CA2105981A1 - Thiazole derivatives - Google Patents

Abstract

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

Description

WO92/1~526 ~ 8 1 pCT/JP92/00279 DESCRIPTION

THIAZOLE DERIVATIYES
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 processes for the preparation thereof, to a pharmaceutical composition comprisins 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 acceptable salts thereof which possess antiulcer activity and H2-receptor antagonism.
Another object of this inve~tion is to provide processes for the preparation of said thiazole derivatives and salt thereof.
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 invèntion is to provide 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) :

2\ N N -----, Y-A-R-R ~ \ li l!
C=N~ ~
R3N~ / S R4 ~10~81 WO92/16~26 PCT/JP~2/00279 ~
_ wherein R1 is amino which may have suitable substituent(s), hydroxy, halogen, cyano, acyl, heterocyclic thio, heterocyclic group ~.
or a group of the formula : :

~-R5 .
-C-R6, in which R5 is hydrogen, cyano or acyl, ~ ..
R is amino or lower alkoxy, and ~ ~
Z is N or CH, ~ :-R2, 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 R2, R3 and R8 are linked together ~o form lower alkylene optionally interrupted by hetero atom, and the other is as defined above, - R is hydrogen or lower alkyl, : ;

R7 N :
Y is ~ or ~ , in which R7 is hydsogen :--or halogen, and .
A is bond or lower alkylene, . :
: - , , provided that (1) when R1 is amino which may have suitable - substituent(s) and A is bond; or -R1 is lower alkylthioureido and A is ~:~
- , lower alkylene, then ~.

.
' ~ ' ;

.

WO 92/16526 PCl'tJP92/00279 Y is ~ , and further (2) when one of R2 and R3 is hydrogen, acyl or lower alkyl which may have halogen, R4 is hydrogen and R is hydrogen, then the other of R and R3 is (C3-C7)-cycloalkyl, lower alkenyl, lower alkynyl or lower alkyl which has suitable substituent(s) excepting halogen.

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

Process 1 XlcHco_y_A_Rl~ C=N-C-NH2 R NH
~II) (III) or a salt thereof or a salt thereof ) R8~
C=N - ~ ~ Y-A-R
R~NH / R4 (I) 3S or a salt thereof ~10 ~ ~ 81 W092/~6s26 PCTtJP~t/00279-~

Process 2 R8 .` 'i .
~ N N Y-A-R1 Elimination of the amino C=N ~ ~ a protective group R3NH S R4 : :

tI-1) or a salt thereof R2 ~ \ IN ~ -A-N~2 ..
C=N ~ ~
R NH S R4 , .
(I-2) or a salt thereof Process 3 R8 . . .
~ N N 1,Y-A-NH2 Acylation :. -R3NH / Si'~ R4 ~ :
. ~.
(I-2) .`~
or a salt thereof - .
~8 -: `.-~ N N Y-A-R
C=N ~

'(I-3) or a salt thereof .

.

W092/16526 2l a~ pcT/Jps2/oo279 Process 4 R8 (R ) 2C=Z-R10 -R \ lY-A-NH2 ( IV) R NH ~ S R4 . .
(I-2) or a salt thereof C=N~
R3NH / . R4 (I-4) or a salt thereof Process S

ll N Y-A-Rl R8 C=N~ 2--N-~l R3NH / R4 ( VI ) (V) or a salt thereof 2 N N Y-A-Rl -C=N~

( I - 5 )

3 5or a salt thereof 8 ~ -W092/16526 PCr/JP92/00279 -Process 6 R ~ H_RI3 2 ~ N N ~ Y-A-CO Rl S C=N ~ 11\ 2 (VII) (I-6) or a salt thereof :

R8 N Y-A-coRl3 ~ .
R 2 ~ ~ I ~ .

R3NH / ~ S ~ 4 (I-7) or a salt thereof Process 7 R8 ~ . Elimination of the hydroxy . .: .
R2 \ N ~ Y-A-R protective group / C=N S 4 R NH R
(I-8) or a salt thereof .

R \ ~ ~ -A-Rd f (I-9) . or a salt thereor 2~Q~
WO 92tl6~26 PCr/JP92/0û279 Process 8 R8 Elimination of the amino C=N--~Y-A-Re protective group R NH ~ R 4 (I-10) or a salt thereof R8 ~ I Y-A-R

R3NH / S/\ R4 ( I - 11 ) or a salt thereof wherein R1, R2, R3, R4, R8, Y and A are each as de~ined above, Ra is protected amino, Rb is acylamino, RC is acylamino having protected hydroxy, Rd is acylamino having hydroxy, Re is acylamino having protected amino, Rf is acylamino having amino, R9 is lower alkylthio or protected hydroxy, R10 is hydrogen, cyano, nitro or acyl, R11 is lower alkyl, R12 is lower alkyl, R is amino which may have suitable - - substituent~s), xl is acid residue, and Z is N or,CH.
In the above and subsequent descriptions of the ''~
. ' ' '~
,.

2~0~ ~31 WO92/16~26 PCT/JP92/00~79~_ present speci~ication, suita~le 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 l to 6 car~on 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 R2 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 C1-C4 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, hydroxypropylamino, etc.), lower alkoxy(lower)alkylamino (e.g. methoxymethylamino, etc.), mono or di(lower)-alkylamino(lower)a~kylamino (e.g. methylaminomethylamino, dimethylaminoethylamino, etc.), protected amino such as 23 0 ~ 9~ ~
WO92~16~26 PCT/JP92/00279 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 te.g. succinimido, phthalimido, etc.), a group of the formula :

--NHC~Ra wherein R10 and Z are each as defined above, and R9 is hydrogen, lower alkylthio, protected hydroxy or amino which may have suitable substituent(s), each of which is as mentioned above or helow, and the like.
~0 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 Cl-C4 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, acy~lic or cyclic ones, such as lower ~1 alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, ~ V~ 98~
WO92/16526 PCT/JP92/00279~- ~

etc.), lower alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl, etc.), lower alkoxycarbonyl (e.g.
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl~ butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc.-), lower alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl, etc.), (C3-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.
benzenesul~onyl, tosyl, etc.), and the like.
The heterocyclic acyl may include heterocyclic carbonyl (e.g. furoyl, thenoyl, nicotinoyl, l-oxonicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl, tetrazolylcarbonyl, tetrahydrofurylcarbonyl, pyperidylcarbonyl, morpholinocarbonyl, etc.), and the like.
The aliphatic acyl substituted with aromatic group~s) may include phenyl(lower)alkanoyl (e.g. phenylacetyl, phenylpropionyl, phenylhexanoyl, etc.), phenyl(lower)-alkoxycarbonyl (e.g. benzyloxycarbonyl, -phenethyloxycarbonyl, etc.), phenoxy(lower)alkanoyl (e.g.
phenoxyacetyl, phenoxypropionyl, etc.), and the like.
The aliphatic acyl substituted with heterocyclic group(s) may include thienylacetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl, thiazolylacetyl, thiadiazolylacetyl, thienylpropionyl, 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.), (C3-C7)-. ., .,.,.. .. , .. ; . .... .... , ,, . , . . . .. . . . . . . , ;

~1 0~
- w092/16526 - 11 - PCT/JP9Z/00279 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 alXylthio (e.g. methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio, etc.), heterocyclic group as mentioned below, heterocyclic(lower)alkylthio (e.g. furylmethylthio, thiazolylmethylthio, etc.), heterocyclic(lower)alkylsulfinyl (e.g.
furylmethylsulfinyl, thia~olylmethylsulfinyl, 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 alkanoyloxy (e.g. formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy, hexanoyloxy, 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(lower)alkanoyl (e.g., methoxyacetyl, ethoxyacetyl, etc.), lower alkoxycarbonyl (e.g. tert-butoxycarbonyl, etc.), lower alkanoyloxy(lower)alXanoyl (e.g., acetoxyacetyl, acetoxypropionyl, 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.
3~ furylmethylthioacetyl, etc.), N-lower alkylthiocarbamoyl ~.10~81 Wo92/16~26 PCT/JP92/0027 (e.g. N-methylthiocarbamoyl, etc.), halo(lower)alkanoyl (eOg. 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 alkyllC3-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 pre~erably heterocyclic group may be 5 or 6-membered aromatic heteromonocyclic group le.g.
furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiadiazolyl, etc.), 5- or 6-membered aliphatic heteromonocyclic group (e.g. morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, dithiacyclopentyl, etc.), unsaturated condensed heterocyclic group containing 1 to 3 nitrogen atom(s) (e.g. indolyi, 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. Pre~erable example of such groups are tr~azolyl having amino and -,: . , . ~ , . . ..
. .

8 ~
WO92/16~26 PCT/JP92/00279 lower alkyl (e.g. 3-amino-1-methyl-lH-triazol-5-yl, etc.), triazolyl having amino (e.g. 3--amino-lH-triazolyl-5-yl, etc.), benzoisothiazolyl having oxo (e.g.
l,l-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 hydroxy-protective group in the term "protected hydroxy" may include aforesaid acyl, ar(lower)alkyl (e.g. benzyl, trityl, etc.) lower alkoxy(lower)alkyl (e.g. methoxymethyl, l-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 te.g. trifluoromethyl, trifluoroethyl, etc.), lower alkoxy(lower)alkyl (e.g.
methoxymethyl, methoxyethyl, methoxypropyl, etc.~, di(lower)alkylamino(lower)alkyl (e.g. dimethylaminomethyl, dimethylaminoethyl, etc.), hydroxy(lower)alkyl (e.g.
hydroxymethyl, hydroxyethyl, etc.), acylamino(lower)~lkyl 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, ~ 1 0 :- ~ 8 1 WO92/16526 - 14 - PCT/JP92/00279~-~

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.), pyridyl(lower)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, ~or 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 1l ( C3-C7)-cycloalkyl" may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the liXe.
,. ' ,~1 0~ q,~l - W O 92/16~26 P~r/JP92/00279 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, S 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, methanesul~onate, 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 ~I-1) to (I-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 o~ the salts o~ these compounds are to be referred to those as exemplified for the object compound (I).

Particularly, the preferred em~odiments of Rl, R2, R3, R4, R8, Y and A are as follows.

R1 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.

.. ... . . . .. . . ... . . .. ..

21~981 WO92/16s26 PCT/JP92/00279--acetoxyacetylamino, acetoxypropionylamino, 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.), (C3-C7)-cycloalkanecarbonylamino (e.g.
cyclopropanecarbonylamino, cyclobutanecarbonylamino, cyclopentanecarbonylamino, cyclohexanecarbonylamino, cycloheptanecarbonylamino, -etc.), ~C3-C7)-cycloalkanecarbonylamino having oxo (e.g. oxocyclohexanecarbonylamino, etc.), heterocycliccarbonylamino such as S- or S-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;
R is hydrogen, lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, pentyl, isopentyl, hexyl, etc.), lower alkoxy(lower)alkyl (e.g. methoxye~hyl, methoxypropyl, etc.), di(lower)alkylamino(lower)alkyl (e.g. dimethylaminoethyl, etc.), (C3-C7)-cycloalkyl (e.g. cyclohexyl, cyclopropyl, cyclopentyl, etc.), lower alkenyl (e.g. allyl, etc.), wos2/16~26 ~ ~ 9 ~1 PCT/JP92/00279 ~ 17 -mono or di or trihalo(lower)alkyl (e.g.
trifluoroethyl, etc.), lower alkynyl (e.g. 2-propynyl, etc.), hydroxytlower)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)alkylfuryl(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 te.g. indolylpropyl, etc.);
R is hydrogen; or lower alkyl (e.g. methyl, etc.); and R is hydrogen; or lower alkyl (e.g. methyl, etc.); or R~ and R3 are linked together to form lower alkylene 5e.g.
ethylene, etc.); and R8 is hydrogen; or R2 and R8 are linked together to form lower alkylene optionally interrupted by oxygen (e.g. -pentamethylene, 3-oxapentamethylene, etc.); and R3 is hydogen;
R4 is hydrogen; or lower alkyl (e.g. methyl, etc.);

Y is ~ or ~ ~ ; and ' ' ' A is bond; or .. ..

2iO~981 wos2/l6526 PCT/JP92/0027'~-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 (I-2) or a salt thereof can be prepared by subjecting the compound (I-1) or a salt thereof to elimination reaction of the amino protective group.
Sui~able method for th.is 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.~. magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth .. . .

WO92/16~26 ~ 8 ~ PCT/JP92/00279 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, 10 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 usin~ a base is often carried out in water or a hydrophilic organic ~ -15 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 thereo~.
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 (I-3) or a salt thereof can be prepared by reacting the compound (I-2) or a salt thereof with an acylating agent.
The compound (I-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 fojrmula : ~
3~ RI4 - OH (VIII) ....
': ' 2~ 0~81 W0~2/~6~2~ PCT/JP92/0027~

in which R14 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 anhydr:ide, 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 acarbamoyl 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(lower)alkylamine, pyridine, N-(lower)alkylmorphorine, N,N-di(lower)alkylbenzylamine, or the like.
This present reaction includes, within its scope, the case that when R2 is hydrogen, it is also acylated during the reaction oc at the post-treating step of the present process.

.. , , .. ~ . .. . . . . . .

W092/~6~26 - 21 - PCT/JP92/00279 Process 4 .
The object compound (I-4) or a salt thereof can be prepared by reacting the compound (I-~) or a salt thereof with the compound (IV).
S 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 (I-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 (I-7) or a salt thereof can be prepared by reacting the compound (I-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, - ~10~81 W092~l6s26 PCT/JP92/0027~-chloroform, methylene chloride r 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 (I-9) or a salt thereof can be prepared by subjecting the compound (I-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 there~ore 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 ~I-11) or a salt thereof can be prepared by subjecting the compound (I-10) or a salt thereof to elimination reaction of the amino protective group. ' This reaction can be carried out in substantially the same manner as Process 2, and therefore the reaction mode and reaction conditions [e.g. solvent, reaction temperature, etc.] of this reaction are to be re~erred to those as explained in Process 2.
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. I
The compo~mds obtained by the above Processes 1 to 8 can be isolated and purified by a conventional method such -~ 23 -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 c2rbon 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,lthere may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly " "~, .

:. . - .
' ~'.

~ ~ n ~
WO92~16~26 PCT/JP92/0027~-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 O.l mg, l mg, lO mg, 50 mg, lO0 mg, 250 mg, 500 mg and lO00 mg of th~ compound (I) may be effective for treating ulcer. In general, amounts between 0.1 mg/body and about 1,OOO mg/body may be administered per day.
In order to illustrate the usefulness of the object compound (I), th~ pharmacological test data of some representative compounds of the compound (I) are shown in the following.

Test comDounds (a) 2-[(Allylamino)(amino)methyleneamino]-4-(6-ureidomethylpyridin-2-yl)thiazole dihydrochloride (b) 4-(6-Acetylaminomethylpyridin-2-yl)-2-~(amino)(2-methoxyethylamino)methyleneamino]thiazole (c) 4-(6-Acetylaminomethylpyridin-2-yl)-2-~(amino)-(cyclohexylamino)methyleneamino]thiazole (d) 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 2~ hours. The animals were anesthetized with l.25 g/kg urethane intraperitoneally. The abdomen was opened and the gastric lumen was perfured with saline WO92/16~26 PCT/JP92/00279 throughout the experiment. The perfusate was titrated byan 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 (l mg/kg) was given intravenously. Drug ef~ect was expressed as maximal inhibition by acid output.

Test Result .: ., .
Test Compound Inhibition (%) . _ ._ -, (a) lO0 . .' - .
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 37C for 3 days lO 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 37ac for 3 days. Incubation was carried out in an atmosphere of 10% CO2. MIC was read after incubation as the lowest -drug concentration that inhibited macroscopic colonial growth.

Test Result Mic (~g/ml) ~ = Compound (b~
Test strain . ~ . , Campylobacter 0 78 pyloridis 8008 _ . - . .: , . .. . - . . - ., . .. . ; ~ , . . . . .
., - - - : , , ;

WO92/16526 PCT/JP92/0027'-Test Compound _ Test strain ~ (c) Helicobacter pyloridis 8008 l.56 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% methylcPllulose solution containing 0.2N HCl, was administered orally at a dose of 200 mg/kg/l0 ml.
One hour later, the animals were sacrificed and theix 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 Test Compc~nd Inhibition ~) (c) 94.6 The following Preparations and Examples are given for the purpose of ill~strating the present invention in more detail.

Preparation 1 Phosphorus oxychloride (7.09 ml) was added dropwise to a solution of 6-hydroxymethy1-2-pyridinecarboxamide (3.60 g) in N,N-dimethylformamide (36 ml) at O to 5C 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 sul~ate and evaporated in vacuo to give 6-chloromethyl-2-pyridinecarbonitrile (3.02 g).
mp : 61-63C
IR (Nujol) : 2240 cm 1 ~R (DMSO-d6, ~) : 4.87 (2H, s), 7.90 (lH, dd, J=1.2Hz and 7.7Hz), 8.03 (lH, dd, J=1.2Hz and 7.7Hz), 8.14 (lH, 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 ~5 6-phthalimidomethyl-2-pyridinecarbonitrile (4.60 g).
mp : 200-201C
IR (Nujol) : 2250, 1775, 1715 cm 1 NMR (DMSO-d6, ~) : 4.99 (2H, s), 7.81 (lH, dd, J=l.OHz and 7.7Hz), 7.85-7.98 (5H, m), 8.06 (lH, t, J=7.7Hz) - ," ' PreParation 3 A solution oflhydrazine hydrate (0.77 g) in methanol ~5 ml) was added dropwise to a suspension of 6-phthalimidomethyl-2-pyridinecarbonitrile (3.74 g) in a - WO 92/16526 PCI`/JP92/0027 -- 28 -- .

mixture of methanol (10 ml) and tetrahydrofuran (15 ml) at ambient temperature with stirr:ing. 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 tne mlxture. 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 : >300C
IR (Nujol) : 2240 cm NMR (DMSO-d6, ~) : 4.27 (2H, s), 7.94 (lH, dd, J=1.2Hz and 7.7Hz), 8.08 (lH, dd, J=1.2Hz and 7.7Hz), 8.16 (lH, 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 ~o give 6-(acetylaminomethyl)-2-pyridinecarbonitrile -(1.72 g).
mp : 91-92C
IR (Nujol) : 3260, 2230, 1650 cm 1 ~MR (DMSO-d6, ~) : 1.92 (3H, s),

4.39 (2H, d, J=6Hz), 7.62 (lH, dd, J=lHz and 7.7Hz), 7.97 (lH, dd, J=lHz and 7.7Hz), 8.03 (lH, t, J=7.7Hz), 8.56 (lH, t, J=6Hz) Pre~aration 5 An ethereal solution of methyl magnesium bromide (3 ~ l 0 ~
- W092/165~6 PCT/JP92~00279 ., :; " ,.

mo~/~) ~17.6 ml) was added dropwise to a solution of 6-(acetylaminomethyl)-2-pyridi.necarbonitrile (3.70 g) in tetrahydrofuran (60 ml) at 5 to 10C with stirring. After the mixture was stirred for two hours at the same S 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 : 88-89C
IR (Nujol) : 3300, 1690, 1650 cm 1 1~NMR (DMSO-d6, ~) : 1.94 (3H, s), 2.64 (3H, s), 4.43 (2H, d, J=6.0Hz), 7.54 (lH, dd, J-lHz and-7.7Hz), 7.82 (lH, dd, J=lHz and 7.7Hz), 8.00 (lH, t, J=7.7Hz), 8.53 (lH, 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 6 ;, ' 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 70C and stirred for two hours. The solvent was evaporated in vacuo and the residue was triturated with diisopropyl ether to give 2-(acetylamino-methyl)-6-bromoacetylpyridine hydrobromide (3.78 g).
IR (Nujol) : 1720, 1620 cm 1 NMR (CD30D, ~) : 2.10 (3H, s), 3.sa (2H, s), 4.83 (2H, s), 7.77 (lH, br s), 8.13 (2H, t, J=8Hz) and 8.70 (lH, t, J=8Hz)

5?6 PCI`/JP92/0027r---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 : 185-186C
IR (Nujol): 3410, 3350, 1690, 1620 cm 1 NMR (DMSO-d6, ~) : 1.93 (3H, s), 2.55 (3H, s), 4.54 (2H, d, J=5.8Hz), 8.44 (lH, s), 8.91 (lH, 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 50C 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, ~): 2.11 (3H, s), 4.63 (2H, d, J=5.3Hz), 4.80 (2H, s), 7.43-7.59 (lH, m), 7. 78-8.08 (2H, m) Preparation 9 Propionic anhydride ~76.3 ml) was added dropwise to a 35 mixture of 6-aminomethyl-2 pyridinecarbonitrile --- W092/16526 ,~ PCT/JP92/00279 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 mlxture 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 NMR ~D~SO-d6, ~) : 1.05 (3H, t, J=7.6Hz), 2.21 (2H, q, J=7.6Hz), 4.40 (2H, d, J=5.8Hz), 7.61 (lH, dd, J=l.OHz, 7.8Hz), 7.91 (lH, dd, J=l.OHz,

7.8Hz), 8.03 (lH, t, J=7.8Hz), 8.50 (lH, t, J=5.8~z) ~.
~ .
Pre~aration 10 The following compound was obtained according to a similar manner to that of Preparation 5.
.: .
2-Acetyl-6-(propionylaminomethyl)pyridine mp : 79C
IR (Nujol) : 3280, 1700, 1640, 1590, 1550 cm 1 NMR (DMSO-d6, ~) : 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.S2 (lH, d, J=7.6Hz), 7.82 (lH, d, J=7.6Hz), 7.96 (lH, t, J=7.6Hz), 8.45 (lH, t, J=6.0Hz) Pre~aration 11 The following compound was obtained according to a similar mannex to that of the former half of Example 17.
4-(6-Acetylaminomethylpyridin-2-yl)-2-aminothiazole mp : 179-180C
IR (Nujol) :l 3380, 3260, 3110, 1655, 1620 cm 1 NMR ~DMSO-d6, ~) : 1.93 (3H, s), 4.36 (2H, dj J=5.9Hz), 7.11 (2H, s), 7.13 (lH, d, J=7.0Hz), - 32 ~

7.26 (lH, s), 7.68 (lH, d, J=7.0Hz), 7.76 (lH, t, J=7.0Hz), 8.45 (lH, 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% agueous potassium carbonate and resulting precipitate was collected by filtration to 1; give 4-(6-acetylaminomethylpyridin-2-yl)-2-(3-benzoylthioureido)thiazole (15.11 g).
mp : 222C (dec.) IR (Nujol) : 3300, 1670, 1640 cm 1 NMR (DMSO-d6, ~) : 1.95 (3H, s), 4.42 (2H, d, J=5.9Hz), 7.19-7.33 (lH, m), 7.49-7.80 (3H, m),

8.82-8.06 (5H, m), 8.50 (lH, t, J=5.9Hz), 12.16 (lH, s), 14.29 (lH, s) PreParation 13 A solution of sodium hydroxlde (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 50-60C
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-3~ methylpyridin-2-yl)-2-thioureidothiazole (5.44 g).

.

- WO92/16~26 ~ 9 8 ~- pCT/JPg2/00279 . , .

mp : 212-213C
IR (Nujol) : 3290, 3190, 1640, 1610 cm 1 NMR (DMSO-d6, + D2O, ~) : 1.~4 (3H, s), 4.41 (2H, s), 7.21-7.30 (lH, m), 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-ace~yl-aminomethylpyridin-2-yl)-2-[(amino)(methylthio)-methyleneamino]thiazole hydriodide.
mp : 195-197C (dec.) IR (Nujol) : 3380, 3280, 3190, 1600 (br) cm NMR (DMSO-d6, + D2O, ~) : 1.98 (3H, s), 2.56 (3H, s), 4.55 (2H, s), 7.44-7.55 ~lH, m), 7.99-7.09 (lH, 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)lby eluting with a mixture of ethyl acetate and methanol (20:1) to give 3~ 6-acetylaminomethyl-2-pyridinecarbonitrile (0.16 g).

21~81 WO92/16526 PCT/JP92/0027g--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 60-70C 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-d6, ~) : 3.94 (3H, s), 5.11 (2H, s), 8.73 (lH, t, J=2.1Hz), 9.30 (lH, d, J=2.1Hz), 9.38 (lH, d, J=2.lHz) PreParation 17 A mixture of 4-l6-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 tempe~ature.
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-d6, ~) : 1.93 (3H, s), 3.07 (3H, d, J=4.4Hz), 4.38 (2H, d, J=5.9Hz), 7.22 (lH, t, J=4.5Hz), 7.71 (lH, s), 7.84 f2H, d, J=4.5Hz), 8.47 (lH, t, J=5.9Hz), 9.19 (lH, br s), 11.77 (lH, s) ' ~ ."
Preparation 18 Methanesulfonic acid (18.6 g) was added to a solution of 2-acetyl-6-(propionylaminomethyl)pyridine (40.0g) in ":.- ~ , :,:'.' ~. ..
::.

2 ~
WO92~16526 PCT/JP92/00279 dioxane (800 ml) at room tempe:rature. The mixture was stirred at room temperature fo:r 15 minutes. Bromine t34.1 g) was added slowly to the mixture at room temperature.
The mixture was heated at 50C 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 50C 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 : 134-136C
IR (Nujol) : 3270, 3160, 1630 cm NMR (DMSO-d6, ~) : 8.37 (lH, t, J=S.9~z), 7.77 (lH, t, J=7.7Hz), 7.68 (lH, dd, J=7.7Hz and l.lHz), 7.24 (lH, s), 7.12 (lH, dd, J=7.7Hz and l.l~z), 7.10 (2H, s), 4.36 (2H, d, J=5.9Hz), 2.21 (2H, q, J=i.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 : 230-231C (dec.) IR (Nujol) : 3290, 1670, 1640 cm 1 NMR (DMSO-d6, ~) : 14.29 (1~, s), 12.23 tlH, s), W09221 ~ 6)~ 81 PCT/JP9~/00279 -8.43 (lH, t, J=5.9Hz), 8.03 (2H, d, J=7.2Hz), 7.95 (lH, s), 7.92-7 83 (2H, m), 7.71 (lH, t, J=7.2Hz), 7.57 (2H, t, J=7.2Hz), 7.24 (lH, 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) PreDaration 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 222C (dec.) IR ~Nujol) : 3270, 1680, 1600 cm 1 NMR (DMSO-d6, ~) : 14.29 (lH, s), 12.23 (lH, 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 (lH, dd, J=3.6Hz and 5.2Hz), 4.34 ~2H, d, J=6.1Hz), 4.05 (2H, q, J=7.1Hz), 1.20 (3H, t, J=7.lHz) Preparation 21 The following compound was obtained according to a similar manner to that o~ Preparation 19. ~ ;~
--2-(3-~enzoylthioureidoj-4-(2-acetylaminomethyl-thiazol-4-yl)thiazole mp : 237-238C ~dec.) ~ ;
IR (Nujol) : 3275, 1670, 1645 cm 1 NMR (DMSO-d6, ~) : 14.26 (lH, s), 12.23 (lH, s), -8.81 (lH, t, J=6.0Hz), 8.02 (2H, d, J=7.0Hz), - 7.88 (lH, s), 7.70 (lH, t, J=7.0Hz), 7.60 (lH, s), 7.57 (2H, t, J=7.0Hz), 4.57 (2H, d, J=~.OHz), 1.92 (3H, s) WO92/16526 ~1 ~S 9 g 1 PCT/JP92/00279 - 37 _ PreParation 22 - ;
A suspension of 2-amino-4-(6-propionylaminomethylpyridin-2-ylthiazole (12.0 g) and conc. hydrochloric acid ~12 ml1 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: 279-281C (dec.) IR (Nujol) : 3300, 1620 cm 1 NMR (DMSO-d6, ~) : 9.60-8.40 (4H, br), 8.07-7.96 (2H, m), 7.80 (lH, s), 7.52 (lH, 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 o~ 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-d6, ~) : 7.83-7.68 (3H, m), 7.24 (lH, 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) 2 1 0 .r~
W092/16526 PCT/JP9t/0~279--PreParation 24 A suspension of 2-amino-4-bromoacetylthiazole hydrobromide ~14.0 g) and N-[(thiocarbamoyl)methyl]-aceta~ide (6.1 g) in ethanol (300 ml) was stirred at room S temperature for 24 hours. The insoluble material was removed by filtration. The so]vent 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-acetylaminomet~ylthiazol-4-yl)-2-aminothiazole (5.83 g).
mp : 201-202C (dec.) IR (Nujol) : 3300, 1740, 1650 cm 1 NMR (DMSO-d6, ~) : 8.77 ~lH, t, J=6.0Hz), 7.50 (lH, s), 7.10 (2H, s), 6.89 (lH, 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-aminothiazole (0.75 g) in methanol (30 ml). The mixture 25 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-aminothiazole hydrochloride (0.35 5).
mp : 218-221C ~dec.) IR (Nujol) : 3200, 1635 cm 1 NMR (DMSO-d6,~ 8.86 (lH, t, J=5.9Hz), 8.01 (lH, s), 7.15 (lH, s), 4.54 (2H, d, J=5.9Hz), 1.92 (3H, s) ~.1 0'i9~

Preparation 26 A mixture of 4-(6-acetyl~lnomethylpyridin-2-yl)-2-(3-methylthioureido)thiazole (1.5 g) and methyl iodide (0.45 ml) in a solution of methanol (lS ml) and tetrahydrofuran l8 ml) was heat:ed under reflux for 9 hours. The solvent was removecL 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 : 187-189C
IR (Nujol) : 3470, 1620, 1600 cm 1 NMR (DMSO-d6, ~) : 1.97 (3H, s), 2.55 (3H, s), 3.07 (3H, s), 4.51 (2H, d, J=5.7Hz), 7.40-7.52 (lH, m), 8.02-8.20 (2~, m), 8.07 (lH, s), 8.67 (lH, 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 60C 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 resul~ing precipitate was collected by filtration to afford 4-(6-propionylamino-methylpyridin-2-yl)-2-thioureidothiazole (14.67 g).
mp : 223-225C (dec.) IR (Nujol) : 3270, 3120, 1640, 1620 cm 1 NMR (DMSO-d6, ~ : 11.65 (lH, br), 9.00-8.00 (3H, br), 7.85 (lH, t, J=7.8Hz), 7.79 (lH, dd, J=7.8Hz and 1.6Hz), 7.73 (lH, s), 7.21 (lH, dd, J=7.8Hzland 1.6Hz), 4.39 (2H, d, J=5.9Hz), ~-2.22 (2H, q, J=7.6 Hz), 1.06 (3H, t, J=7.6Hz) . .. . . : - :, : , , .. . - . -wos2/16s26 PCT/JP~2/00279 -~

Pre~aration 28 The following compound was obtained according to a similar manner to that of Preparation 27.

4-(6-Ethoxycarbonylaminomethylpyridin-2-yl)~2-thioureidothiazole mp : 210-212C (dec.) IR (Nujol) : 3310, 3130, 1690, 1600 cm -NMR (DMSo-d6, ~) : 11.74 (lH, s), 8.77 (lH, br), 8.33 (lH, br), 7.90-7.74 (3H, m), 7.71 (lH, s), 7.23 (lH, dd, J=l.OHz and 7.2Hz), 4.32 (2H, d, J=6.1Hz), 4.04 (2H, q, J=7.1Hz), 1.19 (3H, t, J=7.1Hz) .
Pre~aration 29 -The following compound was obtained according to a similar manner to that of Preparation 27.

4-(2-Acetylaminomethylthiazol-4-yl)-2-thioureidothiazole ~ -mp : 230-231C (dec.) IR (Nujol) : 3270, 1640, 1615 cm 1 NMR (DMSO-d6, ~) : 11.71 (lH, s), 9.00-8.00 (3H, br), 7.81 (lH, s), 7.38 (lH, s), 4.55 (2H, d, J=6.0Hz), 1.92 (3H, s) Pre~aration 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-[1amino)(methy~thio)methyleneamino]-4-~6-propionylaminomethylpyridin-2-yl)thlazole hydriodide (13.68 g).

; ~ r 2 ~ 0 ~
- WO92/16~26 PCT/JP92/00~7 mp : 194-196C (dec.) IR (Nujol) : 3350, 3200, 1650, 1610 cm 1 NMR (DMSO-d6 ~) : 9.29 (2H, br), 8.55 (lH, t, J=5.8Hz), 8.13-8.03 (3H, m), 7.40 (lH, dd, J=2.7Hz and 6.2Hz), 4.50 (2H, d, J=5.3Hz), :~
2.52 (3H, s), 2.24 (2H, q, J=7.5Hz), l.Q6 (3H, t, J=7.5Hz) -Pre~aration 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 155C (dec.) IR (Nujol) : 3350, 1685, 1610 cm 1 NMR (DMSO-d6, ~) : 9.51 (lH, br), 8.40-8.05 (3H, m), 8.05-7.80 (lH, mj, 7.60-7.20 (2~, m), 4.46 (2H, d, J=5.4Hz~, 4.06 (2H, ~, J=7.0Hz), 2.59 (3H, s), 1.20 13H, t, J=7.0Hz) PreParation 32 The following compound was obtained according to a similar manner to that of Preparation 30.
:
2-[(Amino)(methylthio)methyleneamino]-4-(2-acetylaminomethylthiazol-4-yl)thiazole hydriodide mp : 178-180C (dec.) . ~:~
IR (Nujol) : 3250, 1640 cm 1 NMR (DMSO-d6, ~) : 9.53 (lH, br), 8.80 (lH, t, J=6.0Hz), 8.12 (lH, s), 7.52 llH, s), 4.55 (2H, d, J=6.0Hz), 2.57 (3H, s), 1.92 (3H, s) WO92/16526 PCT/JP92/00~79 --Preparation 33 A mixture of 2-(acetylaminometyl)-6-bromoacetyl-pyridine hydrobromide (3.34 g) and diaminomethylenethiourea (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 : 228-229C
IR (Nujol) : 3350, 3150 cm 1 NMR (DMSO-d6, ~) : 3.85 (2H, s), 6.96 (4H, br s), 7.22-7.44 (3H, m), 7.73-7.83 (3H, m) Pre~ation 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 70C for 4 hours. The solvent was removed under reduced pressure to give crude product of 2-acetylaminomethyl-4-bromoacetylthiazole. The abo~e residue was dissolved in ethanol ~50 ml).
Diaminomethylenethiourea (1.3 g) was added to the solution and the mixture was refluxed for 4 hours. The solvent was removed uhder reduced pressure. The residue was dissolved in water and then the solution was alkalized with a saturated a~ueous 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-2 ~ ~ ~ 9 ~ :1 WO~2/16526 PCT/JP92/00279 amino)thiazole (430 mg).
mp : 255-256C
IR (Nujol) : 3250, 1640 cm 1 NMR (DMSO-d6, ~) : 1.91 t3H, s), 4.54 (2H, d, J=5.9Hz), 6.88 (4H, s), 7.02 ~lH, s), 7.79 (lH, s), 8.77 llH, t, J=5.9Hz) Anal. CalCd for C1oH12N6C)S2 4/5H20 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 o methanol and water afforded 4-(2-aminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole dihydrochloride (6.98 g).
mp : >300C
IR (Nujol) : 3300, 1680, 1600 cm 1 NMR (DMSO-d6, ~) : 4.47 (2H, s), 7.59 ~lH, s), 8.41 (4H, s), 8.45 ~lH, s), 8.76 (3H, s), 12.82 (lH, s~
Anal- Calcd- for C8HlON6S2-2HCl-9/1OH2O
C 27.98, H 4.05, N 24.47, Cl 20.64, H2O 4.72 Found: C 27.69, H 3.87, N 24.13, Cl 20.85, H2O 4.38 Preparation 36 The following compound was obtained according to a similar manner to that of Example 15.

4-(6-Aminome~hylpyridin-2-yl)-2-ldiaminomethylene~
amino)thiazole trihydrochloride mp : 288-289C

21nrinXl WO92/16526 PCT/JP92/0~279~-IR ~Nujol) : 3375, 3275, 3175, 1685 cm NMR (D~SO-d6, ~) : 4.25 t2H, ~, J=5.8Hz), 6.12 (3H, br s), 7.46 (lH, d, J=7.7Hz), 7.95 (lH, t, J=7.7Hz), 8.18 (lH, d, J=7.7Hz), 8.33 (lH, s), 8.41 ~4H, s) and 8.62 ~2H, br s) Anal- Calcd. for C1oH12N6S 3HCl 1/3H2o C 33.02, H 4.34, N 23.11 Found : C 33.16, H 4.09, N 22.89 Pre~aration 37 A mixture of 2-~diaminomethyleneamino)-4-~6-propionylaminomethylpyridin-2-yl)thiazole (49.0 g) and conc. hydrochloride acid (134 ml) in ethanol (500 ml) was heated under reflux for 7 hours and after the mixture was cooled to am~ient temperature. To the mixture was added ethanol (500 ml) with stirring and the isoIated precipitate was collected by filtration to give 4-(6-aminomethylpyridin-2-yl)-2-tdiaminomethyleneamino)-thiazole trihydrochloride (52.36 g).
IR (Nujol) : 3375, 3275, 3175, 1685 cm 1 Pre~aration 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 elutin~ with a mixture of chloroform and -methanol (19:1, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo.
-......

WO92/16~26 2 ~ Q ~ PCT/JP~2/00279 The residue was recrystalli~ed 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 : 181C
IR (Nujol) : 3340, 3230, 3130, 1630, 1590 cm NMR ~DMSO-d6, ~) : 1.93 (3H, s), 2.77 (3H, d, J=4.8Hz), 4.37 (2H, d, J=5.9Hz), 7.14-7.21 (lH, m), 7.41 (lH, s), 7.46 (2H, s), 7.74-7.84 (2H, m), 8.45 (lH, t, J=;.9Hz) Pre~aration 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)-t(2,2,2-trifluoroethyl)amino]methyleneamino]thiazole mp : 233C
IR (Nujol) : 3380, 1650, 1620 cm 1 NMR (DMSO-d6, ~) : 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 (lH, s), 7.73-7.88 (4H, m), 8.45 (lH, 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)thiazlole mp : 248-249C (dec.) IR (~ujol) : 3320, 3050, 1720, 1610 cm 1 ~. ~ Q ~
WO92/16~26 PCT/JP92/00279 NMR (DMSO-d6, ~) : 3.92 ~3H, s), 7.00 (4H, s), 7.55 (lH, s), 8.58 (lH, t, J-2.1Hz~, -8.97 (lH, d, J=2.1Hz), 9.31 (lH, d, J=2.1Hz) Anal- Calcd. for C11H11N502S
C 47.64, H 4.00, N 25.26 Found : c 47.35, H 3.90, N 25.00 PreDaration 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~
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-d6, ~) : 3.12-3.22 (lH, m), 3.93-4.07 (2H, m), 7.32 (2H, s), 8.14 (lH, 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-d6, ~): 3.27-3.39 (7H, m), 7.15 (2H, br), 7.94 (lH, br) PreParation 43 A mixture of 2-acetylaminomethyl-6-brom~acetyl-pyridine (2.0 g) and dithiobiuret (1.1 g) in ethanol (30 ml) was heated under reflux for 5 hours and then to the : -~ ~ ' - WO92/16526 PCT/JP92/00~7 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%
i aqueous potassium carbonate. The isolated precipitate was collected by filtration, washed with water and dried to gi~e 4-(6- acetamidomethylpyridin-2-yl) -2- `
thioureidothiazole (1. 4 g).
mp : 212-213C ' .
IR (Nujol) : 3290, 3190, 1640, 1610 cm 1 NMR (DMSO-d6, ~) : 1.94 (3H, s), 4.39 (2H, d, J=5.9Hz), 7.22 (lH, dd, J=1.6Hz, 7.0Hz), 7.73 (lH, s), 7.75-7.94 ~2H, m), 8.48 (lH, t, J=5.9Hz) Pre~aration 44 A solution of 2-acetylaminomethyl-6-cyanopyridine (20.0 g) in dichloromethane (400 ml) was added dropwise to an ethereal solution of methylmagnesium bro~ide (3 mole/Q) O (190.0 ml) at 5C to lSC 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 : 93C
IR (Nujol) : 3280, 1700, 1630 cm 1 NMR (DMSO-d6, ~) : 1.1.0 (3H, t, J=7.3Hz), 1.94 (3H, s), 3.18 (2H, g, ;=7.3Hz), 4.42 (2H, d, J=6.OHz), 7.53 '1,, dd, J=l.OHz, 7.7Hz), 7.82 (lH, dd1 J=l.OHz, ;.7Hz), 7.96 (lH, t, J=7.7Hz), 8.52 (lH, t, J=F.OH7 - ? ~ :

- . : . .: , .

~10 ) 3 ~1 W092/16~26 PCT/3P92/00279--Preparation 45 Bromine (1.1 ml) was added to a mixture of 2-acetylaminomethyl-5-propiony:Lpyridine (4.0 g) and methanesulfonic acid (1.3 ml) in dioxane (60.0 ml) at ambient temperature and the mixture was stirred for 3 hours at 50C. 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 washecl 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-d6, ~) : 1.82 (3H, d, J=6.8Hz), 1.95 (3H, s), 4.45 (2H, d, J=6.0Hz), 6.11 ~lH, g, J=6.8Hz), 7.59 (lH, dd, J=1.3Hz, 7.5Hz), 7.94 -(lH, dd, J=1.3Hz, 7.5Hz), 8.02 (lH, t, J=7.5Hz), --8.55 (lH, t, J=6.0Hz) ~-Example 1 A mixture of cyclobutanecarboxylic acid (0.5 ml), ;
l-hydroxybenzotriazole hydrate (0.8 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (l.0 g) in N,N-dimethylformamide (S ml) was ;
stirred for l hour at ambient temperature. The above mixture was aclded to a mixture of 4-(6-aminomethylpyridin- ~ `
2-yl)-2-tdiaminomethyleneamino)thiazole trihydrochloride (1.5 g) and triet~ylamine ~1.8 ml) in N,N-dimethylformamide (15 ml) and the mixture was stirred for 20 hours at ambient temperature. The reaction mixture `~ ' '`
: ' .

W O 92/16526 ~ P~r/JP92/00279 was added a mixture of ethyl acetate tetrahydrofuran and water and the mixture was adjusted to pH 9.5 with 20go 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 : 242C (dec.) IR (Nujol) : 3400, 3300, 3110, 1645, 1610 cm 1 NMR (DMSO-d6, ~) : 1.75-2.29 (6H, m), 3.05-3.22 (lH, m), 4.37 (2H, d, J=5.9Hz), 6.93 (4H, s), 7.08-7.15 (lH, m), 7.39 (lH, s), 7.76-7.85 (2H, m), 8.28 (lH, t, J=5.9Hz) Anal. Calcd. for C15H18N6OS :
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 : 229C (dec.) IR (Nujol) : 3380, 3340, 1660, 1600 cm 1 NMR (DMSO-d6, ~) : 1.80-2.20 (3H, m), 2.06-2.24 (lH, m), 3.74-3.88 (lH, m), 3.90-4.02 (lH, m), 4.28-4.37 ~lH, m), 4.41 (2H, d, J=5.9Hz), 6.93 (4H, s), 7.07-7.15 (lH, m), 7.36 (lH, s), 7.76-7.82 (2H, m), 8.45 (lH, t, J=5.9~z) Anal. Calcd.,for C15H18N6O2S :
C 52.01, H 5.24, N 24.26 Found : C 51.66, H 5.23, N 24.15 , .. . , ........ , . , . . .. ;. ..

~: ., . ~ ., : :; , :.. ,.: . : :: .:, : . . ::.

2:10ri~
W ~ 92/16526 PC~r/JP92/00279 -~

Example 3 The following compound was obtained according to a similar manner to that of Example 1.

2-(Diaminomethyleneamino)-4-[6-(tetrahydrofuran 3-yl)carbonylaminomethylpyridin-2-yl]thiazole mp : 227C (dec.) IR (Nujol) : 3390, 3260, 3130, 1650, 1605 cm NMR (DMSO-d6, ~) : 1.98-2.10 (2H, m), 2.99-3.15 (lH, m), 3.61-3.82 (3H, m), 3.85-3.95 (lH, m), 4.40 (2H, d, J=5.9Hz), 6.93 (4H, s), 7.10-7.18 (lH, m), 7.41 (lH, s), 7.77-7.82 (2H, m), 8.56 (lH, t, J=5.9Hz) -Anal. Calcd. for C15H18N6O2S : ~ ;
C 52.01, H 5.24, N 24.26 Found : C 51.69, H 5.26, N 24.05 -~ .; -ExamPle 4 The following compound was obtained according to a similar manner to that of Example 1.

2-(Diaminomethyleneamino)-4-r6~ tert- ~ -butoxycarbonylpiperidin-3-yl)carbonylaminomethylpyridin-2-yl]thiazole mp : 214-216C ~ -IR (Nujol) : 3400, 1655, 1610 cm 1 ,~
NMR (DMSO-d6, ~ : 1.15-1.75 (3H, m), 1.40 (9H, s), 1.80-2.00 (1:-, m), 2.26-2.47 (lH, 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 (lH, m), 7.41 :
(lH, s), 7.75-7.84 (2H, m), 8.53 (lH, t, J=5.6HZ) ExamPle 5 A mixture of 2-(diaminomethyleneamino)-4~[6~ tert-';' '.

Wogz/16526 ~ PCT/JP92/00279 ~utoxycarbonylpiperidin-3-yl)carbonylaminomethylpyridin-2-yl]thiazole (l.9 g) and 4N-methanolic hydrogen chloride (40 ml) was stirred for 7 hour~ 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)carbonyl-aminomethylpyridin-2-yl]thiazole (0.47 g).
mp : 227-228C
IR (Nujol) : 3300, 3160, 1650, 1620 cm 1 NMR (D~SO-d6, ~) : 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 (lH, m), 7.39 (lH, s), 7.70-7.86 (2H, m), 8.53 (lH, t, J=5.8Hz) Anal. Calcd. for C16H21N7OS :
C 53.46, H 5.89, N 27.28 Found : C 53.22, H 5.85, N 26.99 Example 6 The following compound was obtained according ~o a similar manner to that of Example 1.

4-[6-(4-Oxocyclohexyl)carbonylaminomethylpyridin-2--yl]-2-(diaminomethyleneamino)thiazole mp : 232C
IR ~Nujol) : 3390, 3390, 1715, 1650, 1605 cm 1 NMR (DMSO-d6, ~) : 1.73-2.21 (4H, m), 2.21-2.57 (4H, m), 2.66-2.85 (lH, m), 4.41 (2H, d, J=5.8Hz), 6.94 (4H, m), 7.15 (lH, t, J=4.7Hz), 7.40 (lH, 2 l n r.~
WO92/16~?i6 PCT/JP~2/00279` A~, s), 7.79 (2H, d, J=4.7Hz), 8.55 (lH, t, J-5.8Hz) Example 7 The f ollowing compound was obtained according to a similar manner to that of Example 1.

2-(Diaminomethyleneamino)-~4-[6-[5-(1,2-dithiacyclopentan-3-yl)valeryl3aminomethylpyridln-2-yl]-thiazole mp : 204-205C
IR (Nujol) : 3400, 1645, 1610 cm 1 NMR (DMSO-d6, ~) : 1.27-1.75 (6H, m), 1.75-1.98 (lH, m), 2.21 (2H, t, J=7.1Hz), 2.30-2.50 (lH, m), 3.02-3.26 ~2H, m), 3.50-3.70 (lH, m), 4.38 (2H, d, J=5.9Hz), 6.93 (4H~ s), 7.15 (lH, t, J=4.4Hz), 7.40 (lH, s), 7.78 (2H, d, J=4.4Hz), 8.42 (lH, t, J=5.9Hz) Anal. Calcd. for C18H24N6OS3 :
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~ pyrrolidinyl)methylphenoxy]-butyric acid (1.7 g), diphenylphosphoryl azide (1.4 ml) and triethylamine (0.9 ml) in dry ben7ene (30 ml) was stirred for 1 hour at 7S-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. ~he mixture was adjusted to p~I 11 with 4N-sodium hydroxide and the - . - . .-.. . . . . . . . ... .. . . . . .

i~ l O ~ ~ 81 WO92/16~26 PCT/JP92/00279 separated organic layer was dried over magnesium sulate.
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 ~rom a mixture of ethanol and diisopropyl `
ether to give 2-(diaminomethyleneamino)-4-[[6-[3-[3-(3-pyrrolidinyl)methylphenoxy]propyl]ureido]-methyI]thiazole (0.44 g).
mp : 174C
IR (Nujol) : 3350, 3320, 1615 cm 1 NMR (DMSO-d6, ~) : 1.69 (4H, s), 1.80-1.92 (2H, m), 2.44 (4H, s), 3.12-3.25 (2H, m), 3.55 ~2H, sj, 3.97 (2H, t, J=6.2Hz), 4.33 (2H, d, J=5.6Hz), 6.33 (lH, t, J=5.6Hz), 6.49 tlH, t, J=5.7Hz), 6.75-7.08 (7H, m), 7.08-7.26 (2H, m), 7.45 (lH, s), 7.76 (2H, d, J=4.4Hz) 25H32N8O2S H2O :
C 57.02, H 6.51, N 21.28, H2O 3.42 Found : C 56.82, H 6.44, N 21.30, H2O 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 conc. hydrochloric acid (7.8 ml) ln 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)amino]methyleneamino]~hiazole trihydrochloride (13-7 g) mp : 198-200C
IR (Nujol) : 3300, 3210, 1675, 1615, 1~00 cm 1 .. - - . ., -- . . : :: : . ... : - . .. . . . . .

~l~)rj ~X ~
W0~2/16526 PCT/JP92/00279 ~-NMR (D20, o) : 4.27 (2H, q, J=8.8Hz), 4.50 (2H, s), 7.58 (lH, d, J=7.5Hz), 8.00 tlH, d, J=7.5Hz), 8.04 (lH, s), 8.13 (lH, t, J=7.5Hz) ExamPle 10 The following compound was obtained according to a similar manner to that of Example 1.

2-[Amino)[2,2,2-trifluoroethyl)amino]methyleneamino]-10 4-(6-cycloheptanecarbonylaminomethylpyridin-2-yl)thiazole mp : 229-230C
IR (Nujol) : 3390, 3360, 1625 cm 1 ~-~
NMR (DMSO-d6-D2O, o) : 1.30-1.92 (12H, m), 2.32-2.50 (lH, m), 4.12 (2H, q, J=9.7Hz), 4.37 (2H, d, ~ -J=5.7Hz), 7.13 (lH, t, J=4.3Hz), 7.50 (lH, s), 7.81 (lH, d, J=4.3Hz), 8.35 (lH, t, J=5.7Hz) Anal. Calcd. for C20H25N6OSF3 :
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% a~ueous 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 methanQl (19:1, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo. The residue was recrystallized from W092/16~26 P~TtJP92/00279 a mixture of methanol, dioxane and diisopropyl e~her to give 4-(6-acetylaminomethylpyridin-2-yl)-2-[(amino)-(n-butylamino)methyleneamino]thiazole (0.48 g).
mp : 145-146C
IR (Nujol) : 3380, 1645, 1605 cm NMR (DMSO-d6, ~) : 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 (lH, d, J=7.2Hz), 7.40 (lX, s), 7.66-7.86 (2H, m), 8.45 (1~, t, J=5.9Hz) Anal- Calcd. for C16H22N60S :
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 : 127-128C
IR (Nujol) : 3410, 3270, 1660, 1595 cm 1 NMR (DMSO-d6, ~) : 1.05-2.00 (lOH, m), 1.93 (3H, s), 3.47-3.70 (lH, m), 4.36 (2H, d, J=6.0Hz), 7.16 (lH, d, J=7.4Hz), 7.33 (2H, s), 7.40 (lH, s), 7.70 (lH, d, J=7.4Hz), 7.80 (lH, t, J=7.4Hz), 8.44 (lH, t, J=6.0Hz) Anal. Calcd. for C18H24N60S
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.

~5~8~
wos~/l65~6 PCT/JP92/00279~-4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)-(2-methoxyethylamino)methyleneamino]thiazole mp : 162-163~C
IR (Nujol) : 3370, 1650, 1595 cm 1 NMR (DMSO-d6, ~) : 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 (lH, m), 7.42 ~lH, s~, 7.70-7.85 (2H, m), 8.45 (lH, t, J=5.9~z) Anal- Calcd. for C15H20N O2S :
c 51.71, H 5.79, N 24.12 Found : C 51.37, H 5.79, N 23.84 Exam~le 14 The following compound was obtained according to a similar manner to that of Example 11.

4-(6-~cetylaminomethylpyridin-2-yI)-2-[(amino)(2-dimethylaminoethylamino)methyleneamino]thiazole mp : 134-136C
IR (Nujol) : 3400, 3360, 3100, 1640, 1590-cm 1 NMR ~DMSO-d6, ~) : 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 (lH, d, J=8.0Hz), 7.40 tlH, s), 7.79 (lH, t, J=8.0Hz), 7.88 (lH, d, J=8.0Hz), 8.45 (lH, t, J=5.9Hz) Example 15 To a solution of 4-(6-acetylaminomethylpyridin-2-yl)-2-[(amino)(2-dimethylaminoethylamino)methyleneami~o]- -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 etherl(2~ ml) was added to a reaction mixture and isolated precipitate was collected by filtration. The precipitate was recrystallized from a mixture of methanol ~.n~ 8~
WO92/16s26 PC~/JP92~00279 and diisopropyl ether to give 4-(6-acetylaminomethylpyridin-2-yl)-2-[(amino)(2-dimethylaminoethylamino)methyleneamino]thiazole trihydrochloride (0.96 g).
S mp : 228-229C
IR (Nujol) : 3190 (br), 1690, 1655, 1605 cm 1 NMR (D20, ~) : 2.18 (3H, s), 3.05 (6H, s), 3.60 (2H, t, J=6.2Hz), 3.99 (2H, t, 3=6.2Hz), 4.82 (2H, s), 7.84 (1~, d, J=7.3Hz), 8.33 (lH, s), 8.34 (lH, d, J=7.3Hz), 8.51 (lH, t, J=7.3Hz) Anal- Calcd- for C16H23N7S-3HCl-l/3H2 C 40.30, H 5.64, N 20.56, Cl 22.30, H2O 1.26 Found: C 40.36, H 5.65, N 20.79, Cl 22.19, H2O 1.19 Example 16 The following compound was obtained according to a similar manner to that of Example 11.

4-(6-Acetylaminomethylpyridin-2-yl)-2-~bis(methyl-amino)methyleneamino]thiazole mp : 277-279C
IR (Nujol) : 3360, 1665, 1590 cm 1 NMR (DMSO-d6, ~) : 1.93 (3H, s), 2.83 (6H, d, J=4.5Hz), 4.37 (2H, d, J=5.9Hz), 7.12-7.20 (lH, m), 7.42 (lH, s), 7.75-7.82 (2H, m), 8.45 (lH, t, J=5.9~z) Anal. Calcd. for C14H1~N6OS :
C 52.81, H 5.70, N 26.39 Found : C 52.50, H 5.64, N 26.10 Example 17 -The followingl compound was obtained according to a similar manner to that of Example 11. .

4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)-(ethylamino)methyleneamino]thiazole 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)methylenamino]thiazole Example 19 The following compound was obtained according to a similar manner to that of Example 11.
4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)-(n-pentylamino)methyleneamino]thazole Example 20 The following compound was obtained according to a 21~ '~81 -W O 92/16526 PC~r/JP92/00279 similar manner to that of Example 11.

4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)-(n-hexylamino)methyleneamino]thiazole NMR (DMSO-d6, ~) : 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 (lH, d, J=7.2Hz), 7.36 (2H, s), 7.40 (lH, s), 7.71 (lH, d, J=7.2Hz), 7.79 (lH, t, J=7.2Hz), 8.45 (lH, t, J=5.9Hz) Exam~le 21 The following compound was obtained according to a similar manner to that of Example 11.
4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)-(isopropylamino)methyleneamino]thiazole NMR (DMSO-d6, ~) : 1.15 (6H, d, J=6.4Hz), 1.93 (3H, s), 3.80-4.00 ~lH, m), 4.37 (2H, d, J=5.9Hz), 7.16 (lH, d, J=7.4Hz), 7.37 ~2H, s), 7.41 (lH, s), 7.71 tlH, d, J=7.4Hz), 7.80 (lH, t, J=7.4Hz), 8.45 ~lH, t, J=5.9Hz) Exam~le 22 The following compound was obtained accordiny to a similar manner to that of Example 11.

4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)- .
(isopentylamino)methyleneamino]thiazole ~ ;~
NMR (DMSO-d6, ~) : 0.92 (6H, d, J=6.6Hz), 1.35-1.50 (2H, m), 1.57-1.80 (lH, m), .
1.93 (3H, s), 3.14-3.28 (2H, m), 4.37 (2H, d, .
J=5.9Hz)~ 7.16 (lH, d, J=7.3Hz), 7.36 (2H, s), 7.40 (lH, s), 7.71 (lH, d, J=7.3Hz), 7.80 (lH, t, J=7.3Hz), 8.45 (lH, t, J=5.9Hz) ~ :

"".~ '''~.
. . .
:~ "

~n~xl.
W092/16526 P~T/JP92/00279 '' ~
Example 23 The ~ollowing compound was obtained according to a similar manner to that of Example 11.

4-(6-Acetylaminomethylpyridin-2-yl)-2-[~amino)-allylamino)methyleneamino]thiazole NMR (DMSO-d6, ~) : 1.93 (3H, s), 3.80-3.93 (2H, s), 4.37 (2H, d, J=5.9Hz), 5.07-5.32 (2H, m), 5.81-6.0I (lH, m), 7.17 (lH, dd, J=1.9Hz and 6.7Hz), 7.44 (lH, s), 7.49 (2H, s), 7.70-7.86 (2H, m), 8.45 (lH, ~, J=5.9Hz) Exam~le 24 The following compound was obtained according to a similar manner to that of Example 11.

4-(6-Acetylaminomethylpyridin-2-yl)-2-[~amino)-cyclopentylamino)methyleneamino]thiazole NMR tDMSO-d6, ~) : 1.32-1.80 (6H, m), 1.80-2.03 (2H, m), 1.93 (3H, s), 3.92-4.12 (lH, m), 4.37 (2H, d, J=5.8Hz), 7.16 (lH, d, J=7.5Hz3, 7.33 (2H, s), 7.40 (lH, s), 7.70 (lH, d, J=7.5Hz), -7.80 (lH, t, J=7.5Hz), 8.45 (lH, t, J=5.8Hz) ExamPle 25 The following compound was obtained according to a similar manner to that of Example 11.

4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)-(cyclopropylamino)methyleneamino]thiazole NMR (DMSO-d6, ~) : 1.40-1.88 (4H, m), 1.93 (3H, s), 3.35-3.55 (lH, m), 4.37 (2H, d, J=5.7Hz), 7.17 (lH, d, J=7.6Hz), 7.40 (lH, s), 7.60 (2H, s), 7.69 ~lH, d, J=7.6Hz), 7.81 (lH, t, J=7.6Hz), 8.45 (lH, t, J=5.7Hz) ~:1 0~8~.
W092/16s26 PCT/JP9~/00279 Exapmle 26 The following compound was obtained according to a similar manner to that of Example 11.

4-(6-Acetylaminomethylpyridin-2-yl)-2-~(amino)- ~-(piperidino)methyleneamino]thia.zole N~R (DMSO-d6, ~ : 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 (lH, d, J=7.4Hz), 7.44 (lH, s), 7.68 (lH, d, J=7.4Hz~, 7.81 (lH, t, J=7.4Hz), 8.24 (2H, s), 8.45 (lH, t, J=5.3Hz) Example 27 The following compound was obtained according to a similar manner to that of Example 11.

4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)-(morpholino)methyleneamino]thiazole NMR (DMSO-d6, ~) : 1.93 (8H, s), 3.47-3.58 (4H~ m), 3.58-3.70 (4H, m), 4.37 (2H, d, J=5.9HZ), 7.17 (lH, d, J=7.5Hz), 7.49 (lH, s), 7.67 (lH, d, J=7.5Hz), 7.81 (lH, t, J=7.5Hz), ;
8.30 (2H, s), 8.45 llH, t, J=5.9Hz) .~: :: .:
Example 28 ::
The following compound was obtained according to a similar manner to that of Example 11. :. -2-[(Amino)(methylamino)methyleneamino]-4-~6- :: :
propionylaminomethylpyridin-2-yl)thiazole : ~ :
mp : 169-170C ~ -IR (Nujol) : 3400, 3350, 3250, 1630, 1600 cm 1 NMR ( DMSO-d61, ~ ) : 8.38 ( lH , t, J=5.9Hz), ::
8.00-7.60 (2H, m), 7.45 (2H, s), 7.40 (lH, s), 7.15 llH, dd, J=2.2Hz and 6.5Hz), 4.38 (2H, d, ~ l ~ r' ~ 8 1 W092/16~26 PCT/JP92/00279 -~

J=5.9Hz), 2.77 (3H, cL, J=4.8Hz), 2.21 t2H, q, J=7.6Hz), 1.06 (3H, t, J=7.6Hz) Anal- Calcd. for C14H1j3N60S
C 52.81, H 5.70, N 26.39 Found : C 53.10, H 5.72, N 25.94 EximPle 29 The following compound was obtained accordin~ to a similar manner to that of Example 11.
2-[(Amino)(n-butylamino)methyleneamino]-4-(6-propionylaminomethylpyridin-2-yl)thiazole mp : 145-147C
IR (Nujol) : 3330, 3230, 3170, 1650, 1610 cm 1 NMR (DMSO-d6, ~) : 8.38 (lH, t, J=5.9Hz), 7.80 (lH, t, 3=7.4Hz), 7.71 (lH, dd, J= ca.
l.OHz and 7.4Hz), 7.40 (lH, s), 7.38 (2H, s), 7.15 (lH, dd, J= ca. l.OHz and 7.4~z), 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.OHzJ
Anal- Calcd. for C17H24N60S
C 56.64, H 6.71, N 23.31 Found : C 56.98, H 6.91, N 23.23 ExamPle 30 The following compound was obtained according to a similar manner to that of Example 11.

2-[(Amino)~cyclohexylamino)methyleneamino]-4-(6-propionylaminomethylpyri in-2-yl)thiazole IR (Nujol) : 3320, 1650 cm 1 NMR (DMSO-d6,~ 8.38 (lH, t, J=5.9Hz), 7.80 tlH, t, J=7.5Hz), 7.70 (lH, dd, J= ca. l.OHz and 7.5Hz), 7.39 (lH, s), 7.33 (2H, s), 7.15 (lH, '' .: ' ' Wo92/16~26 ~1 0 ~ 81 PCT/JP92/00279 dd, J= ca. l.OHz and 7.5Hz), 4.37 (2H, d, J=5.9Hz), 3.66-3.54 (lH, 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 The following compound was obtained according to a similar manner to that of Example 11.

2-[(Amino)(methylamino)methyleneamino]-4-(6-ethoxycarbonylaminomethylpyridin-2-yl)thiazole NMR (DMSO-d6, ~) : 7.85-7.66 (3H, m), 7.47 (2H, s), 7.39 (lH, s), 7.17 ~lH, 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 The following compound was obtained according to a similar manner to that of Example 11.
2-~(Amino)\n-butylamino)methyleneamino]-4-(6-ethoxycarbonylaminomethylpyridin-2-yl)thiazole mp : 141-142C ~ -IR (Nujol) : 3430, 3340, 3230, 1705, 1650, 1610 cm 1 NMR (DMSO-d6, ~) : 7.85-7.70 (3H, m), 7.38 (3H, s), 7.17 (lH, 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, g, J=6.4Hz), 1.51-1.03 ~7H, m), 0.92 ~3H, t, J=7.0Hz) Example 33 A suspension of 2-(diaminomethyleneamino)-4-(5-methoxycarbonylpyridin-3-yl)thiazole (2.0 g), cyclopentylamine (3.7 g) and 28% sodium methoxide methanolic solution (5 ml) in methanol (50 ml) was W092/16S2~ PCT/JP9~/00279 -re~luxed 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). ~he 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 : 243-244C (dec.) IR (Nujol) : 3430, 3370, 3060, 1630, 1590 cm 1 NMR (DMSO-d6, ~) : 9.16 (lH, d, J=2.0Hz), 8.85 (lH, d, J=2.0Hz), 8.56 (lH, d, J=7.0Hz), 8.48 (lH, t, J=2.0Hz), 7.43 (lH, s), 6.94 (4H, s), 4.4-4.15 (lH, m), 2.05-1.85 (2H, m), 1.85-1.45 (6H, m) Anal. Calcd. for C15H18N6OS :
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 : 213-214C (dec.) IR (Nujol) : 3400, 3280, 3060, 1630, 1590 cm 1 NMR (DMSO-d6, ~) : 9.16 (lH, d, J=2.1Hz), 8.85 (lH, d, J=2.1Hz), 8.49-8.47 (2H, m), 7.43 (lH, s), 6.96 (4H, s), 4.00-3.80 (lH, m), 2.00-1.50 (4H, m), 1.50-1.00 t6H, m) :
ExamPle 35 The following compound was obtained according to a similar manner to that of Example 33.

. .
-: `:
~ ~~ O ~ 9 8 ~

4-(5-Cycloheptylaminocarbonylpyridin-3-yl)-2-(diaminomethyleneamino)thiazole mp : 213-214C ~dec.) IR (Nujol) : 3410, 3350, 1640, 1600 cm 1 S NMR (DMSO-d6, ~) : 9.16 (lH, d, J=2.1Hz), 8.84 (lH, d, J=2.1Hz), 8.53 (lH, d, J=7.7Hz), 8.48 (lH, t, J=2.1Hz), 7.42 (lH, s), 6.95 (4H, s), 4.10~3.90 (lH, m), 2.00-1.00 (12H, m) ExamDle 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), l-hydroxybenzotriazole hydrate (1.07 g) and triethylamine (1.24 g) in N,N-dimethylformamide (50 ml) was stirred at room temperature ~or 2 hours. The solvent was removed under reduced pressure. The residue was suspended in wa~er (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 af~orded 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-d6, ,~) : 8.64 (lH, t, J=6.0Hz), 7.76 (lH, s), 7.01 (lH, s), 6.8~ (4H, s), 4.52 (2H, d, J=6.0Hz), 2.45-2.25 ~lH, m), 2.00-1.30 (12H, m) -: . ..

~ lO~J~ L
wo92/l6s26 - 66 - PCT/JP92/00279 --Anal- Calcd. for C16H22N6OS2 :
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 : 245-247C (dec.) - IR tNujol) : 3410, 3330, 1635, 1610 cm 1 NMR (DMSO-d6, ~) : 8.73 (lH, t, J=6.0Hz), 7.78 (lH, s), 7.00 (lH, s), 6.88 (4H, s), 4.54 (2H, d, J-6.0Hz), 2.05 (2H, d, J=608Hz), 1.82-1.50 (6H, m), 1.40-1.10 (3H, m), 1.10-0.70 (2H, m) Anal. Calcd. for C16H22N6OS2 :
C 50.77, H 5.86, N 22.20 Found : C 50.89, H 5.87, N 22.11 Exam~le 38 The following compound was obtained according to a similar manner to that of ~xample 11.
2-[(Amino)(methylamino)methyleneamino]-4-(2- ~;
acetylaminomethylthiazol-4-yl)thiazole mp : 190-192C
IR (Nujol) : 3390, 3250, 1630 cm 1 NMR (DMSO-d6, ~) : 8.73 (lH, t, J=6.0Hz), 7.78 (lH, - s), 7.41 (2H, s), 7.03 (lH, 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-~ t ~
WO92/16526 PCT/JP~2/00279 bromoacetylpyridine (3.0 g) and ~amino)[(2-propynyl)-amino]methylenethiourea (2.1 g) in ethanol (20.0 ml) was stirred for 2 hours at 50C and ethyl acetate (20 ml) was added to the reaction mlxture 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 concentraticn 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]methyleneamino]thiazole (1.4 g).
mp : 169-170C
IR (Nujol) : 3380, 3340, 3260, 1645, 1610 cm 1 NMR (DMSO-d6, ~) : 1.94 ~3H, s), 3.16-3.23 (lH, m), 4.00-4.12 (2H, m), 4.38 (2H, d, J=5.8Hz), 7.06 (lH, s), 7.15-7.25 (1~, m), 7.49 (lH! s), 7.62 (2H, s), 7.73-7.87 (2H, m), 8.46 (lH, 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)methyleneaminojthiazole mp : 181C
IR (Nujol) : 3340, 3230, 3130, 1630, 1590 cm 1 NMR (DMSO-d6, ~) : 1.93 ~3H, s), 2.77 (3H, d, J=4.8Hz), 4.37 (2H, d, J=5.9Hz), 7.14-7.21 (lH, m), 7.41l(1H, s), 7.46 (2H, s), 7.74-7.84 (2H, m), 8.45 (lH, t, J=5.9Hz) '~;
~`

210~
W092/16;26 PCT/JP92/00279 -ExamPle 41 The following compound was obtained according to a similar manner to that of Exclmple 39.

4-(6-Acetylaminomethylpyrldin-2-yl)-2-[(amino)-(butylamino~methyleneamino]-5-methylthiazole mp : 123-130~C
IR (Nujol) : 3390, 3340, 1655, 1610 cm 1 NMR (DMSO-d6, ~) : 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 (lH, d, J=7.3Hz), 7.27 (2H, s), 7.69 (1H, d, J=7.3Hz), 7.77 (lH, t, J=7.3Hz), 8.42 (lH, t, J=5.9Hz) ExamDle 42 The following compound was obtained according to a similar manner to that of Example 11.

4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)[(2- r -methylallyl)amino]methyleneamino]thiazole mp : 173-174C
IR (Nujol) : 3360, 3240, 3190, 1635 cm 1 NMR (DMSO-d6, ~) : 1.74 (3H, s), l.9S (3X, s), 3.81 (2H, d, J=5.5Hz), 4.39 (2H, d, J=5.9Hz), 4.84 (lH, s), 4.91 (lH, s), 7.17 (lH, dd, J=2.2Hz, 6.5Hz), 7.44 (lH, s), 7.49 (2H, s), 7.72-7.87 (2H, m), 8.46 (lH, t, J=5.9Hz) ~xample 43 The following compound was obtained according to a -~
similar manner to that of Example 11.

4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)[(2-hydroxyethyl)amino)methyleneamino]thiazole WO92/16526 2 ~ Q ~ PCTtJPs2~00~7s :

mp : 175-176C
IR (Nujol) : 3280, 3200, 1645, 1600 cm 1 NMR (DMSO-d6, ~) : 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 ~lH, s), 7.16 (lH, d, J=6.3Hz), 7.34 (2H, s), 7.42 (lH, s), 7.70-7.88 (2H, m), 8.45 (lH, 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 : 135C ;
IR (Nujol) : 3420, 3290, 1670, 1640, 1610 cm - .
NMR (DMSO-d6, ~) : 1.66-1.87 t2H, 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 (lH, d, J=7.7Hz), 7.42 ~3H, s), 7.74 (lH, d, J=7.7Hz), 7.80 (lH, t, J=7.7Hz), 8.45 (lH, t, J=5.9Hz) ExamPle 45 The following compound was obtained according to a similar manner to that of Example 11.

4-(6 -Acetylaminomethylpyridin-2-yl)-2-[(amino)[( 2 methylthioethyl)amino]methyleneamino]thiazole mp : 146-147C ! '' .
IR ~Nujol) : 3390, 3280, 1645, 1610 cm 1 NMR (DMSO-d6, ~) : 1.94 (3H, s), 2.12 (3H, sj, 2.66 (2H, t, J=6.7Hz), 3.34-3.50 (2H, m), 4.38 (2H, -d, J=5.9Hz), 7.12-7.22 (lH, m), 7.44 (lH, s), 7.49 (2H, s), 7.74 (2H, m), 8.45 (lH, t, J=5.9Hæ) '` ' ,,",," ,.
, ~10~
W~92/16526 PCT/JP92/00~79 ~-Example 46 The following compound was obtained according to a similar manner to that of Example 11.

2-[[(2-Acetylaminoethyl)amino](amino)methyleneamino]-4-(5-acetylaminomethylpyridln-:2-yl)thiazole mp : 184-185C
IR (Nujol) : 3410, 3310, 1640, 1615 cm 1 NMR (DMSO-d6, ~) : 1.82 (3H, s), 1.93 (3H, s), 3.12-3.35 ~4H, m), 4.37 (2H, d, J=5.9Hz), 7.16 (lH, dd, J=2.2Hz, 6.5Hz), 7.43 (1~, s), 7.~3 (2H, s), 7.72-7.87 (2H, m), 8.01 (lH, br s), ~:
8.45 (lH, 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)methyleneaminoJthiazole mp : 169-170C
IR (Nujol) : 3380, 1650, 1610 cm 1 NMR (DMSO-d6, ~) : 1.93 (3H, s), 4.37 (2H, d, J=5.9Hz), 4.45 (2H, d, J=5.4Hz), 6.34 (lH, d, J=3.1Hz), 6.43 (lH, dd, J=1.8Hz, 3.1Hz)~ 7.17 (lH, d, J=7.7Hz), 7.47 tl~, s), 7.58 (2H, s), 7.64 (lH, s), 7.73 (lH, d, J=7.7Hz), 7.80 (lH, t, J=7.7Hz), 8.46 (lH, t, J=5.9Hz) Exam~le 48 The following compound was obtalned according to a similar manner to that of Example 11.

4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)[[2-(2-pyridyl)ethyl]amino]methyleneamino]thiazole .. .. .. .. . ..

WO92tl6526 ~ t Q ~ 9 8 1 PCT/JP92/00~79 - mp : 145-146C
IR (Nujol) : 3310, 1640, 1620 cm 1 NMR (DMSO-d6, ~) : 1.93 t3H, s), 3.01 (2H, t, J=6.7Hz), 3.56-3.70 ~2H, m), 4.37 l2H, d, J=5.9Hz), 7.16 (lH, d, J=7.7Hz), 7.18-7.30 (lH, m), 7.33 (lH, d, J=7.7Hz), 7.41 (3H, s), 7.62-7.80 ~2H, m), 7.79 (lH, t, J=7.7~z), 8.45 `
(lH, t, J=5.9Hz), 8.S3 (lH, d, J=4.1Hz) Exam~le 49 The following compound W25 obtained according to a similar manner to that of Example 11.

4-(6-Acetylamiinomethylpyridin-2-yl)-2-~(amino)[[2-(3,4-dimethoxyphenethyl)]amino]methyleneamino]thiazole mp : 167-168C
IR (Nujol) : 3280, 1635, 1610 cm 1 NMR (DMSO-d6, ~) : 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 (lH, d, J=7.7Hz), 7.38 (2H, s), 7~40 (lH, s), 7.53-7.68 (lH, m), 7.76 (lH, t, J=7.7Hz), 8.44 (lH, t, J=5.9Hz) `

ExamPle 50 The following compound was obtained according to a similar manner to that of Example 11.
~..., ~...
4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)[[2-(indol-3-yl)ethyl]amino~methyleneamino]thiazole mp : 158-159C
IR (Nujol) : 3420, 3340, 1660 cm 1 NMR tDMSO-d6~ ~): 1.93 ~3H, s), 2.97 t2H, t, ~
J=6.5Hz), 3.44-3.63 (2H, m), 4.37 (2H, d, ~ -~ J=5.8Hz), 6.96-7.27 (3H, m), 7.21 (lH, s), 2ln~
~-092Jl6526 PCT/JP92/00279 -7.30-7.80 t6H, m), 7.41 ~lH, s), 8.44 ~lH, t, J=5.8Hz), 10.85 (lH, s) Exam~le 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-dimethylaminomethylfurrurylthio)ethyl]amino]methylene-amino]thiazole mp : 116-118C
IR (Nujol) : 3470, 3330, 1670, 1645, 1610 cm 1 NMR (DMSO-d6, ~) : 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 (lH, d, J=3.lHz), 6.27 (lH, d, J=3.lHz), 7.14-7.27 (lH, m), 7.44 (lH, s), 7.52 (2H, s), 7.74-7.85 (2H, m), 8.46 ~lH, t, J=5.9Hz) Example 52 The ~ollowing compound was obtained according to a similar manner to thàt of Example 11.

4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)-(dimethylamino)methyleneamino]thiazole mp : 214-215C
IR (Nujol) : 3370, 3300, 1650, 1620 cm 1 NMR (DMSO-d6, ~) : 1.93 (3H, s), 2.99 (6H, s), 4.37 (2H, d, J=5.9Hz), 7.17 (lH, d, J=7.5Hz), 7.43 (lH, s), 7.68 (lH, dt J=7.5Hz), 7.81 (lH, t, J=7.5Hz), 8.12 (2H, s), 8.46 (lH, t, J=5.9Hz) Example 53 The following compound was obtained according to a similar manner to that of Example 11.

snsl ~
- wo92/l6s26 PCT/JP9~/00279 2-[(Amino)(cyclohexylamino)methyleneamino]-4-(6-ethoxycarbonylaminomethylpyridin-2-yl)thiazole mp : 141-142~C
IR (Nujol) : 3350, 1710, 1640 cm NMR (DMSO-d6, ~) : 1.00-1.47 (8H, m), 1.47-1.63 (lH, m), 1.63-1.80 (2H, m), 1.80-1.94 (2H, m), 3.45-3.70 (lH, m), 4.04 (2X, q, J=7.1Hz), 4.30 (2H, d, J=6.2Hz), 7.16 ~lH, d, J=7.7Hz), 7.32 (2H, s), 7.37 (lH, s), 7.65-7.79 (2H, m), 7.81 (lH, t, J=7.7Hz) Example 54 The following compound was obtained according to a similar manner to that of Example ll.
;
2-[(Amino)[(2-methoxyethyl)amino]methyleneamino]-4-(2-acetylaminomethylthiazol-4-yl)thiazole mp : 169-170C
IR (Nujol) : 3410, 3350, 1660, 1600 cm 1 NMR (DMSO-d6, ~) : 1.91 (3H, s), 3.30-3.46 (7H, m), 4.54 ~2H, d, J=6.0Hz), 7.04 (lH, s), 7.38 (2H, br), 7.75 (lH, s), 8.78 (lH, t, J=6.0Hz) ~`~

ExamPle 55 -25 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 : 184-185C -IR (Nujol) : 3400, 3200, 3110, 1660, 1640, 1600 cm 1 ;
NMR (DMSO-d6, ~) : 1.91 (3H, s), 3.86 (2H, t, J=5.4~z), 4.54 (2H, d, J=6.0Hz), 5.11 (lH, dd, J=10.3Hz and 1.7Hz), 5.21 (lH, dd, J=17.2Hz and 1.7Hz), 5.81-6.00 (lH, m), 7.05 (lH, s), 7.47 ~ ':
.
, . .. .

~ 10 ~

(2H, br), 7.75 (lH, s), 8.78 (lH, t, J=6.0Hæ) Exam~le 56 The following compound was obtained according to a similar manner to that of Example ll.

2-[ (Amino)(butylamino)methyleneamino]-4-(2-acetyl-aminomethylthiazol-4-yl)thiazole mp: 177 -178 C
IR (Nujol) : 3400, 3330, 3220, 1660, 1620 cm NMR (DMSO-d6, ~) : O.9l (3H, t, J=7.0Hz), 1.29-1.49 (4H, m), 1.91 (3~, s), 3.18 (2H, q, J=7.0Hz), 4.54 (2H, d, J=6.0Hz), 7.02 (lH, s), 7.36 (2H, s), 7.70 (lH, s), 8.77 (lH, t, J=6.0Hz) ExamDle 57 A solution of 2-[(amino)(methylthio)methyleneamino]-4-t6-ethoxycar~onylaminomethylpyridin-2-yl)thiazole hydriodide t2.0 g) and (2-methoxyethyl)amine tS ml) in ethanol t40 ml) was refluxed for 23 hours. The solvent was removed under reduced pressure. The residue was suspended in water (lO0 ml). The mixture was alkalized with a saturated aqueous~potassium carbonate solution and then extracted with a mixture of ethyl acetate t200 ml) and tetrahydrofuran (30 ml). The extract was dried with magnesium sul~ate and the evaporated in vacuo. The residue was chromatographed on a silica gel column eluting with a mixture of chloroform and methanol (20:l). The appropriate fractions were collected and evaporated in vacuo. The residue was dissolved in methanol (lO ml).
4N-Dioxanic hydrogen chloride tS ml) was added. The mixture was stirred at room temperature for l hour. The solvent was removed under reduced pressure and the residue was crystallized from ethanol. Recrystallization from ethanol afford 2-~(amino)~t2-methoxyethyl)amino~-WO92/16526 ~~ PCT/JP92/002~9 methyleneamino]-4-(6-ethoxycar:bonylaminomethylpyridin- 2-yl)thiazole dihydrochloride (0.85 g).
mp : 204-205C
IR (Nujol) : 3460, 3200, 1690, 1600 cm NMR (DMSO-d6, o) : 1.19 53H, t, J=7.1Hz), 3.62 (4H, br s), 3.38 (3H, s), 4.04 (2H, q, J=7.1Hz), 4.36 (2H, d, J=5.8Hz), 7.31 (lH, dd, J=6.2Hz and 2.4Hz), 7.79 (lH, t, J=5.8Hz), 7.93-8.01 (3H, m), 8.52 (2H, br s), 9.40-9.80 (lH, br), 12.60-13.20 (lH, 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 100C in a sealed tube for 48 hours. Evaporation of the solvent gave a residue, which was puri~ied by column chromatography on silica gel eluting with a mixture of chloroform and met~anol ~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 : 153-154C
IR tNujol) : 3240, 1615 cm 1 ~
NMR (DMSO-d6, ~) : 1.93 (3H, s), 2.81 (3H, d,:.
J=3.1Hz), 2~89 (6H, s), 4.36 (2H, d, J=5.9Hz), -~
7.17 (1~, d, J=6.4Hz), 7.48 (lH, s), 7.72-7.86 (2H, m), 7.97 (lH, ~, J=3.1Hz), 8.46 (lH, t, J=5.9Hz) Example 59 Methyl isocyanate (0.4 ml) was added to a mixture of

9 ~ i WO 92/165~6 - 76 - PCr/JP92/00279 -`

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 ~or 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 or~anic 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 1; 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 : 176-177C
IR (Nujol): 3480, 3330, 1660, 1620, 1595 cm 1 NMR (DMSO-d6, ~) : 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 (lH, m), 6.07 (lH, q, J-4.7Hz), 6.51 (lH, t, J=5.7Hz), 7.17 (lH, 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 isqlated precipitate was collected by filtration to give 2-[ (allylamino)(amino)methyleneamino]-4-(6-ureidomethylpyridin-2-yl)~hiazole (1.2 g).

q ~ 1 mp : 172-175~C
IR (Nujol) : 3410, 3300, 3230, 1650 cm NMR (DMSO~d6, ~) : 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 (lH, m), 6.G3 (1~, t, J-5.8Hz), 7.21 (lX, dd, J=2.4Hz, 6.2Hz), 7.67 (lH, 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 : 172-173C
IR (Nujol) : 3340, 1670, 1630, 1607 cm 1 NMR (DMSO-d6, ~) : 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 (lH, q, J=4.6Hz), 6.51 (lH, t, J=5.7Hz)~ 7.17 (lH, d, J=7.2Hz), 7.39 (2H, s), 7.45 (lH, s), 7.70 (lH, -d, J=7.2Hz), 7.79 (lH, t, J=7.2Hz) `~`-Exam~le 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 : 226-228C
IR ~Nujol) : 3410, 3300, 3220, 3100, 1650, 1630 cm 1 NMR (DMSO-d6, ~) : 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 (lH, t, J=5.8Hz), 7.18 (lH, d, J=7.3Hz), 7.37 (2H, s), 7.45 (lH, 2-10~9~1 Wo92/a6~26 PCT/JP92/00279 s), 7.71 (lH, d, J=7.3Hz), 7.80 (lH, t, J=7.3Hz) Exam~le 63 The following compound was obtained according to a similar manner to that of Example 1.

2-[(Amino)~(2-methoxyethy])amino]methyleneamino]-4-(6-cyclopentylcarbonylaminomethylpyridin-2-yl)thiazole mp : 153-154C
IR (Nujol) : 3425, 3325, 3110, 1650 cm 1 NMR (DMSO-d6, ~) : 1.40-1.95 (8H, m), 2.60-2.80 (lH, m), 3.30-3.56 (4H, m), 3.32 (3H, s), 4.38 (2H, d, J=5.8Hz), 7.12 (1~, dd, J=3.0Hz, 5.5Hz), 7.34 (2H, s), 7.41 (lH, s), 7.72-7.89 (2H, m), 8.38 (lH, t, J=5.8Hz) ExamPle 64 The ~ollowing 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 : >300C
IR (Nujol) : 3310, 3100, 1700, 1640 cm 1 Nk~ (DMSO-d6, ~) : O.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 (lH, s), 8.25 (lX, 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 amixture 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-~(~nino)~(2-methoxyethyl)-clmino]methyleneamino]-4-(6-prop:ionylaminomethylpyridin-2-yl)thiazole (1.2 g).
mp : 144-145C
IR (Nujol) : 3420, 3310, 1640 cm 1 NMR (DMSO-d6, ~) : 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 (lH, m), 7.33 (2H, s), 7.41 (lH, s), 7.70-7.85 (2H, m), 8.38 (lH, 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 : 181C
IR (Nujol) : 3340, 3230, 3130, 1630, 1590 cm 1 NMR (DMSO-d6, ~) : 1.93 (3H, s), 2.77 (3H, d, J=4.8Hz), 4.37 (2H, d, J=5.9Hz), 7.14-7.21 (lH, m), 7.41 (lH, s), 7.46 (2H, s), 7.74-7.84 (2H, m), 8.45 (lH, t, J=5.9Hz) Exam~le 67 A mixture of 4-(6-aminomethylpyridin-2-yl)-2-[(amino)(butylamino)methyleneamino]thiazole trihydrochloricle (4.0 g), triethylamine (4.0 ml) and dimethyl N-cyanodithioiminocarbonate [(CH3S)2C=N-CN] (1.6 g) in dimethylformamide (40.0 ml) was stirred for 3 hours 2 1 U2 ~
W092/16526 PCT/JP~2/00279..

at 40C. To the mixture was added a 28% aqueous ammonia (20.0 ml) and the mixture was stirred for 18 hours at 80C. The solvent was removed ~y concentration. The residue was added a mixture of e.thyl 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 (l.9 g).
IR (Nujol) : 3320, 3180, 2170, 1650 cm 1 NMR (DMSO-d6, ~) : 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 (lH, d, J=7.1Hz), 7.20-7.57 (3H, m), 7.50 (lH, 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)methyleneamino]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-hydroxyacety~aminomethyl-pyridin-2-yl)-2-[(amino!(butylamino)methyleneamino]-thiazole (1.3 g). -mp : 165-166~C
IR (Nujol) : 3360, 1640, 1607 cm 1 NMR (DMSO-d6, ~) : 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 (lH, t, J=5.8Hz), 7.18 (lH, d, J=7.2Hz), 7.39 (3H, s), 7.73 (lH, d, J=7.2Hz), 7.81 (lH, t, J=7.2Hz), 8.42 (lH, t, J=5.8Hz) ~,~ O ~
WO92/16~26 PCT/JP92/00279 Exam~le 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)thia7O1e trihydrochloride (4.0 g) and triethylamine (5.7 ml) in dichloromethane (80.0 ml) under ice-cooling and the mixt:ure 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 w~s 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 t2.4 g).
mp : 171-172C
IR (Nujol) : 3440, 3400, 1735, 1663, 1615 cm 1 NMR (DWSO-d6, ~) : 0.92 (3H, t, J=7.1Hz), 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 (lH, d, J=7.3Hz), 7.38 (2H, s), 7.41 (lH, s), 7.72 (lH, d, J=7.3Hz), 7.81 (lH, t, J=7.3Hz), 8.64 (lH, t, J=5.9Hz) ExamPle 70 The following compound was obtained according to a similar manner to that of Example 69.

4-(6-Acetoxyacetylaminomethylpyridin-2-yl)-2-~(amino)[(2-methoxyethyl)amino]methyleneamino~thiazole mp : 139-190C
IR (Nujol) : 3450, 3390, 1735, 1675 cm 1 NMR (DMSO-d~, ~) : 2.12 (3H, s), 3.30-3.45 (2H, m), 3.33 (3H, s), 3.45-3.55 (2H, m), 4.43 (2H, d, ~ ~ o ~
~092/16~26 PCT/JP92/0027~-~

J=5.9Hz), 4.58 (2H, s), 7.11-7.23 ~lH, m~, 7.31 (2H, s), 7.42 (lH, s), 7.74-7.88 (2H, m), 8.64 (lH, t, J=5.9Hz) Exam~le 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 f or 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 : 204-206C
NMR (DMSO-d6, ~) : 4.21 (2H, br s), 4.53 (2H, s), -5.19-5.48 (2H, m), 5.82-6.07 (lH, m), 7~21 (4~, br s), 7.57-7.70 (lH, m), 8.20-8.36 (2H, m), 8.46 (lH, s), 8.80-9.10 (3H, m) 14Hl7N7OS 2HC1 3/5H20 C 40.39, H 4.92, N 23.55, Cl 17.03, H2O 2.88%
Found: C 40.48, ~ 4.93, N 23.49, Cl 17.20, H2O 2.84%

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

2- r ( Amino)~butylamino)methyleneamino]-4-(6-ureido-methylpyridin-2-yl)thiazole dihydrochloride mp : 232-234C
IR (Nujol) : 3320, 3160, 3050, 1685, 1640, 1610 cm 1 NMR (DMSO-d6, ~) : 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), 5.80-5.70 (5H, br s), 7.50-7.65 (lH, m), 8.12-8.30 (2H, m), 8.35 (lH, s), 8.72-9.00 (3H, m) ~ ;
- ,~
.'':;

-- WQ92/16~26 ~ PCT/JP92/00279 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 : 268-270C (dec.) `~
IR (Nujol) : 3430, 3320, 1660, 162a cm 1 ~R (DMSO-d6, ~) : 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 (lH, t, J=6.1Hz), 7.54 (lH, s), 8.02 (lH, s), 8.56 (2H, s), 9.02 (lH, br), 12.41 (lH, br) Example 74 A mixture of 4-~6-acetylaminomethylpyridin-2-yl)-2-~(allylamino)(amino)methyleneamino]thiazole (8.0 g) and conc. 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 : 164-166C
IR (Nujol) : 3320, 1680, 1630 cm 1 NMR (D2O, ~) : 3.96-4.09 (2H, m), 4.51 (2H, s), 5.32 5.50 (2H, m), 5.98-6.12 (lH, m), 7.59 (lH, d, J=7.8~z), 7.96 (lH, d, J=7.8Hz), 8.04 (lH, s), 8.12 (lH, t, J=7.8Hz) w~2Q16s26 PCT/JP92~00279--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 : 176-178C
IR (Nujol) : 3320, 1680, 1615 cm 1 NMR (D20, ~) : 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 (lH, d, J=7.8Hz), 7.65 (lH, d, J=7.8Hz), 7.92 (lH, s), 7.99 (lH, t, J=7.8Hz) ExamPle 76 The following compound was obtained according to a similar manner to that of Example 74.

2-~(Amino~t(2-methoxyethyl)amino]methyleneamino]~4-(6-aminomethylpyridin-2-yl)thiazole trihydrochloride mp : 282C ~dec.) IR (Nujol) : 3260, 3080, 1670, 1640, 1610 cm 1 NMR (D20, ~) : 3.51 (3H, s), 3.51 (2H, t, J=S.OHz), 3.75 (2H, t, J=5.0Hz), 4.42 (2H, s), 7.43 (lH, d, J=7.7Hz), 7.73 (lH, d, J=7.7Hz), 7.91 (lH,- -s), 7.94 (lH, t, J=7.7Hz) ExamPle 77 The following compound was obtained according to a similar manner to that of Example 74.
- 2-~(Amino)(methylamino)methyleneamino]-4-(6-amino-methylpyridin-2-yl)thiazole trihydrochloride ~ :-mp : 236-238lC
IR (Nujol) : 3200, 1685, 1645, 1620, 1590 cm 1 :~
NMR (D20, ~) : 2.86 (3H, s), 4.46 (2H, s), 7.56 (lH, -" ~ ~

WO92/16526 ~ q ~ ~ PCT/JP92/00279 :

d, J=7.8Hz), 7.92 (lH, d, J=7.8Hz), 7.97 (lH, s), 8.09 (lH, t, J=7.8Hz) Exam~le 78 4N-Dioxanic hydrogen chloride (0.82 ml) was added a solution of 4-~6-acetylaminomethylpyridin-2-yl)-2-[(amino)(methylamino)methyleneamino]thiazole (1.O g) in methanol (S.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-yl)-2-[(amino)-(methylamino)methyleneamino]thiazole hydrochloride (0.855 g).
mp : 220-221C
IR (Nujol) : 3360, 3220, 1685, 1665, 1625 cm 1 NMR (DMSO-d6, ~) : 1.96 (3H, s), 3.04 (3H, d, J=4.8Hz), 4.48 (2H, d, J=5.7Hz), 7;36 (lH, d, J=7.5Hz), 7.98 (lH, t, J=7.5Hz), 8.06 (lHi, s), -8.08 (lH, d, J=7.5Hz), 8.66 (2H, s), 8.68 (lH, t, J=5.7Hz), 8.96 (lH, 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 : 236-238C
IR (Nujol) : 3370, 3290, 3?20, 1685, 1660, 1600 cm 1 NMR (DMSO-d6, ~) : 1.97 (3H, s), 3.04 (3H, d, J=4.8Hz),, 4.53-4.68 (2H, m), 7.49 (lH, d, J=6.5Hz), 8.10-8.35 (3H, m), 8.64 (2H, s), 8.72-8.90 ~lH, m), 9.02 (lH, br s) 210~gl ``
WO92/16526 PCT/JP92/00279 ^

ExamPle 80 Methanesulfonic acid (0.21 ml) was added a solution of 4-(6-acetylaminomethylpyridin-2-yl)-2-[(amino)-(methylamino)methyleneamino]thiazole (1.O g) in methanol (5.0 ml) and the mixture was stirxed 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 : 238-240C
IR (Nujol) : 3330, 3122, 1680, 1600, 1615 cm 1 NMR (DMSO-d6, ~) : 1.94 (3H, s), 2.45 (3H, s), 3.00 (3H, d, J=4.8Hz), 4.40 (2H, d, J=5.9Hz), 7.26 (lH, d, J=7.5Hz), 7.87 (lH, t, J=7.5Hz), 7.92 (lH, s), 7.99 (lH, d, J=7.5Hz), 8.51 (lH, t, J=5.9Hz), 8.60 (2H, s), 9.02 (lH, br s), 11.96 (lH, br s) ExamPle 81 : -The following compound was obtained according to a similar manner to that of Example 80.

4-l6-Acetylaminomethylpyridin-2-yl)-2-E(amino)- -:
(methylamino)methylene&mino~thiazole dimesylate mp : 207-208C : .
IR (Nujol3 : 3300, 3180, 1670, 1630 cm 1 NMR (DMSO-d6, ~) : 1.97 (3X, s), 2.49 (6H, s), 3.02 (3H, d, J=4.8Hz), 4.52 (2H, d, J=5.7Hz), 7.47 ~:
(lH, d, J=7.0Hz), 7.87 (2H, br s), 8.07-8.26 (2H, m), 8.19 (lH, s), 8.66 (2H, s), 8.71 (lH, ::
t, J=5.7Hz), 9.10 (lH, br S )J ' ;

: ~ ' . .

Claims (10)

1. A compound of the formula :

wherein R1 is amino which may have suitable substituent(s), hydroxy, halogen, cyano, acyl, heterocyclic thio, heterocyclic group or a group of the formula :

in which R5 is hydrogen, cyano or acyl, R6 is amino or lower alkoxy, and Z is N or CH, R2, 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 R2, R3 and R8 are linked together to form lower alkylene optionally interrupted by hetero atom, and the other is as defined above, R4 is hydrogen or lower alkyl, Y is or , in which R7 is hydrogen or halogen, and A is bond or lower alkylene, provided that (1) when R1 is amino which may have suitable substituent(s) and A
is bond; or R1 is lower alkylthioureido and A
is lower alkylene, then Y is , and further (2) when one of R2 and R3 is hydrogen, acyl or lower alkyl which may have halogen, R4 is hydrogen and R8 is hydrogen, then the other of R2 and R3 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 R1 is amino which may have suitable substituent(s), hydroxy, halogen, cyano, acyl, heterocyclic thio, heterocyclic group or a group of the formula :

in which R5 is hydrogen, cyano or acyl, R6 is amino or lower alkoxy, and z is N or CH, R2 is (C3-C7)-cycloalkyl, lower alkenyl, lower alkynyl or lower alkyl which has suitable substituent(s) excepting halogen, and R3 and R8 are each hydrogen or lower alkyl; or R2 and R8 are each lower alkyl or are linked together to form lower alkylene optionally interrupted by hetero atom, and R3 is hydrogen or lower alkyl, R4 is hydrogen or lower alkyl, Y is , in which R is hydrogen or halogen, and A is bond or lower alkylene, and pharmaceutically acceptable salt thereof.

3. A compound of claim 2, wherein R1 is amino, acylamino, 2-cyanoquanidino or acyl, R2 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, furyl(lower)alkyl, pyridyl(lower)alkyl or indolyl(lower)alkyl, and R3 and R8 are each hydrogen or lower alkyl; or R2 and R8 are each lower alkyl or are linked together to form lower alkylene optionally interrupted by oxygen, and R is hydrogen or lower alkyl.

4. A compound of claim 3, wherein R1 is amino, ureido, lower alkanoylamino, lower alkoxycarbonylamino, hydroxy(lower)alkanoyl-amino, protected hydroxy(lower)alkanoylamino, lower alkylureido, (C3-C7)-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)alXylureido, (C3-C7)-cycloalkylcarbamoyl or 2-cyanoguanidino.

5. A compound of claim 4, wherein R1 is amino, ureido, lower alkanoylamino, lower alkoxycarbonylamino, lower alkanoyloxy(lower)-alkanoylamino, lower alkylureido, (C3-C7)-cycloalkanecarbonylamino, R2 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(lower)alkylamino-(lower)alkylfuryl(lower)alkylthio(lower)alkyl, furyl(lower)alkyl, pyridyl(lower)alkyl or indolyl(lower)alXyl, R3, R4 and R8 are each hydrogen, Y is , and A is lower alkylene.

6. A process for preparing a compound of the formula :

wherein R1 is amino which may have suitable substituentts), hydroxy, halogen, cyano, acyl, heterocyclic thio, heterocyclic group or a group of the formula :

in which R5 is hydrogen, cyano or acyl, R6 is amino or lower alkoxy, and Z is N or CH, R2, 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 R2, R3 and R8 are linked together to form lower alkylene optionally interrupted by hetero atom, and the other is as defined above, R4 is hydrogen or lower alkyl, Y is or , in which R7 is hydrogen or halogen, and A is bond or lower alkylene, provided that (1) when R1 is amino which may have suitable substituent(s) and A
is bond; or R1 is lower alkylthioureido and A-is lower alkylene, then Y is , and further (2) when one of R2 and R3 is hydrogen, acyl or lower alkyl which may have halogen, R4 is hydrogen and R8 is hydrogen, then the other of R2 and R3 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 :

IMG>

wherein R1, R4, A and Y are each as defined above, and X1 is acid residue, or a salt thereof, with a compound of the formula :

, wherein R2, R3 and R8 are each as defined above, or a salt thereof, to give a compound of the formula :

wherein R1, R2, R3, R8, A and Y are each as defined above, or a salt thereof, or (2) subjecting a compound of the formula :

wherein R2, R3, R4, R8, A and Y are each as defined above, and R? is protected amino, or a salt thereof, to elimination reaction of the amino protective group, to give a compound of the formula :

wherein R2, R3, R4, R8, A and Y are each as defined above, or a salt thereof, or (3) subjecting a compound of the formula :

wherein R2, R3, R4, R8, A and Y are each as defined above, or a salt thereof, to acylation, to give a compound of the formula :

wherein R2, R13, R4, R8, A and Y are each as defined above, and R? is acylamino, or a salt thereof, or (4) reacting a compound of the formula :

wherein R2, R3, R4, R8, A and Y are each as defined above, or a salt thereof, with a compound of the formula :
(R9)2C=Z-R10 wherein R9 is lower alkylthio or protected hydroxy, R10 is hydrogen, cyano, nitro or acyl, and Z is N or CH, to give a compound of the formula :

wherein R2, R3, R4, R8, R9, R10, A, Y and 2 are each as defined above, or a salt thereof, or (5) reacting a compound of the formula :

wherein R1, R3, R4, R11, A and Y are each as defined above, or a salt thereof, with a compound of the formula :

wherein R2 and R8 are each as defined above, to give a compound of the formula :

wherein R1, R2, R3, R4, R8, A and Y are each as defined above, or a salt thereof, or (6) reacting a compound of the formula :

wherein R2, R3, R4, R8, A and Y are each as defined above, and R12 is lower alkyl, or a salt thereof, with a compound of the formula :

wherein R13 is amino which may have suitable substituent(s), to give a compound of the formula :

wherein R2, R3, R4, R13, A and Y are each as defined above, or a salt thereof, or (7) subjecting a compound of the formula :

wherein R2, R3, R4, R8, 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 :

wherein R2, R3, R4, R8, A and Y are each as defined above, and R? is acylamino having hydroxy, or a salt thereof, or (8) subjecting a compound of the formula :

wherein R2, R3, R4, R8, A and Y are each as defined above, and R? 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 R2, R3, R4, R8, A and Y are each as defined above, and R? is acylamino having amino, or a salt thereof.

7. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim l 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.