JPH025755B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel substituted thiazole derivatives,
For more details, please refer to the following formula () In the formula, R is (a) a hydrogen atom or (b) a halogen atom,
Represents a lower alkyl group which may be substituted with a hydroxyl group, lower alkoxy group or lower alkanoyloxy group, Y represents a sulfur atom or a methylene group, provided that when R represents a hydrogen atom or an unsubstituted lower alkyl group The present invention relates to a thiazole derivative or a salt thereof, a method for producing the same, and an antiulcer agent containing the compound of the above formula () or a salt thereof, wherein Y is limited to a methylene group. One of the major causes of ulcers in the stomach or duodenum is the secretion of abnormally large amounts of gastric acid, and the conventional anti-ulcer drugs to deal with this are those that have the effect of neutralizing gastric acid and those that have anticholinergic effects. It is broadly divided into motsu. However, the type that neutralizes gastric acid is short-lasting and weakly effective, and the type that has anticholinergic effects has strong side effects and is undesirable. On the other hand, it is already known that gastric acid secretion is stimulated via histamine _H2 receptors, and recently,
A new type of gastric acid secretion inhibitor that has this histamine H ₂ receptor antagonistic effect has been developed, and several proposals have been made [for example, see JP-A-47-42661, JP-A-53-147069, etc. ]. The compound of the above formula () provided by the present invention is a novel compound that has not been described in conventional literature, has an excellent gastric acid secretion suppressing effect based on histamine H ₂ receptor antagonism, and is a new type of compound. It is a compound useful as an anti-ulcer agent. Throughout this specification, the term "lower" means that the group or compound to which this term is attached has 6 or fewer carbon atoms;
This means that the number is preferably 4 or less. The "lower alkyl group" represented by R in the above formula () may be linear or branched, such as methyl, ethyl, n-
or iso-propyl, n-, iso-, sec- or tert-butyl groups, among which methyl and isopropyl groups are preferred. Furthermore, the alkyl group, especially the methyl group, can be substituted with a halogen atom, a hydroxyl group, a lower alkoxy group, a lower alkanoyloxy group. Here, the "halogen atom" includes four types of fluorine, chlorine, bromine, and iodine, especially fluorine or chlorine, and the "lower alkoxy group" includes, for example, methoxy, ethoxy, n- or
iso-propoxy, n-, iso-, sec- or
Examples of the "lower alkanoyloxy group" include acetyloxy, propionyloxy, and isobutyryloxy groups. Specific examples of substituted alkyl groups represented by R include, for example, hydroxymethyl, hydroxyethyl, 2-hydroxypropyl, chloromethyl, bromoethyl, trifluoromethyl, methoxymethyl, methoxyethyl, ethoxymethyl, acetyl. Examples include oxymethyl, propionyloxymethyl, and isobutyryloxymethyl groups, among which hydroxymethyl, hydroxyethyl, and acetyloxymethyl groups are preferred. Among the compounds of the formula () provided by the present invention, a preferable group of compounds includes R being a hydrogen atom, a methyl group, an isopropyl group, a hydroxymethyl group,
hydroxyethyl group, acetyloxymethyl group,
In particular, compounds of formula () when representing a methyl, hydroxymethyl or acetyloxymethyl group. Thus, representative examples of the compounds of formula () provided by the present invention are as follows. 2-diaminomethyleneamino-4-[2-(chloroacetylamino)ethylthiomethyl]thiazole, 2-diaminomethyleneamino-4-[2-trifluoroacetylamino)ethylthiomethyl]thiazole, 2-diaminomethyleneamino- 4-[2-(3-
Bromopropionylamino)ethylthiomethyl]
Thiazole, 2-diaminomethyleneamino-4-[2-(hydroxyacetylamino)ethylthiomethyl]thiazole, 2-diaminomethyleneamino-4-[2-(2-
hydroxypropionylamino)ethylthiomethyl]thiazole, 2-diaminomethyleneamino-4-[2-(3-
hydroxypropionylamino)ethylthiomethyl]thiazole, 2-diaminomethyleneamino-4-[2-(4-
Hydroxybutyrylamino)ethylthiomethyl]
Thiazole, 2-diaminomethyleneamino-4-[2-(methoxyacetylamino)ethylthiomethyl]thiazole, 2-diaminomethyleneamino-4-[2-(ethoxyacetylamino)ethylthiomethyl]thiazole, 2-diaminomethylene Amino-4-[2-(3-
methoxypropionylamino)ethylthiomethyl]thiazole, 2-diaminomethyleneamino-4-[2-(acetoxyacetylamino)ethylthiomethyl]thiazole, 2-diaminomethyleneamino-4-[2-(3-
acetoxypropionylamino)ethylthiomethyl]thiazole, 2-diaminomethyleneamino-4-[2-(propionyloxyacetylamino)ethylthiomethyl]thiazole, 2-diaminomethyleneamino-4-[2-(pivaloyloxyacetyl) amino)ethylthiomethyl]thiazole, 2-diaminomethyleneamino-4-[4-(formylamino)butyl]thiazole, 2-diaminomethyleneamino-4-[4-(acetylamino)butyl]thiazole, 2-diaminomethylene Amino-4-[4-(isobutyrylamino)butyl]thiazole, 2-diaminomethyleneamino-4-[4-hydroxyacetylamino)butyl]thiazole, 2-diaminomethyleneamino-4-[4-(3-
hydroxypropionylamino)butyl]thiazole, 2-diaminomethyleneamino-4-[4-(methoxyacetylamino)butyl]thiazole, 2-diaminomethyleneamino-4-[4-(acetoxyacetylamino)butyl]thiazole, 2- Diaminomethyleneamino-4-[4-(propionyloxyacetylamino)butyl]thiazole According to the present invention, there are also provided salts of the compound of formula () above. Examples of such salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and acetic acid, propionic acid, lactic acid, citric acid,
Examples include salts with organic acids such as tartaric acid and P-toluenesulfonic acid, among which pharmacologically acceptable salts are suitable. According to the invention, the compound of formula () and its salts are of the formula In the formula, Y has the above meaning, and an amine compound or a reactive derivative thereof is represented by the formula In the formula, R has the above-mentioned meaning. It can be produced by reacting with a carboxylic acid or a reactive derivative thereof, and, if necessary, converting the resulting reaction product into a salt. The above method of the present invention is an amidation reaction of the amine compound of formula () or a reactive derivative thereof with a carboxylic acid of formula () or a reactive derivative thereof. The amine compound of formula () used as one of the starting materials in this amidation reaction is a compound known per se (see, for example, JP-A-53-147069). In addition, its reactive derivatives include:
Any of those used for activating amino groups during amidation reactions in the field of peptide chemistry can be used, and examples include the following. (i) Isocyanate (or isothiocyanate) Q-N=C=O (or S) (-a) (ii) Phosphazo compound Q-N=P-NH-Q (-b-1) or (iii) Phosphoramidide compound (iv) Phosfluoramidate compound O=P(NH-Q) ₃ (-d-1) or In each of the above formulas, Q is , R ₁ and R ₂ are the same or different,
Each represents an alkyl, aryl or aralkyl group, or R ₁ and R ₂ together represent an alkylene or o-phenylene group. On the other hand, the carboxylic acid of formula () used as the other starting material in the above-mentioned amidation reaction is itself a known compound, and its reactive derivative is used as a carboxyl group when carrying out the amidation reaction in the field of peptide chemistry. Any of those used for activation can be used, including the following: In addition, when a hydroxyl group exists in the group R in the carboxylic acid of formula (), it is desirable to protect the hydroxyl group with an acyl group in advance, and these protecting groups can be protected by a conventional method after the amidation reaction. Accordingly, it can be removed, for example, by mild hydrolysis. (i) Acid halide R-COE (-a) in which E is a halogen atom, in particular a chlorine or bromine atom, and R has the meaning given above; (ii) Ester R-COOR ₃ (-b) in the formula , R ₃ is a lower alkyl group, especially a methyl or ethyl group; or an active ester residue, e.g.
_CH2CN ,

[Formula] or

[Formula]; R has the above meaning; (iii) mixed acid anhydride R-COOR ₄ (-c) where R ₄ is an organic or inorganic acid residue, such as acyl such as acetyl or propionyl; group; group-
COOR ₅ (wherein R ₅ is a lower alkyl group having 6 or less carbon atoms); or

[Formula] (wherein R ₁ and R ₂ have the above meanings), R has the above meaning, (iv) activated amide R-COR ₆ (-d) where R ₆ is a substituted or represents an unsubstituted 1-imidazolyl group or 1-pyrazolyl group, R has the above meaning, (v) acid azide R-CON ₃ (-e) where R has the above meaning. The amidation reaction between the amine compound of formula () or its reactive derivative and the carboxylic acid of formula () or its reactive derivative can be carried out according to various methods known per se. For example, the amidation can be carried out by direct condensation of an amine compound of formula () with a carboxylic acid of formula (). Although the reaction can be carried out without a solvent, it is generally carried out in an inert organic solvent, such as a hydrocarbon such as benzene, toluene, or xylene;
Ethers such as tetrahydrofuran, dioxane, dimethoxyethane, and diglyme; amides such as dimethylformamide and dimethylcetamide; halogenated hydrocarbons such as dichloromethane and chloroform; dimethyl sulfoxide, or alcohols such as methanol and ethanol. be able to. The reaction temperature and pressure are not particularly limited and can be varied widely depending on the raw materials used, but the reaction temperature is usually about -78°C to the reflux temperature of the reaction mixture, preferably room temperature to 200°C. and the pressure is advantageously normal pressure.
In addition, the reaction can be carried out in the presence of a condensing agent if necessary, and condensing agents that can be used include:
such as Lewis acids, especially silicon tetrachloride, trichlorophenylsilane and titanium tetrachloride, N-ethyl-
N′-diethylaminopropylcarbodiimide,
N,N'-dicyclohexylcarbodiimide, etc.;
Combination of triarylphosphine and disulfide; examples include strong acidic ion exchange resins such as Amberlite IR-120. Moreover, the amidation according to the present invention is carried out by the above formula ()
between a reactive derivative as described above of an amine compound of formula () and a free carboxylic acid of formula (), or between a free amine compound of formula () and a reactive derivative of a carboxylic acid of formula () as described above; You can also do it with This amidation can also be carried out without using a solvent if necessary, but it is usually carried out in an inert organic solvent such as those mentioned above, especially alcohols (for example, methanol, ethanol, ethylene glycol, glycerin, etc.). is advantageous. Although the reaction temperature and pressure are not critical, the reaction temperature typically ranges from about -78°C to the reflux temperature of the reaction mixture, preferably from about -78°C to 180°C;
The pressure is advantageously normal pressure. In the above amidation reaction, the amount of the carboxylic acid of formula () or its reactive derivative to be used relative to the amine compound of formula () or its reactive derivative is not critical, and may vary widely depending on the type of amidation agent used. Generally, at least 1 mole, preferably in the range of 1 to 10 moles, more preferably in the range of 1 to 2 moles, of the carboxylic acid of formula () or a reactive derivative thereof per mole of the compound of formula () or derivative thereof, although this may vary. It is advantageous to use it in In this way, the compound of the formula () is obtained in high yield. The formula () produced by the method described above
The compounds can be converted into the corresponding salts if desired. The salt-forming reaction can be easily carried out by treating the compound of formula () with an inorganic or organic acid as described above, according to a method known per se. Thus, the compound of the formula () or a salt thereof produced according to the method of the present invention can be prepared from a reaction mixture by a method known per se, such as recrystallization, distillation, column chromatography, thin layer chromatography, etc. can be isolated and/or purified from The substituted thiazole derivatives represented by formula () and salts thereof of the present invention described above have an effect of suppressing gastric acid secretion based on an excellent histamine H ₂ receptor antagonism, and are effective against diseases caused by gastric acid, such as gastric acid secretion. It is also an extremely useful compound for the treatment of duodenal ulcer. The following animal experiments demonstrate that the compound represented by formula () of the present invention has excellent histamine H ₂ receptor antagonism. The compounds of the present invention used in the following animal experiments are represented by the following symbols. Compound A: 2-diaminomethyleneamino-4-[2-(hydroxyacetylamino)ethylthiomethyl)
Thiazole, B: 2-diaminomethyleneamino-4-[2-(acetoxyacetylamino)ethylthiomethyl]
Thiazole, C: 2-diaminomethyleneamino-4-[4-(acetylamino)butyl]thiazole. (1) Histamine _H2 from Guinea pig right atrium specimen
Receptor antagonism A Hartley guinea pig (male: 400-550 g) was beaten on the head to exsanguinate, and the heart was removed. The right atrium was dissected in oxygen-saturated Tyrode's solution and silk sutures were attached to both ends. Suspend the atrium with a tension of 700 mg using silk threads attached to both ends in a Magnus tube (25 ml) containing Tyrode's solution kept at 36°C and ventilating a mixed gas (95% O _{2 :} 5% CO 2 ). did. The contraction movement of the atrium is controlled by a force-displacement transducer (Force-displacement-).
transducer), and the cardiac index was calculated. Histamine (used in the form of diphosphate, the same applies hereinafter) was administered at equal intervals of 1/2 the logarithm of the amount added until the maximum response of increasing cardiac frequency was obtained.
A dose-response curve of histamine was obtained by adding cumulatively into the Magnus tube at concentrations of ×10 ⁻⁸ M to 1×10 ⁻⁴ M. After washing the inside of the Magnus tube several times and stabilizing the atrium for 1 hour, the above procedure was repeated again to obtain a histamine dose-response curve. After washing the Magnus tube several times, the tissue was allowed to stabilize for 50 minutes. Then test compound (1×10 ^-5
M) was added into a Magnus tube, and 20 minutes later, a dose-response curve of histamine in the presence of the test compound was obtained. From the second histamine dose-response curve and the third histamine dose-response curve in the presence of the test compound, JMVan Rossum's method (Arch.int.
Pharmacodyn., 143 , 299, 1963), the _PA2 value of each test compound (the logarithm of the molar concentration of the test compound required to double the histamine concentration in the Magnus tube to produce a given reaction) The negative loga-rithm) was calculated. Cimetidine, a known histamine _H2 receptor antagonist,
The measurement results of the relative potency of the compound of the present invention, set as 100%, are shown in Table 1 below. Table-1 Compound relative potency (%) A 531 B 360 C 248 (2) Heidenhain pouch (Heidenhain pouch)
pouch) Inhibitory effect on histamine-stimulated gastric juice secretion in dogs A Heidenhain pouch was prepared using a male mongrel dog according to a conventional method, and after more than one month had elapsed, the experiment was conducted without anesthesia. Histamine (80 μg/Kg-hr) dissolved in physiological saline was continuously injected intravenously into the forelimbs of fasted dogs, and gastric fluid naturally drained from the pouch was collected every 15 minutes. 45 minutes after the start of the injection, the test compound packed in a capsule was orally administered, and gastric juice collection was continued. The volume and acidity of the collected gastric juice were measured, and the product of the volume and acidity was defined as the total acid (output). The suppression rate of gastric juice secretion was calculated from the amount of gastric juice secretion after administration relative to the amount of gastric juice secretion immediately before administration of the test compound, and a good suppression rate was shown. (3) Toxicity A test compound was dissolved in an equimolar hydrochloric acid solution to a group of three ddY mice (male: 19-22 g), each dose was administered intravenously, and the mice were observed for 72 hours.
As a result, for example, the LD ₅₀ value of compound B is 200 mg/
Kg. Thus, the compound represented by formula (1) of the present invention can be administered orally or parenterally (e.g., intramuscularly, intravenously, subcutaneously, (rectal administration, transdermal administration, etc.). When used as a medicament, the compounds of the invention can be formulated into a variety of forms suitable for oral or parenteral administration. For example, the compounds of the invention may be added to non-toxic excipients, binders, lubricants, disintegrants, preservatives, tonicity agents, stabilizers, dispersants, antioxidants, etc. commonly used in such drugs. It can be formulated using additives such as agents, colorants, flavoring agents, and buffering agents. Depending on the use, such drugs may be in solid form (e.g., tablets, hard capsules, soft capsules, granules, powders, fine granules, pills, pastilles, etc.);
It can be prepared in either semi-solid form (eg suppositories, ointments, etc.) and liquid forms (injections, emulsions, suspensions, syrups, sprays, etc.). Therefore, examples of the above-mentioned non-toxic additives that can be used include starch, gelatin, glucose,
Lactose, fructose, maltose, magnesium carbonate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or its salts, gum arabic, polyethylene glycol, p
-Hydroxybenzoic acid alkyl esters, syrup, ethanol, propylene glycol, petrolatum, carbo wax, glycerin, sodium chloride, sodium sulfite, sodium phosphate, citric acid and the like. The medicament may also contain other therapeutically useful agents. The content of the compound of the invention in the medicament varies depending on its dosage form, but generally in a concentration of 5 to 100% by weight for solid and semisolid forms and 0.1 to 10% for liquid forms. It is desirable to contain the active compound in a concentration of % by weight. The dosage of the compound of the present invention can vary widely depending on the type of warm-blooded animal including humans, route of administration, severity of symptoms, doctor's diagnosis, etc., but in general, it is 0.2 to 80 mg per day. /Kg, preferably 0.5 to 50 mg/Kg. but,
As mentioned above, depending on the severity of the patient's symptoms and the doctor's diagnosis, it is of course possible to administer an amount smaller than the lower limit or larger than the upper limit of the above range.
The above dosage can be administered once a day or in divided doses. The present invention will be further explained below with reference to Examples. Example 1 2[(2-diaminomethyleneaminothiazol-4-yl)methylthio] in methanol (50ml)
Triethylamine (3.03 g) was added to a suspension of ethylamine dihydrochloride (3.04 g), stirred at room temperature for 30 minutes, then chloroacetic anhydride (2.0 g) was added under ice cooling, and further under ice cooling. The mixture was stirred for 30 minutes. Ammonia water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate to obtain 2.2 g of 2-diaminomethyleneamino-4-[2-(chloroacetylamino)ethylthiomethyl]thiazole. NMR (CD ₃ OD, δ): 2.64 (2H, double doublet,
J=8Hz, J=6Hz), 3.41 (2H, double doublet, J=8Hz, J=6Hz), 3.68 (2H, singlet), 4.02 (2H, singlet), 6.59 (1H, singlet ). Example 2 Triethylamine (3.03 g) was added to a suspension of 2-[(2-diaminomethyleneaminothiazol-4-yl)methylthio]ethylamino dihydrochloride (3.04 g) in methanol (30 ml) and brought to room temperature. te30
After stirring for a minute, acetoxyacetyl chloride (2
g) was added dropwise. After stirring for 10 minutes under ice cooling,
A triethylamine aqueous solution was poured into the mixture and extracted with ethyl acetate to obtain 2.9 g of a crude product. After separation and purification with TLC [developing solvent: chloroform:methanol (9:1)], the product was recrystallized from ethanol-ether and 2-diaminomethyleneamino-4-[2-(acetoxyacetylamino)ethylthiomethyl]thiazole White crystals were obtained. Melting point 155.6−157.4
℃. 1R (KBr, cm ^-1 ): 1740, 1660. NMR (CD ₃ OD, δ): 2.15 (3H, singlet),
2.64 (2H, double double line, J=8Hz, J=6
Hz), 3.40 (2H, double double line, J=8Hz, J
= 6Hz), 3.67 (2H, singlet), 4.51 (2H, singlet), 6.54 (1H, singlet). Example 3 In Example 1, using trifluoroacetic anhydride (2.5 g) instead of acetic anhydride, the same procedure as in Example 1 was repeated to prepare 2.5 g of 2-diaminomethyleneamino-4-[2-(trifluoroacetic anhydride). Acetylamino)ethylthiomethyl]thiazole was obtained. NMR (CD ₃ OD, δ): 2.70 (2H, double doublet,
J=8Hz, J=6Hz), 3.49 (2H, double doublet, J=8Hz, J=6Hz), 3.70 (2H, singlet), 6.61 (1H, singlet). Example 4 Triethylamine (2.02 mg) was added to a suspension of 2-[(2-diaminomethyleneaminothiazol-4-yl)methylthio)ethylamine dihydrochloride (304 mg) in methanol (2 ml) at room temperature for 30 min.
The mixture stirred for 1 minute was added to a reaction mixture of methoxyacetic acid (150 mg) and N,N'-dicyclohexylcarbodiimide (350 mg) in tetrahydrofuran (2 ml)-acetonitrile (2 ml) under ice cooling, and the mixture was heated at room temperature for 1 hour. Stir for hours. After removing insoluble materials and treating the solution with potassium carbonate and methanol, it was separated and purified using TLC [developing solvent: chloroform-methanol (9:1)].
mg of 2-diaminomethyleneamino-4-[2-(methoxyacetylamino)ethylthiomethyl]thiazole was obtained. NMR (CD ₃ OD, δ): 2.65 (2H, double doublet,
J=8Hz, J=6Hz), 3.41 (3H, singlet),
3.42 (2H, double double line, J=8Hz, J=6
Hz), 3.68 (2H, singlet), 3.87 (2H, singlet), 6.56 (1H, singlet). Example 5 In Example 4, 264 mg of 2-diaminomethyleneamino-4-[2-(3-hydroxy Propionylamino)ethylthiomethyl]thiazole was obtained. NMR (CD ₃ OD, δ): 2.43 (2H, triplet, J=
6Hz), 2.65 (2H, double double line, J=8Hz,
J=6Hz), 3.49 (2H, double double line, J=8
Hz, J=6Hz), 3.69 (2H, (2 singlet), 3.82
(2H, triplet, J=6Hz), 6.58 (1H, singlet). Example 6 In the same manner as in Example 4, using glycolic acid (160 mg) instead of methoxyacetic acid, 210 mg of 2-diaminomethyleneamino-4
-[2-(hydroxyacetylamino)ethylthiomethyl]thiazole was obtained. NMR (CD ₃ OD, δ): 2.65 (2H, double doublet,
J=8Hz, J=6Hz), 3.44 (2H, double doublet, J=8Hz, J=6Hz), 3.68 (2H, singlet), 3.99 (2H, singlet), 6.55 (1H, singlet ). Example 7 The crude product (110 mg) of 2-diaminomethyleneamino-4-[2-(acetoxyacetylamino)ethylthiomethyl]thiazole obtained in Example 2 was mixed with potassium hydroxide in methanol (5%).
After stirring in a solution (1 ml) at room temperature for 6 hours, extraction was repeated several times with ethyl acetate. The extract was further separated and purified by TLC [developing solvent: chloroform: methanol (4:1)], and 87 mg of 2
-diaminomethyleneamino-4-[2-(hydroxyacetylamino)ethylthiomethyl]thiazole was obtained. Example 8 Acetic anhydride (100 mg) was added to 4-(2-diaminomethyleneaminothiazol-4-yl)butylamine (100 mg) in methanol (1 ml) under ice cooling, and the mixture was stirred for 1 hour. After adding an aqueous sodium hydroxide solution, the mixture was extracted five times with ethyl acetate. After drying with anhydrous magnesium sulfate, the solvent was distilled off and TLC
[Developing solvent: chloroform: methanol (4:
1)] to obtain 2-diaminomethyleneamino-4-[4(acetylamino)butyl]thiazole (105 mg). NMR (CD ₃ OD, δ): 1.58 (4H, multiplet), 1.90
(3H, single line), 2.58 (2H, triple line, J = 6.6
Hz), 3.17 (2H, triple line, J=6.5Hz), 6.31
(1H, single line). Example 9 To 4-(2-diaminomethyleneaminothiazol-4-yl)butylamine (100 mg) in methanol (1 ml) was added acetoxyacetyl chloride (150
mg) was added under dry ice/acetone cooling. After stirring for 10 minutes under ice-cooling, a triethylamine aqueous solution was poured into the mixture, and the mixture was extracted with ethyl acetate. After drying with anhydrous magnesium sulfate, the solvent was distilled off.
Separation and purification using TLC [developing solvent: chloroform:methanol (4:1)] gave 2-diaminomethyleneamino-4-[4-(acetoxyacetylamino)butyl]thiazole (120 mg). NMR (CD ₃ OD, δ): 1.60 (4H, multiplet), 2.12
(3H, single line), 2.59 (2H, triple line, J=6.5
Hz) 3.27 (2H, triple line, J=6.5Hz), 4.50
(2H, singlet), 6.41 (1H, singlet). Example 10 In Example 7, in place of 2-diaminomethyleneamino-4-[2-(acetoxyacetylamino)ethylthiomethyl]thiazole, 2-diaminomethyleneamino-4-[4-( 2 was prepared in the same manner as in Example 7 using acetoxyacetylamino)butyl]thiazole (130 mg).
-diaminomethyleneamino-4-[4-(hydroxyacetylamino)butyl]thiazole (90 mg)
I got it. NMR (CD ₃ OD, δ): 1.59 (4H, multiplet), 2.59
(2H, triple line, J=6.5Hz), 3.26 (2H, triple line, J=6.5Hz), 3.97 (2H, single line), 6.31
(1H, single line). An example of manufacturing a drug containing the compound of the present invention is as follows. Example A: Tablets Example formulations for tablets containing 50 mg and 100 mg of active ingredient per tablet are as follows.

【table】

【table】

[Table] Details of the manufacturing method are as follows. Crystals of 2-diaminomethyleneamino-4-[2-(acetoxyacetylamino)ethylthiomethyl]thiazole are ground, and lactose and starch are added thereto and mixed well. Add 10% starch paste to the above mixed powder and mix with stirring to produce granules. After drying, the particles are sized to a particle diameter of around 840 microns, mixed with talc and magnesium stearate, and tableted. Example B: Capsule

[Table] Thoroughly crush the crystals of 2-diaminomethyleneamino-4-[2-(acetoxyacetylamino)ethylthiomethyl]thiazole, mix them with starch, lactose, and magnesium stearate, and mix well. Fill into capsules.

Claims (1)

[Claims] 1 formula In the formula, R represents (a) a hydrogen atom or (b) a lower alkyl group which may be substituted with a halogen atom, a hydroxyl group, a lower alkoxy group or a lower alkanoyloxy group, and Y represents a sulfur atom or a methylene group. However, when R represents a hydrogen atom or an unsubstituted lower alkyl group, Y is limited to a methylene group. A compound that is a thiazole derivative or a salt thereof. 2 formulas In the formula, R is (a) a hydrogen atom or (b) a halogen atom,
Represents a lower alkyl group which may be substituted with a hydroxyl group, lower alkoxy group or lower alkanoyloxy group, Y represents a sulfur atom or a methylene group, provided that when R represents a hydrogen atom or an unsubstituted lower alkyl group An anti-ulcer agent containing a thiazole derivative or a salt thereof as an active ingredient, wherein Y is limited to a methylene group.