.], etc. , Al lower alkinoyl [eg phenylpropioroyl etc.], eg heterocyclic lower alkenoyl [eg morpholinyl acryloyl, pyridyl acryloyl, thienyl a] Acryloyl, etc.], amino heterocyclic lower alkenoyl [e.g. amino pyridyl acryloyl,
Etc.], lower alkylamino heterocycle lower alkenoyl [eg methylaminopyridylacryloyl, dimethylaminopyridylacryloyl, etc.], acylaminoheterocycle lower alkenoyl, eg lower alkanoylaminoheterocycle lower alkenoyl [eg acetylaminopyridylacryloyl, propionylaminopyridylacryloyl ,
Etc.] etc., lower alkylureido heterocycle lower alkenoyl [eg methylureidopyridylacryloyl, etc.],
Acyl heterocycle lower alkenoyl, such as carboxyheterocycle lower alkenoyl [eg, carboxypyridylacryloyl, etc.], lower alkoxycarbonylheterocycle lower alkenoyl [eg, ethoxycarbonylpyridylacryloyl, etc.], lower alkylcarbamoyl heterocycle lower alkenoyl [eg, methylcarbamoylpyridyl Acryloyl, ethylcarbamoylpyridylacryloyl, dimethylcarbamoylpyridylacryloyl, diethylcarbamoylpyridylacryloyl, isopropylcarbamoylpyridylacryloyl, etc.], lower alkoxy lower alkylcarbamoyl heterocycle lower alkenoyl [eg methoxymethylcarbamoylpyridylacryloyl,
Methoxyethylcarbamoylpyridylacryloyl, methoxypropylcarbamoylpyridylacryloyl, ethoxyethylcarbamoylpyridylacryloyl, bis (methoxyethyl) carbamoylpyridylacryloyl, etc.], hydroxy lower alkylcarbamoyl heterocycle lower alkenoyl [eg hydroxymethylcarbamoylpyridylacryloyl, hydroxyethylcarbamoylpyridyl] Acryloyl, bis (hydroxyethyl) carbamoylpyridylacryloyl, etc.] and the like substituted or unsubstituted heterocycle lower alkenoyl, optionally substituted heterocycle carbonyl [eg furoyl, tenoyl, nicotinoyl, isonicotinoyl, morpholinocarbonyl] , Piperidinocarbonyl, 4-methyl-1-piperazinyl carbonyl , 4-ethyl-1-piperazinyl carbonyl, dimethylamino piperidinocarbonyl, 4
-Methylcarbamoyl-1-piperazinylcarbonyl,
1,2,3,6-tetrahydropyridylcarbonyl, pyrrolidinylcarbonyl, indolylcarbonyl etc.], aryloxycarbonyl optionally substituted with nitro [eg phenyloxycarbonyl, nitrophenyloxycarbonyl etc.], substituted with nitro Optionally lower alkoxycarbonyl [eg, benzyloxycarbonyl, nitrobenzyloxycarbonyl, etc.], for example

Carbamoyl, lower alkylcarbamoyl [eg methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, tert-butylcarbamoyl, pentylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, N-ethyl-N-methyl Carbamoyl etc.], carboxy lower alkyl carbamoyl [eg carboxymethyl carbamoyl, carboxyethyl carbamoyl etc.], esterified carboxy lower alkyl carbamoyl, eg lower alkoxycarbonyl lower alkyl carbamoyl [eg methoxycarbonylmethyl carbamoyl, ethoxycarbonylmethyl carbamoyl, ethoxycarbonyl Ethylcarbamoyl, etc.], lower Kenylcarbamoyl [eg vinylcarbamoyl, allylcarbamoyl etc.], cyclo-lower alkylcarbamoyl [eg cyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylcarbamoyl, cyclohexylcarbamoyl etc.], halo-lower alkanoylcarbamoyl [eg trichloroacetylcarbamoyl etc.], substituted or unsubstituted Arylcarbamoyl, such as arylcarbamoyl [eg, phenylcarbamoyl, tolylcarbamoyl, xylylcarbamoyl, naphthylcarbamoyl, ethylphenylcarbamoyl, etc.], arylthiocarbamoyl [eg, phenylthiocarbamoyl, etc.], lower alkoxyarylcarbamoyl [eg, methoxyphenylcarbamoyl, etc.], halo Arylcarbamoyl [eg fluor Phenylcarbamoyl, chlorophenylcarbamoyl etc.], halo lower alkylarylcarbamoyl [eg trifluoromethylphenylcarbamoyl etc.], nitroarylcarbamoyl [eg nitrophenylcarbamoyl etc.], cyanoarylcarbamoyl [eg cyanophenylcarbamoyl etc.], hydroxy lower alkylarylcarbamoyl [Eg hydroxymethylphenylcarbamoyl, hydroxyethylphenylcarbamoyl etc.], aminoarylcarbamoyl [eg aminophenylcarbamoyl etc.], lower alkylaminoarylcarbamoyl [eg methylaminophenylcarbamoyl, ethylaminophenylcarbamoyl, dimethylaminophenylcarbamoyl etc.], lower Alkanoylaminoarylcarbamoyl [Eg acetylaminophenylcarbamoyl, propionylaminophenylcarbamoyl etc.], N-lower alkanoyl-N-lower alkylaminoarylcarbamoyl [eg N-acetyl-N-methylaminophenylcarbamoyl, N-propionyl-N-methylaminophenylcarbamoyl etc. ], Lower alkoxy lower alkanoylaminoarylcarbamoyl [eg methoxyacetylaminophenylcarbamoyl, methoxypropionylaminophenylcarbamoyl, etc.], lower alkoxycarbonyl loweralkanoylaminoarylcarbamoyl [eg ethoxycarbonylacetylaminophenylcarbamoyl, methoxycarbonylpropionylaminophenylcarbamoyl, Etc.], carboxyaminoarylcarbamoyl [eg. For example, carboxyaminophenylcarbamoyl etc.], lower alkoxycarbonylaminoarylcarbamoyl [eg ethoxycarbonylaminophenylcarbamoyl etc.], ureidoarylcarbamoyl [eg ureidophenylcarbamoyl etc.], lower alkylureidoarylcarbamoyl [eg methylureidophenylcarbamoyl, ethylureidophenyl etc. Carbamoyl etc.], hydroxyimino lower alkylarylcarbamoyl [eg hydroxyiminoethylphenylcarbamoyl etc.], lower alkoxyimino lower alkylarylcarbamoyl [eg methoxyiminoethylphenylcarbamoyl etc.],

Lower alkylhydrazono lower alkylarylcarbamoyl [eg methylhydrazonoethylphenylcarbamoyl, dimethylhydrazonoethylphenylcarbamoyl etc.], optionally substituted heterocyclic arylcarbamoyl [eg oxopyrrolidinylphenylcarbamoyl, oxopyrpyno] Peridinophenylcarbamoyl,
Dioxopyrrolidinylphenylcarbamoyl, oxooxazolidinylphenylcarbamoyl, pyrrolylphenylcarbamoyl, etc.], acylarylcarbamoyl,
For example, carboxyarylcarbamoyl [eg carboxyphenylcarbamoyl etc.], lower alkoxycarbonylarylcarbamoyl [eg ethoxycarbonylphenylcarbamoyl etc.], heterocyclic carbonylarylcarbamoyl [eg morpholinocarbonylphenylcarbamoyl, pyrrolidinylcarbonylphenylcarbamoyl, piperidinocarbonylphenyl Carbamoyl,
1,2,3,6-Tetrahydropyridylcarbonylphenylcarbamoyl, piperazinylcarbonylphenylcarbamoyl, thiomorpholinocarbonylphenylcarbamoyl and the like], lower alkyl-substituted heterocyclic carbonylarylcarbamoyl [eg methylpiperazinylcarbonylphenylcarbamoyl, Ethylpiperazinylcarbonylphenylcarbamoyl etc.], Heterocyclic carbonylarylcarbamoyl substituted with aryl [eg phenylpiperazinylcarbonylphenylcarbamoyl etc.], Heterocyclic carbonylarylcarbamoyl substituted with heterocyclic group [eg pyridylpiperazinyl Carbonylphenylcarbamoyl etc.], heterocyclic carbonylarylcarbamoyl substituted with lower alkanoyl [eg acetylpiperazinyl Rubonylphenylcarbamoyl and the like], heterocyclic carbonylarylcarbamoyl substituted with lower alkoxycarbonyl [eg ethoxycarbonylpiperazinylcarbonylphenylcarbamoyl and the like], heterocyclic carbonylarylcarbamoyl substituted with lower alkylamino [eg methylaminopiperazinyl Carbonylphenylcarbamoyl, dimethylaminopiperidinocarbonylphenylcarbamoyl, etc.], Heterocyclic carbonylarylcarbamoyl substituted with lower alkylcarbamoyl [eg methylcarbamoylpiperazinylcarbonylphenylcarbamoyl etc.], carbamoylarylcarbamoyl [eg carbamoylphenylcarbamoyl etc.] , Lower alkylcarbamoyl arylcarbamoyl [eg methylcarbamoyl E d, ethylcarbamoyl phenylcarbamoyl, dimethylcarbamoyl phenylcarbamoyl, diethylcarbamoyl phenylcarbamoyl, N- ethyl -
N-methylcarbamoylphenylcarbamoyl, N-isopropyl-N-methylcarbamoylphenylcarbamoyl etc.], hydroxy lower alkylcarbamoylarylcarbamoyl [eg hydroxymethylcarbamoylphenylcarbamoyl, hydroxyethylcarbamoylphenylcarbamoyl, bis (hydroxyethyl) carbamoylphenylcarbamoyl etc.] , N- (hydroxy lower alkyl) -N- (lower alkyl) carbamoyl arylcarbamoyl [eg N- (hydroxyethyl)
-N-methylcarbamoylphenylcarbamoyl, etc.],
Lower alkoxy lower alkylcarbamoyl arylcarbamoyl [eg, methoxymethylcarbamoylphenylcarbamoyl, methoxyethylcarbamoylphenylcarbamoyl, bis (methoxyethyl) carbamoylphenylcarbamoyl, bis (ethoxyethyl) carbamoylphenylcarbamoyl, etc.],

N- (lower alkoxy lower alkyl) -N
-(Lower alkyl) carbamoyl arylcarbamoyl [eg N- (methoxyethyl) -N-methylcarbamoylphenylcarbamoyl, N- (methoxypropyl)
-N-methylcarbamoylphenylcarbamoyl, etc.],
Lower alkylamino lower alkylcarbamoyl arylcarbamoyl [eg, methylaminoethylcarbamoylphenylcarbamoyl, dimethylaminoethylcarbamoylphenylcarbamoyl, etc.], N- (loweralkylaminoloweralkyl) -N- (loweralkyl) carbamoylarylcarbamoyl [eg, N- ( Dimethylaminoethyl) -N-methylcarbamoylphenylcarbamoyl, N- (dimethylaminopropyl) -N-methylcarbamoylphenylcarbamoyl and the like], heterocyclic carbamoylarylcarbamoyl [eg morpholinylcarbamoylphenylcarbamoyl, thienylcarbamoylphenylcarbamoyl, pyridylcarbamoyl] Phenylcarbamoyl, pyrimidinylcarbamoylphenylcarbamoyl, etc.], N- ( Ring) -N- (lower alkyl) carbamoyl arylcarbamoyl [e.g. N- pyridyl -
N-methylcarbamoylphenylcarbamoyl etc.], heterocyclic lower alkylcarbamoylarylcarbamoyl [eg pyridylmethylcarbamoylphenylcarbamoyl, pyridylethylcarbamoylphenylcarbamoyl, thienylmethylcarbamoylphenylcarbamoyl etc.], N- (heterocyclic lower alkyl) -N- ( Lower alkyl) carbamoylarylcarbamoyl [eg N-pyridylmethyl-N-methylcarbamoylphenylcarbamoyl etc.], N- (heterocyclic lower alkyl) -N- (lower alkoxy lower alkyl) carbamoylarylcarbamoyl [eg N-pyridylmethyl-N -Methoxyethylcarbamoylphenylcarbamoyl etc.], arylcarbamoylarylcarbamoyl [eg phenylcarbamoylphenylcarboyl] Bamoiru etc.], lower alkylamino-arylcarbamoyl-arylcarbamoyl [e.g. dimethylamino phenylcarbamoyl phenylcarbamoyl, etc.],

Lower alkanoyl arylcarbamoyl [eg acetylphenylcarbamoyl, propionylphenylcarbamoyl etc.] etc., etc., al lower alkylcarbamoyl [eg benzylcarbamoyl, phenethylcarbamoyl etc.], heterocyclic carbamoyl [eg furylcarbamoyl, thienylcarbamoyl, pyridylcarbamoyl, etc. Quinolylcarbamoyl, isoquinolylcarbamoyl, pyrimidinylcarbamoyl, pyrazolylcarbamoyl, etc.], heterocyclic lower alkylcarbamoyl [eg pyridylmethylcarbamoyl, pyridylethylcarbamoyl, thienylmethylcarbamoyl, etc.], arylaminocarbamoyl [eg phenylaminocarbamoyl, etc.], alloy Substitution of lucarbamoyl [eg benzoylcarbamoyl etc.] Unsubstituted carbamoyl or thiocarbamoyl, lower alkylsulfonyl [e.g. mesyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, etc.], arylsulfonyl [e.g. tosyl,
Phenylsulfonyl etc.], lower alkylsulfonyl [eg benzylsulfonyl, phenethylsulfonyl etc.], lower alkenylsulfonyl [eg styrylsulfonyl, cinnamylsulfonyl etc.], phthaloyl,
The following substituted or unsubstituted amino acid residues and the like can be mentioned.

Suitable "amino acid residues" include natural or artificial ones, and such amino acids include glycine, sarcosine, alanine, β-alanine, valine, norvaline, leucine, isoleucine, norleucine, serine, threonine, Cysteine, methionine, phenylalanine, phenylglycine, tryptophan,
Examples thereof include tyrosine, proline, hydroxyproline, glutamic acid, aspartic acid, glutamine, asparagine, lysine, arginine, histidine, ornithine, and the like, more preferable among them are glycine, sarcosine, alanine, β-alanine, and proline. ,
Most preferred is glycine. The amino acid residue may be any of the above-mentioned lower alkyl, the above-mentioned aryl, the above-mentioned acyl, ar-lower alkyl [eg benzyl, phenethyl,
Trityl, etc.], cycloalkyl [eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Cycloheptyl, cyclooctyl, adamantyl, etc.],
Heterocyclic groups described below, heterocyclic lower alkyl [eg pyridylmethyl, pyridylethyl, imidazolylmethyl, furylmethyl, thienylmethyl, morpholinomethyl, piperidinomethyl, etc.], substituted or unsubstituted amidino [eg amidino, methylamidino, N-ethyl- N′-cyanoamidino, etc.] and the like.

Preferable examples of the amino acid residue substituted with the appropriate substituent include amino acid residues substituted with lower alkyl [eg ethylglycyl, isopropylglycyl, dimethylglycyl, diethylglycyl, ethylsarcosyl. , Isopropylsarcosyl, methylalanyl, methyl-β-alanyl, dimethyl-β-alanyl, etc.], an amino acid residue substituted with aryl [eg, N-phenylglycyl, N-tolylglycyl, N-phenylalanyl, N-phenyl] Sarcosyl, etc.], an amino acid residue substituted with al-lower alkyl [eg benzylglycyl, tritylglycyl, phenethylglycyl, benzylsarcosyl, benzylalanyl], an amino acid residue substituted with a heterocyclic group [eg morpholino Glycyl, piperidinoglycyl, pyridylglycy Etc.], an amino acid residue substituted with a heterocyclic lower alkyl [eg pyridylmethylglycyl, imidazolylmethylglycyl, furylmethylglycyl, thienylmethylglycyl etc.], an amino acid residue substituted with a cycloalkyl [eg Cyclopropylglycyl, cyclobutylglycyl, cyclopentylglycyl,
Cyclohexylglycyl, cycloheptylglycyl, cyclooctylglycyl, adamantylglycyl, cyclohexylsarcosyl, cycloheptylsarcosyl, cyclohexylalanyl, etc.], an amino acid residue substituted with an optionally substituted amidino [eg amidinoglycyl , Methylamidinoglycyl, N-ethyl-N′-cyanoamidinoglycyl, etc.], eg, an amino acid residue substituted with alkanoyl [eg formylglycyl, acetylglycyl, acetylsarcosyl, acetylalanyl,
Acetyl-β-alanyl, propionyl glycyl, butyryl glycyl, isobutyryl glycyl, valeryl glycyl, isovaleryl glycyl, pivaloyl glycyl, hexanoyl glycyl, heptanoyl glycyl, etc.], amino acid residue substituted with halo lower alkanoyl Group [eg trifluoroacetylglycyl, trifluoroacetylsarcosyl, trifluoroacetylalanyl, bromoacetylglycyl, heptafluorobutyrylglycyl, etc.], an amino acid residue substituted with a hydroxy lower alkanoyl [eg glycoloylglycyl , Glycoloyl sarcosyl, lactoyl glycyl, lactoyl alanyl, etc.], an amino acid residue substituted with a lower alkylsulfonyloxy lower alkanoyl [eg mesyloxyacetyl glycyl, ethyl sulphonyl Oxyacetylglycyl, mesyloxyacetylsarcosyl, etc.], an amino acid residue substituted with lower alkoxy lower alkanoyl [eg, methoxyacetylglycyl, ethoxyacetylglycyl, methoxyacetylsarcosyl, methoxypropionylalanyl], aryloxy Amino acid residues substituted with lower alkanoyl [eg phenyloxyacetylglycyl,
Phenyloxypropionylglycyl, phenyloxyacetylsarcosyl, etc.], an amino acid residue substituted with a lower alkylthio lower alkanoyl [eg, methylthioacetylglycyl, methylthiopropionylglycyl, etc.],

Lower alkylcarbamoyl Lower alkanoyl substituted amino acid residue [eg methylcarbamoylpropionylglycyl, methylcarbamoylpropionylalanyl etc.], lower alkanoyloxy lower alkanoyl substituted amino acid residue [eg acetyloxyacetylglycyl , Acetyloxyacetylsarcosyl, propionyloxyacetylglycyl, acetyloxypropionylalanyl, etc.], amino acid residues substituted with carboxy lower alkanoyl [eg carboxyacetylglycyl, carboxypropionylglycyl, carboxypropionylsarcosyl, carboxyacetyl Alanyl, etc.], amino acid residue substituted with lower alkoxycarbonyl lower alkanoyl [eg methoxycarbonylacetylglycol] , Ethoxycarbonylpropionylglycyl, methoxycarbonylacetylsarcosyl, etc.], amino acid residues substituted with al-lower alkanoyl [eg phenylacetylglycyl, phenylacetylsarcosyl, phenylpropionylalanyl, phenylpropionylglycyl, naphthylacetyl] Glycyl, phenylbutyrylglycyl, etc.], an amino acid residue substituted with an optionally substituted heterocyclic lower alkanoyl [eg, morpholinoacetylglycyl, thiomorpholinoacetylglycyl, its oxide or dioxide, pyridylacetylglycyl, Morpholinopropionylalanyl,
Imidazolylacetylglycyl, piperidinoacetylglycyl, pyrrolidinylacetylglycyl, hexamethyleneiminoacetylglycyl, methylpiperazinylacetylglycyl, pyridylpiperazinylacetylglycyl, etc.], lower alkenoyl substituted Amino acid residues [eg acryloylglycyl, crotonoylglycyl, 3
-Pentenoylglycyl, 3-butenoylglycyl, 4
-Pentenoylglycyl, 3-butenoylsarcosyl, etc.], an amino acid residue substituted with al-lower alkenoyl [eg cinnamoylglycyl, arosinnamoylglycyl, α-methylcinnamoylglycyl, 4-methyl Cinnamoylglycyl, cinnamoylsarcosyl, etc.], an amino acid residue substituted with a lower alkoxyal lower alkenoyl [eg, methoxycinnamoylglycyl, ethoxycinnamoylglycyl, dimethoxycinnamoylglycyl, etc.], lower alkylenedioxy Amino acid residues substituted with al-lower alkenoyl [eg methylenedioxycinnamoylglycyl, ethylenedioxycinnamoylglycyl, etc.], amino acid residues substituted with nitroar-lower alkenoyl [eg nitrocinnamoylglycyl, etc.] , Lower halo Amino acid residues substituted with lukenoyl [eg chlorocinnamoylglycyl, fluorocinnamoylglycyl etc.], hydroxyal lower alkenoyl substituted amino acid residues [eg hydroxycinnamoylglycyl], hydroxy lower alkoxyal lower An amino acid residue substituted with alkenoyl [eg hydroxymethoxycinnamoylglycyl, hydroxyethoxycinnamoylglycyl, etc.],

Amino acid residue substituted with amino lower alkoxy al lower alkenoyl [eg aminoethoxycinnamoylglycyl etc.], amino acid residue substituted with lower alkylamino lower alkoxy al lower alkenoyl [eg methylaminomethoxycinnamoylglyce] Sill,
Dimethylaminoethoxycinnamoylglycyl etc.], an amino acid residue substituted with a heterocyclic lower alkoxyal lower alkenoyl [eg pyridylmethoxycinnamoylglycyl etc.], an optionally substituted heterocyclic al lower alkenoyl substituted Amino acid residue [eg morpholinosyn namoylglycyl, methylpiperazinylcinnamoylglycyl, pyrrolidinylcinnamoylglycyl, oxopyrrolidinylcinnamoylglycyl, oxopiperidinocinnamoylglycyl, dioxopyrrolidinylcinnamoylglycyl , Oxooxazolidinylcinnamoylglycyl, pyrrolylcinnamoylglycyl, etc.],

Amino acid residues substituted with aminoar lower alkenoyl [eg aminocinnamoylglycyl etc.], aminoalkyl residues substituted with lower alkylaminoar lower alkenoyl [eg methylaminocinnamoylglycyl, dimethylaminocinnamoylglyce] Sill, etc.],
Amino acid residue substituted with acylaminoar lower alkenoyl, for example, amino acid residue substituted with lower alkanoylaminoar lower alkenoyl [eg acetylaminocinnamoylglycyl, propionylaminocinnamoylglycyl, etc.], hydroxy lower alkanoylaminoalkyl Amino acid residue substituted with lower alkenoyl [eg hydroxyacetylaminocinnamoylglycyl, hydroxypropionylaminocinnamoylglycyl, etc.], lower alkoxy lower alkanoylaminoal amino acid residue substituted with lower alkenoyl [eg methoxyacetylaminocin Namoylglycyl, methoxypropionylaminocinnamoylglycyl, etc.], an amino acid residue substituted with a halo lower alkanoylaminoar lower alkenoyl [eg Roacetylaminocinnamoylglycyl, bromobutyrylaminocinnamoylglycyl, etc.], amino lower residue alkanoylaminoar lower alkenoyl substituted amino acid residue [eg aminoacetylaminocinnamoylglycyl, aminopropionylaminocinnamoylglycyl , Etc.], lower alkylamino lower alkanoylaminoal lower alkenoyl-substituted amino acid residue [eg, methylaminoacetylaminocinnamoylglycyl, dimethylaminoacetylaminocinnamoylglycyl, etc.], lower alkanoylamino lower alkanoylaminoal Amino acid residue substituted with lower alkenoyl [eg acetylaminoacetylaminocinnamoylglycyl, acetylaminopropionylaminocinnamoylglycyl, etc.], cal Amino acid residue substituted with xy lower alkanoylamino ar lower alkenoyl [eg, carboxyacetylaminocinnamoylglycyl, carboxypropionylaminocinnamoylglycyl, etc.], lower alkoxycarbonyl lower alkanoylaminoar lower alkenoyl substituted amino acid residue Group [eg ethoxycarbonylacetylaminocinnamoylglycyl, ethoxycarbonylpropionylaminocinnamoylglycyl, etc.], lower alkoxycarbonyl lower alkenoylaminoar lower alkenoyl substituted amino acid residue [eg ethoxycarbonylacryloylaminocinnamoylglycyl Sil, etc.], an amino acid residue substituted with a halo lower alkoxycarbonylamino ar lower alkenoyl [eg chloroethoxycarbonyl] Ruaminocinnamoylglycyl, etc.], an amino acid residue substituted with a heterocyclic lower alkanoylaminoal lower alkenoyl [eg pyridylacetylaminocinnamoylglycyl, etc.], an amino acid residue substituted with aroylaminoar lower alkenoyl [Eg benzoylaminocinnamoylglycyl, etc.], amino acid residue substituted with heterocyclic carbonylaminoar lower alkenoyl [eg nicotinoylaminocinnamoylglycyl, isonicotinoylaminocinnamoylglycyl, morpholinocarbonylaminocinnamoylglycyl] Sill, etc.],

Amino acid residue substituted with lower alkylsulfonylaminoal lower alkenoyl [eg mesylaminocinnamoyl, ethylsulfonylaminocinnamoylglycyl, etc.], etc., N- (lower alkanoyl) -N-
Amino acid residue substituted with (lower alkyl) aminoar lower alkenoyl [eg N-acetyl-N-methylaminocinnamoylglycyl, N-acetyl-N-ethylaminocinnamoylglycyl, N-propionyl-N-
Methylaminocinnamoylglycyl, etc.], N- (lower alkoxy lower alkanoyl) -N- (lower alkyl)
Amino acid residue substituted with aminoar lower alkenoyl [eg, N-methoxyacetyl-N-methylaminocinnamoylglycyl, N-methoxypropionyl-N-methylaminocinnamoylglycyl, etc.], N- (lower alkanoyl)- Amino acid residue substituted with N- (heterocycle lower alkyl) aminoar lower alkenoyl [eg N
-Acetyl-N-pyridylmethylaminocinnamoylglycyl, etc.], amino acid residues substituted with ureidoal lower alkenoyl [eg ureidocinnamoylglycyl, etc.], amino acid residues substituted with lower alkylureidoal lower alkenoyl [eg For example, methylureido cinnamoylglycyl, ethylureido cinnamoylglycyl, dimethylureido cinnamoylglycyl, etc.],

Heterocyclic ureidoal lower alkenoyl substituted amino acid residues [eg pyridylureidocinnamoylglycyl, pyrimidinylureidocinnamoylglycyl, thienylureidocinnamoylglycyl,
Etc.], an amino acid residue substituted with an acylar lower alkenoyl, for example, an amino acid residue substituted with a lower alkanoyl al lower alkenoyl [eg formylcinnamoylglycyl, acetylcinnamoylglycyl, propionylcinnamoylglycyl, etc.], carboxy Amino acid residue substituted with al-lower alkenoyl [eg carboxycinnamoylglycyl, etc.], lower alkoxycarbonyl amino residue substituted with al-lower alkenoyl [eg methoxycarbonylcinnamoylglycyl, ethoxycarbonylcinnamoylglycyl, Etc.], an amino acid residue substituted with carbamoylal lower alkenoyl [eg carbamoylcinnamoylglycyl, etc.], an amino acid residue substituted with lower alkylcarbamoylal lower alkenoyl [eg. For example, methylcarbamoylcinnamoylglycyl, ethylcarbamoylcinnamoylglycyl, dimethylcarbamoylcinnamoylglycyl, propylcarbamoylcinnamoylglycyl, isopropylcarbamoylcinnamoylglycyl, diethylcarbamoylcinnamoylglycyl, N-methyl-N-ethyl. Carbamoylcinnamoylglycyl etc.], an amino acid residue substituted with a hydroxy lower alkylcarbamoylal lower alkenoyl [eg hydroxyethylcarbamoylcinnamoylglycyl, bis (hydroxyethyl) carbamoylcinnamoylglycyl], N- (hydroxylower Alkyl) -N- (lower alkyl) carbamoyl ar Lower alkenoyl substituted amino acid residue [eg N-hydroxyethyl-N-methylcalcyl] Moylcinnamoylglycyl, etc.], an amino acid residue substituted with a lower alkoxy lower alkylcarbamoylal lower alkenoyl [eg methoxymethylcarbamoylcinnamoylglycyl, methoxyethylcarbamoylcinnamoylglycyl, bis (methoxyethyl) carbamoylcinnamoyl] Luglycyl, ethoxyethylcarbamoylcinnamoylglycyl, methoxypropylcarbamoylcinnamoylglycyl, bis (ethoxyethyl) carbamoylcinnamoylglycyl, etc.], N- (lower alkoxy lower alkyl) -N- (lower alkyl) carbamoyl lower Amino acid residue substituted with alkenoyl [eg N-methoxyethyl-N-methylcarbamoylcinnamoylglycyl, etc.], substituted with heterocyclic carbamoyl al lower alkenoyl Substituted amino acid residues [eg morpholinylcarbamoylcinnamoylglycyl, thienylcarbamoylcinnamoylglycyl, pyridylcarbamoylcinnamoylglycyl, pyrimidinylcarbamoylcinnamoylglycyl, etc.], substituted with a heterocyclic carbonylar lower alkenoyl Amino acid residues [eg morpholinocarbonylcinnamoylglycyl, pyrrolidinylcarbonylcinnamoylglycyl, piperidinocarbonylcinnamoylglycyl, etc.], amino acid residues substituted with al-lower alkinoyl [eg phenylpropioro Ilglycyl etc.], an amino acid residue substituted with a heterocycle lower alkenoyl [eg morpholinyl acryloyl glycyl, pyridyl acryloyl glycyl, thienyl acryloyl glycyl etc.], amino complex Amino acid residue substituted with lower alkenoyl [eg aminopyridylacryloylglycyl, etc.], lower alkylaminoheterocycle Amino acid residue substituted with lower alkenoyl [eg methylaminopyridylacryloylglycyl, dimethylaminopyridylacryloylglycyl, Etc.], an amino acid residue substituted with an acylamino heterocycle lower alkenoyl, for example, an amino acid residue substituted with a lower alkanoylamino heterocycle lower alkenoyl [eg, acetylaminopyridylacryloylglycyl, propionylaminopyridylacryloylglycyl, etc.], etc. , An amino acid residue substituted with a lower alkylureido heterocycle lower alkenoyl [eg, methylureidopyridylacryloylglycyl, etc.], an amino substituted with an acyl heterocycle lower alkenoyl Acid residues, eg amino acid residues substituted with carboxyheterocycle lower alkenoyl [eg carboxypyridylacryloylglycyl, etc.], lower alkoxycarbonylheterocycle Lower amino acid residues substituted with lower alkenoyl [eg ethoxycarbonylpyridylacryloylglycyl , Etc.], an amino acid residue substituted with a lower alkylcarbamoyl heterocycle lower alkenoyl [eg, methylcarbamoylpyridylacryloylglycyl, ethylcarbamoylpyridylacryloylglycyl, dimethylcarbamoylpyridylacryloylglycyl, diethylcarbamoylpyridylacryloylglycyl, isopropylcarbamoyl] Pyridyl acryloyl glycyl, etc.], lower alkoxy lower alkylcarbamoyl heterocycle lower alkenoyl substituted ami Acid residue [eg methoxymethylcarbamoylpyridylacryloylglycyl, methoxyethylcarbamoylpyridylacryloylglycyl, methoxypropylcarbamoylpyridylacryloylglycyl, ethoxyethylcarbamoylpyridylacryloylglycyl, bis (methoxyethyl) carbamoylpyridylacryloylglycyl, etc. ],

Hydroxy lower alkylcarbamoyl heterocycle Amino acid residue substituted with lower alkenoyl [eg hydroxymethylcarbamoylpyridylacryloylglycyl, hydroxyethylcarbamoylpyridylacryloylglycyl, bis (hydroxyethyl) carbamoylpyridylacryloylglycyl, etc.], etc. , Etc., an amino acid residue substituted with a substituted or unsubstituted heterocyclic lower alkenoyl, an amino acid residue substituted with a heterocyclic thio lower alkanoyl [eg pyridylthioacetylglycyl, pyrimidinylthioacetylglycyl, imidazolylthiopropionylglycyl Etc.], an amino acid residue substituted with an optionally substituted heterocyclic carbonyl [eg, morpholinocarbonylglycyl, indolylcarbonylglycyl,
4-methyl 1-piperazinyl carbonyl glycyl,
Etc.], an amino acid residue substituted with a cyclo lower alkylcarbonyl [eg cyclopropylcarbonylglycyl,
Cyclopentylcarbonylglycyl, cyclohexylcarbonylglycyl, cyclohexylcarbonylsarcosyl, etc.], an amino acid residue substituted with a lower alkoxycarbonyl [eg, methoxycarbonylglycyl, tertiary butoxycarbonylglycyl, tertiary butoxycarbonylsarcosyl, Tertiary butoxycarbonylalanyl, etc.],
Amino acid residues substituted with aryloxycarbonyl [eg phenoxycarbonylglycyl etc.], amino acid residues substituted with aroyl lower alkanoyl [eg phenyloxalylglycyl, benzoylpropionylglycyl etc.], amino acid residues substituted with aroyl Group [eg, benzoylglycyl, naphthoylglycyl, benzoylsarcosyl, benzoylalanyl, etc.], amino acid residue substituted with nitroaryloxycarbonyl [eg, nitrophenyloxycarbonylglycyl, etc.], amino acid residue substituted with carbamoyl A group [eg, carbamoylglycyl, carbamoylalanyl, carbamoylsarcosyl, carbamoyl-β-alanyl, etc.], an amino acid residue substituted with a lower alkylcarbamoyl [eg, methylcarbamoylglycyl , Ethylcarbamoyl glycyl,
Propylcarbamoylglycyl, isopropylcarbamoylglycyl, methylcarbamoylsarcosyl, ethylcarbamoylalanyl, isopropylcarbamoyl-β
-Alanyl, pentylcarbamoylglycyl, etc.], an amino acid residue substituted with a lower alkoxycarbonyl lower alkylcarbamoyl [eg, methoxycarbonylmethylcarbamoylglycyl, ethoxycarbonylmethylcarbamoylglycyl, etc.], an amino acid residue substituted with a lower alkenylcarbamoyl Groups [eg vinylcarbamoylglycyl, allylcarbamoylglycyl, allylcarbamoylsarcosyl, etc.], amino acid residues substituted with cyclo-lower-alkylcarbamoyl [eg cyclopropylcarbamoylglycyl, cyclohexylcarbamoylglycyl, cyclohexylcarbamoylsarcosyl, etc.] , Amino acid residues substituted with arylcarbamoyl [eg phenylcarbamoylglycyl, naphthylcarbamoylglycyl, tolylca Vamoylglycyl, ethylphenylcarbamoylglycyl, phenylcarbamoylalanyl, phenylcarbamoylsarcosyl, etc.], an amino acid residue substituted with a lower alkoxyarylcarbamoyl [eg methoxyphenylcarbamoylglycyl, ethoxyphenylcarbamoylglycyl, methoxyphenylcarbamoylalanyl] Etc.], an amino acid residue substituted with a halo lower alkylarylcarbamoyl [eg trifluoromethylphenylcarbamoylglycyl, trifluoromethylphenylcarbamoylalanyl, trifluoromethylphenylcarbamoylsarcosyl, etc.], substituted with a haloarylcarbamoyl Amino acid residues [eg chlorophenylcarbamoylglycyl, fluorophenylcarbamoylglycyl, fluorophene [Lucarbamoylalanyl, etc.], an amino acid residue substituted with hydroxy lower alkylarylcarbamoyl [eg, hydroxymethylphenylcarbamoylglycyl, hydroxyethylphenylcarbamoylglycyl, hydroxyethylphenylcarbamoylalanyl, etc.], substituted with nitroarylcarbamoyl Amino acid residue [eg nitrophenylcarbamoylglycyl etc.], amino acid residue substituted with cyanoarylcarbamoyl [eg cyanophenylcarbamoylglycyl etc.], amino acid residue substituted with aminoarylcarbamoyl [eg aminophenylcarbamoylglycyl etc. Etc.], an amino acid residue substituted with a lower alkylaminoarylcarbamoyl [eg methylaminophenylcarbamoylglycyl, ethylaminophen Nylcarbamoylglycyl, dimethylaminophenylcarbamoylglycyl, etc.], an amino acid residue substituted with a lower alkanoylaminoarylcarbamoyl [eg, acetylaminophenylcarbamoylglycyl, propionylaminophenylcarbamoylglycyl], N
Amino acid residue substituted with-(lower alkanoyl) -N- (lower alkyl) aminoarylcarbamoyl [eg N-acetyl-N-methylaminophenylcarbamoylglycyl, N-propionyl-N-methylaminophenylcarbamoylglycyl, etc. ], An amino acid residue substituted with a lower alkoxy lower alkanoylaminoarylcarbamoyl [eg, methoxyacetylaminophenylcarbamoylglycyl, methoxypropionylaminophenylcarbamoylglycyl, etc.], an amino acid substituted with a lower alkoxycarbonyl lower alkanoylaminoarylcarbamoyl A residue [eg ethoxycarbonylacetylaminophenylcarbamoylglycyl, methoxycarbonylpropionylaminophenylcarbamoylglycyl, etc.],

Amino acid residues substituted with carboxyaminoarylcarbamoyl [eg carboxyaminophenylcarbamoylglycyl etc.], amino acid residues substituted with lower alkoxycarbonylaminoarylcarbamoyl [eg ethoxycarbonylaminophenylcarbamoylglycyl etc.], Amino acid residues substituted with ureidoarylcarbamoyl [eg ureidophenylcarbamoylglycyl etc.], aminoalkyl residues substituted with lower alkylureidoarylcarbamoyl [eg methylureidophenylcarbamoylglycyl, ethylureidophenylcarbamoylglycyl etc.], Amino acid residue substituted with hydroxyimino lower alkylarylcarbamoyl [eg hydroxyiminoethylphenylcarbamoylglycyl ], An amino acid residue substituted with a lower alkoxyimino lower alkylarylcarbamoyl [eg, methoxyiminoethylphenylcarbamoylglycyl, etc.], an lower alkylhydrazono amino acid residue substituted with a lower alkylarylcarbamoyl [eg, methylhydrazonoethylphenyl Carbamoylglycyl,
Dimethylhydrazonoethylphenylcarbamoylglycyl etc.], an amino acid residue substituted with an optionally substituted heterocyclic arylcarbamoyl [eg oxopyrrolidinylphenylcarbamoylglycyl, oxopiperidinophenylcarbamoylglycyl, dioxo] Pyrrolidinylphenylcarbamoylglycyl, oxooxazolidinylphenylcarbamoylglycyl, pyrrolylphenylcarbamoylglycyl, etc.], an amino acid residue substituted with an acylarylcarbamoyl, eg, an amino acid residue substituted with a lower alkanoylarylcarbamoyl A group [eg acetylphenylcarbamoylglycyl, propionylaminophenylcarbamoylglycyl, etc.], an amino acid residue substituted with a heterocyclic carbonylarylcarbamoyl [eg mol Rinocarbonylphenylcarbamoylglycyl, piperidinocarbonylphenylcarbamoylglycyl, piperazinylcarbonylphenylcarbamoylglycyl, thiomorpholinocarbonylphenylcarbamoylalanyl, pyrrolidinylcarbonylphenylcarbamoylglycyl, 1,2,3,6- Tetrahydropyridylcarbonylphenylcarbamoylglycyl etc.],
Amino acid residues substituted with carboxyarylcarbamoyl [eg carboxyphenylcarbamoylglycyl etc.], amino acid residues substituted with lower alkoxycarbonylarylcarbamoyl [eg methoxycarbonylphenylcarbamoylglycyl, ethoxycarbonylphenylcarbamoylglycyl etc.], Amino acid residue substituted with lower alkylcarbamoylarylcarbamoyl [eg methylcarbamoylphenylcarbamoylglycyl, dimethylcarbamoylphenylcarbamoylglycyl, diethylcarbamoylphenylcarbamoylglycyl, N-ethyl-N-methylcarbamoylphenylcarbamoylglycyl, N- Isopropyl-N-methylcarbamoylphenylcarbamoylglycyl and the like], compounds having lower alkyl Amino acid residue substituted with a ring carbonyl arylcarbamoyl [eg methylpiperazinylcarbonylphenylcarbamoylglycyl, ethylpiperazinylcarbonylphenylcarbamoylglycyl, etc.], an amino acid residue substituted with a heterocyclic carbonylarylcarbamoyl having aryl [Eg phenylpiperazinylcarbonylphenylcarbamoyl etc.], an amino acid residue substituted with a heterocyclic carbonylarylcarbamoyl having a heterocyclic group [eg pyridylpiperazinylcarbonylphenylcarbamoylglycyl etc.],

Amino acid residue substituted with heterocyclic carbonylarylcarbamoyl having lower alkanoyl [eg acetylpiperazinylcarbonylphenylcarbamoylglycyl, etc.], amino acid residue substituted with heterocyclic carbonylarylcarbamoyl having lower alkoxycarbonyl [Eg, ethoxycarbonylpiperazinylcarbonylphenylcarbamoylglycyl, etc.], an amino acid residue substituted with a heterocyclic carbonylarylcarbamoyl having lower alkylamino [eg, methylaminopiperazinylcarbonylphenylcarbamoylglycyl,
Dimethylaminopiperidinocarbonylphenylcarbamoylglycyl etc.], an amino acid residue substituted with a heterocyclic carbonylarylcarbamoyl having lower alkylcarbamoyl [eg methylcarbamoylpiperazinylcarbonylphenylcarbamoylglycyl etc.], hydroxy lower alkylcarbamoyl aryl Amino acid residue substituted with rucarbamoyl [eg, hydroxymethylcarbamoylphenylcarbamoylglycyl, hydroxyethylcarbamoylphenylcarbamoylglycyl, bis (hydroxyethyl) carbamoylphenylcarbamoylglycyl, etc.], N- (hydroxy lower alkyl) -N
Amino acid residue substituted with-(lower alkyl) carbamoylarylcarbamoyl [eg N- (hydroxyethyl) -N-methylcarbamoylphenylcarbamoylglycyl etc.], amino acid residue substituted with lower alkoxy lower alkylcarbamoylarylcarbamoyl [ For example, methoxymethylcarbamoylphenylcarbamoylglycyl, methoxyethylcarbamoylphenylcarbamoylglycyl, bis (methoxyethyl) carbamoylphenylcarbamoylglycyl, bis (ethoxyethyl) carbamoylphenylcarbamoylglycyl, etc.],
Amino acid residue substituted with N- (lower alkoxy lower alkyl) -N- (lower alkyl) carbamoylarylcarbamoyl [eg N- (methoxyethyl) N-methylcarbamoylphenylcarbamoylglycyl, N-
(Methoxypropyl) -N-methylcarbamoylphenylcarbamoylglycyl etc.], an amino acid residue substituted with a lower alkylamino lower alkylcarbamoylarylcarbamoyl [eg methylaminoethylcarbamoylphenylcarbamoylglycyl, dimethylaminoethylcarbamoylphenylcarbamoylglycyl Etc.], N
Amino acid residue substituted with-(lower alkylamino lower alkyl) -N- (lower alkyl) carbamoylarylcarbamoyl [eg N- (dimethylaminoethyl)
-N-methylcarbamoylphenylcarbamoylglycyl, N- (dimethylaminopropyl) -N-methylcarbamoylphenylcarbamoylglycyl, etc.], an amino acid residue substituted with a heterocyclic carbamoylarylcarbamoyl [eg morpholinylcarbamoylphenylcarbamoylglycyl] Sil, thienylcarbamoylphenylcarbamoylglycyl, pyridylcarbamoylphenylcarbamoylglycyl, pyrimidinylcarbamoylphenylcarbamoylglycyl, etc.], an amino acid residue substituted with N- (heterocycle) -N- (lower alkyl) carbamoylarylcarbamoyl [eg, N-pyridyl-N-methylcarbamoylphenylcarbamoylglycyl, etc.], an amino acid residue substituted with a heterocyclic lower alkylcarbamoylarylcarbamoyl [For example pyridyl methylcarbamoyl phenylcarbamoyl glycyl, pyridyl ethylcarbamoyl phenylcarbamoyl glycyl, thienyl methylcarbamoyl phenylcarbamoyl glycyl etc.], N
Amino acid residue substituted with-(heterocyclic lower alkyl) -N- (lower alkyl) carbamoylarylcarbamoyl [eg, N-pyridylmethyl-N-methylcarbamoylphenylcarbamoylglycyl, etc.], N- (heterocyclic lower alkyl) -N- (lower alkoxy lower alkyl) carbamoylarylcarbamoyl substituted amino acid residue [eg N-pyridylmethyl-N-methoxyethylcarbamoylphenylcarbamoylglycyl etc.],

Arylcarbamoyl Arylcarbamoyl substituted amino acid residue [eg phenylcarbamoylphenylcarbamoylglycyl etc.], lower alkylaminoarylcarbamoylarylcarbamoyl substituted amino acid residue [eg dimethylaminophenylcarbamoylphenylcarbamoylglycyl etc. ], Etc., amino acid residues substituted with arylthiocarbamoyl [eg, phenylthiocarbamoylglycyl, naphthylthiocarbamoylglycyl, phenylthiocarbamoylalanyl, phenylthiocarbamoylsarcosyl, etc.], amino acids substituted with lower alkylcarbamoyl A residue [eg, benzylcarbamoylglycyl, benzylcarbamoylsarcosyl, benzylcarbamoylalanyl, etc.],
Amino acid residues substituted with aroylcarbamoyl [eg benzoylcarbamoylglycyl etc.], amino acid residues substituted with heterocyclic carbamoyl [eg pyridylcarbamoylglycyl, pyridylcarbamoylalanyl, pyridylcarbamoylsarcosyl, thienylcarbamoylglycyl, Pyrazolylcarbamoylglycyl, pyrimidinylcarbamoylglycyl, quinolylcarbamoylglycyl, isoquinolylcarbamoylglycyl, etc.], an amino acid residue substituted with a heterocyclic lower alkylcarbamoyl [eg pyridylmethylcarbamoylglycyl, pyridylethylcarbamoylglycyl , Thienylmethylcarbamoylglycyl etc.], an amino acid residue substituted with arylaminocarbamoyl [eg phenylaminocarbamoylglycyl etc.], Amino acid residues substituted with lower alkenylsulfonyl [eg, styrylsulfonylglycyl, cinnamylsulfonylglycyl, etc.], amino acid residues substituted with lower alkylsulfonyl [eg, mesylglycyl, ethylsulfonylglycyl, mesylsarcosyl, mesylalanyl, etc.] , An amino acid residue substituted with phthaloyl [eg phthaloylglycyl, phthaloylalanyl, phthaloyl-β-alanyl, etc.], an amino acid residue having an unsubstituted amino acid residue [eg glycylglycyl,
Alanylglycyl, sarcosylglycyl, prolylglycyl, glycylsarcosyl, prolylsarcosyl, etc.],
Amino acid residue having a substituted amino acid residue [eg an amino acid residue having an amino acid residue substituted with lower alkyl (eg dimethylglycylglycyl, diethylglycylglycyl, dimethylglycylsarcosyl, ethylsarcosylglycyl, isopropyl Sarcosylglycyl, ethylglycylglycyl, propylglycylglycyl, isopropylglycylglycyl, ethylglycylalanyl,
Dimethylglycylalanyl, dimethylalanylglycyl, dimethyl-β-alanylglycyl, etc.), an amino acid residue having an amino acid residue substituted with a heterocyclic group (for example, morpholinoglycylglycyl, piperidinoglycylglycyl, pyridylglycy) Ruglycyl, piperidinosarcosylglycyl, etc.), an amino acid residue having an amino acid residue substituted with a heterocyclic lower alkyl (eg pyridylmethylglycylglycyl, imidazolylmethylglycylglycyl, furylmethylglycylglycyl, thienyl) Methylsarcosylglycyl etc.), an amino acid residue having an amino acid residue substituted with cycloalkyl (eg cyclopropylglycylglycyl, cyclobutylglycylglycyl,
Cyclopentylglycylglycyl, cyclohexylglycylglycyl, cycloheptylglycylglycyl, cyclooctylglycylglycyl, adamantylglycylglycyl, cyclohexylsarcosylglycyl, cycloheptylsarcosylglycyl, cyclohexylglycylsarcosyl, cyclohexylglycyl Alanyl etc.), an amino acid residue having an amino acid residue substituted with aryl (eg phenylglycylglycyl, phenylsarcosylglycyl etc.), an amino acid residue having an amino acid residue substituted with acyl {eg with alkanoyl An amino acid residue having a substituted amino acid residue (for example, acetylglycylglycyl, acetylprolylglycyl, propionylglycylglycyl, acetylalanylglycyl, etc.),
An amino acid residue having an amino acid residue substituted with a lower alkoxycarbonyl (eg, tertiary butoxycarbonylglycylglycyl, tertiary butoxycarbonylprolylglycyl, etc.), an amino acid residue having an amino acid residue substituted with phthaloyl (Eg, phthaloylglycylglycyl, etc.), amino acid residues having amino acid residues substituted with al-lower alkyl (eg, benzylglycylglycyl, etc.), etc., and amino acid residues substituted with acyl, etc. To be

A suitable "heterocyclic group" is an oxygen atom,
A saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero atom such as a sulfur atom and / or a nitrogen atom, for example, 3 to 8 containing -1 to 4 nitrogen atoms. Member, preferably 5 or 6 membered, unsaturated heteromonocyclic group such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, dihydrotriazinyl and the like; 3 to 8 membered, preferably 4 to 6 membered, saturated heteromonocyclic groups containing ~ 4 nitrogen atoms, such as azetidinyl,
Pyrrolidinyl, imidazolidinyl, piperidyl, pyrazolidinyl, piperazinyl and the like; -7 to 12-membered unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indoridinyl, benzimidazolyl, quinolyl, isoquinolyl, tetrahydroquinolyl , Indazolyl, benzotriazolyl, imidazopyridyl and the like; -3 to 8-membered, preferably 5- or 6-membered unsaturated heteromonocyclic group containing one oxygen atom, such as furyl; -1 to 2 oxygens 7-12 membered unsaturated condensed heterocyclic group containing an atom, for example, benzofuryl, piperonyl, etc .; 3-8 membered, preferably 5 or 6 membered, unsaturated heteromonocyclic group containing one sulfur atom, for example, Thienyl and the like; -7 to 12-membered unsaturated condensed heterocyclic group containing 1-2 sulfur atoms, for example, benzothi Nyl etc .; -3 to 8 membered, preferably 5 or 6 membered, unsaturated heteromonocyclic group containing 1-2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl, etc .; -3 to 8-membered, preferably 5- or 6-membered, saturated heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, morpholinyl and the like;

-7- to 12-membered unsaturated condensed heterocyclic group containing 1-2 oxygen atoms and 1-3 nitrogen atoms, for example, benzoxazolyl, benzooxadiazolyl and the like; 3 to 8 membered, preferably 5 or 6 membered, unsaturated heteromonocyclic group containing 1 sulfur atom and 1 to 3 nitrogen atom, for example, thiazolyl, isothiazolyl, thiazolinyl, thiadiazolyl, etc .; A 3- to 8-membered, preferably 5- or 6-membered, saturated heteromonocyclic group containing a sulfur atom and 1 to 3 nitrogen atoms, such as thiazolidinyl; -1 to 2 sulfur atoms and 1 to 3 members And a 7 to 12-membered unsaturated condensed heterocyclic group containing a nitrogen atom, such as benzothiazolyl, benzothiadiazolyl, benzothiazinyl, benzothiazolinyl, and the like. The expression "aryl which may have a suitable substituent", "ar lower alkyl which may have a suitable substituent" or "heterocyclic group which may have a suitable substituent". Suitable substituents therein are the above-mentioned halogens; the above-mentioned halo lower alkyls; the above-mentioned lower alkyls; the above-mentioned acyls; the above-mentioned aryls; aryls substituted with substituents such as halogen and cyano [eg chlorophenyl, cyanophenyl Etc.]; ar lower alkyl substituted with hydroxy [eg hydroxybenzyl etc.]; lower alkoxy [eg methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy etc.]; oxo; Nitro; amino; lower alkyl as described above, acyl, ar lower alkyl as described above [eg benzyl Phenethyl, trityl, etc.], heterocyclic lower alkyl [e.g. pyridylmethyl, etc.], carboxy-lower alkyl [e.g. carboxymethyl, carboxyethyl, etc.], lower alkylamino methylene [e.g. dimethylaminomethylene, diethylaminomethylene, etc.],
Amino substituted with N-methylpyrrolidinylidene or the like; the above heterocyclic group; heterocyclic group substituted with oxo [eg pyrrolidonyl, etc.];

[Chemical 10] [Wherein R ¹ , R ² , R ³ ,

[Chemical 11] Q, X ¹ , Y ¹ and Y ² each have the same meaning as defined above] and the like. Preferable "leaving group" includes halogen [eg fluorine, chlorine, bromine, iodine], arenesulfonyloxy [eg benzenesulfonyloxy, tosyloxy etc.], alkanesulfonyloxy [eg mesyloxy, ethanesulfonyloxy etc.] and the like. Acid residues. Suitable salt of the target compound [I] is a conventional pharmaceutically acceptable non-toxic salt such as alkali metal salt [eg sodium salt, potassium salt etc.], alkaline earth metal salt [eg Calcium salt, magnesium salt, etc.], ammonium salt, salt with organic base [eg trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, etc.], Organic acid addition salts [eg formate, acetate, trifluoroacetate, maleate, tartrate, oxalate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], inorganic acid addition salts [ For example hydrochloride,
Examples thereof include hydrobromide salts, sulfate salts, phosphate salts, etc., salts with amino acids [eg arginine salts, aspartate salts, glutamate salts, etc.], and intramolecular salts. Regarding the salts of the compounds [Ia] to [Ib] in the production methods 1 and 2, these compounds are included in the range of the compound [I]. Therefore, preferable examples of the salts of these compounds include:
Examples of the target compound [I] may be mentioned. The production method of the target compound [I] is described in detail below.

Production Method 1 The object compound [Ia] or its salt can be produced by reacting the compound [II] or its salt with the compound [III] or its salt. Compounds [II] and [II
Suitable salts of I] may be the same as those exemplified for compound [I]. This reaction is usually
It is carried out in a conventional solvent such as methanol, ethanol, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide. The reaction temperature is not particularly limited, and the reaction is usually carried out at room temperature or under heating or heating.

Process 2 The object compound [Ib] or its salt can be prepared by reacting the compound [IV] or its salt with the compound [V] or its salt. Suitable salts of the compounds [IV] and [V] may be the same as those exemplified for the compound [I]. The reaction includes alkali metal [eg lithium, sodium, potassium etc.], their hydroxides or carbonates or hydrogencarbonates [eg sodium hydroxide, potassium carbonate, potassium hydrogencarbonate etc.], alkali metal alkoxides [eg sodium methoxide]. , Sodium ethoxide, potassium tert-butoxide, etc.] and the like. This reaction is
It is usually carried out in a conventional solvent such as tetrahydrofuran, dioxane, N, N-dimethylformamide, acetone and the like. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating. The object compound [I] and the starting compound can also be produced by the methods in Examples and Production Examples described later, or by methods similar thereto or by ordinary methods. The compound obtained by the above methods can be isolated and purified by a conventional method such as pulverization, recrystallization, chromatography or reprecipitation. Compound [I] and other compounds may include one or more stereoisomers and structural isomers due to an asymmetric carbon atom and a double bond, and all the isomers and their mixtures are included in the present invention. It is included in the range. For the purpose of treatment, the compounds [I] of the present invention and pharmaceutically acceptable salts thereof may be administered orally, parenterally such as intravenous injection, intramuscular injection, subcutaneous injection or intraarticular injection, and transdermally. External use, enteral administration,
The compound in the form of a mixture with a pharmaceutically acceptable carrier such as a solid, semi-solid or liquid organic or inorganic excipient suitable for rectal administration, vaginal administration, inhalation, instillation, nasal drop, sublingual administration and the like. It can be used in the form of a pharmaceutical preparation containing any of the above as an active compound. Pharmaceutical formulations include capsules, tablets,
Dragees, granules, suppositories, solutions, lotions, suspensions,
Examples thereof include emulsions, ointments, gels and creams. If desired, these preparations may be mixed with auxiliary substances, stabilizers, wetting or emulsifying agents, buffers, and other conventional additives. The dose of the compound [I] will vary depending on the patient's age and condition, but is about 0.1 as the compound [I].
mg, 1 mg, 10 mg, 50 mg, 100 mg, 25
An average single dose of 0 mg, 500 mg, 1000 mg is effective for the prevention and / or treatment of the following diseases. Generally, 0.1 mg / individual to about 1,000 per day
A dose between mg / individual may be administered.

[0032]

INDUSTRIAL APPLICABILITY In order to illustrate the usefulness of the objective compound [I], the pharmacological test data of some representative examples of the compound [I] are shown below. ³ H-bradykinin receptor binding inhibition (i) Test method (a) Preparation of crude ileal membrane sample Male Hartley guinea pigs are killed by decapitation. The ileum is removed and homogenized in buffer (50 mM trimethylaminoethanesulfonic acid (TES), 1 mM 1,10-phenanthroline, pH 6.8). The homogenate was centrifuged (1000 xg, 20 min) to remove tissue clumps and the supernatant was centrifuged (100,000 xg, 6 min).
0 minutes) to obtain pellets. Pellet the buffer (5
0 mM TES, 1 mM 1,10-phenanthroline,
Resuspend in 140 mg / l bacitracin, 1 mM dithiothreitol, 0.1% bovine serum albumin, pH 6.8) and homogenize with a glass-Teflon homogenizer to obtain a suspension. This is called a crude membrane suspension. The obtained membrane suspension is stored at −80 ° C. until use. (B) Binding of ³ H-bradykinin to the membrane Thaw the frozen crude membrane suspension. In the binding assay, ³ H-
Bradykinin (0.06 nM) and drug (1 x 10 ^-5
M) with 50 μl of membrane suspension to a final volume of 250 μl
Incubate at room temperature for 60 minutes. Separation of receptor bound ³ H-bradykinin from free one was accomplished by immediate filtration under reduced pressure, using ice-cold buffer (50
Wash 3 times with 5 ml of mM Tris-HCl, pH 7.5).
Binding in the presence of 0.1 μM bradykinin is defined as non-cross-linked. The radioactivity retained on the washed filter is measured using a liquid scintillation counter.

(Ii) Test results

[Table 1] The effect of the target compound [I] on bradykinin-induced airway contraction and carrageenin-induced paw edema was demonstrated by British Journal of Pharmacology (British J
The first of the of the Pharmacology
02, pp. 774-777 (1991). From the above test results,
The object compound [I] or a pharmaceutically acceptable salt thereof has a strong activity as a bradykinin antagonist, and bradykinin or its analogs in humans or animals, such as allergy, inflammation, autoimmune disease, shock, pain, etc. For the prevention and / or treatment of various diseases induced by
More specifically, asthma, cough, bronchitis, rhinitis, rhinorrhea, obstructive pulmonary disease [eg emphysema, etc.], sputum, pneumonia, systemic infrastructure response syndrome [sy]
Stemicinflammatory response
se syndrome (SIRS)], septic shock, irritable shock, endotoxin shock, adult respiratory distress syndrome, disseminated intravascular coagulation, arthritis, rheumatism, osteoarthritis, low back pain, inflammation-induced bone resorption, conjunctivitis, spring catarrh , Uveitis, iritis, iridocyclitis, headache,
Migraine, toothache, backache, superficial pain, cancer pain, postoperative pain, tendon pain, trauma [eg, wound, burn (burn), etc.], rash (skin), redness (erythema), eczema or skin Inflammation [eg contact dermatitis, atopic dermatitis, etc.], urticaria, shingles pain, pruritus, psoriasis, lichen, inflammatory bowel disease [eg ulcerative colitis, Crohn's disease, etc.], diarrhea, hepatitis, pancreatitis , Gastritis, esophagitis, food allergy, ulcer, irritable bowel syndrome, nephritis, angina, periodontitis, edema, hereditary vascular edema, cerebral edema, hypotension, thrombosis, myocardial infarction, cerebrovascular Spasm,
Congestion, blood clot, gout, central nervous system disorder, premature birth, arteriosclerosis,
It is useful for the prevention and / or treatment of post-gastrectomy dumping syndrome, carcinoid syndrome, fluctuation of sperm motility, diabetic neuropathy, neuralgia, rejection at the time of transplantation and the like. Furthermore, since bradykinin is known to be involved in the release of mediators such as prostaglandins, leukotrienes, tachykinins, histamines, thromboxanes, etc., the target compound [I] is used for the treatment of diseases induced by those mediators. It is expected to be useful for prevention and / or treatment.

[0034]

EXAMPLES The present invention will be described in detail below with reference to production examples and examples. Example 1 2-Amino-3- (2,6-dichlorobenzyloxy)
A mixture of pyridine (2.69 g) and 2-bromoacetophenone (2.59 g) in ethanol (27 ml) is heated at reflux for 14 hours, cooled and concentrated under reduced pressure. The obtained solid is collected by filtration to obtain 8- (2,6-dichlorobenzyloxy) -2-phenylimidazo [1,2-a] pyridine hydrochloride (3 g) as a white solid. mp: 178-179 ° C NMR (DMSO-d ₆ , δ): 5.58 (2H, s), 7.38-7.75 (8H), 7.
96 (2H, d, J = 7Hz), 8.50 (1H, d, J = 7Hz), 8.78 (1H, s)

Example 2 2-Amino-3- (2,6-dichlorobenzyloxy)
Pyridine (15 g) and ethyl 2-chloroacetoacetate (1
A mixture with 1.93 g) in ethanol (150 ml) is heated to reflux for 24 hours, cooled and concentrated under reduced pressure. The residue is partitioned between ethyl acetate and aqueous sodium hydrogen carbonate solution. The organic layer is washed with water, dried, concentrated under reduced pressure and the solid obtained is purified by flash chromatography on silica gel to give 8- (2,6-dichlorobenzyloxy) -3-ethoxycarbonyl. -2-
Methylimidazo [1,2-a] pyridine (6.2 g) is obtained as a white solid. mp: 160-161 ° C NMR (CDCl ₃ , δ): 1.43 (3H, t, J = 7Hz), 2.71 (3H, s),
4.42 (2H, q, J = 7Hz), 5.49 (2H, s), 6.83-6.98 (2H, m),
7.19-7.41 (3H, m), 8.99 (1H, d, J = 7Hz)

Example 3 In the same manner as in Example 2, the following compound is obtained. (1) 4 from 2-amino-3- (2,6-dichlorobenzyloxy) pyridine and 2-chlorocyclohexanone
-(2,6-dichlorobenzyloxy) -6,7,8,
9-Tetrahydropyrido [1,2-a] benzimidazole is obtained. mp: 193-194 ° C NMR (CDCl ₃ , δ): 1.82-2.04 (4H), 2.73 (2H, t, J = 6H
z), 2.84 (2H, t, J = 6Hz), 5.47 (2H, s), 6.61 (1H, d, J = 8
Hz), 6.71 (1H, t, J = 8Hz), 7.18-7.40 (3H), 7.50 (1H, d,
J = 6Hz) (2) From 2-methyl-3- (2,6-dichlorobenzyloxy) pyridine and bromoacetone to 8- (2,6-
Dichlorobenzyloxy) -2-methylindolizine is obtained. NMR (CDCl ₃ , δ): 2.27 (3H, s), 5.36 (2H, s), 6.14 (1
H, d, J = 8Hz), 6.27-6.40 (2H), 7.08 (1H, s), 7.11-7.57
(4H)

Example 4 2-Bromomethyl-1,3-dioxolane (372 m
g) and water (15 ml) to a mixture of concentrated hydrochloric acid (0.23
ml) dropwise at room temperature for 2.5 hours and then at 80 ° C. for 3 hours.
Stir for 0 minutes. After cooling to room temperature, sodium hydrogen carbonate (244 mg) and 2-amino-3- (2,6-dichlorobenzyloxy) pyridine (479 mg) were added,
Stir at room temperature for 3 hours. Add dioxane (10 ml) and reflux for 9.5 hours. The reaction mixture is concentrated and extracted 3 times with dichloromethane. The organic layers are combined, washed with brine and dried over magnesium sulfate. Evaporate the solvent,
The residue is purified by silica gel column chromatography to give 8- (2,6-dichlorobenzyloxy) imidazo [1,2-a] pyridine (140 mg) as crystals. mp: 148-149 ° C NMR (CDCl ₃ , δ): 5.49 (2H, s), 6.58-6.78 (2H), 7.19
-7.40 (3H), 7.57 (2H, s), 7.82 (1H, d, J = 7Hz)

Example 5 8-Hydroxy-2-methylimidazo [1,2-a] pyridine (104 mg), 2-chloromethylquinoline (2
14 mg) and potassium carbonate (386 mg) in N, N
-The mixture is stirred in dimethylformamide (3 ml) at 70 ° C for 2 hours. The mixture is cooled and diluted with water. The oil that separates is extracted with dichloromethane. The organic layer is washed with water, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 8- (2-
Quinolylmethoxy) -2-methylimidazo [1,2-
a] Pyridine (53 mg) is obtained as crystals. mp: 68-71 ° C NMR (CDCl ₃ , δ): 2.50 (3H, s), 5.60 (2H, s), 6.45-6.
56 (2H, m), 7.33 (1H, s), 7.56 (1H, t, J = 7.5Hz), 7.65-
7.85 (4H, m), 8.11 (1H, d, J = 7.5Hz), 8.18 (1H, d, J = 7.5
Hz)

Example 6 Sodium hydride (60% oil, 335 mg) N,
To a suspension of N-dimethylformamide (8 ml), 2,6
-Add dichlorobenzyl alcohol (1.48 g) under ice cooling. After stirring at room temperature for 1 hour, the reaction mixture is cooled with an ice-water bath. 5-chloro-2-methylimidazo [1,2-a] pyridine hydrochloride (850 mg) was added thereto,
Stir at room temperature for 24 hours. Water is added, the precipitate formed is filtered off and the residue obtained is taken up with ethyl acetate. With water 2
Wash twice, dry over magnesium sulfate, and remove the solvent in vacuo. The obtained residue is recrystallized from benzene-diisopropyl ether to give 5- (2,6-dichlorobenzyloxy) -2-methylimidazo [1,2-a] pyridine (1.10 g). mp: 149-150 ° C NMR (CDCl ₃ , δ): 2.41 (3H, s), 5.52 (2H, s), 6.23 (1
H, m), 7.09-7.48 (6H)

Example 7 In the same manner as in Example 5 or 6, the following compound was obtained. (1) 2-Methyl-8- (1-naphthylmethoxy) imidazo [1,2-a] pyridine mp: 112-113 ° C NMR (CDCl ₃ , δ): 2.46 (3H, s), 5.78 (2H, s) ), 6.46-6.
58 (2H, m), 7.30 (1H, s), 7.40-8.13 (8H, m) (2) 3-Bromo-8-mesyloxymethyl-2-methylimidazo [1,2-a] pyridine and 2, From 6-dichlorophenol to 3-bromo-8- (2,6-dichlorophenoxymethyl) -2-methylimidazo [1,2-
a] Pyridine is obtained. mp: 158-159 ° C NMR (CDCl ₃ , δ): 2.47 (3H, s), 5.51 (2H, s), 6.91-7.
10 (2H, m), 7.32 (2H, d, J = 9Hz), 7.67, 8.03 (each 1H,
d, J = 7Hz) (3) 2-Methyl-8- (2-pyridylmethoxy) imidazo [1,2-a] pyridine The physical properties are those of dihydrochloride. mp: 209-211 ° C NMR (DMSO-d ₆ , δ): 2.51 (3H, s), 5.71 (2H, s), 7.32-
7.60 (2H), 7.72 (1H, m), 8.02-8.36 (3H), 8.53 (1H,
m), 8.77 (1H, m) (4) 8-diphenylmethoxy-2-methylimidazo [1,2-a] pyridine mp: 111-113 ° C NMR (CDCl ₃ , δ): 2.46 (3H, s), 5.78 (2H, s), 6.49-6.
59 (2H, m), 7.31 (1H, s), 7.40-8.15 (12H, m) (5) 8- [3- (2-Cyanophenyl) -7-benzofurylmethoxy] -2-methylimidazo [1 , 2-a] pyridine NMR (CDCl ₃ , δ): 2.47 (3H, s), 5.71 (2H, s), 6.51-6.
61 (2H, m), 7.28-7.80 (11H, m), 8.10 (1H, d, J = 7.5Hz)

(6) 8- [2,6-dichloro-3- (N-
Methyl-N-acetylamino) benzyloxy] -2-
Methyl-5,6,7,8-tetrahydroimidazo [1,
2-a] pyridine NMR (CDCl ₃ , δ): 1.70-2.42 (4H), 1.79 (3H, s), 2.25
(3H, s), 3.16 (3H, s), 3.80 (1H, m), 4.02 (1H, m), 4.7
0 (1H, t, J = 3Hz), 4.93 (1H, d, J = 10Hz), 5.09 (1H, d, J = 10)
Hz), 6.60 (1H, s), 7.18 (1H, d, J = 9Hz), 7.37 (1H, d, J =
9Hz) (7) 8-Hydroxy-2-methylimidazo [1,2-
a] pyridine and 2,3,5,6-tetrachloro-
1,4-Bis (2-methyl-8-imidazo [1,2-a] pyridyloxymethyl) -2,3,5,6-tetrachlorobenzene is obtained from 1,4-bis (chloromethyl) benzene. mp:> 250 ° C NMR (DMSO-d ₆ , δ): 2.42 (6H, s), 5.72 (4H, s), 7.43
(2H, t, J = 7Hz), 7.70 (2H, d, J = 7Hz), 8.12 (2H, s), 8.51
(2H, d, J = 7Hz) (8) 3-Acetyl-8- (2,6-dichlorobenzyloxy) -2-methylimidazo [1,2-a] pyridine mp: 214-215 ° C NMR (CDCl ₃ , δ): 2.62 (3H, s), 2.80 (3H, s), 5.50 (2
H, s), 6.90-7.00 (2H, m), 7.21-7.49 (3H, m), 9.41 (1H,
dd, J = 7.5Hz and 1.5Hz) (9) 8- [2,6-dichloro-3- (N-methyl-N-
Acetylamino) benzyloxy] -2,3-dimethylimidazo [1,2-a] pyridine mp: 192-195 ° C NMR (CDCl ₃ , δ): 1.85 (3H, s), 2.39 (3H, s), 2.42 (3
H, s), 3.20 (3H, s), 5.49 (2H, s), 6.62 (1H, d, J = 8Hz),
6.75 (1H, t, J = 8Hz), 7.28 (1H, d, J = 9Hz), 7.44 (1H, d, J
= 9Hz), 7.52 (1H, d, J = 8Hz) (10) 8- [2,6-dichloro-3- (N-methyl-N)
-Acetylamino) benzyloxy] -2-methylimidazo [1,2-a] pyridine mp: 159-161 ° C NMR (CDCl ₃ , δ): 1.86 (3H, s), 2.44 (3H, s), 3.20 ( 3
H, s), 5.50 (2H, s), 6.55-6.75 (2H), 7.29 (1H, d, J = 9H
z), 7.33 (1H, s), 7.46 (1H, d, J = 9Hz), 7.74 (1H, d, J = 7
Hz) (11) 8-chloro-2-methylimidazo [1,2-a]
Pyrazine and N-acetyl-2,4-dichloro-3-
From hydroxymethyl-N-methylaniline to 8- [2,
6-Dichloro-3- (N-methyl-N-acetylamino) benzyloxy] -2-methylimidazo [1,2-
a] Obtain pyrazine. mp: 209-210 ° C NMR (CDCl ₃ , δ): 1.87 (3H, s), 2.46 (3H, s), 3.19 (3
H, s), 5.80 (1H, d, J = 10Hz), 5.85 (1H, d, J = 10Hz), 7.27
(1H, d, J = 8Hz), 7.35-7.48 (3H, m), 7.70 (1H, d, J = 5Hz) (12) 8-hydroxy-2-methylimidazo [1,2-
a] Pyridine and 2,6-dichloro-3-nitrobenzyl methanesulfonate to 8- (2,6-dichloro-3
-Nitrobenzyloxy) -2-methylimidazo [1,
2-a] pyridine is obtained. mp: 183-185 ℃

Example 8 A mixture of sodium hydride (60% oil, 15 mg) and dimethyl sulfoxide (1 ml) is stirred at 60 ° C for 1 hour and cooled to room temperature. To this mixture was added 2,6 bromide.
-Dichlorobenzyltriphenylphosphonium (188
(mg) and stirred at room temperature for 30 minutes. 2-methyl-8
-Imidazo [1,2-a] pyridine carbaldehyde (5
(0 mg) was added, and the mixture was further stirred for 1 hr, poured into water, and extracted 3 times with ethyl acetate. The organic layers are combined, washed with water and brine, dried over magnesium sulphate and evaporated. The residue is purified by preparative thin layer chromatography to give 8- (2,6-dichlorostyryl) -2-methylimidazo [1,2-a] pyridine (64 mg) as an oil. NMR (CDCl ₃ , δ): 2.50 (3H, s), 6.78 (1H, t, J = 7Hz),
7.06-7.41 (4H), 7.55 (1H, d, J = 16Hz), 8.00 (1H, d, J = 7H
z), 8.05 (1H, d, J = 16Hz)

Example 9 3-Bromo-2-methyl-8-imidazo [1,2-a]
Pyridinecarboxylic acid (100 mg), methylene chloride (2
ml) and N, N-dimethylformamide (1 drop), oxalyl chloride (100 mg) is added and the mixture is stirred for 1 hour and evaporated. The residue was dissolved in methylene chloride and triethylamine (0.0
8 ml) and 2,6-dichlorophenol (70 mg) are added and the mixture is stirred for 30 minutes. Wash twice with aqueous sodium hydrogen carbonate then brine, dry over magnesium sulfate and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 30: 1 v / v) to give 3-bromo-8-
(2,6-Dichlorophenoxycarbonyl) -2-methylimidazo [1,2-a] pyridine (57 mg) is obtained. mp: 165-166 ° C NMR (CDCl ₃ , δ): 2.56 (3H, s), 7.08 (1H, t, J = 7Hz),
7.13-7.29 (1H, t, J = 9Hz), 7.41 (2H, d, J = 9Hz), 8.35 (2
(H, d, J = 7Hz)

Example 10 8-Amino-2-methylimidazo [1,2-a] pyridine hydrochloride (367 mg) and 2- (p-tolyl) -3-benzothiophenecarbaldehyde (504 mg) in ethanol ( Sodium cyanoborohydride (138 mg) is added in one portion to the mixture in 15 ml). The mixture is stirred at room temperature for 24 hours and then concentrated under reduced pressure. The residue is extracted with ethyl acetate, washed with water, dried and concentrated under reduced pressure. The obtained residue is crystallized from diisopropyl ether to give 8- [2- (p-tolyl) -3-benzothienylmethylamino] -2-methylimidazo [1,2-a] pyridine (95 mg). NMR (DMSO-d ₆ , δ): 2.25 (3H, s), 2.39 (3H, s), 4.62
(2H, d, J = 4Hz), 5.80 (1H, d, J = 8Hz), 6.14 (1H, t, J = 4Hz),
6.46 (1H, t, J = 8Hz), 7.35-7.56 (7H), 7.66 (1H, t, J = 8H
z), 7.97-8.12 (2H)

Example 11 A mixture of 2-methyl-8- (dimethylcarbamoylthio) imidazo [1,2-a] pyridine (736 mg), potassium hydroxide (221 mg) and ethanol (7.4 ml) was refluxed for 24 hours. After that, it was cooled to room temperature, and N-acetyl-3-bromomethyl-2,4-dichloro-N-methylaniline (1.245 g) was added dropwise. After stirring the mixture at room temperature overnight, the solvent is evaporated. The residue was purified by silica gel column chromatography and crystallized from ethanol to give 3-bromo-8- [2,6-dichloro-3- (N
-Methyl-N-acetylamino) benzylthio] -2-
Methylimidazo [1,2-a] pyridine (435 mg)
To get mp: 196-197 ° C NMR (CDCl ₃ , δ): 1.73, 2.51, 3.10 (each 3H, s), 4.5
9, 4.70 (each 1H, d, J = 13Hz), 6.80 (1H, t, J = 7Hz), 7.1
3 (1H, d, J = 7Hz), 7.15, 7.38 (each1H, d, J = 9Hz), 8.01
(1H, d, J = 7Hz)

Example 12 3-Bromo-8- [2,6-dichloro-3- (N-methyl-N-acetylamino) benzylthio] -2-methylimidazo [1,2-a] pyridine (100 mg) To a dichloromethane (2 ml) solution, m-chloroperbenzoic acid (46 mg) was added under ice cooling. After stirring the mixture at room temperature for 30 minutes, it is washed with 3% aqueous sodium thiosulfate solution and then saturated aqueous sodium hydrogen carbonate solution, and the solvent is evaporated.
The residue was purified by preparative thin layer chromatography, then crystallized from ethyl acetate-diethyl ether to give 3-bromo-8- [2,6-dichloro-3- (N-methyl-N-
Acetylamino) benzylsulfinyl] -2-methylimidazo [1,2-a] pyridine (57 mg) is obtained. mp: 147-148 ° C NMR (CDCl ₃ , δ): 1.71 (1.5H, s), 1.79 (1.5H, s), 2.4
0 (1.5H, s), 2.43 (1.5H, s), 3.06 (1.5H, s), 3.14 (1.5
H, s), 4.81 (0.5H, d, J = 12Hz), 4.83 (0.5H, d, J = 12Hz),
5.13 (0.5H, d, J = 12Hz), 5.15 (0.5H, d, J = 12Hz), 7.00-7.
72 (4H), 8.18 (1H, d, J = 7Hz)

Example 13 (1) 3-Bromo-8- [2,6-dichloro-3- (N-
To a solution of methyl-N-acetylamino) benzylthio] -2-methylimidazo [1,2-a] pyridine (100 mg) in dichloromethane (2 ml) was added m-chloroperbenzoic acid (114 mg) under ice cooling. Mix the mixture at room temperature 3
After stirring for an hour, the mixture is washed with a 3% aqueous sodium thiosulfate solution and then with a saturated aqueous sodium hydrogen carbonate solution, and the solvent is distilled off. The residue was purified by preparative thin layer chromatography,
3-Bromo-8- [2,6-dichloro-3- (N-methyl-N-acetylamino) benzylsulfonyl] -2-
Methylimidazo [1,2-a] pyridine is obtained as an oil. (2) Dissolve the obtained oil in methanol (2 ml),
A 10% methanol solution of hydrogen chloride (0.5 ml) is added, and the mixture is stirred at room temperature for 10 minutes. The solvent was distilled off, and ethyl acetate-
Crystallization from methanol gave 3-bromo-8- [2,6-
Dichloro-3- (N-methyl-N-acetylamino) benzylsulfonyl] -2-methylimidazo [1,2-
a] Pyridine hydrochloride (67 mg) is obtained. mp: 154 ° C. (dec.) NMR (CDCl ₃ + CD ₃ OD, δ): 1.78, 2.70, 3.11 (each 3H,
s), 5.59 (1H, br s), 7.20-7.35 (2H), 7.46 (1H, d, J = 9H
z), 7.94 (1H, br d, J = 5Hz), 8.56 (1H, br s)

Example 14 8- (1-Naphthylmethoxy) -2-methylimidazo [1,2-a] pyridine (58 mg) in ethanol (1
ml) solution at room temperature with N-chlorosuccinimide (2
9 mg) is added at once. After stirring at the same temperature for 30 minutes, water was added thereto and the mixture was extracted with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to give 3-chloro-8-
(1-naphthylmethoxy) -2-methylimidazo [1,
2-a] Pyridine (36 mg) is obtained. mp: 152 ° C NMR (CDCl ₃ , δ): 2.46 (3H, s), 5.79 (2H, s), 6.58 (1
H, d, J = 7.5Hz), 6.71 (1H, t, J = 7.5Hz), 7.40-8.13 (8H, m)

Example 15 In analogy to Example 14 or using N-bromosuccinimide or N-iodosuccinimide in place of N-chlorosuccinimide, the following compound is obtained. (1) 3-Bromo-8- [2,6-dichloro-3- (N-
Methyl-N-acetylamino) benzyloxy] -2-
Methyl-5,6,7,8-tetrahydroimidazo [1,
2-a] pyridine NMR (CDCl ₃ , δ): 1.80 (3H, s), 1.82-2.02 (2H), 2.21
(3H, s), 2.23-2.40 (2H), 3.16 (3H, s), 3.63 (1H, m),
3.98 (1H, m), 4.66 (1H, t, J = 3Hz), 4.91 (1H, d, J = 10Hz),
5.06 (1H, d, J = 10Hz), 7.18 (1H, d, J = 9Hz), 7.38 (1H, d,
J = 9Hz) (2) 3-Bromo-8- (2,6-dichlorobenzyloxy) -2-methylindolizine NMR (DMSO-d ₆ , δ): 2.18 (3H, s), 5.37 (2H, s) ), 6.40
(1H, s), 6.52 (1H, d, J = 8Hz), 6.69 (1H, t, J = 8Hz), 7.43
-7.64 (3H), 7.73 (1H, d, J = 8Hz) (3) 1-Bromo-8- (2,6-dichlorobenzyloxy) -2-methylindolizine NMR (DMSO-d ₆ , δ): 2.13 (3H, s), 5.33 (2H, s), 6.58
(1H, d, J = 8Hz), 6.73 (1H, t, J = 8Hz), 7.43-7.64 (4H), 7.
80 (1H, d, J = 8Hz) (4) 3-Bromo-8- (2,6-dichlorostyryl)-
2-methylimidazo [1,2-a] pyridine mp: 121-122 ° C NMR (CDCl ₃ , δ): 2.50 (3H, s), 6.92 (1H, t, J = 7Hz),
7.11 (1H, t, J = 8Hz), 7.48 (3H, d, J = 8Hz), 7.52 (1H, d, J =
16Hz), 8.01 (1H, d, J = 7Hz), 8.05 (1H, d, J = 16Hz) (5) 1,4-bis (3-bromo-2-methyl-8-imidazo [1,2-a ] Pyridyloxymethyl) -2,3
5,6-Tetrachlorobenzene mp:> 250 ° C NMR (CDCl ₃ + CD ₃ OD, δ): 2.42 (6H, s), 5.59 (4H, s),
6.81 (2H, d, J = 7Hz), 6.95 (2H, t, J = 7Hz), 7.90 (2H, d, J =
7Hz) (6) 8- [2,6-dichloro-3- (N-acetyl-N)
-Methylamino) benzyloxy] -3-iodo-2-
Methylimidazo [1,2-a] pyridine mp: 190-192 ° C NMR (CDCl ₃ , δ): 1.84 (3H, s), 2.49 (3H, s), 3.20 (3
H, s), 5.50 (2H, s), 6.71 (1H, d, J = 7Hz), 6.86 (1H, t, J =
7Hz), 7.30 (1H, d, J = 9Hz), 7.47 (1H, d, J = 9Hz), 7.80 (1
H, d, J = 7Hz) (7) 3-Bromo-8- [2,6-dichloro-3- (N-
Methyl-N-acetylamino) benzyloxy] -2-
Methylimidazo [1,2-a] pyrazine mp: 205-210 ° C NMR (CDCl ₃ -CD, OD 3drops) δ: 1.86 (3H, s), 2.47 (3H, s), 3.19 (3H, s), 5.83
(1H, d, J = 10Hz), 5.87 (1H, d, J = 10Hz), 7.33 (1H, d, J = 8H
z), 7.49 (1H, d, J = 8Hz), 7.59 (1H, d, J = 5Hz), 7.78 (1H,
(d, J = 5Hz)

Example 16 8- [2,6-Dichloro-3- (N-methyl-N-acetylamino) benzyloxy] -3-iodo-2-methylimidazo [1,2-a] pyridine (200 mg) To N, N-dimethylformamide (2 ml) solution of was added sodium thiomethoxide (139 mg) at room temperature.
After stirring for 2 hours, the mixture is partitioned between dichloromethane and water. The aqueous layer is extracted twice with dichloromethane and the combined organic layers are washed with water and brine and dried. The solvent was evaporated and the residue was purified by silica gel column chromatography (dichloromethane-methanol) to give 8-
[2,6-Dichloro-3- (N-methyl-N-acetylamino) benzyloxy] -2-methyl-3-methylthioimidazo [1,2-a] pyridine (57 mg) is obtained. NMR (CDCl ₃ , δ): 1.86 (3H, s), 2.48 (3H, s), 2.50 (3
H, s), 3.20 (3H, s), 5.52 (2H, s), 6.73 (1H, d, J = 7Hz),
6.86 (1H, t, J = 7Hz), 7.29 (2H, s), 7.80 (1H, d, J = 7Hz)

Example 17 3-Acetyl-8- (2,6-dichlorobenzyloxy) -2-methylimidazo [1,2-a] pyridine (3
50 ml) in ethanol (7 ml) and tetrahydrofuran (3 ml) in sodium borohydride (46 ml)
(mg) at room temperature and stirred at the same temperature for 2 hours. The precipitate formed is filtered off, washed with ethanol, dried and
-(2,6-Dichlorobenzyloxy) -3- (1-hydroxyethyl) -2-methylimidazo [1,2-a]
Pyridine (130 mg) is obtained. mp: 225-227 ° C NMR (DMSO-d ₆ , δ): 1.50 (3H, d, J = 8Hz), 2.28 (3H, s),
5.20 (1H, m), 5.38 (2H, s), 6.25-6.38 (2H, m), 7.48-
7.66 (3H, m), 8.18 (1H, dd, J = 7.5Hz and 1.5Hz)

Example 18 8- (2,6-Dichlorobenzyloxy) -3- (1-
Hydroxyethyl) -2-methylimidazo [1,2-
a] pyridine (693 mg), triethylamine (0.
3 ml) and dichloromethane (7 ml),
Methanesulfonic acid chloride (0.16 ml) was added dropwise in a dry ice-carbon tetrachloride bath, and the mixture was stirred at the same temperature for 1.5 hours and then at room temperature for another 2 hours. The mixture obtained is washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (dichloromethane-methanol) to give 8- (2,6-dichlorobenzyloxy) -2-methyl-3-vinylimidazo [1,2-a] pyridine (1
50 mg) is obtained. mp: 169-172 ° C NMR (CDCl ₃ , δ): 2.53 (3H, s), 5.4-5.52 (4H), 6.63-
6.90 (3H), 7.20-7.40 (3H), 7.82 (1H, d, J = 8Hz)

Example 19 8- (2,6) was added to a suspension of lithium aluminum hydride (716 mg) in tetrahydrofuran (50 ml) under ice cooling.
-Dichlorobenzyloxy) -3-ethoxycarbonyl-2-methylimidazo [1,2-a] pyridine (3.0
0 g), and the mixture is stirred at the same temperature for 1 hour. In the reaction mixture,
Below 10 ° C, 3% aqueous sodium hydroxide solution (3.75
ml) is added dropwise, the formed precipitate is filtered off, and the filtrate is concentrated. The residue obtained is crystallized from acetonitrile,
8- (2,6-Dichlorobenzyloxy) -3-hydroxymethyl-2-methylimidazo [1,2-a] pyridine (1.40 g) is obtained. mp: 220-221 ° C NMR (DMSO-d ₆ , δ): 2.28 (3H, s), 4.72 (2H, s), 5.08
(1H, br s), 5.38 (2H, s), 6.76-6.94 (2H), 7.45-7.68
(3H, m), 7.98 (1H, d, J = 7Hz)

Example 20 8- (2,6-Dichlorobenzyloxy) -3- was added to a suspension of sodium hydride (40% oil, 10.4 mg) in N, N-dimethylformamide (1.0 ml). Hydroxymethyl-2-methylimidazo [1,2-a] pyridine (80 mg) was added under ice cooling, and the mixture was stirred at the same temperature for 10 minutes, and then allyl bromide (0.23 ml) was added. 3 at room temperature
After stirring for an hour, pour into water and extract with dichloromethane three times.
The organic layers are combined, washed with water, dried and concentrated, and the residue obtained is purified by preparative thin layer chromatography to give 3-allyloxymethyl-8- (2,6-dichlorobenzyloxy) -2. -Methylimidazo [1,2-a] pyridine (2
6 mg) is obtained. mp: 87-90 ° C NMR (CDCl ₃ , δ): 2.46 (3H, s), 3.96 (2H, d, J = 6Hz),
4.78 (2H, s), 5.15-5.38 (2H, m), 5.45 (2H, s), 5.80-
6.02 (1H, m), 6.62-6.81 (2H, m), 7.19-7.41 (3H, m),
7.83 (1H, d, J = 7Hz)

Example 21 8- (2,6-Dichlorobenzyloxy) -3-ethoxycarbonyl-2-methylimidazo [1,2-a] pyridine (1.5 g), 1N aqueous sodium hydroxide solution (4.
A mixture of 35 ml), ethanol (4 ml) and tetrahydrofuran (4 ml) is refluxed for 8 hours. The reaction mixture is concentrated and the residue is partitioned between saturated aqueous sodium hydrogen carbonate solution and dichloromethane. The aqueous layer was separated, washed with dichloromethane, adjusted to pH 4 with 1N hydrochloric acid, and the formed precipitate was collected by filtration to give 8- (2,6-dichlorobenzyloxy) -3-carboxy-2-methylimidazo [ 1,
2-a] Pyridine (800 mg) is obtained as a white powder. mp: 197-199 ° C NMR (DMSO-d ₆ , δ): 2.53 (3H, s), 5.41 (2H, s), 6.98-
7.22 (2H), 7.48-7.68 (3H), 8.94 (1H, d, J = 7Hz)

Example 22 8- (2,6-Dichlorobenzyloxy) -3-carboxy-2-methylimidazo [1,2-a] pyridine (6
Oxalyl chloride (0.3 ml) was added dropwise to a mixture of 0 mg), N, N-dimethylformamide (1 drop) and dichloromethane (2 ml) under ice cooling. After stirring for 30 minutes at room temperature, the solvent is distilled off. The residue was dissolved in tetrahydrofuran, and a saturated tetrahydrofuran solution of ammonia (2
ml). The mixture obtained is partitioned between water and dichloromethane-methanol, the organic layer is separated and dried. The solvent was evaporated and the residue was crystallized from methanol to give 8- (2,6-dichlorobenzyloxy) -3.
-Carbamoyl-2-methylimidazo [1,2-a] pyridine (48 mg) is obtained. mp:> 250 ° C NMR (DMSO-d ₆ , δ): 2.52 (3H, s), 5.41 (2H, s), 6.96
(1H, t, J = 7Hz), 7.09 (1H, d, J = 7Hz), 7.32-7.48 (2H), 7.
49-7.68 (3H), 8.79 (1H, d, J = 7Hz)

Example 23 In the same manner as in Example 22, the following compound is obtained. (1) From 8- (2,6-dichlorobenzyloxy) -3-carboxy-2-methylimidazo [1,2-a] pyridine and morpholine, 8- (2,6-dichlorobenzyloxy) -3-morpholino Carbonyl-2-methylimidazo [1,2-a] pyridine is obtained. mp: 190-191 ° C NMR (CDCl ₃ , δ): 2.48 (3H, s), 3.60-3.81 (8H), 5.47
(2H, s), 6.71-6.86 (2H), 7.19-7.40 (3H), 8.14 (1H, d
d, J = 5, 1 Hz) (2) 8- (2,6-dichlorobenzyloxy) -3-carboxy-2-methylimidazo [1,2-a] pyridine and 2- (2,2-propynyl alcohol) 6-Dichlorobenzyloxy) -3- (2-propynyloxycarbonyl) -2-methylimidazo [1,2-a] pyridine is obtained. mp: 195-196 ° C NMR (CDCl ₃ , δ): 2.51 (1H, t, J = 2Hz), 2.73 (3H, s),
4.97 (2H, d, J = 2Hz), 5.50 (2H, s), 6.88-6.99 (2H), 7.2
0-7.41 (3H), 8.98 (1H, m)

Example 24 The following salt compound was obtained in the same manner as in Example 13- (2). (1) 8- (2,6-dichlorostyryl) -2-methylimidazo [1,2-a] pyridine hydrochloride mp: 95-98 ° C NMR (CDCl ₃ , δ): 2.51 (3H, s), 7.35 -7.70 (6H), 8.19
(1H, s), 8.39,8.88 (each 1H, d, J = 7Hz) (2) 8- [2,6-dichloro-3- (N-methyl-N-
Acetylamino) benzyloxy] -2-methyl-3-
Methylthioimidazo [1,2-a] pyridine hydrochloride NMR (CDCl ₃ -CD ₃ OD, δ): 1.86 (3H, s), 2.57 (6H, s),
3.20 (3H, s), 5.70 (2H, s), 7.39-7.61 (5H), 8.21 (1H,
d, J = 6Hz)

Example 25 (1) 8- (2,6-dichloro-3-nitrobenzyloxy) -2-methylimidazo [1,2-a] pyridine (1
99 mg) and iron (powder, 156 mg) in acetic acid (2 m
The suspension in l) -ethanol (1 ml) mixture is heated to reflux for 1 hour. Treatment according to a conventional method gives 8- (3-amino-2,6-dichlorobenzyloxy) -2-methylimidazo [1,2-a] pyridine (205 mg). NMR (DMSO-d ₆ , δ): 2.27 (3H, s), 5.30 (2H, s), 5.70
(2H, s), 6.64-7.00 (3H), 7.24 (1H, d, J = 8Hz), 7.65 (1
H, s), 8.09 (1H, d, J = 7Hz) (2) 8- (3-amino-2,6-dichlorobenzyloxy) -2-methylimidazo [1,2-a] pyridine (2
To a mixture of 80 mg), pyridine (137 mg) and N, N-dimethylformamide (2.24 ml) was added phthalimidoacetyl chloride (194 mg) under ice cooling, and the mixture was stirred at the same temperature for 2 hours. Pour water into the resulting mixture,
The mixture is stirred and the resulting precipitate is collected by filtration to give 8- [2,6-dichloro-3- (phthalimidoacetylamino) benzyloxy] -2-methylimidazo [1,2-a] pyridine (416 mg). (3) 8- [2,6-dichloro-3- (phthalimidoacetylamino) benzyloxy] -2-methylimidazo [1,2-a] pyridine (390 mg) in N, N-dimethylformamide (1.95 ml) ) Under ice-cooling, potassium tertiary butoxide (129 mg) was added to the solution, and the solution was stirred at the same temperature for 15 minutes.
Stir for minutes. Further, methyl iodide (163 mg) was added at the same temperature and the mixture was stirred for 1 hour, and then water was added to the reaction mixture. The obtained residue was collected by filtration to give 8- [2,6-dichloro-3- (N-
Methyl-N-phthalimidoacetylamino) benzyloxy] -2-methylimidazo [1,2-a] pyridine (337 mg) is obtained. mp: 221-223 ° C

Production Example 1 In the same manner as in Example 2, 8-hydroxy-2,3-dimethylimidazo [1,2-a] pyridine was prepared from 3-hydroxy-2-aminopyridine and 3-bromo-2-butanone. obtain. NMR (CDCl ₃ , δ): 2.36 (3H, s), 2.41 (3H, s), 6.69 (1
H, d, J = 7Hz), 6.79 (1H, t, J = 7Hz), 7.35 (1H, d, J = 7Hz),
9.05 (1H, br s)

Production Example 2 8-Hydroxy-2-methylimidazo [1,2-a] pyridine (1.00 g), platinum (IV) oxide (500 m
A mixture of g) and acetic acid (20 ml) is stirred under hydrogen flow (4 atm) at 50 ° C. for 18 hours. The catalyst is filtered off and the filtrate is concentrated. The residue is purified by silica gel column chromatography (dichloromethane-methanol) to give 8-hydroxy-2-methyl-5,6,7,8-tetrahydroimidazo [1,2-a] pyridine (204 mg). mp: 162-164 ° C NMR (CDCl ₃ , δ): 1.80-2.40 (4H), 2.20 (3H, s), 3.75
-4.02 (2H), 4.92 (1H, t, J = 5Hz), 6.50 (1H, s)

Production Example 3 In the same manner as in Example 5, 3-hydroxy-2-methylpyridine and 2,6-dichlorobenzyl bromide were used to give 3-
(2,6-Dichlorobenzyloxy) -2-methylpyridine is obtained. mp: 74-75 ° C NMR (CDCl ₃ , δ): 2.42 (3H, s), 5.26 (2H, s), 7.11 (1
H, dd, J = 8,5Hz), 7.18-7.42 (4H), 8.12 (1H, d, J = 5Hz) Production Example 4 In the same manner as in Example 14, 8-ethoxycarbonyl-2
From 3-methylimidazo [1,2-a] pyridine and N-bromosuccinimide, 3-bromo-8-ethoxycarbonyl-2-methylimidazo [1,2-a] pyridine is obtained. mp: 76-78 ° C NMR (CDCl ₃ , δ): 1.44 (3H, t, J = 7Hz), 2.56 (3H, s),
4.50 (2H, q, J = 7Hz), 6.98 (1H, t, J = 7Hz), 7.96, 8.23 (e
(ach 1H, d, J = 7Hz)

Production Example 5 In the same manner as in Example 19, from 3-bromo-8-ethoxycarbonyl-2-methylimidazo [1,2-a] pyridine to 3-bromo-8-hydroxymethyl-2-methylimidazo [ 1,2-a] pyridine is obtained. mp: 123-125 ° C NMR (CDCl ₃ , δ): 2.46 (3H, s), 5.01 (2H, s), 6.89 (1
H, t, J = 7Hz), 7.17,7.99 (each 1H, d, J = 7Hz) Production Example 6 3-Bromo-8-hydroxymethyl-2-methylimidazo [1,2-a] pyridine (200 mg) and A solution of triethylamine (118 mg) in methylene chloride (4 ml) was added to methanesulfonic acid chloride (105 mg) under ice cooling.
And stir for 30 minutes. The reaction mixture is washed with saturated aqueous sodium hydrogen carbonate solution and then with brine, dried over magnesium sulfate, and the solvent is evaporated. The residue was crystallized from diethyl ether to give 3-bromo-8-mesyloxymethyl-2-methylimidazo [1,2-a] pyridine (1
72 mg) is obtained. mp: 104-106 ° C NMR (CDCl ₃ , δ): 2.49, 3.16 (each 3H, s), 5.15 (2H,
s), 6.98 (1H, t, J = 7Hz), 7.39, 8.09 (each 1H, d, J = 7H
z)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location A61K 31/495 ABE 31/50 AAH 31/505 ABN C07D 487/04 140 7019-4C 144 7019-4C (72) Inventor Hirokazu Tanaka 3-10-21 Hanayashiki Manor, Takarazuka-shi

Claims (2)

[Claims] 1. A general formula: [Wherein R ¹ is hydrogen, a lower alkyl group, a lower alkenyl group, a hydroxy lower alkyl group, a substituted hydroxy lower alkyl group, a lower alkylthio group, a hydroxy group,
A lower alkoxy group, a halo lower alkyl group, an acyl group or halogen, R ² represents hydrogen, a lower alkyl group, a halo lower alkyl group, an acyl group or an aryl group, or R ¹ and R ² are bonded to each other. To form a lower alkylene group, R ³ is hydrogen, a lower alkyl group, a halo lower alkyl group or an acyl group, R ⁴ is an aryl group which may have a suitable substituent, and a suitable substituent. Optionally a lower alkyl group or a heterocyclic group optionally having a substituent, a compound of the formula: Is And Q is O, NH, S, SO, SO ₂ , CO
O or lower alkenylene group, X ¹ is N or C—R
⁵ , R ⁵ are hydrogen or halogen, X ² , X ³ , and X ⁴ are N or CH, and Y ¹ and Y ² are single bond or lower alkylene group. ] The heterocyclic compound shown by these, and its salt. 2. A preventive and / or therapeutic agent for a disease induced by bradykinin or an analog thereof, which comprises the compound according to claim 1 or a salt thereof as an active ingredient.