WO1994029304A1

WO1994029304A1 - Thienylthiazole derivatives

Info

Publication number: WO1994029304A1
Application number: PCT/JP1994/000850
Authority: WO
Inventors: Yousuke Katsura; Tetsuo Tomishi; Shigetaka Nishino; Mitsuko Hamano; Hisashi Takasugi
Original assignee: Fujisawa Pharmaceutical Co Ltd
Current assignee: Fujisawa Pharmaceutical Co Ltd
Priority date: 1993-06-04
Filing date: 1994-05-30
Publication date: 1994-12-22
Anticipated expiration: 1995-12-04
Also published as: GB9311613D0; JPH08500129A

Abstract

This invention relates to new thienylthiazol derivatives having antiulcer activity, H2-receptor antagonism and antimicrobial activity, and represented by general formula (I), wherein R1 is hydrogen or alkyl optionally substituted with alkoxy, R2 is hydrogen or alkyl optionally substituted with alkoxy, R3 is hydrogen or lower alkyl, R4 is amino optionally substituted with acyl, A is a single bond or lower alkylene, and Q is hydrogen or lower alkyl, provided that when R?1 and R2¿ are both hydrogen, then (1) R4 is amino substituted with esterified carboxy, or (2) Q is lower alkyl, and pharmaceutically acceptable salts thereof, to processes for the preparation thereof and to a pharmaceutical composition comprising the same.

Description

DESCRIPTION

THIENYLTHIAZOLE DERIVATIVES TECHNICAL FIELD

This invention relates to new thienylthiazole

derivatives and pharmaceutically acceptable salts thereof which are useful as a medicament. BACKGROUND ART

Some thienylthiazole derivatives have been known as antiulcer agent, for example, in EP Patent Application Publication No. 0 183 191 and JP Patent Application

Publication No. 59-225186.

DISCLOSURE OF INVENTION

This invention relates to new thienylthiazole

derivatives and pharmaceutically acceptable salts thereof.

More particularly, it relates to new thienylthiazole derivatives and pharmaceutically acceptable salts thereof which have antiulcer activity, H₂-receptor antagonism and antimicrobial activity, to processes for the preparation thereof, to a pharmaceutical composition comprising the same and to a method for the treatment and/or prevention of gastritis, ulcer (e.g. gastric ulcer, duodenal ulcer, anastomotic ulcer, etc.), Zollinger-Ellison Syndrome, reflux esophagitis, upper gastrointestinal bleeding, infectious diseases, and the like in human beings and animals.

Accordingly, one object of this invention is to provide new thienylthiazole derivatives and

pharmaceutically acceptable salts thereof which possess antiulcer activity, H₂-receptor antagonism and

antimicrobial activity.

Another object of this invention is to provide processes for the preparation of said thienylthiazole derivatives and salts thereof.

A further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said thienylthiazole derivatives or

pharmaceutically acceptable salts thereof.

Still further object of the compound is to provide a therapeutical method for the treatment and/or prevention of aforesaid diseases in human beings or animals, using said thienylthiazole derivatives and pharmaceutically acceptable salts thereof.

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

wherein R¹ is hydrogen or alkyl optionally substituted with alkoxy,

R² is hydrogen or alkyl optionally substituted

with alkoxy,

R³ is hydrogen or lower alkyl,

R⁴ is amino optionally substituted with acyl, A is a single bond or lower alkylene, and Q is hydrogen or lower alkyl,

provided that when R¹ and R² are both hydrogen,

then 1) R⁴ is amino substituted with esterified carboxy, or

2) Q is lower alkyl,

and pharmaceutically acceptable salts thereof. The object compound (I) or its salt can be prepared by the following processes.

Process 1

2

Process 2

χ

Process 3

Process 4

wherein R¹, R², R³, R⁴, A and Q are each as defined above,

R⁵ is lower alkyl,

χ¹ is acid residue, and

R⁴ _a is amino substituted with acyl. As to the formula in the above and subsequent

description of the present specification, the following points are to be noted. That is, in case that the

compound has the group of the following formula :

(wherein R¹ and R² are each as defined above) in its molecule, said compound may include tautomeric isomers. Therefore, said group can be represented by the formula :

(wherein R¹ and R² are each as defined above), and said group of the formula (A) can also be alternatively represented by its tautomeric formula :

(wherein R¹ and R² are each as defined above).

That is, both of the said group of the formulae (A) and (A') are in the state of tautomeric equilibrium which can be represented by the following equilibrium :

(wherein R¹ and R² are each as defined above).

These types of tautomerism between the formulae (A) and (A') as stated above have been well known in the arts, and it is obvious to a person skilled in the art that both of the tautomeric isomers are equilibrated and lie in the reciprocally convertible state, and accordingly it is to be understood that such isomers are included within the same category of the compound per se. Accordingly, the both of the tautomeric forms are clearly included within the scope of the present invention. In the present specification, the object and starting compounds including the group of such tautomeric isomers are represented by using one of the expressions therefor, i.e. the formula :

only for the convenient sake.

In the above and subsequent descriptions of the present specification, suitable examples of the various definitions to be included within the scope of the

invention are explained in detail in the following. The term "lower" is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.

The lower moiety in the term "cyclo(lower)alkyl" is intended to mean a group having 3 to 6 carbon atoms.

The term "alkyl" may include lower alkyl and higher alkyl.

The term "alkoxy" may include lower alkoxy and higher alkoxy.

Suitable "lower alkyl" and lower alkyl moiety in the terms "ar(lower)alkyl" and "lower alkoxy(lower)alkyl" may be a straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, methylbutyl, ethylbutyl or the like.

Suitable "cyclo(lower)alkyl" may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Suitable "aryl" may be phenyl, naphthyl, phenyl substituted with lower alkyl [ e . g . tolyl, mesityl,

cumenyl, xylyl, diethylphenyl, diisopropylphenyl, di-tert-butylphenyl, etc.] and the like.

Suitable "ar(lower)alkyl" may be benzyl, phenethyl, diphenylmethyl, triphenylmethyl, naphthylmethyl, and the like.

Suitable "lower alkoxy" and lower alkoxy moiety in the term "lower alkoxy(lower) alkyl" may be methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy and the like, in which

preferable one is C₁-C₄ ones.

The term "higher" is intended to mean 7 to 20 carbon atoms, unless otherwise provided.

Suitable "higher alkyl" may be a straight or branched one such as heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, ethylhexyl, methylheptyl, methyloctyl, methylnonyl, methyldecyl, ethylheptyl, ethyloctyl, ethylnonyl, ethyldecyl or the like, in which preferable one is one having 7 to 10 carbon atoms and the most preferable one is heptyl, octyl or ethylhexyl.

Suitable "higher alkoxy" may be a straight or

branched one such as heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy,

tetradecyloxy, pentadecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy, eicosyloxy, ethylhexyloxy, methylheptyloxy, methyloctyloxy, methylnonyloxy,

methyldecyloxy, ethylheptyloxy, ethyloctyloxy,

ethylnonyloxy, ethyldecyloxy or the like, in which

preferable one is ethylhexyloxy.

Suitable "lower alkylene" may be a straight or branched one such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, ethylethylene, or the like, in which preferable one is C₁-C₄ ones and the most preferable one is methylene or ethylene.

Suitable "acyl" and acyl moiety in the term

"acylamino" may include carboxy; esterified carboxy;

carbamoyl optionally substituted with substituent(s) selected from the group consisting of lower alkyl,

cyclo(lower)alkyl, aryl, ar(lower)alkyl, lower

alkoxy(lower)alkyl and a heterocyclic group; lower

alkanoyl; aroyl; a heterocycliccarbonyl; lower

alkylsulfonyl; and the like.

The esterified carboxy may be substituted or

unsubstituted lower alkoxycarbonyl [e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, hexyloxycarbonyl, 2-iodoethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.], substituted or unsubstituted aryloxycarbonyl [e.g. phenoxycarbonyl,

4-nitrophenoxycarbonyl, 2-naphthyloxycarbonyl, etc.], substituted or unsubstituted ar(lower)alkoxycarbonyl [e.g. benzyloxycarbonyl, phenethyloxycarbonyl,

benzhydryloxycarbonyl, 4-nitrobenzyloxycarbonyl, etc.] and the like, in which preferable one is unsubstituted lower alkoxycarbonyl or unsubstituted ar(lower)alkoxycarbonyl and the most preferable one is methoxycarbonyl,

ethoxycarbonyl or benzyloxycarbonyl.

The lower alkanoyl may be formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and the like, in which preferable one is C₁-C₄ ones and the most preferable one is acetyl.

The aroyl may be benzoyl, naphthoyl, benzoyl

substituted with lower alkyl [e.g. toluoyl, xyloyl, etc.] and the like.

Suitable heterocyclic moiety in the term

"heterocycliccarbonyl" may include saturated or

unsaturated, monocyclic or polycyclic one containing at least one hetero atom such as nitrogen atom, oxygen atom or sulfur atom.

The preferred examples of thus defined "heterocyclic group" may be unsaturated, 3 to 8-membered, more

preferably 5 or 6-membered heteromonocyclic group

containing 1 to 4-nitrogen atom(s), for example, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridyl N-oxide,

dihydropyridyl, tetrahydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, triazolyl, tetrazinyl, tetrazolyl, etc.;

saturated, 3 to 8-membered, more preferably 5 or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.;

unsaturated, condensed heterocyclic group containing 1 to 5 nitrogen atom(s), for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.;

unsaturated, 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) for example, oxazolyl, isoxazolyl, oxadiazolyl. etc . ;

saturated, 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholino, 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 heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl,

thiadiazolyl, etc.;

unsaturated, 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s), for example, thienyl, 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 heteromonocyclic group containing an oxygen atom, for example, furyl, etc.;

unsaturated, condensed heterocyclic group containing

1 to 2 sulfur atom(s), for example, benzothienyl, etc.; unsaturated, condensed heterocyclic group containing

1 to 2 oxygen atom(s), for example, benzofuranyl, etc.; and the like.

Suitable "acid residue" may include halogen (e.g. fluoro, chloro, bromo, iodo), arenesulfonyloxy (e.g.

benzenesulfonyloxy, tosyloxy, etc.), alkanesulfonyloxy

(e.g. mesyloxy, ethanesulfonyloxy, etc.), and the like, in which preferable one is halogen.

Preferable compound (I) is one which has alkyl optionally substituted with alkoxy for R¹, hydrogen for

R², hydrogen or lower alkyl for R³ , amino optionally substituted with lower alkanoyl, esterified carboxy or carbamoyl for R⁴, lower alkylene for A, and hydrogen or lower alkyl for Q. More preferable compound (I) is one which has lower alkyl optionally substituted with lower alkoxy for R¹, hydrogen for R², hydrogen for R³, lower alkanoylamino for R⁴, lower alkylene for A, and hydrogen for Q.

Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and may include an acid addition salt such as an inorganic acid addition salt (e.g. hydrochloride, hydroiodide, hydrobromide, sulfate, phosphate, etc.), an organic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.) or the like.

The processes for preparing the object compound (I) are explained in detail in the following.

Process 1

The compound (I) or its salt can be prepared by reacting a compound (II) or its salt with a compound (III) or its salt.

Suitable salts of the compounds (II) and (III) may be the same as those exemplified for the compound (I).

This reaction is usually carried out in a solvent such as an 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 2

The compound (I) or its salt can be prepared by reacting a compound (IV) with a compound (V) or its salt.

Suitable salt of the compound (V) may be the same as those exemplified for the compound (I). The reaction is usually carried out in a conventional solvent such as an 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.

Process 3

The compound (lb) or its salt can be prepared by subjecting a compound (Ia) or its salt to deacylation reaction.

Suitable salt of the compound (la) may be the same as those exemplified for the compound (I).

Suitable salt of the compound (Ib) may be an acid addition salt as exemplified for the compound (I).

This reaction is carried out in accordance with a conventional method such as hydrolysis, reduction or 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[2.2.2]octane,

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 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 4

The compound (la) or its salt can be prepared by reacting a compound (lb) or its salt with an acylating agent.

Suitable salt of the compound (lb) may be an acid addition salt as exemplified for the compound (I).

The compound (lb) may be used in the form of its conventional reactive derivative at the amino group.

The acylating agent can be represented by the

compound of the formula : R⁶ _ OH (VI) in which R⁶ is acyl as defined above and its conventional reactive derivative at the hydroxy group.

The suitable example may be an acid halide (e.g. acid chloride, etc.), an acid anhydride, an activated amide, an activated ester, and the like.

In this reaction, when the compound (VI) 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 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, and the like.

In case the acyl group to be introduced is a

carbamoyl type acyl, the acylating agent is usually used in the form of cyanate, isocyanate or an alkali metal salt thereof.

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. The starting compounds (II) and (IV) or salts thereof can be prepared by the following Processes.

Process A

Process B

Process C

Process D

wherein R¹, R³, R⁴, R⁵, A, Q and X¹ are each as defined above,

R⁷ is acyl,

X² is acid residue, and

X³ is acid residue.

The above-mentioned Processes for preparing the starting compounds (II) and (IV) are explained in detail in the following.

Process A

The compound (IXa) can be prepared by reacting a compound (VII) or its salt with a compound (VIII).

Suitable salt of the compound (VII) may be the same as those exemplified for the compound (I). The reaction is usually carried out in a conventional solvent such as water, an 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 B

The compound (X) or its salt can be prepared by subjecting a compound (IX) or its salt to deacylation reaction.

Suitable salts of the compounds (IX) and (X) may be the same as those exemplified for the compound (I).

This reaction is carried out in accordance with substantially the same manner as Process 3, and therefore the reaction mode and reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those explained in Process 3.

Process C

The compound (II) or its salt can be prepared by a compound (X) or its salt with a compound (XI).

Suitable salts of the compounds (II) and (X) may be the same as those exemplified for the compound (I).

The reaction is usually carried out in a conventional solvent such as water, an 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 D

The compound (IV) can be prepared by reacting a compound (XII) with a compound (XIII).

The reaction is preferably carried out in the

presence of a Lewis acid such as aluminum halide (e.g. aluminum chloride, aluminum bromide, etc.), titanium halide (e.g. titanium tetrachloride, etc.) or the like.

The reaction is usually carried out in a conventional solvent such as carbon disulfide, dichloromethane, dichloroethane, benzene or any other organic solvent which does not adversely influence the reaction.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.

The compounds obtained by the above Processes 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 thienylthiazole derivatives (I) and

pharmaceutically acceptable salts thereof possess

antiulcer activity and H₂-receptor antagonism, and the 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.

For therapeutic purpose, the compound (I) and a pharmaceutically acceptable salt thereof of the present invention can be used in a form of pharmaceutical

preparation containing one of said compounds, as an active ingredient, in admixture with a pharmaceutically

acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external(topical) administration. The pharmaceutical preparations may be capsules, tablets, dragees, granules, suppositories, solution, suspension, emulsion, or the like. If desired, there may be included in these

preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.

While the dosage of the compound (I) will vary depending upon the age and condition of the patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg,

100 mg, 250 mg, 500 mg and 1000 mg of the compound (I) may be effective for treating ulcer. In general, amounts between 0.1 mg/body and about 1,000 mg/body may be

administered per day.

In order to illustrate the usefulness of the object compound (I), the pharmacological test data of some representative compounds of the compound (I) are shown in the following. Test A (Anti-microbial activity)

Test Method

In vitro antimicrobial activity was determined by the agar dilution method. Test strain was precultured in Brucella broth Agar with 3% hours serum and 2% starch as 37°C for 3 days, and 10⁵ cfu/ml were inoculated with a multipoint ireplicater onto Brucella agar plus 7% horse blood plate containing serial 2-fold dilutions of each drug and incubated at 37°C 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

Test B (Inhibition of HCl-aspirin ulcer)

Test Method

Seven male Sprague-Dawley rats, aged 6 weeks and weighing about 200 g were used per group for the study on HCl-aspirin ulcer after the fast for 24 hours. Each of the test compounds (32 mg/kg) suspended in 0.1%

methylcellulose solution was administered orally 30 minutes before aspirin administration. Aspirin, suspended in 0.1% methylcellulose solution containing 0.2N HCl, was administered orally at a dose of 200 mg/kg/10 ml. One hour later, the animals were sacrificed and their stomachs were removed. The stomach was then fixed with 2%

formalin. The length of ulcers was measured for each animal, and percentage of inhibition was calculated by comparing the mean length of ulcers (mm) in the test animals with that in the control animals.

Test Result

The following Preparations and Examples are given for the purpose of illustrating the present invention in more detail.

Preparation 1

Benzoyl chloride (8.2 g) was added slowly to a solution of sodium thiocyanate (5.1 g) in acetone (200 ml) under refluxing. The mixture was refluxed for 10 minutes. 4-(5-Acetylaminomethyl-2-thienyl)-2-aminothiazole (12.3 g) was added to the mixture. The mixture was refluxed for 7.5 hours. The resulting precipitate was collected by filtration. The precipitate was washed with water and then acetone to afford 4-(5-acetylaminomethyl-2-thienyl)-2-(3-benzoylthioureido)thiazole (15.1 g).

mp : 239-240°C (dec.)

IR (Nujol) : 3290, 1630 cm^-1

NMR (DMSO-d₆, δ) : 1.87 (3H, s), 4.41 (2H, d,

J=5.8Hz), 6.94 (1H, d, J=3.5Hz), 7.38 (1H, d, J=3.5Hz), 7.53 (1H, s), 7.60 (2H, t, J=7.7Hz), 7.70 (1H, dt, J=1.5 and 7.7Hz), 8.03 (2H, dd, J=7.7 and 1.5Hz), 8.50 (1H, t, J=5.8Hz), 12.20 (1H, s), 14.21 (1H, s) Preparation 2

An aqueous sodium hydroxide solution (3.5 g in 30 ml) was added to a suspension of 4-(5-acetylaminomethyl-2-thienyl)-2-(3-benzoylthioureido)thiazole (15.0 g) in methanol (200 ml) at ambient temperature. The mixture was heated at 60°C for 5 hours. The mixture was concentrated and then water (100 ml) was added. The mixture was

neutralized with 6N hydrochloric acid. The resulting precipitate was collected by filtration to afford 4-(5-acetylaminomethyl-2-thienyl)-2-thioureidothiazole (11.0 g). mp : 204-206°C (dec.)

IR (Nujol) : 3250, 1620 cm^-1

NMR (DMSO-d₆, δ) : 1.86 (3H, s), 4.38 (2H, d,

J=5.8Hz), 6.91 (1H, d, J=3.7Hz), 7.29 (1H, s), 7.30 (1H, d, J=3.7Hz), 8.10 (1H, br), 8.48 (1H, t, J=5.8Hz), 8.77 (1H, br), 11.78 (1H, br)

Preparation 3

A suspension of 4-(5-acetylaminomethyl-2-thienyl)-2-thioureidothiazole (11.9 g) and methyl iodide (7.6 g) in methanol (120 ml) was refluxed for 5 hours. The solvent was removed under reduced pressure. The residue was washed with ethyl acetate to afford 4-(5-acetylaminomethyl-2-thienyl)-2-[(amino)(methylthio)-methyleneamino]thiazole hydroiodide (11.8 g).

mp : 178-179°C (dec.)

IR (Nujol) : 3290, 1630 cm^-1

NMR (DMSO-d₆, δ) : 1.86 (3H, s), .2.56 (3H, s), 4.39 (2H, d, J=5.8Hz), 6.94 (1H, d, J=3.6Hz), 7.40 (1H, d, J=3.6Hz), 7.46 (1H, s), 8.49 (1H, t, J=5.8Hz), 9.58 (1H, br) Preparation 4

Aluminum chloride (2.65 g) was added slowly to a solution of N-[(3-methyl-2-thienyl)methyl]acetamide (1.4 g) and chloroacetyl chloride (1.4 g) in dichloromethane (100 ml) with cooling on an ice bath. The mixture was stirred at ambient temperature for 2 hours and then poured into ice-water (100 ml). The organic layer was collected and dried over magnesium sulfate. The solvent was removed under reduced pressure to afford N-[(5-chloroacetyl-3-methyl-2-thienyl)methyl]acetamide (1.99 g).

mp : 181-182°C

IR (Nujol) : 3300, 1670, 1650 cm^-1

NMR (DMSO-d₆, δ) : 1.86 (3H, s), 2.19 (3H, s), 4.36 (2H, d, J=5.9Hz), 4.98 (2H, s), 7.76 (1H, s), 8.55 (1H, t, J=5.9Hz)

Preparation 5

A mixture of aluminum chloride (18.6 g) and

chloroacetyl chloride ( 11. 9 g) in methylene chloride (80 ml) was stirred at ambient temperature for 30 minutes. To the resulting solution was added 2-(ethoxycarbonylaminomethyl)thiophene (13 g) at ambient temperature under stirring and the mixture was stirred for 20 minutes at 25 to 35°C. The reaction mixture was poured into an

ice-water and extracted with chloroform. The extract was washed with saturated aqueous sodium bicarbonate solution and brine, and dried over magnesium sulfate. The solvent was concentrated in vacuo and the precipitate was

collected by filtration to give 2-chloroacetyl-5-(ethoxycarbonylaminomethyl) thiophene (14.3 g).

NMR (DMSO-d₆, δ) : 1.17 (3H, t, J=7Hz), 4.02 (2H, q, J=7Hz), 4.38 (2H, d, J=6Hz), 5.00 (2H, s), 7.09 (1H, d, J=3.8Hz), 7.88 (1H, d, J=3.8Hz), 7.90 (1H, m) Preparation 6

The following compounds were obtained according to a similar manner to that of Preparation 5.

1) 2-Chloroacetyl-5-(2-methoxycarbonylaminoethyl)- thiophene

NMR (DMSO-d₆, δ) : 3.00 (2H, t, J=7Hz ), 3.27 (2H, m), 3.52 (3H, s), 5.02 (2H, s), 7.05 (1H, d, J=3.8Hz), 7.32 (1H, m), 7.90 (1H, d, J=3.8Hz)

2) 2-Chloroacetyl-5-(2-ethoxycarbonylaminoethyl)- thiophene

mp : 75-82°C

IR (Nujol) : 3340, 1680, 1520 cm^-1

NMR (DMSO-d₆, δ) : 1.14 (3H, t, J=7Hz), 2.96 (2H, t,

J=6.8Hz), 3.24 (2H, m), 4.00 (2H, q, J=7Hz), 5.01 (2H, s), 7.05 (1H, d, J=3.9Hz), 7.23 (1H, m), 7.90 (1H, d, J=3.9Hz) Preparation 7

To a mixture of aluminum chloride (4.4 g),

chloroacetyl chloride (3.39 g) and dichloromethane (10 ml) was added 3-acetylaminomethylthiophene (4.66 g) at -5°C and then stirred for 20 minutes at the same temperature. After stirred for an hour at ambient temperature, the resulting mixture was diluted with ice-water and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and

evaporated in vacuo. The residue was chromatographed on silica gel (2% methanol in chloroform) to give

4-acetylaminomethyl-2-chloroacetylthiophene (1.52 g).

mp : 133-134°C

IR (Nujol) : 3270, 1665, 1640, 1550 cm^-1

NMR (DMSO-d₆, δ) : 1.87 (3H, s), 4.24 (2H, d,

J=5.7Hz), 5.05 (2H, s), 7.82 (1H, d, J=l.1Hz), 7 . 88 ( 1H , d , J=1 . 1Hz ) , 8 . 37 ( 1H , t , J=5 . 7Hz )

Preparation 8

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

4-[5-(2-Aminomethyl)-2-thienyl]-2-(diaminomethyleneamino)thiazole dihydrochloride

NMR (DMSO-d₆, δ) : 2.96-3.21 (4H, m), 6.99 (1H, d, J=3.6Hz), 7.49-7.55 (2H, m), 8.32-8.43 (6H, m)

Example 1

A suspension of 4-(5-acetylaminomethyl-2-thienyl)-2-[(amino)(methylthio)methyleneamino]thiazole hydroiodide (2.0 g) and 2-methoxyethylamine (5 ml) in ethanol (30 ml) was refluxed for 72 hours. The solvent was removed under reduced pressure and the residue was suspended in water (100 ml). The mixture was alkalized with an aqueous potassium carbonate solution and then was extracted with a mixture of ethyl acetate (200 ml) and tetrahydrofuran (50 ml) . The extract was dried over magnesium sulfate and then was evaporated in vacuo. The residue was

chromatographed on a silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1). Recrystallization from ethyl acetate afforded 4-(5-acetylaminomethyl-2-thienyl)-2-[(amino)(2-methoxyethylamino)methyleneamino]thiazole (0.77 g).

mp : 141-142°C

IR (Nujol) : 3250, 1630, 1590 cm^-1

NMR (DMSO-d₆, δ) : 1.84 (3H, s), 3.28-3.30 (5H, m),

3.43 (2H, q, J=4.6Hz), 4.37 (2H, d, J=5.8Hz), 6.88 (1H, d, J=3.6Hz), 6.94 (1H, s), 7_*23 (1H, d, J=3.6Hz), 7.35 (2H, br), 8.44 (1H, t,

J=5.8Hz) Example 2

The following compounds were obtained according to a similar manner to that of Example 1. 1) 4-(5-Acetylaminomethyl-2-thienyl)-2- [(amino)(methylamino)methyleneamino]thiazole

mp : 165-166°C

IR (Nujol) : 3300, 1630 cm^-1

NMR (DMSO-d₆, δ) : 1.85 (3H, s), 2.73 (3H, d,

J=4.8Hz), 4.37 (2H, d, J=5.9Hz), 6.88 (1H, d,

J=3.6Hz), 6.93 (1H, s), 7.23 (1H, d, J=3.6Hz), 7.51 (2H, s), 8.44 (1H, t, J=5.9Hz)

2) 4-(5-Acetylaminomethyl-2-thienyl)-2-[(amino)(n- butylamino)methyleneamino]thiazole

mp : 173-174°C

IR (Nujol) : 3360, 3100, 1680, 1600 cm^-1

NMR (DMSO-d₆, δ) : 0.91 (3H, t, J=6.9Hz), 1.34-1.49 (4H, m), 1.85 (3H, s), 3.16 (2H, q, J=6.4Hz), 4.37 (2H, d, J=5.8Hz), 6.88 (1H, d, J=3.6Hz),

6.92 (1H, s), 7.22 (1H, d, J=3.6Hz), 7.31 (2H, s), 8.44 (1H, t, J=5.8Hz)

3) 4-(5-Acetylaminomethyl-2-thienyl)-2- [(amino)(ethylamino)methyleneamino]thiazole

mp : 168-169°C

IR (Nujol) : 3320, 3100, 1650, 1600 cm^-1

NMR (DMSO-d₆, δ) : 1.12 (3H, t, J=7.1Hz), 1.85 (3H, s), 3.11-3.25 (2H, m), 4.37 (2H, d, J=5.8Hz), 6.88 (1H, d, J=3.6Hz), 6.92 (1H, s), 7.22 (1H, d, J=3.6Hz), 7.39 (2H, br), 8.44 (1H, t,

J=5.8Hz)

4) 4-(5-Acetylaminomethyl-2-thienyl)-2-[(amino)(3- methylbutylamino)methyleneamino]thiazole mp : 192-193°C

IR (Nujol) : 3370, 3200, 1640, 1610 cm^-1

NMR (DMSO-d₆, δ) : 0.91 (6H, d, J=6.6Hz), 1.35-1.46 (2H, m), 1.62-1.75 (1H, m), 1.85 (3H, s), 3.13- 3.23 (2H, m), 4.37 (2H, d, J=5.8Hz), 6.88 (1H, d, J=3.6Hz), 6.92 (1H, s), 7.21 (1H, d, J=3.6Hz), 7.29 (2H, br), 8.43 (1H, t, J=5.8Hz)

5) 4-(5-Acetylaminomethyl-2-thienyl)-2-[(amino)(n- hexylamino)methyleneamino]thiazole

mp : 129-130°C

IR (Nujol) : 3250, 1650, 1600 cm^-1

NMR (DMSO-d₆, δ) : 0.87 (3H, t, J=6.5Hz), 1.20-1.40 (6H, m), 1.40-1.60 (2H, m), 1.85 (3H, s), 3.11- 3.20 (2H, m), 4.37 (2H, d, J=5.8Hz), 6.88 (1H, d, J=5.8Hz), 6.91 (1H, s), 7.21 (1H, d, J=3.6Hz), 7.32 (2H, br s), 8.43 (1H, t, J=5.8Hz)

6) 4-(5-Acetylaminomethyl-2-thienyl)-2-[(amino)(n- octylamino)methyleneamino]thiazole

mp : 144-145°C

IR (Nujol) : 3380, 1640, 1590 cm^-1

NMR (DMSO-d₆, δ) : 0.85 (3H, t, J=6.6Hz), 1.20-1.40 (10H, m), 1.40-1.60 (2H, m), 1.85 (3H, s), 3.10- 3.20 (2H, m), 4.37 (2H, d, J=5.6Hz), 6.87 (1H, d, J=3.6Hz), 6.91 (1H, s), 7.21 (1H, d, J=3.6Hz), 7.31 (2H, br s), 8.42 (1H, t, J=5.6Hz)

7) 4-(5-Acetylaminomethyl-2-thienyl)-2-[(amino)(3- ethoxypropylamino)methyleneamino]thiazole

mp : 112-113°C

IR (Nujol) : 3250, 3120, 1660, 1580 cm^-1

NMR (DMSO-d₆, δ) : 1.11 (3H, t, J=7.0Hz), 1.69-1.79 (2H, m), 1.85 (3H, s), 3.16-3.26 (2H, m), 3.37- 3.47 (4H, m), 4.37 (2H, d, J=5.8Hz), 6.88 (1H, d, J=3.6Hz), 6.92 (1H, s), 7.22 (1H, d,

J=3.6Hz), 7.39 (2H, br s), 8.43 (1H, t, J=5.8Hz)

8) 4-(5-Acetylaminomethyl-2-thienyl)-2-[(amino)-[3-(n- propoxy)propylamino]methyleneamino]thiazole

mp : 107-108°C

IR (Nujol) : 3250, 3100, 1640, 1600 cm^-1

NMR (DMSO-d₆, δ) : 0.86 (3H, t, J=7.3Hz), 1.42-1.60 (2H, m), 1.70-1.76 (2H, m), 1.85 (3H, s), 3.17- 3.26 (2H, m), 3.29-3.36 (2H, m), 3.43 (2H, t,

J=6.2Hz), 4.37 (2H, d, J=5.8Hz), 6.87 (1H, d, J=3.5Hz), 6.92 (1H, s), 7.22 (1H, d, J=3.5Hz), 7.39 (2H, s), 8.43 (1H, t, J=5.8Hz) 9) 4-(5-Acetylaminomethyl-2-thienyl)-2-[(amino)[3-(n- butoxy)propylamino]methyleneamino]thiazole

mp : 96-97°C

IR (Nujol) : 3230, 3100, 1630, 1600 cm^-1

NMR (DMSO-d₆, δ) : 0.87 (3H, t, J=7.1Hz), 1.23-1.37 (2H, m), 1.42-1.55 (2H, m), 1.69-1.79 (2H, m),

1.85 (3H, s), 3.16-3.26 (2H, m), 3.32-3.46 (4H, m), 4.37 (2H, d, J=5.8Hz), 6.88 (1H, d, J=3.5Hz), 6.92 (1H, s), 7.22 (1H, d, J=3.5Hz), 7.39 (2H, br s), 8.44 (1H, t, J=5.8Hz)

10) 4-(5-Acetylaminomethyl-2-thienyl)-2-[(amino)(3- isopropoxypropylamino)methyleneamino]thiazole

mp : 99-101°C

IR (Nujol) : 3400, 3320, 1630, 1610 cm^-1

NMR (DMSO-d₆, δ) : 1.08 (6H, d, J=6.1Hz), 1.62-1.77

(2H, m), 1.85 (3H, s), 3.16-3.26 (2H, m), 3.40- 3.59 (3H, m), 6.88 (1H, d, J=3.6Hz), 6.92 (1H, s), 7.22 (1H, d, J=3.6Hz), 7.38 (2H, br s), 8.43 (1H, t, J=5.8Hz) 11 ) 4- ( 5-Acetylaminomethyl-2-thienyl ) -2- [ ( amino ) ( n- propylamino)methyleneamino]thiazole

mp : 187-189°C

IR (Nujol) : 3330, 3100, 1660, 1600 cm^-1

NMR (DMSO-d₆, δ) : 0.93 (3H, t, J=7.3Hz), 1.44-1.62 (2H, m), 1.86 (3H, s), 3.08-3.18 (2H, m), 4.38 (2H, d, J=5.8Hz), 6.88 (1H, d, J=3.6Hz), 6.92 (1H, s), 7.22 (1H, d, J=3.6Hz), 7.37 (2H, br s), 8.47 (1H, t, J=5.8Hz)

12) 4-(5-Acetylaminomethyl-2-thienyl)-2-[(amino)(n- pentylamino)methyleneamino]thiazole

mp : 166-167°C

IR (Nujol) : 3350, 1640, 1605, 1540 crn^-1

NMR (DMSO-d₆, δ) : 0.89 (3H, t, J=6.6Hz), 1.26-1.44

(4H, m), 1.45-1.58 (2H, m), 1.85 (3H, s), 3.11- 3.20 (2H, m), 4.37 (2H, d, J=5.8Hz), 6.88 (1H, d, J=3.5Hz), 6.93 (1H, s), 7.22 (1H, d, J=3.5Hz), 7.31 (3H, br s), 8.45 (1H, t, J=5.8Hz)

13) 4-(5-Acetylaminomethyl-2-thienyl)-2-[(amino)(n- heptylamino)methyleneamino]thiazole

mp : 166-167°C

IR (Nujol) : 3300, 1650, 1600, 1530 cm^-1

NMR (DMSO-d₆, δ) : 0.86 (3H, t, J=6.7Hz), 1.21-1.43

(8H, m), 1.45-1.59 (2H, m), 1.85 (3H, s), 3.10- 3.20 (2H, m), 4.37 (2H, d, J=5.8Hz), 6.88 (1H, d, J=3.6Hz), 6.92 (1H, s), 7.22 (1H, d, J=3.6Hz), 7.33 (3H, br s), 8.46 (1H, t, J=5.8Hz)

14) 4-(5-Acetylaminomethyl-2-thienyl)-2-[(amino)(2- ethylbutylamino)methyleneamino]thiazole

mp : 136-137°C

IR (Nujol) : 3350, 3200, 1640, 1605, 1540 cm^-1

NMR (DMSO-d₆, δ) : 0.88 (3H, t, J=6.9Hz), 1.28-1.49 (5H, m), 1.85 (3H, s), 3.10-3.15 (2H, m), 4.38 (2H, d, J=5.8Hz), 6.88 (1H, d, J=3.6Hz), 6.92 (1H, s), 7.22 (1H, d, J=3.6Hz), 7.14-7.30 (3H, br s), 8.45 (1H, t, J=5.8Hz)

15) 4-(5-Acetylaminomethyl-2-thienyl)-2-[(amino)(2- methylbutylamino)methyleneamino]thiazole

mp : 131-132°C

IR (Nujol) : 3350, 1640, 1605, 1540 crn^-1

NMR (DMSO-d₆, δ) : 0.86-0.94 (6H, m), 1.06-1.24 (1H, m), 1.39-1.64 (2H, m), 1.85 (3H, s), 2.94-3.17 (2H, m), 4.38 (2H, d, J=5.8Hz), 6.88 (1H, d, J=3.6Hz), 6.92 (1H, s), 7.22 (1H, d, J=3.6Hz), 7.20-7.32 (3H, br s), 8.46 (1H, t, J=5.8Hz)

16) 4-(5-Acetylaminomethyl-2-thienyl)-2-[(amino)(2- ethylhexylamino)methyleneamino]thiazole

mp : 103-104°C

IR (Nujol) : 3400, 3230, 1640, 1610 cm^-1

NMR (DMSO-d₆, δ) : 0.88 (6H, t, J=7.2Hz), 1.20-1.60

(9H, m), 1.85 (3H, s), 3.07-3.17 (2H, m), 4.37 (2H, d, J=5.8Hz), 6.88 (1H, d, J=3.6Hz) , 6.92 (1H, s), 7.10-7.30 (3H, m), 8.44 (1H, t,

J=5.8Hz)

17) 4-(5-Acetylaminomethyl-2-thienyl)-2-[(amino)(3- methoxypropylamino)methyleneamino]thiazole

mp : 116-117°C

IR (Nujol) : 3230, 1640, 1610 cm^-1

NMR (DMSO-d₆, δ) : 1.67-1.80 (2H, m), 1.85 (3H, s),

3.16-3.25 (5H, m), 3.40 (2H, t, J=6.2Hz), 4.37 (2H, d, J=5.8Hz), 6.88 (1H, d, J=3.5Hz), 6.93 (1H, s), 7.22 (1H, d, J=3.5Hz), 7.40 (2H, br s), 8.45 (1H, t, J=5.8Hz) 18) 4-(5-Acetylaminomethyl-2-thienyl)-2-[(amino)[3-(2- ethylhexyloxy)propylamino]methyleneamino]thiazole mp : 77-78°C

IR (Nujol) : 3330, 3130, 1660, 1600 cm^-1

NMR (DMS0-d₆, δ) : 0.79-0.87 (6H, m), 1.15-1.40 (8H, m), 1.40-1.55 (1H, m), 1.65-1.80 (2H, m), 1.85 (3H, s), 3.17-3.27 (4H, m), 3.43 (2H, t,

J=6.1Hz), 4.37 (2H, d, J=5.8Hz), 6.88 (1H, d, J=3.5Hz), 6.93 (1H, s), 7.22 (1H, d, J=3.5Hz), 7.40 (2H, br s), 8.45 (1H, t, J=5.8Hz)

19) 4-(5-Acetylaminomethyl-2-thienyl)-2-[(amino)[2-(n- propoxy)ethylamino]methyleneamino]thiazole

mp : 121-122°C

IR (Nujol) : 3360, 3200, 1640, 1600 cm^-1

NMR (DMSO-d₆, δ) : 0.87 (3H, t, J=7.3Hz), 1.44-1.62 (2H, m), 1.85 (3H, s), 3.30-3.50 (4H, m), 4.37 (2H, d, J=5.8Hz), 6.88 (1H, d, J=3.5Hz), 6.94 (1H, s), 7.23 (1H, d, J=3.5Hz), 7.33 (2H, br s), 8.46 (1H, t, J=5.8Hz)

20) 4-(5-Acetylaminometyl-2-thienyl)-2-[(amino)(2- isopropoxyethylamino)methyleneamino]thiazole

mp : 149-150°C

IR (Nujol) : 3380, 3200, 1640, 1610 cm^-1

NMR (DMSO-d₆, δ) : 1.11 (6H, d, J=6.1Hz), 1.85 (3H, s), 3.25-3.40 (2H, m), 3.47 (2H, t, J=4.8Hz), 3.54-3.66 (1H, m), 4.37 (2H, d, J=5.7Hz), 6.88 (1H, d, J=3.5Hz), 6.94 (1H, s), 7.24 (1H, d, J=3.5Hz), 7.43 (2H, br s), 8.48 (1H, t, J=5.7Hz)

Example 3

A suspension of N-[(5-chloroacetyl-3-methyl-2-thienyl)methyl]acetamide (1.0 g) and amidinothiourea (0.48 g) in acetone (20 ml) was refluxed for 9 hours. The resulting precipitate was collected by filtration to afford 4-(5-acetylaminomethyl-4-methyl-2-thienyl)-2-(diaminomethyleneamino)thiazole hydrochloride (0.72 g). mp : 253-254°C

IR (Nujol) : 3270, 3100, 1680, 1610 cm^-1'

NMR (DMSO-d₆, δ) : 1.84 (3H, s), 2.17 (3H, s), 4.31 (2H, d, J=5.7Hz), 7.35 (1H, s), 7.44 (1H, s), 8.33 (4H, s), 8.43 (1H, t, J=5.7Hz), 12.60 (1H, s)

Example 4

A mixture of 4-(5-acetylaminomethyl-4-methyl-2-thienyl)-2-(diaminomethyleneamino)thiazole hydrochloride (630 mg) in water (20 ml) was alkalized to pH 11 with an aqueous potassium carbonate solution. The resulting precipitate was collected by filtration.

Recrystallization from a mixture of methanol,

tetrahydrofuran and diisopropyl ether afforded 4-(5-acetylaminomethyl-4-methyl-2-thienyl)-2-(diaminomethyleneamino)thiazole (430 mg).

mp : 228-230°C (dec.)

IR (Nujol) : 3340, 3200, 1640, 1620 cm^-1

NMR (DMSO-d₆, δ) : 1.83 (3H, s), 2.15 (3H, s), 4.29 (2H, d, J=5.6Hz), 6.88 (1H, s), 6.92 (4H, s), 7.13 (1H, s), 8.34 (1H, t , J=5. 6Hz )

Example 5

A solution of 3-methoxy-3-methylbutylphthalimide (8.7 g) and hydrazine hydrate (1.76 g) in ethanol (100 ml) was refluxed for 3 hours. 4-(5-Acetylaminomethyl-2-thienyl)-2-[(amino)(methylthio)methyleneamino]thiazole hydroiodide (4.0 g) was added to the reaction mixture. The mixture was refluxed for 45 hours. The insoluble material was removed by filtration. The solvent was removed under reduced pressure and the residue was dissolved in a mixture of water (100 ml) and tetrahydrofuran (30 ml). The mixture was adjusted to pH 10 with a 30% potassium carbonate solution and then was extracted with ethyl acetate (150 ml). The extract was dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was chromatographed on a silica gel column eluting with a mixture of chloroform and methanol (50:1). The solvent was removed under reduced pressure.

Recrystallization from a mixture of methanol,

tetrahydrofuran and diisopropyl ether afforded 4-(5-acetylaminomethyl-2-thienyl)-2-[(amino)(3-methoxγ-3-methylbutylamino)methyleneamino]thiazole (0.57 g).

mp : 192-193°C

IR (Nujol) : 3350, 3100, 1660, 1610 cm^-1

NMR (DMSO-d₆, δ) : 1.13 (6H, s), 1.65-1.73 (2H, m),

1.85 (3H, s), 3.12-3.24 (5H, m), 4.37 (2H, d, J=5.8Hz), 6.88 (1H, d, J=3.5Hz), 6.92 (1H, s), 7.22 (1H, d, J=3.5Hz), 7.41 (2H, br s), 8.44 (1H, t, J=5.8Hz)

Example 6

A suspension of 2-acetylaminomethyl-5-chloroacetylthiophene (1.5 g), N-(2-ethoxyethyl)amidinothiourea acetate (1.6 g) and sodium hydrogen carbonate (1.2 g) in ethanol (30 ml) was heated at 55°C for 4.5 hours. The solvent was removed under reduced pressure and the residue was dissolved in a mixture of water (70 ml) and

tetrahydrofuran (20 ml). The mixture was adjusted to pH 10 with 30% potassium carbonate solution and then was extracted with ethyl acetate (150 ml). The extract was dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was crystallized from ethyl acetate. Recrystallization from a mixture of methanol and water afforded 4-(5-acetylaminomethyl-2-thienyl)-2-[(amino)(2-ethoxyethylamino)methyleneamino]- thiazole (810 mg).

mp : 145-146°C

IR (Nujol) : 3350, 1640, 1600 cm^-1

NMR (DMSO-d₆, δ) : 1.13 (3H, t, J=7.0Hz), 1.85 (3H, s), 3.32-3.37 (2H, m), 3.43-3.54 (4H, m), 4.37

(2H, d, J=5.8Hz), 6.88 (1H, d, J=3.6Hz), 6.93 (1H, s), 7.23 (1H, d, J=3.6Hz), 7.40 (2H, br), 8.43 (1H, t, J=5.8Hz) Example 7

The following compounds were obtained according to a similar manner to that of Example 6.

1) 4-[5-(2-Acetylaminoethyl)-2-thienyl]-2-[(amino)(2- methoxyethylamino)methyleneamino]thiazole

mp : 130-131°C

IR (Nujol) : 3300, 1650, 1590, 1510 crn^-1

NMR (DMSO-d₆, δ) : 1.81 (3H, s), 2.88 (2H, t,

J=7.0Hz), 3.23-3.45 (6H, m), 6.80 (1H, d,

J=3.6Hz), 6.90 (1H, s), 7.24 (1H, d, J=3.6Hz),

7.55 (3H, br s), 8.00 (1H, t, J=5.5Hz)

2 ) 4-(5-Acetylaminomethyl-4-methyl-2-thienyl)-2- [(amino)(2-ethoxyethylamino)methyleneamino]thiazole mp : 141-142°C

IR (Nujol) : 3460, 3320, 3200, 1640 cm^-1

NMR (DMSO-d₆, δ) : 1.13 (3H, t, J=7.0Hz), 1.83 (3H, s), 2.14 (3H, s), 3.25-3.40 (2H, m), 3.43-3.53 (4H, m), 4.29 (2H, d, J=5.7Hz), 6.89 (1H, s), 7.12 (1H, s), 7.39 (2H, br s), 8.33 (1H, t,

J=5.7Hz)

Example 8

A suspension of 4-acetylaminomethyl-2-chloroacetylthiophene (1.4 g), N-(n-butyl)amidinothiourea (1.15 g) and sodium hydrogen carbonate (2 g) in methanol (15 ml) was refluxed for an hour. After removal of the solvent, the residue was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and then evaporated in vacuo. The residue was chromatographed on silica gel eluting with 3% methanol in chroloform to give 4-(4-acetylaminomethyl-2-thienyl)-2-[(amino)(n-butylamino)methyleneamino]thiazole (0.67 g).

mp : 144-145°C

IR (Nujol) : 3280, 1640, 1590, 1515 cm^-1

NMR (DMSO-d₆, δ) : 0.91 (3H, t, J=7.1Hz), 1.30-1.60 (4H, m), 1.86 (3H, s), 3.10-3.30 (2H, m), 4.20 (5.5Hz), 6.95 (1H, s), 7.16 (1H, d, J=1.1Hz), 7.28 (1H, d, J=l.1Hz), 7.30 (2H, br s), 8.29

(1H, t, J=5.5Hz)

Example 9

A mixture of 2-chloroacetyl-5-(ethoxycarbonylaminomethyl)thiophene (2.62.g). and

guanidinothiourea (1.8 g) in ethanol (50 ml) was refluxed for 5 hours under stirring. The reaction mixture was poured into water and the resulting mixture was adjusted to pH 8.5 with aqueous 20% potassium carbonate solution and extracted with a mixture of chloroform and methanol.

The extract was washed with brine and dried over magnesium sulfate, and the solvent was evaporated in vacuo and the residue was recrystallized from a mixture of ethyl acetate and acetone to give 2-diaminomethyleneamino-4-(5-ethoxycarbonylaminomethyl-2-thienyl)thiazole (1.66 g). mp : 190°C (dec.)

NMR (DMSO-d₆, δ) : 1.72 (3H, t, J=7Hz), 4.02 (2H, q, J=7Hz), 4.31 (2H, d, J=6Hz), 6.86 (1H, d,

J=3.6Hz), 6.92 (1H, s), 6.92-7.12 (4H, m), 7.23 (1H, d, J=3.6Hz), 7.73 (1H, m) Example 10

The following compounds were obtained according to a similar manner to that of Example 9. 1) 2-Diaminomethyleneamino-4-[5-(2- methoxycarbonylaminoethyl)-2-thienyl]thiazole

mp : 182-184°C (dec.)

NMR (DMS0-d₆, δ) : 2.98 (2H, t, J=7Hz), 3.23 (2H, m), 3.53 (3H, s), 6.79 (1H, d, J=3.6Hz), 6.88 (1H, s), 6.91 (4H, m), 7.23 (1H, d, J=3.6Hz),

7.28 (1H, m)

2 ) 2-Diaminomethyleneamino-4-[5-(2- ethoxycarbonylaminoethyl)-2-thienyl]thiazole

mp : 165-167°C (dec.)

IR (Nujol) : 3400, 1695, 1670, 1605, 1540 cm^-1

NMR (DMS0-d₆, δ) : 1.15 (3H, t, J=7Hz), 2.89 (2H, t, J=7Hz), 3.21 (2H, m), 4.00 (2H, q, J=7Hz), 6.79 (1H, d, J=3.6Hz), 6.89 (1H, s), 6.80-6.91 (4H, m), 7.23 (1H, d, J=3.6Hz), 7.23 (1H, m)

3 ) 2-[(Amino)(n-butylamino)methyleneamino]-4-[5-(2- ethoxycarbonylaminoethyl)-2-thienyl]thiazole

mp : 171-173°C

IR (Nujol) : 3320, 3250, 3090, 1690, 1638, 1530 cm^-1

NMR (DMSO-d₆, δ) : 0.95 (3H, t, J=7Hz), 1.15 (3H, t, J=7Hz), 1.23-1.69 (4H, m), 2.93 (2H, t, J=7Hz), 3.19-3.29 (2H, m), 3.35-3.41 (2H, m), 4.02 (2H, q, J=7Hz), 6.88 (1H, d, J=3.6Hz), 7.27 (1H, m), 7.41 (1H, d, J=3.6Hz), 7.59 (1H, s), 8.62 (2H, br s), 9.18 (1H, br s)

Example 11

A suspension of 2-chloroacetyl-5-(2-methoxycarbonylaminoethyl)thiophene (1.0 g) and N-methylamidinothiourea (500 mg) in ethanol (10 ml) was heated at 55°C for 6 hours. The solvent was removed under reduced pressure and the residue was dissolved in a mixture of water (50 ml) and tetrahydrofuran (20 ml). The mixture was adjusted to pH 10 with 30% potassium carbonate solution and then was extracted with ethyl acetate (100 ml). The extract was dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was chromatographed on a silica gel column eluting with a mixture of chloroform and methanol (100:1).

Recrystallization from ethyl acetate afforded 4-[5-(2-methoxycarbonylaminoethyl)-2-thienyl)-2-[(amino)(methylamino)methyleneamino]thiazole (370 mg). mp : 124-125°C

IR (Nujol) : 3420, 3340, 1680, 1630, 1590 cm^-1

NMR (DMSO-d₆, δ) : 2.73 (3H, d, J=4.8Hz), 2.89 (2H, t, J=7.1Hz), 3.18-3.28 (2H, m), 3.53 (3H, s), 6.80 (1H, d, J=3.5Hz), 6.89 (1H, s), 7.23 (1H, d, J=3.5Hz), 7.27 (1H, t, J=5.6Hz), 7.49 (2H, br s)

Example 12

The following compounds were obtained according to a similar manner to that of Example 11.

1 ) 4-[5-(2-Ethoxycarbonylaminoethyl)-2-thienyl]-2- [(amino)(methylamino)methyleneamino]thiazole

mp : 146-147°C

IR (Nujol) : 3370, 1700, 1630, 1590 cm^-1

NMR (DMSO-d₆, δ) : 1.15 (3H, t, J=7.1Hz), 2.73 (3H, d, J=4.8Hz), 2.89 (2H, t, J=7.1Hz), 3.18-3.25 (2H, m), 3.98 (2H, q, J=7.1Hz), 6.79 (1H, d, J=3.5Hz), 6.88 (1H, s), 7.21-7.23 (2H, m), 7.47 (2H, -br s) 2) 4-[5-(2-Acetylaminoethyl)-2-thienyl]-2-[(amino)(n- butylamino)methyleneamino]thiazole

mp : 131-133°C

IR (Nujol) : 3350, 1645, 1600, 1510 cm^-1

NMR (DMSO-d₆, δ) : 0.92 (3H, t, J=7.1Hz), 1.29-1.54 (4H, m), 1.81 (3H, s), 2.88 (2H, t, J=7.0Hz), 3.12-3.22 (2H, m), 3.23-3.36 (2H, m). 6.80 (1H, d, J=3.6Hz), 6.88 (1H, s), 7.22 (2H, d, J=3.6Hz), 7.29 (3H, br s), 7.99 (1H, t, J=5.4Hz)

3) 4-[5-(2-Acetylaminoethyl)-2-thienyl]-2-[(amino)(3- methylbutylamino)methyleneamino]thiazole

mp : 101-104°C

IR (Nujol) : 3200, 1625, 1580, 1520 crn^-1

NMR (DMSO-d₆, δ) : 0.91 (6H, d, J=6.6Hz), 1.36-1.47

(2H, m), 1.64-1.74 (1H, m), 1.81 (3H, s), 2.88 (2H, t, J=7.1Hz), 3.14-3.30 (4H, m), 6.80 (1H, d, J=3.6Hz), 6.89 (1H, s), 7.22 (1H, d, J=3.6Hz), 7.28 (1H, br s), 8.00 (1H, t, J=5.6Hz)

Example 13

A suspension of 2-chloroacetyl-5-(2-ethoxycarbonylaminoethyl)thiophene (1.0 g), N-(2-ethoxyethyl)amidinothiourea acetate (910 mg) and sodium hydrogen carbonate (670 mg) in ethanol (20 ml) was heated at 55°C for 5 hours. The solvent was removed under reduced pressure and the residue was dissolved in a mixture of water (50 ml) and tetrahydrofuran (20 ml). The mixture was adjusted to pH 10 with a 30% potassium

carbonate solution and then was extracted with ethyl acetate (100 ml). The extract was dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was chromatographed on a silica gel column eluting with a mixture of chloroform and methanol (200:1). The desired fractions were collected and the solvent was removed under reduced pressure. The residue was dissolved in a mixture of methanol (10 ml) and 4N dioxanoic hydrogen chloride solution (10 ml). The mixture was stirred at ambient temperature for 10 minutes. The solvent was removed under reduced pressure. Recrystallization from a mixture of ethanol and diisopropyl ether afforded 2-[(amino)(2τethoxyethylamino)methyleneamino]-4-[5-(2-ethoxycarbonylaminoethyl)-2-thienyl]thiazole hydrochloride (460 mg) .

mp : 134-135°C

IR (Nujol) : 3320, 3090, 1690, 1640 cm^-1

NMR (DMSO-d₆, δ) : 1.14 (3H, t, J=7.0Hz), 1.15 (3H, t, J=7.1Hz), 2.92 (2H, t, J=7.0Hz), 3.19-3.30 (2H, m), 3.50-3.60 (6H, m), 3.98 (1H, q,

J=7.1Hz), 6.87 (1H, d, J=3.6Hz), 7.25 (1H, t,

J=5.6Hz), 7.41 (1H, d, J=3.6Hz), 7.45 (1H, s), 8.48 (2H, br s), 9.35 (1H, br)

Example 14

A solution of 2-(2-acetylaminoethyl)-5-chloroacetylthiophene (1.0 g) and N-methylamidinothiourea (0.54 g) in ethanol (20 ml) was refluxed for 4 hours.

After the mixture was concentrated in vacuo, and the residue was basified with 20% aqueous potassium carbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was chromatographed on silica gel (5% methanol in chloroform) to give an oil. The free base was converted to oxalate in a usual manner to afford 4-[5-(2-acetylaminoethyl)-2-thienyl]-2-[(amino)(methylamino)methyleneamino]thiazole oxalate (1.5 g).

mp : 179-180°C

IR (Nujol) : 3200, 1700, 1630, 1560 cm^-1

NMR (DMSO-d₆, δ) : 1.82 (3H, s), 2.85-2.94 (5H, m), 3.25-3.34 (4H, m), 6.85 (1H, d, J=3.6Hz), 7.23 (1H, s), 7.37 (1H, d, J=3.6Hz), 8.02 (1H, t, J=5.4Hz), 8.47 (3H, br s) Example 15

A solution of 2-acetyl-4-acetylaminothiophene (916 mg) and phenyltrimethylammonium tribromide (2.63 g) in tetrahydrofuran (15 ml) was stirred for an hour at ambient temperature. The mixture was diluted with brine (30 ml) and extracted with ethyl acetate (20 ml). The organic layer was dried over anhydrous magnesium sulfate, and evaporated in vacuo. The obtained residue containing 4-acetylamino-2-bromoacetylthiophene, and 3-[(amino)(n-butylamino)methylene]thiourea (870 mg) were dissolved in acetonitrile (20 ml) and refluxed for 2 hours. After removal of the solvent, the residue was diluted with water and alkalized with an aqueous potassium carbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was chromatographed on silica gel eluting with 5% methanol in chloroform to give 4-(4-acetylamino-2-thienyl)-2-[(amino)(n-butylamino)-methyleneamino]thiazole (0.30 g).

mp : 125-126°C

IR (Nujol) : 3340, 3160, 1680, 1630, 1570, 1550 cm^-1

NMR (DMSO-d₆, δ) : 0.91 (3H, t, J=7.2Hz), 1.30-1.51 (4H, m), 2.01 (3H, s), 3.10-3.22 (2H, m), 6.96 (1H, s), 7.30 (1H, d, J=1.4Hz), 7.34 (1H, d, J=1.4Hz), 10.28 (1H, s)

Example 16

A suspension of N-(5-chloroacetyl-3-methyl-2-thienylmethyl)acetamide (1.0 g) and N-methylamidinothiourea (540 mg) in ethanol (20 ml) was heated at 55°C for 3.5 hours. The resulting precipitate was collected by filtration. Recrystallization from a mixture of methanol and diisopropyl ether afforded 4-(5-acetylaminomethyl-4-methyl-2-thienyl)-2- [(amino)(methylamino)methyleneamino]thiazole hydrochloride (580 mg) .

mp : 255-256°C

IR (Nujol) : 3260, 3050, 1690, 1640 cm^-1

NMR (DMS0-d₆, δ) : 1.84 (3H, s), 2.17 (3H, s), 2.95 (3H, d, J=4.6Hz), 4.31 (2H, d, J=5.7Hz), 7.32 (1H, s), 7.42 (1H, s), 8.41 (1H, t, J=5.7Hz),

8.65 (3H, br s), 12.30 (1H, br s)

Example 17

The following compounds were obtained according to a similar manner to that of Example 16.

1 ) 4-(5-Acethylaminometyl-4-methyl-2-thienyl)-2- [(amino)(n-butylamino)methyleneamino]thiazole

hydrochloride

mp : 244-245°C

IR (Nujol) : 3210, 1680, 1610 cm^-1

NMR (DMSO-d₆, δ) : 0.95 (3H, t, J=7.2Hz), 1.30-1.55 (2H, m), 1.55-1.70 (2H, m), 1.84 (3H, s), 2.17 (3H, s), 3.25-3.45 (2H, m), 4.32 (2H, d,

J=5.7Hz), 7.28 (1H, s), 7.45 (1H, s), 8.42 (1H, t, J=5.7Hz), 8.51 (2H, br s), 9.15 (1H, br s), 12.35 (1H, br s)

2) 4-(5-Acetylaminomethyl-4-methyl-2-thienyl)-2- [(amino)(3-methylbutylamino)methyleneamino]thiazole hydrochloride

mp : 238-239°C

IR (Nujol) : 3320, 1680, 1610 cm^-1

NMR (DMSO-d₆, δ) : 0.94 (6H, d, J=6.5Hz), 1.48-1.58 (2H, m), 1.67-1.77 (1H, m), 1.83 (3H, s), 2.17 (3H, s), 3.25-3.43 (2H, m), 4.32 (2H, d,

J=5.8Hz), 7.27 (1H, s), 7.45 (1H, s), 8.41 (1H, t, J=5.8Hz), 8.51 (2H, br s), 9.15 (1H, br s), 12.43 (1H, br s)

Example 18

A suspension of 4-(5-acetylaminomethyl-2-thienyl)-2-[(amino)(3-methylbutylammo)methyleneamino]thiazole (1.8 g) and concentrated hydrochloric acid (8 ml) in ethanol (80 ml) was refluxed for 31 hours. After cooling, the resulting precipitate was collected by filtration to afford 4-(5-aminomethyl-2-thienyl)-4-[(amino)(3-methylbutylamino)methyleneamino]thiazole dihydrochloride (1.3 g).

mp : >250°C

IR (Nujol) : 3260, 1700, 1640, 1600 cm^-1

NMR (DMSO-d₆, δ) : 0.94 (6H, d, J=6.5Hz), 1.47-1.58 (2H, m), 1.67-1.80 (1H, m), 3.36-3.42 (2H, m), 4.21 (2H, q, J=4.9Hz), 7.27 (1H, d, J=3.7Hz), 7.52 (1H, d, J=3.7Hz), 7.60 (1H, s), 8.59 (3H, br s), 8.68 (2H, br s), 9.01 (1H, br s), 12.80 (1H, br s)

Example 19

The following compounds were obtained according to a similar manner to that of Example 18.

1) 4-(5-Aminomethyl-2-thienyl)-2-[(amino)(n-hexylamino)- methyleneamino]thiazole dihydrochloride

mp : 278-282°C

IR (Nujol) : 3260, 1700, 1630, 1600 cm^-1

NMR (DMSO-d₆, δ) : 0.88 (3H, t, J=6.7Hz), 1.20-1.50 (6H, m), 1.50-1.75 (2H, m), 3.35-3.44 (2H, m), 4.10-4.30 (2H, br s), 7.27 (1H, d, J=3.7Hz), 7.53 (1H, d, J=3.7Hz), 7.60 (1H, s), 8.62-8.70 ( 5H , m) , 9 . 03 ( 1H , br s ) , 12 . 80 ( 1H, br s )

2) 4-(5-Aminomethyl-2-thienyl)-2-[(amino)(n- pentylamino)methyleneamino]thiazole dihydrochloride mp : >250°C

IR (Nujol) : 3250, 1730, 1700, 1640, 1600, 1540 cm^-1 NMR (DMSO-d₆, δ) : 0.89 (3H, t, J=6.7Hz), 1.30-1.48 (4H, m), 1.53-1.68 (2H, m), 3.35-3.44 (2H, m),

4.22 (2H, s), 7.28 (1H, d, J=3.7Hz), 7.54 (1H, d, J=3.7Hz), 7.61 (1H, s), 8.62-8.71 (5H, m),

9.06 (1H, s), 12.85 (1H, s)

3) 4-(5-Aminomethyl-2-thienyl)-2-[(amino)(n- heptylamino)methyleneamino]thiazole dihydrochloride mp : >250°C

IR (Nujol) : 3300, 1700, 1640, 1600, 1540 cm^-1

NMR (DMSO-d₆, δ) : 0.86 (3H, t, J=6.8Hz), 1.23-1.52 (8H, m), 1.54-1.68 (2H, m), 3.35-3.50 (2H, m), 4.24 (2H, s), 7.26 (1H, d, J=3..7Hz), 7.53 (1H, d, J=3.7Hz), 7.60 (1H, s), 8.52-8.63 (5H, m),

9.08 (1H, s), 12.68 (1H, s)

4) 4-(5-Aminomethyl-2-thienyl)-2-[(amino)(n- octylamino)methyleneamino]thiazole dihydrochloride mp : 279-281°C

IR (Nujol) : 3250, 1700, 1640 cm^-1

NMR (DMSO-d₆, δ) : 0.85 (3H, t, J=6.7Hz), 1.15-1.50 (10H, m), 1.50-1.70 (2H, m), 3.30-3.50 (2H, m),

4.23 (3H, q, J=5.6Hz), 7.26 (1H, d, J=3.6Hz), 7.53 (1H, d, J=3.6Hz), 7.60 (1H, s), 8.57-8.67

(4H, m), 9.01 (1H, br s), 12.75 (1H, br s)

Example 20

A mixture of 4-[5-(2-aminoethyl)-2-thienyl]-2-(diaminomethyleneamino)thiazole dihydrochloride (1.5 g) and triethylamine (2.4 ml) in N,N-dimethylformamide (15 ml) and tetrahydrofuran (15 ml) was added benzyl

chloroformate (3.0 g) at 0°C. The solution was stirred at 0°C for 1 hour, diluted with water, and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (5% methanol in chloroform) to give 4-{5-[2-benzyloxycarbonylamino]-ethyl-2-thienyl}-2-(diaminomethyleneamino)thiazole (0.52 g).

mp : 197-199°C

IR (Nujol) : 3300, 1680, 1590, 1530 cm^-1

NMR (DMSO-d₆, δ) : 2.90 (2H, t, J=7.0Hz), 3.21-3.31 (2H, m), 5.02 (2H, s), 6.79 (1H, d, J=3.5Hz), 6.88 (1H, s), 7.00 (4H, br s), 7.23 (1H, d,

J=3.5Hz), 7.29-7.37 (5H, m), 7.44 (1H, t,

J=5.7Hz)

Example 21

A suspension of 4-(5-aminomethyl-2-thienyl)-2- [(amino)(3-methylbutylammo)methyleneamino]thiazole dihydrochloride (1.1 g) and potassium cyanate (270 mg) in water (10 ml) was stirred at ambient temperature for 4 hours. The reaction mixture was adjusted to pH 10 with 30% potassium carbonate solution. The resulting,

precipitate was collected by filtration.

Recrystallization from methanol afforded 2-[(amino)(3-methylbutylamino)methyleneamino]-4-(5-ureidomethyl-2-thienyl)thiazole (0.5 g).

mp : 166-167°C

IR (Nujol) : 3410, 3300, 1650, 1600 cm^-1

NMR (DMSO-d₆, δ) : 0.91 (6H, d, J=6.6Hz), 1.35-1.45 (2H, m), 1.62-1.72 (1H, m), 3.13-3.22 (2H, m), 4.30 (2H, d, J=5.9Hz), 5.54 (2H, s), 6.46 (1H, t, J=5.9Hz), 6.85 (1H, d, J=3.6Hz), 6.90 (1H, s), 7.21 (1H, d, J=3.6Hz), 7.34 (2H, br s)

Example 22

The following compounds were obtained according to a similar manner to that of Example 21.

1) 2-[(Amino)(n-hexylamino)methyleneamino]-4-(5- ureidomethyl-2-thienyl)thiazole

mp : 170-171°C

IR (Nujol) : 3470, 3400, 3320, 1640, 1590 cm^-1

NMR (DMSO-d₆, δ) : 0.87 (3H, t, J=6.6Hz), 1.20-1.40 (6H, m), 1.40-1.60 (2H, m), 3.10-3.19 (2H, m),

4.30 (2H, d, J=5.9Hz), 5.54 (2H, s), 6.46 (1H, t, J=5.9Hz), 6.85 (1H, d, J=3.6Hz), 6.90 (1H, s), 7.21 (1H, d, J=3.6Hz), 7.36 (2H, br s)

2) 4-(5-Ureidomethyl-2-thienyl)-2-[(amino)(n- pentylamino)methyleneamino]thiazole

mp : 115-116°C

IR (Nujol) : 3250, 1630, 1540 cm^-1

NMR (DMSO-d₆, δ) : 0.89 (3H, t, J=6.8Hz), 1.32-1.45 (4H, m), 1.50-1.65 (2H, m), 3.21-3.30 (2H, m),

4.31 (2H, d, J=5.9Hz), 5.62 (2H, br s), 6.58 (1H, t, J=5.9Hz), 6.88 (1H, d, J=3.6Hz), 7.19 (1H, s), 7.30 (1H, d, J=3.6Hz), 8.00 (3H, br s)

3) 4-(5-Ureidomethyl-2-thienyl)-2-[(amino)(n- heptylamino)methyleneamino]thiazole

mp : 122-123°C

IR (Nujol) : 3300, 1640, 1600, 1550, 1510 cm^-1

NMR (DMSO-d₆, δ) : 0.86 (3H, t, J=6.7Hz), 1.21-1.42 (8H, m), 1.45-1.67 (2H, m) , 3.18-3.28 (2H, m), 4.31 (2H, d, J=5.9Hz), 5.60 (2H, br s), 6.55 (1H, t, J=5.9Hz), 6.88 (1H, d, J=3.6Hz), 7.14 (1H, s), 7.28 (1H, d, J=3.6Hz), 7.90 (3H, br s) 4) 2-[(Amino)(n-octylamino)methyleneamino]-4-(5- ureidomethyl-2-thienyl)thiazole

mp : 165-166°C

IR (Nujol) : 3400, 1640, 1590 cm^-1

NMR (DMSO-d₆, δ) : 0.85 (3H, t, J=6.7Hz), 1.20-1.40 (10H, m), 1.40-1.60 (2H, m), 3.10-3.20 (2H, m), 4.30 (2H, d, J=5.9Hz), 5.56 (2H, s), 6.47 (1H, t, J=5.9Hz), 6.85 (1H, d, J=3.5Hz), 6.90 (1H, s), 7.21 (1H, d, J=3.5Hz), 7.37 (2H, br s)

Claims

C L A I M S 1. A compound of the formula :

wherein R¹ is hydrogen or alkyl optionally

substituted with alkoxy,

R² is hydrogen or alkyl optionally

substituted with alkoxy,

R³ is hydrogen or lower alkyl,

provided that when R¹ and R² are both hydrogen,

then 1) R⁴ is amino substituted with

esterified carboxy, or

2) Q is lower alkyl,

and pharmaceutically acceptable salts thereof. 2. A compound according to claim 1,

wherein R⁴ is amino substituted with acyl, and

A is lower alkylene.

3. A compound according to claim 2,

wherein R¹ is alkyl optionally substituted with

alkoxy,

R² is hydrogen, and

R⁴ is amino substituted with lower alkanoyl, esterified carboxy or carbamoyl.

4. A compound according to claim 3, wherein R¹ is lower alkyl optionally substituted with lower alkoxy,

R⁴ is amino substituted with lower alkanoyl, and

Q is hydrogen.

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

wherein R¹ is hydrogen or alkyl optionally

substituted with alkoxy,

R² is hydrogen or alkyl optionally

substituted with alkoxy,

R³ is hydrogen or lower alkyl,

R⁴ is amino optionally substituted with acyl,

A is a single bond or lower alkylene, and Q is hydrogen or lower alkyl,

provided that when R¹ and R² are both hydrogen,

then 1) R⁴ is amino substituted esterified carboxy, or

2) Q is lower alkyl,

or salts thereof, which comprises. a) reacting a compound of the formula )

or its salt with a compound of the formula R²- NH₂ (III) or its salt to provide a compound of the formula

or its salt, in the above formulas,

R¹, R², R³, R⁴, A and Q are each as defined above, and

R⁵ is lower alkyl, or b) reacting a compound of the formula

with a compound of the formula

or its salt to provide a compound of the formula

or its salt, in the above formulas,

R¹, R², R³, R⁴, A and Q are each as defined above, and

X¹ is acid residue, or c) subjecting a compound of the formula

or its salt to deacylation reaction to provide a compound of the formula :

or its salt, in the above formulas,

R¹, R², R³, A and Q are each as defined above, and

R⁴ _a is amino substituted with acyl, or d) reacting a compound of the formula

or its salt with an acylating agent to provide a compound of the formula :

or its salt, in the above formulas,

R¹, R², R³, R⁴ _a, A and Q are each as defined above.

6. A pharmaceutical composition comprising a compound of claim 1, as an active ingredient, in association with a pharmaceutically acceptable, substantially non- toxic carrier or excipient.

7. A compound of claim 1 for use as a medicament.

8. A method for the treatment and/or prevention of

gastritis, ulcer, Zollinger-Ellison Syndrome, reflux esophagitis, upper gastrointestinal bleeding or infectious diseases which comprises administering the effective amount of a compound of claim 1 to human beings or animals.

9. Use of a compound of claim 1 for the manufacture of a medicament for the treatment and/or prevention of gastritis, ulcer, Zollinger-Ellison Syndrome, reflux esophagitis, upper gastrointestinal bleeding or infectious diseases in human beings or animals.