JPH07507296A - Oxazole derivatives and their use as anti-ulcer agents and H2-receptor antagonists - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Oxazole derivatives and their use as anti-ulcer agents and R2-receptor antagonists Technical field The present invention relates to novel compounds and pharmaceutically acceptable salts thereof.

More specifically, the present invention provides novel antiulcer and R3 receptor antagonistic activities. standard oxazole derivatives and pharmaceutically acceptable salts thereof; and a method for treating ulcers in humans or animals. .

Disclosure of invention The object of the present invention is to develop novel oxalamines possessing anti-ulcer activity and R2-receptor antagonistic activity. An object of the present invention is to provide sol derivatives and pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a method for producing the oxazole derivative and its salt. There are many things.

Furthermore, the object of the present invention is to provide the oxazole derivative or its pharmaceutically acceptable salt. An object of the present invention is to provide a pharmaceutical composition containing it as an active ingredient.

Furthermore, it is an object of the present invention to provide a therapeutic method for treating ulcers in humans or animals. It is about providing law.

The oxazole derivative of the present invention is novel and is represented by the following general formula (1).

(In the formula, R1 may have an appropriate substituent; R2 and R3 are each an aliphatic hydrocarbon group which may have dihydrogen or a suitable substituent, A is lower alkylene, and Y means pyridinediyl or furandiyl) target compound (1) or its The salt can be produced by the production method explained in the reaction formula below.

K Gota earth (!I) or its salt or its salt Atsushita Mata or its salt (+-2) or its salt Manufacturing method (+-2) or its salt (+-1) or its salt Atsushi's infestation ([-2) or its salt (+-3) or its salt Atsushi Kentago ni erasure 1 The next day sent to Arrangement ■ ([-2) or its salt Shobutsu launches Atsushi Hirototo Manufacturing method 1 prong Next day's chief priest Production method top soil Shodota Jodan manufacturing method souvenirs (In the formula, R', R', R', A and Y have the same meanings as above, and R' a is anora amino, R'b is acylamino with a protected hydroxy, R'c is with a hydroxy acylamino, R4 is hydrogen, cyano, nitro or acyl, R8 is hydrogen, acyl lukylthi, protected hydroxy or amino acid which may have suitable substituents. of, R'a is amino which may have a suitable substituent, R@ is lower alkyl or aryl. reel, R7 is an amino protecting group, R=, R11, R13 and R14 are each lower alkyl, R9 is protected Hydroxy, R” is hydrogen or lower alkyl, R12 is a heterocyclic group, Rls is acyl, X is =CH- or =N-1 Xl is S or 0, Zl is halogen or acyloxy, and Z2. Z3 and Z4 are each acid In the above and later descriptions of this specification, there are Preferred examples of the various definitions involved are described in detail below.

“The term lower J refers to carbon atoms containing 1 to 6 carbon atoms, preferably carbon atoms, unless otherwise specified. It means a group having 1 to 4 children.

"Aliphatic hydrocarbon group" is 1 to 10, preferably 1 to 6, more preferably 1 Saturated or unsaturated, straight-chain or branched aliphatic hydrocarbons containing ~4 carbon atoms means an elementary group.

Suitable "aliphatic hydrocarbon groups" include alkyl (e.g. methyl, ethyl, Lopyl, isopropyl, butyl, isobutyl, 5ec-butyl, tert-butyl pentyl, neopentyl, isopentyl, tert-pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), alkenyl (e.g. vinyl, l- propenyl, allyl, 1-methylallyl, 1 or 2 or 3-butenyl, l or or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5- hexenyl), and alkynyl (e.g. ethynyl, 1-propynyl, propynyl), Pargyl, l-methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, l or 2 or 3 or 4 or 5-/\ xynyl, etc.).

Preferred “substituents” for “aliphatic hydrocarbon groups that may have appropriate substituents” lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy) xy, butoxy, isobutoxy, tert-butoxy, pentyloxy, neope pentyloxy, tert-pentyloxy, hexyloxy, etc.), (C, -C, ) Cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohebutyl, etc.), mono- or di- or trihalo(lower) atom (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, lolomethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl tribromomethyl, l or 2-fluoroethyl, ■ or 2-bromoethyl 1- or 2-chloroethyl, I, 1-difluoroethyl, 2,2-difluoroethyl (loethyl, etc.), halogen (e.g., chlorine, bromine, fluorine, iodine), carboxy , protected carboxy, hydroxy, protected hydroxy, suitable substituents ( For example, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, etc.) aryl (e.g., phenyl, naphthyl, etc.), nitro, amino, which may have protected amino, di(lower) alkylamino (e.g. dimethylamino, diethylamino, diisopropylamino, ethylmethylamine isopropylmethylamino (ruamino, ethylpropylamino, etc.), acyl, cyano, mercapto, lower alkyl Killthio (e.g. methylthio, ethylthio, propylthio, isopropylthio) , butylthio, etc.), imide, and heterocyclic groups.

Suitable "lower alkyl" includes methyl, ethyl, propyl, isopropyl, Butyl, isobutyl, 5ec-butyl, tert-butyl, pentyl, isopene Straight chain or branched C,-C,alkyl such as thyl, neopentyl, hexyl, etc. C+C-alkyl is preferred.

Suitable [lower alkoxy] include methoxy, ethoxy, propoxy, and isopoxy. Examples include ropoxy, butoxy, pentyloxy, hexyloxy and the like.

Suitable "lower alkylthio" include methylthio, ethylthio, and propylthio. , isopropoxy, butylthio, isobutylthio, tert-butylthio, Examples include thiolthio, hexylthio, and the like.

Suitable acid residues include halogens such as chlorine, bromine, fluorine and iodine. can be mentioned.

Suitable "halogens" include chlorine, bromine, fluorine and iodine.

Suitable "lower alkylenes" include methylene, ethylene, trimethylene, and propylene. Straight chain or is a branched lower alkylene, preferably a C,-C4 alkylene, most preferably a branched lower alkylene; Includes tyrene and ethylene.

Suitable "amino which may have a suitable substituent" is a group commonly used in the pharmaceutical field. amino, mono- or di(lower) alkylamino (e.g. methylamine tylamino (artificial thylamino, butylamino, etc.), lower alkenylamino (e.g. vinylamine propenylamino, etc.), lower alkynylamino (such as ethynyl hydroxy (lower) alkylamino (e.g., human propynylamino), Droxymethylamino, hydroxyethylamino, hydroxypropylamino, etc. ), lower alkoxy (lower) alkylamino (e.g. methoxymethylamino, etc.) ), mono- or di(lower)alkylamino(lower)alkylamino (e.g. thylaminomethylamine (dimethylaminoethylamino, etc.), acylamino (acylamino) Protected amino heterocyclic amino (heterocyclic groups are as described below) such as ), one or more, preferably 1 to 3, suitable substituents such as amino and oxo cyclo(lower) alkenylamino [for example, (l-amino-3,4-dio xo-1-cyclobuten-2-yl)amino), etc.], imides (e.g. succinyl imide, phthalimide, etc.), formula: (wherein, X is =CH- or =N-1 R4 is hydrogen, cyanonitro or acyl, and Rs is hydrogen, alkyl group, means protected hydroxy or amino which may have a suitable substituent; Examples include the groups shown in the above and below).

Preferred acyl groups in "acyl" and "acylamino" include carbon Rubamic acid, sulfonic acid, carboxylic acid or carbonic acid and their thioacid derivatives Carbamoyl, thiocarbamoyl, sulfamoyl, fatty acyl, aromatic group acyl, heterocyclic acyl, and even if substituted with aromatic or heterocyclic groups. Examples include good aliphatic acyl.

Fatty acyls include lower alkanoyls (e.g. formyl, acetyl, pro- pionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, xanoyl), lower alkanesulfonyl (e.g. mesyl, ethanesulfonyl) , propanesulfonyl, etc.), lower alkoxycarbonyl (e.g., metquine carbonyl), Bonyl, ethoxycarbonyl, propanesulfonyl, isopropoxycarbonyl , butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl ), lower alkenoyl (e.g., acryloyl, methacryloyl, chlorine, (C,-C7) cycloalkanecarbonyl (e.g. cyclopropyl), (C,-C7)cycloalkanecarbonyl carbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexyl xanecarbonyl, cyclohebutanecarbonyl, etc.), lower alkylthio (e.g. , methoxalyl, ethoxalyl, etc.), lower alkanoylcarbonyl (e.g. Saturated or unsaturated acyclic or cycloaliphatic acyl such as can be lost.

Aromatic acyls include aroyl (e.g. benzoyl, nitrobenzoyl, tribenzoyl), (e.g., benzenesulfonyl), arenesulfonyl (e.g., benzenesulfonyl), , Tosil, etc.).

Heterocyclic acyl includes heterocyclic carbonyl (e.g. furoyl, thenoyl, nicicoyl). Chinoyl, l-oxonicotinoyl, isonicotinoyl, thiazolylcarbonyl , thiadiazolylcarbonyl, tetrazolylcarbonyl, tetrahydrofurica carbonyl, piperidylcarbonyl, morpholinocarbonyl, etc.).

Aliphatic acyl substituted with an aromatic group includes phenyl (lower) alkanoyl ( For example, phenylacetyl, phenylpropionyl, phenylhexanoyl, etc.) , phenyl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl , phenethyloxycarbonyl, etc.), phenoxy(lower)alkanoyl (e.g. , phenylacetyl, phenoxypropionyl, etc.).

Aliphatic acyl substituted with a heterocyclic group includes chenyl acetyl, imidazolyl, Acetyl, furylacetyl, tetrazolylacetyl, thiazolyl acetyl, thia Diazolylacetyl, thenylpropionyl, thiadiazolylpropionyl, etc. Can be mentioned.

These acyl groups may be further substituted with the following suitable substituents. suitable Examples of substituents include hydroxy, amino, guanidino, carboxy, alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, pen) (C,-Ct)cycloalkyl (e.g. cyclopropyl, hexyl, etc.), (C,-Ct)cycloalkyl cyclobutyl, cyclopentyl, cyclohexyl, cyclohebutyl, etc.), low alkenyl (e.g. vinyl, allyl, etc.), halogen (e.g. chlorine, bromine, iodine, fluorine), lower alkoxy (e.g. methoxy, ethoxy, propoxy , isopropoxy, butoxy, pentyloxy, hexyloxy, etc.), lower alkyl Koxycarbonyl(lower)alkoxy (e.g. metonekylponylmethoxy, etc.) ), lower alkylthio (e.g. methylthio, ethylthio, propylthio, iso (propylthio, butylthio, pentylthio, hexylthio, etc.), complex compounds such as those listed below. Barocyclic groups, heterocyclic (lower) alkylthio (e.g. furylmethylthio, thiazinyl) methylthio, etc.), heterocyclic (lower) alkylsulfinyl (e.g., furylmethyl sulfinyl, thiazolylmethylsulfinyl, etc.), nitro, heterocyclic (lower) a alkylaryloxy(low m)alkyl (e.g. pyrrolidinylmethylphenoxy) cypropyl, etc.), acyl as mentioned above, protected amino (the amino protected part is ), aryl (e.g., phenyl), aroyl (e.g., benzoyl), ), aryl (e.g., benzyloxy, tolyloxy, etc.), acyloxy, For example, lower alkanoyloxy (e.g., formyloxy, acetyloxy, ropionyloxy, butyryloxy, isobutyryloxy, valeryloxy, i protected substances such as sovaleryloxy, pivaloyloxy, hexanoyloxy, etc.) hydroxy, lower alkylamino (e.g., methylamino, dimethylamino) tylamino, etc.), amino protecting groups described below, and the like. A suitable replacement like this Suitable examples of acyl having groups include lower alkoxy (lower) alkanoyl ( For example, methoxyacetyl, ethoxyacetyl, etc.), lower alkoxycarbonyl (e.g., tert-butoquinocarbonyl, etc.), lower alkanoylamino (lower ) alkanoyl (e.g. acetoxyacetyl, acetoxypropionyl, etc.), N-lower alkylcarbamoyl (e.g., N-methylcarbamoyl, N-ethyl carbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, etc.) , aroylthiocarbamoyl (e.g. benzoylthiocarbamoyl, etc.), complex Cyclic (lower)alkylthio(lower)alkanoyl (e.g., furylmethylthioacetate) N-lower alkylthiocarbamoyl (e.g. N-methylthiocarbamoyl), N-lower alkylthiocarbamoyl (e.g. moyl, etc.), halo(lower)alkanoyl (e.g., trifluoroacetyl, etc.), Hydroxy (lower) alkanoyl (e.g. hydroxyacetyl, etc.), amino ( (lower) alkanoyl (e.g., aminoacetyl, etc.), lower alkylamino (lower ) alkanoyl (e.g. dimethylaminoacetyl, etc.), lower alkylthio (lower alkanoyl (e.g., methylthioacetyl, etc.), lower alkoxycarbonyl (lower)alkoxy(lower)alkanoyl (e.g., methoxycarbonylmeth) quinacetyl, etc.), N-lower alkoxycarbonylamino (lower) alkanoyl (for example, N-t-ptoxocarponylaminoacetyl, etc.), lower alkyl (C 2-C,)cycloalkanecarbonyl (e.g., methylcyclopropanecarbonyl) ), N-aminocarbamoyl, N-guanidinocarbamoyl, N-lower alkyl Examples include kylsulfamoyl (eg, N-methylsulfamoyl, etc.).

Preferred "heterocyclic groups" and preferred "heterocyclic groups" and "heterocyclic thio" As a heterocyclic moiety, a heteroatom such as an oxygen atom, a sulfur atom, a nitrogen atom, etc. A saturated or unsaturated monocyclic or polycyclic heterocyclic group having at least one It will be done. Particularly preferred heterocyclic groups are 5- or 6-membered aromatic heteromonocyclic groups (e.g. lolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiadiazolyl, etc.), 5- or 6-membered aliphatic heteromonocyclic groups (e.g. morpholinyl, pyrrolidinyl, imi dazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, dithiacyclopene ), unsaturated fused heterocyclic groups having 1 to 3 nitrogen atoms (such as benzoyl), midazolyl, etc.), unsaturated containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms Fused heterocyclic groups (e.g., benzothiazolyl, benzisothiazolyl, benzothia diazolyl, etc.). The heterocyclic moiety defined in this way is H. Suitable substituents such as halogen such as chlorine, lower alkyl as defined above It may have. Suitable examples of heterocyclic groups having substituents include amino and and lower alkyl (e.g., 3-amino-1-methyl-IH -thiazol-5-yl, etc.), triazolyl containing amino (e.g., 3-amino), -IH-thiazolyl-5-yl, etc.), benzisothiazolyl with oxo ( For example, 1,1-dioxobenziisothiazine, etc.) can be mentioned.

Suitable "imides" include succinimide, phthalimide, and the like.

"Suitable amino protecting groups for protected amino J include benzyl, benzyl Aryl (lower) alkyl such as hydryl, phenethyl, etc., and An example is acyl.

Suitable hydroxy protecting groups for "protected hydroxy" include the above-mentioned sil, aryl (lower) alkyl (e.g. benzyl, trityl, etc.), lower alkyl koxy(lower)alkyl (e.g., methoxymethyl, ■-methyl-1-methoxy ethyl, methoxypropyl, etc.), tetrahydropyranyl, aryl (e.g. phenyl, etc.), lower alkyl (eg, methyl, ethyl, etc.), and the like.

Suitable "acylamino having a protected hydroxo" is as exemplified above. protected hydroxy-substituted acylamino (as above), e.g. , lower alkanoyloxy (lower) alkanoylamino (e.g. acetoxy Protected hydroxy (lower) alkanoylamino such as cetyl amino, etc.) Can be mentioned.

Preferred "hydroxy-containing acylamino" is an acylamino substituted with hydroxy. amino (as above), e.g. hydroxy(lower)alkanoylamino (For example, hydroxyacetylamino, etc.).

Suitable "acylamino having a protected amino" are the above-mentioned protected amino acids. amino and substituted anora-amino (as above), e.g. lower alkoxy Cycarbonylamino (lower) alkanoylamino (e.g. t-butoxycarboxylamino) Protected amino (lower) alkanoids such as nylaminoacetylamino, etc.) Ruamino is mentioned.

Suitable “acylamino with amino” is an amino-substituted acylamino ( (as described above), for example, amino(lower)alkanoylamino (e.g. (minoacetylamino, etc.).

Suitable examples of "r(CsCt)cycloalkyl" include cyclopropyl, cycloalkyl, Examples include butyl, cyclopentyl, cyclohexyl, cyclohebutyl, and the like.

Suitable "lower alkenyl" includes vinyl, l-propenyl, allyl, 1-methyl Tyrallyl, 1 or 2 or 3-butenyl, ■ or 2 or 3 or 4-peneyl entenyl, 1 or 2 or 3 or 4 or 5-hexenyl, and the like.

Suitable "lower alkynyl J" includes ethynyl, l-propynyl, propargyl , 1-methylpropargyl, l or 2 or 3-butynyl, ■ or 2 or 3 or 4-pentynyl, l or 2 or 3 or 4 or 5-hexynyl, etc. Can be mentioned.

Suitable "aryl" include phenyl, tolyl, quinryl, mesityl, cumenyl. and naphthyl, preferably C, -C, and the like. It is an aryl.

Preferred examples of acyloxy include aliphatic acyloxy and aromatic acyloxy. Examples include shi. As aliphatic acyloxy, lower alkanoyloxy (e.g. acetyloxy, propionyloxy, etc.), lower alkylsulfonyloxy (For example, mesyloxy, ethanesulfonyloxy, etc.). aromatic As acyloxy, aroyloxy (e.g. benzoyloxy, tolyloxy) oxy), arenesulfonyloxy (e.g. benzenesulfonyloxy, tolyloxy, etc.).

"Pyridinediyl" means divalent pyridine such as pyridine-2,6-diyl. Taste. “Frandiyl” refers to divalent furans such as furan-2,5-diyl. means.

Suitable pharmaceutically acceptable salts of the target compound (1) are conventional non-toxic salts and organic Acid addition salts (e.g., formate, acetate, trifluoroacetate, maleate, tartrate) acid salts, methanesulfonates, benzenesulfonates, toluenesulfonates, etc.) , inorganic acid addition salts (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.), acidic Examples include salts with amino acids (e.g. aspartate, glutamate, etc.) Ru.

Regarding the salts of compounds (1-1) to (T-17) in Production Method 1-16, this These compounds are also included in the scope of compound (1), and therefore, these compounds For suitable examples of salts of compounds, see those exemplified as salts of target compound (I). do it.

In particular, preferred examples of R1, R1, R3 and A are shown below.

R1 is amino; lower alkanoylamino (e.g. acetylamino), lower alkanoyl Rukoxycarbonylamino (e.g., ethoxycarbonylamino, etc.), lower alkyl Kanoyloxy(lower)alkanoylamino (e.g., acetoxyacetylamino) ), ureido and lower alkylureido (e.g. 3-methylureido etc.) ), or guanidino (e.g. 2-cyano-3-methyl Guanidino etc.): R2 is hydrogen: alkyl (e.g. methyl, n-butyl, isobutyl, n-pentyl lower alkyl, isopentyl, n-hexyl, n-hebutyl, n-octyl, etc.) Kenyl (e.g., vinyl, etc.), lower alkynyl (e.g., propargyl, etc.): Low alkoxo(lower)alkyl (e.g. methoxyethyl, etc.); mono or dimeric or trihalo(lower)alkyl (e.g. 2. 2. 2-trifluoroethyl etc.): (Ct-C,)cycloalkyl(lower)alkyl (e.g. cyclopropyl lower alkylthio (lower)alkyl (methylthioethyl, etc.); Ryl (lower) alkyl (e.g. 2-phenylethyl etc.) R3 is hydrogen: and A is lower alkylene (eg, methylene, etc.).

The method for producing the object compound (1) of the present invention will be explained in detail below.

Manufacturing method I The target compound (1) or a salt thereof is obtained by combining compound (m or a salt thereof with compound (IID) It can be produced by reaction.

This reaction usually involves ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, Tetrahydrofuran, N, N-dimethylformamide, N, N-dimethyla Cetamide, dioxane, water, alcohol (e.g. methanol, ethanol, etc.) ), acetic acid, formic acid, etc., or their common solvents that do not adversely affect the reaction. It is carried out in a mixed solvent.

Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling to heating.

Alternatively, the target compound (1) or a salt thereof can be converted into a compound (II) or a salt thereof. It can be produced by reacting with compound (IV).

This reaction is preferably carried out in the presence of a base or acid. Suitable bases and acids Please refer to the explanation of manufacturing method 2.

The reaction is usually carried out using ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, or tetrachloromethane. Lahydrofuran, N, N-dimethylformamide, N, N-dimethylacetate Amides, dioxane, water, alcohols (e.g. methanol, ethanol, etc.), Commonly used solvents that do not adversely affect the reaction, such as acetic acid, formic acid, etc., or a mixture thereof carried out in a solvent.

Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling to heating.

The target compound (1-2) or a salt thereof is obtained by deacylating the compound (1-1) or a salt thereof. It can be produced by subjecting it to a chemical reaction.

Suitable methods for this deacylation reaction include conventional methods such as hydrolysis and reduction. It will be done. Hydrolysis is preferably carried out in the presence of a base or an acid.

Suitable bases include, for example, alkali metal hydroxides (e.g. sodium hydroxide, hydroxide potassium oxide, etc.), alkaline earth metal hydroxides (e.g., magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonates (e.g., sodium carbonate, carbonate alkaline earth metal carbonates (e.g. magnesium carbonate, calcium carbonate, etc.), alkaline earth metal carbonates (e.g. magnesium carbonate, calcium carbonate, ), alkali metal bicarbonates (e.g., sodium bicarbonate, alkali metal acetates (e.g., sodium acetate, potassium acetate, etc.) , alkaline earth metal phosphates (e.g. magnesium phosphate, calcium phosphate etc.), alkali metal hydrogen phosphates (e.g., disodium hydrogen phosphate, phosphoric acid water) inorganic bases such as dipotassium), and tri(lower)alkylamines (e.g. (e.g., trimethylamine, triethylamine, etc.), picoline, N-methylpyrroli gin, N-methylmorpholine, 1. 5-diazabicyclo(4,3,0) nona- 5-one, 1, 4-diazabicyclo[2,2°2]-octane, 1. 5-ji Examples include organic bases such as azabicyclo(5,4,0)undecene-5 and the like.

Hydrolysis using bases is often performed using water or hydrophilic organic solvents or mixtures thereof. Hydrochloric acid (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, etc.) may be used in the mixed solvent.

This hydrolysis is usually carried out in an organic solvent, water or a mixed solvent thereof.

The reaction temperature is not particularly limited, but the reaction is usually carried out at room temperature or at or under heating. It will be done.

Manufacturing method 3 The target compound (1-1) or a salt thereof is an acyl compound (1-2) or a salt thereof. It can be produced by reacting with a curing agent.

Can compound (T-2) be used in the form of a commonly used reactive derivative at the amino group? I'll come.

The acylating agent has the formula: %formula%( (wherein R'' means acyl as defined above) and its hydride It is a commonly used reactive derivative of the roxy group.

Suitable examples include acid halides (e.g. acid chlorides, etc.), acid anhydrides, activated Examples include amides, activated esters, and the like.

When the acyl group to be introduced is a carbamoyl type acyl, the acylating agent is usually cyanide. used in the form of salts or isocyanates.

This reaction typically involves water, alcohol (e.g., methanol, ethanol, etc.), Setone, dioxane, acetonitrile, chloroform, dichloromethane, ethyl chloride Tyrene, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, Commonly used solvents such as N, N-dimethylacetamide, pyridine, acetic acid, or reactions in other organic solvents that do not adversely affect the These commonly used solvents are water and It can also be used as a mixed solvent.

Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling to heating.

This reaction also works with alkali metal bicarbonates, tri(lower)alkylamines, gin, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzi The reaction may also be carried out in the presence of an inorganic or organic base such as amine, etc.

Manufacturing method 4 Target compound (T-3) or a salt thereof is obtained by converting compound (1-2) or a salt thereof into a compound It can be produced by reacting with (V).

This reaction is typically performed using an alcohol (e.g. methanol, ethanol, propane). ), tetrahydrofuran, dioxane, dimethyl sulfoxide, N, N- Commonly used solvents that do not adversely affect the reaction, such as dimethylformamide, or It is carried out in a mixed solvent of

The reaction temperature is not particularly limited, and the reaction is usually performed at room temperature or at or under heating. It will be done.

Manufacturing method 5 The target compound (1-4) or a salt thereof is obtained by converting the compound (1-3) or a salt thereof into a compound. It can be produced by reacting with (Vl).

This reaction is typically performed using an alcohol (e.g. methanol, ethanol, propane). ), tetrahydrofuran, dioxane, dimethyl sulfoxide, N, N- Commonly used solvents that do not adversely affect the reaction, such as dimethylformamide, or It is carried out in a mixed solvent of

When compound (Vl) is a liquid, it can also be used as a solvent.

The reaction temperature is not particularly limited, and the reaction temperature is usually room temperature, heating, or under heating. Compound (T-6) or a salt thereof can be obtained by hydrolyzing compound (I-5) or a salt thereof. It can be produced by subjecting it to a reaction.

This reaction is usually carried out according to the conventional method of converting a nitrile into an amide.

This reaction typically involves water, alcohol (e.g. methanol, ethanol, propane tools, etc.), tetrahydrofuran, dioxane, dimethyl sulfoxide, N.

Commonly used solvents that do not adversely affect the reaction such as N-dimethylformamide or It is carried out in a mixed solvent thereof.

The reaction temperature is not particularly limited, but the reaction temperature is usually room temperature, heating, or under heating. Compound (1-8) or a salt thereof is an amino-binding compound (1-7) or a salt thereof. It can be produced by subjecting it to a protective group elimination reaction.

Just look at it.

Manufacturing method 8 Target compound (1-9) or a salt thereof is obtained by converting compound (T-8) or a salt thereof into a compound It can be produced by reacting with (V[+).

This reaction can be carried out in substantially the same manner as Production Method 1. For the reaction method and reaction conditions (e.g. solvent, reaction temperature, etc.), see the explanation of production method I. do it.

Manufacturing method 9 Target compound (1-10) or a salt thereof is obtained by combining compound (I-2) or a salt thereof. It can be produced by reacting with a substance (VIm).

This reaction is typically performed using an alcohol (e.g. methanol, ethanol, propane). ), tetrahydrofuran, dioxane, dimethyl sulfoxide, N, N- Commonly used solvents that do not adversely affect the reaction, such as dimethylformamide, or It is carried out in a mixed solvent of

The reaction temperature is not particularly limited, but the reaction usually takes place at room temperature or at or under heating. It will be done.

Manufacturing method IO Target compound (1) or a salt thereof is obtained by converting compound (IX) or a salt thereof into compound (X) Alternatively, it can be produced by reacting with a salt thereof.

This reaction can be carried out in substantially the same manner as Production Method 5, so For the reaction method and reaction conditions (e.g., solvent, reaction temperature, etc.), see the explanation of Production Method 5. do it.

Manufacturing method 11 The target compound (+-12) or its salt is the compound (1-11) or its salt. It can be produced by reacting with compound (Xl).

This reaction is typically performed using an alcohol (e.g. methanol, ethanol, propane). ), tetrahydrofuran, dioxane, dimethyl sulfoxide, N, N- Commonly used solvents that do not adversely affect the reaction, such as dimethylformamide, or It is carried out in a mixed solvent of

The reaction temperature is not particularly limited, or the reaction usually occurs at room temperature or at or under heating. It will be done.

Manufacturing method 12 Target compound (1-13) or a salt thereof is obtained by combining compound (I72) or a salt thereof. It can be produced by reacting with compound (XI or a salt thereof).

This reaction typically involves water, acetone, dioxane, acetonitrile, chloroform, Dichloromethane, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-di Commonly used like methylformamide, N, N-dimethylacetamide, pyridine or other organic solvents that do not adversely affect the reaction. these The commonly used solvents can also be used as mixed solvents with water.

Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling to heating.

This reaction also works with alkali metal bicarbonates, tri(lower)alkylamines (e.g. (eg, triethylamine, etc.), pyridine, N-(lower) alkylmorpholine, N.

In the presence of an inorganic or organic base such as N-di(lower)alkylbenzylamine etc. Target compound (XIV) or a salt thereof is obtained by converting compound (1-8) or a salt thereof into a compound (Xllll) or a salt thereof.

This reaction is typically performed using an alcohol (e.g. methanol, ethanol, propane). ), tetrahydrofuran, dioxane, dimethyl sulfoxide, N, N- Commonly used solvents that do not adversely affect the reaction, such as dimethylformamide, or It is carried out in a mixed solvent of

The reaction temperature is not particularly limited, but the reaction temperature is usually room temperature, heating, or under heating. Compound (1-14) or a salt thereof is a compound (XIV) or a salt thereof. It can be produced by reacting with (XV) or a salt thereof.

This reaction can be carried out in substantially the same manner as Production Method 5, so For the reaction method and reaction conditions (e.g., solvent, reaction temperature, etc.), see the explanation of Production Method 5. do it.

Manufacturing method 15 The target compound (1-16) or a salt thereof is a compound (1-15) or a different salt. can be produced by subjecting it to an elimination reaction of the hydroxy protecting group.

This reaction can be carried out in substantially the same manner as Production Method 2. The reaction method and reaction conditions (e.g. solvent, reaction temperature, etc.) (see the explanation of am2 next day) Just refer to it.

Manufacturing method 16 The target compound (1-17) or a salt thereof can be obtained by converting the compound (1-2) or another salt. It can be produced by reacting with a compound (XVD or a salt thereof).

This reaction is typically performed with an alcohol (e.g., methanol, ethanol, bromine, etc.) ), tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethyl fluoride, etc.), tetrahydrofuran, dioxane, dimethyl sulfoxide, Adversely affects reactions like Lumamide 1! Sana t1 commonly used solvents (others) It is carried out in a mixed solvent.

The reaction temperature is not particularly limited, but usually cs+ is heated at room temperature or under heat. The reaction takes place.

This reaction can also be used for tri(lower) ryuki J raremin((?Iet!,)IJ ethyl It may also be carried out in the presence of an inorganic or organic base such as an amine (1).

Although some of the above starting compounds are new, such compounds (as prepared below (F The method described herein or any known method for producing structurally similar compounds It can be manufactured from this method.

For example, compound (11) can be synthesized by the following steps.

(In the formula, A1 is lower alkylene, R'a is acylamino, Z’a is halogen, and Zlb means acyloxy) The compounds obtained by the above production methods 1 to 16 are subjected to pulverization, recrystallization, column chromatography, It can be isolated and purified by conventional methods such as precipitation and reprecipitation.

Each target compound (1) has an optical anisotropy based on an asymmetric carbon atom or a double bond. Although stereoisomers such as sexual or geometric isomers may exist, such isomers and and mixtures thereof are all included within the scope of this invention.

Furthermore, regarding compound (1), the following formula (A) has a tautomeric relationship with the following formula (B). It is well known that these isomers are essentially the same. It is.

Therefore, both these tautomeric forms are clearly included within the scope of the present invention. herein In this case, the target compound and the starting compound are combined into one structure, including such tautomers. It is expressed using the formula.

The novel oxazole derivatives ()) and pharmaceutically acceptable salts thereof of the present invention have anti-ulcer properties. It has tumor activity and Hl-receptor antagonistic activity, and is associated with gastritis, ulcers (e.g. gastric ulcers, (denal ulcer, anastomotic ulcer, etc.), Zollinger-erinone (Zollinger ulcer) -ε1lison) syndrome, reflux esophagitis, upper gastrointestinal bleeding, etc. Ru.

Furthermore, the compound (1) of the present invention and its pharmaceutically acceptable salt are Helco Pathogenic microorganisms such as B. pylori (recently, human gastric mucus gel It has strong antibacterial activity against gram-negative rods discovered in

For therapeutic purposes, the compounds of the present invention (D and their pharmaceutically acceptable salts) may be administered orally or Pharmaceutically acceptable such as organic or inorganic solid or liquid excipients suitable for parenteral administration in the form of a pharmaceutical preparation containing said compound as an active ingredient in admixture with a suitable carrier. can be used. Pharmaceutical preparations include capsules, tablets, sugar-coated tablets, granules, and Liquids, suspensions, emulsions and the like can be mentioned. Supplements in these preparations as desired ingredients, stabilizing agents, wetting agents or emulsifying agents, buffering agents and other commonly used additives. Additives may also be included.

The dosage of compound (T) varies depending on the age and condition of the patient, but ) average single dose of approximately 0. 1mg, 1mg, I Omg, 50mg5100m g, 250 mg, 500 mg and 1000 mg are effective in treating ulcers. one Generally, doses of 0.1 mg/individual to about 1,000 mg/individual should be administered per day. Bye.

In order to demonstrate the usefulness of target compound (1), pharmacological tests of representative compounds of compound (1) were conducted. The experimental results are shown below.

test compound (a) 4-(6-acetylaminomethylpyridin-2-yl')-2-((ami (b) (n-butylamino)methyleneaminocooxazole (b) 4=(6-acetic acid tylaminomethylpyridin-2-yl)-2-((amino)(isobutylamino) ) Methyleneaminocooxazole (c) 4-(6-acetylaminomethylviridi) (n-2-yl)-2-((amino)(n-pentylamino)methyleneaminocho Xazole (d) 4-(6-acetylaminomethylpyridin-2-yl)-2- ((amino)(n-hexylamino)methyleneamino)oxazole(e)2- ((amino)(n-butylamino)methyleneamino)-4-(6-ureitomethyl Lupyridin-2-yl)oxazole test A (H2 in isolated guinea pig atria) - receptor antagonism): test method An atrial fragment removed from a guinea pig is placed in an organ containing Tyrode's solution. In a bath at 30°C 195% 02-5% CO2 ventilation condition, initial tension 0. 3-0. Suspended with 6g. Using a transducer and polygraph to measure the atrial rate and The contraction amplitude was recorded. Histamine (1XI O”g/mI) was added to the bath solution. , the increase in heart rate after administration was measured. of test compound (l x I O"@g/ml) The addition was made 30 minutes after washing away the histamine. Before administration of test compound and administration 30 The inhibitory effect of the test compound was determined by comparing the histamine-induced increase in beat rate after 1 min. I calculated it.

Test B (gastric acid secretion from the perfused stomach in anesthetized rats) Test method Sprague-Dawley male rat (weight 2 50 g) was used. Rats were fasted for 24 hours (but had free access to water). set). Rats were anesthetized by intraperitoneal administration of 1.25 g/kg urethane. Ta. The abdomen was opened and the gastric cavity was perfused with saline throughout the study. 25mM sodium hydroxide The perfusate was titrated using an automatic titrator using Lithium as the titrant. Gastric acid secretion is hiss Induction was induced by intravenous infusion of tamin (3 mg/kg/hour). reached a plateau Thereafter, the test compound (1 mg/kg) was administered intravenously. The drug efficacy is the maximum inhibition rate of acid secretion It was shown.

Test C (HCI-Aspirin Ulcer Inhibition) Test Method Sprague-Dawley male rats (6 weeks old, After fasting for 24 hours, a group of 7 animals weighing 200 g (weight: 200 g) was subjected to an HCl-aspirin ulcer test. used in the experiment. Each test compound (32 mg/kg) was administered at 0. 1% methylcellulose It was suspended in a solution and administered orally 30 minutes before aspirin administration. 0.2N HCI included [Aspirin suspended in 0.1% methylcellulose solution, 200mg/kg/l It was administered orally at a dose of 0 ml.

One hour later, the rats were sacrificed and the stomachs were removed. The stomach was fixed in 2% formalin. Each movement Measure the length of the ulcer on the object, and calculate the average length of the ulcer between the control animal and the test animal (m). The inhibition rate was calculated by comparing m).

In vitro antibacterial activity was measured by the agar dilution method. The test strain was added to 3% horse blood. Brucella broth agar containing starch and 2% starch 7% horse preincubation at 37°C for 14 days and containing each test compound in a 2-fold dilution series. 10’ cfu/ with a multipoint replicator on platelet-added Pulsella agar ml was inoculated and cultured at 37°C for 3 days. Cultivation is performed in a 10% CO2 atmosphere. It was. After culturing, the minimum drug concentration at which colony growth was inhibited was determined by microscopic observation as MIC. And so. The data below shows the MIC against clinical isolates.

MIC (μg/ml) The present invention will be explained in further detail with reference to Production Examples and Examples below.

Manufacturing example 1 2-acetylaminomethyl-6-bromoacetylpyridine (135.0g) and A mixture of potassium acetate (97.7 g) and potassium acetate (97.7 g) in acetone (2.0 J) was refluxed for 14 hours. Heated under flowing water. The solvent was removed by concentration under reduced pressure. Add ethyl acetate and A mixture of water and water was added, and the pH was adjusted to 0 with a 20% aqueous potassium carbonate solution. separation The organic layer was washed with brine and dried over magnesium sulfate. By concentrating the solvent The residue was triturated in ethyl acetate to give 2-acetylaminomethyl-6-acetate. Doxyacetylpyridine (94.5g) was obtained.

Melting point: 116-118℃ IR (Nujol): 3240. +740.1715.1640cm -'NMR (DMSO-d,, δ): 1.94 (3H, s), 2.16 (3H, s).

4.43 (2) 1. d, J=5.9Hz), 5.58 (2H,s), 7.60 (IH, d, J = 7.5Hz).

7.84 (IH, d, J=7.5Hz), 8.01 (lH, t, J= 7.5Hz).

8.52 (IH, t, J=5.9Hz) Production example 2 Sodium dicyanamine (25,0 g) was dissolved in 2-methoxyethylamine (22,2 m1) and concentrated hydrochloric acid (21,3 ml) (7) solution and stirred at 95-100″c Stir for hours. Water was added to the mixture, and the mixture was extracted with chloroform.

The extract layer was dried over magnesium sulfate and the solvent was removed by concentration under reduced pressure.

The residue was recrystallized from a mixed solvent of dioxane and ethyl acetate to give 2-cyano-1- (2-methoxyethyl)guanidine (12.8 g) was obtained.

Melting point: 84-85°C [R (nujia-ru'): 3300.　3150.　2180. 1655 Cm-'N&lR(D!1lso-d,,δ): 3.18-3.30 (2 ratio m), 3.25 (3H, s).

3.31-3.42 (2H, m), 6.67 (2H, s), 6.80 (IH,s) Example 1 2-acetylaminomethyl-6-acedoxyacetylpyridine (3,0 g), N -cyanodiaminomethyleneamine (1,0 g) and 5N hydrochloric acid (5,3 ml) The mixture in dioxane (9ml) was stirred at room temperature for 19 hours.

A mixture of ethyl acetate, tetrahydrofuran and water was added to the reaction mixture for 20 minutes. The pH was adjusted to 9.5 with a % potassium carbonate aqueous solution. Wash the separated organic layer with brine. and dried with magnesium sulfate.

The residue obtained by evaporating the solvent was subjected to silica gel column chromatography (eluent column chromatography). It was purified with loloform:methanol=9:1 v/v).

Collect the eluted fractions containing the desired product and evaporate the solvent under reduced pressure. Ta. Dissolve the residue in a mixed solvent of methanol, dioxane and diisopropyl ether. 4-(6-acetylaminomethylpyridin-2-yl)-2-(di Aminomethyleneamino)oxazole (0.75g) was obtained.

Melting point + 215-216℃ (decomposition) IR (Nujol): 3275. 1655.　1630.　1600　c m-'NMR (DMSO-d,, δ): 1.92 (3H, s), 4. 34 (2H, d, J=5.9)1z).

6.92 (4H, s), 7.14 (IH, d, J=7.0Hz), 7 ．． 65 (IH, d, J=7.0Hz>.

7.78 (IH, t, J=7.0H2), 7.90 (IH, s), 8 ．． 44 (IH, t, J=5.9Hz) Elemental analysis C1□H,, N, O, ・1 /IOH! Calculated value of O: C52, 20, H5, +8. N 30.44. ot o　o,es Actual value: C52, 35, H5, 21, N 30.14. H2O0 ,71 Example 2 The following compound was obtained in the same manner as in Example 1.

(+)4-(6-acetylaminomethylpyridin-2-yl)-2-((amino )(Methylamino)methyleneamino)oxazole Melting point: 214-215°C [R (Nujol): 3350.3250.　3180.　1640. 1 605c+n-'NMR (DMSO-d,, δ): 1.93 (3H, s), 2.76 (3H, d, J=4.7Hz).

4.34 (2H, d, J = 5.9Hz), 7.15 (IH, d, J = 5.7 )1z), 7.41 (2H,s).

7.65 (IH, d, J=7.5Hz), 7.79 (IH, t, J= 7.5Hz), 7.91 (IH, s).

8.43 (1) 1. t, J=5.9Hz) Elemental analysis C+J+*NgO2 Calculated value: C54,16,)I 5.59. N 29.15 Actual value: C5 3,88,H5,40,N 28.91 (2) 4-(6-acetylaminomethyl pyridin-2-yl)-2-((amino)(n-butylamino)methyleneamide c) Oxazole melting point: 181-182°C IR (Nujol): 3400.　3340.　3120.　1640.　 1615 cm-'NMR (DMSO-d,, δ) + 0.92 (3H, t , J=7.1H2), 1.26-1.64 (4H, m).

1.93 (3H, s), 3.12-3.27 (28, m), 4.34 ( 2H, d, J = 5.91 (z).

7.15 (it(, t, J=7.5Hz), 7.36 (2H, s), 7.62 (II(,d, J=7.5Hz).

7.79 (IH, t, J=7.5)1z), 7.91 (IH, s), 8.44 (1) 1. t, J=5.9Hz) Elemental analysis C,,822N,0 ．．・Calculated value of l/lOH, o ・C57, 85, H6, 74, N 25.30.　 H, OO, 54 actual measurement value: C57, 84, H6, 95, N 25. To, H to0.77(3)4-(6-acetylaminomethylpyridin-2-yl)- 2-((amino)(2-methoxyethylamino)methyleneaminocooxazole Melting point +67-168°C IR (Nujol’): 3400.3300. +645.　1620.　 1600 cm-'NMR (DMSO-d, δ): 1.93 (3H, S), 3.30-3.55 (4H, m).

3.31 (3H, s), 4.35 (2H, d, J=5.9Hz), 7.15 (IH, d,, I=7.5Hz).

7.39 (2H, s), 7.65 (IH, d, J=7.5Hz), 7.79 (IH, t, J=7.5Hz).

7.92 (IH, S), 8.44 (IH, t, J = 5.9H2) elemental content Analysis Calculated value of C+ 5HzNsOs: C54,21,H6,0? , N2 5.29 Actual measurement value: C54,00, H5,87, N 24.89 (4) 4-(6 -acetylaminomethylpyridin-2-yl)-2-((amino)(isobutyl Amino)methyleneamino)oxazole Melting point: 180-181”C IR (Nujol): 3380.3180.　1640. 1600cm -'NMR (DMSO-d,, δ): 0.93 (6) 1. d, J= 6.6Hz), 1.70-1.90 (IH, m).

1.93 (3H, s), 3.04 (2H, t, J=6.2Hz), 4 ．． 35 (2H, d, J=5.9Hz).

7.15 (IH, d, J=7.6Hz), 7.33 (2H, s), 7 ．． 62 (IH, d, J=7.6Hz).

7.79 (IH, t, J=7.6Hz), 7.91 (IH, s), 8 ．． 44 (IH, t, J=5.9Hz) Elemental analysis C+, HzN*02 Calculated value: C58,17, H6,71,N 25.44 Actual value: C58,44 , H6,86,N 25.32 (5) 4-(6-acetylaminomethylpyridine -2-yl)-2-((amino)(n-pentylamino)methyleneamino)oxy Sasol melting point: 178-179℃ [R (Nujol): 3410.3310.　3120.　1670. 1 640. 1610 cm-'NMR (DlilSO-do, δ): 0. 89 (3H, t, J=6.6Hz), 1.24-1.45 (48, m) .

1.45-1.62 (2H, m), 1.93 (3H, s), 3.12-3. 28 (2) 1. m).

4.34 (2H, d, J = 5.9Hz), 7.15 (IH, d, J = 7.4 Hz), 7.35 (2) 1. s).

7.62 (IH, d, J=7.4Hz), 7.79 (IH, t, J= 7.4Hz), 7.91 (IH,s).

8.44 (IH, t, J=5.9Hz) Elemental analysis of C,, H,, N, 02 Calculated value: C59.28, H7.02, N 24.40 Actual value: C59.54 ,H7,21,N 24.1+(6)4-(6-acetylaminomethylpyridine -2-yl)-2-((amino)(isopentylamino)methyleneaminocoki Sasol melting point +61-162°C IR (Nujol): 3380. 3+80.　1640.　1600　c m-'NMR (DMSO-d,, δ): 0.91 (6H, d, J=6 ．． 6) 1z), 1.35-1.50 (2H, m).

1.57-1.80 (2H, m), 1.93 (3H, s), 3.16-3 ．． 29 (2H, m).

4.34 (2H, d, J = 5.9Hz), 7.15 (IH, d, J = 7.5 )1z), 7.35 (2H,s).

7.62 (+8. d, J = 7.5Hz), 7.79 (IH, t, J =7.5Hz), 7.91 (IH,s).

8.44 (IH, t, J=5.9Hz) Elemental analysis of C+7H24N-Ox Calculated value: C59,28, H7,02, N 24.40 Actual value: C59,50, H7,25,N 24.21(7)4-(6-acetylaminomethylpyridine- 2-yl)-2-((amino)(n-hexolamino)methyleneaminocooxa Sol melting point +78-179°C [R (l shawl) + 3420.　3290.　3120. +675.　 1640. 1610 cm-'NMR (DMSO-d,, δ): 0.8 8 (3H, t, J=6.4Hz), 1.20-1.43 (6H, m).

1.43-1.60 (2H, m), 1.94 (3H, s), 3.12- 3.18 (2H, m).

4.36 (2H, d, J=5.9Hz), 7.16 (IH, d, J= 7.5Hz), 7.37 (2H, s).

7.63 (IL d, J=7.5Hz), 7.79 (IH, t, J= 7.5Hz), 7.92 (IH, s).

8.44 (IH, t, J=5.9Hz) Elemental analysis of C,, H,, N, 02 Calculated value: C60,32, H7,3+, N23.45 Actual value: C60,1 6, H7, 64, N 23.26 Example 3 4-(6-acetylaminomethylpyridin-2-yl)-2-(diaminomethylene (amino)oxazole (6,0g) and concentrated hydrochloric acid (18,2ml) in ethanol The warm mixture (60ml) was heated under reflux for 15 hours. Add to the reaction mixture at room temperature Add acetone (180 ml), collect the resulting precipitate by filtration, and Nomethylpyridin-2-yl)-2-(Noaminomethyleneamino)oxazole - Obtained trihydrochloride (6.1 g).

Melting point: 255-257"C [R (l shawl): 3370. 3250.3+70. 3070. + 690.　1630. 1600 cm-'NMR (0, 0, δ): 4. 52 (2H, S), 7.64 (IH, d, J = 7.9Hz).

7.98 (IH, d, J=7.9Hz), 8.18 (IH, t, J=7 ．． 9Hz), 8.39 (+8.s) Example 4 The following compound was obtained in the same manner as in Example 3.

(1) 4-(6-aminomethylpyridin-2-yl)-2-((amino)(methylate) Methyleneaminocooxazole trihydrochloride Melting point: 236-238° C (decomposition) IR (l shawl): 3300.3230.　1690.　1630. 1 610 am-'NMR (D, O, δ): 3.05 (3H, s), 4. 48 (2H, s), 7.59 (IH, d, J = 7.9Hz).

7.96 (IH, d, 7.9Hz), 8.13 (IH, t, J=7 ．． 9Hz), 8.34 (IH, 5) (2) 4-(6-aminomethylpyridine -2-yl)-2-((amino)(n-butylamino)methyleneaminocooxa Sol trihydrochloride Melting point: 164-166℃ IR (l shawl): 3410 (br), +690. 1620 (br) cm-'NMR (DMR, δ): 0.88 (3H, t, J=7.3H z), 1.25-1.48 (2H, m).

1.48-1.70 (2 ratio m), 3.27 (2H, t, J = 7.0Hz) , 4.42 (2H, s).

7.54 (IH, d, J=7.8Hz), 7.84 (1) 1. d, J=7.8Hz).

8.07 (IH, t, J=7.8Hz), 8.28 (IH, 5) (3) 4-'(6-aminomethylpyridin-2-yl)-2-((amino)(n- 7\xylamino)methyleneamino)oxazole trihydrochloride Melting point: 178- 181°C (decomposition) IR (l shawl): 3420.3260.　1700. +630cn + -'NMR (D, 0. δ): 0.90 (3H, t, J = 6.9H z), 1.26-1.57 (6H, m).

1.57-1.84 (2H, m), 3.38 (2) 1. t, J=6. 9Hz), 4.48 (21!, s).

7.58 (IH, d, J=7.8Hz), 7.89 (l) 1. d, J=7.8Hz).

8.10 (IH, t, J=7.8Hz), 8.33 (IH, s) Examples 5 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino ) Oxazole trihydrochloride (2.5g), triethylamine (3.1ml) and and N-dimethylform of dimethyl N-cyanodithioiminocarbonate (1.2 g). A warm mixture of Muamide (50ml) was stirred at room temperature for 4 hours. 40% methylamine An aqueous solution (12.5 ml) was added to the reaction mixture and stirred at the same temperature for 4 hours. after that, The mixture was added to a mixture of ethyl acetate, tetrahydrofuran and water. separated The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. I let it happen. The residue was subjected to silica gel chromatography (eluent: chloroform/methano methanol, dioxane and diisopropylene. Recrystallized from a mixed solvent of lopyl ether, 2-(diaminomethyleneamino)-4 -(6-(2-cyano-3-methylamino)methylpyridin-2-yl]oxa Sol (0.69 g) was obtained.

Melting point: 178-+80°C (decomposition) IR (l shawl): 3450.　3300.21?0. 1655. 1 610 cm-'NMR (DMSO-d,, δ): 2.76 (31 (, d, J=4.6Hz), 4.43 (2H, d, J=5.61(z).

6.94 (4t(,s), 7, +4 (IH, d, J=7.5Hz), 7.2 6 (IH, q, J = 4.6Hz).

7.57 (IH, t, J=5.6Hz), 7.69 (IH, d, J= 7.5Hz).

7.83 (Ill, t, , l = 7.5Hz), 7.92 (IH, s) elements Elementary analysis C+ +H+ +N+O・HtO calculation value C47, 13, H5, 17, N 38.05. H, 05, 44 actual measurement value/C46, 93, H5, +2. N 37.90. HtO5,51 Example 6 4-(6-aminomethylpyridin-2-yl)-2-((amino)(methylamino) c) Methyleneaminocooxazole trihydrochloride (3.0g) and triethyl acetate Ethyl chloroformate was added to a warm mixture of dichloromethane (60 ml) and dichloromethane (4.9 ml). (1.0 ml) was added under water cooling, and the mixture was stirred at room temperature for 4.5 hours.

The solvent was removed by concentration and the residue was dissolved in tetrahydrofuran, ethyl acetate and water. Added the mixture. The mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate solution and separated. The separated organic layer was washed with brine and dried over magnesium sulfate.

The solvent was evaporated and the residue was subjected to gel column chromatography (eluent column). Purification was performed using loloform:methanol (19:1 v/v). solution containing the desired product. The separated fractions were collected and the solvent was evaporated under reduced pressure. The residue is diluted with methanol and Recrystallized from a mixed solvent of xane and diisopropyl ether to give 2-((amino)( methylamino)methyleneamino)-4-(6-ethoxycarponylaminomethyl Pyridin-2-yl)oxazole (1.2 g) was obtained.

Melting point: 161-+62°C IR (l shawl): 3330.　1685. 1645.　1610cm "NMR (DMSO-d,, δ): 1. +9 (3H, t, J=7. 1) 1z), 2.77 (3H, d, J = 4.7Hz).

4.04 (2) 1. q, J=7.1Hz), 4.28 (2H, d, J=6 ．． 1Hz).

7.15 (IH, d, J=7.411z), 7.42 (2H, s), 7. 66 (IH, d, J = 7.41 (z).

7.70 (IH, t, J=6.1) 1z), 7.80 (IH, t, J=7 ．． 4Hz), 7.89 (IH, s) Elemental analysis CxH1*N@Os・115 Calculated value of H,0・C52,23,H5,76,N 26.10. HtOi, 12 actual measurements: C52, 24, H5, 73, N 26.21. HtO1,07 Example 7 4-(6-aminomethylpyridin-2-yl)-2-((amino)(n-butyl (amino)methyleneamino)]oxazole trihydrochloride (1.4g) and cyanide A warm mixture of potassium chloride (0.6 g) in water (30 ml) was stirred at room temperature for 14 hours. . The mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate solution, ethyl acetate and Extraction was performed with a mixed solvent of tetrahydrofuran. Wash the extract with saline and sulfuric acid mug. dried with nesium. The solvent was removed by concentration and the residue was dissolved in methanol and dioxane. 2-((amino)( n-butylamino)methyleneamino)-4-(6-ureitomethylpyridine-2 -yl)oxazole (0.47 g) was obtained.

Melting point: 169-170°C (decomposed) IR (l shawl): 3430.3340.3220. 1655. 16 15 cm-'NMR (DIJSO-d, δ): 0.92 (3 ratio t, J=7.1Hz), 1.26-1.60 (4H, m).

3, 10-3.28 (2H, m), 4.27 (2H, d, J=5.8Hz) , 5.69 (2H, s).

6.54 (I) I, t, J = 5.8Hz), 7.16 (LH, d, J =7.5Hz), 7.36 (2H, s).

7.60 (If (, d, J = 7.5Hz), 7.79 (IH, t, J =7.5Hz), 7.93 (IH, s) Elemental analysis C+ sHt +NtOt ・1/2H20(') Calculated value: C52,93, H6,51,N 28.80. Hzo 2.65 Actual value: C53.07, H6.56, N 28.82.　 H,02,81 Example 8 The following compound was obtained in the same manner as in Example 7.

2-[(amino)(n-hexylamihamethyleneamino)-4-(6-ureito Methylpyridin-2-yl)oxazole Melting point = 190°C (decomposition) IR: 3420.3330.3200.1650.161 5 cm-'NMR (DMSO-dl, δ) + 0.88 (3H, t, J=6.4Hz), 1.15-1.43 (6H, m).

1.43-1.63 (2H, m), 3.10-3.28 (2H, m).

4.28 (2H, d, J=5.7Hz), 5.70 (2H, s), 6 ．． 55 (IH, t, J=5.7Hz).

7.16 (IH, d, J=7.5Hz), 7.35 (2H, s), 7 ．． 60 (IH, d, J=7.5Hz).

7.79 (IH, t, J=7.5Hz), 7.93 (IH, S) elemental content Analysis C1, HzsN70xO) Calculated value: C56,81, H7,01, N27 ．． 28 Actual measurement value: C56,55, H7,08, N 27.09 Example 9 4-(6-aminomethylpyridin-2-yl)-2-((amino)(n-butyl Amihamethyleneamino]oxazole trihydrochloride (1.1g) and triethyl Amine (1,2 ml) in tetrahydrofuran (22 ml) and methanol (5 ml) ml) to the mixture in the mixed solvent, add methyl isocyanate (0.2 ml) and stir at room temperature. Stirred for 2 hours. The solvent was removed by concentration and the residue was dissolved in tetrahydrofuran and acetic acid. A mixture of ethyl and water was added. Mixture with 20% potassium carbonate aqueous solution 1)8 9. 5, and the separated organic layer was dried with magnesium sulfate. Concentrate the solvent The residue was removed from a mixed solvent of ethanol and diisopropyl ether. It crystallizes into 2-((amino)(n-butylamino)methyleneamide-4-(6- (3-methylureido)methylpyridin-2-yl]oxazole (0.38g ) was obtained.

Melting point: 183-185℃ (decomposition) IR (Nujol): 3350.3250.3180. 1645. 16 00cm-'NMR (DMSO-d,, δ): 0.92 (3H, t, J=7.1Hz), 1.26-1.60 (4H, m).

2.59 (3H, d, J=4.6Hz), 3.13-3.30 (2H, m).

4.29 (2H, d, J=5.7Hz), 6.05 (IH, q, J= 4.6Hz).

6.50 (IH, t, J=5.7Hz), 7.15 (IH, d, J= 7.5) 1z), 7.38 (2H, s).

7.60 (IH, d, J=7.58Z), 7.79 (IH, t, J= 7.51 (z), 7.93 (IH, s) Elemental analysis C+ *HxsN, rO *-1/38!0(7) Calculated value: C54, 69, H6, 79, N 27.90 ．． Actual HtO1,71 value: C54,82, H6,94, N 27.44.　 HtO1,83 production example 3 The following compound was obtained in the same manner as in Production Example 2.

(1) 2-cyano-1-(2,2,2-trifluoroethyl)guanidine melting point: 　112-115℃ IR (Nujol): 3420.3320.2160. 1650cm "NMR (Dλls'0-ds, δ): 3.84-4.06 (2H, m) , 7.09 (2H, s), 7.38 (IH, 5) (2) 2-cyano-1 -(2-methylthioethyl)guanidine melting point + 67-68℃ IR (Nujol): 3410.3330.　1150.2170. 16 35 cm-'NMR (DMSO-d,, δ): 2.06 (3H, s) , 2.54 (2H, t, , l'6.9Hz).

3.10-3.39 (2H, m), 6.75 (28, s), 6.85 (IH, 5) (3) 2-cyano-1-propargylguanidine Melting point: 120- +22°C IR (Nujol): 3400.3320.3220.2170. 164 0 cm-'NMR (DMSO-d,, δ): 3.10-3.20 (I H, m), 3.82-3.90 (2H, m).

6.86 (2H, s), 7.13 (IH, 5) (4) 2-cyano-1-cy Clopropylmethylguanidine Melting point: 108-110"C [R (7 diiii-R): 3300.　3200.2130.　1640　cm −+NMR(DMSO-d,,δ)+0.08-0.30(21(,m ), 0.30-0.52 (28, m).

0.80-1.10 (IH, m), 2.88-3.00 (2H, m), 6.63 (2H, s).

6.87 (IH, 5) (5) 2-cyano-1-(2-phenylethyl)guanidine melting point 88-90℃ IR (Nujol): 3310.3200.2160. 1640cm -'NLIR (DMSO-d,, δ): 2.73 (2H, t, J=7. 7Hz), 3.24-3.33 (21(,m).

6.50-6.90 (2H, br), 7.17-7.34 (5H, m) ( 6) 2-cyano-1-(2-ethoxyethyl)guanidine IR (film): 　3400.2150. 1650cm-’NMR (DMSO-d,,δ) : 1.12 (3H, t, J=7.0)lz), 3.06-3.62 (6H, m).

6.50-6.90 (3H, br) (7) 2-cyano-1-(3-methoxypropyl)guanidine IR (film) : 3350 (br), 2170. 1635cm-'NMR(DM SO-d,, δ): 1.54-1.73 (2H, m), 3.00-3. 17 (2H, m).

3.22 (3H, s), 3.32 (2H, t, J=6.2Hz), 6.66 (2H, s).

6.82 (IH, 5) (8) 2-cyano-■-(3-ethoxypropyl)guanidine IR (film) : 3320.3170.2150. 1630 cm -'NλIR (DM SO-dl, δ) River, 10 (3H, t, J=6.9Hz), 1.54-1.7 0 (2H, m).

3.43 (2H, q, J=6.9Hz), 3.32-3.46 (6H, m).

6.66-6.79 (3H, br) (9) 2-Soarno-1-(3-propoxypropyl)guanidine Melting point: 110 −　III″C IR (nuji-i-ru) + 3300.3180.2150. 1650c m-'NMR (DMSO-di, δ'): 0.86 (3H, t, J= 7.3Hz), 1.40-1.78 (48, m).

3.05-3.14 (2t (, m), 3.26-3.45 (4H, m), 6.65-6.78 (3H, br) (10) 2-cyano-1-(3-isopropylene) Ropoxyprovir) guanidine [R (film): 3400.3170.2 150.1640 cm NMR (DMSO-dl, δ): 1.07 (6 )1. d, J=6.1Hz), 1.55-1.72 (2H, m).

3.00-3.14 (28, m), 3.32-3.40 (2H, m).

3.44-3.59 (IH, m), 6.66-6.77 (3) 1. br ) (11) 2-cyano-1-(4-methoxybutyl)guanidine melting point +05- 107°C IR (Nujol): 3420.3200.3120.2150. 167 0.　1630. 1610 cm-'NMR (DMSO-d,, δ'): 1.39-1.55 (4H, m), 2.99-3.08 (2H, at) .

3.21 (38,s), 3.30 (2H,t, J=6.1)1z), 6.63-6.80 (3H, br) Example 10 The following compound was obtained in the same manner as in Example 1.

(1) 4-(6-acetylaminomethylpyridin-2-yl)-2-((amino )(n-hebutylamino)methyleneaminocooxazole Melting point: 166-+ 67°C [R (Nujol): 3400.3260.3100.　1670. 16 30. 1605 cm -'NλIR (DMSO-d,, δ): 0.86 (3H, t, J=6.7)1z), 1.20-1.45 (8H, br) .

1.45-1.60 (2 ratio m), 1.92 (3H, s), 3.13-3. 20 (2H, m).

4.41 (2H, d, J=5.9Hz), 7.15 (IH, d, J= 7.61(z).

7.33 (2H, br), 7.62 (IH, d, I'7.6Hz).

7.78 (IH, t, J・7.6Hz), 7.90 (IH, S), 8.4 5 (lt(, t, J□5.9Hz) (2) 4-(6-acetylaminomethylpi lysin-2-yl)-2-((amino)(n-octylamino)methyleneamino Cooxazole melting point: 136-137°C IR (Nujol): 3420.　3220.　3060.3+00. 1 660. 1605 cm-'NMR (DlilSO-d, δ): 0. 85 (3H, t, J=6.8Hz), 1.14-1.50 (+28. m).

1.92 (3H, s), 3.13-3.23 (21 (, m), 4.34 (2H, d, J=5.9Hz).

7.15 (IH, d, J=7.5Hz), 7.35 (2H, br), 7.62 (IH, d, J=7.5Hz).

7.78 (IH, t, J=7.5Hz), 7.90 (IH, S), 8 ．． 44 (IH, t, J=5.9Hz) Elemental analysis C2°N2°N, 0.・I /4H20 calculated value: C61,44,H7,86,N 21.49 Actual value: C61,69,H8,05,N2+,32(3)4-(6-acetylaminomethyl tylpyridin-2-yl)-2-((amino)(2,2,2-trifluoroethyl Methylene amino cooxazole melting point 218-219℃ [R (Nujol): 3345.　1660.　1635. 1610a m-'NλIR (DMSO-d,, δ): 1.93 (3H, s), 4 ．． 00-4.25 (2H, m).

4.36 (2H, d, J=5.9Hz), 7.17 (IH, d, J=6. 9Hz).

7.69 (IH, d, J=6.9Hz), 7.81 CI ratio t, J=6 ．． 9Hz), 7.99 (IH, s).

8.45 (IH, t, J=5.9) IZ) Elemental analysis C,, H, IN, 0. Calculated value of F: C47, 19, H4, 29, N 23.59 Actual value: C47, 03, H4, +8. N 23.4+(4) 4-(6-acetylaminomethylpi lysin-2-yl)-2-((amino)(neopentylamino)methyleneamino Cooxazole melting point: 162-+63°C IR (Nujol): 3370.　3270.3180.　1650. 1 600 cm ”’NMR (DMSO-d,,δ): 0.9.1 (9 ratio S), 1.93 (3H, S).

3.06 (2H, d, J=5.7Hz), 4.34 (21(, d, J25. 9Hz).

7.14 (l ratio d, J=7.6Hz), 7.60 (I)1. d, J= 7.6Hz).

7.79 (l ratio t, J=7.6Hz), 7.90 (lit, s), 8. 44 (1 ratio t, J=5.9Hz) Elemental analysis Calculated value of C+7H24N*Oz : C59,28,l(7,02,N 24.40 actual measurement value・C59,2+,H 7,27,N 24.43(5) 4-(6-acetylaminomethylpyridine-2 -yl)-2-((amino)(tert-butylamino)methyleneaminocoki Sasol melting point: 164-165°C IR (Nujol): 3380.3330.　1660. 1610cm -'NMR (DMSO-d,, δ): 1.38 (9H, s), 1.9 3 (3H, s).

4.35 (2H, d, J=5.9Hz), 6.40 (IH, br s).

7.15 (IH, d, J=7.4Hz), 7.28 (2H, br s) .

7.64 (IH, d, J=7.48Z), 7.79 (IH, t, J= 7.4Hz).

7.92 (IH, s), 8.45 (IH, t, J=5.9Hz) Elemental analysis C, @H,,N,0. Calculated value: C58,1? , H6, 71, N 25. 44 actual measurement value: C58,08,H6,72,N 25.31 (6) 4-(6-A cetyl aminomethylpyridin-2-yl)-2-((amino)(cyclopropyl) Methylamino) methylene amide oxazole Melting point: 187-188°C IR (Nugetar): 3400.3320. 1620cm-’NMR (DMSO-d,, δ): 0.20-0.30 (2H, m), 0.42-0 ．． 57 (2H, m).

0.92-1.14 (IH, m), 1.93 (3H, s), 3.04- 3.19 (2) 1. m).

4.34 (2H, d, J=5.9Hz), 7.15 (IH, d, J= 7.5Hz).

7.38 (2) 1. br s), 7.64 (IH, d, J=7.5H z).

7.79 (IH, t, J=7.5Hz), 7.91 (IH, s), 8 ．． 43 (1) 1. t, J=5.9Hz) Elemental analysis C+-Hz. N102 Calculated value: C58, 52,) I 6.14. N 25.59 Actual value: C5 8,66,H6,19,N 25.41(7)4-(6-acetylaminomethyl pyridin-2-yl)-2-((amino)(2-methylthioethylamino)methy Renamino)oxazole Melting point: 174-175°C IR (Nujol): 3370. 1645.　1600. 1180c m-'NMR (DMSO-d,, δ): 1.93 (3H, s), 2.1 1 (3H, s).

2.65 (2H, t, J=6.7Hz), 3.35-3.48 (2) 1 ．． m).

4.34 (2H, d, J=5.9Hz), 7.15 (IH, d, J= 7.2Hz).

7.47 (2H, br s), 7.67 (IH, d, J=7.2Hz) .

7.79 (IH, t, J=7.2)1z), 7.92 (IH, s), 8.44 (IH, t, J=5.9Hz) Elemental analysis CIIH2°N, 0. S Calculated value of -115H,O: C51,+8. H5, 78, N 23.87. N 201°02 actual measurement value: C51, 23, H5, 82, N 23.79. N20 o, 97(8) 4-(6-acetylamitumedelpyridin-2-yl)-2- ((amino)(propargylamino)methyleneaminocooxazole melting point: 2 10-211°C IR (Nunoyor): 3460.　3280.　3190. 1650c m-'NMR (DItlSO-d,, δ): 1.94 (3) 1. s) , 3.13-3.20 (IH, m).

4.00-4.12 (2H, m), 4.36 (2H, d, J=5.9Hz) , 7.02 (IH, br s), 7.17 (If(, d, J=6.9Hz ), 7.60 (2H, brs).

7.68 (IH, d, J=6.9Hz), 7.80 (1 ratio t, J=6. 9Hz), 7.97 (IH, s).

8, = 15 (IH, t, J = 5.9Hz) Elemental analysis C,, total of H□N602 Calculated value C57, 68,)I 5. +6. N 26.91 Actual value: C57.4 2,H5,32,N 26.88(9)4-(6-acetylaminomethylpyridi (2-yl)-2-((amino)(2-phenylethylamino)methyleneamine Nocooxazole melting point 87-89°C IR (Nujol): 3390.　3260.　3+00.　1635.　 1005 cm-'NMR (D) JSO-d,, δ): 1.92 (3H , s), 2.84 (2H, t, J=7.2Hz).

3.41-3.51 (2H, m'), 4.34 (2H, d, J: 5.9 Hz).

7, 12-7.36 (811, m), 7.50-7.60 (IH, br) .

7.78 (IH, t, J=7.8Hz), 7.91 (IH, s).

8.44 (I) 1. t, J=5.9Hz) (IQ') 4-(6-acetyl (aminomethylpyridin-2-yl)-2-((amino)(2-toginethyl) Amino) methylene amino cooxazole Melting point 155-157°C IR (Nushor): 3400.　3320.　3+00.　1640.　 1605 cm-'NMR (DMSO-d,, δ): 1.15 (3) 1 ．． t, J=7.0Hz), 1.92 (3H, s).

3.34-3.54 (6L m), 4.34 (2H, d, J=5.9Hz) .

7.15 (IH, d, J=7.5Hz), 7.40 (2H, br).

7.65 (IH, d, J=7.5Hz), 7.78 (IH, t, J=7. 5H2), 7.91 (IH, s).

8.44 (IH, t, J=5.9Hz) Elemental analysis of C+-Hz2NsOz Calculated value: C55,48, H6,40,N 24.26 Actual value: C55,24 , H6,61,N 23.88 (11) 4-(6-acetylaminomethylpyridi (2-yl)-2-((amino)(3-methoxypropylamino)methylenea Mino)oxazole Melting point: 157-158°C IR (Nujol): 3380.3320.3120.1635. 161 0 cm-'NMR (DMSO-d@, δ): 1.66-1.83 (2 H, m), 1.93 (3H, s).

3.17-3.31 (2H, m), 3.25 (3H, s), 3.40 (2 H, t, J = 6.2Hz).

4.34 (2H, d, J=5.9Hz), 7.15 (IH, d, J= 7.5Hz).

7.40 (2H, br s), 7.64 (IH, d, J=7.5Hz) .

7゜79 (IH, t, J=7.5Hz), 7.91 (IH, s), 8.4 4 (IH, t, J=5.9Hz) Elemental analysis Calculated value of C1Jz2N*Ot C 55, 48, H6, 40, N 24.26 Actual value: C55, 19, H6, 33 , N 23.90 (+2) 4-(6-acetylaminomethylpyridin-2-yl )-2-((amino)(3-ethquinpropylamino)methyleneaminocooxa Sol melting point: 140-141°C IR (Nujol): 3390.3300.3+00.　1670. 16 30. 1600 cm-'NMR (DMSO-dl, δ): 1. +2 (3H, t, J=7.0Hz), 1.67-1.80 (2H, m).

1.92 (3) 1. s), 3.19-3.48 (6H, m), 4.34 (2H, d, J=5.9f(z).

7.14 (IH, d, J=7.48x), 7.38 (2N, br).

7.63 (I ratio d, J=7.4Hz), 7.79 CI! (, t, J=7 ．． 4Hz), 7.91 (I ratio s), 8.44 (IH, t, J = 5.9Hz ) Elemental analysis Calculated value of C+iHt<NeCh・C56,65,H6,71,N 23.22 Actual value: C56,49, H6,94, N 23.27 (13) 4- (6-acetylaminomethylpyridin-2-yl)-2-((amino)(3-propylene) Lopoquine propylamino)methyleneaminocooxazole NMR (D&1SO- d,, δ): 0.86 (3H, t, J=7.3H2), 1.45-1. 82 (4H, m).

1.93 (3H, s), 3.05-3.47 (6H, l11), 4.3 5 (2H, d, J=5.9Hz).

7.14 (IH, d, J=7.4Hz), 7.41 (2) 1. br) .

7.63 (IH, d, J=7.4Hz), 7.79 (IH, t, J= 7.4Hz).

7.91 (IH, s), 8.45 (II (, t, J=5.9Hz) (1 4) 4-(6-acetylaminomethylpyridine-2-ino-2-[(amino) (3-isopropoxypropylamino)methyleneamino)oxazole Melting point: 135-136℃ [R (Nujol): 3370.3170. 1630cm-’NMR (DMSO-d,, δ): 1.09 (6H, d, J=6.1)1z), 1.64-1.77 (21(,m).

1.93 (3H, s), 3.19-3.29 (2H, m), 3.40- 3.59 (3H, m).

4.34 (2H, d, J=5.9Hz), 7.15 (IH, d, J= 7.6Hz).

7.38 (2H, br), 7.63 (IH, d, J=7.6Hz).

7.79 (IH, t, J=7.6Hz), 7.91 (1) 1. s), 8.44 (11 (,t, J=5.9Hz) Elemental analysis C,,H□N60. Calculated value: C57,73, H7,00, N22.45 actual measurement (il[: C5 7,83,H7,19,N 22.31 (15) 4-(6-acetylaminomethyl lupyridin-2-yl)-2-((amino)(4-methoxybutylamino)methy Renamino)oxazole NMR (DMSO-d,, δ): 1.40-1. 65 (4H, m), 1.92 (3H, S).

3, 15-3.40 (7) 1. m), 4.33 (2H, d, J=6. 0Hz).

7.14 (IH, d, J=7.6H2), 7.30 (2) 1. br), 7 ．． 62 (IH, d, J=7.6Hz).

7.79 (18,t, J=7.6Hz), 7.90 (IH,s), 8 ．． 44 (IH, t, J=6.0Hz) Example 11 4-(6-acetylaminomethylpyridin-2-yl)-2-((amino)(2 -phenylethylamino)methyleneaminocooxazole (500mg) meta Add 4N hydrogen chloride-dioxane (0.73ml) to a solution of alcohol (20ml) at room temperature. I added it. The mixture was stirred at room temperature for 1 hour. Diisopropyl ether (80ml ) and stirred at room temperature for 1 hour. The precipitate formed was collected by filtration.

Recrystallized from a mixed solvent of methanol and diisopropyl ether to give 4-(6- acetylaminomethylpyridin-2-yl)-2-((ryomino)(2-phenyl) Ethylamino)methyleneaminocooxazole dihydrochloride (0.5 g) was obtained.

Melting point: 214-215°C (decomposition) IR (Nujol): 3240.3110.3060.　1700. 16 40 cm-'NMR (DMSO-d,, δ): 1.94 (3) 1.　 s), 2.95 (2H, t, J=7.3Hz).

3.60-3.80 (2H, m), 4.45 (2H, d, J=5.8) 1z).

7.23-7.39 (7H, m), 7.75 (IH, d, J=7.8H z).

7.98 (IH, t, J=7.8Hz), 8.52 (IH, s).

8.59 (IH, t, J=5.8Hz), 8.74 (IH, br), 8.96 (IH, br) Elemental analysis C1°HtzN*Ox・2) Calculation of ICI Value: C53,22, H5,36,N 18.62 Actual value: C53,02,H 5,44,N 18.29 Example 12 The following compound was obtained in the same manner as in Example 3.

(1) 4-(6-aminomethylpyridin-2-yl)-2-((amino)(n- Pentylamino) methylene amino cooxazole trihydrochloric acid base magnetic point: 188-1 90℃ [R (Nujol): 3290.　1700. 1635cm-’NM R(0,0,δ): 0.83 (3H, t, J=6.8Hz), 1.1 6-1.40 (4H, at).

1.50-1.70 (2H, m), 3.25 (28, t, J=7.0H z), 4.40 (2H, s).

7.50 (IH, d, J = 7.9 Flz), 7.79 (IH, d, J =7.9Hz).

8.03 (IH, t, J=7.9Hz), 8.25 (IH, 5) (2) 2-((Ryomino)(n-hebutylamino)methyleneamino)-4-(6-amino Methylpyridin-2-yl)oxazole 3-hydrochloric acid base magnetic point: 221-222° C (decomposition) [R (Nujol): 3420.3270.3030.1690.1610 cm-'NMR (DMSO-d,, δ): 0.86 (3H, t, J =6.8Hz), 1.10-1.50 (8H, m).

1.50-1.70 (2H, m), 3.30-3.50 (2H, m).

4.23 (2H, d, J=5.6Hz), 7.48 (IH, dd, J =7.1Hz, 1.5Hz).

7.91-8.02 (2H, m), 8.67 (5H, br) (3) 2-( (amino)(n-octylamino)methyleneamino)-4-(6-aminomethyl rubiridin-2-yl)oxazole, 3-hydrochloric acid base magnetic point, 2+8-220℃ IR (Nujicol): 3270. 1690.1630cm-'NMR (DMSO-d,, δ): 0.85 (38, t, , I'6.8Hz), 1.26 (IOH, br).

1.59 (2H, br), 3.20-3.40 (2H, m), 4.10 -4.30 (2H, m).

7.46 (Il, d, J = 6.1Hz), 7.90-8.02 (2H , m), 8.54 (2H, br).

8.62 (IH, s), 8.90 (2H, br) (4) 4-(6-amino Methylpyridin-2-yl)-2-((amino)(isopentylamino)methylene Amino cooxazole 3-hydrochloric acid base magnetic point: 184-186℃ IR (Nujol): 3510.3430.3320.1700.1630 cm - 'NMR (0, 0, δ) + 0.98 (61 (, d, J = 6. 3H7), 1.52-1.86 (3H, m).

3.4o (2H, t, J=7.1Hz), 4.45 (2H, s).

7.55 (IH, d, J-7, 9Hz), 7.89 (IH, d, J= 7.9Hz).

8.09 (IH, t, J=7.9Hz), 8.32 (II, 5) (5 )2-[(amino)(2-phenylethylamino)methyleneamino]-4-(6 -aminomethylpyridin-2-yl)oxazole 3-hydrochloric acid base magnetic point: 202- 204°C IR (Nujol): 3150.　3050. +680.　1630.　 1590 cm-’NLIR (DMSO-d,,δ): 2.85-3.1 0 (2H, m), 3.60-3.80 (2H, m).

4.22 (2H, m), 7.24-7.52 (6H, m), 7.78 (IH, br).

7.95. -8.02 (IH, m), 8.50-9.05 (5H, m) ( 6) 2-((amino)(2-ethoxyethylamino)methyleneamino)-4- (6-aminomethylpyridin-2-yl)oxazole 3-hydrochloric acid base magnetic point: 15 8-160℃ (decomposition) IR (Nujol): 3300.3140. +680.　1630. 1 600 cm-'NMR (DMSO-d,, δ): 1.16 (3H, t , J=7.0Hz), 3.42-3.60 (6H, m).

4.15-4.30 (2) 1. m), 7.48 (IH, d, J=7 ．． 4Hz).

7.88 (IH, d, J = 7.4Hz), 7.98 (1B, t, J =7.41(z).

8.67 (5H, br), 9.08 (IH, br) Example 13 The following compound was obtained in the same manner as in Example 7.

(1) 2-((amino)(n-pentylamino)methyleneamide-4-(6-u) Late methylpyridin-2-yl)oxazole Melting point: 197-198℃ (min. solution) [R (Nujol): 3430.3340.3220. 1655. 16 15 cm-'NMR (DMSO-d,, δ): 0.89 (3H, S, J=6.5Hz), 1.20-1.43 (4H, m).

1.43-1.65 (2H, m), 3.10-3.30 (2H, m).

4.28 (2H, d, J=5.7Hz), 5.72 (2H, s), 6 ．． 56 (IH, t, J□5.7Hz).

7.16 (IH, d, J=7.5Hz), 7.36 (28, s), ? . 61 (18, d, J=7.5Hz).

7.79 (II(, t, J=7.5H2), 7.94 (IH, S') element Elementary analysis Calculated values of C,, H,, N, 02: C55, 64, H6, 71, N 2 8.39 Actual value: C55,55,H6,95,N 28.13(2)2-(( amino)(n-heptylamino)methyleneamino)-4-(6-ureitomethyl Pyridin-2-yl)oxazole Melting point: +68-169°C IR (Nujol): 3430.3330.3170.　1650. 16 10 cm-'NMR (DMSO-d,, δ): 0.86 (3H, t, J=6.7Hz), 1.29-1.51 (IOH, m).

3.18-3.24 (2H, m), 4.27 (2H, d, J=5.7H z), 5.68 (2H, s).

6.54 (IH, t, J=5.7Hz), 7.17 (IH, d, J= 7.5Hz).

? , 45 (2H, br), 7.62 (IH, d, J4.5Hz).

7.80 (Il, t, J=7.5Hz), 7.98 (IH, s) element Analysis CuHttllvOt -1/2H2017) Calculated value I C56,53, )l　7.38. N 25.64 Actual value: C56,74, H7,28, N 25.47(3)2-((amino)(n-octylamino)methyleneamino)- 4-(6-ureitomethylpyridin-2-yl)oxazole Melting point: 141- 142°C rR (l shawl): 3400.　3350.3250.　1670. 1 620 cm-'NMR (DMSO-d,, δ): 0.85 (3H, t , J□6.8Hz), 1.10-1.65 (12H, m).

3, 10-3.25 (2H, m), 4.26 (2H, d, J = 5.7H z), 5.68 (2H, s).

6.53 (IH, t, J=5.7Hz), 7.15 (IH, d, J= 7.6Hz).

7.38 (2H,br), 7.60 (It(,d, J=7.6)1z) .

7.78 (IH, t, J=7.6Hz), 7.92 (IH, s) Elemental analysis C+*Hx*Nq02" l/4HtO (D calculated value: C58, 22, H7, 59, N 25.0+actual value: C5g, 46. H7, 63, N 25.1 2(4) 2-(,(amino)(isopentylamino)methyleneamino)-4 -(6-ureitomethylpyridin-2-yl)oxazole melting point + 181-1 82°C IR (Nujol): 3430.3340.3220. 1655. 16 20 cm-'NMR (DMSO-d,, δ): 0.91 (6H, t, J=6.5Hz), 1.32-1.53 (2H, m).

1.53-1.80 (IH, m), 3.14-3.31 (2H, m).

4.28 (2H, d, J=5.5Hz), 5.70 (2H, s).

6.55 (IH, t, J=5.5Hz>, 7.16 (IH, d, J= 7.6Hz).

7.36 (2H, s), 7.60 (IH, d, J=7.6Hz).

7.79 (IH, t, J=7.6Hz), 7.93 (IH, s) elemental content Analysis Calculated values of C,, H, N, 02・l15H,0: C55,06, H6,76, N 28.09. H2O1.03 actual measurement value C55.2+, 86.9+, N 27.93. Hto 1.15(5) 2-((amino)(2-phenylethyl methyleneamino]-4-(6-ureitomethylpyridin-2-yl) Oxazole melting point: 210-211″C IR (Nujol): 3470.3360.3330.3200.1660 ．． 1640.1610 c+n-'NMR (DMSO-d,, δ): 2. 84 (2H, t, J=7.1Hz), 3.36-3.50 (2) 1. m) .

4.27 (2H, d, J = 5.81 (z), 5.68 (2H, s).

6.53 (IH, t, J=5.8Hz), 7.14-7.57 (9) 1 ．． m).

7.79 (IH, t, J=7.8Hz), 7.94 (IH, s) elemental content Analysis Calculated values of C+-HuN70i/I/2H20: C58,75, H5,71 , N 25.24 Actual value: C59.02, H5,65, N 24.90 (6) 2-((amino)(2-ethoxyethylamino)methyleneamino)-4-(6- Uratemethylpyridin-2-yl)oxazole Melting point: 115-116℃ IR (Nujol): 3500.3370.3170.　1650. 16 00 cm-'NMR (DIJSO-d,, δ) + 1.15 (3H, t , J=7.0Hz), 3.35-3.54 (6H, m).

4.27 (2H, d, J=5.8Hz), 5.69 (2) 1. s).

6.53 (IH, t, J=5.8H2), 7.16 (IH, d, J=7. 48Z).

7.38 (2H, br), 7.63 (IH, d, J=7.4Hz).

7.79 (IH, t, J=7.4H2), 7.93 (IH, S) elemental analysis Calculated value of C+sH2+N70s・1/2H,O: C50,55,H6,22 , N 27.51 Actual value: C50, 83, H6, 34, N 27.44 Example 14 The following compound was obtained in the same manner as in Example 5.

(1) 2-(diaminomethyleneamino)-4-(6-(1-methylamino-2- Nitrovinyl)aminomethylcopyridin-2-yl]oxazole Melting point: >2 50°C IR (Nujol): 3430.3300.3210.　1630. 15 45 am -'NMR (DCI-0,0,6): 3.16 (3H, s) .

5.18, 5.32 (total 2H, each s).

7.84, 7.93 (total IH, each d, J=8.I) I z).

8.28, 8.30 (total IH, each d, J = 8.1Hz ).

8.53, 8.54 (total IH, each t, J=8.1Hz) .

8.62, 8.64 (total IH, each s) Elemental analysis C1z HxN*Oz・Calculated value of I/4H,0・C46,36,H4,94,N 33. 27. H2O1,34 actual measurement value: C46,44, H5,12, N 33.31 ．． 1(201,21(2)2-((aminoXn-butylamino)methyleneamino )-4-(6-(2-cyano-3-methylguanidino)methylpyridin-2-y ]Oxazole melting point: 207-208°C IR (Nujol): 3500.　3360.　3220.　2170.　 1650. 1600 cm”NλtR(DMSO-d,,δ): 0.9 2 (3H, t, J=7.IHz), 1.26-1.60 (4H, m).

2.76 (3H, d, J=4.6Hz), 3.14-3.29 (2) 1 ．． m).

4.43 (28, d, J=5.61(z), 7.14 (1 ratio d, J=7. 5Hz).

7.26 (l ratio q, J=4.6Hz), 7-37 (2H, s), 7.5 7 (1) 1. t, J=5.6Hz).

7.64 (IH, d, J=7.5Hz), 7.83 (IH, t, J=7. 5Hz), 7.91 (IH, s) Elemental analysis Calculated values of C,, H,, N, 0: C55,27, H6,28, N 34.12 actual measurement C55,00, H6,4 1, N 33.93 Production example 4 The following compound was obtained in the same manner as in Production Example 1.

2-acetylaminomethyl-5-acetoquine acetylfuran IR (film): 　3350.3280. 1740.1665 cm-’NMR (DMSO- d,, δ) Heat, 86 (31 (, s), 2.13 (3H, s).

4.33 (2H, d, J=5.7Hz), 5.17 (2H, s).

6.51 (IH, d, J=3.5Hz), 7.51 (IH, d, J= 3.5t(z).

8.48 (IH, t, J=5.7H2) Example 15 The following compound was obtained in the same manner as in Example 1.

(1) 4-(5-acetylaminomethylfuran-2-yl)-2-(diaminomethyl tyreneamino)oxazole Melting point: 232-234°C (decomposition) IR (Nujol): 3390.3330.　1670.　1620　cm -'NMR (DMSO-ds, δ): 1.85 (3H, s), 4.26 (2H, d, J=5.5Hz).

6.30 (IH, d, J=3.2Hz), 6.52 (IH, d, J= 3.2Hz).

6.89 (41 (, S), 7.61 (lH, S), 8.35 (IH, t, J = 5.51 (Z) (2) 4-(5-acetylaminomethylfuran-2- yl)-2-((amino)(n-butylamino)methyleneaminocooxazole Melting point: 94-95°C IR (Nujol) + 3370.3270.　3200.　1650. 1 620 cm”NMR (DMSO-dl, δ): 0.90 (3H, t, J=7. I) Iz), 1.25-1.58 (4H, m).

1.85 (3H, s), 3.10-3.24 (28, m).

4.25 (2H, d, J=5.5H2), 6.30 (IH, d, J= 3.2Hz).

6.49 (IH, d, J=3.2Hz), 7.30 (2H, s), 7.60 (IH, s).

8.34 (IH, t, J=5.5Hz) Elemental analysis C15l (-1NsOs Calculated value: C56,4+, H6,63,N 21.93 Actual value: C56, 33, H6, 76, N 21.78 Example 16 4-(5-acetylaminomethylfuran-2-yl)-2-(diaminomethylene 'Diamino)oxazole (0.5 g) in methanol (7.5 ml) at medium temperature. , 4N hydrogen chloride-dioxane (0.95ml) was added and stirred at room temperature for 30 minutes. .

Diisopropyl ether (20 ml) was added to the mixture and the separated precipitate was filtered. Therefore, I collected it. The precipitate was recrystallized from a mixed solvent of methanol and ethyl acetate, 4-(5-acetylaminomethylfuran-2-yl')-2-(diaminomethylene (amino)oxazole hydrochloride (0.45 g) was obtained.

Melting point: 2+4-215°C IR (Nujol): 3440.　3190. 3070. 1677, 1610 cm-'NMR (DMSO-d, δ): 1.86 (3H, s), 4.28 (2H, d, J=5.5Hz).

6.37 (IH, d, J=3.3Hz), 6.80 (IH, d, J= 3.3Hz).

8.16 (18, s), 8.36 (4 ratio S), 8.41 (Il, t, J =5.51(z) Elemental analysis CI+H+5NsO*' 1 (CI-1/48! Calculated value of 0: C43, 43, H4, 80, N 23.02. CI 11.65 ．． H*01.48 Actual value: C43,28, H4,87, N22.72.　 CI 11.81. Hzo 1.60

Claims (1)

[Claims] 1. formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R1 is amino which may have a suitable substituent, R2 and R2 are an aliphatic hydrocarbon group which may each have hydrogen or an appropriate substituent, A is lower alkylene, and Y means pyridinediyl or furandiyl) and their A pharmaceutically acceptable salt of. 2. R1 is amino, mono- or di(lower) alkylamino, lower alkenylamine No, lower alkynylamino, hydroxy (lower) alkylamino, lower alkoxy (lower) alkylamino, mono- or di(lower) alkylamino (lower) alkylamino Kylamino, acylamino, heterocyclic amino, cycloalkenylamino, imidoma or expression: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (wherein, X is =CH- or =N-, R4 is hydrogen, cyano, nitro or acyl, and R5 is hydrogen, alkylthio, means protected hydroxy or amino optionally with suitable substituents ), and R2 and R3 are hydrogen, alkyl, and lower alkyl, respectively. Nyl, lower alkynyl, lower alkoxy (lower) alkyl, mono or di or trihalo(lower)alkyl, (C3-C7)cycloalkyl(lower)alkyl, Claims that are lower alkylthio(lower)alkyl or aryl(lower)alkyl A compound according to item 1 of the scope. 3. R1 is amino, acylamino, or formula: ▲ Numerical formulas, chemical formulas, tables, etc. are available▼ (wherein, X is =CH- or =N-, R4 is hydrogen, cyano, nitro or acyl, and R5 is hydrogen, alkylthio, means protected hydroxy or amino optionally with suitable substituents ), and R2 and R3 are each hydrogen, lower alkyl or lower 3. The compound according to claim 2, which is alkoxy(lower)alkyl. 4. R1 is amino, lower alkanoylamino, lower alkoxycarbonylamino , lower alkanoyloxy (lower) alkanoylamino, ureido, lower alkyl 4. A compound according to claim 3 which is a roureido or a guanidino. 5. R1 is amino, lower alkanoylamino, lower alkoxycarbonylamino , lower alkanoyloxy (lower) alkanoylamino, ureido, lower alkyl Loureido or Guanidino, R2 is hydrogen, lower alkyl or lower alkoxy (lower) alkyl, and R3 4. The compound according to claim 3, wherein is hydrogen. 6. R1 is amino, acetylamino, ethoxycarbonylamino, acetoxyamino Cetyl amino, ureido, 3-methylureido or 2-cyano-3-methylglyceride Anijino, R2 is hydrogen, methyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl or 2-methoxyethyl, R3 is hydrogen, and A compound according to claim 1, wherein A is methylene. 7. formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R1 is amino which may have a suitable substituent, R2 and R3 are hydrogen or lower alkyl which may have a suitable substituent, and A is a method for producing a compound represented by (A means lower alkylene) or a salt thereof. So, (1) Formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R1 and A each have the same meaning as above, and Z1 is halogen or acyl. and a compound represented by the formula: ▲mathematical formula, chemical formula, There are tables etc.▼ (wherein R2 and R3 each have the same meanings as above) By formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ A compound represented by (wherein R1, R2, R3 and A each have the same meanings as above) or or get the salt, or (2) Formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R2, R3 and A each have the same meaning as above, and R1a is acyl amino By subjecting a compound represented by ,formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (wherein R2, R3 and A each have the same meanings as above) or a compound thereof get salt or ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (wherein R2, R3 and A each have the same meanings as above) or a compound thereof By subjecting the salt to acylation reaction, formula: ▲Mathematical formula, chemical formula, table, etc.▼ A compound represented by (wherein R1a, R2, R3 and A each have the same meanings as above) or a manufacturing method comprising obtaining a salt thereof. 8. formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R2 and R3 may each have hydrogen or a suitable substituent. lower alkyl, A is lower alkylene, X is =CH- or =N-, R4 is hydrogen, cyano, nitro or acyl, and Rsa has a suitable substituent This is a method for producing a compound or a salt thereof. So, (1) Formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (wherein R2, R3 and A each have the same meanings as above) or a compound thereof With the salt of, the formula: (R6-X1)zC=X-R4 (In the formula, R4 has the same meaning as above, R6 is lower alkyl or aryl, and X1 means S or O) by reacting with a compound represented by the formula (1-3): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(1-3) (In the formula, R2, R3, A, R4, R5 and X1 each have the same meaning as above) or a salt thereof is obtained, (2) The compound of the above formula (1-3) or a salt thereof and the formula: H-R5a (In the formula, R5a has the same meaning as above), the formula: ▲ mathematical formula, chemical formula There are tables, etc.▼ (wherein R2, R3, A, R4, R5a and X each have the same meanings as above) A manufacturing method comprising obtaining a compound or a salt thereof. 9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient A pharmaceutical composition comprising a pharmaceutically acceptable carrier as a pharmaceutically acceptable carrier. 10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof is administered to humans or or to an animal. 11. Anti-ulcer use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof Use as a drug, H2-receptor antagonist and antibacterial agent.