Thiazole and imidazole derivatives and antiulcer composition containing same

Abstract: A thiazole or imidazole derivative having the general formula (I): wherein: R¹ and R², which may be the same or different, each independently represent a hydrogen atom, or a phenyl or heteroaryl group, or R¹ and R² may together form a benzene ring which may be optionally substituted by a halogen atom or a lower alkyl optionally substituted by a halogen atom, lower alkoxy or nitro group; A represents a sulfur atom or -NH-; B represents a lower alkoxy group optionally substituted by a halogen atom; a five- or six-membered saturated heterocyclic ring containing one nitrogen or oxygen atom which ring may be optionally substituted; a six-membered saturated heterocyclic ring containing one oxygen atom plus one nitrogen atom; a group -XR³ where X represents a group -NR⁴ wherein R³ and R⁴, which may be the same or different, each independently represent a lower alkyl group; or a group -NHC(=Y)R⁵ where Y represents an oxygen or sulfur atom or a group =NCN or =CHNO₂, and R⁵ represents a group -NHR⁶ or -SR⁶ wherein R⁶ represents a lower alkyl group optionally substituted by a halogen atom; m is an integer from 1 to 4; and n is an integer from 0 to 2; and their pharmacologically acceptable salts. The compounds has an antiulcerative activity.

Description: The present invention relates to the use of thiazole or imidazole derivatives for the manufacture of a medicament for treating ulcerative conditions caused by Helicobacter pylori . This invention also concerns the use of an antiulcer composition efficacious for treating and preventing gastric and duodenal ulcers, which contains them as an effective ingredient. H 2 -receptor antagonists represented by "Cimetidine" and muscarine receptor blockers such as "Pirenzepine" have been used as antiulcer agents. In addition, the development of "Omeprazole" and "NC-1300" based on benzimidazole derivatives that are H + /K + -ATPase inhibitors possessing new mechanisms is now in the making. It has been reported that some benzothiazole derivatives possess an inhibitory action on H + /K + -ATPase ("J. Med. Chem.", 1983, 31, pp. 1778-1785). We have filed patent applications relating to some relevant techniques (Japanese Patent Application Nos. 293689/1988 and 320468/1988). Some 2-thio, 2-sulfinyl or 2-sulfonyl-thiazole derivatives have been known with their synthetic processes (e.g. European Patent No. 61425 specification). However, these compounds are described as an antirheumatic agent. Never until now are they reported to have an antiulcer action. Some benzothiazole derivatives containing a thiolcarbamoyl group have been known and synthesized by conventional processes so far available in the art (e.g. "J. Heterocycl. Chem.", 24(4), pp. 945-8). This is also true of some benzothiazole derivatives containing an urea group (U.S. Patent No. 2,410,407). However, these are different from the compounds of this invention represented by formula (I) in terms of the group "B". Never until now are they reported to process an antiulcer action. It is therefore a primary object of this invention to provide a novel version of thiazole or imidazole derivative having an improved antiulcer activity. In order to achieve this object and in search of valuable antiulcer agents, we have synthesized a variety of compounds, and have now found that some thiazole or imidazole derivatives are efficacious against ulcers. Thus, the present invention provides use of a thiazole or imidazole derivative having the general formula (I): wherein R 1 and R 2 , which may be the same or different, each independently represents a hydrogen atom, or a phenyl group or a five- or six-membered heterocyclic aromatic ring containing at least one heteroatom selected from nitrogen, oxygen and sulfur, or R 1 and R 2 may together form a benzene ring which may be optionally substituted by a halogen atom or nitro group; A represents a sulfur atom or -NH-; B represents a C 1-4 alkoxy group optionally substituted by a halogen atom; or a group -NHC(=Y)R 5 wherein Y represents an oxygen or sulfur atom or a group =NCN or =CHNO 2 , and R 5 represents a group -NHR 6 or -SR 6 wherein R 6 represents a C 1-4 alkyl group optionally substituted by a halogen atom; m represents an integer from 1 to 4; and n represents 0, 1 or 2; and their pharmacologically acceptable salts; provided that (1) when R 1 and R 2 represent said hydrogen atom, phenyl group or heterocyclic aromatic ring, then A represents a sulfur atom and B represents a C 1-4 alkoxy group; (2) when R 1 and R 2 together represent said benzene ring optionally substituted by halogen, then A represents a sulfur atom and B represents said -NHC(=Y)R 5 group; and (3) when R 1 and R 2 together represent said benzene ring substituted by a nitro group, then B represents said C 1-4 alkoxy group optionally substituted by a halogen atom, for the manufacture of a medicament for treating ulcerative conditions caused by Helicobacter pylori . Compounds of formula (I), which have an antiulcer activity, are useful in the treatment of ulcer condition. Accordingly, the present invention provides a pharmaceutical composition which comprises at least one compound selected from compounds of the general formula (I) and their pharmaceutically acceptable salt. The compounds according to the present invention are represented by the above-mentioned formula (I). The alkyl group moiety of the lower alkyl or alkoxy group means a straight or branched C 1-4 alkyl group. In the compounds of formula (I), R 1 and R 2 , which may be the same or different, each independently represent a hydrogen atom or a phenyl or heteroaryl group. The term "heteroaryl group" means a five- or six-membered heterocyclic aromatic ring containing at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur atoms, for example, a pyridyl group, a five- or six-membered heterocyclic aromatic ring containing one oxygen or sulfur atom, for example, thienyl and furanyl group, and a five- or six-membered heterocyclic aromatic ring containing one oxygen atom or one sulfur atom plus one nitrogen atom, for example, a thiazolyl group. R 1 and R 2 may also form together a benzene ring which may be optionally substituted by halogen atoms and nitro groups. Preferred classes of compound of general formula (I) are those wherein R 1 and R 2 each independently represents a hydrogen atom or a phenyl or heteroaryl group. Another preferred class of such compounds is that wherein R 1 and R 2 together form a benzene ring which may be optionally substituted by a halogen atom or nitro group. A further preferred class of compounds of general formula (I) is that wherein R 1 and R 2 form together a benzene ring, A is a sulfur atom and B is the group -NHC(=Y)R 5 . In this class of compounds, the benzene ring formed by the combination of R 1 with R 2 may be substituted by halogen atoms. The compounds of formula (I) may exist in the form of their salts. With the use of salts in mind, pharmaceutically acceptable salts are preferred. Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid salts such as hydrochlorides, hydrobromides, acetates, succinates and lactates; basic salts with suitable bases such as sodium, potassium, calcium, ammonium, triethylamine and ethanolamine; and amino acid salts with a suitable amino acid such as lysine, arginine and aspartic acid. It will be appreciated that the compounds of formula (I) have asymmetric carbon atom, and all optical and geometric isomers of compounds of formula (I) are embraced by the invention. Compounds of general formula (I) according to the present invention may be synthesized by any processes as described below. The compounds of general formula (I) wherein n = 0 having the general formula (Ia): (wherein A, R 1 , R 2 and m are as defined in general formula (I) and B 1 represents a lower alkoxy group optionally substituted by a halogen atom.) may be obtained by the following process (i) or (ii). Process (i ) Compounds of formula (Ia) may be prepared by reaction of a compound having the general formula (II): (wherein R 1 and R 2 are as defined in general formula (I)) with a compound having the general formula (III): Z 1 (CH 2 ) m -B 1 (wherein m is as defined in general formula (I), B 1 is as defined above, and Z 1 is a halogen atom or an acyloxy or sulfonyloxy group) in the presence of a hydrogenated metal, preferably hydrogenated sodium or sodium hydroxide, and in an inert solvent, e.g. N,N-dimethylformamide. It is understood that the synthesis of Compound (II) may be carried out according to known procedures (see "Aus. J. Chem.", 33, 2291 (1980); Japanese Patent Laid-Open Publication No 130660/1978; "J. Chem. Soc.", Perkin Trans. I. 1017 (1978); and East German Patent No 127812). Process (ii) Compounds of formula (Ia) may be also prepared by a compound having the general formula (IV): (wherein R 1 and R 2 are as defined in general formula (I) and Z 2 is a halogen atom) with a compound having the general formula (V): HS(CH 2 ) m -B 1 (wherein m and B 1 are as defined in general formulae (I) and (Ia), respectively) in the presence of hydrogenated metal, preferably hydrogenated sodium or sodium hydroxide, and in an inert solvent, e.g. N,N-dimethylformamide. It is noted that the synthesis of Compound (IV) may be carried out by known procedures (French Patent No. 2,152,345). The compounds of general formula (I) wherein n=0 having the general formula (Ib): (wherein A, R 1 , R 2 , Y, R 5 and m are as defined in general formula (I)) may be obtained by any one of the following processes (iii), (iv) and (v). Compound (Ib) is a general term of all compounds (Ib'), (Ib'') and (Ib''') obtained by processes (iii), (iv) and (v). Process (iii) A compound having the general formula (Ib'): (wherein A, R 1 , R 2 and m are as defined in general formula (I), Y 1 is an oxygen or sulfur atom, and R 5 represents a group -NHR 6 wherein R 6 is as defined in general formula (I)) may be prepared by reaction of a compound having the general formula (V): (wherein A, R 1 , R 2 and m are as defined in general formula (I)) with a compound having the general formula (VI): Y 1 =C=R 5a (wherein Y 1 is a sulfur or oxygen atom and R 5a represents a group =NR 6 in which R 6 is as defined in general formula (I)) in an alcohol such as ethanol. Process (iv) A compound having the following general formula (Ib''): (wherein A, R 1 , R 2 and m are as defined above, Y 2 is a group =NCN or =CHNO 2 , and R 5b is a group -SR 6 where R 6 is as defined in general formula (I)) may be prepared by reaction of a compound having the above general formula (V) with a compound having the general formula (VII): (wherein Y 2 is a group =NCN or =CHNO 2 ) in an alcohol such as ethanol. Process (v) A compound having the general formula (Ib'''): (wherein A, R 1 , R 2 and m are as defined in general formula (I), Y 3 is a group =NCN or =CHNO 2 , and R 5 C is a group -NHR 6 where R 6 is as defined in general formula (I)) may be prepared by reaction of compounds of formula (Ib'') obtained by process (iv) with a compound having the general formula (VIII): H 2 N-R 5c (wherein R 5c is a group -NHR 6 where R 6 is as defined in general formula (I)) in an inert solvent, e.g. methyl cellosolve. Through the processes (i) to (v) it is possible to obtain the compounds of formula (I) wherein n = 0, i.e. compounds of formulae (Ia) and (Ib). The compounds of formula (I) wherein n = 1 and 2 may be obtained from the compounds of formulae (Ia) and (Ib), prepared by the above processes. A sulfoxide compound having the general formula (Ic): (wherein A, B, R 1 , R 2 and m are as defined in general formula (I)) may be obtained by reacting the compound of general formulae (Ia) and (Ib) with 1 to 1.2 molar equivalents of an oxidizing agent in an inert solvent. If the amount of the oxidizing agent is increased to 1 to 1.5 molar equivalents in the oxidizing reaction, then it is possible to obtain a sulfone compound having the general formula (Id): (wherein A, B, R 1 , R 2 and m are as defined in general formula (I)). The oxidizing agents used for these oxidizing reactions, for instance, may include peroxide derivatives such as hydrogen peroxide, m-chloroperbenzoic acid and sodium periodate, manganese dioxide, tert-butylhydroperoxide and N-bromosuccinimide. The solvents used, for example, may include water, acetic acid, a halogenated alkyl such as methylene chloride, ketones such as acetone and other general-purpose solvents. Preferably, the oxidizing reactions may be carried out with hydrogen peroxide in acetic acid in the presence of sodium tungstate or with m-chloroperbenzoic acid in methylene chloride. The compounds according to the invention possess an antiulcerative activity and may be used as antiulcerative agent. The antiulcerative composition containing the compounds of formula (I) or their salts as main ingredients may be generally available in the form of oral administration such as capsules, tablets and powders. These preparations may be formulated in conventional manners with ordinarily used vehicles, extenders, binders, wetting agents, disintegrators, surface active agents, lubricants, dispersants, buffers, preservatives, dissolution aids, and so on. Although the dose varies dependent upon the conditions, age and sex of patients and other factors, the suitable daily dose as employed for adult is 0.5 to 10 mg which may be conveniently administered in one or three doses. The present invention will now be explained more specifically with reference to the following examples. Example 1 2-[(2-ethoxyethyl)thio]-4-(3-pyridyl)thiazole Dissolved-in 2.5 ml of N,N-dimethylformamide were 0.50 g of 2-mercapto-4-(3-pyridyl)-thiazole oxalate (1.82 mmol), and 0.10 g (4.17 mmol) of sodium hydride were added to the solution, which was stirred at room temperature. One hour later, 0.40 ml (3.65 mmol) of 2-chloroethyl ethyl ether were added to the suspension, which was then stirred for 2 hours at 80°C. The reaction solution was diluted with 50 ml of chloroform, followed by addition of 50 ml of a 5% saline solution and washing. After separation of the chloroform layer, the organic layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo . The residues were then purified by silica gel chromatography to obtain 45 g of the title compound as an yellow oily form (93% yield). 1 H-NMRδ (CDCl 3 ) 1.22 (3H, t), 3.4-3.9 (6H, m), 7.33 (1H, ddd), 7.43 (1H, s), 8.16 (1H, ddd), 8.56 (1H, dd), 9.10 (1H, dd). EI-MS m/s: 266 (M + ), 194. Example 2 2-[(2-ethoxyethyl)sulfinyl]-4-(3-pyridyl)thiazole Dissolved in 1.7 ml of acetic acid were 0.33 g (1.24 mmol) of the compound obtained in Example 1, and 0.15 ml (1.32 mmol) of a 30% aqueous solution of hydrogen peroxide and a catalytic amount of sodium tungstate were successively added to the solution, which was stirred at room temperature for 4 hours. The reaction solution was poured on 34 ml of water, neutralized with sodium hydrogencarbonate and extracted with 34 ml of chloroform. After separation of the chloroform layer, the organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo . The residues were purified by silica gel chromatography to obtain 0.27 g of white crystalline powders (77% yield). 1 H-NMRδ (CDCl 3 ) 1.16 (3H, t), 3.3-3.6 (4H, m), 3.94 (2H, t), 7.37 (1H, ddd), 7.86 (1H, s), 8.18 (1H, dt), 8.61 (1H, dd), 9.12 (1H, d). EI-MS m/s: 282 (M + ), 210, 194. Examples 3-20 were performed according to either one of the procedures described in Examples 1 and 2, thereby obtained the following title compounds. Example 3 2-[(2-ethoxyethyl)thio]-4-(4-pyridyl)thiazole 1 H-NMRδ (CDCl 3 ) 1.22 (3H, t), 3.4-3.9 (6H, m), 7.57 (1H, s), 7.74 (2H, dd), 8.65 (2H, dd). EI-MS m/s: 266 (M + ), 194. Example 4 2-[(2-ethoxyethyl)sulfinyl)-4-(4-pyridyl)thiazole 1 H-NMRδ (CDCl 3 ) 1.16 (3H, t), 3.3-3.6 (4H, m), 3.94 (2H, t), 7.79 (2H, d), 8.69 (2H, d). EI-MS m/s: 282 (M + ), 210, 194. Example 5 2-[(2-ethoxyethyl)thio]-4-(2-pyridyl)thiazole 1 H-NMRδ (CDCl 3 ) 1.22 (3H, t), 3.4-3.9 (6H, m), 7.1-7.3 (1H, m), 7.7-8.0 (1H, m), 7.96 (1H, s), 8.10 (1H, d), 8.5-8.6 (1H, m). EI-MS m/s: 266 (M + ), 194. Example 6 2-[(2-ethoxyethyl)sulfinyl]-4-(2-pyridyl)thiazole 1 H-NMRδ (CDCl 3 ) 1.17 (3H, t), 3.3-3.7 (4H, m), 3.9-4.0 (2H, m), 7.2-7.3 (1H, m), 7.7-7.9 (1H, m), 8.08 (1H, s), 8.6-8.7 (1H, m). EI-MS m/s: 282 (M + ), 210, 194. 2-[(2-diisopropylaminoethyl)sulfinyl-4-(3-pyridyl)thiazole 1 H-NMRδ (CDCl 3 ) 1.05 (12H, dd), 3.0-3.3 (6H, m), 7.36 (1H, ddd), 7.85 (1H, s), 8.17 (1H, dt), 8.61 (1H, dd), 9.13 (1H, dd). EI-MS m/s: 338 (M + +1), 210, 194. Example 7 2-[(2-ethoxyethyl)thio]-4-phenylthiazole 1 H-NMRδ (CDCl 3 ) 1.21 (3H, t), 3.4-3.9 (6H, m), 7.3-7.4 (3H, m), 7.33 (1H, s), 7.8-7.9 (2H, m). EI-MS m/s: 265 (M + ), 193. Example 8 2-[(2-ethoxyethyl)sulfinyl]-4-phenylthiazole 1 H-NMRδ (CDCl 3 ) 1.17 (3H, t), 3.3-3.7 (4H, m), 3.9-4.0 (2H, m), 7.3-7.5 (3H, m), 7.74 (1H, s), 7.8-7.9 (2H, m). EI-MS m/s: 281 (M + ), 209, 193. Example 9 2-[(2-ethoxyethyl))thio]-5-phenylthiazole 1 H-NMRδ (CDCl 3 ) 1.21 (3H, t), 3.4-3.8 (6H, m), 7.3-7.5 (5, m), 7.79 (1H, s). EI-MS m/s: 265 (M + ), 193. Example 10 2-[(2-ethoxyethyl)sulfinyl]-5-phenylthiazole 1 H-NMRδ (CDCl 3 ) 1.16 (3H, t), 3.3-3.6 (4H, m), 3.9-4.0 (2H, m), 7.4-7.6 (5H, m), 8.04 (1H, s). EI-MS m/s: 281 (M + ), 209, 193. Example 11 2-[(2-ethoxyethyl)thio]-4-(3-thienyl)thiazole 1 H-NMRδ (CDCl 3 ) 1.21 (3H, t), 3.4-3.9 (6H, m), 7.17 (1H, s), 7.3-7.5 (2H, m), 7.7-7.8 (1H, m). EI-MS m/s: 271 (M + ), 199. Example 12 2-[(2-ethoxyethyl)sulfinyl]-4-(3-thienyl)thiazole 1 H-NMRδ (CDCl 3 ) 1.17 (3H, t), 3.3-3.6 (4H, m), 3.9-4.0 (2H, m), 7.4-7.5 (2H, m), 7.58 (1H, s), 7.7-7.8 (1H, m). EI-MS m/s: 287 (M + ), 215, 199. Example 13 2-[(2-ethoxyethyl)thio]-4-(2-thienyl)thiazole 1 H-NMRδ (CDCl 3 ) 1.21 (3H, t), 3.4-3.9 (6H, m), 7.04 (1H, dd), 7.18 (1H, s), 7.26 (1H, dd), 7.42 (1H, dd). EI-MS m/s: 271 (M + ), 199. Example 14 2-[(2-ethoxyethyl)sulfinyl]-4-(2-thienyl)thiazole 1 H-NMRδ (CDCl 3 ) 1.17 (3H, t), 3.3-3.6 (4H, m), 3.9-4.0 (2H, m), 7.07 (1H, dd), 7.32 (1H, dd), 7.46 (1H, dd), 7.59 (1H, s). EI-MS m/s: 287 (M + ), 215, 199. Example 15 2-[(2-ethoxyethyl)thio]-4-(2-furanyl)thiazole 1 H-NMRδ (CDCl 3 ) 1.21 (3H, t), 3.4-3.9 (6H, m), 6.46 (1H, dd), 6.77 (1H, d), 7.27 (1H, s), 7.42 (1H, dd). EI-MS m/s: 255 (M + ), 183. Example 16 2-[(2-ethoxyethyl)sulfinyl]-4-(2-furanyl)thiazole 1 H-NMRδ (CDCl 3 ) 1.16 (3H, t), 3.3-3.6 (4H, m), 3.9-4.0 (2H, m), 6.49 (1H, dd), 6.81 (1H, d), 7.46 (1H, dd), 7.66 (1H, s). EI-MS m/s: 271 (M + ), 199, 183. Example 17 2-[(2-ethoxyethyl)thio]-4-(2-thiazolyl)thiazole 1 H-NMRδ (CDCl 3 ) 1.22 (3H, t), 3.4-3.9 (6H, m), 7.34 (1H, d), 7.83 (1H, d), 7.84 (1H, s). EI-MS m/s: 272 (M + ), 200. Example 18 2-[ (2-ethoxyethyl)sulfinyl]-4-(2-thiazolyl)thiazole 1 H-NMRδ (CDCl 3 ) 1.16 (3H, t), 3.4-3.6 (4H, m), 3.93 (2H, t), 7.40 (1H, d), 7.87 (1H, d), 8.22 (1H, s). EI-MS m/s: 288 (M + ), 216, 200. Example 19 N-(5-chlorobenzothiazol-2-yl)thioethyl-N'-ethylurea Dissolved in 10 ml of ethanol was 1.00 g (4.09 mmol) of 2-(2-aminoethylthio)-5-chlorobenzothiazole, and 0.36 ml (4.55 mmol) of ethyl isocyanate were added to the solution, which was stirred at room temperature for 15 minutes. The precipitated white crystals were then filtered out to obtain 1.15 g of the title compound (89% yield). 1 H-NMRδ (CDCl 3 ) 0.97 (3H, t), 2.9-3.2 (2H, m), 3.3-3.4 (4H, m), 5.8-5.9 (1H, br), 6.1-6.2 (1H, br), 7.41 (1H, dd), 7.91 (1H, d), 8.04 (1H, d). EI-MS m/s: 315 (M + ), 229, 201. Example 20 N-(5-chlorobenzothiazol-2-yl)sulfinylethyl-N'-ethylurea Dissolved in a mixed solution of 5.8 ml of acetic acid and 5.8 ml of methylene chloride were 1.15 g (3.65 mmol) of the compound obtained in Example 21, and 0.41 ml (4.02 mmol) of a 30% aqueous solution of hydrogen peroxide and a catalytic quantity of sodium tungstate were successively added to the solution, which was stirred at room temperature for 1 hour. The reaction solution was poured on 116 ml of water, neutralized with sodium hydrogencarbonate and extracted with 116 ml of chloroform. After separation of the chloroform layer, the organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo . The residues were purified by silica gel chromatography to obtain 0.96 g of white crystalline powders (79% yield). 1 H-NMRδ (CDCl 3 ) 0.93 (3H, t), 2.8-3.1 (2H, m), 3.4-3.5 (4H, m), 5.9-6.0 (1H, br), 6.2-6.3 (1H, br), 7.61 (1H, dd), 8.20 (1H, d), 8.31 (1H, d). EI-MS m/s: 331 (M + ), 201. Examples 21 and 22 were performed according to either one of the procedures described in Examples 19 and 20 to obtain the title compounds. Example 21 N-(5-chlorobenzothiazol-2-yl)thioethyl-N'-(2-chloroethyl)urea 1 H-NMRδ (CDCl 3 ) 3.3-3.5 (8H, m), 6.2-6.4 (2H, br), 7.36 (1H, dd), 7.87 (1H, d), 7.99 (1H, d). EI-MS m/s: 349 (M + ), 228, 201. Example 22 N-(5-chlorobenzothiazol-2-yl)sulfinylethyl-N'-(2-chloroethyl)urea 1 H-NMRδ (CDCl 3 ) 3.2-3.5 (8H, m), 6.2-6.4 (2H, br), 7.61 (1H, dd), 8.19 (1H, d), 8.31 (1H, d). EI-MS m/s: 365 (M + ), 201. Example 23 N-(5-chlorobenzothiazol-2-yl)thioethyl-N'-ethylthiourea 1 H-NMRδ (CDCl 3 ) 1.19 (3H, t), 3.4-3.6 (4H, m), 3.9-4.1 (2H, m), 6.4-6.5 (1H, br), 6.8-6.9 (1H, br), 7.29 (1H, dd), 7.67 (1H, d), 7.78 (1H, d). EI-MS m/s: 331 (M + ), 228, 201. Example 24 N-(5-chlorobenzothiazol-2-yl)thioethyl-N'-cyano-S-methylisourea Dissolved in 20 ml of ethanol was 1.19 g (8.18 mmol) of 2-(2-aminoethylthio)-5-chlorobenzothiazole, and 25 ml of an ethanol solution of 2.00 g (8.18 mmol) of N-cyano-S,S'-dimethyldithioiminocarbonate were added to the solution, which was stirred overnight at room temperature. The precipitated white crystals were filtered out to obtain 2.67 g of the title compound (95% yield). 1 H-NMRδ (CDCl 3 ) 2.50 (3H, s), 3.6-3.7 (4H, m), 7.42 (1H, dd), 7.91 (1H, d), 8.05 (1H, d), 8.0-8.1 (1H, br). EI-MS m/s: 342 (M + ), 228, 201. Example 25 N-(5-chlorobenzothiazol-2-yl)thioethyl-N'-cyano-N''-ethylguanidine Dissolved in 80 ml of methyl cellosolve were 1.60 g (4.67 mmol) of the compound obtained in Example 26, and 42 ml of a methyl cellosolve solution of 4.20 g (93.3 mmol) of ethylamine were added to the solution, which was heated with stirring at 80°C for 4 hours. The solvent was removed in vacuo and the residue was purified by silica gel chromatography to obtain 0.56 g of white crystalline powders (35% yield). 1 H-NMRδ (CDCl 3 ) 0.97 (3H, t), 3.0-3.1 (2H, m), 3.4-3.5 (4H, m), 6.9-7.0 (1H, br), 7.1-7.2 (1H, br), 7.37 (1H, dd), 7.99 (1H, d). EI-MS m/s: 339 (M + ), 228, 201. Example 26 N-(5-chlorobenzothiazol-2-yl)sulfinylethyl-N'-cyano-N''-ethylguanidine Dissolved in 8 ml of methylene chloride were 0.20 g (0.59 mmol) of the compound obtained in Example 27, and 0.15 g (0.59 mmol) of m-chloroperbenzoic acid with a 70% purity were added to the solution, which was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue was purified by silica gel chromatography to obtain 0.20 g of white crystalline powders (95% yield). 1 H-NMRδ (CDCl 3 ) 1.21 (3H, t), 3.1-3.9 (6H, m), 5.8-5.9 (1H, br), 6.4-6.5 (1H, br), 7.48 (1H, dd), 7.92 (1H, d), 8.06 (1H, d). EI-MS m/s: 355 (M + ), 201. Examples 27 and 28 were performed according to either one of the procedures described in Examples 24 and 25 to obtain the title compounds. Example 27 1-(5-chlorobenzothiazol-2-yl)thioethylamino-1-methylthio-2-nitroethene 1 H-NMRδ (CDCl 3 ) 2.45 (3H, s), 3.6-3.8 (4H, m), 6.5-6.6 (1H, br), 7.39 (1H, dd), 7.94 (1H, br), 8.01 (1H, d). EI-MS m/s: 361 (M + ), 228, 201. Example 28 N-(5-chlorobenzothiazol-2-yl)thioethyl-N'-ethyl-2-nitro-1,1-ethenediamine 1 H-NMRδ (CDCl 3 ) 1.12 (3H, t), 3.1-3.4 (2H, m), 3.5-3.6 (4H, br), 7.43 (1H, ddd), 8.05 (1H, d), 8.15 (1H, br). EI-MS m/s: 358 (M + ), 228, 201. Example 29 5-trifluoromethyl-2-[(2-ethoxyethyl)thio]benzothiazole 1 H-NMRδ (CDCl 3 ) 1.22 (3H, t), 3.5-3.9 (6H, m), 7.51 (1H, dd), 7.83 (1H, d), 8.10 (1H, d). EI-MS m/s: 307 (M+), 235. Example 30 5-trifluoromethyl-2-[(2-ethoxyethyl)sulfinyl]-benzothiazole 1 H-NMRδ (CDCl 3 ) 1.06 (3H, t), 3.4-3.6 (4H, m), 3.95 (2H, t), 7.71 (1H, dd), 8.13 (1H, d), 8.33 (1H, s). EI-MS m/s: 323 (M + ), 251, 203. Example 31 5-nitro-2-[(2-ethoxyethyl)thio]benzothiazole 1 H-NMRδ (CDCl 3 ) 1.23 (3H, t), 3.5-3.9 (6H, m), 7.90 (1H, d), 8.18 (1H, dd), 8.67 (1H, d). EI-MS m/s: 284 (M + ), 212. Example 32 5-nitro-2-[(2-ethoxyethyl)sulfinyl]benzothiazole 1 H-NMRδ (CDCl 3 ) 1.03 (3H, t), 3.4-3.6 (4H, m), 3.97 (2H, t), 8.16 (1H, d), 8.37 (1H, dd), 8.89 (1H, s). EI-MS m/s: 300 (M + ), 228. The following example illustrates pharmaceutical compositions according to the present invention. The term "active ingredient" is used to represent a compound of formula (I). Example 33 (Pharmaceutical Composition) (a) Oral tablet mg/tablet Active Ingredient 15 Lactose 49.2 Starch 30 Polyvinylpyrrolidone 6 Microcrystalline Cellulose 18 Colloidal Silica 1.2 Magnesium Stearate 0.6 Total 120 (b) Oral Capsule mg/tablet Active Ingredient 25 Lactose 100 Starch 13 TC-5 10 Magnesium Stearate 2 Total 150 The structures of the above-mentioned compounds are set out in Tables 1 and 2. The compounds of formula (I) have been found to possess an antiulcer activity. Water-immersion induced stress ulcer Wister male rats (11-week age) fasted for 18 hours were placed in a restraint cage, which was in turn immersed to a depth of the pectoral region in water at 20 to 22°C to leave the rats under stress for six hours. Then, the rats were drawn up from the water and put down by vertebral dislocation. Afterwards, the stomach was removed, infused with 5 ml of a 5% aqueous solution of formalin and was wholly immersed in the same solution for 30 minutes for fixation. The fixed sample was dissected along the curvature ventriculi major, and the ulcer regions were measured along their major length (in mm) by means of slide calipers. The total sum of the measurements per rat is a value of ulcer index. The compounds under test shown in TABLE 3, suspended in 0.5% carboxymethylcellulose (CMC), were administered to the rats at a single dose of 30 mg/kg body weight of the compound one hour prior to the stressing. To a control group, only 0.5% CMC was administrated. The antiulcer activity was calculated according to the following equation: The results are set forth in Table 3. Compound of Example No. Inhibition (%) 2 72.5 10 52.5 12 62.7 20 63.1 22 70.1 23 64.2 26 57.0 30 61.3 32 60.7 Omeprazole 90.0 Ethanol-induced ulcer Five (5) ml/kg of 100% ethanol was orally administrated to Donryu masculine rats fasted for 48 hours and dehydrated for 24 hours. Then, the compounds under test, suspended in 0.5% CMC, were orally administered to the rats at a dose of 5 ml/kg body weight. One hour later, the rats were put down in similar manners as mentioned above test to remove and treat the stomach. A control group, to which only 0.5% CMC was administered, showed a nearly 100% erosion. Antimicrobial activity Helicobacter pylori is Gram negative microaerophile which has been recently isolated from human tunica mucosa ventriculi and seems to serve for pathopoiesis and recurrence of ulcer in alimentary canal. The compounds of formula (I) show an antimicrobial activity to inhibit the growth of Helicobacter pylori . The antimicrobial activity was demonstrated using the agar plate dilution method established by the Japan chemotherapy society. The media used were that of Muller-Hinton liquid medium (BBL) contained 7% horse serum and of Heart-Infusin agar medium (Difco) contained 5% horse defibrinized blood. The culture was incubated for two days at 37°C using Gaspack (BBL) without a catalyst. MINIMUM GROWTH INHIBITION CONCENTRATION (µg/ml) Compound Helicobacter p HI-0001 HI-0015 12 50 100 21 12.5 12.5 23 0.025 0.025 25 12.5 12.5 32 6.25 6.25 Aminobenzylpenicillin 0.025 0.20 Ofloxacin 0.78 0.78

Claims: Use of a thiazole or imidazole derivative having the general formula (I): wherein R 1 and R 2 , which may be the same or different, each independently represents a hydrogen atom, or a phenyl group or a five- or six-membered heterocyclic aromatic ring containing at least one heteroatom selected from nitrogen, oxygen and sulfur, or R 1 and R 2 may together form a benzene ring which may be optionally substituted by a halogen atom or nitro group; A represents a sulfur atom or -NH-; B represents a C 1-4 alkoxy group optionally substituted by a halogen atom; or a group -NHC(=Y)R 5 wherein Y represents an oxygen or sulfur atom or a group =NCN or =CHNO 2 , and R 5 represents a group -NHR 6 or -SR 6 wherein R 6 represents a C 1-4 alkyl group optionally substituted by a halogen atom; m represents an integer from 1 to 4; and n represents 0, 1 or 2; and their pharmacologically acceptable salts; provided that (1) when R 1 and R 2 represent said hydrogen atom, phenyl group or heterocyclic aromatic ring, then A represents a sulfur atom and B represents a C 1-4 alkoxy group; (2) when R 1 and R 2 together represent said benzene ring optionally substituted by halogen, then A represents a sulfur atom and B represents said -NHC( = Y)R 5 group; and (3) when R 1 and R 2 together represent said benzene ring substituted by a nitro group, then B represents said C 1-4 alkoxy group optionally substituted by a halogen atom, for the manufacture of a medicament for treating ulcerative conditions caused by Helicobacter pylori . Use as claimed in claim 1, wherein R 1 and R 2 each represents a hydrogen atom or a phenyl or said heterocyclic aromatic ring. Use as claimed in claim 1, wherein R 1 and R 2 together form a benzene ring which may be optionally substituted by a halogen atom or nitro group. Use as claimed in claim 3, wherein R 1 and R 2 together form a benzene ring which may be optionally substituted by a halogen atom; A represents a sulfur atom; and B represents a group -NHC(=Y)R 5 . Use according to any of claims 1 to 5, wherein the medicament is a pharmaceutical composition comprising a pharmaceutically effective amount of said thiazole or imidazole derivative together with at least one pharmaceutically acceptable carrier.

Inventors: HIRANO FUMIYA, MACHINAMI TOMOYA, SHIBAHARA SEIJI, YASUFUKU KAZUE, YUDA YASUKATSU, HIRANO, FUMIYA, MACHINAMI, TOMOYA, SHIBAHARA, SEIJI, YASUFUKU, KAZUE, YUDA, YASUKATSU, HIRANO, FUMIYA, C/O MEIJI SEIKA K.K., MACHINAMI, TOMOYA, C/O MEIJI SEIKA K.K., SHIBAHARA, SEIJI, C/O MEIJI SEIKA K.K., YASUFUKU, KAZUE, C/O MEIJI SEIKA K.K., YUDA, YASUKATSU, C/O MEIJI SEIKA K.K.
Applicants: MEIJI SEIKA CO, MEIJI SEIKA KABUSHIKI KAISHA
Application year: 1991
Main classification: C07D277
IPC codes: A61K31, A61P1, C07D405, C07D277, C07D233, C07D403, C07D235, C07D417