WO1992016526A1

WO1992016526A1 - Thiazole derivatives

Info

Publication number: WO1992016526A1
Application number: PCT/JP1992/000279
Authority: WO
Inventors: Hisashi Takasugi; Yousuke Katsura; Yoshikazu Inoue; Tetsuo Tomishi
Original assignee: Fujisawa Pharmaceutical Co., Ltd.
Priority date: 1991-03-13
Filing date: 1992-03-09
Publication date: 1992-10-01
Also published as: JPH06505724A; EP0575614A1; CA2105981A1

Abstract

Thiazole derivatives of formula (I) or a salt thereof, which are useful as antiulcer agent, H2-receptor antagonist or antimicrobial agent.

Description

DESCRIPTION

THIAZOLE DERIVATIVES

5 This invention relates to new thiazole derivatives and pharmaceutically acceptable salts thereof.

More particularly, it relates to thiazole derivatives and pharmaceutically acceptable salts thereof which have antiulcer activity and H₂-receptor antagonism, to 10 processes for the preparation thereof, to a pharmaceutical composition comprising the same and to a method for the treatment of ulcer in human being or animals.

Accordingly, one object of this invention is to provide new thiazole derivatives and pharmaceutically 15 acceptable salts thereof which possess antiulcer activity and H_-receptor antagonism.

Another object of this invention is to provide processes for the preparation of said thiazole derivatives and salt thereof. 20 A further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said thiazole derivatives or pharmaceutically acceptable salts thereof.

Still further object of this invention is to provide 25 a therapeutical method for the treatment of ulcer in human being or animals.

The thiazole derivatives of this invention are new and can be represented by the following general formula (I) :

30

35 _ ^•> _

wherein R is amino which may have suitable substituent(s), hydroxy, halogen, cyano, acyl, heterocyclic thio, heterocyclic group or a group of the formula :

Z-R-

-C-R⁶

in which R is hydrogen, cyano or acyl, """ R is amino or lower alkoxy, and

Z is N or CH, R 2, R3 and R8 are each hydrogen, acyl, lower alkyl which may have suitable substituent(s),

(C₃-C₇)-cycloalkyl, lower alkenyl or lower 5 alkynyl; or two of R 2 , R3 and R8 are linked together to form lower alkylene optionally interrupted by hetero atom, and the other is as defined above, 0 R4 is hydrogen or lower alkyl,

IS —HI—(j^N— , in which R7 is hydrogen

5 or halogen, and is bond or lower alkylene.

provided that 0 (1) when R1 is amino which may have suitable substituent(s) and A is bond; or

R iiss lloowweerr aallkkyylltthhiioouurreido and A is lower alkylene, then Y is and further

(2) when one of R 2 and R3 is hydrogen, acyl or lower alkyl which may have halogen, 4 R is hydrogen and g

R is hydrogen, then the other of R 2 and R3 is

(C₃-C₇)-cγcloalkyl, lower alkenyl, lower alkynyl or lower alkyl which has suitable substituent(s) excepting halogen.

The object compound (I) or a salt thereof can be prepared by processes as illustrated in the following reaction schemes.

Process 1

(ID (III) or a salt thereof or a salt thereof

(I) or a salt thereof Process 2

N N- -y-A-R. Elimination of the amino protective group

C=N-

R³NH

(1-1) or a salt thereof

(1-2) or a salt thereof

Process 3

Acylation

(1-2) or a salt thereof

(1-3) or a salt thereof Process 4

( 1-2 ) or a salt thereof

(1-4) or a salt thereof

Process 5

(V) or a salt thereof

(1-5) or a salt thereof Process 6

(1-6) or a salt thereof

(1-7) or a salt thereof

Process 7

,8 Elimination of the hydroxy

N N- -Y-A-R. protective group

\

C=N-

R³NH R^'

(1-8) or a salt thereof

(1-9) or a salt thereof Process 8

Elimination of the amino

R'

N N- -Y-A-R protective group

R"

C=N-

R³NH

( 1-10 ) or a salt thereof

(1-11) or a salt thereof

wherein R , R , R , R , R , Y and A are each as defined above,

R is protected amino, R, 1 i.s acylammo,

R is acylamino having protected hydroxy, R 1- is acylamino having hydroxy,

R is acylamino having protected amino.

R_f is acylamino having amino. R 9 is lower alkylthio or protected hydroxy,

R is hydrogen, cyano, nitro or acyl,

R is lower alkyl, R 12 is lower alkyl, R 13 is am o which may have suitable substituent(s) ,

X is aicciidd rreessi.due, and is N or CH.

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 alkoxy" may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, and the like.

Suitable "lower alkylthio" may include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio, hexylthio, and the like.

Suitable "acid residue" may include halogen such as chloro, bromo, fluoro and iodo.

Suitable "lower alkylene" and lower alkylene moiety formed by linkage of R 2 and R3 may be straight or branched one such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, and the like, in which the preferable one is C--C. alkylene and the most preferable one is methylene and ethylene. 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, ethylamino, butylamino, etc.), lower alkenylamino (e.g. vinylamino, propenylamino, etc.), lower alkynylamino (e.g. ethynylamino, propynylamino, etc. ) , hydroxy(lower)- alkylamino (e.g. hydroxymethylamino, hydroxyethylamino, hydroxypropylammo, etc.), lower alkoxy(lower)alkylamino (e.g. methoxymethylamino, etc. ) , mono or di(lower)- alkylamino(lower)alkylamino (e.g. methylaminomethylamino, dimethylaminoethylamino, etc.), protected amino such as acylamino, in which acyl is as mentioned below, heterocyclic amino, in which heterocyclic group is as mentioned below, cyclo(lower)alkenylamino which may have one or more, preferably one to three suitable substituent(s) such as amino and oxo [e.g.

(l-amino-3,4-dioxo-l-cyclobuten-2-yl)amino, etc.], imino (e.g. succinimido, phthalimido, etc.), a group of the formula :

Z-R¹⁰

II ₉

-NHC-R a'.

10 wherein R and Z are each as defined above, and q . R Si is hydrogen, lower alkylthio, protected hydroxy or amino which may have suitable substituent(s) , each of which is as mentioned above or below, and the like.

Suitable "lower alkyl" may be a straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl or the like, in which the preferable one is C--C. alkyl and the more preferable one is methyl or ethyl.

Suitable "acyl" and the acyl group in the term "acylamino" may include carbamoyl, thiocarbamoyl, 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 acid, and their thio 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, ethanesulfonyl, propanesulfonyl, etc.), lower alkoxycarbonyl (e.g. me hoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc.), lower alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl, etc.),

(C.,-C₇)-cycloalkanecarbonyl (e.g. cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, etc.), lower alkoxalyl (e.g. methoxalyl, ethoxalyl, etc.), lower alkanoylcarbonyl (e.g. pyruvoyl, etc.), and the like.

The aromatic acyl may include aroyl (e.g. benzoyl, nitrobenzoyl, 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, tetrazolylcarbonyl, tetrahydrofurylcarbonyl, pyperidylcarbonyl, morpholinocarbonyl, etc. ) , and the like.

The aliphatic acyl substituted with aromatic group(s) may include phenyKlower)alkanoyl (e.g. phenylacetyl, phenylpropionyl, phenylhexanoyl, etc.), phenyl(lower)- alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethylo.xycarbonyl, etc. ), phenoxy(lower)alkanoy1 (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, thiadiazolyl- propionyl, and the like.

These acyl groups may be further substituted with suitable substituent(s) such as hydroxy, amino, guanidino, carboxy, oxo, lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, etc.), (C,-C₇)- cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 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 alkoxycarbonyl(lower)alkoxy (e.g. methoxycarbonylmethoxy, etc.), lower alkylthio (e.g. methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio, etc.), heterocyclic group as mentioned below, heterocyclic(lower)alkylthio (e.g. furylmethylthio, thiazolylmethy1thio, etc.), heterocyclic(lower)alkylsulfinyl (e.g. furylmethylsulfinyl, thiazolylmethylsulfinyl, etc.), nitro, heterocyclic(lower)alkylaryloxy(lower)alkyl (e.g. pyrrolidinylmethylphenoxypropyl, etc.), 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., phenoxy, tolyloxy, etc.), protected hydroxy such as acyloxy, for example, lower alkanoylσxy (e.g. for yloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy, hexanσyloxy, etc.), lower alkylamino (e.g. methylamino, dimethylamino, ethylamino, etc. ) , amino-protective group as aftermentioned, and the like, and the preferable acyl having such substituent(s) may be lower alkoxy(lowerJalkanoyl (e.g., methoxyacetyl, ethoxyacetyl, etc.), lower alkoxycarbonyl (e.g. tert-butoxycarbonyl, etc.), lower alkanoyloxy(lower)alkanoyl (e.g., acetoxyacetyl, acetσxypropionyl, etc.), N-lower alkylcarbamoyl (e.g. N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, etc. ) , aroylthiocarbamoyl (e.g. benzoylthiocarbamoyl, etc.) , heterocyclic(lower)alkylthio(lower)alkanoyl (e.g. furylmethylthioacetyl, etc.), N-lower alkylthiocarbamoyl (e.g. N-methylthiocarbamoyl, 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. methoxycarbonylmethoxyacetyl, etc.), N-lower alkoxycarbonylamino(lower)alkanoyl (e.g. N-t-butoxycarbonylaminoacetyl, etc.), lower alkyl(C₃~C₇)- cycloalkanecarbonyl (e.g. methylcyclopropanecarbonyl, etc.), N-aminocarbamoyl, N-guanidinocarbamoyl, N-lower alkylsulfamoyl (e.g. N-methylsulfamoyl, etc. ) .

Suitable "heterocyclic group" and heterocyclic moiety in the terms "heterocyclic amino" and "heterocyclic thio" 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. furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyri idinyl, pyridazinyl, thiazolyl, thiadiazolyl, etc.), 5- or 6-membered aliphatic heteromonocyclic group (e.g. morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, dithiacyclopentyl, etc. ), unsaturated condensed heterocyclic group containing 1 to 3 nitrogen atom(s) (e.g. indolyl, benzimidazolyl, 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 groups are triazolyl having amino and lower alkyl (e.g. 3-amino-l-methyl-lH-triazol-5-yl, etc.), triazolyl having amino (e.g. 3-amino-lH-triazolyl-5-yl, etc.), benzoisothiazolyl having oxo (e.g. 1,1-dioxobenzoisothiazolyl, etc. ) . Suitable amino-protective group in the term

"protected amino" may include ar(lower)alkyl such as benzyl, benzhydryl, phenethyl and the like, and acyl as mentioned above.

Suitable hydros-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, aryl (e.g. phenyl, etc. ) , lower alkyl (e.g. methyl, ethyl, etc.), and the like.

Suitable "halogen" may be chloro, bromo, fluoro and iodo.

Suitable "lower alkyl which may have suitable substituent(s)" is conventional one used in a pharmaceutical field and may include lower alkyl as mentioned above, mono or di or trihalo(lower)alkyl such as trifluoro(lower)alkyl (e.g. trifluoromethyl, trifluoroethyl, etc.), lower alkoxy(lower)alkyl (e.g. methoxymethyl, methoxyethyl, methoxypropyl, etc. ) , di(lower)alkylamino(lower)alkyl (e.g. dimethylaminomethyl, dimethylaminoethy1, etc.) , hydroxy(lower)alkyl (e.g. hydroxymethyl, hydroxyethyl, etc. ) , acylamino(lower)alkyl such as lower alkanoylamino(lower)alkyl (e.g. acetylaminomethyl, acetylaminoethyl, etc.) , ar(lower)alkyl, in which the aryl moiety may be substituted by lower alkoxy, such as di(lower)alkoxyphenyl(lower)alkyl (e.g. dimethoxyphenethyl, etc. ) , lower alkylthio(lower)alkyl which may have suitable substituent(s) such as lower alkylthio(lower)alkyl (e.g. methylthiomethyl. methylthioethyl, etc.) and di(lower)alkylamino(lower)- alkylfuryl(lower)alkylthio(lower)alkyl (e.g. dimethylaminomethylfurfurylthioethyl, etc. ) , heterocyclic(lower)alkyl, in which heterocyclic moiety is as mentioned above, such as furyl(lower)alkyl (e.g. furfuryl, furylethyl, etc.), pyridyKlower)alkyl (e.g. pyridylmethyl, pyridylethyl, etc.) and indolyl(lower)alkyl (e.g. indolylmethyl, indolylethyl, indolylpropyl, etc. ), and the like. Suitable "acylamino having protected hydroxy" may include acylamino as mentioned above which is substituted by a protected hydroxy as exemplified above, for example, protected hydroxy(lower)alkanoylamino such as lower alkanoyloxy(lower)alkanoylamino (e.g. acetoxyacetylamino, etc.), and the like.

Suitable "acylamino having hydroxy" may include acylamino as mentioned above which is substituted by hydroxy, for example, hydroxy(lower)alkanoylamino (e.g. hydroxyacetylamino, etc.) , and the like. Suitable "acylamino having protected amino" may include acylamino as mentioned above which is substituted by a protected amino as exemplified above, for example, protected amino(lower)alkanoylamino such as lower alkoxycarbonylamino(lower)alkanoylamino (e.g. t-butoxycarbonylaminoacetylamino, etc.), and the like. Suitable "acylamino having amino" may include acylamino as mentioned above which is substituted by amino, for example, amino(lower)alkanoylamino (e.g. aminoacetylamino, etc. ) , and the like. Suitable "lower alkylthioureido" may include 3-lower alkylthioureido (e.g. 3-methylthioureido, etc.), and the like.

Suitable "(C₃-C₇)-cycloalkγl" may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Suitable "lower alkenyl" may include vinyl, 1-propenyl, allyl, 2-butenyl, 2-methylallyl, 2-pentenyl, and the like, preferably one having 2 to 4 carbon atoms.

Suitable "lower alkynyl" may include ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 2-pentynyl, and the like, preferably one having 2 to 4 carbon atoms.

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, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, 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 compounds (1-1) to (1-11), (II), (III), and (V) in the Processes 1 to 8, 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, R2, R 3, R4, R8, Y and A are as follows.

R is amino, acylamino, for example, ureido, lower alkanoylamino (e.g. formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, pivaloylamino, etc.), lower alkoxycarbonylamino (e.g. methoxycarbonylamino, ethoxycarbonylamino, butoxycarbonylamino, isobutoxycarbonylamino, etc.), hydroxy(lower)alkanoylamino (e.g. hydroxyacetylamino, etc.), protected hydroxy(lower)alkanoylamino such as lower alkanoyloxy(lower)alkanoylamino (e.g. acetoxyacetylamino, acetoxypropiσnylamino, etc. ), lower alkylureido such as 3-lower alkylureido (e.g.

3-methylureido, 3-ethylureido, 3-propylureido,

3-isopropylureido, etc. ) , (C₃-C₇)-cycloalkyl(lower)alkanoylamino (e.g. cyclohexylacetylamino, etc.) ,

(c,-C₇)-eyeloalkanecarbonylamino (e.g. eyelopropanecarbonylamino, cyclobutanecarbonylamino, cyclopentanecarbonylamino, cyclohexanecarbonylamino, cycloheptanecarbonylamino, etc. ) , (C--C₇)-cycloalkanecarbonylamino having oxo

(e.g. oxocyclohexanecarbonylamino, etc. ) , heterocycliccarbonylamino such as 5- or 6-membered heteromonocycliccarbonylamino (e.g. furoylamino, nicotinoylamino, tetrahydrofurylcarbonylamino, pyperidylcarbonylamino, etc. ), heterocyclic(lower)alkanoylamino such as 5- or

6-membered heteromonocyclic(lower)alkanoylamino (e.g. dithiacyclopentylvalerylamino, etc.), heterocyclic(lower)alkylaryloxy(lower)alkylureido such as 5- or 6-membered heteromonocyclic(lower)- alkylaryloxy(lower)alkylureido (e.g. pyrrolidinylmethylphenoxypropylureido, etc. ) , acyl such as (C₃-C₇)-cycloalkylcarbamoyl (e.g. cyclopentylcarbamoyl, cyclohexylcarbamoyl, cycloheptylcarbamoyl, etc.), or 2-cyanoguanidino; hydrogen, lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, pentyl, isopentyl, hexyl, etc.), lower alkoxy(lower)alkyl (e.g. methoxyefehyl, methoxypropyl, etc.) , di{lower)alkylamino(lower)alkyl

(e.g. daimethylaminoethyl, etc. ) ,

(C₃~C₇)-cycloalkyl (e.g. cyclohexyl, cyclopropyl, cyclopentyl, etc.) , lower alkenyl (e.g. allyl, etc.), mono or di or trihalo(lower)alkyl (e.g. trifluoroethyl, etc.), lower alkynyl (e.g. 2-propynγl, etc.), hydroxy(lower)alkyl (e.g. hydroxyethyl, etc. ) , acylamino(lower)alkyl such as lower alkanoylamino- (lower)alkyl, (e.g. acetylaminoethyl, etc. ) , ar(lower)alkyl, in which the aryl moiety may be substituted by lower alkoxy, such as di(lower)alkoxyphenyl(lower)alkyl (e.g. dimethoxyphenethyl, etc.), lower alkylthio(lower)alkyl (e.g. methylthioethyl, etc. ) , di(lower)alkylamino(lower)alkyIfuryl(lower)alkylthio- (lower)alkyl (e.g. dimethylaminomethylfurfuryl- thioethyl, etc.), heterocyclic(lower)alkyl, such as furyl(lower)alkyl (e.g. furfuryl, etc.), pyridyl(lower)alkyl (e.g. pyridylethyl, etc.) and indolyl(lower)alkyl (e.g. indolylpropyl, etc.) ; 3 . R is hydrogen; or lower alkyl (e.g. methyl, etc. ) ; and R is hydrogen; or lower alkyl (e.g. methyl, etc. ) ; or ^A and R are linked together to form lower alkylene (e.g. ethylene, etc. ) ; and

R is hydrogen; or R 2 and R8 are linked together to form lower alkylene optionally interrupted by oxygen (e.g. pentamethylene, 3-oxapentamethylene, etc.); and

R 3 i.s hydogen;

4 R is hydrogen; or lower alkyl (e.g. methyl, etc.);

A is bond; or lower alkylene (e.g. methylene, 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) or a salt thereof.

This reaction is usually conducted in a conventional solvent which does not adversely influence the reaction such as methyl acetate, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, acetone, 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 elimination reaction of the amino protective group.

Suitable method for this elimination 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.), ammonia, 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, 1,4-diazabicyclo[2,2,2]octane, 1,5-diazabicyclo[5,4,0]- undecene-5 or the like. The hydrolysis using a base is often carried out 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, sulfuric 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 (1-3) 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 :

R¹⁴ - OH (VIII) in which 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 this reaction, when the compound (VIII) is used in a free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as l-(3-dimethylaminopropyl)-3- ethylcarbodiimide, 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, dioxane, acetonitrile, chloroform, dichloromethane, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, 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(lowerJalkylamine, pyridine,

N-(lower)alkylmorphorine, N,N-di(lower)alkylbenzylamine, or the like. This present reaction includes, within its scope, the

2 case that when R is hydrogen, it is also acylated during the reaction or at the post-treating step of the present process. Process 4

The object compound (1-4) 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, 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 5 The object compound (1-5) or a salt thereof can be prepared by reacting the compound (V) or a salt thereof with the compound (VI) .

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 (VI) 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 (1-7) or a salt thereof can be prepared by reacting the compound (1-6) or a salt thereof with the compound (VII) .

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.

Process 7

The object compound (1-9) or a salt thereof can be prepared by subjecting the compound (1-8) 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 8 The object compound (1-11) or a salt thereof can be prepared by subjecting the compound (1-10) or a salt thereof to elimination reaction of the amino protective group.

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 8 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.

The new thiazole derivatives (I) and pharmaceutically acceptable salts thereof possess antiulcer activity and H₂-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 are 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, inadmixture 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) 2-[(Allylamino) (amino)methyleneamino]-4-(6- ureidomethylpyridin-2-yl)thiazole dihydrochloride

(b) 4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino) (2- methoxyethyla ino)methyleneamino]thiazole

(c) 4-(6-Acetylaminomethylpyridin-2-yl)-2-[ (amino)- (cyclohexylamino)methyleneamino]thiazole

( ) 4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)- (cyclopropylamino)methyleneamino]thiazole

Test A (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 antotitrator 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

Test B (Anti-microbial activity)

Test Method

In vitro antimicrobial activity was determined by the agar dilution method. Test strain was precultured in

Brucella broth containing 5% horse serum at 37°C for 3

4 days 10 cfu 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°C for 3 days. Incubation was carried out in an atmosphere of 10% CO-. MIC was read after incubation as the lowest drug concentration that inhibited macroscopic colonial growth.

Test Result

Mic (μg/ml)

Test C (Inhibition of HCl-aspirin ulcer)

Test Method

Seven male Sprague-Dawley rats, aged 6 weeks and weighing 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 mg/kg) suspended in 0.1% 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. Preparation 1

Phosphorus oxychloride (7.09 ml) was added dropwise to a solution of 6-hydroxymethyl-2-pyridinecarboxamide (3.60 g) in N,N-dimethylformamide (36 ml) at 0 to 5°C with stirring and the mixture was stirred for further 6 hours at the same temperature. The solvent was evaporated in vacuo and the residue was dissolved in water (100 ml). The solution was made basic with aqueous potassium carbonate and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated in vacuo to give 6-chloromethyl-2-pyridinecarbonitrile (3.02 g) . mp : 61-63°C IR (Nujol) : 2240 cm^"1

NMR (DMSO-d₆, 6) : 4.87 (2H, s), 7.90 (1H, dd, J=1.2Hz and 7.7Hz), 8.03 (1H, dd, J=1.2Hz and

7.7Hz), 8.14 (1H, t, J=7.7Hz)

Preparation 2

A mixture of 6-chloromethyl-2-pyridinecarbonitrile (2.75 g) and potassium phthalimide (3.35 g) in

N,N-dimethylformamide (27.5 ml) was stirred at ambient temperature for 4 hours. After the solvent was evaporated in vacuo, water (50 ml) was added to the residue and the resulting precipitate was collected by filtration to give 6-phthalimidomethyl-2-pyridinecarbonitrile (4.60 g) . mp : 200-201°C

IR (Nujol) : 2250, 1775, 1715 cm^"1 NMR (DMSO-d₆, δ) : 4.99 (2H, s), 7.81 (1H, dd, J=1.0Hz and 7.7Hz), 7.85-7.98 (5H, m) , 8.06 (1H, t, J=7.7Hz)

Preparation 3

A solution of hydrazine hydrate (0.77 g) in methanol (5 ml) was added dropwise to a suspension of 6-phthalimidomethyl-2-pyridinecarbonitrile (3.74 g) in a mixture of methanol (10 ml) and tetrahydrofuran (15 ml) at ambient temperature with stirring. After the mixture was stirred for two hours, diluted hydrochloric acid (prepared by concentrated hydrochloric acid (1.38 ml) and water (6.91 ml) was dropped to the mixture. After stirring for three hours, the solvent was evaporated in vacuo. The residue was mixed with water (20 ml) and an insoluble material was filtered off. The filtrate was evaporated in vacuo to give 6-aminomethyl-2-pyridinecarbonitrile hydrochloride (2.40 g) . mp : >300°C IR (Nujol) : 2240 cm^"1 NMR (DMSO-dg, δ) : 4.27 (2H, s) , 7.94 (1H, dd,

J=1.2Hz and 7.7Hz), 8.08 (1H, dd, J=1.2Hz and 7.7Hz), 8.16 (1H, t, J=7.7Hz), 8.83 (3H, br s)

Preparation 4

Acetic anhydride (1.29 ml) was added dropwise to a mixture of 6-aminomethyl-2-pyridinecarbonitrile hydrochloride (2.10 g) in pyridine (21 ml). The solution was stirred for four hours at ambient temperature and evaporated in vacuo. The residue was mixed with aqueous potassium carbonate and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated in vacuo to give 6-(acetylaminomethyl)-2-pyridinecarbonitrile (1.72 g). mp : 91-92°C

IR (Nujol) : 3260, 2230, 1650 cm^"1 NMR (DMSO-dg, δ) : 1.92 (3H, s) , 4.39 (2H, d, J=6Hz), 7.62 (1H, dd, J=lHz and

7.7Hz), 7.97 (1H, dd, J=lHz and 7.7Hz), 8.03 (1H, t, J=7.7Hz), 8.56 (1H, t, J=6Hz)

Preparation 5 An ethereal solution of methyl magnesium bromide (3 mole/i ) (17.6 ml) was added dropwise to a solution of 6-(acetylaminomethyl)-2-pyridinecarbonitrile (3.70 g) in tetrahydrofuran (60 ml) at 5 to 10°C with stirring. After the mixture was stirred for two hours at the same temperature, cold water (15 ml) was dropped to the mixture under ice-cooling and evaporated in vacuo. The residue was mixed with water and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography by eluting with a mixture of ethyl acetate and methanol (50:1) to give 2-acetyl-6-(acetylaminomethyl)pyridine (2.70 g) . mp : 88-89°C

IR (Nujol) : 3300, 1690, 1650 cm^-1 NMR (DMSO-dg, δ) : 1.94 (3H, s), 2.64 (3H, s),

4.43 (2H, d, J=6.0Hz), 7.54 (1H, dd, J=lHz and 7.7Hz), 7.82 (1H, dd, J=lHz and 7.7Hz), 8.00 (1H, t, J=7.7Hz), 8.53 (1H, t, J=6Hz)

Preparation 6

A solution of bromine (1.56 g) in acetic acid (5 ml) was added dropwise to a solution of 2-acetyl-6- (acetylaminomethyl)pyridine (1.87 g) and 30 weight % hydrogen bromide-acetic acid solution (4.2 ml) in a mixture of acetic acid (40 ml) and methanol (10 ml) at ambient temperature with stirring. The mixture was warmed to 60 to 70°C and stirred for two hours. The solvent was evaporated in vacuo and the residue was triturated with diisσpropyl ether to give 2-(acetylamino- methyl)-6-bromoacetylpyridine hydrobromide (3.78 g) . IR (Nujol) : 1720, 1620 cm^"1 NMR (CD₃OD, δ) : 2.10 (3H, s), 3.90 (2H, s),

4.83 (2H, s), 7.77 (1H, br s), 8.13 (2H, t, J=8Hz) and 8.70 (1H, t, J=8Hz) Preparation 7

A suspension of l-bromo-2,3-butanedione (47 g) and N-[ (thiocarbamoyl)methyl]acetamide (30 g) in acetone (600 ml) was refluxed for 3 hours. The resulting precipitate was collected by filtration to afford

4-acetyl-2-(acetylaminomethyl)thiazole (41.8 g) . mp : 185-186°C

IR (Nujol) : 3410, 3350, 1690, 1620 cm^"1 NMR (DMSO-dg, δ) : 1.93 (3H, s), 2.55 (3H, s), 4.54 (2H, d, J=5.8Hz), 8.44 (1H, s),

8.91 (1H, t, J=5.8Hz)

Preparation 8

Bromine (9.9 ml) was added dropwise to a mixture of 2-acetyl-6-(acetylaminometyl)pyridine (37.0 g) in dioxane (740 ml) and 4N-dioxanic hydrogen chloride (48.1 ml) at ambient temperature with stirring. After the mixture was stirred at 50°C for 3 hours. To the mixture was added a diisopropyl ether (600 ml) and the mixture was stirred under ice-cooling for 30 minutes. The isolated precipitate was collected by filtration. The precipitate was added to water and the mixture was adjusted to pH 8 with 20% aqueous potassium carbonate. The aqueous mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was dried over magnesium sulfate and evaporated in vacuo to give 2-(acetylamino- methyl)-6-bromoacetylpyridine (50.3 g) as an oil. IR (Film) : 1710, 1650 cm^"1 NMR (CDC1₃, δ) : 2.11 (3H, s), 4.63 (2H, d, J=5.3Hz), 4.80 (2H, s), 7.43-7.59 (1H, m) ,

7.78-8.08 (2H, m)

Preparation 9

Propionic anhydride (76.3 ml) was added dropwise to a mixture of 6-aminomethyl-2-pyridinecarbonitrile hydrochloride (84.1 g) in water (800 ml) under keeping pH 7~8 with 40% aqueous potassium carbonate at ambient temperature and the mixture was stirred at the same temperature for 30 minutes. The aqueous mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated to give

6-(propionylaminomethyl)-2-pyridinecarbonitrile (54.2 g) . IR (Film) : 3280, 2240, 1640, 1590, 1535 cm^"1 NMR (DMSO-dg, δ) : 1.05 (3H, t, J=7.6Hz), 2.21 (2H, q, J=7.6Hz), 4.40 (2H, d, J=5.8Hz), 7.61 (1H, dd, J=1.0Hz, 7.8Hz), 7.91 (1H, dd, J=1.0Hz, 7.8Hz), 8.03 (1H, t, J=7.8Hz), 8.50 (1H, t, J=5.8Hz)

Preparation 10

The following compound was obtained according to a similar manner to that of Preparation 5.

2-Acetyl-6-(propionylaminomethyl)pyridine mp : 79°C

IR (Nujol) : 3280, 1700, 1640, 1590, 1550 cm^"1

NMR (DMSO-dg, δ) : 1.06 (3H, t, J=7.6Hz), 2.22 (2H, q, J=7.6Hz), 2.64 (3H, s), 4.44 (2H, d, J=6.0Hz), 7.52 (1H, d, J=7.6Hz), 7.82 (1H, d, J=7.6Hz), 7.96 (1H, t, J=7.6Hz), 8.45 (1H, t, J=6.0Hz)

Preparation 11

The following compound was obtained according to a similar manner to that of the former half of Example 17.

4-(6-Acetylaminomethylpyridin-2-yl)-2-aminothiazole mp : 179-180°C

IR (Nujol) : 3380, 3260, 3110, 1655, 1620 cm^"1 NMR (DMSO-dg, δ) : 1.93 (3H, s), 4.36 (2H, d, J=5.9Hz), 7.11 (2H, s), 7.13 (1H, d, J=7.0Hz), 7.26 ( 1H, s ) , 7. 68 ( 1H, d, J=7. 0Hz ) , 7.76 ( 1H, t, J=7. 0Hz ) , 8. 45 ( 1H, t, J=5. 9Hz)

Preparation 12 Benzoyl chloride (15.7 ml) was dropped to a refluxing solution of ammonium thiocyanate (11.3 g) in acetone (640 ml) and the mixture was refluxed for 20 minutes. 4-(6-Acetylaminomethylpyridin-2-yl)-2-aminothiazole (32.0 g) was added portionwise to the refluxing mixture. After the mixture was refluxed for 3 hours, the solvent was evaporated in vacuo and the residue was mixed with ethyl acetate, tetrahydrofuran and water. The mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate and resulting precipitate was collected by filtration to give 4-{6-acetylaminomethylpyridin-2-yl)-2-(3- benzoylthioureido)thiazole (15.11 g) . mp : 222°C (dec.)

IR (Nujol) : 3300, 1670, 1640 cm^"1 NMR (DMSO-dg, δ) : 1.95 (3H, s), 4.42 -(2H, d, J=5.9Hz), 7.19-7.33 (1H, m) , 7.49-7.80 (3H, m) ,

8.82-8.06 (5H, m) , 8.50 (1H, t, J=5.9Hz), 12.16 (1H, s), 14.29 (1H, s)

Preparation 13 A solution of sodium hydroxide (0.8 g) in water (8 ml) was added to a suspension of 4-(6-acetylaminomethyl- pyridin-2-yl)-2-(3-benzoylthioureido)thiazole (8.0 g) in methanol (80 ml) and the mixture was stirred at 50-60°C for 1 hour. Following evaporation in vacuo, the residue was mixed with water and the mixture was adjusted to pH

7.5 with 6N-hydrochloric acid. The mixture was extracted with the mixture of tetrahydrofuran and ethyl acetate and extract layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 4-(6-acetylamino- methylpyridin-2-yl)-2-thioureidothiazole (5.44 g) . mp : 212-213 °C

IR (Nujol) : 3290, 3190, 1640, 1610 cm^'1 NMR (DMSO-dg, + D₂0, δ) : 1.94 (3H, s), 4.41 (2H, s), 7.21-7.30 (1H, ), 7.75-7.92 (3H, m)

Preparation 14

A mixture of 4-(6-acetylaminomethylpyridin-2-yl)-2- thioureidothiazole (5.3 g) and methyl iodide (1.2 ml) in a solution of methanol (53 ml) and tetrahydrofuran (25 ml) was heated under reflux for 4.5 hours. The solvent was removed by concentration in vacuo and resulting residue was triturated with ethyl acetate to give 4-(6-acetyl- aminomethylpyridin-2-yl)-2-[(amino) (methylthio)- methyleneamino]thiazole hydriodide. mp : 195-197°C (dec.)

IR (Nujol) : 3380, 3280, 3190, 1600 (br) cm^"1 NMR (DMSO-dg, + D₂0, δ) : 1.98 (3H, s), 2.56 (3H, s), 4.55 (2H, s), 7.44-7.55 (1H, m), 7.99-7.09 (1H, m), 7.18-8.24 (2H, m)

Preparation 15

A mixture of 2-acetylaminomethylpyridine N-oxide (1.00 g) and dimethyl sulfate (0.63 ml) was stirred for three hours. Dimethyl sulfoxide (6 ml) and potassium cyanide (392 mg) were added to the mixture and the solution was stirred for two hours at ambient temperature. Additional potassium cyanide (392 mg) was added to the mixture and which was further stirred for two hours. After the solvent was removed by concentration, the residue was mixed with water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (15 g) by eluting with a mixture of ethyl acetate and methanol (20:1) to give 6-acetylaminomethyl-2-pyridinecarbonitrile (0.16 g) . IR (Nujol) : 3260, 2230, 1650 cm^"1

Preparation 16

Bromine (6.0 g) was added slowly to a solution of 5-acetyl-3-pyridinecarboxylic acid methyl ester (6.0 g) in dioxane (50 ml) at room temperature. The mixture was stirred at room temperature for 1 hour and then heated at 60-70°C for 5 hours. The resulting precipitate was collected by filtration to afford 5-bromoacetyl-3- pyridinecarboxylic acid methyl ester hydrobromide (10.0 g) . IR (Nujol) : 3060, 1735, 1705 cm^"1

NMR (DMSO-dg, δ) : 3.94 (3H, s), 5.11 (2H, s) , 8.73 (1H, t, J=2.1Hz), 9.30 (1H, d, J=2.1Hz), 9.38 (1H, d, J=2.lHz)

Preparation 17

A mixture of 4-(6-acetylaminomethylpyridin-2-yl)- 2-aminothiazole (7.0 g) and methyl isothiocyanate (6.2 g) in ethanol (140 ml) was heated under reflux for 40 minutes and then the mixture was cooling to ambient temperature. To the mixture was added ethyl acetate (140 ml) and isolated precipitate was collected by filtration to give 4-(6-acetylaminomethylpyridin-2-yl)-2-(3- methylthioureido)thiazole (1.88 g) . mp: 226-228°C

IR (Nujol) : 3290, 1640, 1590 cm^"1

NMR (DMSO-dg, δ) : 1.93 (3H, s), 3.07 (3H, d,

J=4.4Hz), 4.38 (2H, d, J=5.9Hz), 7.22 (1H, t, J=4.5Hz), 7.71 (1H, s), 7.84 (2H, d, J=4.5Hz), 8.47 (1H, t, J=5.9Hz), 9.19 (1H, br s), 11.77

(1H, s)

Preparation 18

Methanesulfonic acid (18.6 g) was added to a solution of 2-acetyl-6-(propionylaminomethyl)pyridine (40.0g) in dioxane (800 ml) at room temperature. The mixture was stirred at room temperature for 15 minutes. Bromine (34.1 g) was added slowly to the mixture at room temperature. The mixture was heated at 50°C for 3 hours. To the mixture sodium hydrogencarbonate (65.2 g) , thiourea (17.7 g) and methanol (800 ml) was added. The mixture was heated at 50°C for 4 hours. The solvent was removed under reduced pressure and the residue was dissolved in water (700 ml). The mixture was extracted with a mixture of ethyl acetate (700 ml) and tetrahydrofuran (700 ml). The extract was dried with magnesium sulfate and then was evaporated. The residue was crystallized from acetone to afford 2-amino-4-(6-propionylaminomethylpyridin-2-yl)- thiazole (26.9 g) . mp : 134-136°C

IR (Nujol) : 3270, 3160, 1630 cm^-1

NMR (DMSO-dg, δ) : 8.37 (1H, t, J=5.9Hz), 7.77 (1H, t, J=7.7Hz), 7.68 (1H, dd, J=7.7Hz and 1.1Hz), 7.24 (1H, s), 7.12 (1H, dd, J=7.7Hz and 1.1Hz), 7.10 (2H, s), 4.36 (2H, d, J=5.9Hz), 2.21 (2H, q, J=7.7Hz), 1.05 (3H, t, J=7.7Hz)

Preparation 19

Benzoyl chloride (7.7 g) was added slowly to a solution of sodium thiocyanate (4.8 g) in acetone (220 ml) under refluxing and the mixture was refluxed for 15 minutes. 2-Amino-4-(6-propionylaminomethylpyridin-2-yl)- thiazole (12.0 g) was added to the mixture. The mixture was refluxed for 4 hours. The resulting precipitate was collected by filtration and was washed with water and then acetone to afford 2-(3-benzoylthioureido)-4-(6- propionylaminomethylpyridin-2-yl)thiazole (16.5 g) . mp : 230-231°C (dec.) IR (Nujol) : 3290, 1670, 1640 cm^'1 NMR (DMSO-dg, δ) : 14.29 (1H, s), 12.23 (1H, s). 8.43 (1H, t, J=5.9Hz), 8.03 (2H, d, J=7.2Hz), 7.95 (1H, s), 7.92-7.83 (2H, m) , 7.71 (1H, t, J=7.2Hz), 7.57 (2H, t, J=7.2Hz), 7.24 (1H, dd, J=2.8Hz and 6.0Hz), 4.42 (2H, d, J=5.9Hz), 2.23 (2H, q, J=7.6Hz), 1.07 (3H, t, J=7.6Hz)

Preparation 20

The following compound was obtained according to a similar manner to that of Preparation 19.

2-{3-Benzoylthioureido)-4-(6- ethoxycarbonylaminomethylpyridin-2-yl)thiazole mp : 221 to 222°C (dec.) IR (Nujol) : 3270, 1680, 1600 cm^"1 NMR (DMSO-dg, δ) : 14.29 (1H, s), 12.23 (1H, s),

8.03 (2H, dd, J=1.5Hz and 7.1Hz), 7.92-7.87 (3H, m), 7.83-7.67 (2H, m) , 7.57 (2H, b, J=7.1Hz), 7.26 (1H, dd, J=3.6Hz and 5.2Hz), 4.34 (2H, d, J=6.1Hz), 4.05 (2H, q, J=7.lHz), 1.20 (3H, t, J=7.1Hz)

Preparation 21

2-(3-Benzoylthioureido)-4-(2-acetylaminomethyl- thiazol-4-yl)thiazole mp : 237-238°C (dec.) IR (Nujol) : 3275, 1670, 1645 cm^"1 NMR (DMSO-dg, δ) : 14.26 (1H, s), 12.23 (1H, s),

8.81 (1H, t, J=6.0Hz), 8.02 (2H, d, J=7.0Hz), 7.88 (1H, s), 7.70 (1H, t, J=7.0Hz), 7.60 (1H, s), 7.57 (2H, t, J=7.0Hz), 4.57 (2H, d, J=6.0Hz), 1.92 (3H, s) Preparation 22

A suspension of 2-amino-4-(6- propionylaminomethylpyridin-2-ylthiazole (12.0 g) and cone, hydrochloric acid (12 ml) in ethanol was refluxed for 27 hours. The resulting precipitate was collected by filtration to afford 2-amino-4-(6-aminomethylpyridin-2- yl)thiazole trihydrochloride (8.9 g) . mp : 279-281°C (dec.) IR (Nujol) : 3300, 1620 cm^"1 NMR (DMSO-dg, δ) : 9.60-8.40 (4H, br) , 8.07-7.96

(2H, m), 7.80 (1H, s), 7.52 (1H, dd, J=1.6Hz and 6.8Hz), 4.30 (2H, q, J=5.7Hz)

Preparation 23 Ethyl chloroformate (3.7 g) was added slowly to a suspension of 2-amino-4-(6-aminomethylpyridin-2-yl)- thiazole trihydrochloride (8.9 g) and triethylamine (11.4 g) in N,N-dimethylformamide (80 ml) and tetrahydrofuran (80 ml) with cooling on an ice bath. The mixture was stirred with cooling for 1.5 hours and then at room temperature for 1 hours. The solvent was removed under reduced pressure. The residue was dissolved in water (300 ml). The mixture was alkalized with a saturated aqueous potassium carbonate solution and then was extracted with a mixture of ethyl acetate (500 ml) and tetrahydrofuran (100 ml). The extract was dried over magnesium sulfate and then was evaporated to afford 2-amino-4-(6- ethoxycarbonylaminomethylpyridin-2-yl)thiazole (10.51 g) . IR (Film) : 3300, 1720 cm^"1 NMR (DMSO-dg, δ) : 7.83-7.68 (3H, m) ,

7.24 (1H, s), 7.18-7.12 (3H, m) , 4.30 (2H, d, J=6.2Hz), 4.04 (2H, q, J=7.1Hz), 1.19 (3H, t, J=7.1Hz) Preparation 24

A suspension of 2-amino-4-bromoacetylthiazole hydrobromide (14.0 g) and N-[ (thiocarbamoyl)methyl]- acetamide (6.1 g) in ethanol (300 ml) was stirred at room temperature for 24 hours. The insoluble material was removed by filtration. The solvent was removed under reduced pressure. The residue was suspended in water (300 ml). The mixture was alkalized to pH 10 with a saturated aqueous potassium carbonate solution and then was extracted with a mixture of ethyl acetate (500 ml) and tetrahydrofuran (100 ml). The extract was dried over magnesium sulfate and then was evaporated to afford 4-(2-acetylaminomethylthiazol-4-yl)-2-aminothiazole (5.83 g⁾. p : 201-202°C (dec.)

IR (Nujol) : 3300, 1740, 1650 cm^"1

NMR (DMSO-dg, δ) : 8.77 (1H, t, J=6.0Hz),

7.50 (1H, s), 7.10 (2H, s) , 6.89 (1H, s) , 4.52 (2H, d, J=6.0Hz), 1.91 (3H, s)

Preparation 25

4N-Dioxanoic hydrogen chloride (10 ml) was added to a suspension of 4-(2-acetylaminomethylthiazol-4-yl)-2- a inothiazole (0.75 g) in methanol (30 ml). The mixture was stirred at room temperature for 40 minutes, and diisopropyl ether (50 ml) was added. The resulting precipitate was collected by filtration. Recrystallization from a mixture of methanol and dioxane afforded 4-(2-acetylaminomethylthiazol-4-yl)-2- a inothiazole hydrochloride (0.35 g) . mp : 218-221°C (dec.) IR (Nujol) : 3200, 1635 cm^"1 NMR (DMSO-dg, δ) : 8.86 (1H, t, J=5.9Hz),

8.01 (1H, s), 7.15 (1H, s) , 4.54 (2H, d, J=5.9Hz), 1.92 (3H, s) Preparation 26

A mixture of 4-(6-acetylaminomethylpyridin-2-yl)^'-2- (3-methylthioureido)thiazole (1.5 g) and methyl iodide (0.45 ml) in a solution of methanol (15 ml) and tetrahydrofuran (8 ml) was heated under reflux for 9 hours. The solvent was removed by concentration and the residue was triturated with ethyl acetate to give 4-(6-acetylaminomethylpyridin-2-yl)-2-[ (methylamino)- (methylthio)methyleneamino]thiazole hydriodide (1.44 g) . mp : 187-189°C

IR (Nujol) : 3470, 1620, 1600 cm^"1 NMR (DMSO-dg, δ) : 1.97 (3H, s), 2.55 (3H, s), 3.07 (3H, s), 4.51 (2H, d, J=5.7Hz), 7.40-7.52 (1H, m) , 8.02-8.20 (2H, m) , 8.07 (1H, s), 8.67 (1H, t, J=5.7Hz)

Preparation 27

A solution of sodium hydroxide (3.7 g) in water (30 ml) was added to a suspension of 2-(3-benzoylthioureido)- 4-(6-propionylaminomethylpyridin-2-yl)thiazole (16.5 g) in methanol (300 ml) at room temperature. The mixture was heated at 60°C for 4.5 hours. The solvent was removed under reduced pressure. The residue was dissolved in water (200 ml). The mixture was neutralized with 6N hydrochloric acid. The resulting precipitate was collected by filtration to afford 4-(6-propionylamino- methylpyridin-2-yl)-2-thioureidothiazole (14.67 g) . mp : 223-225°C (dec.)

IR (Nujol) : 3270, 3120, 1640, 1620 cm^"1 NMR (DMSO-dg, δ) : 11.65 (1H, br) , 9.00-8.00 (3H, br), 7.85 (1H, t, J=7.8Hz), 7.79 (1H, dd, J=7.8Hz and 1.6Hz), 7.73 (1H, s), 7.21 (1H, dd, J=7.8Hz and 1.6Hz), 4.39 (2H, d, J=5.9Hz), 2.22 (2H, q, J=7.6 Hz), 1.06 (3H, t, J=7.6Hz) Preparation 28

The following compound was obtained according to a similar manner to that of Preparation 27.

4-(6-Ethoxycarbonylaminomethylpyridin-2-yl)-2- thioureidothiazole mp : 210-212°C (dec.)

IR (Nujol) : 3310, 3130, 1690, 1600 cm^"1 NMR (DMSO-dg, δ) : 11.74 (1H, s) , 8.77 (1H, br) , 8.33 (1H, br), 7.90-7.74 (3H, m) , 7.71 (1H, s),

7.23 (1H, dd, J=1.0Hz and 7.2Hz), 4.32 (2H, d, J=6.1Hz), 4.04 (2H, q, J=7.lHz), 1.19 (3H, t, J=7.1Hz)

Preparation 29

4-(2-Acetylaminomethylthiazol-4-yl)-2- thioureidothiazole p : 230-231°C (dec.)

IR (Nujol) : 3270, 1640, 1615 cm^"1

NMR (DMSO-dg, δ) : 11.71 (1H, s), 9.00-8.00 (3H, br), 7.81 (1H, s), 7.38 (1H, s), 4.55 (2H, d, J=6.0Hz), 1.92 (3H, s)

Preparation 30

A suspension of 4-(6-propionylaminomethylpyridin- 2-yl)-2-thioureidothiazole (14.67 g) and methyl iodide (7.77 g) in methanol (300 ml) was refluxed for 3 hours. The solvent was removed under reduced pressure. The residue was crystallized from ethyl acetate to afford 2-[(amino) (methylthio)methyleneamino]-4-(6- propionylaminomethylpyridin-2-yl)thiazole hydriodide (13.68 g). mp : 194-196 ° C ( dec . )

IR (Nujol) : 3350, 3200, 1650, 1610 cm^'1

NMR (DMSO-dg δ) : 9.29 (2H, br), 8.55 (1H, t,

J=5.8Hz), 8.13-8.03 (3H, m) , 7.40 (1H, dd, J=2.7Hz and 6.2Hz), 4.50 (2H, d, J=5.8Hz),

2.52 (3H, s), 2.24 (2H, q, J=7.5Hz),

1.06 (3H, t, J=7.5Hz)

Preparation 31 The following compound was obtained according to a similar manner to that of Preparation 30.

2-[ (Amino) (methylthio)methyleneamino]-4-(6- ethoxycarbonylaminomethylpyridin-2-yl)thiazole hydriodide mp : 153 to 155°C (dec.)

IR (Nujol) : 3350, 1685, 1610 cm^"1

NMR (DMSO-dg, δ) : 9.51 (1H, br) , 8.40-8.05 (3H, m) , 8.05-7.80 (1H, m), 7.60-7.20 (2H, m) , 4.46 (2H, d, J=5.4Hz), 4.06 (2H, q, J=7.0Hz), 2.59 (3H, s), 1.20 (3H, t, J=7.0Hz)

Preparation 32

The following compound was obtained according to a similar manner to that of Preparation 30.

2-[(Amino) (methy1thio)methyleneamino]-4-(2- acetylaminomethylthiazol-4-yl)thiazole hydriodide mp : 178-180°C (dec.) IR (Nujol) : 3250, 1640 cm^"1 NMR (DMSO-dg, δ) : 9.53 (1H, br),

8.80 (1H, t, J=6.0Hz), 8.12 (1H, s), 7.52 (1H, s), 4.55 (2H, d, J=6.0Hz), 2.57 (3H, s), 1.92 (3H, s) _{Λ ≠t}

- 42 -

Preparation 33

A mixture of 2-(acetylaminometyl)-6-bromoacetyl- pyridine hydrobromide (3.34 g) and diammomethylenethiourea (1.01 g) in methanol (50 ml) was refluxed for 10 hours with stirring. The resulting precipitate was collected, dissolved in water (50 ml) and the solution was made basic with aqueous potassium carbonate. The separated product was collected and washed with water to give 4-(6-aminomethylpyridin-2-yl)-2- (diaminomethyleneamino)thiazole (0.90 g) . mp : 228-229°C IR (Nujol) : 3350, 3150 cm^"1

NMR (DMSO-dg, δ) : 3.85 (2H, s), 6.96 (4H, br s), 7.22-7.44 (3H, m) , 7.73-7.83 (3H, )

Preparation 34

Bromine (2.2 g) was added slowly to a solution of 4-acetyl-2-acetylaminomethylthiazole (2.2 g) in acetic acid (20 ml) and water (20 ml), and the mixture was heated at 70°C for 4 hours. The solvent was removed under reduced pressure to give crude product of 2-acetylaminomethyl-4-bromoacetylthiazole. The above residue was dissolved in ethanol (50 ml).

Diammomethylenethiourea (1.3 g) was added to the solution and the mixture was refluxed for 4 hours. The solvent was removed under reduced pressure. The residue was dissolved in water and then the solution was alkalized with a saturated aqueous potassium carbonate solution. The resulting precipitate was collected by filtration. The filtrate was extracted by ethyl acetate and then the solvent was removed under reduced pressure. The residue and the precipitate were chromatographed on an alumina column eluting with a mixture of chloroform and methanol (10:1). Recrystallization from water afforded 4-(2-acetylaminomethylthiazol-4-yl)-2-(diaminomethylene- amino)thiazole (430 mg) . mp : 255-256°C IR (Nujol) : 3250, 1640 cm^"1 NMR (DMSO-dg, δ) : 1.91 (3H, s), 4.54 (2H, d,

J=5.9Hz), 6.88 (4H, s), 7.02 (1H, s), 7.79 (1H, s), 8.77 (1H, t, J=5.9Hz) Anal. Calcd. for C₁₀H₁₂NgOS₂-4/5^0 :

C 38.65, H 4.41, N 27.04 Found : C 38.51, H 4.31, N 27.00

Preparation 35

Concentrated hydrochloric acid (72.4 ml) was added slowly to a suspension of 4-(2-acetylaminomethylthiazol- 4-yl)-2-(diaminomethyleneamino)thiazole (6.58 g) in ethanol (280 ml). The mixture was refluxed for 2 hours. The resulting precipitate was collected by filtration. Recrystallization from a mixture of methanol and water afforded 4-(2-aminomethylthiazol-4-yl)-2- (diaminomethyleneamino)thiazole dihydrochloride (6.98 g) . mp : >300°C

IR (Nujol) : 3300, 1680, 1600 cm^"1 NMR (DMSO-dg, δ) : 4.47 (2H, s) , 7.59 (1H, s), 8.41 (4H, s), 8.45 (1H, s), 8.76 (3H, s), 12.82 (1H, s) Anal. Calcd. for CgH₁₀NgS_2'2HCl_'9/10H₂O

C 27.98, H 4.05, N 24.47, Cl 20.64, H₂0 4.72 Found: C 27.69, H 3.87, N 24.13, Cl 20.85, H₂0 4.38

Preparation 36 The following compound was obtained according to a similar manner to that of Example 15.

4-(6-Aminomethylpyridin-2-yl)-2-(diaminomethylene¬ amino)thiazole trihydrochloride mp : 288-289°C IR (Nujol) : 3375, 3275, 3175, 1685 cm^"1 NMR (DMSO-dg, δ) : 4.25 (2H, q, J=5.8Hz),

6.12 (3H, br s), 7.46 (1H, d, J=7.7Hz), 7.95 (1H, t, J=7.7Hz), 8.18 (1H, d, J=7.7Hz), 8.33 (1H, s), 8.41 (4H, s) and 8.62 (2H, br s)

Anal. Calcd. for C^H^NgS HCl-1/3^0 :

C 33.02, H 4.34, N 23.11 Found : C 33.16, H 4.09, N 22.89

Preparation 37

A mixture of 2-(diaminomethyleneamino)-4-(6- propionylaminomethylpyridin-2-yl)thiazole (49.0 g) and cone, hydrochloride acid (134 ml) in ethanol (500 ml) was heated under reflux for 7 hours and after the mixture was cooled to ambient temperature. To the mixture was added ethanol (500 ml) with stirring and the isolated precipitate was collected by filtration to give 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)- thiazole trihydrochloride (52.36 g). IR (Nujol) : 3375, 3275, 3175, 1685 cm^"1

Preparation 38

A mixture of 4-(6-acetylaminomethylpyridin-2-yl)-2- [(amino) (methylthio)methyleneamino]thiazolehydriodide (2.0 g) and 30 wt % methylamine-methanol solution (2.0 g) in ethanol (40 ml) was refluxed for 27 hours. The solvent was removed by concentration and residue was added to a mixture of tetrahydrofuran, ethyl acetate and water. The mixture was adjusted to pH 9.5 with potassium carbonate and a separated organic layer was washed with brine, dried over magnesium sulfate. Evaporation of a solvent gave a residue, which was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (19:1, V/V) . The eluted fractions containing the desired product were collected and evaporated in vacuo. The residue was recrystallized from a mixture of methanol, dioxane and diisopropyl ether to give 4-(6-acetylamino- methylpyridin-2-yl)-2-[(amino) (methylamino)- methyleneamino]thiazole (0.38 g) . mp : 181°C

IR (Nujol) : 3340, 3230, 3130, 1630, 1590 cm^"1 NMR (DMSO-dg, δ) : 1.93 (3H, s), 2.77 (3H, d,

J=4.8Hz), 4.37 (2H, d, J=5.9Hz), 7.14-7.21 (1H, m), 7.41 (1H, s), 7.46 (2H, s), 7.74-7.84 (2H, m), 8.45 (1H, t, J=5.9Hz)

Preparation 39

The following compound was obtained according to a similar manner to that of Preparation 38 excepting using 2,2,2-trifluoroethylamine in place of 30 wt % methylamine-methanol.

4-(6-Acetylaminomethylpyridin-2-yl)-2-[ (amino)- [(2,2,2-trifluoroethyl)amino]methyleneamino]thiazole mp : 233°C

IR (Nujol) : 3380, 1650, 1620 cm^"1

NMR (DMSO-dg, δ) : 1.93 (3H, s), 4.04-4.22 (2H, m) , 4.38 (2H, d, J=5.9Hz), 7.10-7.27 (2H, m) , 7.52 (1H, s), 7.73-7.88 (4H, m) , 8.45 (1H, t, J=5.9Hz)

Preparation 40

The following compound was obtained according to a similar manner to that of the former half of Preparation 33.

2-(Diaminomethyleneamino)-4-(5-methoxycarbonyl- pyridin-3-yl)thiazole mp : 248-249°C (dec.) IR (Nujol) : 3320, 3050, 1720, 1610 cm^"1 NMR (DMSO-dg, δ) : 3.92 (3H, s), 7.00 (4H, s), 7.55 (1H, s), 8.58 (1H, t, J=2.lHz,, 8.97 (1H, d, J=2.1Hz), 9.31 (1H, d, J=2.1Hz)

Anal. Calcd. for ^cτι^Hn^N5°2^{S :}

C 47.64, H 4.00, N 25.26 Found : C 47.35, H 3.90, N 25.00

Preparation 41

A mixture of (amino) (methylthio)methylenethiourea hydrogeniodide (6.0 g) and propargylamine (4.5 ml) in ethanol (60.0 ml) was stirred for 5 days at ambient temperature. Evaporation of the solvent gave a residue, which was purified by column chromatography on alumina eluting with a mixture of chloroform and methanol (19:1, V/V) . The eluted fractions containing the desired product were collected and evaporated to give

(amino)[(2-propynyl)amino]methylene thiourea (3.1 g) as an oil.

IR (Film) : 3330, 2050, 1670, 1620 (br) cm^"1 NMR (DMSO-dg, δ) : 3.12-3.22 (1H, m) , 3.93-4.07 (2H, m), 7.32 (2H, s), 8.14 (1H, s)

Preparation 42

The following compound was obtained according to a similar manner to that of Preparation 41.

(Amino) [N-(2-methoxyethyl)amino]methylenethiourea IR (Film) : 3300, 1620 cm^"1

NMR (DMSO-dg, δ): 3.27-3.39 (7H, m) , 7.15 (2H, br) , 7.94 (1H, br)

Preparation 43

A mixture of 2-acetylaminomethyl-6-bromβacetyl- pyridine (2.0 g) and dithiobiuret (1.1 g) in ethanol (30 ml) was heated under reflux for 5 hours and then to the mixture was added ethyl acetate (30 ml) with stirring at ambient temperature. The isolated precipitate was collected by filtration. To the precipitate was added a water and the mixture was adjusted to pH 7.5 with 20% aqueous potassium carbonate. The isolated precipitate was collected by filtration, washed with water and dried to give 4-(6-acetamidomethylpyridin-2-yl)-2- thioureidothiazole (1.4 g) . mp : 212-213°C IR (Nujol) : 3290, 3190, 1640, 1610 cm^"1

NMR (DMSO-dg, δ) : 1.94 (3H, s), 4.39 (2H, d,

J=5.9Hz), 7.22 (1H, dd, J=1.6Hz, 7.0Hz), 7.73 (1H, s), 7.75-7.94 (2H, m) , 8.48 (1H, t, J=5.9Hz)

Preparation 44

A solution of 2-acetylaminomethyl-6-cyanopyridine (20.0 g) in dichloromethane (400 ml) was added dropwise to an ethereal solution of methylmagnesium bromide (3 mole/il) (190.0 ml) at 5°C to 15°C with stirring and then the mixture was stirred for 2.5 hours at the same temperature. The reaction mixture was dropped to an ice-water (500 ml) and the mixture was adjusted to pH 7.5 with 6N-hydrochloric acid. The separated organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 2-acetylaminomethyl-6-propionylpyridine (21.3 g) . mp : 93°C

IR (Nujol) : 3280, 1700, 1630 cm^"1 NMR (DMSO-dg, δ) : 1.10 (3H, t, J=7.3Hz), 1.94 (3H, s), 3.18 (2H, q, J^'-=7.3Hz), 4.42 (2H, d, J=6.0Hz), 7.53 :il, dd, J=1.0Hz, 7.7Hz), 7.82 (1H, dd, J=1.0Hz, V.7Hz), 7.96 (1H, t, J=7.7Hz), 8.52 (1H, t, J=f.0B-s Preparation 45

Bromine (1.1 ml) was added to a mixture of 2-acetylaminomethyl-6-propionylpyridine (4.0 g) and ethanesulfonic acid (1.3 ml) in dioxane (60.0 ml) at ambient temperature and the mixture was stirred for 3 hours at 50°C. To the mixture was added diisopropyl ether (60 ml) and the mixture was stirred for 30 minutes at ambient temperature. The isolated precipitate was collected by filtration. To the precipitate was added a mixture of ethyl acetate and water and the mixture was adjusted to pH 8 with 20% aqueous potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was removed by concentration and the residue was triturated with ethyl acetate to give 2-acetylaminomethyl-6-(2-bromo- propionyl)pyridine (4.5 g) . mp : 63-67°C

IR (Nujol) : 3280, 1700, 1635 cm^"1

NMR (DMSO-dg, δ) : 1.82 (3H, d, J=6.8Hz), 1.95 (3H, s), 4.45 (2H, d, J=6.0Hz), 6.11 (1H, q,

J=6.8Hz), 7.59 (1H, dd, J=1.3Hz, 7.5Hz), 7.94 (1H, dd, J=1.3HZ, 7.5Hz), 8.02 (1H, t, J=7.5Hz), 8.55 (1H, t, J=6.0Hz)

Example 1

A mixture of cyclobutanecarboxylic acid (0.5 ml), 1-hydroxybenzotriazole hydrate (0.8 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.0 g) in N,N-dimethylformamide (5 ml) was stirred for 1 hour at ambient temperature. The above mixture was added to a mixture of 4-(6-aminomethγlpyridin- 2-yl)-2-(diaminomethyleneamino)thiazole trihydrochloride (1.5 g) and triethylamine (1.8 ml) in N,N-dimethylformamide (15 ml) and the mixture was stirred for 20 hours at ambient temperature. The reaction mixture was added a mixture of ethyl acetate tetrahydrofuran and water and the mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was removed by concentration and the residue was recrystallized from a mixture of N,N-dimethylformamide and ethyl acetate to give 4-(6-cyclobutanecarbonyl- aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole

(0.86 g). mp : 242°C (dec. )

IR (Nujol) : 3400, 3300, 3110, 1645, 1610 cm^"1

NMR (DMSO-dg, δ) : 1.75-2.29 (6H, m) , 3.05-3.22 (1H, m), 4.37 (2H, d, J=5.9Hz), 6.93 (4H, s),

7.08-7.15 (1H, m), 7.39 (1H, s), 7.76-7.85 (2H, m), 8.28 (1H, t, J=5.9Hz)

Anal. Calcd. for C- 15_CH-1_o8N6,0S :

C 54.53, H 5.49, N 25.44 Found : C 54.40, H 5.50, N 25.24

Example 2

The following compound was obtained according to a similar manner to that of Example 1.

2-(Diaminomethyleneamino)-4-[6-(tetrahydrofuran-2- yl)carbonylaminomethylpyridin-2-yl]thiazole mp : 229°C (dec.)

IR (Nujol) : 3380, 3340, 1660, 1600 cm^"1 NMR (DMSO-dg, δ) : 1.80-2.20 (3H, m) , 2.06-2.24 (1H, m), 3.74-3.88 (1H, m) , 3.90-4.02 (1H, m) , 4.28-4.37 (1H, m) , 4.41 (2H, d, J=5.9Hz),

6.93 (4H, s), 7.07-7.15 (1H, m) , 7.36 (1H, s), 7.76-7.82 (2H, m) , 8.45 (1H, t, J=5.9Hz)

Anal. Calcd. for ^ci5^Hιo^N6°2^{S :}

C 52.01, H 5.24, N 24.26 Found : C 51.66, H 5.23, N 24.15 Example 3

2-{Diaminomethyleneamino)-4-[6-(tetrahydrofuran-3- yl)carbonylaminomethylpyridin-2-yl]thiazole mp : 227°C (dec.)

IR (Nujol) : 3390, 3260, 3130, 1650, 1605 cm^"1 NMR (DMSO-dg, δ) : 1.98-2.10 (2H, m) , 2.99-3.15 (1H, m), 3.61-3.82 (3H, m), 3.85-3.95 (1H, m), 4.40

(2H, d, J=5.9Hz), 6.93 (4H, s), 7.10-7.18 (1H, m), 7.41 (1H, s), 7.77-7.82 (2H, m) , 8.56 (1H, t, J=5.9Hz)

Anal. Calcd. for ^ci5^Hιg^N6⁰2^{S :} C 52.01, H 5.24, N 24.26

Found : C 51.69, H 5.26, N 24.05

Example 4

2-(Diaminomethyleneamino)-4-[6-(1-tert- butoxycarbonylpiperidin-3-yl)carbonylaminomethylpyridin- 2-yl] hiazole mp : 214-216°C

IR (Nujol) : 3400, 1655, 1610 cm^"1

NMR (DMSO-dg, δ) : 1.15-1.75 (3H, m) , 1.40 (9H, s), 1.80-2.00 (1H, m), 2.26-2.47 (1H, m) , 2.52-2.96 (2H, m), 3.75-4.10 (2H, m) , 4.38 (2H, d, J=5.6Hz), 6.92 (4H, s), 7.07-7.18 (1H, m) , 7.41

(1H, s), 7.75-7.84 (2H, m) , 8.53 (1H, t, J=5.6Hz)

Example 5 A mixture of 2-(diaminomethyleneamino)-4-[6-(1-tert- butoxycarbonylpiperidin-3-y1)carbonylaminomethylpyridin-2- yl]thiazole (1.9 g) and 4N-methanolic hydrogen chloride (40 ml) was stirred for 7 hours at ambient temperature. To the reaction mixture was added a tetrahydrofuran (40 ml) and the isolated precipitate was collected by filtration. The precipitate was added to water and adjusted to pH 13 with 5N-sodium hydroxide. The mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of methanol, dioxane and diisopropyl ether to give 2-(diaminomethyleneamino)-4-[6-(3-piperidyl)carbony1- aminomethylpyridin-2-yl]thiazole (0.47 g) . mp : 227-228°C

IR (Nujol) : 3300, 3160, 1650, 1620 cm^"1 NMR (DMSO-dg, δ) : 1.23-1.92 (4H, m) , 2.22-3.30 (5H, m), 4.37 (2H, J=5.8Hz), 6.93 (4H, s), 7.06-7.19 (1H, m), 7.39 (1H, s), 7.70-7.86 (2H, m) , 8.53 (1H, t, J=5.8Hz)

Anal. Calcd. for C-gH^ -_^OS :

C 53.46, H 5.89, N 27.28 Found : C 53.22, H 5.85, N 26.99

Example 6

4-[6-(4-Oxocyclohexyl)carbonylaminomethylpyridin-2- yl]-2-(diaminomethyleneamino)thiazole mp : 232°C

IR (Nujol) : 3390, 3390, 1715, 1650, 1605 cm^"1

NMR (DMSO-dg, δ) : 1.73-2.21 (4H, m) , 2.21-2.57 (4H, m), 2.66-2.85 (1H, m), 4.41 (2H, d, J=5.8Hz), 6.94 (4H, m) , 7.15 (1H, t, J=4.7Hz), 7.40 (1H, s) , 7.79 ( 2H, d, J=4.7Hz ) , 8.55 ( 1H, t, J=5. 8Hz )

Example 7

2-(Diaminomethyleneamino)-4-[6^'-[5-(l,2- dithiacyclopentan-3-yl)valeryl]aminomethylpyridin-2-yl]- thiazole mp : 204-205°C

IR (Nujol) : 3400, 1645, 1610 cm^"1

NMR (DMSO-dg, δ) : 1.27-1.75 (6H, m) , 1.75-1.98 (1H, m), 2.21 (2H, t, J=7.1Hz), 2.30-2.50 (1H, m) , 3.02-3.26 (2H, m) , 3.50-3.70 (1H, m) , 4.38 (2H, d, J=5.9Hz), 6.93 (4H, s), 7.15 (1H, t,

J=4.4Hz), 7.40 (1H, s), 7.78 (2H, d, J=4.4Hz), 8.42 (1H, t, J=5.9Hz)

Anal. Calcd. for ^CIR^H2 ^N6^OS3 ^:

C 49.52, H 5.54, N 19.25 Found : C 49.40, H 5.53, N 18.99

Example 8

A mixture of 4-[3-(l-pyrrolidinyl)methylphenoxy]- butyric acid (1.7 g), diphenylphosphoryl azide (1.4 ml) and triethylamine (0.9 ml) in dry benzene (30 ml) was stirred for 1 hour at 75-80°C. To the mixture was added a mixture of 4-(6-aminomethylpyridin-2-yl)-2- (diaminomethyleneamino)thiazole trihydrochloride (1.5 g) and triethylamine (1.8 ml) in a solution of tetrahydrofuran (30 ml) and methanol (30 ml) at ambient temperature and the mixture was stirred for 5 hours at the same temperature. The solvent was removed by concentration and the residue was added a mixture of ethyl acetate, tetrahydrofuran and water. The mixture was adjusted to pH 11 with 4N-sodium hydroxide and the separated organic layer was dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (4:1, V/V) . The eluted fractions containing the desired product were collected and evaporated in vacuo. The residue was recrystallized from a mixture of ethanol and diisopropyl ether to give 2-(diaminomethyleneamino)-4- [ [6-[3-[3-(3-pyrrolidinyl)methylphenoxy]propyl]ureido]- methyl]thiazole (0.44 g) . mp : 174°C

IR (Nujol) : 3350, 3320, 1615 cm^"1

NMR (DMSO-dg, δ) : 1.69 (4H, s), 1.80-1.92 (2H, m) , 2.44 (4H, s), 3.12-3.25 (2H, m) , 3.55 (2H, s), 3.97 (2H, t, J=6.2Hz), 4.33 (2H, d, J=5.6Hz),

6.33 (1H, t, J=5.6Hz), 6.49 (1H, t, J=5.7Hz), 6.75-7.08 (7H, m) , 7.08-7.26 (2H, m) , 7.45 (1H, s), 7.76 (2H, d, J=4.4Hz) Anal. Calcd. for C₂₅H₃₂Ng0₂SΗ₂0 : C 57.02, H 6.51, N 21.28, H₂0 3.42

Found : C 56.82, H 6.44, N 21.30, H₂0 3.50

Example 9

A mixture of 4-(6-acetylaminomethylpyridin-2-yl)-2- [(amino)[2,2,2-trifluoroethyl)amino]methyleneamino]- thiazole (3.5 g) and cone, hydrochloric acid (7.8 ml) in ethanol (35 ml) was heated under reflux for 24 hours and then the mixture was cooling to ambient temperature. To the mixture was added ethanol (200 ml) with stirring and the isolated precipitate was collected by filtration to give 4-(6-aminomethylpyridin-2-yl)-2-[(amino;)[(2,2,2- trifluoroethyl) mino] ethyleneamino]thiazole trihydrochloride (3.7 g) . mp : 198-200°C IR (Nujol) : 3300, 3210, 1675, 1615, 1400 cm^"1 NMR (D₂0, δ) : 4.27 (2H, g, J=8.8Hz), 4.50 (2H, s), 7.58 (1H, d, J=7.5Hz), 8.00 (1H, d, J=7.5Hz), 8.04 (1H, s), 8.13 (1H, t, J=7.5Hz)

Example 10

2-[Amino) [2,2,2-trifluoroethyl)amino]methyleneamino]- 4-(6-cycloheptanecarbonylaminomethylpyridin-2-yl)thiazole mp : 229-230°C

IR (Nujol) : 3390, 3360, 1625 cm^"1

NMR (DMSO-dg-D₂0, δ) : 1.30-1.92 (12H, m) , 2.32-2.50 (1H, m), 4.12 (2H, q, J=9.7Hz), 4.37 (2H, d, J=5.7Hz), 7.13 (1H, t, J=4.3Hz), 7.50 (1H, s),

7.81 (1H, d, J=4.3Hz), 8.35 (1H, t, J=5.7Hz) Anal. Calcd. for C_2QH₂₅NgOSF₃ :

C 52.85, H 5.54, N 18.49 Found : C 52.98, H 5.68, N 18.18

Example 11

A mixture of 4-(6-acetylaminomethylpyridin-2-yl)-2- [(amino) (methylthio)methyleneamino]thiazole hydriodide (1.5 g) and n-butylamine (1.6 ml) in ethanol (30 ml) was heated under reflux for 40 hours. The solvent was removed by concentration and residue was added to a mixture of ethyl acetate, tetrahydrofuran and water. The mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate and a separated organic layer was washed with brine and dried over magnesium sulfate. Evaporation of a solvent gave a residue, which was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (19:1, V/V) . The eluted fractions containing the desired product were collected and evaporated in vacuo. The residue was recrystallized from a mixture of methanol, dioxane and diisopropyl ether to give 4-{6-acetylaminomethylpyridin-2-yl)-2-[ (amino)- (n-butylamino)methyleneamino]thiazole (0.48 g) . mp : 145-146°C IR (Nujol) : 3380, 1645, 1605 cm^"1

NMR (DMSO-dg, δ) : 0.92 (3H, t, J=7.0Hz), 1.24-1.60 (4H, m), 1.93 (3H, s), 3.10-3.30 (2H, m) , 4.37 (2H, d, J=5.9Hz), 7.16 (1H, d, J=7.2Hz), 7.40 (1H, s), 7.66-7.86 (2H, m) , 8.45 (1H, t, J=5.9Hz)

Anal. Calcd. for C-gH^NgOS :

C 55.47, H 6.40, N 24.26 Found : C 55.25, H 6.48, N 24.03

Example 12

The following compound was obtained according to a similar manner to that of Example 11.

4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)- (cyclohexylamino)methyleneamino]thiazole mp : 127-128°C

IR (Nujol) : 3410, 3270, 1660, 1595 cm^"1 NMR (DMSO-dg, δ) : 1.05-2.00 (10H, m), 1.93 (3H, s), 3.47-3.70 (1H, m) , 4.36 (2H, d, J=6.0Hz), 7.16 (1H, d, J=7.4Hz), 7.33 (2H, s), 7.40 (1H, s),

7.70 (1H, d, J=7.4Hz), 7.80 (1H, t, J=7.4Hz), 8.44 (1H, t, J=6.0Hz) Anal. Calcd. for C₁₈H₂₄NgOS :

C 58.04, H 6.49, N 22.56 Found : C 58.11, H 6.38, N 22.30

Example 13

The following compound was obtained according to a similar manner to that of Example 11. 4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)- (2-methoxyethylamino)methyleneamino]thiazole mp : 162-163°C

IR (Nujol) : 3370, 1650, 1595 cm^"1 NMR (DMSO-dg, δ) : 1.93 (3H, s), 3.27-3.52 (4H, m) ,

3.32 (3H, s), 4.37 (2H, d, J=5.9Hz), 7.10-7.21 (1H, m), 7.42 (1H, s), 7.70-7.85 (2H, m) , 8.45 (1H, t, J=5.9Hz)

Anal. Calcd. for ^ci5^H20^N6°2^{S :} C 51.71, H 5.79, N 24.12

Found : C 51.37, H 5.79, N 23.84

Example 14

4-(6-Acetylaminomethylpyridin-2-yl)-2-[(.amino) (2- dimethylaminoethylamino)methyleneamino]thiazole mp : 134-136°C IR (Nujol) : 3400, 3360, 3100, 1640, 1590 cm^"1 NMR (DMSO-dg, δ) : 1.93 (3H, s), 2.24 (6H, s), 2.40-2.55 (2H, m) , 3.24-3.44 (2H, m), 4.36 (2H, d, J=5.9Hz), 7.16 (1H, d, J=8.0Hz), 7.40 (1H, s), 7.79 (1H, t, J=8.0Hz), 7.88 (1H, d, J=8.0Hz), 8.45 (1H, t, J=5.9Hz)

Example 15

To a solution of 4-(6-acetγlaminomethylpyridin-2-yl)- 2-1 (amino) (2-dimethylaminoethylamino)methyleneamino]- thiazole (0.9 g) in methanol (9 ml) was added a

4N-dioxanic hydrogen chloride (2.5 ml) and the mixture was stirred for 30 minutes at ambient temperature. Diisopropyl ether (20 ml) was added to a reaction mixture and isolated precipitate was collected by filtration. The precipitate was recrystallized from a mixture of methanol and diisopropyl ether to give

4-(6-acetylaminomethylpyridin-2-yl)-2-[(amino) (2- dimethylaminoethylamino)methyleneamino]thiazole trihydrochloride (0.96 g) . mp : 228-229°C

IR (Nujol) : 3190 (br), 1690, 1655, 1605 cm^"1 NMR (D₂0, δ) : 2.18 (3H, s), 3.05 (6H, s) ,

3.60 (2H, t, J=6.2Hz), 3.99 (2H, t, J=6.2Hz), 4.82 (2H, s), 7.84 (1H, d, J=7.3Hz), 8.33 (1H, s), 8.34 (1H, d, J=7.3Hz),

8.51 (1H, t, J=7.3Hz) Anal. Calcd. for C₁₆H₂₃N₇OS^«3HCl^«l/3H₂0 :

C 40.30, H 5.64, N 20.56, Cl 22.30, H₂0 1.26 Found: C 40.36, H 5.65, N 20.79, Cl 22.19, H₂01.19

Example 16

4-(6-Acetylaminomethylpyridin-2-yl)-2-[bis(methyl- amino)methyleneamino]thiazole mp : 277-279°C

IR (Nujol) : 3360, 1665, 1590 cm^"1 NMR (DMSO-dg, δ) : 1.93 (3H, s) , 2.83 (6H, d, J=4.5Hz), 4.37 (2H, d, J=5.9Hz), 7.12-7.20 (1H, m), 7.42 (1H, s), 7.75-7.82 (2H, m) , 8.45 (1H, t, J=5.9Hz) Anal. Calcd. for C-.H-gNgOS :

C 52.81, H 5.70, N 26.39 Found : C 52.50, H 5.64, N 26.10

Example 17

The following compound was obtained according to a similar manner to that of Example 11. 4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)- (ethylamino)methyleneamino]thiazole

NMR (DMSO-dg, δ) : 1.13 (3H, t, J=7.1Hz), 1.93 (3H, s), 3.14-3.30 (2H, m) , 4.37 (2H, d, J=5.9Hz), 7.16 (1H, dd, J=1.2Hz abd 7.2Hz), 7.41 (3H, s),

7.73 (1H, d, J=7.2Hz), 7.80 (1H, t, J=7.2Hz), 8.45 (1H, t, J=5.9Hz)

Example 18 The following compound was obtained according to a similar manner to that of Example 11.

4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)- (n-propylamino)methyleneamino]thiazole NMR (DMSO-dg, δ) : 0.93 (3H, t, J=7.3Hz), 1.41-1.64

(2H, m), 1.93 (3H, s), 3.09-3.22 (2H, m), 4.37 (2H, d, J=5.9Hz), 7.17 (1H, d, J=7.3Hz), 7.41 (3H, s), 7.73 (1H, d, J=7.3Hz), 7.80 (1H, t, J=7.3Hz), 8.45 (1H, t, J=5.9Hz)

Example 19

4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)- (n-pentylamino)methyleneamino]thiazole

NMR (DMSO-dg, δ) : 0.89 (3H, t, J=6.5Hz), 1.10-1.70 (6H, m), 1.94 (3H, s), 3.03-3.31 (2H, m), 4.38 (2H, d, J=5.9Hz), 7.17 (1H, d, J=7.0Hz), 7.39 (2H, s),

7.41 (1H, s), 7.60-7.92 (2H, m) , 8.46 (1H, t, J=5.9Hz)

Example 20 The following compound was obtained according to a similar manner to that of Example 11.

4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)- (n-he.xylamino)methyleneamino]thiazole NMR (DMSO-dg, δ) : 0.87 (3H, t, J=6.5Hz), 1.18-1.64

(8H, m), 1.93 (3H, s), 3.12-3.30 (2H, m) , 4.37 (2H, d, J=5.9Hz), 7.16 (1H, d, J=7.2Hz), 7.36 (2H, s), 7.40 (1H, s), 7.71 (1H, d, J=7.2Hz), 7.79 (1H, t, J=7.2Hz), 8.45 (1H, t, J=5.9Hz)

Example 21

4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)- (isopropylamino)methyleneamino]thiazole

NMR (DMSO-dg, δ) : 1.15 (6H, d, J=6.4Hz), 1.93 (3H, s), 3.80-4.00 (1H, m), 4.37 (2H, d, J=5.9Hz), 7.16 (1H, d, J=7.4Hz), 7.37 (2H, s),

7.41 (1H, s), 7.71 (1H, d, J=7.4Hz), 7.80 (1H, t, J=7.4Hz), 8.45 (1H, t, J=5.9Hz)

Example 22 The following compound was obtained according to a similar manner to that of Example 11.

4-(6-Acetylaminomethylpyridin-2-yl)-2-[ (amino)- (isopentylamino)methyleneamino]thiazole NMR (DMSO-dg, δ) : 0.92 (6H, d, J=6.6Hz),

1.35-1.50 (2H, m), 1.57-1.80 (1H, m) , 1.93 (3H, s), 3.14-3.28 (2H, m) , 4.37 (2H, d, J=5.9Hz), 7.16 (1H, d, J=7.3Hz), 7.36 (2H, s), 7.40 (1H, s), 7.71 (1H, d, J=7.3Hz), 7.80 (1H, t, J=7.3Hz), 8.45 (1H, t, J=5.9Hz) Example 23

4-(6-Acetylaminomethylpyridin-2-yl)-2-[ (amino)- allylamino)methyleneamino]thiazole

NMR (DMSO-dg, δ) : 1.93 (3H, s), 3.80-3.93 (2H, s), 4.37 (2H, d, J=5.9Hz), 5.07-5.32 (2H, m) , 5.81-6.01 (1H, m), 7.17 (1H, dd, J=1.9Hz and 6.7Hz), 7.44 (1H, s), 7.49 (2H, s),

7.70-7.86 (2H, m) , 8.45 (1H, t, J=5.9Hz)

Example 24

4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)- cyclopentylamino)methyleneamino]thiazole

NMR (DMSO-dg, δ) : 1.32-1.80 (6H, m) , 1.80-2.03 (2H, m), 1.93 (3H, s), 3.92-4.12 (1H, m) , 4.37 (2H, d, J=5.8Hz), 7.16 (1H, d, J=7.5Hz), 7.33 (2H, s), 7.40 (1H, s), 7.70 (1H, d, J=7.5Hz), 7.80 (1H, t, J=7.5Hz), 8.45 (1H, t, J=5.8Hz)

Example 25

4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)- (cyclopropylamino)methyleneamino]thiazole

NMR (DMSO-dg, δ) : 1.40-1.88 (4H, m) , 1.93 (3H, s), 3.35-3.55 (1H, m) , 4.37 (2H, d, J=5.7Hz), 7.17 (1H, d, J=7.6Hz), 7.40 (1H, s), 7.60 (2H, s), 7.69 (1H, d, J=7.6Hz), 7.81 (1H, t, J=7.6Hz), 8.45 (1H, t, J=5.7Hz) Exapmle 26

4-(6-Acetylaminomethylpyridin-2-yl)-2-[ (amino)- (piperidino)methyleneamino]thiazole

NMR (DMSO-dg, δ) : 1.40-1.70 (6H, m) , 1.93 (3H, s), 3.45-3.60 (4H, m) , 4.37 (2H, d, J=5.9Hz), 7.17 (1H, d, J=7.4Hz), 7.44 (1H, s), 7.68 (1H, d, J=7.4Hz), 7.81 (1H, t, J=7.4Hz),

8.24 (2H, s), 8.45 (1H, t, J=5.9Hz)

Example 27

4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)- (morpholino)methyleneamino]thiazole

NMR (DMSO-dg, δ) : 1.93 (3H, s), 3.47-3.58 (4H, m) , 3.58-3.70 (4H, m) , 4.37 (2H, d, J=5.9Hz),

7.17 (1H, d, J=7.5Hz), 7.49 (1H, s), 7.67 (1H, d, J=7.5Hz), 7.81 (1H, t, J=7.5Hz), 8.30 (2H, s), 8.45 (1H, t, J=5.9Hz)

Example 28

2-[ (Amino) (methylamino)methyleneamino]-4-(6- propionyla inomethylpyridin-2-yl)thiazole mp : 169-170°C

IR (Nujol) : 3400, 3350, 3250, 1630, 1600 cm^"1

NMR (DMSO-dg, δ) : 8.38 (1H, t, J=5.9Hz),

8.00-7.60 (2H, m), 7.45 (2H, s), 7.40 (1H, s), 7.15 (1H, dd, J=2.2Hz and 6.5Hz), 4.38 (2H, d. J=5.9Hz), 2.77 (3H, d, J=4.8Hz), 2.21 (2H, q, J=7.6Hz), 1.06 (3H, t, J=7.6Hz) Anal. Calcd. for C₁₄H-gNgOS :

C 52.81, H 5.70, N 26.39 Found : C 53.10, H 5.72, N 25.94

Example 29

2-[(Amino) (n-butylamino)methyleneamino]-4-(6- propionylaminomethylpyridin-2-yl)thiazole mp : 145-147°C

IR (Nujol) : 3330, 3230, 3120, 1650, 1610 cm^"1 NMR (DMSO-dg, δ) : 8.38 (IH, t, J=5.9Hz),

7.80 (IH, t, J=7.4Hz), 7.71 (IH, dd, J= ca. l.OHz and 7.4Hz), 7.40 (IH, s), 7.38 (2H, s), 7.15 (IH, dd, J= ca. l.OHz and 7.4Hz), 4.38 (2H, d, J=5.9Hz), 3.24-3.15 (2H, m) , 2.21 (2H, q, J=7.6Hz), 1.54-1.28 (4H, m) , 1.06 (3H, t,

J=7.6Hz), 0.92 (3H, t, J=7.0Hz) .Anal. Calcd. for C₁₇H₂.NgOS :

C 56.64, H 6.71, N 23.31 Found : C 56.98, H 6.91, N 23.23

Example 30

2-[(Amino)(cyclohexylamino)methyleneamino]-4-(6- propionylaminomethylpyridin-2-yl)thiazole IR (Nujol) : 3320, 1650 cm^'1

NMR (DMSO-dg, δ) : 8.38 (IH, t, J=5.9Hz), 7.80 (IH, t, J=7.5Hz), 7.70 (IH, dd, J= ca. l.OHz and 7.5Hz), 7.39 (IH, s), 7.33 (2H, s), 7.15 (IH, dd, J= ca. l.OHz and 7.5Hz), 4.37 (2H, d,

J=5.9Hz), 3.66-3.54 (IH, m) , 2.21 (2H, q,

J=7.6Hz), 1.90-1.80 (2H, m) , 1.80-1.45 (3H, m) ,

1.45-1.10 (5H, m), 1.06 (3H, t, J=7.6Hz)

Example 31

2-[ (Amino) (methylamino)methyleneamino]-4-(6- ethoxycarbonylaminomethylpyridin-2-yl)thiazole

NMR (DMSO-dg, δ) : 7.85-7.66 (3H, m) , 7.47 (2H, s), 7.39 (IH, s), 7.17 (IH, dd, J=1.9Hz and 6.8Hz), 4.31 (2H, d, J=6.1Hz), 4.04 (2H, q, J=7.1Hz), 2.77 (3H, d, J=4.7Hz), 1.19 (3H, t, J=7.1Hz)

Example 32

2-[ (Amino) (n-butylamino)methyleneamino]-4-(6- ethoxycarbonylaminomethylpyridin-2-yl)thiazole mp : 141-142°C

IR (Nujol) : 3430, 3340, 3230, 1705, 1650, 1610 cm^"1 NMR (DMSO-dg, δ) : 7.85-7.70 (3H, m) , 7.38 (3H, s),

7.17 (IH, dd, J= ca. l.OHz and 6.4Hz), 4.30 (2H, d, J=6.1Hz), 4.04 (2H, q, J=7.1Hz), 3.19 (2H, q, J=6.4Hz), 1.51-1.03 (7H, m) , 0.92 (3H, t, 3=1.0Hz)

Example 33

A suspension of 2-(diaminomethyleneamino)-4-(5- methoxycarbonylpyridin-3-yl)thiazole (2.0 g) , cyclopentylamine (3.7 g) and 28% sodium methaxide methanolic solution (5 ml) in methanol (50 ml) was refluxed for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in water (50 ml) . The mixture was extracted with a mixture of ethyl acetate (150 ml) and tetrahydrofuran (50 ml). The extract was dried over magnesium sulfate and then was evaporated. Recrystallization from a mixture of methanol and diisopropyl ether afforded 4-(5-cyclopentylaminocarbonyl- pyridin-3-yl)-2-(diaminomethyleneamino)thiazole (0.2 g) . mp : 243-244°C (dec.) IR (Nujol) : 3430, 3370, 3060, 1630, 1590 cm^"1

NMR (DMSO-dg, δ) : 9.16 (IH, d, J=2.0Hz), 8.85 (IH, d, J=2.0Hz), 8.56 (IH, d, J=7.0Hz), 8.48 (IH, t, J=2.0Hz), 7.43 (IH, s), 6.94 (4H, s), 4.4-4.15 (IH, ), 2.05-1.85 (2H, m) , 1.85-1.45 (6H, m)

Anal. Calcd. for C-j-H-gNgOS :

C 54.53, H 5.49, N 25.44 Found : C 54.24, H 5.58, N 25.33

Example 34

The following compound was obtained according to a similar manner to that of Example 33.

4-(5-Cyclohexylaminocarbonylpyridin-3-yl)-2- (diaminomethyleneamino)thiazole mp : 213-214°C (dec.)

IR (Nujol) : 3400, 3280, 3060, 1630, 1590 cm^"1 NMR (DMSO-dg, δ) : 9.16 (IH, d, J=2.lHz), 8.85 (IH, d, J=2.1Hz), 8.49-8.47 (2H, m), 7.43 (IH, s), 6.96 (4H, s), 4.00-3.80 (IH, m) , 2.00-1.50 (4H, m), 1.50-1.00 (6H, m)

Example 35

The following compound was obtained according to a similar manner to that of Example 33. 4-(5-Cycloheptylaminocarbonylpyridin-3-yl)-2- (diaminomethyleneamino)thiazole mp : 213-214°C (dec.)

IR (Nujol) : 3410, 3350, 1640, 1600 cm^"1 NMR (DMSO-dg, δ) : 9.16 (IH, d, J=2.lHz), 8.84 (IH, d, J=2.1Hz), 8.53 (IH, d, J=7.7Hz), 8.48 (IH, t, J=2.lHz), 7.42 (IH, s), 6.95 (4H, s), 4.10-3.90 (IH, m), 2.00-1.00 (12H, m)

Example 36

A suspension of 4-(2-aminomethylthiazol-4-yl)-2- (diaminomethyleneamino)thiazole dihydrochloride (2.0 g) , cycloheptanecarboxylic acid (1.02 g) , 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.50 g), 1-hydroxybenzotriazole hydrate (1.07 g) and triethylamine (1.24 g) in N,N-dimethylformamide (50 ml) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was suspended in water (200 ml) . The mixture was alkalized to pH 11 with a saturated aqueous potassium carbonate solution and then extracted with a mixture of ethyl acetate (250 ml) and tetrahydrofuran (50 ml). The extract was dried over magnesium sulfate and then was evaporated. The residue was chromatographed on a silica gel column eluting with a mixture of chloroform and methanol = 10:1. Recrystallization from a mixture of methanol, tetrahydrofuran and diisopropyl ether afforded 4-(2-cycloheptanecarbonylaminomethylthiazol-4-yl)-2- (diaminomethyleneamino)thiazole (0.72 g) . mp : 243-245°C (dec.) IR (Nujol) : 3370, 1650, 1610 cm^"1

NMR (DMSO-dg, δ) : 8.64 (IH, t, J=6.0Hz), 7.76 (IH, s), 7.01 (IH, s), 6.89 (4H, s), 4.52 (2H, d, J=6.0Hz), 2.45-2.25 (IH, m) , 2.00-1.30 (12H, m) Anal. Calcd. for C_lgH₂₂NgOS₂ :

C 50.77, H 5.86, N 22.20 Found : C 50.37, H 5.99, N 22.50

Example 37

The following compound was obtained according to a similar manner to that of Example 36.

4-(2-Cyclohexylmethanecarbonylaminomethylthiazol-4- yl)-2-(diaminomethyleneamino)thiazole mp : 245-247°C (dec.)

IR (Nujol) : 3410, 3330, 1635, 1610 cm^"1 NMR (DMSO-dg, δ) : 8.73 (IH, t, J=6.0Hz), 7.78 (IH, s), 7.00 (IH, s), 6.88 (4H, s), 4.54 (2H, d,

J=6.0Hz), 2.05 (2H, d, J=6.8Hz), 1.82-1.50 (6H, m), 1.40-1.10 (3H, m) , 1.10-0.70 (2H, m) .Anal. Calcd. for C₁₆H₂₂NgOS₂ :

C 50.77, H 5.86, N 22.20 Found : C 50.89, H 5.87, N 22.11

Example 38

2-[(Amino) (methylamino)methyleneamino]-4-(2- acetylaminomethylthiazol-4-yl)thiazole mp : 190-192°C

IR (Nujol) : 3390, 3250, 1630 cm^"1

NMR (DMSO-dg, δ) : 8.73 (IH, t, J=6.0Hz), 7.78 (IH, s), 7.41 (2H, s), 7.03 (IH, s), 4.54 (2H, d, J=6.0Hz), 2.76 (3H, d, J=4.8Hz), 1.92 (3H, s)

Example 39 A mixture of 2-acetylaminomethyl-6- bromoacetylpyridine (3.0 g) and (amino) [ (2-propynyl)- amino]methylenethiourea (2.1 g) in ethanol (20.0 ml) was stirred for 2 hours at 50°C and ethyl acetate (20 ml) was added to the reaction mixture at ambient temperature under stirring. The isolated precipitate was collected by filtration and the precipitate was added to a mixture of tetrahydrofuran, ethyl acetate and water. The mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate and the separated organic layer was dried over magnesium sulfate. The solvent was removed by concentration and the residue was recrystallized from a mixture of methanol, dioxane and diisopropyl ether to give 4-(6-acetylamino- methylpyridin-2-yl)-2-[ (amino)[ (2-propynyl)- amino] ethyleneamino]thiazole (1.4 g) . mp : 169-170°C

IR (Nujol) : 3380, 3340, 3260, 1645, 1610 cm^"1 NMR (DMSO-dg, δ) : 1.94 (3H, s), 3.16-3.23 (IH, m) , 4.00-4.12 (2H, m), 4.38 (2H, d, J=5.8Hz), 7.06 (IH, s), 7.15-7.25 (IH, m) , 7.49 (IH, s), 7.62 (2H, s), 7.73-7.87 (2H, m) , 8.46 (IH, t,

J=5.8Hz)

Example 40

The following compound was obtained according to a similar manner to that of Example 39.

4-(6-Acetylaminomethylpyridin-2-yl)-2-[ (amino)- (methylamino)methyleneamino]thiazole mp : 181°C IR (Nujol) : 3340, 3230, 3130, 1630, 1590 cm^"1 NMR (DMSO-dg, δ) : 1.93 (3H, s) , 2.77 (3H, d,

J=4.8Hz), 4.37 (2H, d, J=5.9Hz), 7.14-7.21 (IH, m), 7.41 (IH, s), 7.46 (2H, s), 7.74-7.84 (2H, m), 8.45 (IH, t, J=5.9Hz) Example 41

4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)- (butylamino)methyleneamino]-5-methylthiazole mp : 129-130°C

IR (Nujol) : 3390, 3340, 1655, 1610 cm^"1 NMR (DMSO-dg, δ) : 0.91 (3H, t, J=7.0Hz), 1.26-1.60 (4H, m) , 1.91 (3H, s), 2.67 (3H, s),

3.16 (2H, q, J=6.3Hz), 4.37 (2H, d, J=5.9Hz), 7.13 (IH, d, J=7.3Hz), 7.27 (2H, s) , 7.69 (IH, d, J=7.3Hz), 7.77 (IH, t, J=7.3Hz), 8.42 (IH, t, J=5.9Hz)

Example 42

4-(6-Acetylaminomethylpyridin-2-y1)-2-[(amino) [ (2- methylallyl)amino]methyleneamino]thiazole mp : 173-174°C

IR (Nujol) : 3360, 3240, 3190, 1635 cm^'1 NMR (DMSO-dg, δ) : 1.74 (3H, s), 1.95 (3H, s) , 3.81 (2H, d, J=5.5Hz), 4.39 (2H, d, J=5.9Hz),

4.84 (IH, s), 4.91 (IH, s), 7.17 (IH, dd, J=2.2Hz, 6.5Hz), 7.44 (IH, s), 7.49 (2H, s) , 7.72-7.87 (2H, m), 8.46 (IH, t, J=5.9Hz)

Example 43

4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino) [(2- hydroxyethyl)amino] ethyleneamino]thiazole mp : 175-176°C

IR (Nujol) : 3280, 3200, 1645, 1600 cm^"1

NMR (DMSO-dg, δ) : 1.94 (3H, s) , 3.32-3.46 (2H, m) ,

3.46-3.66 (2H, m) , 4.37 (2H, d, J=5.7Hz), 4.92 (IH, s), 7.16 (IH, d, J=6.3Hz), 7.34 (2H, s),

7.42 (IH, s), 7.70-7.88 <2H, m) , 8.45 (IH, t,

J=5.7Hz)

Example 44 The following compound was obtained according to a similar manner to that of Example 11.

4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)[(3- methoxypropyl)amino]methyleneamino]thiazole mp : 135°C

IR (Nujol) : 3420, 3290, 1670, 1640, 1610 cm^"1 NMR (DMSO-dg, δ) : 1.66-1.87 (2H, m) , 1.94 (3H, s), 3.17-3.33 (2H, m) , 3.25 (3H, s), 3.33-3.48 (2H, m), 4.38 (2H, d, J=5.9Hz), 7.17 (IH, d, J=7.7Hz), 7.42 (3H, s), 7.74 (IH, d, J=7.7Hz),

7.80 (IH, t, J=7.7HZ), 8.45 (IH, t, J=5.9Hz)

Example 45

4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino) [(2- methylthioethyl)amino]methyleneamino]thiazole mp : 146-147°C IR (Nujol) : 3390, 3280, 1645, 1610 cm^"1

NMR (DMSO-dg, δ) : 1.94 (3H, s), 2.12 (3H, s), 2.66 (2H, t, J=6.7Hz), 3.34-3.50 (2H, m) , 4.38 (2H, d, J=5.9Hz), 7.12-7.22 (IH, m) , 7.44 (IH, s), 7.49 (2H, s), 7.74 (2H, m) , 8.45 (IH, t, J=5.9Hz) Example 46

2-[[(2-Acetylaminoethyl)amino](amino)methyleneamino]' 4-(6-acetylaminomethylpyridin-2-yl)thiazole mp : 184-185°C

IR (Nujol) : 3410, 3310, 1640, 1615 cm^"1 NMR (DMSO-dg, δ) : 1.82 (3H, s), 1.93 (3H, s), 3.12-3.35 (4H, m) , 4.37 (2H, d, J=5.9Hz), 7.16

(IH, dd, J=2.2Hz, 6.5Hz), 7.43 (IH, s), 7.53 (2H, s), 7.72-7.87 (2H, m) , 8.01 (IH, br s), 8.45 (IH, t, J=5.9Hz)

Example 47

The following compound was obtained according to a similar manner to that of .Example 11.

4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)- (furfurylamino)methyleneamino]thiazole mp : 169-170°C

IR (Nujol) : 3380, 1650, 1610 cm^"1

NMR (DMSO-dg, δ) : 1.93 (3H, s) , 4.37 (2H, d,

J=5.9Hz), 4.45 (2H, d, J=5.4Hz), 6.34 (IH, d, J=3.1Hz), 6.43 (IH, dd, J=1.8Hz, 3.1Hz), 7.17

(IH, d, J=7.7Hz), 7.47 (IH, s), 7.58 (2H, s), 7.64 (IH, s), 7.73 (IH, d, J=7.7Hz), 7.80 (IH, t, J=7.7Hz), 8.46 (IH, t, J=5.9Hz)

Example 48

4-(6-Acetylaminomethylpyridin-2-yl)-2-[ (amino) [[2-(2- pyridyl)ethyl]amino]methyleneamino]thiazole mp : 145-146°C

IR (Nujol) : 3310, 1640, 1620 cm^"1 NMR (DMSO-dg, δ) : 1.93 (3H, s), 3.01 (2H, t, J=6.7Hz), 3.56-3.70 (2H, m) , 4.37 (2H, d, J=5.9Hz), 7.16 (IH, d, J=7.7Hz), 7.18-7.30 (IH, m), 7.33 (IH, d, J=7.7Hz), 7.41 (3H, s), 7.62-7.80 (2H, m) , 7.79 (IH, t, J=7.7Hz), 8.45 (IH, t, J=5.9Hz), 8.53 (IH, d, J=4.1Hz)

Example 49

4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino) [ [2- (3,4-dimethoxyphenethyl) ]amino]methyleneamino]thiazole mp : 167-168°C

IR (Nujol) : 3280, 1635, 1610 cm^"1 NMR (DMSO-dg, δ) : 1.93 (3H, s), 2.77 (2H, t,

J=6.9Hz), 3.37-3.53 (2H, m) , 3.70 (3H, s), 3.72 (3H, s), 4.36 (2H, d, J=5.9Hz), 6.75-6.92 (3H, m), 7.16 (IH, d, J=7.7Hz), 7.38 (2H, s), 7.40

(IH, s), 7.53-7.68 (IH, m) , 7.76 (IH, t,

J=7.7Hz), 8.44 (IH, t, J=5.9Hz)

Example 50

4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino) [ [2- (indol-3-y1)ethyl]amino]methyleneamino]thiazole mp : 158-159°C

IR (Nujol) : 3420, 3340, 1660 cm^"1

NMR (DMSO-dg, δ): 1.93 (3H, s), 2.97 (2H, t, J=6.5Hz), 3.44-3.63 (2H, m) , 4.37 t2H, d, J=5.8Hz), 6.96-7.27 (3H, m) , 7.21 (IH, s). 7.30-7. 80 ( 6H, m) , 7. 41 ( IH, s ) , 8 .44 ( IH, t, J=5.8Hz ) , 10.85 ( IH, s )

Example 51 The following compound was obtained according to a similar manner to that of Example 11.

4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino) [[2-(5- dimethylaminomethylfurfurylthio)ethyl]amino]methylene- amino]thiazole mp : 116-118°C

IR (Nujol) : 3470, 3330, 1670, 1645, 1610 cm^"1 NMR (DMSO-dg, δ) : 1.93 (3H, s) , 2.20 (6H, s), 2.64 (2H, t, J=6.7Hz), 3.33-3.46 (2H, m) , 3.50 (2H, s), 3.83 (2H, s), 4.37 (2H, d, J=5.9Hz), 6.23

(IH, d, J=3.1Hz), 6.27 (IH, d, J=3.1Hz), 7.14-7.27 (IH, m) , 7.44 (IH, s), 7.52 (2H, s), 7.74-7.85 (2H, m), 8.46 (IH, t, J=5.9Hz)

Example 52

4-(6-Acetylaminomethylpyridin-2-yl)-2-[( mino)- (dimethylamino)methyleneamino]thiazole mp : 214-215°C

IR (Nujol) : 3370, 3300, 1650, 1620 cm^"1 NMR (DMSO-dg, δ) : 1.93 (3H, s) , 2.99 (6H, s) , 4.37 (2H, d, J=5.9Hz), 7.17 (IH, d, J=7.5Hz), 7.43 (IH, s), 7.68 (IH, d, J=7.5Hz), 7.81 (IH, t,

J=7.5Hz), 8.12 (2H, s), 8.46 (IH, t, J=5.9Hz)

Example 53

The following compound was obtained according to a similar manner to that of Example 11. 2-[(Amino) (cyclohexylamino)methyleneamino]-4-(6- ethoxycarbonylaminomethylpyridin-2-yl)thiazole mp : 141-142°C

IR (Nujol) : 3350, 1710, 1640 cm^"1 NMR (DMSO-dg, δ) : 1.00-1.47 (8H, m) , 1.47-1.63 (IH, m), 1.63-1.80 (2H, m) , 1.80-1.94 (2H, m) , 3.45-3.70 (IH, m) , 4.04 (2H, q, J=7.lHz), 4.30 (2H, d, J=6.2Hz), 7.16 (IH, d, J=7.7Hz), 7.32 (2H, s), 7.37 (IH, s), 7.65-7.79 (2H, m) , 7.81 (IH, t, J=7.7Hz)

Example 54

2- [ (Amino)[ (2-methoxyethyl)amino]methyleneamino]-4- (2-acetylaminomethylthiazol-4-yl)thiazole mp : 169-170°C

IR (Nujol) : 3410, 3350, 1660, 1600 cm^"1 NMR (DMSO-dg, δ) : 1.91 (3H, s), 3.30-3.46 (7H, m) ,

4.54 (2H, d, J=6.0HZ), 7.04 (IH, s), 7.38 (2H, br), 7.75 (IH, s), 8.78 (IH, t, J=6.0Hz)

Example 55 The following compound was obtained according to a similar manner to that of Example 11.

2-[ (Amino) (allylamino)methyleneamino]-4-(2- acetylaminomethylthiazol-4-yl)thiazole mp : 184-185°C

IR (Nujol) : 3400, 3200, 3110, 1660, 1640, 1600 cm^"1 NMR (DMSO-dg, δ) : 1.91 (3H, s) , 3.86 (2H, t,

J=5.4Hz), 4.54 (2H, d, J=6.0Hz), 5.11 (IH, dd, J=10.3Hz and 1.7Hz), 5.21 (IH, dd, J=17.2Hz and 1.7Hz), 5.81-6.00 (IH, m) , 7.05 (IH, s), 7.47 ( 2H, br) , 7.75 ( IH, s ) , 8.78 ( IH, t, J=6. 0Hz )

Example 56

2-[ (Amino) {butylamino)methyleneamino]-4-(2-acetyl- aminomethylthiazol-4-yl)thiazole mp : 177-178°C IR (Nujol) : 3400, 3330, 3220, 1660, 1620 cm^"1

NMR (DMSO-dg, δ) : 0.91 (3H, t, J=7.0Hz), 1.29-1.49 (4H, m), 1.91 (3H, s), 3.18 (2H, q, J=7.0Hz), 4.54 (2H, d, J=6.0Hz), 7.02 (IH, s), 7.36 (2H, s), 7.70 (IH, s), 8.77 (IH, t, J=6.0Hz)

Example 57

A solution of 2-[ (amino) (methylthio)methyleneamino]- 4-(6-ethoxycarbonylaminomethylpγridin-2-yl)thiazole hydriodide (2.0 g) and (2-methoxyethyl)amine (5 ml) in ethanol (40 ml) was refluxed for 23 hours. The solvent was removed under reduced pressure. The residue was suspended in water (100 ml). The mixture was alkalized with a saturated aqueous potassium carbonate solution and then extracted with a mixture of ethyl acetate (200 ml) and tetrahydrofuran (30 ml). The extract was dried with magnesium sulfate and the evaporated in vacuo. The residue was chromatographed on a silica gel column eluting with a mixture of chloroform and methanol (20:1). The appropriate fractions were collected and evaporated in vacuo. The residue was dissolved in methanol (10 ml). 4N-Dioxanic hydrogen chloride (5 ml) was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was crystallized from ethanol. Recrystallization from ethanol afford 2-[(amino) [(2-methoxyethyl)amino]- methyleneamino]-4-(6-ethoxycarbonylaminomethylpyridin-2- yl)thiazole dihydrochloride (0.85 g) . mp : 204-205°C

IR (Nujol) : 3460, 3200, 1690, 1600 cm^"1 NMR (DMSO-dg, δ) : 1.19 (3H, t, J=7.lHz), 3.62 (4H, br s), 3.38 (3H, s), 4.04 (2H, q, J=7.lHz), 4.36 (2H, d, J=5.8Hz), 7.31 (IH, dd, J=6.2Hz and 2.4Hz), 7.79 (IH, t, J=5.8Hz), 7.93-8.01 (3H, m), 8.52 (2H, br s), 9.40-9.80 (IH, br) , 12.60-13.20 (IH, br)

Example 58

A mixture of 4-(6-acetylaminomethylpyridin-2-yl)-2- [(methylamino) (methylthio)methyleneamino]thiazole hydroiodide (1.5 g) and 50% aqueous dimethylamine (3.0 ml) in ethanol (30.0 ml) was heated at 100°C in a sealed tube for 48 hours. Evaporation of the solvent gave a residue, which was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (19:1, V/V) . The eluted fractions containing the desired product were collected and evaporated in vacuo. The residue was recrystallized from a mixture of methanol, dioxane and diisopropyl ether to give 4-(6-acetylaminomethylpyridin- 2-yl)-2-[ (dimethylamino) (methylamino)methyleneamino]- thiazole (0.4 g) . mp : 153-154°C

IR (Nujol) : 3240, 1615 cm^"1

NMR (DMSO-dg, δ) : 1.93 (3H, s) , 2.81 (3H, d,

J=3.lHz), 2.89 (6H, s), 4.36 (2H, d, J=5.9Hz), 7.17 (IH, d, J=6.4Hz), 7.48 (IH, s), 7.72-7.86

(2H, m), 7.97 (IH, q, J=3.1Hz), 8.46 (IH, t, J=5.9Hz)

Example 59 Methyl isocyanate (0.4 ml) was added to a mixture of 2-[ (allylamino) (amino)methyleneamino]-4-(6-aminomethyl- pyridin-2-yl)thiazole trihydrochloride (2.0 g) and triethylamine (2.1 ml) in a mixture of tetrahydrofuran (30.0 ml) and methanol (10.0 ml) and the mixture was stirred for 3 hours at ambient temperature. The reaction mixture was added to a mixture of ethyl acetate and water and the mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (19:1, V,V) . The eluted fractions containing the desired product were collected and evaporated in vacuo. The residue was recrystallized from a mixture of ethanol, dioxane and diisopropyl ether to give 2-[(allylamino) (amino)- methyleneamino]-4-[6-(3-methylureido)methylpyridin-2-yl]- thiazole (0.43 g) . mp : 176-177°C IR (Nujol) : 3480, 3330, 1660, 1620, 1595 cm^"1

NMR (DMSO-dg, δ) : 2.59 (3H, d, J=4.7Hz), 3.80-3.94 (2H, m), 4.33 (2H, d, J=5.7Hz), 5.05-5.31 (2H, m), 5.82-6.10 (IH, m) , 6.07 (IH, q, J=4.7Hz), 6.51 (IH, t, J=5.7Hz), 7.17 (IH, dd, J=1.5Hz, 7.0Hz), 7.35-7.63 (3H, m), 7.70-7.88 (2H, m)

Example 60

A mixture of 2-[(allylamino) (amino)methyleneamino]-4- (6-aminomethylpyridin-2-yl)thiazole trihydrochloride (2.0 g) and potassium cyanate (0.8 g) in water (20.0 ml) was stirred for 5 hours at ambient temperature and the mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate. The isolated precipitate was collected by filtration to give 2-[(allylamino) (amino)methyleneamino]- 4-(6-ureidomethylpyridin-2-yl)thiazole (1.2 g) . mp : 172-175°C

IR (Nujol) : 3410, 3300, 3230, 1650 cm^"1

NMR (DMSO-dg, δ) : 3.88-4.05 (2H, m) , 4.31 (2H, d,

J=5.8Hz), 5.10-5.38 (2H, m) , 5.73 (2H, s), 5.83-6.06 (IH, m) , 6.63 (IH, t, J=5.8Hz), 7.21

(IH, dd, J=2.4Hz, 6.2Hz), 7.67 (IH, s),

7.74-7.92 (2H, m) , 7.96 (2H, s)

Example 61 The following compound was obtained according to a similar manner to that of Example 59.

2-[ (Amino) (butylamino)methyleneamino]-4-[6-(3- methylureido)methylpyridin-2-yl]thiazole mp : 172-173°C

IR (Nujol) : 3340, 1670, 1630, 1607 cm^"1 NMR (DMSO-dg, δ) : 0.92 (3H, t, J=7.1Hz), 1.25-1.62 (4H, m), 2.59 (3H, d, J=4.6Hz), 3.10-3.30 (2H, m), 4.32 (2H, d, J=5.7Hz), 6.07 (IH, q, J=4.6Hz), 6.51 (IH, t, J=5.7Hz), 7.17 (IH, d,

J=7.2Hz), 7.39 (2H, s), 7.45 (IH, s) , 7.70 (IH, d, J=7.2Hz), 7.79 (IH, t, J=7.2Hz)

Example 62 The following compound was obtained according to a similar manner to that of Example 60.

2-[ (Amino) (butylamino)methyleneamino]-4-(6- ureidomethylpyridin-2-yl)thiazole mp : 226-228°C

IR (Nujol) : 3410, 3300, 3220, 3100, 1650, 1630 cm^"1 NMR (DMSO-dg, δ) : 0.92 (3H, t, J=7.1Hz), 1.26-1.60 (4H, m), 3.11-3.29 (2H, m) , 4.30 (2H, d, J=5.8Hz), 5.70 (2H, s), 6.56 (IH, t, J=5.8Hz), 7.18 (IH, d, J=7.3Hz), 7.37 (2H, s), 7.45 (IH, s ) , 7.71 ( IH, d, J=7. 3Hz ) , 7. 80 ( IH, t, J=7.3Hz)

Example 63

2-[(Amino) [(2-methoxyethyl)amino]methyleneamino]-4- (6-cyclopentylcarbonylaminomethylpyridin-2-yl)thiazole mp : 153-154°C IR (Nujol) : 3425, 3325, 3110, 1650 cm^"1

NMR (DMSO-dg, δ) : 1.40-1.95 (8H, m) , 2.60-2.80 (IH, m), 3.30-3.56 (4H, m) , 3.32 (3H, s), 4.38 (2H, d, J=5.8Hz), 7.12 (IH, dd, J=3.0Hz, 5.5Hz), 7.34 (2H, s), 7.41 (IH, s), 7.72-7.89 (2H, m) , 8.38 (IH, t, J=5.8Hz)

Example 64

The following compound was obtained according to a similar manner to that of Example 9.

2-[(Amino) (butylamino)methyleneamino]-4-(2-amino- methylthiazol-4-yl)thiazole dihydrochloride mp : >300°C

IR (Nujol) : 3310, 3100, 1700, 1640 cm^"1 NMR (DMSO-dg, δ) : 0.93 (3H, t, J=7.2Hz), 1.30-1.50

(2H, m), 1.50-1.70 (2H, m) , 3.38 (2H, m) , 4.48 (2H, br), 7.58 (IH, s), 8.25 (IH, s), 8.50-9.30 (6H, br)

Example 65

Propionic anhydride (0.7 ml) was added to a mixture of 2-[(amino) [(2-methoxyethyl)amino]methyleneamino]-4- (6-methylaminopyridin-2-yl)thiazole trihydrochloride (2.0 g) and triethylamine (2.8 ml) in tetrahydrofuran (40.0 ml) at ambient temperature and the mixture was stirred for 2 hours at the same temperature. The mixture was added a mixture of ethyl acetate, tetrahydrofuran and water and the separated organic layer was dried over magnesium sulfate. The solvent was removed by concentration and the residue was recrystallized from a mixture of methanol and diisopropyl ether to give 2-[ (amino) [ (2-methoxyethyl)- amino]methyleneamino]-4-(6-propionylaminomethylpyridin- 2-yl)thiazole (1.2 g) . mp : 144-145°C IR (Nujol) : 3420, 3310, 1640 cm^"1

NMR (DMSO-dg, δ) : 1.06 (3H, t, J=7.6Hz), 2.21 (2H, q, J=7.6Hz), 3.30-3.55 (4H, m) , 3.33 (3H, s) , 4.38 (2H, d, J=5.9Hz), 7.10-7.21 (IH, m) , 7.33 (2H, s), 7.41 (IH, s), 7.70-7.85 (2H, m) , 8.38 (IH, t, J=5.9Hz)

Example 66

The following compound was obtained according to a similar manner to that of Example 65.

4-(6-Acetylaminomethylpyridin-2-yl)-2-[ (amino)- (methylamino)methyleneamino]thiazole mp : 181°C

J=4.8Hz), 4.37 (2H, d, J=5.9Hz), 7.14-7.21 (IH, m), 7.41 (IH, s), 7.46 (2H, s) , 7.74-7.84 (2H, m), 8.45 (IH, t, J=5.9Hz)

Example 67

A mixture of 4-(6-aminomethylpyridin-2-yl)-2- [ (amino) (butylaraino)methyleneamino]thiazole trihydrochloride (4.0 g ) , triethylamine (4.0 ml) and dimethyl N-cyanodithioiminocarbonate [ (CH₃S)₂C=N-C ] (1.6 g) in dimethylformamide (40.0 ml) was stirred for 3 hours at 40°C. To the mixture was added a 28% aqueous ammonia (20.0 ml) and the mixture was stirred for 18 hours at^' 80°C. The solvent was removed by concentration. The residue was added a mixture of ethyl acetate, tetrahydrofuran and water and the mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate. The separated organic layer was dried over magnesium sulfate and evaporated in vacuo to give 2-[(amino) (butylamino)- methyleneamino]-4-[6-(2-cyanoguanidino)methylpyridin-2- yl]thiazole (1.9 g) .

IR (Nujol) : 3320, 3180, 2170, 1650 cm^'1

NMR (DMSO-dg, δ) : 0.92 (3H, t, J=6.9Hz), 1.25-1.60

(4H, m), 3.10-3.30 (2H, m) , 4.42 (2H, d, J=5.0Hz), 7.00 (2H, s), 7.17 (IH, d, J=7.1Hz), 7.20-7.57 (3H, m), 7.50 (IH, s), 7.70-7.90 (2H, m)

Example 68

10% methanolic ammonia (17.0 ml) was added to a solution of 4-(6-acetoxyacetylaminomethylpyridin-2-yl)- 2-[(amino) (butylamino) ethyleneamino]thiazole (1.7 g) in tetrahydrofuran (20.0 ml) under ice cooling and the mixture was stirred for 2.5 hours at ambient temperature. The solvent was removed by concentration and the residue was recrystallized from a mixture of ethanol, dioxane and diisopropyl ether to give 4-(6-hydroxyacetylaminomethyl- pyridin-2-yl)-2-[(amino) (butylamino)methyleneamino]- thiazole (1.3 g) . p : 165-166°C

IR (Nujol) : 3360, 1640, 1607 cm^"1 NMR (DMSO-dg, δ) : 0.92 (3H, t, J=7.0Hz), 1.26-1.65

(4H, m), 3.10-3.32 (2H, m) , 3.93 (2H, d, J=5.8Hz), 4.45 (2H, d, J=5.8Hz), 5.65 (IH, t, J=5.8Hz), 7.18 (IH, d, J=7.2Hz), 7.39 (3H, s), 7.73 (IH, d, J=7.2Hz), 7.81 (IH, t, J=7.2Hz), 8.42 (IH, t, J=5.8Hz) Example 69

A solution of acetoxyacetyl chloride (1.5 g) in dichloromethane (6.0 ml) was added dropwise to a mixture of 2-[ (amino) (butylamino)methyleneamino]-4-(6- aminomethylpyridin-2-yl)thiazole trihydrochloride (4.0 g) and triethylamine (5.7 ml) in dichloromethane (80.0 ml) under ice-cooling and the mixture was stirred for 3 hours at the same temperature. To the reaction mixture was added a solution of dichloromethane and water and the mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate. The isolated precipitate was collected by filtration and dried in vacuo. The precipitate was recrystallized from a mixture of methanol, dioxane and diisopropyl ether to give 4-(6-acetoxyacetylaminomethyl- pyridin-2-yl)-2-[(amino)(butylamino)methyleneamino]- thiazole (2.4 g) . mp : 171-172°C

IR (Nujol) : 3440, 3400, 1735, 1663, 1615 cm^"1 NMR (DMSO-dg, δ) : 0.92 (3H, t, J=7.lHz), 1.26-1.60 (4H, m), 2.12 (3H, s), 3.11-3.28 (2H, m) , 4.43

(2H, d, J=5.9Hz), 4.58 (2H, s), 7.16 (IH, d, J=7.3Hz), 7.38 (2H, s), 7.41 (IH, s), 7.72 (IH, d, J=7.3Hz), 7.81 (IH, t, J=7.3Hz), 8.64 (IH, t, J=5.9Hz)

Example 70

The following compound was obtained according to a similar manner to that of Example 69.

4-(6-Acetoxyacetylaminomethγlpyridin-2-yl)-2-

[ (amino) [ (2-methoxyethyl)amino]methyleneamino]thiazole mp : 189-190°C

IR (Nujol) : 3450, 3390, 1735, 1675 cm^"1 NMR (DMSO-dg, δ) : 2.12 (3H, s), 3.30-3.45 (2H, m) , 3.33 (3H, s), 3.45-3.55 (2H, m) , 4.43 (2H, d. J=5. 9Hz ) , 4. 58 ( 2H, s) , 7.11-7.23 ( IH, m) , 7.31 ( 2H, s) , 7.42 ( IH, s ) , 7.74-7.88 ( 2H, m) , 8.64 ( IH, t, J=5 . 9Hz )

Example 71

To a solution of 2-[(allylamino) (amino)- methyleneamino]-4-(6-ureidomethylpyridin-2-yl)thiazole (1.1 g) in methanol (11.0 ml) was added a 4N-dioxanic hydrogen chloride (2.5 ml) and the mixture was stirred for 1 hour at ambient temperature. The isolated precipitate was collected by filtration and the precipitate was recrystallized from an aqueous acetone to give 2-[ (allylamino) (amino)methyleneamino]-4-(6-ureido- methylpyridin-2-yl)thiazole dihydrochloride (0.66 g) . mp : 204-206°C

NMR (DMSO-dg, δ) : 4.21 (2H, br s), 4.53 (2H, s),

5.19-5.48 (2H, m) , 5.82-6.07 (IH, m) , 7.21 (4H, br s), 7.57-7.70 (IH, m), 8.20-8.36 (2H, m), 8.46 (IH, s), 8.80-9.10 (3H, m) Anal. Calcd. for C₁₄H₁₇N₇OS«2HCl_'3/5H₂0 :

C 40.39, H 4.92, N 23.55, Cl 17.03, H₂0 2.88% Found: C 40.48, H 4.93, N 23.49, Cl 17.20, H₂02.84%

Example 72 The following compound was obtained according to a similar manner to that of Example 71.

2-[(Amino) (butylamino)methyleneamino]-4-(6-ureido- methylpyridin-2-yl)thiazole dihydrochloride mp : 232-234°C

IR (Nujol) : 3320, 3160, 3050, 1685, 1640, 1610 cm^"1 NMR (DMSO-dg, δ) : 0.93 (3H, t, J=7.2Hz), 1.30-1.52 (2H, m), 1.52-1.72 (2H, m) , 3.38-3.57 (2H, m) , 4.49 (2H, s), 5.80-6.70 (5H, br s), 7.50-7.65 (IH, m), 8.12-8.30 (2H, m) , 8.35 (IH, s),

8.72-9.00 (3H, m) Example 73

A solution of 2-[ (amino) (butylamino)methyleneamino]- 4-(2-aminomethylthiazol-4-yl)thiazole dihydrochloride (1.2 g) and potassium cyanate (0.5 g) in water (30 ml) was stirred for 5 hours at room temperature. The resulting precipitate was collected by filtration. Recrystallization from a mixture of methanol and diisopropyl ether afford 2-[ (amino) (butylamino)- methyleneamino]-4-(2-ureidomethylthiazol-4-yl)thiazole hydrochloride (0.6 g) . mp : 268-270°C (dec.)

IR (Nujol) : 3430, 3320, 1660, 1620 cm^"1 NMR (DMSO-dg, δ) : 0.92 (3H, t, J=7.2Hz), 1.30-1.50 (2H, m), 1.50-1.70 (2H, m) , 3.40 (2H, m) , 4.48 (2H, d, J=6.1Hz), 5.83 (2H, s), 6.92 (IH, t,

J=6.1Hz), 7.54 (IH, s), 8.02 (IH, s), 8.56 (2H, s), 9.02 (IH, br), 12.41 (IH, br)

Example 74 A mixture of 4-(6-acetylaminomethylpyridin-2-yl)-2- [ (allylamino) (amino)methyleneamino]thiazole (8.0 g) and cone, hydrochloric acid (20.2 ml) in ethanol (80 ml) was heated under reflux for 15 hours. The solvent was removed by concentration and the residue was triturated with isopropyl alcohol. The precipitate was collected by filtration to give 2-[(allylamino)(amino)methyleneamino]- 4-(6-aminomethylpyridin-2-yl)thiazole trihydrochloride (8.94 g). mp : 164-166°C IR (Nujol) : 3320, 1680, 1630 cm^"1

NMR (D₂0, δ) : 3.96-4.09 (2H, m) , 4.51 (2H, s),

5.32-5.50 (2H, m) , 5.98-6.12 (IH, m) , 7.59 (IH, d, J=7.8Hz), 7.96 (IH, d, J=7.8Hz), 8.04 (IH, s), 8.12 (IH, t, J=7.8Hz) - 84 -

Example 75

The following compound was obtained according to a similar manner to that of Example 74.

2-[ (Amino) (butylamino)methyleneamino]-4-(6-amino- methylpyridin-2-yl)thiazole trihydrochloride mp : 176-178°C

IR (Nujol) : 3320, 1680, 1615 cm^"1

NMR (D₂0, δ) : 0.88 (3H, t, J=7.2Hz), 1.21-1.45 (2H, m), 1.45-1.65 (2H, m) , 3.10 (2H, t, J=6.8Hz),

4.43 (2H, s), 7.49 (IH, d, J=7.8Hz), 7.65 (IH, d, J=7.8Hz), 7.92 (IH, s), 7.99 (IH, t, J=7.8Hz)

Example 76 The following compound was obtained according to a similar manner to that of Example 74.

2-[(Amino) [(2-methoxyethyl).amino]methyleneamino]-4- (6-aminomethylpyridin-2-yl)thiazole trihydrochloride mp : 282°C (dec.)

IR (Nujol) : 3260, 3080, 1670, 1640, 1610 cm^"1 NMR (D₂0, δ) : 3.51 (3H, s), 3.51 (2H, t, J=5.0Hz), 3.75 (2H, t, J=5.0Hz), 4.42 (2H, s), 7.43 (IH, d, J=7.7Hz), 7.73 (IH, d, J=7.7Hz), 7.91 (IH, s), 7.94 (IH, t, J=7.7Hz)

Example 77

2-[(Amino) (methylamino)methyleneamino]-4-(6-amino- methylpyridin-2-yl)thiazole trihydrochloride mp : 236-238°C

IR (Nujol) : 3200, 1685, 1645, 1620, 1590 cm^"1 NMR (D₂0, δ) : 2.86 (3H, s) , 4.46 (2H, s) , 7.56 (IH, d, J=7 . 8Hz ) , 7. 92 ( IH, d, J=7 . 8Hz ) , 7. 97 ( IH, s ) , 8. 09 ( IH, t, J=7. 8Hz )

Example 78 4N-Dioxanic hydrogen chloride (0.82 ml) was added a solution of 4-(6-acetylaminomethylpyridin-2-yl)-2- [ (amino) (methylamino)methyleneamino]thiazole (1.0 g) in methanol (5.0 ml) and the mixture was stirred for 15 minutes at ambient temperature. To the mixture was added a diisopropyl ether (5 ml) and the isolated precipitate was collected by filtration. The precipitate was recrystallized from an aqueous isopropyl alcohol to give 4-(6-acetylaminomethylpyridin-2-y1)-2-[(amino)- (methylamino)methyleneamino]thiazole hydrochloride (0.85 g). mp : 220-221°C

IR (Nujol) : 3360, 3220, 1685, 1665, 1625 cm^"1

NMR (DMSO-dg, δ) : 1.96 (3H, s), 3.04 (3H, d,

J=4.8Hz), 4.48 (2H, d, J=5.7Hz), 7.36 (IH, d, J=7.5Hz), 7.98 (IH, t, J=7.5Hz), 8.06 (IH, s),

8.08 (IH, d, J=7.5Hz), 8.66 (2H, s), 8.68 (IH, t, J=5.7Hz), 8.96 (IH, br s)

Example 79 The following compound was obtained according to a similar manner to that of Example 78.

4-(6-Acetylaminomethylpyridin-2-yl)-2-[ (amino)- (methylamino)methyleneamino]thiazole dihydrochloride mp : 236-238°C

IR (Nujol) : 3370, 3290, 3220, 1685, 1660, 1600 cm^"1 NMR (DMSO-dg, δ) : 1.97 (3H, s) , 3.04 (3H, d, J=4.8Hz), 4.53-4.68 (2H, m) , 7.49 (IH, d, J=6.5Hz), 8.10-8.35 (3H, m) , 8.64 (2H, s), 8.72-8.90 (IH, m) , 9.02 (IH, br s) Example 80

Methanesulfonic acid (0.21 ml) was added a solution of 4-(6-acetylaminomethylpyridin-2-yl)-2-[ (amino)- (methylamino)methyleneamino]thiazole (1.0 g) in methanol (5.0 ml) and the mixture was stirred for 1 hour at ambient temperature. To the mixture was added a diisopropyl ether (5.0 ml) and the isolated precipitate was collected by filtration. The precipitate was recrystallized from aqueous isopropyl alcohol to give 4-(6-acetylaminomethylpyridin-2-yl)-2-[(amino) (methyl¬ amino)methyleneamino]thiazole mesylate (0.9 g) . mp : 238-240°C

IR (Nujol) : 3330, 3122, 1680, 1600, 1615 cm^"1 NMR (DMSO-dg, δ) : 1.94 (3H, s), 2.45 (3H, s), 3.00 (3H, d, J=4.8Hz), 4.40 (2H, d, J=5.9Hz), 7.26

(IH, d, J=7.5Hz), 7.87 (IH, t, J=7.5Hz), 7.92 (IH, s), 7.99 (IH, d, J=7.5Hz), 8.51 (IH, t, J=5.9Hz), 8.60 (2H, s), 9.02 (IH, br s) , 11.96 (IH, br s)

Example 81

The following compound was obtained according to a similar manner to that of Example 80.

4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)- (methylamino)methyleneamino]thiazole dimesylate mp : 207-208°C

IR (Nujol) : 3300, 3180, 1670, 1630 cm^"1 NMR (DMSO-dg, δ) : 1.97 (3H, s), 2.49 (6H, s), 3.02 (3H, d, J=4.8Hz), 4.52 (2H, d, J=5.7Hz), 7.47

(IH, d, J=7.0Hz), 7.87 (2H, br s), 8.07-8.26 (2H, m), 8.19 (IH, s), 8.66 (2H, s), 8.71 (IH, t, J=5.7Hz), 9.10 (IH, br s)

Claims

- CLAIMS A compound of the formula wherein R is amino which may have suitable substituent(s) , hydroxy, halogen, cyano, acyl, heterocyclic thio, heterocyclic group or a group of the formula : Z-R- -C-R in which R is hydrogen, cyano or acyl, R is amino or lower alkoxy, and Z is N or CH, •5 R"", R 3 and R8 are each hydrogen, acyl, lower alkyl which may have suitable substituent(s) , (C3-C,)-cycloalkyl, lower alkenyl or lower alkynyl; or two of R 2, R3 and R8 are linked together to form lower alkylene optionally interrupted by hetero atom, and the other is as defined above, 4 R is hydrogen or lower alkyl. is —(fIi- 4(N— , in which R7 is hydrogen or halogen, and A is bond or lower alkylene, provided that ι (1) when R is amino which may have suitable substituen (s) and A is bond; or R is lower alkylthioureido and A is lower alkylene, then Y is —fc—H-fj—1 , and further (2) when one of R 2 and R3 is hydrogen, acyl or lower alkyl which may have halogen, 4 R is hydrogen and Q R is hydrogen, then 2 3 the other of R and R is (C3~C7)-cycloalkyl, lower alkenyl, lower alkynyl or lower alkyl which has suitable substituent(s) excepting halogen. 2. A compound of the formula : wherein R is amino which may have suitable substituent(s) , hydroxy, halogen, cyano, acyl, heterocyclic thio, heterocyclic group or a group of the formula : Z-R5 11 6 -C-R6 in which R is hydrogen, cyano or acyl, R is amino or lower alkoxy, and Z is N or CH, 2 R is (C3~C7)-cycloalkyl, lower alkenyl, lower alkynyl or lower alkyl which has suitable substituent(s) excepting halogen, and 3 8 R and R are each hydrogen or lower alkyl; or 2 8 R and R are each lower alkyl or are linked together to form lower alkylene optionally interrupted by hetero atom, and R3 is hydrogen or lower alkyl, 4 R is hydrogen or lower alkyl, Y is , in which R 7 is hydrogen or halogen, and A is bond or lower alkylene, and pharmaceutically acceptable salt thereof, A compound of claim 2, wherein R is amino, acylamino, 2-cyanoquanidino or acyl, 2 R is (C3~C7)-cycloalkyl, lower alkenyl, lower alkynyl, lower alkoxy(lower)alkyl, di(lower)alkylamino(lower)alkyl, hydroxy(lower)alkyl, acylamino(lower)alkyl, lower alkoxyar(lower)alkyl, lower alkylthio(lower)alkyl, di(lower)alkylamino(lower)alkylfuryl(lower)- alkylthio(lower)alkyl, furyKlower)alkyl, pyridyl(lower)alkyl or indolyl(lower)alkyl, and R 3 and R8 are each hydrogen or lower alkyl; or R 2 and R8 are each lower alkyl or are linked together to form lower alkylene optionally interrupted by oxygen, and 3 R is hydrogen or lower alkyl. 4. A compound of claim 3, wherein R is amino, ureido, lower alkanoylamino, lower alkoxycarbonylamino, hydroxy(lower)alkanoyl¬ amino, protected hydroxy(lower)alkanoylamino, lower alkylureido, (C3-C,)-cycloalkyl(lower)- alkanoylamino, (C3-C7)-cycloalkanecarbonylamino, (C3-C7)-cycloalkanecarbonylamino having oxo, 5- or 6-membered heteromonocycliccarbonylamino, 5- or 6-membered heteromonocyclic(lower)alkanoyl¬ amino, 5- or 6-membered heteromonocyclic(lower)- alkylaryloxy(lower)alkylureido, (C3-C7)-cycloalkylcarbamoyl or 2-cyanoguanidino. 5. A compound of claim 4, wherein R is amino, ureido, lower alkanoylamino, lower alkoxycarbonylamino, lower alkanoyloxy(lower)- alkanoylamino, lower alkylureido, (C3~C7)- cycloalkanecarbonylamino, 2 R is (C3~C7)-cycloalkyl, lower alkenyl, lower alkynyl, lower alkoxy(lower)alkyl, di(lower)alkylamino(lower)alkyl, hydroxy(lower)- alkyl, lower alkanoylamino(lower)alkyl, di(lower)alkoxyphenyl(lower)alkyl, lower alkylthio(lower)alkyl, di(lover)alkylamino- (lower)alkylfuryl(lower)alkylthio(lower)alkyl, furyl(lower)alkyl, pyridyl(lower)alkyl or indolyl(lower)alkyl, R3, R4 and R8 are each hydrogen. A is lower alkylene. A process for preparing a compound of the formula wherein R is amino which may have suitable substituent(s) , hydroxy, halogen, cyano, acyl, heterocyclic thio, heterocyclic group or a group of the formula : Z-R5 -C-R 5 in which R is hydrogen, cyano or acyl, R is amino or lower alkoxy, and Z is N or CH, R 2, R3 and R8 are each hydrogen, acyl, lower alkyl which may have suitable substituent(s) , (C3-C7)-cycloalkyl, lower alkenyl or lower alkynyl; or two of R 2, R3 and R8 are linked together to form lower alkylene optionally interrupted by he ero atom, and the other is as defined above, 4 R s hydrogen or lower alkyl. is t in which R is hydrogen or halogen, and A is bond or lower alkylene, provided that

(1) when R is amino which may have suitable substituen (s) and A is bond; or

R is lower alkylthioureido and A is lower alkylene, then

Y is and further

(2) when one of R 2 and R3 is hydrogen, acyl or lower alkyl which may have halogen,

4 R is hydrogen and o

R is hydrogen, then ό 3 the other of R and R is

(C₃-C₇)-cycloalkyl, lower alkenyl, lower alkynyl or lower alkyl which has suitable substituent(s) excepting halogen, or a salt thereof, which comprises (1) reacting a compound of the formula

wherein R 1, R4, A and Y are each as defined above, and

X is acid residue, or a salt thereof, with a compound of the formula

wherein R 2, R3 and R8 are each as defined above, or a salt thereof, to give a compound of the formula :

1 2 3 8 wherein R , R , R , R , A and Y are each as defined above, or a salt thereof, or

(2) subjecting a compound of the formula

wherein R , R , R , R , A and Y are each as defined above, and

i ,s protected amino, or a salt thereof, to elimination reaction of the amino protective group, to give a compound of the formula :

wherein R 2, R3, R4, R8, A and Y are each as defined above, or a salt thereof, or

(3) subjecting a compound of the formula :

Λ Q wherein R , R , R , R , A and Y are each as defined above, or a salt thereof, to acylation, to give a compound of the formula :

wherein R , R , R , R , A and Y are each as defined above, and R. is acylamino, or a salt thereof, or

(4) reacting a compound of the formula :

~~i *5 A O wherein R , R , R , R , A and Y are each as defined above, or a salt thereof, with a compound of the formula :

(R⁹)₂C=Z-R¹⁰

9 wherein R is lower alkylthio or protected hydroxy,

R is hydrogen, cyano, nitro or acyl, and

Z is N or CH, to give a compound of the formula :

wherein R 2, R3, R4, R8, R9, R10, A, Y and Z are each as defined above, or a salt thereof, or

(5) reacting a compound of the formula :

wherein R , R , R , R , A and Y are each as defined above, or a salt thereof, with a compound of the formula :

2 g wherein R and R are each as defined above, to give a compound of the formula :

1 *"1 A Q wherein R , R , R , R , R , A and Y are each as defined above, or a salt thereof, or

(6) reacting a compound of the formula :

*D A O wherein R , R , R , R , A and Y are each as defined above, and R 12 is lower alkyl, or a salt thereof, with a compound of the formula :

H-R¹³

wherein R 13 is amino which may have suitable substituent(s), to give a compound of the formula :

wherein R , R , R , R , A and Y are each as defined above, or a salt thereof, or

(7) subjecting a compound of the formula :

wherein R , R , R , R , A and Y are each as defined above, and R is acylamino having protected hydroxy, or a salt thereof, to elimination reaction of the hydroxy protective group, to give a compound of the formula :

*i A Q wherein R , R , R , R , A and Y are each as defined above, and ι R, is acylamino having hydroxy, or a salt thereof, or

(8) subjecting a compound of the formula :

wherein R , R , R , R , A and Y are each as defined above, and Rg is acylamino having protected amino, or a salt thereof, to elimination reaction of the amino protective group, to give a compound of the formula :

wherein R , R , R , R , A and Y are each as defined above, and R_c is acylamino having amino, or a salt thereof.

7. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers.

8. A method for the treatment of H₂~receptor mediated diseases, which comprises administering a compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof to human or animals.

9. A use of a compound of claim 1 or 2 as a medicament.

10. A use of a compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof as antiulcer agent, H₂-receptor antagonist or antimicrobial agent.