FURYLTHIAZOLE AND THEIR USE AS H2-RECEPTOR ANTAGONISM AND ANTIMICROBIAL

Abstract: This invention relates to furylthiazole derivatives represented by formula (I), wherein each symbol is as defined in the specification and pharmaceutically acceptable salts thereof which have antiulcer activity, H2-receptor antagonism and antimicrobial activity, to processes for the preparation thereof, to a pharmaceutical composition comprising the same and to a method for the treatment of ulcer and infectious diseases in human being or animals.

Description: DESCRIPTION Furylthiazole and their use as H2-receρtor antagonism and antimicrobial. Technical Field 5 This invention relates to new furylthiazole derivatives and pharmaceutically acceptable salts thereof. More particularly, it relates to furylthiazole derivatives and pharmaceutically acceptable salts thereof which have antiulcer activity, H 2 -receptor antagonism and antimicrobial 10 activity, to processes for the, preparation thereof, to a pharmaceutical composition comprising the same and to a method for the treatment of ulcer and infectious diseases in human being or animals. Background Art 15 in European Patent Application Publication No. 355,612, there are disclosed furylthiazole derivatives having antiulcer activity and H 2 -receptor antagonism. Disclosure of the Invention One object of this invention is to provide new 20 furylthiazole derivatives and pharmaceutically acceptable salts thereof which possess antiulcer activity, H2-receptor antagonism and antimicrobial activity. Another object of this invention is to provide processes j for the preparation of said furylthiazole derivatives and salt '+ 25 thereof. A further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said furylthiazole derivatives or pharmaceutically acceptable salts thereof. Still further object of this invention is to provide a therapeutical method for the treatment of ulcer and infectious diseases in human being or animals. The furylthiazole derivatives of this invention are new and can be represented by the following general formula (I) : wherein R 1 is methyl, ethyl, propyl, butyl, hexyl, lower alkoxyflower)alkyl, lower alkenyl, lower alkynyl, cyelo(lower)alkyl, heterocyclic(lower)alkyl or hydroxy(lower)alkyl, R 2 is hydrogen, R a is hydrogen or lower alkyl, R 4 is amino, acyl, acylamino, lower alkylisothioureido, heterocyclic amino, heterocyclic group, or a group of the formula : X-R 5 -(NH) n -C II-_ ' R β in which n is 0 or 1, X is =CH- or =N-, R 5 is hydrogen, cyano, nitro or acyl, and <*__ 5 R" is hydrogen, lower alkyl, lower alkylthio, lower alkoxy or amino which may have suitable substituent(s), and A is lower alkylene or -CONH- . or 10 A-R 4 is heterocyclic group, and Q is hydrogen or lower alkyl, provided that when R 1 is methyl, then R 4 is amino, lower alkanoylamino or a group of the formula : 15 X-R 5 -(NH) a -C-R β in which n, X, R s and R e are each as defined above. The object compound (I) or a salt thereof can be prepared 20 by processes as illustrated in the following reaction schemes. Process 1 25 (II) or a salt thereof 93/03028 (I) or a salt thereof Process 2 Deacyl ion (1-1) or a salt thereof (1-2) or a salt thereof Process 3 Acylation or a salt (1-1) or a salt thereof Process 4 (1-2) or a salt thereof (1-3) or a salt thereof Process 5 (1-3) or a salt thereof (1-4) or a salt thereof Process 6 Hydrolysis (1-5) or a salt thereof (1-6) or= a salt thereof Process 7 Elimination of the amino-protective group (1-7) or a salt thereof (1-8) or a salt thereof or a salt thereof (1-9) or a salt thereof Process 9 (1-2) or a salt thereof (1-10) or a salt thereof Process 10 (1-11) or a salt thereof (1-12) or a salt thereof Process 11 (1-12) or a salt thereof (1-13) or a salt thereof Process 12 Reduction (1-11) or a salt thereof (1-14) or a salt thereof Process 13 (X) or a salt thereof (i) or a salt thereof 93 Process 14 (1-12) or a salt thereof ( 1-15) or a sal t thereof Process 15 (1-15) or a salt thereof (1-16) or a salt thereof Process 16 (1-17) or a salt thereof (1-18) or a salt thereof Process 17 (XIII) or a salt thereof (1-19) or a salt thereof 9 Process 18 (1-19) or a salt thereof (1-20) or a salt thereof Process 19 Ring closure (1-20) or a salt thereof (1-21) or a salt thereof Process 20 (1-2) or a salt thereof (1-22) or a salt thereof Process 21 Oxidation (1-23) or a salt thereof (1-24) or a salt thereof Process 22 (1-8) or a salt thereof (1-25) or a salt thereof Process 23 (1-25) or a salt thereof (1-26) or a salt thereof Process 24 Elimination of the hydroxy protective group (1-27) or a salt thereof Process 25 eof (1-2) * or a salt thereof ( 1-29) or a salt thereof Process 26 (1-13) or a salt thereof Q R^H^ N π [I- -U-A-CONHR 12 R 2 NH^ S R 8 (1-30) or a salt thereof wherein R 1 , R 2 , R 8 , R*, R 5 , R β , X, A and Q are each as defined above, R 4 a is acylamino, R*b is acylamino including thio, R*c is acylamino including sulfinyl, R*d is acylamino including protected hydroxy, R*e is acylamino including hydroxy, R 6 a is amino which may have suitable substltuent(s) or lower alkoxy, R 7 is lower alkyl or aryl, R 8 is a ino-protective group, R 9 *, R 11 , R 18 , R 15 , R lτ and R 18 are each lower alkyl, R 10 is protected hydroxy, R 14 is hydrogen or lower alkyl, R lβ is heterocyclic group, X 1 is S or 0, Z 1 , Z 2 , Z 3 and Z 4 are each acid residue, and A 1 is lower alkylene or bond. In the above and subsequent descriptions of the present specification, suitable examples of the various definitions to be included within the scope of the invention are explained in detail in the following. The term "lower" is intended to mean a group having 1 to 6 carbon atom(s) preferably 1 to 4 carbon atom(s), unless otherwise provided. Suitable "lower alkyl" and lower alkyl moiety in the term "lower alkylthio" may be a straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl or the like, in which the preferable one is Ci-C* alkyl and the more preferable one is methyl or ethyl. Suitable "lower alkoxy" may be methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy or the like, in which the preferable one is &-C* alkoxy, the more preferable one is C1-C2 alkoxy and the most preferable one is methoxy. Suitable "acyl" and the acyl moiety in the term "acylamino" may include carbamoyl, thiocarba oyl, sulfamoyl, an aliphatic acyl, an aromatic acyl, a heterocyclic acyl and an aliphatic acyl substituted with aromatic or heterocyclic group(s) derived from carbamic, sulfonic, carboxylic or carbonic acids and their thϊo acids. The aliphatic acyl may include saturated or unsaturated, acyclic or cyclic ones, such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, pivaloyl, hexanoyl, etc.), lower alkanesulfonyl (e.g. mesyl, ethanesul onyl, propanesul onyl, etc.), lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, etc.), lower alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl, etc.), (C 3 -C7)cycloalkanecarbonyl (e.g. cyclohexanecarbonyl, etc.), lower alkoxalyl (e.g. methoxalyl, ethoxalyl, etc.), lower alkanoylcarbonyl (e.g. pyruvoyl, etc.), lower alkanoyloxy(lower)alkanoyl (e.g. acetoxyacetyl, acetoxypropionyl, etc.,), and the like. The aromatic acyl may include aroyl (e.g. benzoyl, nitorobenzoyl, toluoyl, xyloyl;, etc.), arenesulfonyl (e.g. benzenesulfonyl, tosyl, etc.), and the like. The heterocyclic acyl may include heterocyclic carbonyl (e.g. furoyl, thenoyl, nicotinoyl, 1-oxonicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl, tetrazol Icarbonyl, morpholinocarbonyl, etc.), and the like. The aliphatic acyl substituted with aromatic group(s) may include phenyl(lower)alkanoyl (e.g. phenylacetyl, phenylpropionyl, phenylhexanoyl, etc.), phenyl(lower)- alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.), ρhenoxy(lower)alkanoyl (e.g. phenoxyacetyl, phenoxypropionyl, etc.), and the like. The aliphatic acyl substituted with heterocyclic group(s) may include thienylacetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl, thiazolylacetyl, thiadiazolylacetyl, thienylpropionyl, thiadiazolylpropionyl, and the like. These acyl groups may be further substituted with suitable substituent(s) such as hydroxy, amino, carboxy, lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, etc.), lower alkenyl (e.g. vinyl, allyl, etc.), halogen (e.g. chloro, bromo, iodo, fluoro), lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, etc.), lower alkylthio (e.g. ethylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio, etc.), heterocyclic(lower)alkylthio (e.g. furyl ethylthio, thiazolyl ethylthio, etc.), heterocyclic(lower)alkylsul inyl (e.g. furylmethylsul inyl, thiazolylmethylsulfinyl, etc.), nitro, acyl as mentioned above, protected amino in which the amino protective moiety may be the same as those herein, aryl (e.g. phenyl, etc,), aroyl (e.g. benzoyl, etc.), aryloxy (e.g. benzyloxy, tolyloxy, etc.), protected hydroxy such as acyloxy, for example, lower alkanoyloxy (e.g. formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyrylόxy, valeryloxy, isovaleryloxy, pivaloyloxy, hexanoyloxy, etc.), lower alkylamino (e.g. methylamino, ethylamino, etc.), amϊno-protective group as aftermentioned, and the like, and the preferable acyl having such substituent(s) may be lower alkoxy(lower)alkanoyl (e.g. methoxyacetyl, ethoxyacetyl, etc.), lower alkanoyloxy(lower)- alkanoyl (e.g. acetoxyacetyl, etc.), N-lower alkylcarbamoyl (e.g. N-methylcarbamoyl, N-ethylcarbamoyl, N-isopropylcarbamoyl, etc.), aroylthiocarbamoyl (e.g . . benzoylthiocarbamoyl, etc.), etc. Suitable "heterocyclic group" and heterocyclic moiety in the term "heterocyclic amino" may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like. Especially preferably heterocyclic group may be 5 or 6-membered aromatic heteromonocyclic group (e.g. pyrrolyl, i idazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiadiazolyl, etc.), 5- or 6-membered aliphatic heteromonocyclic group (e.g. morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, etc.), unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) (e.g. benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, etc.), and the like. Thus defined heterocyclic moiety may have suitable substituent(s) such as amino, oxo, halogen as chloro, lower alkyl as defined above, and the like. Preferable example of such a group is thiazolyl having lower alkyl (e.g. 4- methy1thiazolyl, etc.). 2.0 Suitable "amino-protective group" may include ar(lower)- alkyl such as benzyl, benzhydryl, phenethyl and the like, and acyl as mentioned above. Suitable hydroxy-protective group in the term "protected hydroxy" may include aforesaid acyl, ar(lower)alkyl (e.g. benzyl, trityl, etc.) lower alkoxy(lower)alkyl (e.g. methoxymethyl, 1-methyl-l-methoxyethyl, methoxypropyl, etc.), tetrahydropyranyl, lower alkyl as aforementioned and the like. Suitable "acid residue" may include halogen such as chloro, bromo, fluoro and iodo. Suitable "lower alkylene" may be straight or branched one such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylnene, and the like, in which the preferable one is Cι-C 4 alkylene and the most preferable one is methylene and ethylene. Suitable "lower alkylisothioureido" may include 2-lower alkylisothioureido such as 2-methylisothioureido, 2- ethylisothioureido, 3-proρylisothioureido, and the like. Suitable "amino which may have suitable substituent(s)" is conventional one used in a pharmaceutical field and may include amino, mono or di(lower)alkylamino (e.g. methylamino, dimethylamino, ethylamjno, butylamino, etc.), lower alkenylamino (e.g. vinylamino, propenylamino etc.), lower alkynylamino (e.g. ethynylamino, propynylamino, etc.), hydroxy(lower)- alkylamino (e.g. hydroxymethylamino, hydroxyethylamino, hydroxypropylamino, etc.), lower alkoxy(lower)alkylamino (e.g. iπethoxymethylamino, etc.), mono or di(lower)alkylamino(lower)- alkylamino (e.g. methylaminomethylamino, di ethylaminoethyl- a ino, etc.), and the like. Suitable "acylamino including thio" may include acylamino as mentioned above, in which the optional carbon atom of the acyl moiety is replaced by a thio group, for example, heterocyclic(lower)alkylthio(lower)alkanoylamino such as 5- or 6-membered aromatic heteromonocyclic(lower)alkylthio(lower)- alkanoylamino (e.g. furylmethylthioacetylamino, thiazolylmethyl- thioacetylamino, etc.), and the like. Suitable "acylamino including sulfinyl" may include acylamino as mentioned above, in which the optional carbon atom of the acyl moiety is replaced by a sulfinyl group, for example, heterocyclic(Iower)alkylsulfinyl(lower)alkanoylamino such as 5- or 6-membered aromatic heteromonocyclic(lower)- alkylsulfinyl(lower)alkanoylamino (e.g. furylmethylsulfinyl- acetyla ino, thiazolylmethylsulfinylacetylamino, etc.), and the like. Suitable "acylamino including protected hydroxy" may include acylamino as mentioned above which is substituted by a protected hydroxy as exemplified above, for example, protected hydroxy(lower)alkylureido such as lower alkanoyloxy(lower)- alkylureido (e.g. acetyloxyethylureido, etc.), and the like. Suitable "acylamino including hydroxy" may include acylamino as mentioned above which is substituted by hydroxy such as hydroxy(lower)alkylureido (e.g. hydroxyethylureido, 2 *2 etc. ), and the like. Suitable "aryl" may include phenyl, tolyl, xylyl, mesityl, cumenyl, naphthyl, and the like, in which the preferred one is Cβ-Cio aryl. Suitable "lower alkoxy(lower)alkyl π may include methoxymethyl, methoxyethyl, methoxypropyl, ethoxyethyl, 1- methyl-1-methoxyethyl, and the like. Suitable "lower alkenyl" may include vinyl, 1-ρropenyl, allyl, 1-butenyl, 2-butenyl, 2-pentenyl, and the like, preferably one having 2 to 4 carbon atoms, in which the most preferred one is allyl. Suitable "lower alkynyl" may include ethynyl, 1-propynyl, 2-ρropyπyl, 3-butynyl, and the like, preferably one having 2 to 4 carbon atoms, in which the most preferred one is 2-propynyl. Suitable "cyclo(lower)alky ' may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. "Heterocyclic(lower)alkyl" means lower alkyl as mentioned above which is substituted by a heterocyclic group such as those exemplified above, and the preferred example may include pyridyl(lower)alkyl such as pyridylmethyl, pyridylethyl, and the like. Suitable "hydroxy(lower) lkyl" may include hydroxymethyl, hydroxyethyl, hydroxypropyl, and the like. Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and include an organic acid addition salt [e.g. formate, acetate, 2;3 trifluoroacetate, maleate, tartrate, methanesul onate, benzenesulfonate, toluenesufonate, etc.], an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], a salt with an acidic amino acid [e.g. aspartic acid salt, glutamic acid salt, etc.], and the like. With respect to the salt of the compound (1-1) to (1-30) in the Process 1 to 26, it is to be noted that these compounds are included within the scope of the compound (I), and accordingly the suitable examples of the salts of these compounds are to be referred to those as exemplified for the object compound (I). Particularly, the preferred embodiments of R 1 , R 8 , R 4 , A and are as follows. R 1 is ethyl; propyl; butyl; hexyl; lower alkoxy(lower)alkyl (e.g. methoxyethyl, ethoxyetyl, methoxypropyl, etc. ); lower alkenyl (e.g. allyl, etc.); lower alkynyl (e.g. propynyl, etc.); cyclo(lower)alkyl (e.g. cyclohexyl, etc.); pyridyKlower)alkyl (e.g. pyridylethyl, etc.); or hydroxy(lower)alkyl (e.g. hydroxyethyl, etc.); R 3 is hydrogen; R 4 is amino; acylamino such as ureido, lower alkanoylamino (e.g. acetylamino, etc.), lower alkoxycarbonylamino (e.g. methoxycarbonylamino, etc. ) and lower alkanoyloxy(lower)alkanoylamino (e.g. acetoxyacetylamino, etc.); hydroxy(lower)alkanoylamino (e.g. hydroxyacetyla ino, etc. ); or 2-cyano-3-lower alkylguanidino (e.g. 2-cyano-3- methylguanidino, etc. ); A is lower alkylene (e.g. methylene, etc.); and Q is hydrogen; or lower alkyl (e.g. methyl, etc.). The processes for preparing the object compounds (I) of the present invention are explained in detail in the following. Process 1 The object compound (I) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (III). This reaction is usually conducted in a conventional solvent which does not adversely influence the reaction such as ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, N,N-dimethylformamide, N,N- dimethylacetamide, dioxane, water, alcohol [e.g. methanol, ethanol, etc.], acetic acid, formic acid, etc. or a mixture thereof. The reaction temperature Is not critical and the reaction is usually conducted under cooling to heating. Process 2 The object compound (1-2) or a salt thereof can be prepared by subjecting the compound (1-1) or a salt thereof to deacylation. Suitable method for this deacylation reaction may include conventional one such as hydrolysis, reduction or the like. The hydrolysis is preferably carried out in the presence of a base or an acid. Suitable base may include, for example, an inorganic base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkali metal acetate (e.g. sodium acetate, potassium acetate, etc.), alkaline earth metal phosphate (e.g. magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphate (e.g. disodium hydrogen phosphate, dipotassium.hydrogen phosphate, etc.), or the like, and an organic base such as tri(lower)alkylamine (e.g. trimethylamine, triethylamine, etc.), picoline, N- methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo- [4.3.0]non-5-one, l,4-diazabicyclo[2.2.2]octane, 1,5- diazabicyclo[5.4.0]undecene-5 or the like. The hydrolysis using a base is often Carried but in water or a hydrophilic organic solvent or a mixed solvent thereof. Suitable acid may include an organic acid (e.g. formic acid, acetic acid, propionic acid, etc. ) and an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfurlc acid, etc. ). The present hydrolysis is usually carried out in an organic solvent, water or a mixed solvent thereof. The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating. Process 3 The object compound (1-1) or a salt thereof can be prepared by reacting the compound (1-2) or a salt thereof with an acylating agent. The compound (1-2) may be used in the form of its conventional reactive derivative at the amino group. The acylating agent can be represented by the compound of the formula : R 20 - OH in which R 20 is acyl as defined above and its conventional reactive derivative at the hydroxy group. The suitable example may be an acid halide (e.g. acid chloride, etc.), an acid anhydride, an activated amide, an activated ester, and the like.. In case the. acyl group to be introduced is a carbamoyl type acyl, the acylating agent is usually used in the form of cyanate or isocyanate. The reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, didxane, acetonitrile, chloroform, dichloromethane, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N- dimethylformamide, N,N-dimethy.lacetamide, pyridine, acetic acid or any other organic solvent which does not adversely influence the reaction. These conventional solvents may also be used in a mixture with water. The reaction temperature is not critical, and the reaction is usually carried out under cooling to warming. The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N- dϊ(lower)alkylbenzylamine, or the like. Process 4 The object compound (1-3) or a salt thereof can be prepared by reacting the compound (1-2) or a salt thereof with the compound (IV). This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g.. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxaήe, dimethyl sulfoxide, N,N- dimethylformamide or a mixture thereof. The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating. Process 5 The object compound (1-4) or a salt thereof can be prepared by reacting the compound (1-3) or a salt thereof with the compound (V). This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N- dimethylformamide or a mixture thereof. In case that the compound (V) is liquid, it can be also used as a solvent. The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating. Process 6 The object compound (1-6) or a salt thereof can be prepared by subjecting the compound (1-5) or a salt thereof to hydrolysis reaction. This reaction is usually carried out in a conventional manner for transforming nitrile to amide. This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N- dimethylformamide or a.mixture thereof. The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or . heating. Process 7 The object compound (1-8) or a salt thereof can be prepared by subjecting the compound (1-7) or a salt thereof to elimination reaction of the amino-protective group. This reaction can be carried out in substantially the same manner as Process 2, and therefore the reaction mode and reaction conditions [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 2. Process 8 The object compound (1-9) or a salt thereof can be prepared by reacting the compound (1-8) or a salt thereof with the compound (VI). This reaction can be carried out in substantially the same manner as Process 1, and therefore the reaction mode and reaction conditions [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 1. Process 9 The object compound (1-10) or a salt thereof can be prepared by reacting the compound (1-2) or a salt thereof with the compound (VII). This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N- dimethylformamide or a mixture thereof. The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating. Process 10 The object compound (1-12) or a salt thereof can be prepared by reacting the compound (I-ll) or a salt thereof with the compound (VIII). This reaciton is usually carried out in the presence of dry hydrogen chloride gas. This reaction is usually carried out in a conventional solvent such as alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N- dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating. The object compound(1-12) can be used as a starting compound of Process 15 mentioned hereinbelow with or without isolation. Process 11 The object compound (1-13) or a salt thereof can be prepared by reacting the compound (1-12) or a salt thereof with the compound (IX). This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sul oxide, N,N- dimethylformamide or a mixture thereof. The reaction temperature is not critical, and the reaction is usually carried out. at ambient temperature or under warming or heating. Process 12 The object compound (1-14). or a salt thereof can be prepared by subjecting the compound (I-ll) or a salt thereof to reduction. The reduction may include, for example, reduction with an alkali metal borohydride (e.g. sodium borohydride, etc.), and the like. This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N- dimethylformamide or a mixture thereof. The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating. Process 13 The object compound (I) or a salt thereof can be prepared by reacting the compound (X) or a salt thereof with the compound (XI) or a salt thereof. This reaction can be carried out in substantially the same manner as Process 5, and therefore the reaction mode and reaction conditions [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 5. Process 14 The object compound (1-15) or a salt thereof can be prepared by subjecting the compound (1-12) or a salt thereof to hydrolysis. This reaction is usually carried out in a conventional solvent such as a mixture of water and alcohol [e.g. methanol, etc.I or any other solvent which does not adversely influence the reaction. The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating. Process 15 The object compound (1-16.) or a salt thereof can be prepared by subjecting the compound (1-15) or a salt thereof to a idation. This reaction is usually carried out in the presence of ammonia gas. This reaction is usually carried out in a conventional solvent such as alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N- dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. The reaction temperature is not critical, and the reaction Is usually carried out at ambient temperature or under warming or heating. Process 16 The object compound (1-18) or a salt thereof can be prepared by reacting the compound (1-17) or a salt thereof with the compound (XII). This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N- dimethylformamide or a mixture thereof. The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating. Process 17 The object compound (1-19) or a salt thereof can be prepared by reacting the compound (XIII) or a salt thereof with hydrazine. This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N- dimethylformamide or a mixture thereof. The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating. Process 18 The object compound (1-20) or a salt thereof can be prepared by reacting the compound (1-19) or a salt thereof with S-(lower)alkylisothiourea or a salt thereof. This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol,- ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N- dimethylformamide or a mixture thereof. The reaction temperature is not critical, and the reaction is usually carried out-at ambient temperature or under warming or heating. Process 19 The object compound (1-21) or a salt thereof can be prepared by subjecting the compound (1-20) or a salt thereof to ring closure. This reaction is usually carried out in the presence of ammonium hydride. This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N- dimethylformamϊde or a mixture thereof. The reaction temperature is not critical, and the reaction is usually carried out. at ambient temperature or under warming or heating. Process 20 The object compound (1-22) or a salt thereof can be prepared by reacting the compound (1-2) or a salt thereof with the compound (XIV) or a salt thereof. This reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, dichloromethane, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, N,N- dimethylacetamide, pyridine or any other organic solvent which does not adversely influence the reaction. These conventional solvents may also be used in a mixture with water. The reaction temperature is not critical, and the reaction is usually carried out under cooling to warming. The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine (e.g. triethylamine, etc.), pyridine, N- (lowerJalkylmorpholine, N,N-di(lower)alkylbenzylamine, or the like. Process 21 The object compound (1-24) or a salt thereof can be prepared by oxidizing the compound (1-23) or a salt thereof. The oxidizing agent to be used in this reaction may include an inorganic peracid or a salt thereof (e.g. periodic acid, persulfuric acid, or sodium or potassium salt thereof, etc.), an organic peracid or a salt thereof (e.g. perbenzoic acid, in¬ chloroperbenzoic acid, perfor ic acid, peracetic acid, chlo operacetic acid, trifluoroperacetic acid, or sodium or potassium salt thereof, etc.), ozone hydrogen peroxide, urea- hydrogen peroxide, N-halosuccinimide (e.g. N-bromosuccinimide, N-chlorosuccinimide, etc.), hypochlorite compound (e.g. tert- butyl hypochlorite, etc.), permanganate (e.g. potassium permanganate, etc.), of any other conventional oxidizing agent which can oxidide a sulfide group to a sulfoxide group. The present reaction can also be carried out in the presence of a compound comprising Group Vb or VIb metal in the Periodic Table of elements, for example, tungstic acid, molybdic acid, vanadic acid, etc., or an alkali or an alkaline earth metal salt thereof. The present oxidation reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, acetic acid, chloroform, methylene chloride, acetone, methanol, ethanol, tetrahydrofuran, N,N- dimethylforma ide or a mixture thereof. The reaction temperature is not critical, and the reaction is usually carried out under cooling to at ambient temperature. Process 22 The compound (1-25) or a salt thereof can be prepared by reacting the compound (1-8) or a salt thereof with the compound (XV) or a salt thereof. This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N- dimethylformamide or a mixture thereof. The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating. Process 23 The object compound (1-26) or a salt thereof can be prepared by reacting the compound (1-25) or a salt thereof with the compound (XVI) or a salt thereof. This reaction can be carried out in substantially the same manner as Process 5, and therefore the reaction mode and reaction conditions [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 5. Process 24 The object compound (1-28) or a salt thereof can be prepared by subjecting the compound (1-27) or a salt thereof to elimination reaction of the hydroxy-protective group. This reaction can be carried out in substantially the same manner as Process 2, and therefore the reaction mode and reaction conditions [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 2. Process 25 The object compound (1-29) or a salt thereof can be prepared by reacting the compound (1-2) or a salt thereof with the compound (XVII) or a salt thereof. This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sul oxide, N,N- dimethylformamide or a mixture.thereof. The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating. The reaction may also be carried out in the presence of an Inorganic.or organic base such as tri(lower)alkylamine (e.g. triethylamine, etc.), or the like. Process 26 The object compound (1-30) or a salt thereof can be prepared by subjecting the compound (1-13) or a salt thereof to hydrolysis. The hydrolysis is preferably carried out in the presence of a base or an acid. This reaciton is usually carried out in a conventional solvent which dose not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N- dimethyl ormamide or a. mixture thereof. The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating. Among the starting compounds, some of them are new and such compounds can be prepared by the.methods of Preparation mentioned below and by any process known in the art for preparing structurally analogous compounds thereto. The compounds obtained by the above Processes 1 to 26 can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation or the like. It is to be noted that each of the object compound (I) may include one or more stereoisomer such as optical isomer(s) and geometrical isomer(s) due to asymmetric carbon atom(s) and double bond(s) and all such isomers and mixture thereof are included within the scope of this invention. Furthermore, with regard to the compound (I), it is to be noted that the following formula (A) is well known to lie to tautomeric relation with the following formula (B), and accordingly, it is to be understood that both of the isomers are substantially the same. 93/03028 R*NH \ > R*NH C=N- " C-NH- R 2 NH / < R 2 N (A) (B) Accordingly, the both of the tautomeric forms are clearly included within the scope of the present invention. In the present specification, the object and starting compounds including the group of such tautomeric isomers are represented by using one of the expressions- The new furylthiazole derivatives (I) and pharmaceutically acceptable salts thereof possess antiulcer activity and ,H 2 - receptor antagonism, and are useful for a therapeutic treatment of gastritis, ulcer (e.g. gastric ulcer, duodenal ulcer, anastomotic ulcer, etc.), Zollinger-Ellison syndrome, reflux esophagitis, upper gastrointestinal bleeding, and the like. And further, the compound (I) and pharmaceutically acceptable salts thereof of the present invention possess high antimicrobial activity against pathogenic microorganisms such as Campylobacter pyloridis, helicobacter pyloridis, and the like, which is a gram-negative bacillus that has recently been found beneath the mucus gel of the human stomach. For therapeutic purpose, the compound (I) and a pharmaceutically acceptable salt thereof of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral or parenteral administration. The pharmaceutical preparations may be capsules, tablets, dragees, granules, solution, suspension, emulsion, or the like. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives. While the dosage of the compound (I) will vary depending upon the age and condition of the patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound (I) may be effective for treating ulcer. In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day. In order to illustrate the usefulness of the object compound (I), the pharmacological test data of some representative compounds of the compound (I) are shown in the following. Test Compounds (a) 4-(5-AcetyIaminomethylfuran-2-yl)-2-[(amino)(n- butylamino)methyleneamino]thiazole (b) 4-(5-Acetylaminomethylfuran-2-yl)-2-[(amino)(n- 93/03028 hexylamino)methyleneamino]thiazole (c) 4-(5-AcetyIaminomethylfuran-2-yl)-2-[(amino)- (2-methoxyethylamino)methyleneamino]thiazole (d) 4-(5-Acetylaminomethylfuran-2-yl)-2-[(amino)- [2-(2-pyridyl)ethylamino]methyieneamino]thlazole (e) 4-(5-Acetylaminomethylfuran-2-yl)-2-[(amino)- (allylamino)methyleneamino]thiazole Test A (H 2 -receρtor antagonism in isolated guinea-pig atrium): Test Method The atrial strip isolated from guinea-pig was suspended under an initial tension 0.3 to 0.6 g in an organ bath containing Tyrode solution at 30'C. aerated 95% 0 2 - 5% C0 2 gas. The beating rate and amplitude of contraction of the atrium were recorded by means of a transducer and a polygraph. Histamine (1 x 10 ~ β g/ml) was added to the bathing fluid and the increase in beating rate after dosing was measured. Addition of test compounds (1 x 10 _B g ml) was made 30 minutes after washing out histamine. Inhibitory effect of test compound was calculated by comparing histamine-induced increases in beating rate before and 30 minutes after dosing with the test compounds. 3/030 Test Result Test B (Gastric secretion from lumen perfused stomach in anesthetized rats) : Test Method Male Sprague-Dawley rats weighing about 250 g were used. Rats were deprived of food but allowed free access to water for 24 hours. The animals were anesthetized with 1.25 g/kg urethane intraperitoneally. The abdomen was opened and the gastric lumen was perfured with saline throughout the experiment. The perfusate was titrated by an autotitrator with 25 mM sodium hydroxide as a titrant. Gastric secretion was stimulated by intravenous infusion with histamine (3 mg/kg/hr). After reaching plateau, test compound (1 mg/kg) was given intravenously. Drug effect was expressed as maximal inhibition by acid output. Test Result 93/03028 Test C (Anti- icrobial activity) Test Method In vitro antimicrobial activity was determined by the agar dilution method. Test strain was precultured in Brucella broth Agar containing 5% horse serum at 37°C for 3 days, and 10 4 cfu/ml were inoculated with a multipoint replicater onto Brucella agar plus 5% lysed horse blood plate containing serial 2-fold dilutions of each drug at 37 . for 3 days. Incubation was carried out in an atmosphere of 10S_ C0 2 . MIC was read after incubation as the lowest drug concentration that inhibited macroscopic colonial growth. Test Results MIC g/ml ) Test D (Inhibition of HCl-aspirin ulcer) Test Method Seven male Sprague-Dawley rats, aged 6 weeks and weighing 93/03028 about 200 g were used per group for the study on HCl-aspirin ulcer after the fast for 24 hours. Each of the test compounds (32 g/kg) suspended in 0.IS. methylcellulose solution was administered orally 30 minutes before aspirin administration. Aspirin, suspended in 0.1% methylcellulose solution containing 0.2N HCl, was administered orally at a dose of 200 mg/kg/10 ml. One hour later, the animals were sacrificed and their stomachs were removed. The stomach was then fixed with 2% formalin. The length of ulcers was measured for each animal, and percentage of inhibition was calculated by comparing the mean length of ulcers (mm) in the test animals with that in the control animals. Test Result The following Preparations and Examples are given for the purpose of illustrating the present invention in more detail. 93/03028 Preparation 1 A suspension of 4-(5-acetylarainomethylfuran-2-yl)-2- thioureidothiazole (12.6 g) and methyl iodide (7.2 g) in methanol (200 ml) was refluxed for 5.5 hours. The solvent was removed under reduced pressure. The residue was washed with ethyl acetate to afford 4-(5-acetylaminomethyIfuran-2-yl)-2-(2- methylisothioureldo)thiazole hyiriodide (15.7 g). mp : 188 to 190 β C (dec. ) IR (Nujol) : 3280, 1630, 1580 cm" 1 NMR (DMSO-d β , δ ) : 1.87 (3H, s), 2.60 (3H, s), 4.29 (2H, d, J=5.5Hz), 6.36 (IH, d, J=3.3Hz), 6.89 (IH, d, J=3.3Hz), 7.31 (IH, s), 8.38 (IH, t, J=5.5Hz), 9.67 (IH, br) Preparation 2 A suspension of 2-acetami.domethyl-5-chloroacetyl-3- methylfuran (24.8 g) and thiourea (8.2 g) in ethanol (250 ml) was stirred at room temperature for 2 hours. The resulting precipitate was collected by filtration and then dissolved in water (200 ml). The mixture was alkalized with an aqueous potassium carbonate solution. The resulting precipitate was collected by filtration to afford 4-(5-acetylaminomethyl-4- methyIfuran-2-yl)-2-aminothiazoIe (16.7 g). mp : 218 to 220 °C IR (Nujol) : 3350, 3150, 1640, 1620 cm" 1 NMR (DMSO-dβ, δ ) • 1.81 (3H, s), 1.98 (3H, s), 93/03028 4.20 (2H, d, J=5.4Hz) , 6.34 (IH, s) , 6.60 ( IH, s) , 7.08 (2H, s) , 8. 26 ( IH, t, J=5. 4Hz) Preparation 3 Benzoyl chloride (8.9 g) was added slowly to a solution of sodium thiocyanate (5.5 g) in;acetone (200 ml) under refluxing. The mixture was refluxed for 15 minutes 4-(5-acetylaminomethyl- 4-methylfuran-2-yl)-2-aminothlazole (13.2 g) was added to the mixture under refluxing. The mixture was refluxed for 8 hours. The resulting precipitate was collected by filtration. The precipitate was washed with water and then acetone to afford 4-(5-acetylaminomethyl-4-methylfuran-2-yl)-2-benzoylthioureido~ thiazole (15.1 g). mp : 215 to 217 X. (dec.1 IR (Nujol) : 3290, 1630 cm- 1 NMR (DMSO-dβ, δ ) • 1.74 (3H, s), 1.83 (3H, s), 4.25 (2H, d, J=5.4Hz), 6.65 (IH, s), 7.34 (IH, s), 7.57 (2H, t, J=7.3Hz), 7.70 (IH, dt, J=1.5 and 7.3Hz), 8.02 (2H, dd, J=7.3 and 1.5Hz), 8.33 (IH, t, J=5.4Hz), 12.21 (IH, br), 14.22 (IH, br) Preparation 4 An aqueous sodium hydroxide solution (3.5 g in 30 ml) was added to a suspension of 4-(5-acetylaminomethyl-4-methylfuran- 2-yl)-2-benzoylthioureidothiazble (15.0 g) in methanol (200 ml). 93/03028 The mixture was heated at 60'C for 9 hours. The solvent was removed under reduced pressure. Water (200 ml) was added. The solution was neutralized with! 6N hydrogen chloride solution. The resulting precipitate was collected by filtration to afford 4-(5-acetylaminomethyl-4-methylfuran-2-yl)-2-thioureidothiazole (10.9 g). mp : 222 to 225 TQ IR (Nujol) : 1620 cm" 1 NME (DMSO-dβ, δ ) • 1.82 ; (3H, s), 2.01 (3H, s), 4.23 (2H, d, J=5.4Hz), 6.54 (IH, s), 7.10 (IH, s), 8.20 (IH, br), 8.28 (1H, t, J=5.4Hz), 8.76 (IH, br), 11.76 (IH, s) Preparation 5 The following compound was obtained according to a similar manner to that of Preparation 1. 4-(5-Acetylaminomethyl-4-methylfuran-2-yl)-2-(2-methylisothio¬ ureido)thiazole hydrIodide (7..5 g). mp : 172 to 173 V (dec.) IR (Nujol) : 3220, 1590 cm" 1 NMR (DMS0-d β , δ ) 1.82 j(3H, s), 2.01 (3H, s), 2.52 (3H, s),. 4.23 (2H, d, J=5.4Hz), 6 74 (IH, s), 7.20 (IH, s), 8.30 (IH, t, J=5.4Hz), 9.38 (IH, br) Example 1 A suspension of 4-.(5-acetylaminomethylfuran-2-yl)-2-(2- 93/03028 methylisothioureido)thiazole hydroiodide (2.0 g) and n- butyla ine (5 ml) in ethanol (40 ml) was refluxed for 42 hours. The solvent was removed under reduced pressure and the residue was dissolved in water (100 ml). The mixture was alkalized to pH 10 with a saturated aqueous potassium carbonate solution and then extracted with a mixture of ethyl acetate (200 ml) and tetrahydrofuran (50 ml). The extract was dried with magnesium sulfate and then evaporated. Recrystallization from ethyl acetate afforded 4-(5-acetylaminomethylfuran-2-yl)-2-[(amino)- (n-butylamino)methyleneamino]thiazole (0.30 g). mp : 147 to 148 β C IR (Nujol) : 3460, 3310, 3200, 1640, 1610 cπr 1 NMR (DMSO-dβ, δ ) : 0.91 (3H, t, J=7.0Hz), 1.29 - 1.48 (4H, m),; 3.16 (2H, q, J=7.0Hz), 4.26 (2H, d, J=5.5Hz), 6.30 (IH, d, J=3.1Hz), 6.54 (IH, d, J*=3.1Hz), 6.77 (IH, s), 7.32 (2H, br), 8.34 (IH, t, J=5.5Hz) Anal. Calcd. for C_.eH21N5.O2S : C 53.71, H 6.31, N 20.88 Found : C 53.99, H 6.41, N 20.68 Example 2 The following compounds were obtained according to a similar manner to that of Example 1. (1) 4-(5-Acetylamlnomethylfuran-2-yl)-2-[(amino)(n-hexylamino)- methyleneamino]thiazole 93/03028 mp : 138 to 139 V IR (Nujol) : 3460, 3220, 1630, 1590 cm" 1 NMR (DMS0-d β , δ ) ' 0.87 (3H, t, J=6.4Hz), 1.05 - 1.60 (8H, m)-, 1.85 (3H, s), 3.16 (2H, q, J=6.4HZ), 4.26 (2H, d, J=5.5Hz), 629 (IH, d, J=3.1Hz), 6.54 (IH, d, J=3.1Hz), 7.06 (IH, S), 7.32 (2H, s), 8.34 (IH, t, J=5.5Hz) Anal. Calcd. for • 1/2H 2 0 : C 54.82, H 7.04, N 18.80 Found : C 55.21, H 7.17, N 18.81 (2) 4-(5-AcetyIamlnomethyl uran-2-yl )-2-[ (amino) (2-methoxy- ethylamino)methyleneamino] thiazole mp : 137 to 138 * C IR (Nujol) : 3480, 3300, 3100, 1650, 1590 cm" 1 NMR (DMSO-dβ, c ) : 1.85 (3H, s), 3.28 - 3.45 (4H, m), 4.26 (2H, d, J=5.5Hz), 6.30 (IH, d, J=3.2Hz), 659 (IH, d, J=3.2Hz), 6.78 (IH, s), 7.05 - 7.60 (12H, br),.8.34 (IH, t, J=5.5Hz) (3) 4-(5-AcetylaminomethyIfuran-2-yl)-2-[(amino)[2-(2-pyridyl)~ ethylamino]methyleneamino;]thiazole p : 67 to 68 °C IR (Nujol) : 3520,.3380, 3280, 1630, 1590 cm" 1 NMR (DMS0-d β , δ ) • 1.85 (3H, s), 2.98 (2H, t, J=6.9Hz), 3.58 (2H, q, J=6.9Hz), 4.26 (2H, d, J=5.5Hz), 5 ϊ 6.29 (IH, d, J=3.1Hz), 6.53 (IH, d, J=3.1Hz), 6.77 (IH, s), 7.23 (IH, ddd, J=l_lHz, 4.9Hz and 7.6Hz), 7.32 (IH, br, d, J=7.6Hz), 7.40 (2H, br), 7.72 (IH, dt, J=l.lHz and 7.6Hz), 8.35 (IH, t, J=5.5Hz), 8.51 (IH, ddd, J=0.8Hz, 1.1Hz and 4.9Hz), Anal. Calcd. for Cι.HιoN β 0 2 S - H 2 0 : C 51.42, H 5.75, N 19.99 Found : C 51.38, H 5.82, N 19.89 (4) 4-(5-Acetylaminomethylfuran-2-yl)-2-[(amino)(allylamino)- methyleneamino] thiazole mp : 160 to 161 °C IR (Nujol) : 3380, 3180, 3100, 1650, 1600 cm" 1 NMR (DMSO-dβ, δ ) - 1.85 (3H, s), 3.84 (2H, t, J=5.3Hz), 4.26 (2H, d, J=5.5Hz), 5.12 (IH, dd, J=1.6Hz and 10.3Hz), 5.22 (IH, dd, J=1.6Hz and 17.2Hz), 5.81 - 6.00 (IH, m), 6.30 (IH, d, J=3.2Hz), 6.57 (IH, d, J=3.2Hz). 6.80 (IH, s), 7.43 (2H, s), 8.34 (IH, t, J=5.5Hz), Anal. Calcd. for Ci HιτN 5 0 2 S : C 52.65, H 5.37, N 21.93 Found : C 52.85, H 5.63, N 21.62 (5) 4-(5-Acetylaminomethylfuran-2-yl)-2-[(amino)(cyclohexyl- amino)methyleneamino]thiazole p : 154 to 155 93/03028 IR (Nujol) : 3390, 3060, 1665, 1590 cor 1 NMR (DMSO-dβ, δ ) : 1.30 - 1.90 (13H, m), 3.54 (IH, br), 4.26 (2H, d, J=5.5Hz), 6.30 (IH, d, J=3.2Hz), 6.53 (IH, d, J=3.2Hz), 6.76 (IH, s), 7.26 (2H, br), 8.34 (IH, t, J=5.5Hz) (6) 4-(5-Acetylaminomethylfuran-2-yl)-2-[(amino)(methylamlno)- methy1eneamino]thiazo1e mp : 188 to 189 . IR (Nujol) : 3400, 3350, 1630, 1585 cπr 1 NMR (DMS0-dβ, δ ) : 1.85 (3H, s), 2.74 (3H, d, J=4.8Hz), 4.26 (2H, d, J=5.5Hz), 6.29 (IH, d, J=3.2Hz), 6.60 (IH, d, J=3.2Hz), 6.77 (IH, s), 7.42 (2H, br), 8.35 (IH, t, J=5.5Hz) Anal. Calcd. for Ci2Hι 8 5 02S : C 49.13, H 5.15, N 23.87 Found : C 49.31, H 5.04, N 23.84 Example 3 A solution of 4-(5-acetylarainomethylfuran-2-yl)-2-[(amino)- (allyIamlno)methyleneamino]thiiazole (4.77 g) and cone- hydrochloric acid (5 ml) in ethanol (100 ml) was refluxed for 33 hours. After cooling, the resulting precipitate was collected by filtration to afford 4-(5-aminomethylfuran-2-yl)- 2-[(amino)(allylamino)methyIeneamino]thiazole dihydrochloride (3.7 g). mp : 259 to 260 * C- (dec. ) 3/03 IR (Nujol) : 3230, 3170, 1680, 1630 cm" 1 NMR (DMSO-dβ, δ ) 4.12 (4H, br), 5.25 (IH, dd, J=1.4Hz and 10.4Hz), 5.34 (IH, dd, J=1.4Hz and 17.3Hz), 5.87 - 6.01 (IH, m), 6.68 (IH, d, J=3.3Hz), 6.95 (IH, d, J=3.3Hz), 7.41 (IH, s), 8.30 - 9.30 (6H, br), 12.50 - 13.05 (IH, br), Example 4 The following compounds were obtained according to a similar manner to that of Example 3. (1) 4-(5-Aminomethylfuran-2-yl)-2-[(amino)(2-methoxyethylamino)- methyleneamino]thiazole dihydrochloride mp : 252 to 253 β C (dec.) IR (Nujol) : 3450, 3250, 1680, 1640, 1600 cm" 1 NMR (DMSO-dβ, δ ) : 3.35 (3H, s), 3.59 (4H, br), 4.13 (2H, br d, J=44Hz), 6.70 (IH, d, J=3.2Hz), 6.88 (IH, d, J=3.2Hz), 7.41 (IH, s), 8.60 - 8.68 (5H, br). 9.40 (IH, br), 12.99 (IH, br) (2) 4-(5-Aminomethylfuran-2-yl )-2-[ (amino) (n-butylamino)- methyleneamino] thiazole dihydrochloride mp : 270 to 276 β C (dec. ) IR (Nujol ) : 3410, 3340, 3080, 2700, 2620, 1700, 1640 cm- 1 NMR (DMSO-dβ , δ ) • 0.93 (3H, t, J=7.2Hz) , 93/03028 1.31 - 1. 63 (4H, mh 3.40 (2H, m) , 4. 12 (2H, br) , 6. 68 (IH, d, J=3.2Hz) , 6.92 (IH, d, J=3. 2Hz) , 7.40 (IH, s) , 8. 63 :(5H, br ) , 9.04 ( IH, br ) , 12.80 (IH, br) (3) 4-(5-AminomethyIfuran-2-yl)-2-[(amino)[2-(2-pyridyl)- ethylamino]methyleneaminp]thiazole trihydrochloride mp r 266 to 268 °0 (dec.) IR (Nujol) : 3210, 1660, 1600 cm" 1 NMR (DMSO-dβ, δ ) : 3.34 (2H, t, J=4.9Hz), 3.93 (2H, q, J=4.9H ), 4.14 (2H, q, J=5.5Hz), 6.66 (IH, d, J=3.4Hz), 6.91 (IH, d, J=3.4Hz), 7.40 (IH, s), 7.76 (IH, m), 7.96 (IH, m), 8.33 (IH, m), 8.62 - 8.86 (6H, m), 9.13 (IH, br) Example 5 A solution of 4-(5-aminomethylfuran-2-yl)-2-[(amino)- (ally1amino)methyleneamino]thiazole dihydrochloride (1.5 g) and potassium cyanate (0.73 g) in -water (30 ml) was stirred at room temperature for 4 hours. The resulting precipitate was collected by filtration. Recrystallization from a mixture of methanol and diisopropyl ether afforded 2-[(amino)(allyla ino)- methyleneamlnoI-4-(5-ureldomethylfuran-2-yl)thiazole hemi hydrochloride (0..50 g). mp : 120 to 122 "C (dec.) IR (Nujol) : 3420, 3230, 3120, 1620 cπr 1 3/03028 NMR (DMSO-dβ, δ) : 3.94; (2H, br), 4.20 (2H, d, J=5.7Hz), 5.18 (IH, dd, J=10.0 and 1.5Hz), 5.26 (IH, dd, J=16.0 and 1.5Hz), 5.59 (2H, s), 5.85 - 5.99 (IH, m), 6.28 (IH, d, J=3.2Hz), 6.42 (IH, t, J=5.7Hz), 6.69 (IH, d, J=3.2Hz), 7.03 (IH, s), 7.97 (2H, br), Anal. Calcd. for CuHiβNβOaS • 1/2HC1 • H*0 : C 43.78, H 5.23, N 23.57 Found : C 44.03, H 5.07, N 23.59 Example 6 The following compounds were obtained according to a similar manner to that of Example 5. (l) 2-[(Amino)(2-methoxyethylamino)methyleneamino]-4-(5- ureidomethylfuran-2-yl)thiazole mp : 152 to 155 °C (dec. ) IR (Nujol) : 3390, 3330, 3200, 3110, 1660, 1590 cm "1 NMR (DMSO-dβ, δ ) : 3.30 - 3.45 (7H, m), 4.19 (2H, d, J=5.7H-5), 5.57 (2H, s), 6.26 (IH, d, J=3.2Hz), 6.38 (IH, t, J-=5.7Hz), 6.58 (IH, d, J=3.2Hz), 6.78 (IH, s), 7.35 (2H, br) Anal. Calcd. for Cι 3 Hι«Nei0 3 S • 1/2H 2 0 : C-44.95, H 5.51, N 24.19, H 2 02.59 Found : C 144.94, H 5.62, N 23.96, H 2 02.88 (2) 2-[ (Amino) (n-butylamino)methyleneamino]-4-(5- ureidomethylf-uran-2-yl) thiazole mp : 123 to 124 °C IR (Nujol) : 3230, 1650, 1610 cm" 1 NMR (DMS0-dβ f δ ) : 0.91 (3H, t, J=7.0Hz), 1.29 - 1.48 (4H, m), 3.16 (2H, q, J=6.3Hz), 4.19 (2H, d, J=5.7Hz), 5.56 (2H, s), 6.25 (IH, d, J=3.2Hz), 6.37 (IH, t, J=5.7Hz), 6.54 (IH, d, J=3.2Hz), 6.76 (IH, s), 7.32 (2H, s) Anal. Calcd. for Cι*H2oNβ0 2 S- 1/2H 2 0 : C 48.68, H 6.13, N 24.33, H 2 02.61 Found : C 48.36, H 6.04, N 24.18, H 2 02.81 (3) 2-[(Amino)[2-(2-pyrldyl)ethylamino]methyleneamino]-4-(5- ureidomethyl uran-2-yI)thiazole p : 127 to 128 °C (dec.) IR (Nujol) : 3430, 3310, 3200, 1640 cπr 1 NMR (DMSO-dβ, δ) ■ 2.98 (2H, t, J=6.8Hz), 3.58 (2H, q, J=6.8Hz), 4.19 (2H, d, J=5.7Hz), 5.56 (2H, s), 6.25 (IH, d, J=3.1Hz), 6.38 (IH, t, J=5.7Hz), 6.53 (IH, d, J=3.1Hz), 6.76 (IH, s), 7.23 (IH, dd, J=7.6Hz and 4.5Hz), 7.32 (IH, br d, J=7.6Hz), 7.40 (2H, s), 7.72 (IH, dt, J=7.6Hz and 1.8Hz), 8.51 (IH, br d, J=4.5Hz) Anal. Calcd. for • 2H2O : 3/03028 C 48; 5, H 5. 50, N 23. 26, H 2 0 8. 55 Found : C 48. 12, H 5.35, N 23. 07, H 2 0 8. 77 Example 7 The following compounds were obtained according to a similar manner to that of Example 1. (1) 4-(5-Acetylaminomethyl-4--methylfuran-2-yl)-2-[(amino)- (methylamino)methyleneamino]thiazole mp : 171 to 172 V IR (Nujol) : 3400, 3260, 3120, 1630 cur 1 NMR (DMSO-dβ, δ ) : 1.82 (3H, s), 2.00 (3H, s), 2.74 (3H, d, J=4.8Hz), 4.22 (2H, d, J=5.4Hz), 6.50 (IH, s), 6.73 (IH, s), 7.41 (2H, br), 8.27 (IH, t,.J=5.4Hz) Anal. Calcd. for CιsHιτN 5 0 S • I/IOH2O : C 50.50, H 5.61, N 22.65 Found : C 50.34, H 5.48, N 22.59 (2) 4-(5-Acetylaminomethyl-4-methylfuran-2-yl)-2-[(amino)- (2-methoxyethylamino)methyleneamino]thiazole mp : 152 to 154 * C IR (Nujol) : 3450, 3320, 3200, 3130, 1640, 1600 cπr 1 NMR (DMSO-dβ, δ ) • 1.82 (3H, s), 1.99 (3H, s), 3.30 (3H, s), 3.36 (2H, t, J=4.5Hz), 3.43 (2H, q, J=4.5Hz), 4.21 (2H, d, J=5.4Hz), _, - ^ -. o 3/03028 6.49 (IH, s) , 6. 74 ( IH, s) , 7.35 (2H, br) , 8. 27 (IH, t, J=5.4Hz) Anal. Calcd. for Ci βfoiNsOsS : C 51.27, H 6.02, N 19. 93 Found : C 50.97, H 6.06, N 19. 65 (3) 4-(5-Acetylaminomethylfuraη-2-yl )-2-[ (amino) (2- hydroxyethylamino)methyleneamino]thiazole mp : 181 to 182 β C IR (Nujol) : 3450, 3350, 3280, 1630, 1600 cπr 1 NMR (DMSO-dβ, δ ) 1.85 (3H, s), 3.20 - 3.29 (2H, ), 3.47 - 3.55 (2H, m)» 4.26 (2H, d, J=5.5Hz), 4.87 (IH, t, J=5.0Hz), 6.29 (IH, d, J=3.2Hz), 6.61 (IH, d, J=3.2Hz), 6.77 (IH, s), 7.34 (2H, br), 8.32 (IH, t, J=5.5Hz) Example 8 The following compound was obtained according to a similar manner to that of Example 3. 4-(5-Aminomethylfuran-2-yl)-2-[(amino)(n-hexylamino)- methyleneamino]thiazole dihydrochloride. mp : 273 to 276 IR (Nujol) : 3310, 3250, 1700, 1640 cπr 1 NMR (DMSO-dβ, δ ) : 0.87, (3H, t, J=6.6Hz), 1.20 -.1.50 (6H, m), 1.50 - 1.70 (IH, d, J=3.2Hz), 3.37 (2H, m), 4.13 (2H, br), 6.68 (IH, d, J=3.2Hz), 6.42 (IH, d, J=3.2Hz), 7.40 (IH, s), 8.60 (4H, brs), 93/03028 9.02 (IH, br), 12.80 (IH, br) Example 9 The following compound was obtained according to a similar manner to that of Example 5. 2-[(Amino)(n-hexylamino)methyleneamino]-4-(5-ureidomethyl- furan-2-yl)thiazole. mp : 98 to 100 t IR (Nujol) : 3320, 1640 cm" 1 NMR (DMSO-dβ, δ ) : 0.87 (3H, t, J=6.4Hz), 1.10 - 1.40 (6H, m), 1.40 - 1.60 (2H, m), 3.16 (2H, q, J=5.7Hz), 4.19 (2H, d, J*=5.7Hz), 5.56 (2H, s), 6.25 (IH, d, J=3.2Hz), 6.38 (IH, t, J=5.7Hz), 6.54 (IH, d, J=3.2Hz), 6.76 (IH, S), 7.31 (2H, br) Anal. Calcd. for Cι H 2 4N β 0 2 S • 2/3H 2 0 : C 51. 05, H 6. 78, N 22. 32 Found : C 51. 14, H 6. 80, N 22. 50 Example 10 A solution of acetoxyacetyl chloride (1.3 g) in dlchloromethane (10 ml) was added slowly to a solution of 4-(5- aminomethylfuran-2-yl)-2-[(amino)(2-methoxyethy1amino)- methyleneamino]thiazole dihydrochloride (3.0 g) and triethylamine (2.0 g) in dlchloromethane (40 ml) with cooling on an ice bath. The mixture was stirred for 8 hours with cooling 93/03028 on an ice bath. The solvent was removed under reduced pressure. The residue was suspended in water (100 ml). The mixture was alkalized with an aqueous potassium carbonate solution and then was extracted with a mixture of ethyl acetate (250 ml) and tetrahydrofuran (50 ml). The extract was dried with magnesium sulfate. The solvent was removed under reduced pressure. Recrystallization from a mixture of ethanol and water to afford 4-(5-acetoxyacetylaminomethylfuran-2-yl)-2-[(amIno)(2- methoxyethylamIno)methyleneamino]thlazoIe (2.4 g). mp : 112 to 113 V IR (Nujol) : 3350, 1750, 1660 cm" 1 NMR (DMSO-dβ, δ ) ' 2.09 (3H, s), 3.30 (3H, s), 3.36 (2H, t, J=4.5HZ), 3-43 (2H, q, J=4.5Hz), 4.32 (2H, , : J=5.6Hz), 4.49 (2H, s), 6.30 (IH, d, J=3.2Hz), 6.59 (IH, d, J=3.2Hz), 6.78 (IH, s) , 7.35 (2H, br) , 8.55 (IH, t, J=5. 6Hz) Anal. Calcd. for Ci βfo iNβOa S • I/3H2O : C 46.99, H 5.55, N 17. 13 Found : C 47. 17, H 5.45, N 16. 82 Example 11 The following compound was obtained according to a similar manner to that of Example 10. 2-[(Amino)(2-methoxyethylamlno)methyleneamlno]-4-(5- methoxycarbonyIaminomethylfuran-2-yl)thiazole. mp : 93 to 95 T. IR (Nujol ) : 3310, 3200, 1700, 1660, 1590 cπr 1 NMR (DMSO-dβ , δ ) : 3.30 - 3.50 (7H, m) , 3.56 (3H, s) , 4.20 (2H, d, J=5.8Hz), 6. 28 (IH, d, J=3.2Hz) , 6.58 (IH, d, J=3.2Hz) , 6.77 (IH, s) , 7.35 (2H, br) , 7. 69 (IH, t, J=5.8Hz) Anal . Calcd. for Cι ,Hι β N 8 0 < S • 1/2H*0 : C 46.40, H 5.56, N 19.32 Found : C 46.38, H 5.42, N 19.18 Example 12 The following compounds were obtained according to a similar manner to that of Example 1. (1) 4-(5-Acetylaminomethylfuran-2-yl)-2-[(amino)(ethylamlno)- methyleneamino]thiazole mp : 170 to 171 °C IR (Nujol) : 3470, 3280, 3100, 1650, 1600 cπr 1 NMR (DMSO-dβ, δ ) : 1.10 (3H, t, J=7.1Hz), 1.85 (3H, s), 3.12 - 3.25 (2H, m),- 4.26 (2H, d, J=5.5Hz), 6.29 (IH, d, J=3.2Hz), 6.56 (IH, d, J=3.2Hz), 6.77 (IH, s), 7.38 (2H, br), 8.35 (IH, t, J=5.5Hz) Anal. Calcd. for : C 50.80, H 5.57, N 22.78 Found : C 50.89, H 5.47, N 22.45 (2) 4-(5-Acetylaminomethylfuran-2-yl)-2-[(amino)(n-propylamino)- methyleneamlno]thiazole mp : 155 to 156 β C . „„„„ 3/03028 IR (Nujol ) : 3460, 3320,. 3210, 1640, 1600 cπr 1 NMR (DMSO-dβ , δ ) ■ 0.91 (3H, t, J=7.3Hz) , 1.42 - 1. 60 (2H, m)., 1. 85 (3H, s), 3.08 - 3. 17 (2H, m) , 4. 26 (2H, d, J=5.5Hz) , 6.30 ( IH, d, J=3.2Hz) , 6.55 (IH, d, J=3.2Hz) , 6. 77 (IH, s) , 7.33 (2H, br), 8.35 (IH, t, J=5.5Hz) (3) 4-(5-Acetylamlnomethylfuran-2-yl)-2-[(amino)(2-ethoxyethyl- amino)methyleneamino]thiazole mp : 144 to 145 β C IR (Nujol) : 3460, 3300, 3100, 1650, 1590 cπr 1 NMR (DMSO-dβ, <5 ) : 1.14 (3H, t, J=7.0Hz), 1.85 (3H, s), 3.31 - 3.33 (2H, m), 3.43 - 3.53 (4H, m), 4.26 (2H, d, J=5.5Hz), 6.29 (IH, d, J=3.2Hz), 6.59 (IH, d, -1=3.2Hz), 6.78 (IH, s), 7.37 (2H, br), 8.34 (IH, t, J=5.5Hz) Anal. Calcd. for Ci5H2i 5 0«S : C 51.27, H 6.02, N 19.93 Found : C 51.30, H 6.15, N 19.88 (4) 4-(5-Acetylamlnomethylfuran-2-yl)-2-[(amino)(3-methoxy- proρylamino)methyleneamino]thiazole mp : -135 to 136 °C IR (Nujol) : 3280, 3130, 1650, 1600 cπr 1 NMR (DMSO-dβ, δ ) '• 1.66 - 1.79 (2H, m), 1.85 (3H, s), 3.16 - 3.23 (5H, m), 3.33 - 3.42 (2H, m), 4.26 (2H, d, J=5.5Hz), 6.30 (IH, d, J=3.2Hz), 6.56 (IH, d, J=3.2Hz), 6.77 (IH, S), 7.37 (2H, br), 8.34 (IH, t, J=5.5Hz) Anal. Calcd. for C ϊ5 H2iN s 0 3 S : C 51.27, H 6.02, N 19.93 Found : C 51.29, H 6.07, N 19.79 Example 13 The mixture of 2-acetylaminomethyl-5-chloroacetylfuran (2.7 g) and N-propargylamidinothiourea (2.5 g) In ethanol (20.0 ml) was stirred for 3 hours at 70 β C. To the reaction mixture was added an ethyl acetate (20.0 ml) and isolated precipitate was collected by filtration. The precipitate was recrystallized from a mixture of methanol and diisopropyl ether to give 4-(5-acetylaminomethyl- furan-2-yl)-2-[(amino)(propargylamino)methyleneamino]thiazole hydrochloride (1.55 g). mp : 209 to 210 Ip IR (Nujol) : 3280, 3180, 1630 cm" 1 NMR (D 2 0, δ ) 2.07 (3H, s), 2.91 (IH, t, J=2.4Hz), 4.10 (2H, d, J=2.4Hz), 4.40 (2H, S), 6.38 (IH, d, J=3.3Hz), 6.53 (IH, d, J=3.3Hz), 7.12 (IH, S) Anal. Calcd. for Ci Hι 5 N 3 0 2 S» HCl • 1/3H 2 0 : C 46.73, H 4.67, N 19.46, Cl 9.85, H 2 01.67 Found : C 46.96, H 4.69, N 19.15, Cl 9.81, H 2 0 1.71 Example 14 93/03028 A suspension of 4-(5-acetoxyacetylaminomethylfuran-2-yl)-2- [(amino)(2-methoxyethylamino)methyleneamino]thlazole (1.6 g) in a saturated methanolic ammonia solution (50 ml) was stirred for 3 hours with cooling on an ice bath. The solvent was removed under reduced pressure. Recrystallization from methanol afforded 2-[(amino)(2-methoxyethylamino)methyleneamino]-4-(5- hydroxyacetylaminomethylfuran-2-yl)thiazole (0.9 g). mp : 104 to 105 * C IR (Nujol) : 3620, 3430, 3110, 1660, 1620 cm- 1 NMR (DMSO-dβ, δ ) : 3.30 (3H, S), 3.36 (2H, t, J*=4.5Hz), 3.43 (2H, q, J*=4.5Hz), 3.85 (2H, d, J=5.9Hz), 4.32 (2H, d, ' 5.49 (IH, t, J=5.9Hz), 6.28 (IH, d, J=3.2Hz), 6.58 (IH, d, J=3.2Hz), 6.77 (IH, s)., 7.34 (2H, br), 8.19 (IH, t, J=6.0Hz) Anal. Calcd. for CnHigNsOiS - 7/4H 8 0 : C 43.68, H 5.89, N 18.19 Found : C 43.87, H 5.83, N 18.17 Example 15 A mixture of 2-[(amino)(allylamino)methyleneamlno]-4-(5- ureidomethylfuran-2-yl)thiazole hemi hydrochloride (950 mg) in water (20 ml) was alkalized with 20% aqueous potassium carbonate solution to pH 10. The mixture was stirred at room temperature for 1 hour and then was extracted with a mixture of ethylacetate (150 ml) and tetrahydrofuran (50 ml). The extract was dried with magnesium sulfate. The solvent was removed 93/03028 under reduced pressure. Recrystallization from a mixture of methanol and water afforded 2-[(amino)(allylamino)- methyleneamino]-4-(5-ureidomethylfuran-2-yl)thlazole (650 rag), mp : 88 to 89 β C IR (Nujol) : 3430, 3220, 1630, 1600 cm" 1 NMR (DMSO-dβ, δ ) : 3.84 (2H, t, J=5.4Hz), 4.19 (2H, d, J-=5.7Hz), 5.12 (IH, dd, J=10.3 and 1.7Hz), 5.22 (IH, dd, J=17.2 and 1.7Hz), 5.56 (2H, s), 5.81 - 6.00 (IH, m), 6.25 (IH, d, J=3.2Hz), 6.38 (IH, t, J=5.7Hz), 6.57 (IH, d, J=3.2Hz), 6.79 ( IH, s) , 7.43 (2H, br) Anal. Calcd. for CnHi βNβOiS • H 2 0 : C 46. 14, H 5.36, N 24.84 Found : C 46.02, H 5.34, N 24. 80 Example 16 The following compounds were obtained according to a similar manner to that of Example 3. (1) 4-(5-Amlnomethylfuran-2-yl)-2-[(amino)(methyla ino)- methyleneamlno]thiazole dihydrochloride mp : 269 to 270 °C (dec.) IR (Nujol) : 3300, 1700, 1640 cm" 1 NMR (DMSO-dβ, δ ) : 3.16 (3H, d, J=4.9Hz), 4.12 (2H, br), 6.68 (IH, d, J=3.3Hz), 7.05 (IH, d, J=3.3Hz), 7.41 (IH, s), 8.63 - 8.90 (6H, br), 12.91 (IH, br) 93/03028 (2) 4-(5-Amlnomethylf uran-2-yl)-2-[ (amino) (ethylamino)- methyleneami no] thiazole dihydrochloride mp : 275 to 277 * C IR (Nujol) : 3310, 1700, 1640 Cm" 1 NMR (DMSO-dβ, δ ) : 1.21 (3H, t, J=7.1Hz), 3.30 - 3.50 (2H, m), 4.12 (2H, br), 6.68 (IH, d, J=3.3Hz 6.96 (IH, d, J=3.3Hz), 7.40 (IH, s), 8.64 (5H, br), 8.97 (IH, br) (3) 4-(5-Aminomethylfuran-2-yl)-2-[ (amino) (n-propylamino)- methyleneamino] thiazole dihydrochloride mp : 272 to 274 ID (dec.) IR (Nujol) : 3450, 3270, 1680, 1630 cur 1 NMR (DMSO-dβ, δ ) ■ 0.96 (3H, t, J=7.3Hz), 1.53 - 1.67 (2H, m), 3.34 - 3.42 (2H, m), 4.12 (2H, br), 6.69 (IH, d, J=3.2Hz), 6.94 (IH, d, J=3.2Hz), 7.42 (IH, s), 8.70 (5H, br s), 9.08 (IH, br), 12.89 (IH, br) (4) 4-(5-Aminomethylfuran-2-yI)-2-[(amlno)(2-ethoxyethylamino)- methyleneamino]thiazole dihydrochloride mp : 266 to 268 "C (dec.) IR (Nujol) : 3300, 3250, 1700, 1640 cm" 1 NMR (DMSO-dβ., δ) : 1.13 (3H, t, J=7.0Hz), 3.48 - 3.62 (6H, m), 4.12 (2H, br), 6.69 (IH, d, J=3.2Hz), 6.91 (IH, d, J=3.2Hz), 3/03028 7. 41 ( IH, s) , 8. 61 - 8. 68 (5H, br) , 9.34 ( IH, br ) , 13.01 ( IH, br) (5) 4-(5-Aminomethylfuran-2-yl)-2-[(amino)(3-methoxypropyl- amino)methyleneamino]thiazole dihydrochloride mp : 263 to 265 * C (dec.) IR (Nujol) : 3300, 3090, 1690, 1640 cm" 1 NMR (DMSO-dβ, δ ) • 1.82 - 1.91 (2H, m), 3.24 (3H, s), 3.40 - 3.49 (4H, m), 4.14 (2H, br), 6.69 (IH, d, J=3.3Hz), 6.95 (IH, d, J=3.3Hz), 7.41 (IH, s), 8.66 (5H, br), 9.09 (IH, br), 12.83 (IH, br) Example 17 The following compounds were obtained according to a similar manner to that of Example 5. (1) 2-[(Amino)(ethylamino)methyleneamino]-4-(5-ureidomethyl- furan-2-yl)thiazole mp : 184 to 185 * C IR (Nujol) : 3320, 1630 cm" 1 NMR (DMSO-dβ, δ ) • 1.10 (3H, t, J=7.1Hz), 3.12 - 3.25 (2H, m), 4.19 (2H, d, J=5.7Hz), 5.56 (2H, s), 6.25 (IH, d, J=3.2Hz), 6.38 (IH, t, J=5.7Hz), 6.55 (IH, d, J=3.2Hz), 6.76 (IH, s), 7.38 (2H, br) Anal. Calcd. for & 2 H, ■ βNβ0 2 S • I/2H2O : 3/03028 C 45.41, H 5.40, N 26.48 Found : C 45.31, H 5.49, N 26.40 (2) 2-[(Amino)(n-proρylamino)methyleneamino]-4-(5-ureidomethyl- furan-2-yl)thiazole mp : 173 to 174 V IR (Nujol) : 3430, 3350, 3120, 1630, 1600 cm" 1 NMR (DMSO-dβ, δ ) : 0.92 (3H, t, J=7.3Hz), 1.42 - 1.60 (2H, m), 3.08 - 3.1 (2H, m), 4.19 (2H, d, J=5.7Hz), 5.57 (2H, s), 6.25 (IH, d, J=3.2Hz), 6.38 (IH, t, J=5.7Hz), 6.54 (IH, d, J=3.2Hz), 6.76 (IH, s), 7.33 (2H, br s) Anal. Calcd. for Cι 3 HιβNβθ2S • 1/lOHjO : C 48.16, H 5.66, N 25.92 Found : C 48.14, H 5.81, N 25.69 (3) 2-[(Amino)(3-methoxypropylamlno)methyleneam!no]-4-(5- ureidomethylfuran-2-yl)thiazole mp : . 164 to 165 "C IR (Nujol) : 3370, 3300, 3250, 3130, 1660, 1640, 1610 cur 1 NMR (DMSO-dβ, δ ) : 1.66 - 1.79 (2H, m), 3.16 - 3.24 (5H, m), 3.36 - 3.45 (2H, tn), 4.19 (2H, d, J=5.7Hz), 5.56 (2H, s), 6.25 (IH, d, J=3.2Hz), 6.38 (IH, t, J=5.7Hz), 6.56 (IH, d, J=3.2Hz), 6.77 (IH, s), 7.38 (2H, br) Anal. Calcd. for Cu oNβOaS. I/IOH 2 O : 3/03028 C 47.47, H 5.75, N 23.73 Found : C 47.38, H 5.69, N 23.42 (4) 2-[(Amino)(2-ethoxyethylamino)methyleπeamino]-4-(5- ureidomethylfuran-2-yl)thiazole mp : 174 to 175 V IR (Nujol) : 3330, 3180, 1650, 1620 cm" 1 NMR (DMSO-dβ, δ ) : 1.14 (3H, t, J=7.0Hz), 3.34 - 3.53 (6H, m), 4.19 (2H, d, J-=5.7Hz), 5.57 (2H, s), 6.25 (IH, d, J=3.2Hz), 6.38 (IH, t, J=5.7Hz), 6.59 (IH, d, J=3.2Hz), 6.77 (IH, s), 7.36 (2H, br) Anal. Calcd. for CufooNβOsS : C 47.71, H 5.72, N 23.85 Found : C 47.39, H 5.99, N 23.55 Example 18 A solution of 4-(5-aminomethylfuran-2-yl)-2-[(amino)(3- methoxyρroρylamino)methyleneamino]thiazole (1.0 g), triethyl¬ amine (800 mg) and dimethyl N-cyanodithioiminocarbonate (460 mg) in N,N-dimethylformamide (20 ml) was heated at 70 ϊ for 4.5 hours. After cooling, 30% ethanolic methylamine solution (20 ml) was added and the mixture was stirred for 24 hours at room temperature. The solvent was removed under reduced pressure. The residue.was dissolved in water (50 ml) and tetrahydrofuran (50 ml). The mixture was alkalized with 20% aqueous potassium carbonate solution to pH 10 and then was extracted with ethyl 93/03028 acetate (200 ml). The extract was dried with magnesium sulfate. The solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column eluting with chloroform : methanol = 20 : 1. The solvent was removed under reduced pressure and the residue was crystallized from ethyl acetate. Recrystallization from a mixture of methanol and diisopropyl ether afforded 2-[(amino)(3-methoxypropylamino)- methyleneamlno]-4-[5-(2-cyano-3-methylguanidlno)methylfuran-2- yl]thiazole (270 mg). mp : 129 to 131 IR (Nujol) : 3400, 3260, 3120, 2170, 1670, 1630 cm" 1 NMR (DMSO-dβ, δ ) ' 1.66 - 1.79 (2H, m), 2.71 (3H, d, J=4.6Hz), 3.17 - 3.24 (5H, m), 3.36 - 3.42 (2H, m), 4.34 (2H, d, J=5.6Hz), 6.31 (IH, d, J=3.2Hz), 6.58 (IH, d, J=3.2Hz), 6. 77 ( IH, s) , 7. 14 ( IH, q, J=4. 6Hz) , 7.39 (2H, br) , 7. 48 (IH, t, - J=5.6Hz) Anal . Calcd. for Cι βH2 N 8 0 2 S « I/IOH2 O : C 48. 99, H 5. 70, N 28. 57 Fouηd : C 48.77, H 5. 73, N 28. 29 Example 19 The following compounds were obtained according to a similar manner to that of Example 18. (1) 2-[(Amino)(methylamino)methyIeneamino]-4-[5-(2-cyano-3- methylguanidlno)methylfuran-2-yl]thlazoIe 3/03028 mp : 110 to 111 V (dec.) IR (Nujol) : 3380, 3230, 2170, 1655 cπr 1 NMR (DMSO-dβ, δ ) - 2.71 (3H, d, J=4.7Hz), 2.74 (3H, d, J=4.9Hz), 4.34 (2H, d, J=5. 6Hz) , 6.31 ( IH, d, J=3.2Hz) , 6.61 (IH, d, J=3.2Hz) , 6.77 (IH, S) , 7. 13 (IH, q, J=4. 7Hz), 7.35 - 7.50 (3H, br) Anal . Calcd. for CuHi βN.OS : C 46.98, H 4.85, N 33.71 Found : C 46.85, H 4.89, N 33.46 (2) 2-[(Amino)(ethylamino)methyleneamino]-4-[5-(2-cyano-3- methylguanidlno)methylfuran-2-yl]thiazole mp : 172 to 173 IR (Nujol) : 3440, 3360, 3250, 2150, 1630, 1600 cm" 1 NMR (DMSO-dβ, δ ) - 1.11 (3H, t, J=7.1Hz), 2.71 (3H, d, J=4.6Hz), 3.12 - 3.25 (2H, m), 4.34 (2H, d, J=5.7Hz), 6.31 (IH, d, J=3.2Hz), 6.57 (IH, d, J=3.2Hz), 6.76 (IH, s), 7.13 (IH, q, J=4.6Hz), 7.38 (2H, br), 7.48 (IH, t, J*=5.7Hz) Anal . Calcd. for CnHi βNβOS • I/IOH2O : C 48.29, H 5.27, N 32. 18 Found : C 48.32, H 5.30, N 31.89 (3) 2-[ (Amino) (n-proρylamlno)methyleneamino]-4-[5-(2-cyano-3- methylguanidlno)methylfuran-2-yl] thiazole 93/03028 mp : 189 to 190 C IR (Nujol) ϊ 3490, 3440, 3220, 2150, 1630, 1600 eπr 1 NMR (DMSO-dβ, δ ) ■ 0.92 (3H, t, J=7.3Hz), 1.42 - 1.60 (2H, m), 2.71 (3H, d, J=4.7Hz), 3.08 - 3.18 (2H, m), 4.34 (2H, d, J=5.7Hz), 6.31 (IH, d, J=3.2Hz)., 6.56 (IH, d, J=3.2Hz), 6.76 (IH, s), 7.13 (IH, q, J=4.7Hz), 7.33 (2H, br), 7.47 (IH, t, J=5.7Hz) (4) 2-[(Amino)(n-butylamino)methyleneamino]-4-[5-(2-cyano-3- methylguanidino)methylfuran-2-yl]thiazole mp r 190 to 191 " C IR (Nujol) : 3480, 3400, 3230, 2150, 1650 cm- 1 NMR (DMSO-dβ, δ ) - 0.91 (3H, t, J=6.9Hz), 1.26 - 1.52 (4H, m), 2.71 (3H, d, J=4.6Hz), 3.12 - 3.21 (2H, m), 4.34 (2H, d, J=5.7Hz), 6.31 (IH, d, J=3.2Hz), 6.55 (IH, d, J=3.2Hz), 6.76 (IH, s), 7.13 (IH, q, J=4.6Hz), 7.32 (2H, br), 7.47 (iH, t, J=5.7Hz) Anal. Calcd. for CιβH I1 N,0S : C 51.32, H 5.92, N 29.92 Found : C 50.90, H 6.09, N 29.82 (5) 2-[ (Amino) (al lyIamino)methyleneamino]-4-[5-(2-cyano-3- methylguanidino)methylfuran-2-yl] thiazole mp : 166 to 167 *C IR (Nujol ) : 3420, 3200, 2140, 1630, 1600 cπr 1 NMR (DMSO-dβ , δ ) Ϊ 2. 71 (3H, d, J=4. 7Hz) , 3.80 - 3.90 (2H, m), 4.34 (2H, d, J=5.7Hz), 5.11 (IH, dd, J*=1.7 and 10.2Hz), 5.22 (IH, dd, J=1.7 and 17.2Hz), 5.81 - 5.97 (IH, m), 6.31 (IH, d, J=3.2Hz), 6.59 (IH, d, J=3.2Hz), 6.79 (IH, s), 7.13 (IH, q, J*=4.7Hz), 7.35 - 7.50 (3H, br) Anal. Calcd. for CieH_.iN.0S-.1/4H 2 0 : C 49.64, H 5.14, N 30.88 Found : C 49.71, H 5.08, N 30.73

Claims: CLAIMS 1. A compound of the formula : wherein R 1 is methyl, ethyl, propyl, butyl, hexyl, lower alkoxy(lower)alkyl, lower alkenyl, lower 10 alkynyl, cyclo(lower)alkyl, heterocyclic(lower)alkyl or hydroxy(lower)alkyl, R 2 is hydrogen, R 8 is hydrogen or lower alkyl, 15 R 4 is amino, acyl, acylamino, lower alkyllsothioureldo, heterocyclic amino, heterocyclic group, or a group of the formula : X-R s 20 II -(NH) a -C-R β in which n is 0 or 1, X is =CH- or =N-, R 5 is hydrogen, cyano, nitro or 25. acyl, and R β is hydrogen, lower alkyl, lower 3/03028 alkylthio, lower alkoxy or amino which may have suitable substituent(s), and A Is lower alkylene or.-CONH- ; or A-R 4 is heterocyclic group, and Q is hydrogen or lower alkyl, provided that when R 1 is methyl, then R 4 is amino, lower alkanoylamino or a group of the formula : X-R 5 in: which n, X, R 8 and R β are each as defined above, and pharmaceutically acceptable salt thereof. 2. A compound of claim 1, wherein R 1 is lower alkoxy(lower)alkyl, lower alkenyl, lower alkynyl, cyclo(iower)alkyl, pyridyl(lower)alkyl or hydroxy(lower)alkyl, R 4 is acylamino or 2-cyano-3-lower alkylguanidlno, and A is lower alkylene. 3. A compound of claim 2, wherein R 4 is ureido, lower alkanoylamino, lower alkoxycarbonylaraino, lower alkanoyloxy(lower)alkanoylamino, hydroxy(lower)alkanoylamino or 2-cyano-3-lower 93/03028 alkylguanidlno. 4. A compound of claim 3, wherein R 1 is methoxyethyl, ethoxyethyl, methoxypropyl, cyclohexyl, propenyl, propynyl, pyridylethyl or hydroxyethyl, R 3 is hydrogen, R 4 is ureido, acetylamino, methoxycarbonylamino, acetoxyacetyla lno, hydroxyacetylamlno or 2-cyano-3-methylguanldino, A is methylene, and Q Is hydrogen or methyl. 5. A compound of claim 1, wherein R 1 is methyl, ethyl, propyl, butyl or hexyl, R 4 is acylamino or 2-cyaπo-3-lower alkylguanidlno, and A is lower alkylene. 6. A compound of claim 5, wherein R 4 is ureido, lower alkanoylamino or 2-cyano-3-lower alkylguanidlno. 7. A process for preparing a compound of the formula : 8 wherein R 1 is methyl, ethyl, propyl, butyl, hexyl, lower alkoxy(lower)alkyl, lower alkenyl, lower alkynyl, cyclo(lower)alkyl, heterocyclic(lower)alkyl or hydroxy(lower)alkyl, R* is hydrogen, R 8 Is hydrogen or lower alkyl, R 4 is amino, acyl, acylamino, lower alkyllsothioureldo, heterocyclic amino, heterocyclic group, or a group of the formula : X-R β in which n is 0 or 1, X is =CH- or =N-, R* is hydrogen, cyano, nitro or acyl, and R β is hydrogen, lower alkyl, lower alkylthio, lower alkoxy or amino which may have suitable substituent(s), and A is lower alkylene or -CONH- ; or A-R 4 is heterocyclic group, and Q is hydrogen or lower alkyl, provided that when R 1 is methyl, then R 4 is amino, lower alkanoylamino or 93/03028 a group of the formula : X-R 5 in which n, X, R 5 and R β are each as defined above, or a salt thereof, which comprises (1) subjecting a compound of the formula : wherein R 1 , R 2 , R 3 , A and are each as defined above, and R 4 a is acylamino, or a salt thereof, to deacylation reaction, to give a compound of the formula . * wherein R 1 , R 2 , R 3 , A and Q are each as defined above, or a salt thereof, or (2) subjecting a compound of the formula : /03028 wherein R 1 , R 2 , R 8 , A and are each as defined above, or a salt thereof, to acylatlon reaction, to give a compound of the formula : wherein R 1 , R 2 , R 8 , R 4 a, A and Q are each as defined above, or a salt thereof, or (3) reacting a compound of the formula : wherein R 2 , R 3 , R 4 , A and Q are each as defined above, and R 18 is lower alkyl, or a salt thereof, with a compound of the formula : wherein R 1 is as defined above, 3/03028 or a salt thereof, to give a compound of the formula : wherein R 1 , R 2 , R 3 , R 4 , A and Q are each as defined above, or a salt thereof, or (4) reacting a compound of the formula : wherein R 3 , R*. A and Q are each as defined above, and Z l is acid residue, or a salt thereof, with a compound of the formula : S R^H II C=N-C-NHι R 2 NH wherein R 1 and R 2 are each as defined above, to give a compound of the formula : /03028 wherein R 1 , R 1 , R 8 , R 4 , A and Q are each as defined above, or a salt thereof, or (5) reacting a compound of the formula : wherein R 1 , R 2 , R 3 , A and Q are each as defined above, or a salt thereof, with a compound of the formula : (R r -X 1 )»C*=X-R 8 wherein R 8 and X are each as defined above, R 7 is lower alkyl or aryl, and X 1 is S or 0, to give a compound of the formula : wherein R\ R 2 , R 3 , R 5 , R\ X, X 1 , A and Q are each as defined above, or a salt thereof, or 6) reacting a compound of the formula : /03028 -R τ wherein R 1 , R 1 , R 8 , R s , R 7 , X, X 1 , A and Q are each as defined above, or a salt thereof, with a compound of the formula : H - R β a wherein R β a Is amino which may have suitable substituent(s) or lower alkoxy, to give a compound of the formula : wherein R 1 , R 2 , R 8 , R 6 , R 8 a, X, A and Q are each as defined above, or a salt thereof, or (7) subjecting a compound of the formula : /03 wherein R 1 , R 2 , R 3 , A and Q are each as defined above, and R-d is acylamino including protected hydroxy, or a salt thereof, to elimination reaction of the hydroxy protective group, to give a compound of the formula : wherein R 1 , R 2 , R a , A and are each as defined above, and R e is acylamino including hydroxy, or a salt thereof. 8. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers. 9. A method for the treatment.of ulcer which comprises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to human or animals. 10. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof as antiulcer agent, H 2 -receptor antagonist and antimicrobial agent.

Inventors: INOUE YOSHIKAZU, KATSURA YOUSUKE, TAKASUGI HISASHI, TOMISHI TETSUO, INOUE, YOSHIKAZU, KATSURA, YOUSUKE, TAKASUGI, HISASHI, TOMISHI, TETSUO
Applicants: FUJISAWA PHARMACEUTICAL CO, FUJISAWA PHARMACEUTICAL CO., LTD.
Application year: 1992
Main classification: A61K31
IPC codes: A61K31, A61P1, A61P31, C07D417