Thiazole compounds of formula ##STR1## are provided which have antiulcer activity and H.sub.2 -receptor antagonism, wherein R.sup.2 is lower alkyl or lower alkoxy(lower)alkyl, R.sup.3 is hydrogen, A is methylene and R.sup.1 is lower alkyl.

This invention relates to new compounds and pharmaceutically acceptable 
salts thereof. 
More particularly, it relates to new thiazole derivatives and 
pharmaceutically acceptable salts thereof which have antiulcer activity 
and H.sub.2 -receptor antagonism, to processes for the preparation 
thereof, to a pharmaceutical composition comprising the same and to a 
method for the treatment of ulcer in human being or animals. 
Accordingly, one object of this invention is to provide new thiazole 
derivatives and pharmaceutically acceptable salts thereof which possess 
antiulcer activity and H.sub.2 -receptor antagonism. 
Another object of this invention 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 invention is to provide a method for the 
prophylactic or therapeutic 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): 
##STR2## 
wherein R.sup.2 is hydrogen, or lower alkyl which may have suitable 
substituent(s), 
R.sup.3 is hydrogen, lower alkyl, lower alkoxy, or halogen, 
A is lower alkylene and 
Q is a group of the formula: 
EQU --CO--R.sup.1 
(in which R.sup.1 is an organic group), or carbamimidoyl which may have 
suitable substituent(s), 
with proviso that 
when Q is carbamimidoyl which may have suitable substituent(s), 
then R is lower alkoxy. 
The object compound (I) or a salt thereof can be prepared by processes as 
illustrated in the following reaction schemes. 
##STR3## 
wherein R.sup.1, R.sup.2, R.sup.3, A and Q are each as defined above 
R.sup.4 and R.sup.6 are each lower alkyl, 
R.sup.7 and R.sup.8 are each substituent, 
R.sub.a.sup.1 is protected hydroxy(lower)alkyl, 
R.sub.b.sup.1 is hydroxy(lower)alkyl, R.sub.c.sup.1 is amino(lower)alkyl, 
R.sub.d.sup.1 is acylamino(lower)alkyl, X.sup.1 is acid residue, and 
M.sup.1 is an alkali metal. 
The starting compounds (II), (IV) and (VI) or salts thereof can be prepared 
by the following Processes. 
##STR4## 
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, X.sup.1, A and Q are each as 
defined above, 
R.sup.5 is acyl, 
R.sup.9 is lower alkyl, 
R.sup.10 is hydrogen or thiocarbamoyl, 
R.sup.11 is cyano or lower alkanoyl, 
Y is an alkaline earth metal, 
A.sup.1 is lower alkylene, 
M.sup.2 is an alkali metal, 
X.sup.2 and X.sup.5 are each halogen and 
X.sup.3, X.sup.4 and X.sup.6 are each acid residue. 
Suitable pharmaceutically acceptable salts of the object compound (I) are 
conventional non-toxic salts and may include e.g. a salt with a base or an 
acid addition salt such as a salt with an inorganic base, for example, an 
alkali metal salt (e.g. sodium salt, potassium salt, etc.), an alkaline 
earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium 
salt; a salt with an organic base, for example, an organic amine salt 
(e.g. triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, 
triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine 
salt, etc.); an inorganic acid addition salt (e.g. hydrochloride, 
hydriodide, hydrobromide, sulfate, phosphate, etc.); an organic carboxylic 
or sulfonic acid addition salt (e.g. formate, acetate, trifluoroacetate, 
maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, 
etc.); a salt with a basic or acidic amino acid (e.g. arginine, aspartic 
acid, glutamic acid, etc.). 
In the above and subsequent descriptions of the present specification, 
suitable example and illustration of the various definitions which the 
present invention intends to include within the scope thereof are 
explained in detail as follows. 
The term "lower" is used to intend a group having 1 to 6, preferably 1 to 
4, carbon atom(s), unless otherwise provided. 
The term "higher" is used to intend a group having 7 to 20 carbon atoms 
unless otherwise provided. 
Suitable "organic group" may include lower alkyl (e.g., methyl, ethyl, 
propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, 
tert-pentyl, hexyl, etc.), hydroxy(lower)alkyl, protected 
hydroxy(lower)alkyl, lower alkoxy (e.g. methoxy, ethoxy, propoxy, 
isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy, 
etc.), amino, amino(lower)alkyl, protected amino(lower)alkyl, 
lower alkenyl (e.g., vinyl, 1-propenyl, allyl, 1-methylallyl, 1 or 2 or 
3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl, 
etc.), 
lower alkynyl (e.g., ethynyl, 1-propynyl, propargyl, 1-methylpropargyl, 1 
or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or 
5-hexynyl, etc.), 
aryl (e.g., phenyl, naphthyl, etc.), 
ar(lower)alkyl such as phenyl(lower)alkyl (e.g., benzyl, phenethyl, 
phenylpropyl, etc.), and the like. 
Suitable "lower alkyl" and "lower alkyl moiety" in the terms 
"hydroxy(lower)alkyl", "protected hydroxy(lower)alkyl", 
"amino(lower)alkyl", "acylamino(lower)alkyl" and "protected 
amino(lower)alkyl" may include straight or branched one such as methyl, 
ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, and the like, in 
which more preferable example may be C.sub.1 -C.sub.4 alkyl. 
Suitable "substituent" in the term "lower alkyl which may have suitable 
substituent(s)" may include lower alkyl (e.g., methyl, ethyl, propyl, 
isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, t-pentyl, hexyl, 
etc.), lower alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, 
isobutoxy, t-butoxy, pentyloxy, neopentyloxy, t-pentyloxy, hexyloxy, 
etc.), lower alkenyl (e.g., vinyl, 1-propenyl, allyl, 1-methylallyl, 1 or 
2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl, 
etc.), lower alkynyl (e.g., ethynyl, 1-propynyl, propargyl, 
1-methylpropargyl, 1-methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 
4-pentynyl, 1 or 2 or 3 or 4 or 5-hexynyl, etc.), mono(or di or 
tri)halo(lower)alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, 
chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, 
tribromomethyl, 1 or 2-fluoroethyl, 1 or 2-bromoethyl, 1 or 2-chloroethyl, 
1,1-difluoroethyl, 2,2-difluoroethyl, etc.), halogen (e.g., chlorine, 
bromine, fluorine, iodine), carboxy, protected carboxy, hydroxy, protected 
hydroxy, aryl (e.g., phenyl, naphthyl, etc.) which may have suitable 
substituent(s) (e.g., lower alkyl, lower alkenyl, lower alkynyl, lower 
alkoxy, etc.), ar(lower)alkyl such as phenyl(lower)alkyl (e.g., benzyl, 
phenethyl, phenylpropyl, etc.), carboxy(lower)alkyl, protected 
carboxy(lower)alkyl, nitro, amino, protected amino, di(lower)alkylamino 
(e.g., dimethylamino, diethylamino, diisopropylamino, ethylmethylamino, 
isopropylmethylamino, ethylmethylamino, ethylpropylamino, etc.), 
hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, acyl, cyano, mercapto, 
lower alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, 
butylthio, etc.), imino, heterocyclic group, and the like. 
Suitable "substituent" for R.sup.7 and R.sup.8 and "substituent" in the 
term "carbamimidoyl which may have suitable substituent(s)" may include 
lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 
t-butyl, pentyl, neopentyl, t-pentyl, hexyl, etc.), lower alkoxy (e.g., 
methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, t-butoxy, pentyloxy, 
neopentyloxy, t-pentyloxy, hexyloxy, etc.), lower alkenyl (e.g., vinyl, 
1-propenyl, allyl, 1-methylallyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 
4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl, etc.), lower alkynyl (e.g., 
ethynyl, 1-propynyl, propargyl, 1-methylpropargyl, 1-methylpropargyl, 1 or 
2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or 5-hexynyl, 
etc.), mono(or di or tri)halo(lower)alkyl (e.g., fluoromethyl, 
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, 
trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, 1 or 
2-fluoroethyl, 1 or 2-bromoethyl, 1 or 2-chloroethyl, 1,1-difluoroethyl, 
2,2-difluoroethyl, etc.), halogen (e.g., chlorine, bromine, fluorine, 
iodine), carboxy, protected carboxy, hydroxy, protected hydroxy, aryl 
(e.g., phenyl, naphthyl, etc.), ar(lower)alkyl such as phenyl(lower)alkyl 
(e.g., benzyl, phenethyl, phenylpropyl, etc.), carboxy(lower)alkyl, 
protected carboxy(lower)alkyl, nitro, amino, protected amino, 
di(lower)alkylamino (e.g., dimethylamino, diethylamino, diisopropylamino, 
ethylmethylamino, isopropylmethylamino, ethylmethylamino, 
ethylpropylamino, etc.), hydroxy(lower)alkyl, protected 
hydroxy(lower)alkyl, acyl, cyano, mercapto, lower alkylthio (e.g., 
methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.), imino, 
and the like. 
Suitable "protected amino moiety" in the term "protected amino(lower)alkyl" 
may include acylamino and the like. 
Suitable "protected hydroxy" and "protected hydroxy moiety" in the term 
"protected hydroxy(lower)alkyl" may include acyloxy and the like. 
Suitable "acyl" and "acyl moiety" in the terms "acylamino", "acyloxy" and 
"acylamino(lower)alkyl" may include carbamoyl, aliphatic acyl group and 
acyl group containing an aromatic ring, which is referred to as aromatic 
acyl, or heterocyclic ring, which is referred to as heterocyclic acyl. 
Suitable example of said acyl may be illustrated as follows: 
carbamoyl; 
Aliphatic acyl such as lower or higher alkanoyl (e.g. formyl, acetyl, 
propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, 
hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, 
tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, 
octadecanoyl, nonadecanoyl, icosanoyl, etc.); 
lower or higher alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, 
t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.); 
lower or higher cycloalkylcarbonyl (e.g. cyclopropylcarbonyl, 
cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohenylcarbonyl, etc.); 
lower or higher alkylsulfonyl (e.g. methylsulfonyl, ethylsulfonyl, etc.); 
lower or higher alkoxysulfonyl (e.g. methoxysulfonyl, ethoxysulfonyl, 
etc.); or the like; 
Aromatic acyl such as 
aroyl (e.g. benzoyl, toluoyl, naphthoyl, etc.); 
ar(lower)alkanoyl [e.g. phenyl(lower)alkanoyl (e.g. phenylacetyl, 
phenylpropanoyl, phenylbutanoyl, phenylisobutylyl, phenylpentanoyl, 
phenylhexanoyl, etc.), naphthyl(lower)alkanoyl (e.g. naphthylacetyl, 
naphthylpropanoyl, naphthylbutanoyl, etc.), etc.]; 
ar(lower)alkenoyl [e.g. phenyl(lower)alkenoyl (e.g. phenylpropenoyl, 
phenylbutenoyl, phenylmethacryloyl, phenytpentenoyl, phenylhexenoyl, 
etc.), naphthyl(lower)alkenoyl (e.g. naphthylpropenoyl, naphthylbutenoyl, 
naphthylpentenoyl, etc.), etc]; 
ar(lower)alkoxycarbonyl [e.g. phenyl(lower)alkoxycarbonyl (e.g. 
benzyloxycarbonyl, etc.), etc.]; 
aryloxycarbonyl (e.g. phenoxycarbonyl, naphthyloxycarbonyl, etc.); 
aryloxy(lower)alkanoyl (e.g. phenoxyacetyl, phenoxypropionyl, etc.); 
arylcarbamoyl (e.g. phenylcarbamoyl, etc.); 
arylthiocarbamoyl (e.g. phenylthiocarbamoyl, etc.); 
arylglyoxyloyl (e.g. phenylglyoxyloyl, naphthylglyoxyloyl, etc.); 
arylsulfonyl (e.g. phenylsulfonyl, naphthylsulfonyl, etc.); or the like; 
Heterocyclic acyl such as 
heterocycliccarbonyl; 
heterocyclic(lower)alkanoyl (e.g. thienylacetyl, thienylpropanoyl, 
thienylbutanoyl, thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, 
thiadiazolylacetyl, tetrazolylacetyl, etc.); 
heterocyclic(lower)alkenoyl (e.g. heterocyclicpropenoyl, 
heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl, etc.); 
heterocyclicglyoxyloyl (e.g. thiazolylglyoxyloyl, thienylglyoxyloyl, etc.); 
or the like. 
Suitable "heterocyclic group" and "heterocyclic moiety" in the terms 
"heterocycliccarbonyl", "heterocyclic(lower)alkanoyl", 
heterocyclic(lower)alkenoyl and "heterocyclicglyoxyloyl" means saturated 
or unsaturated, monocyclic or polycyclic heterocyclic group containing at 
least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the 
like. And, especially preferable heterocyclic group may be heterocyclic 
group such as 
unsaturated 3 to 8-membered more preferably 5 or 6-membered 
heteromonocyclic group containing 1 to 4-nitrogen atom(s), for example, 
pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, 
dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 
4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), 
tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; 
saturated 3 to 8-membered (more preferable 5 or 6-membered)heteromonocyclic 
group containing 1 to 4 nitrogen atom(s), for example pyrrolidinyl, 
imidazolidinyl, piperidinino, piperazinyl, etc.; 
unsaturated condensed heterocyclic group containing 1 to 4 nitrogen 
atom(s), for example, indolyl, isoindolyl, indolinyl, indolizinyl, 
benzimidazolyl, quinolyl, dihydroquinolyl, isoquinolyl, indazolyl, 
benzotriazolyl, etc.; 
unsaturated 3 to 8-membered (more preferably 5 or 
6-membered)heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 
to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl 
(e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc.; 
saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic 
group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for 
example, morpholinyl, sydnonyl, etc.; 
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) 
and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, 
etc.; 
unsaturated 3 to 8-membered (more preferably 5 or 
6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 
to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl 
(e.g. 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 
1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.; 
saturated 3 to 8-membered (more preferably 5 or 6-membered) 
heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 
nitrogen atom(s), for example, thiazolidinyl, etc.; 
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) 
heteromonocyclic group containing 1 to 2 sulfur atom(s), for example, 
thienyl, dihydrodithiinyl, dihydrodithionyl, etc.; 
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) 
and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, 
benzothiadiazolyl, etc.; 
unsaturated 3 to 8-membered (more preferably 5 to 6-membered) 
heteromonocyclic group containing an oxygen atom, for example, furyl, 
etc.; 
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) 
heteromonocyclic group containing an oxygen atom and 1 to 2 sulfur 
atom(s), for example, dihydroxathiinyl, etc.; 
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s), 
for example benzothienyl (e.g. benzo[b]thienyl, etc.), benzodithiinyl, 
etc.; 
unsaturated condensed heterocyclic group containing an oxygen atom and 1 to 
2 sulfur atom(s), for example, benzoxathiinyl, etc. and the like. 
The acyl moiety as stated above may have one to five, same or different, 
suitable substituent(s) such as halogen (e.g. fluorine, chlorine, bromine 
or iodine), lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, 
isobutyl, t-butyl, pentyl, hexyl, etc.); 
lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, 
t-butoxy, pentyloxy, hexyloxy, etc.), hydroxy, carboxy, protected hydroxy, 
protected carboxy, mono(or di or tri)halo(lower)alkyl, 
N,N-di(lower)alkylamino (e.g. N,N-dimethylamino, N,N-diethylamino, 
N,N-dipropylamino, N,N -dibutylamino, N,N-dipentylamino, N,N-dihexylamino, 
N-methyl-N-ethylamino, N-methyl-N-butylamino, etc. ), or the like. 
Suitable "alkali metal" may include lithium, sodium, potassium and the 
like. 
Suitable "alkaline earth metal" may include magnesium, calcium and the 
like. 
Suitable "acid residue" may include halogen (e.g., fluorine, chlorine, 
bromine, iodine), acyloxy [e.g., sulfonyloxy (e.g., phenylsulfonyloxy, 
tosyloxy, mesyloxy, etc.), lower alkanoyloxy (e.g., acetyloxy, 
propionyloxy, etc.), etc.] and the like. 
Suitable "halogen" may include fluorine, bromine, chlorine and iodine. 
Suitable "lower alkoxy" may include methoxy, ethoxy, propoxy, isopropoxy, 
butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the 
like. 
Suitable "lower alkanoyl" may include formyl, acetyl, propanoyl, butanoyl, 
2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl and the 
like. 
Suitable "lower alkylene" may include straight or branched one such as 
methylene, ethylene, trimethylene, tetramethylene, pentamethylene, 
hexamethylene, methylmethylene, ethylethylene, propylene, and the like, in 
which more preferable example may be C.sub.1 -C.sub.4 alkylene. 
The processes for preparing the object and starting compounds are explained 
in detail in the following. 
Process (1) 
The 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. 
The reaction is usually carried out in a conventional solvent such as 
alcohol (e.g., methanol, ethanol, etc.), tetrahydrofuran, 
N,N-dimethylformamide, dichloromethane, acetone, acetic acid, or any other 
solvent which does not adversely influence the reaction. 
The reaction temperature is not critical and the reaction is usually 
carried out under warming to heating. 
Process (2) 
The compound (Ia) or a salt thereof can be prepared by reacting the 
compound (IV) or a salt thereof with the compound (V). 
The reaction is usually carried out in a conventional solvent such as 
water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, t-butyl 
alcohol, etc.), tetrahydrofuran, dioxane, dichloromethane, chloroform, 
dimethyl acetamide, decalin, tetralin, N,N-dimethylformamide or any other 
organic solvent which does not adversely influence the reaction. Among 
these solvents, hydropholic solvents may be used in a mixture with water. 
The reaction temperature is not critical and the reaction is usually 
carried out under cooling to warming. 
Process (3) 
The compound (I) or a salt thereof can be prepared by reacting the compound 
(VI) or a salt thereof with the compound (VII) or a salt thereof. 
This reaction is usually carried out in a solvent such as alcohol (e.g. 
methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, 
methylene chloride, ethylene chloride, chloroform, diethyl ether or any 
other solvent which does not adversely affect the reaction. 
The reaction temperature is not critical and the reaction is usually 
carried out under warming to heating. 
Process (4) 
The compound (Ig) or a salt thereof can be prepared by reacting the 
compound (IV) or its reactive derivative at the amino group, or a salt 
thereof with the compound (VIII) or its reactive derivative at the carboxy 
group, or a salt thereof. 
Suitable reactive derivative at the amino group of the compound (IV) may 
include Schiff's base type imino or its tautomeric enamine type isomer 
formed by the reaction of the compound (IV) with a carbonyl compound such 
as aidehyde, ketone or the like; a silyl derivative formed by the reaction 
of the compound (IV) with a silyl compound such as 
bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide [e.g. 
N-(trimethylsilyl)acetamide], bis(trimethylsilyl)urea or the like; a 
derivative formed by reaction of the compound (IV) with phosphorus 
trichloride or phosgene, and the like. 
Suitable reactive derivative at the carboxy group of the compound (VIII) 
may include an acid halide, an acid anhydride, an activated amide, an 
activated ester, and the like. Suitable examples of the reactive 
derivatives may be an acid chloride; an acid azide; a mixed acid anhydride 
with an acid such as substituted phosphoric acid [e.g. dialkylphosphoric 
acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric 
acid, halogenated phosphoric acid, etc.], dialkylphosphorous acid, 
sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [e.g. 
methanesulfonic acid, etc.], aliphatic carboxylic acid [e.g. acetic acid, 
propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic 
acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.] 
or aromatic carboxylic acid [e.g. benzoic acid, etc.]; a symmetrical acid 
anhydride; an activated amide with imidazole, 1-hydroxy-1H-benzotriazole, 
4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an 
activated ester [e.g. cyanomethyl ester, methoxymethyl ester, 
dimethyliminomethyl [(CH.sub.3).sub.2 .dbd.CH--] ester, vinyl ester, 
propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, 
trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, 
phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl 
thioester, benzothiazolyl thioester, carboxymethyl thioester, pyranyl 
ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.], or an 
ester with a N-hydroxy compound [e.g. N,N-dimethylhydroxylamine, 
1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 
1-hydroxy-1H-benzotriazole, etc.], and the like. These reactive 
derivatives can optionally be selected from them according to the kind of 
the compound (VIII) to be used. 
The reaction is usually carried out in a conventional solvent such as 
water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, 
acetonitrile, chloroform, methylene chloride, ethylene chloride, 
tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any 
other organic solvent which does not adversely influence the reaction. 
These conventional solvent may also be used in a mixture with water. 
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 N,N'-dicyclohexylcarbodiimide; 
N-cyclohexyl-N'-morpholinoethylcarbodiimide; 
N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide; 
N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide; 
N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide; 
N,N'-carbonyl-bis(2-methylimidazole); 
pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine, 
ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl 
polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl 
chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride; 
lower alkyl haloformate [e.g. ethyl chloroformate, isopropyl 
chloroformate, etc.]; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium 
salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt; 
1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-called 
Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with 
thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus 
oxychloride, etc.; or the like. 
The reaction may also be carried out in the presence of an inorganic or 
organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, 
pyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, or the 
like. 
The reaction temperature is not critical, and the reaction is usually 
carried out under cooling to warming. 
Process (5) 
The compound (Ic) or a salt thereof can be prepared by subjecting the 
compound (Ib) or a salt thereof to elimination reaction of the hydroxy 
protective group. Suitable method of this reaction may include 
conventional one such as hydrolysis, reduction and the like. 
(i) For Hydrolysis: 
The hydrolysis is preferably carried out in the presence of a base or an 
acid including Lewis acid. 
Suitable base may include an inorganic base and an organic base such as an 
alkali metal [e.g. sodium, potassium, etc.], the hydroxide or carbonate or 
bicarbonate thereof, alkali metal lower alkoxide (e.g. sodium methoxide, 
sodium ethoxide, etc.], hydrides [e.g. lithium aluminum hydride, etc.], 
trialkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, 
1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.21octane, 
1,8-diazabicyclo[5.4.0]undec-7-ene, or the like. 
Suitable acid may include an organic acid [e.g. formic acid, acetic acid, 
propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an 
inorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, 
hydrogen chloride, hydrogen bromide, etc.]. The elimination using Lewis 
acid such as trihaloacetic acid [e.g. trichloroacetic acid, 
trifluoroacetic acid, etc.] or the like is preferably carried out in the 
presence of cation trapping agents [e.g. anisole, phenol, etc.]. 
The reaction is usually carried out in a solvent such as water, an alcohol 
[e.g. methanol, ethanol, etc.], methylene chloride, tetrahydrofuran, a 
mixture thereof or any other solvent which does not adversely influence 
the reaction. A liquid base or acid can be also used as the solvent. The 
reaction temperature is not critical and the reaction is usually carried 
out under cooling to warming. 
(ii) For reduction: 
Reduction is carried out in a conventional manner, including chemical 
reduction and catalytic reduction. 
Suitable reducing agents to be used in chemical reduction are a combination 
of a metal (e.g. tin, zinc, iron, etc.) or metallic compound (e.g. 
chromium chloride, chromium acetate, etc.) and an organic or inorganic 
acid (e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, 
p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.). 
Suitable catalysts to be used in catalytic reduction are conventional ones 
such as platinum catalysts (e.g. platinum plate, spongy platinum, platinum 
black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium 
catalysts (e.g. spongy palladium, palladium black, palladium oxide, 
palladium on carbon, colloidal palladium, palladium on barium sulfate, 
palladium on barium carbonate, etc.), nickel catalysts (e.g. reduced 
nickel, nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g. reduced 
cobalt, Raney cobalt, etc.), iron catalysts (e.g. reduced iron, Raney 
iron, etc.), copper catalysts (e.g. reduced copper, Raney copper, Ullman 
copper, etc.) and the like. The reduction is usually carried out in a 
conventional solvent which does not adversely influence the reaction such 
as water, methanol, ethanol, propanol, N,N-dimethylformamide, 
tetrahydrofuran, or a mixture thereof. Additionally, in case that the 
above-mentioned acids to be used in chemical reduction are in liquid, they 
can also be used as a solvent. 
The reaction temperature of this reduction is not critical and the reaction 
is usually carried out under cooling to warming. 
Process (6) 
The compound (Ie) or a salt thereof can be prepared by subjecting the 
compound (Id) or its reactive derivative at the amino group or a salt 
thereof to acylation reaction. 
Suitable acylating agent to be used in the present acylation reaction may 
include the compound of the formula: 
EQU R.sup.12 --OH (XXXV) 
(wherein R.sup.12 is acyl) 
or its reactive derivative or a salt thereof. 
Suitable reactive derivative at the amino group of the compound (Id) may 
include Schiff's base type imino or its tautomeric enamine type isomer 
formed by the reaction of the compound (Id) with a carbonyl compound such 
as aidehyde, ketone or the like; a silyl derivative formed by the reaction 
of the compound (Id) with a silyl compound such as 
N,O-bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide or the like; a 
derivative formed by the reaction of the compound (Id) with phosphorus 
trichloride or phosgene, and the like. 
Suitable reactive derivative of the compound (XXXV) may include an acid 
halide, an acid anhydride, an activated amide, an activated ester, 
isocyanate, and the like. The suitable example may be an acid chloride, an 
acid azide; a mixed acid anhydride with an acid such as substituted 
phosphoric acid (e.g. dialkylphosphoric acid, phenylphosphoric acid, 
diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric 
acid, etc.), dialkylphosporous acid, sulfurous acid, thiosulfuric acid, 
alkanesulfonic acid (e.g. methanesulfonic acid, ethanesulfonic acid, 
etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g. 
pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or 
trichloroacetic acid, etc.) or aromatic carboxylic acid (e.g. benzoic 
acid, etc.); a symmetrical acid anhydride; an activated amide with 
imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or 
tetrazole; or an activated ester (e.g. cyanomethy1 ester, methoxymethyl 
ester, dimethyliminomethyl [(CH.sub.3).sub.2 .dbd.CH--] ester, vinyl 
ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, 
trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, 
phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl 
thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, 
piperidyl ester, 8-quinolyl thioester, etc.), or an ester with a N-hydroxy 
compound (e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, 
N-hydroxysuccinimide, N-hydroxybenzotriazole, N-hydroxyphthalimide, 
1-hydroxy-6-chloro-lH-benzotriazole, etc.); substituted or unsubstituted 
aryl isocyanate; substituted or unsubstituted aryl isothiocyanate, and the 
like. These reactive derivatives can optionally be selected from them 
according to the kind of the compound (XXXV) to be used. 
The reaction is usually carried out in a conventional solvent such as 
water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, 
ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, 
pyridine or any other organic solvents which do not adversely influence 
the reaction. These conventional solvents may also be used in a mixture 
with water. 
When the compound (XXXV) is used in free acid form or its salt form in the 
reaction, the reaction is preferably carried out in the presence of a 
conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; 
N-cyclohexyl-N'-morpholinoethylcarbodiimide; 
N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide; 
N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide; 
N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide; 
N,N-carbonylbis-(2-methylimidazole); pentamethyleneketene-ethoxyacetylene; 
1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; 
isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); 
phosphorus trichloride; thionyl chloride; oxalyl chloride; 
triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 
2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intra-molecular salt; 
1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-called 
Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with 
thionyl chloride, phosgene, phosphorus oxychloride, etc.; or the like. 
The reaction may also be carried out in the presence of an inorganic or 
organic base such as an alkali metal bicarbonate, tri(lower)alkylamine 
(e.g. triethylamine, diisopropylethylamine, etc.), pyridine, 
N-(lower)alkylmorphorine, N,N-di(lower)alkylbenzylamine, or the like. The 
reaction temperature is not critical, and the reaction is usually carried 
out under cooling to heating. 
Process (7) 
The compound (Id) or a salt thereof can be prepared by subjecting the 
compound (Ie) or a salt thereof to deacylation reaction. 
This reaction can be carried out in a similar manner to that of the 
aforementioned Process (5), and therefore the reagents to be used and the 
reaction conditions (e.g., solvent, reaction temperature, etc.) can be 
referred to those of the Process (5). 
Process (8)--1 
The compound (XXIII) or a salt thereof can be prepared by reacting the 
compound (IV) or a salt thereof with the compound (XXII) or a salt 
thereof. 
This reaction is usually carried out in a solvent such as water, alcohol 
(e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, 
tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, 
chloroform, diethyl ether or any other solvent which does not adversely 
affect the reaction. 
The reaction temperature is not critical and the reaction is usually 
carried out under cooling to heating. 
Process (8)--2 
The compound (If) or a salt thereof can be prepared by reacting the 
compound (XXIII) or a salt thereof with the compound (XXIV) or a salt 
thereof. 
This reaction is usually carried out in a solvent such as water, alcohol 
(e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, 
tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, 
chloroform, diethyl ether or any other solvent which does not adversely 
affect the reaction. 
The reaction temperature is not critical and the reaction is usually 
carried out under cooling to heating. 
Process (A)--1 
The compound (XI) can be prepared by reacting the compound (IX) with the 
compound (X). 
This reaction can be carried out in accordance with the method disclosed in 
the Preparation 1 described later or a similar manner thereto. 
Process (A)--.circle. 2.times. 
The compound (XII) or a salt thereof can be prepared by subjecting the 
compound (XI) to reduction reaction. 
This reduction can be carried out in accordance with the method disclosed 
in the Preparation 2 described later or a similar manner thereto. 
Process (B) 
The compound (XIV) or a salt thereof can be prepared by subjecting the 
compound (XIII) or a salt thereof to elimination reaction of the carbonyl 
protective group. 
This reaction can be carried out in accordance with the method disclosed in 
the Preparation 3 described later or a similar manner thereto. 
Process (C) 
The compound (XVa) or a salt thereof can be prepared by reacting the 
compound (XIV) or its reactive derivative at the amino group, or a salt 
thereof with the compound (VIII) or its reactive derivative at the carboxy 
group, or a salt thereof. 
This reaction can be carried out in a similar manner to that of the 
aforementioned Process (4), and therefore the reagents to be used and the 
reaction conditions (e.g., solvent, reaction temperature, etc.) can be 
referred to those of the Process (4). 
Process (D) 
The compound (IIa) or a salt thereof can be prepared by subjecting the 
compound (XV) or a salt thereof to halogenation reaction. 
This halogenation is usually carried out by using a conventional 
halogenating agent such as halogen (e.g. chlorine, bromine, etc.), 
phosphorus trihalide (e.g. phosphorus tribromide, phosphorus trichloride, 
etc.), phosphorus pentahalide (e.g. phosphorus pentachloride, phosphorus 
pentabromide, etc.), phosphorus oxychloride, thionyl halide (e.g. thionyl 
chloride, thionyl bromide, etc.) and the like. 
This reaction is usually carried out in a solvent such as alcohol (e.g., 
methanol, ethanol, etc.), benzene, dioxane, N,N-dimethylformamide, 
tetrahydrofuran, methylene chloride, ethylene chloride, chloroform, 
diethyl ether or any other solvent which does not adversely affect the 
reaction. 
The reaction temperature is not critical and the reaction is usually 
carried out under cooling to warming. 
Process (E) 
The compound (XVII) or a salt thereof can be prepared by reacting the 
compound (IIa) or a salt thereof with the compound (XVI) or a salt 
thereof. 
The reaction is usually carried out in a conventional solvent such as 
alcohol (e.g., methanol, ethanol, etc.), tetrahydrofuran, 
N,N-dimethylformamide, dichloromethane, acetic acid, or any other solvent 
which does not adversely influence the reaction. 
The reaction temperature is not critical and the reaction is usually 
carried out under warming to heating. 
Process (F)--1 
The compound (XIX) or a salt thereof can be prepared by reacting the 
compound (XVIIa) or a salt thereof with the compound (XVIII) or a salt 
thereof. 
The reaction is usually carried out in a conventional solvent such as 
water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, t-butyl 
alcohol, etc.), acetone, tetrahydrofuran, dioxane, dichloromethane, 
chloroform, dimethyl acetamide, N,N-dimethylformamide or any other organic 
solvent which does not adversely influence the reaction. Among these 
solvents, hydrophilic solvents may be used in a mixture with water. 
The reaction temperature is not critical and the reaction is usually 
carried out under cooling to warming. 
Process (F)--2 
The compound (XX) or a salt thereof can be prepared by reacting the 
compound (XIX) or a salt thereof to deacylation. 
This reaction is carried out in accordance with a conventional method such 
as hydrolysis, reduction or the like. 
This reaction can be carried out in a similar manner to that of the 
aforementioned Process (5) and therefore the reagents to be used and the 
reaction conditions (e.g., solvent, reaction temperature, etc.) can be 
referred to those of the Process (5). 
Process (F)--3 
The compound (VI) or a salt thereof can be prepared by reacting the 
compound (XX) or a salt thereof with the compound (XXI). 
The reaction is usually carried out in a conventional solvent such as 
water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, t-butyl 
alcohol, etc.), tetrahydrofuran, dioxane, dichloromethane, chloroform, 
dimethyl acetamide, N,N-dimethylformamide or any other organic solvent 
which does not adversely influence the reaction. Among these solvents, 
hydrophilic solvents may be used in a mixture with water. 
The reaction temperature is not critical and the reaction is usually 
carried out under cooling to warming. 
Process (G) 
The compound (IV) or a salt thereof can be prepared by reacting the 
compound (Ig) or a salt thereof to deacylation. 
This reaction is carried out in accordance with a conventional method such 
as hydrolysis, reduction or the like. 
This reaction can be carried out in a similar manner to that of the 
aforementioned Process (5) and therefore the reagents to be used and the 
reaction conditions (e.g., solvent, reaction temperature, etc.) can be 
referred to those of the Process (5). 
Process (H)--1 
The compound (XXVII) or a salt thereof can be prepared by reacting the 
compound (XXV) or a salt thereof with the compound (XXVI). 
This reaction is usually carried out in a solvent such as water, alcohol 
(e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, 
tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, 
chloroform, diethyl ether or any other solvent which does not adversely 
affect the reaction. 
The reaction temperature is not critical and the reaction is usually 
carried out under cooling to heating. 
Process (H)--2 
The compound (XXVIII) or a salt thereof can be prepared by subjecting the 
compound (XXVII) or a salt thereof to amidation reaction. 
This reaction can be carried out in accordance with the method disclosed in 
the Preparations 16 and 19 described later or similar manners thereto. 
Process (I) 
The compound (XXIX) or a salt thereof can be prepared by reacting the 
compound (XXVIII) or its reactive derivative at the amino group, or a salt 
thereof with the compound (VIII) or its reactive derivative at the carboxy 
group, or a salt thereof. 
This reaction can be carried out in a similar manner to that of the 
aforementioned Process (4), and therefore the reagents to be used and the 
reaction conditions (e.g., solvent, reaction temperature, etc.) can be 
referred to those of the Process (4). 
Process (J) 
The compound (XXXII) or a salt thereof can be prepared by reacting the 
compound (XXX) or a salt thereof with the compound (XXXI). 
This reaction is usually carried out in a solvent such as benzene, 
tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, 
chloroform, diethyl ether or any other solvent which does not adversely 
affect the reaction. 
The reaction temperature is not critical and the reaction is usually 
carried out under cooling to heating. 
Process (K) 
The compound (II) or a salt thereof can be prepared by reacting the 
compound (XXXIII) or a salt thereof with the compound (XXXIV) or a salt 
thereof. 
This reaction can be carried out in accordance with the method disclosed in 
the Preparation 17 described later or a similar manner thereto. 
Suitable salts of the object and starting compounds and their reactive 
derivatives in Processes (1).about.(8) and (A).about.(K) can be referred 
to the ones as exemplified for the compound (I). 
The compounds obtained by the above Processes (1).about.(8) and 
(A).about.(K) can be isolated and purified by a conventional method such 
as pulverization, recrystallization, column chromatography, 
reprecipitation or the like. 
It is to be noted that each of the object compound (I) may include one or 
more stereoisomer such as optical isomer(s) and geometrical isomer(s) due 
to asymmetric carbon atom(s) and double bond(s) and all such isomers and 
mixture thereof are included within the scope of this invention. 
The new thiazole derivatives (I) and pharmaceutically acceptable salts 
thereof possess antiulcer activity and H.sub.2 -receptor antagonism, and 
are useful for a prophylactic or 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 Helicobacter pylori, which is a 
gram-negative bacillus that has recently been found beneath the mucus gel 
of the human stomach. Actually, the compound (I) of the present invention 
inhibited the growth of Helicobacter pylori. 
The object compound (I) or its pharmaceutically acceptable salts can 
usually be administered to mammals including human being in the form of a 
conventional pharmaceutical composition such as oral dosage form (e.g., 
capsule, micro-capsule, tablet, granule, powder, troche, syrup, aerosol, 
inhalation, suspension, emulsion, etc.), injection dosage form or 
suppository, or the like. 
The pharmaceutical composition of this invention can contain various 
organic or inorganic carrier materials, which are conventional used for 
pharmaceutical purpose, such as excipient (e.g. sucrose, starch, mannit, 
sorbit, lactose, glucose, cellulose, talc, calcium phosphate, calcium 
carbonate, etc.), binding agent (e.g. cellulose, methyl cellulose, 
hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, 
polyethyleneglycol, sucrose, starch, etc.), disintegrator (e.g. starch, 
carboxymethyl cellulose, calcium salt of carboxymethyl cellulose, 
hydroxypropylstarch, sodium glycole-starch, sodium bicarbonate, calcium 
phosphate, calcium citrate, etc.), lubricant (e.g. magnesium stearate, 
talc, sodium laurylsulfate, etc.), flavoring agent (e.g. citric acid, 
mentol, glycine, orange powders, etc.), preservative (e.g. sodium 
benzoate, sodium bisulfite, methylparaben, propylparaben, etc.), 
stabilizer (e.g. citric acid, sodium citrate, acetic acid, etc.), 
suspending agent (e.g. methyl cellulose, polyvinylpyrrolidone, aluminum 
stearate, etc.), dispersing agent, aqueous diluting agent (e.g. water), 
base wax (e.g. cacao butter, polyethyleneglycol, white petrolatum, etc.). 
While the dosage of the compound (I) will vary depending upon the age and 
condition of the patient, an average single dose of about 0.1 mg, 1 mg, 10 
mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound (I) may be 
effective for treating ulcer. In general, amounts between 0.1 mg/body and 
about 1,000 mg/body may be administered per day. 
In order to illustrate the usefulness of the object compound (I), the 
pharmacological test data of some representative compounds of the compound 
(I) are shown in the following. 
Test compounds 
(a) 4-(3-Ureidomethylphenyl)-2-(diaminomethyleneamino)thiazole 
(b) 
4-(3-Acetylaminomethylphenyl)-2-[[(amino)(methylamino)methylene]amino]thia 
zole 
(c) 
4-(3-Acetylaminomethylphenyl)-2-[[(amino)(ethylamino)methylene]amino]thiaz 
ole 
Test A (Gastric secretion in Heidenhain pouch dogs): 
Test Method 
Beagle dogs, weighing about 8-13 kg, were used for the study on gastric 
secretion. The animals were surgically provided with a vagally denervated 
Heidenhain pouch. One month or more later, the dogs were fasted overnight. 
Gastric secretion was stimulated by an intravenous infusion of 
tetragastrin (10 .mu.g/kg/hr). Gastric juice was collected at 15 minutes 
intervals. After the secretion plateau had been established, test compound 
(3.2 mg/kg) suspended in 0.1% methyl cellulose solution was administered 
orally. Gastric juice was collected at 15 minutes intervals over 3 hours 
period. Acid concentration was determined by titrating an aliquot against 
0.1N sodium hydroxide using automatic titrator (Hiranuma RAT-11 Type). 
Total acid output was calculated by multiplying the volume of gastric 
juice by acid concentration, and percentage inhibition was calculated by 
comparing total acid output before adminstration of test compound with 
that after administration of test compound. 
Test Result 
______________________________________ 
Test Compound Inhibition (%) 
______________________________________ 
(b) 88.1 
______________________________________ 
Test B (Inhibition of stress ulcer): 
Test Method 
Five male Sprague-Dawley rats, aged 7 weeks, were fasted but allowed free 
access to water for 24 hours. Animals were placed in a restraint cage and 
immersed to a level of the xiphoid in a water bath kept 22.degree. C. for 
7 hours. Each of the test compounds (32 mg/kg) suspended in 0.1% 
methylcellulose solution was administered orally just before the stress 
subjection. Animals were sacrificed and stomachs were removed. After 
fixing with 2% formalin, stomachs were opened along the greater curvature 
and area of ulcers was measured. Percentage inhibition was calculated by 
comparing the mean area of ulcers (mm.sup.2) in the test group with that 
in the control group. 
Test Result 
______________________________________ 
Test Compound Inhibition (%) 
______________________________________ 
(c) 88.1 
______________________________________ 
Test C (Gastric secretion from lumen perfused stomach in anesthetized 
rats): 
Test Method 
Male Sprague-Dawley rats weighing about 250 g were used. Rats were deprived 
of food but allowed free access to water for 24 hours. The animals were 
anesthteized with 1.25 g/kg urethane intraperitoneally. The abdomen was 
opened and the gastric lumen was perfused with saline throughout the 
experiment. The perfusate was titrated continuously against 25 mM sodium 
hydroxide to maintain the perfusate solution at pH 7.0. Gastric secretion 
was stimulated by intravenous infusion with histamine (3 mg/kg/hr). After 
reaching plateau, test compound (1 mg/kg) was given intravenously at a 
volume of 2 ml/kg. Effect of drug was expressed as maximal inhibition of 
acid output calculated by the amount of sodium hydroxide required. 
Test Result 
______________________________________ 
Test Compound Inhibition (%) 
______________________________________ 
(a) 99 
______________________________________ 
Preferred embodiments of the object compound (I) are as follows. 
R.sup.2 is hydrogen, or lower alkyl which may have one to three suitable 
substituent(s) [more preferably lower alkyl which may have one or two 
substituent(s) selected from the group consisting of lower alkoxy, 
hydroxy, protected hydroxy, di(lower)alkylamino, heterocyclic group and 
aryl which may have suitable substituent(s); most preferably lower alkyl 
which may have lower alkoxy, hydroxy, acyloxy, di(lower)alkylamino, 
pyridyl, imidazolyl or lower alkoxyphenyl], 
R.sup.3 is hydrogen, lower alkyl, lower alkoxy or halogen, 
A is C.sub.1 -C.sub.4 alkylene [more preferably methylene], 
Q is a group of the formula: 
EQU --CO--R.sup.1 
(in which R.sup.1 is lower alkyl, amino, protected amino, 
hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, lower alkoxy, 
amino(lower)alkyl, or protected amino(lower)alkyl [more preferably lower 
alkyl, amino, acylamino, hydroxy(lower)alkyl, acyloxy(lower)alkyl, lower 
alkoxy, amino(lower)alkyl, or acylamino(lower)alkyl; most preferably lower 
alkyl, amino, acylamino, hydroxy(lower)alkyl, lower 
alkanoyloxy(lower)alkyl, lower alkoxy, amino(lower)alkyl, lower 
alkanoylamino(lower)alkyl, or lower alkoxycarbonylamino(lower)alkyl]), or 
carbamimidoyl which may have one to three suitable substituent(s) [more 
preferably carbamimidoyl which may have one or two suitable substituent(s) 
selected from the group consisting of cyano and lower alkyl; [most 
preferably carbamimidoyl which has cyano and lower alkyl], 
with proviso that 
when Q is carbamimidoyl which may have one to three suitable 
substituent(s), 
then R.sup.3 is lower alkoxy. 
The following Preparations and Examples are given for the purpose of 
illustrating the present invention in more detail. 
Preparation 1 
A suspension of 3-acetylbenzonitrile (50.0 g), ethylene glycol (34.0 g) and 
boron trifluoride etherate (1 ml) in benzene (200 ml) was heated at 
100.degree. C. by means of a Dean-Stark apparatus for 5 hours. After 
cooling, a saturated aqueous sodium hydrogencarbonate solution (200 ml) 
was added. The benzene layer was collected and then dried with sodium 
sulfate. The solvent was removed under reduced pressure to afford 
3-(2-methyl-1,3-dioxolan-2-yl)benzonitrile (65.0 g) (oil). 
IR (Film): 2970, 2880, 2230, 1580 cm.sup.-1 
NMR (CDCl.sub.3, .delta.): 1.64 (3H, s), 3.73-3.79 (2H, m), 4.04-4.11 (2H, 
m), 7.46 (1H, td, J=7.7 and 0.5 Hz), 7.59 (1H, dt, J=7.5 and 1.5 Hz), 7.73 
(1H, dt, J=7.7 and 1.5 Hz), 7.80 (1H, dt, 
J=1.5 and 0.5 Hz) 
Preparation 2 
A solution of 3-(2-methyl-1,3-dioxolan-2-yl)benzonitrile (65.6 g) in 
tetrahydrofuran (400 ml) was added to a suspension of lithium aluminum 
hydride (26.3 g) in tetrahydrofuran (400 ml) with cooling on an ice-water 
bath under nitrogen stream for 1 hour. The mixture was stirred at room 
temperature for 2 hours. Ethyl acetate (200 ml) was added slowly with 
cooling on an ice bath and then ice-water (200 ml) was added very slowly 
with cooling on an ice bath. The resulting precipitate was removed by 
filtration. The solvent was removed under reduced pressure. Chloroform 
(300 ml) was added to the residue. The mixture was washed with water (100 
ml) and then dried with magnesium sulfate. The solvent was removed under 
reduced pressure to afford 3-(2-methyl-1,3-dioxolan-2-yl)benzylamine (57.2 
g) (oil). 
IR (Film): 3300, 2980, 2880, 1650 cm.sup.-1 
NMR (CDCl.sub.3, .delta.): 1.66 (3H, s), 3.75-3.82 (2H, m), 3.88 (2H, s), 
4.01-4.08 (2H, m), 7.23-7.42 (4H, m) 
Preparation 3 
A solution of 3-(2-methyl-1,3-dioxolan-2-yl)benzylamine (57.2 g) in 1N 
hydrochloric acid (500 ml) and methanol (500 ml) was stirred at room 
temperature for 2 hours. The solvent was removed under reduced pressure. 
The residue was dissolved in methanol. The resulting precipitate was 
removed by filtration. The solvent was removed under reduced pressure. 
Recrystallization from a mixture of ethanol and acetone afforded 
3-acetylbenzylamine hydrochloride (31.2 g). 
mp: 145.degree.-146.degree. C. 
IR (Nujol): 3180, 1680, 1610 cm.sup.-1 
NMR (DMSO-d.sub.6, .delta.): 2.61 (3H, s), 4.11 (2H, s), 7.58 (1H, t, J=7.7 
Hz), 7.76 (1H, d, J=7.7 Hz), 7.97 (1H, d, J=7.7 Hz), 8.15 (1H, s), 8.50 
(3H, br s) 
Preparation 4 
Acetyl chloride (2.5 g) was added slowly to a suspension of 
3-acetylbenzylamine hydrochloride (5.0 g) and triethylamine (6.0 g) in 
dichloromethane (50 ml) with cooling on an ice-water bath. The mixture was 
stirred at room temperature for 10 hours. The solvent was removed under 
reduced pressure. The residue was dissolved in water (100 ml). The 
solution was alkalified with an aqueous potassium carbonate solution. The 
mixture was extracted with ethyl acetate (150 ml). The solution was dried 
with magnesium sulfate. The solvent was removed under reduced pressure to 
afford 3'-acetylaminomethylacetophenone (3.2 g) (oil). 
IR (Film): 3250, 3070, 1680, 1640 cm.sup.-1 
NMR (DMSO-d.sub.6, .delta.): 1.88 (3H, s), 2.57 (3H, s), 4.31 (2H, d, J=6.0 
Hz), 7.43-7.54 (2H, m), 7.82-7.87 (2H, m), 8.43 (1H, t, J=6.0 Hz) 
Preparation 5 
Conc. hydrochloric acid (10 ml) was added slowly to a suspension of 
4-(3-acetylaminomethylphenyl)-2-(diaminomethyleneamino)thiazole (2.8 g) in 
ethanol (100 ml). The mixture was refluxed for 18 hours. After cooling, 
the resulting precipitate was collected by filtration to afford 
4-(3-aminomethylphenyl)-2-(diaminomethyleneamino)thiazole dihydrochloride 
(1.75 g). 
mp: 219.degree.-220.degree. C. (dec.) 
IR (Nujol): 3300, 1680, 1605 cm.sup.-1 
NMR (DMSO-d.sub.6, .delta.): 4.09 (2H, q, J=5.4 Hz), 7.47 (2H, d, J=4.9 
Hz), 7.79 (1H, s), 7.94-7.97 (1H, m), 8.25 (1H, s), 8.38 (4H, s), 8.61 
(3H, br), 12.80 (1H, br) 
Preparation 6 
The following compound was obtained according to a similar manner to that 
of Example 1 as mentioned below. 
4-(3-Acetylaminomethylphenyl)-2-aminothiazole 
mp: 172.degree.-173.degree. C. 
IR (Nujol): 3300, 3120, 1640, 1610 cm.sup.-1 
NMR (DMSO-d.sub.6, .delta.): 1.87 (3H, s), 4.26 (2H, d, J=5.9 Hz), 6.97 
(1H, s), 7.06 (2H, s), 7.13 (1H, d, J=7.6 Hz), 7.30 (1H, t, J=7.6 Hz), 
7.64-7.68 (2H, m), 8.35 (1H, t, J=5.9 Hz) 
Preparation 7 
A suspension of 4-(3-acetylaminomethylphenyl)-2-aminothiazole (2.0 g) and 
benzoyl isothiocyanate (1.32 g) in acetone (40 ml) was refluxed for 5 
hours. The resulting precipitate was collected by filtration to afford 
4-(3-acetylaminomethylphenyl)-2-(3-benzoyl-2-thioureido)thiazole (2.94 g). 
mp: 225.degree.-226.degree. C. (dec.) 
IR (Nujol): 3260, 1680, 1640 cm.sup.-1 
NMR (DMSO-d.sub.6, .delta.): 1.89 (3H, s), 4.31 (2H,, d, J=5.9 Hz), 7.24 
(1H, d, J=7.7 Hz), 7.40 (1H, t, J=7.6 Hz), 7.57 (2H, t, J=7.7 Hz), 
7.67-7.84 (4H, m), 8.03 (2H, dd, J=1.5 and 7.1 Hz), 8.41 (1H, t, J=5.9 
Hz), 12.21 (1H, s), 14.27 (1H, s) 
Preparation 8 
Aqueous sodium hydroxide solution (0.5 g in 4 ml water) was added to a 
suspension of 
4-(3-acetylaminomethylphenyl)-2-(3-benzoyl-2-thioureido)thiazole (2.0 g) 
in methanol (40 ml). The mixture was heated at 60.degree. C. for 8.5 
hours. The solvent was removed under reduced pressure. The residue was 
dissolved in water (50 ml). The mixture was neutralized with 
6N-hydrochloric acid. The resulting precipitate was collected by 
filtration to afford 4-(3-acetylamino-methylphenyl)-2-thioureidothiazole 
(2.0 g). 
mp: 228.degree.-230.degree. C. 
IR (Nujol): 3400, 3300, 1620 cm.sup.-1 
NMR (DMSO-d.sub.6, .delta.): 1.89 (3H, s), 4.29 (2H, d, J=5.9 Hz), 7.20 
(1H, d, J=7.6 Hz), 7.37 (1H, t, J=7.6 Hz), 7.50 (1H, s), 7.73 (1H, d, 
J=7.6 Hz), 7.74 (1H, s), 8.37 (1H, t, J=5.9 Hz), 8.78 (1H, br), 11.73 (1H, 
s) 
Preparation 9 
A suspension of 4-(3-acetylaminomethylphenyl)-2-thioureidothiazole (5.75 g) 
and methyl iodide (3.73 g) in methanol (100 ml) was refluxed for 2.5 
hours. The solvent was removed under reduced pressure. The residue was 
crystallized from a mixture of methanol and ethyl acetate to afford 
4-(3-acetylaminomethylphenyl)-2-(2-methyl-1-isothioureido)thiazole 
hydriodide (6.3 g). 
mp: 114.degree.-115.degree. C. (dec.) 
IR (Nujol): 3250, 1630 cm.sup.-1 
NMR (DMSO-d.sub.6, .delta.): 1.89 (3H, s), 2.56 (3H, s), 4.30 (2H, d, J=5.8 
Hz), 7.23 (1H, d, J=7.7 Hz), 7.40 (1H, t, J=7.7 Hz), 7.66 (1H, s), 
7.75-7.76 (2H, m), 8.39 (1H, t, J=5.8 Hz), 9.53 (1H, br) 
Preparation 10 
A suspension of 
4-(3-acetylaminomethylphenyl)-2-amino(2-methoxyethylamino)methyleneamino]t 
hiazole (5.5 g) in concentrated hydrochloric acid (10 ml) and ethanol (100 
ml) was refluxed for 16 hours. After cooling, acetone was added. The 
mixture was stirred at room temperature and then the resulting precipitate 
was collected by filtration. Recrystallization from ethanol afforded 
4-(3-aminomethylphenyl)-2-[[(amino)(2-methoxyethylamino)methylene]amino]th 
iazole dihydrochloride (5.55 g). 
mp: 240.degree.-242.degree. C. (dec.) 
IR (Nujol): 3350, 1680, 1620 cm.sup.-1 
NMR (DMSO-d.sub.6, .delta.): 3.36 (3H, s), 3.62 (4H, br), 3.95-4.18 (2H, 
br), 7.49-7.51 (2H, m), 7.77 (1H, s), 7.85-8.05 (1H, m), 8.17 (1H, br s), 
8.60 (4H, br), 9.45-9.70 (1H, br), 12.75-12.97 (1H, br) 
Preparation 11 
The following compound was obtained according to a similar manner to that 
of Preparation 10. 
2-[(Amino)(2-hydroxyethylamino)methyleneamino]-4(3-aminomethylphenyl)thiazo 
le dihydrochloride 
mp: 219.degree.-220.degree. C. (dec.) 
IR (Nujol): 3350, 1680, 1610 cm.sup.-1 
NMR (DMSO-d.sub.6, .delta.): 3.50-3.80 (4H, m), 4.07 (2H, d, J=5.5 Hz), 
4.29 (1H, br), 7.47-7.50 (2H, m), 7.79 (1H, s), 7.90-8.05 (1H, m), 8.21 
(1H, br s), 8.35-9.00 (5H, br), 9.73 (1H, br), 12.95 (1H, br) 
Preparation 12 
The following compound was obtained according to a similar manner to that 
of Preparation 5. 
4-(3-Aminomethyl-4-methoxyphenyl)-2-(diaminomethyleneamino)thiazole 
NMR (DMSO-d.sub.6, .delta.): 3.69 (2H, s), 3.81 (3H, s), 6.96-6.87 (6H, m), 
7.65 (1H, dd, J=2.2 and 8.4 Hz ), 7.77 ( 1H, d, J=2.2 Hz ) 
Preparation 13 
To a solution of N-(3-cyanobenzyl)acetamide (7.7 g) in methylene dichloride 
(150 ml) and tetrahydrofuran (50 ml) was added dropwise a solution of 
methyl magnesium bromide in ether (3 mol/l, 52 ml) at 10.degree. to 
20.degree. C. under stirring and the resulting mixture was stirred at the 
same condition for 6 hours. The reaction mixture was poured into water and 
the resultant mixture was adjusted to pH 7 with 6N hydrochloric acid and 
extracted with ethyl acetate. The extract was washed with brine and 
magnesium sulfate. The solvent was evaporated in vacuo and the residue was 
subjected to column chromatography on silica gel. The fractions eluted 
with a mixture of chloroform and ethyl acetate (8:2) were collected and 
the solvent was evaporated in vacuo to give 
3'-(acetylaminomethyl)acetophenone (4.7 g) (oil). 
NMR (DMSO-d.sub.6, .delta.): 1.91 (3H, s), 2.57 (3H, s), 4.34 (2H, m), 
7.43-7.92 (4H, m), 8.44 (1H, m) 
Preparation 14 
The following compound was obtained according to a similar manner to that 
of Example 1. 
4-(3-Acetylaminomethylphenyl)-2-thioureidothiazole 
Preparation 15 
A solution of 3-cyanobenzyl chloride (13.3 g) in N,N-dimethylformamide (30 
ml) was added dropwise to a suspension of potassium phthalimide (15.9 g) 
in N,N-dimethylformamide (160 ml) at ambient temperature under stirring 
and the resultant mixture was stirred for 12 hours at ambient temperature. 
The reaction mixture was poured into water and the precipitate was 
collected by filtration. The precipitate was dissolved in a mixture of 
ethyl acetate and tetrahydrofuran and the resultant solution was washed 
with brine and dried over magnesium sulfate. The solvent was concentrated 
in vacuo and the precipitate was collected by filtration to give 
N-(3-cyanobenzyl)phthalimide (17.1 g). 
mp: 147.degree.-149.degree. C. 
IR (Nujol): 2220, 1765, 1700, 1605, 1580 cm.sup.-1 
NMR (DMSO-d.sub.6, .delta.): 4.85 (2H, s), 7.52-7.96 (8H, m) 
Preparation 16 
A solution of hydrazine hydrate (4.0 g) in methanol was added dropwise to a 
mixture of N-(3-cyanobenzyl)phthalimide (17.0 g) in tetrahydrofuran (150 
ml) and methanol (120 ml) at ambient temperature under stirring and the 
resultant mixture was stirred for 3 hours at ambient temperature. To the 
reaction mixture was added dropwise 6N-hydrochloric acid (25 ml) and the 
mixture was stirred for one hour at ambient temperature. The reaction 
mixture was evaporated in vacuo. To the residue was added water (60 ml) 
and the mixture was stirred at 10 minutes and filtrated. The filtrate was 
washed with ethyl acetate and adjusted to pH 8.0 with 20% potassium 
carbonate solution. Acetic anhydride (15 ml) was added dropwise to the 
resulting solution at 8.degree. to 20.degree. C. under stirring and the 
mixture was stirred for one hour at 10.degree. to 20.degree. C. The 
reaction mixture was extracted with ethyl acetate, and extract was washed 
with brine and dried over magnesium sulfate. The solvent was evaporated in 
vacuo and the residue was recrystallized from a mixture of ethyl acetate 
and diisopropyl ether to give N-(3-cyanobenzyl)acetamide (7.45 g). 
mp: 94.degree.-96.degree. C. 
IR (Nujol): 3280, 2220, 1640, 1540 cm.sup.-1 
NMR (DMSO-d.sub.6, .delta.): 1.90 (3H, s), 4.30 (2H, d, J=6 Hz), 7.49-7.62 
(2H, m), 7.65-8.93 (2H, m), 8.43 (1H, m) 
Preparation 17 
Chloroacetyl chloride (17 g) was added dropwise to a mixture of aluminum 
chloride (13.3 g) in dichloroethane (60 ml) at ambient temperature under 
stirring and the mixture was stirred for one hour. To the resulting 
mixture was added N-(2-methylbenzyl)acetamide (13.3 g) at ambient 
temperature and the mixture was stirred at 25.degree. to 50.degree. C. for 
1.5 hours. The reaction mixture was poured into ice water and extracted 
with a mixture of ethyl acetate and tetrahydrofuran. The extract was 
washed with brine and dried over magnesium sulfate. The solvent was 
concentrated in vacuo and the residue was washed with ethyl acetate and 
diisopropyl ether to give N-(4-chloroacetyl-2-methylbenzyl)acetamide (5.8 
g). 
IR (Nujol): 3280, 1690, 1640, 1550 cm.sup.-1 
NMR (DMSO-d.sub.6, .delta.): 1.89 (3H, s), 2.35 (3H, s), 4.27 (2H, d, J=5.7 
Hz), 5.14 (2H, s), 7.34 (1H, d, J=8.4 Hz), 7.80 (2H, m), 8.32 (1H, m) 
Preparation 18 
A solution of 3'-chloromethyl-4'-methoxyacetophenone (10.0 g) in 
N,N-dimethylformamide (30 ml) was added slowly to a suspension of 
potassium phthalimide (9.4 g) in N,N-dimethylformamide (70 ml) at room 
temperature and then the mixture was stirred for 9 hours at room 
temperature. After removed of the insoluble material, the solvent was 
removed under reduced pressure. The residue was suspended in water (100 
ml). The mixture was extracted with ethyl acetate (300 ml). The extract 
was dried with magnesium sulfate. The solvent was removed under reduced 
pressure to afford 3'-phthalimidomethyl-4'-methoxyacetophenone (11.94 g). 
IR (Nujol): 1620 cm.sup.-1 
NMR (DMSO-d.sub.6, .delta.): 2.47 (3H, s), 3.91 (3H, s), 4.77 (2H, s), 7.14 
(1H, d, J=8.6 Hz), 7.62 (1H, d, J=2.0 Hz), 7.82-7.98 (5H, m) 
Preparation 19 
Hydrazine hydrate (3.06 g) was added to a suspension of 
3'-phthalimidomethyl-4'-methoxyacetophenone (15.74 g) in methanol (150 ml) 
and tetrahydrofuran (150 ml) at room temperature and the mixture was 
stirred at room temperature for 24 hours. Dilute hydrochloric acid (conc. 
hydrochloric acid (5 ml) in water (100 ml)) was added slowly to the 
mixture with cooling and the mixture was stirred at room temperature for 1 
hour. The mixture was concentrated. Water (100 ml) was added thereto and 
the mixture was alkalized to pH 10 with 30% aqueous potassium carbonate 
solution and extracted with ethyl acetate (300 ml). The extract was dried 
with magnesium sulfate. The solvent was removed under reduced pressure to 
afford 3'-aminomethyl-4'-methoxyacetophenone (4.45 g). 
IR (Film): 3370, 1670, 1600 cm.sup.-1 
NMR (DMSO-d.sub.6, .delta.): 2.52 (3H, s), 3.66 (2H, s), 3.87 (3H, s), 7.04 
(1H, d, J=8.6 Hz), 7.86 (1H, dd, J=2.3 and 8.6 Hz), 7.98 (1H, d, J=2.3 Hz) 
Preparation 20 
A solution of 3'-aminomethyl-4'-methoxyacetophenone (4.45 g) and acetic 
anhydride (5.58 g) in methanol (40 ml) and tetrahydrofuran (40 ml) was 
stirred for 1 hour at room temperature. The solvent was removed under 
reduced pressure and the residue was dissolved in a saturated aqueous 
sodium hydrogencarbonate solution (100 ml). The mixture was extracted with 
ethyl acetate (300 ml). The extract was dried with magnesium sulfate. The 
solvent was removed under reduced pressure to afford 
3'-acetylamino-methyl-4'-methoxyacetophenone (3.59 g). 
IR (Nujol): 3290, 1660, 1630, 1600 cm.sup.-1 
NMR (DMSO-d.sub.6, .delta.): 1.89 (3H, s), 2.51 (3H, s), 3.89 (3H, s), 4.23 
(2H, d, J=5.9 Hz), 7.09 (1H, d, J=8.6 Hz), 7.76 (1H, d, J=2.2 Hz), 7.92 
(1H, dd, J=8.6 and 2.2 Hz), 8.27 (1H, t, J=5.86 Hz)