WO1997003077A1

WO1997003077A1 - Benz- or pyrido-imidazole derivatives

Info

Publication number: WO1997003077A1
Application number: PCT/KR1996/000081
Authority: WO
Inventors: Han Yong Yoo; Kae Jong Chung; Man Sik Chang; Sung Gyu Kim; Wahn Soo Choi; Dae Pil Kang; Jeong Min Lee; Jang Hoon Paek; Kyu Bong Kim; Sung Hoon Park; Young Hun Kim; Young Heui Kim; Kwi Hyon Seo
Original assignee: Yungjin Pharmaceutical Co Ltd
Current assignee: Yungjin Pharmaceutical Co Ltd
Priority date: 1995-07-12
Filing date: 1996-06-01
Publication date: 1997-01-30
Anticipated expiration: 1998-01-12
Also published as: KR0156327B1

Abstract

A benz- or pyrido-imidazole compounds represented by general formula (I), wherein R is hydrogen atom, a hydroxy group, a C1-C6 lower alkyl group, a C1-C6 lower alkoxy group, a substituted or unsubstituted phenyl or pyridyl group, a substituted or unsubstituted guanidino group, or an amino group having a general formula: NR3R4 in which R3 and R4, identical to or different from each other, represent hydrogen atom, a C1-C6 lower alkyl group, a C3-C6 cyclic alkyl group, a substituted or unsubstituted phenyl or pyridyl group, a C1-C6 lower alkoxy group, a C2-C6 alkyl group, or phenyl alkyl group; R1 and R2, identical to or different from each other, are hydrogen atom, a C1-C6 lower alkyl group, a C1-C6 lower alkoxy group, an amino group which may be substituted with a C1-C2 alkyl group, a C1-C6 alkoxy carbonyl group, a halogen atom, a cyano group, a C1-C6 alkylthio group, or a C1-C6 acyl group; R6 is hydrogen atom, a C1-C6 lower alkyl group, a C1-C3 lower alkoxy group, a halogen atom, or a hetero atom; n is an integer from 0 to 4, inclusive; and X is a nitrogen atom or CR5 wherein R5 is hydrogen atom, a C1-C6 lower alkyl group, a C1-C6 lower alkoxy group, or a halogen atom, or its pharmaceutically acceptable salts are disclosed. These compounds show excellent anti-ulcer activity.

Description

BENZ- OR PYRIDO-IMIDAZOLE DERIVATIVES

FIELD OF THE INVENTION

The Present invention is related to new benz- or pyrido-imidazole derivatives or their pharmaceutically acceptable salts useful as anti-ulcer agents, and to a method for producing them.

BACKGROUND OF THE INVENTION

It has been reported that the gastrointestinal ulcers may be caused by a excessive secretion of acids such as hydrochloric acid or pepsin as well as by an action of anti-inflammatory agents such as indomethacin, toxic chemicals, pathogenic virus or toxic microorganisms. In particular, since it had been reported that H⁺/K⁺ ATPase, an enzyme which plays an important role during the last step of the acid secretion in stomach cell affects the gastric acidity, omeprazole (Am. J. Physiol., 1983, 245, G 64-71) had been developed which is an effective inhibitor against the enzyme so that it can be used to suppres gastric acid secretion and treat gastric ulcers. However, there has been still a need to develop agents which are capable of reinforcing various defensive factors against the above described factors causing gastrointestinal ulcers.

The present inventors made extensive researches to provide novel compounds which can effectively inhibit H⁺/K⁺ ATPase. And a result thereof, they found out that the compounds represented by the general formula (I) given below showed not only a potent inhibitory activity against H⁺/K⁺ ATPase so .that they can suppress the secretion of the gastric juices but also a significant reinforcing activity on defensive factors in the living body.

SUMMARY OF THE INVENTION

Therefore, an object of the present invention is to provide new benz- or pyrido-imidazole derivatives represented by the following general formula ( I ) :

wherein

R is hydrogen atom, a hydroxy group, . a Ci - C₆ lower alkyl group, a Ci - C₆ lower alkoxy group, a substituted or unsubstituted phenyl or pyridyl group, a substituted or unsubstituted guanidino group, or an amino group having a general formula : NR₃R. in which R₃ and R, identical to or different from each other, represent hydrogen atom, a Ci - C₆ lower alkyl group, a C₃ - C₆ cyclic alkyl group, a substituted or unsubstituted phenyl or pyridyl group, a Ci ^■ ₆ lower alkoxy group, a C₂ - C₆ alkyl group, or phenyl alkyl group; Ri and R₂, identical to or different from each other, are hydrogen atom, a Ci - C₆ lower alkyl group, a Ci - C₆ lower alkoxy group, an amino group which may be substituted with a C_; - C₂ alkyl group, a Ci - C₆ alkoxy carbonyl group, a halogen atom, a cyano group, a Ci - C₆ alkylthio group, or a Ci - C₆ acyl group; R₆ is hydrogen atom, a C - C₆ lower alkyl group, a Ci - C₃ lower alkoxy group, a halogen atom, or a hetero atom; n is an integer from 0 to 4 , inclusive; and

X is a nitrogen atom or CR₅ wherein R₅ is hydrogen atom, a Ci - C₆ lower alkyl group, a Ci - C₆ lower alkoxy group, or a halogen atom; with proviso that all alkyl and alkoxy groups may be linear or branched, said halogen atom means fluorine, chlorine or bromine atom, and said hetero atom includes N, 0 and S, or their pharmaceutically acceptable salts.

According to the present invention, a method for producing the compounds is also provided. The above and other objects and features of the present invention will be apparent to the skilled in the art from the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

The pharmaceutically acceptable salts of the compound

(I) of the present invention include acid-addition salts of the compound (I) with pharmaceutically acceptable organic and inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphorous, sulfuric, nitrous, citric, formic, fumaric, maleic, tartaric, or malonic acids, an alkylsulfonic acid such as methansulfonic acid, or an arylsulfonic acid such as p-toluene sulfonic acid.

The compound represented by the general formula (I) may be prepared from the compound represented by the general formula (II) by the reactions shown in the following reaction scheme I. [Reaction Scheme I]

herein, R, R_{l t} R₂, R₆, n and X have the same meanings as defined above. he reaction shown in Reaction Scheme I will be described in more detail hereinafter .

The compound (I) of the present invention may be prepared by reacting the compound (II) or its salt with the compound (III) in a solvent. The examples of the solvent, which may be employed for the reaction, may include, not limited thereto, methanol. ethanol. propanol. butanol. dimethylformamide and the like. The reaction may be carried out at a temperature between room temperature and boiling point of the solvent employed. The resulting compound (I) may be obtained in the form of halogenated hydrogen salts, which can be neutralized with an alkaline in an aqueous solution system to give the compound (I) . Thus obtained compound (I) can be converted to its pharmaceutically acceptable acid addition salts with inorganic or organic acids. The examples of the inorganic or organic acids include those stated in the above.

The compound (II) employed for preparing the compound (I) according to the present invention is novel. Therefore, the compound (II) and its production method are also included in the present invention. The compound (II) may be prepared by the process shown in the following Reaction Scheme II. [Reaction Scheme II]

Wherein, R, R_l7 R₂, R& , n and X have the same meanings as defined above.

The compound (IV) is reacted with piperidine in a solvent, for example, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, or dioxan, in the presence of an organic base such as triethylamine or an inorganic base such as sodium carbonate or potassium carbonate to give the compound (V) . If the base is not employed, piperidine is preferably employed in an amount of more than 2 equivalents. The compound (V) is heated to its boiling point in anhydrous acetic acid in the presence of zinc chloride to carry out a reductive cyclization so that the compound (VI) can be obtained. The reaction is known as "t-amino effect" (Adv. Heterocyclic Chem., 1972, 14 , 178) . When the acetyl group of the compound (VI) is hydrolyzed with sodium or potassium hydroxide in alcohols, water or mixtures thereof, there is obtained the compound (VII) , which is then oxidized by following known methods to convert its hydroxyl group to ketone group so that the compound (VIII) can be obtained. Examples of oxidizing agents which may be employed in the oxidation of the compound

(VII) may include, not limited thereto, manganese dioxide, pyridiniumchloro chromate (PCC) , pyridinium dichromate (PDC) , dimethyl sulfoxide/oxalyl chloride and the like. Among others, Swern's oxidation using dimethylsulfoxide/oxalyl chloride is preferred [J. Org. Chem., 43, 2480 (1978)].

The compound (III) is subjected to enolation with a base such as potassium t-butoxide, or n-butyl lithium in a solvent, which has no effect on the reaction, such as tetrahydrofuran, dioxan, N,N-dimethylformamide, or dichloromethane. Then, it is reacted with a halogenating agent such as bromine, N-bromosuccinimide, N-chlorosuccinimide, or is contacted with bromine solution or chlorine gas in a solvent such as con. hydrobromic acid solution or acetic acid to give a halogenated compound (III) or its salts. When a halogenating agent is used, the temperature is preferably in a range from -20°C to 10°C and an equivalent amount of the halogenating agent is advantageously used. When bromine solution or chlorine gas is used, the reaction temperature is preferably in a range from room temperature to about 80°C.

The novel benz- or pyrido-imidazole derivatives represented by the general formula (I) or their pharmaceutically acceptable salts effectively inhibit H⁺/K⁺ ATPase, a proton carrying enzyme, so that they can advantageously used for inhibiting the secretion of gastric juices or treating gastrointestinal ulcers.

The methods and results of pharmacological experiments and acute toxicity experiments carried out using the representative compounds (I) of the present invention are described below. 1. Inhibition of H⁺/K⁺ ATPase

Inhibition of H⁺/K⁺ ATPase, a proton carrying enzyme, was measured by following the procedure of Saccomani et al . [Biochim. Biophy. Acta., 465, 311-330 (1977)] . Thus, a homogenate of the gastric mucose membrane of rabbit was used to prepare vesicles containing H⁺/K⁺ ATPase by employing differential centrifugation and discontinuous density gradient centrifugation in Ficoll. The vesicles containing the enzyme were preincubated in a solution (o.5mi_.) containing 1 X 10^'4M, 1 X 10^"5M, 1 X lθ^"6M, or 1 X 10^'7M of the inventive compound(Example 21) and 5 mM of imidazole buffer (pH 7.4) at a temperature of about 37°C for about 30 minutes. omeprazole was used as a control. A solution containing 2 mM of magnesium chloride, 40 mM of imidazole buffer (pH 7.4), 10 mM of potassium chloride and 10 mM of ATP was added to the mixture. The resulting mixture was incubated at 37°C for 15 minutes and the reaction was terminated by adding 1 mi of ice-cold 22% solution of trichloroacetic acid. Enzyme activity was calculated by measuring the separated inorganic phosphate by following the method of Fiske and Subbarow [J. Biol. Chem., 66, 375-440 (1925)] . The concentrations (ICso) of the test compounds which inhibit the enzyme activity by 50% are shown in Table 1. 2. Inhibition of Gastric Secretion

Inhibition of gastric secretion was measured by following the procedure of Shay ligation (Gastroenterology, 1954, 26, 903) . Thus, male Sprague-Dawley rats weighing 180 - 200g were starved for 24 hours and their pylorus were ligated. Then, the inventive compound (Example 21) or omeprazole as a positive control was administered into duodenum. Four hours later, the stomach was removed, and the acidity and amount of gastric juice were measured. By comparing the measured values with the acidity and amount of the gastric juice of the stomach of the reference group to which no test compound was administered, the inhibition of gastric secretion was calculated. The effective dose (ED₅₀) of the test compounds which inhibit the gastric secretion by 50% are shown in Table 1. Table 1

3. Ulcer Inhibition 1) Inhibition of ethanol-induced lesion

Inhibition activity of the inventive compound on the ethanol-induced ulcer was measured by using male sprague-Dawley rats weighing 180 - 200g. Thus, rats were starved for 24 hours, and the inventive compound (Example 21) or omeprazole as a positive control was orally administered. Thirty minutes later, absolute ethanol (5 mi /kg) was orally administered. 1.5 hours later, the stomach was removed, and the degree of the wound of the stomach was measured. By comparing the measured values with the degree of the lesion of the stomach the reference group to which no teεt compound was administered, the effective dose (ED₅o) of the test compounds which inhibit the lesion by 50% were calculated and are shown in Table 2. 2) Inhibition of mepirizole-induced ulcers. Inhibition activity of the inventive compound on the mepirizole-induced ulcer was measured by using male sprague-Dawley rats weighing 200 - 230g. Thus, rats were not starved, and the inventive compound (Example 21) or omeprazole as a positive control was orally administered. Thirty minutes later, mepirizole suspended in 1% CMC (250mg/kg) was orally administered. After administration, the rats were starved for 24 hours, and the duodena were removed. The degree of the ulcer thereof was measured. By comparing the measured values with the degree of the ulcer of the duodena of the reference group to which no test compound was administered, the effective dose (ED₅₀) of the test compounds which inhibit the ulcer by 50% were calculated and are shown in Table 2.

3) Inhibition of indomethacin-induced lesions Inhibition activity of the inventive compound on the indomethacin-induced lesions was measured by using male Sprague-Dawley rats. Thus, rats were starved for 48 hours and prohibited from being supplied with water for 2 hours, and 35 mg/kg of indomethacin (Sigma Co.) as a causative of gastric lesions was subcutaneously administered. Before Indomethacine treatment, the inventive compound (Example 21) or omeprazole as a positive control was orally administered, and the inhibitions of lesions by the action of the test compounds were observed. The effective doses (ED50) of the test compounds which inhibit the lesions by 50% were measured and are shown in Table 2.

4) Inhibition of stress-induced ulcer

Inhibition activity of the inventive compound on the stress-induced ulcer was evaluated by using male Sprague-Dawley rats. Thus, rats were starved for 24 hours prior to carrying out the experiment.

Stress is an important factor for causing gastric lesions, and was applied to rats by immersing them in water.

Thirty minutes prior to immersing rats into water, the inventive compound (Example 21) or omeprazole as a positive control was orally administered, and the inhibitions of ulcer oy the action of the test compounds were observed. The effective doses (ED:..-) of the test compounds which inhibit the lesions by 50% were measured and are shown in Table 2. 5) Inhibition of acetic acid-induced ulcer

Inhibition activity of the inventive compound on the acetic acid-induced ulcer was evaluated by using male sprague-Dawley rats. Thus, rats were starved for 5 hours prior to carrying out the experiment. 20 Microliter of 30% acetic acid was injected into the submucosal layer of the stomach using a microsyringe to induce a circular ulcer on the stomach. Various doses of the inventive compound (Example 21) or omeprazole as a positive control were orally administered for 10 days, and the healing of ulcer by the action of the test compounds were observed. The percentages of the healing of the ulcer were calculated by comparing them with that of reference group.

Table 2

Anti -ulcer activity (ED₅o, mg/kg)

Test Compound

Ethanol Mepirizole Indomethacin Stress Acetic acid^*

Control

17.1 2.8 1.2 4.4 27.1 (Omefrzole)

Inventive

11.1 18.6 0.5 21.4 38.7 (Ex. 21)

Percentage of healing in 30 mg/kg

4. Acute Toxicity

ICR mice (male and female) were orally administered with high doses (maximum dose : 5 g/kg) of inventive compound (Example 21) and were ^observed for their sudden death or a lasting of morbid conditions for 14 days. A median lethal dose (LD₅o) , an index of acute toxicity was measured and is shown in Table 3.

Table 3

Dose No. of No. of Lethality LD50

Compound Sexuality (mg/kg) animals Death (%) (mg/kg)

0 5 0 0

50 5 0 0

Male 1191 1000 5 1 20

2000 5 5 100

Ex. 21

0 5 0 0

50 5 0 0

Female 807 640 5 1 20

1000 5 4 80

The present invention will be described in more detail by way of Examples. Reference Example 1 Preparation of 3-bromo-1,2- dihydropyrido[1,2-a]benzimidazole -4 (3H) -one (A) 2-Piperidinylnitrobenzene

100 ml of piperidine was added to 50.00g (0.317 mole) of 2-chloronitrobenzene, and the resulting mixture was heated to reflux under stirring for 4 hours. The reaction solution was cooled, and 300 ml of distilled water was added thereto. The mixture was extracted with chloroform, and the oil phase was washed with 2N-hydrochloric acid twice, dried over sodium sulfate, distilled under reduced pressure to give 57.38g (88%) of the titled compound as orange crystals. "H - NMR ( CDCI3 ) : δ 1 . 5 - 1 . 9 (m, 6H ) , 3 . 0 ( t , 4H) , 7 . 0 - 7 . 8 (m, 4H)

(B) 4 -Acetoxy-1, 2,3,4 - tetrahydropyrido [1, 2 -a]benzimidazole

57.00g (0.276 mole) of 2 -piperidinylnitrobenzene prepared in (A) above was dissolved in 300 ml of anhydrous acetic acid, and 39.56g (0.290 mole) of zinc chloride was added thereto. The mixture was heated to reflux under stirring for 24 hours and then cooled to room temperature. The reaction mixture was concentrated under reduced pressure, and 500 ml of distilled water was added to the residue, neutralized with sodium bicarbonate and extracted with chloroform. The extract was dried over sodium sulfate, distilled under reduced pressure to give the titled compound (50%) as brown oil, which will be used for the reaction (c) below. ^XH-NMR (CDC1₃) : δ 2.1(s, 3H) , 2.1-2.4(m, 4H) , 4.0-4.3(m,

2H) , 6.2(t, IH) , 7.3(m, 3H) , 7.8(m, IH)

(C) 4-hydroxy-1,2, 3,4-tetrahydropyrido [1,2-a]benzimidazole

16.00g of 4-Acetoxy-l,2,3,4-tetrahydropyrido [1,2-a] benzimidazole prepared in (B) above was dissolved in 160 ml of methanol, and 20 ml of 4N-sodium hydroxide solution was added thereto. The mixture was stirred for 1 hour at room temperature and concentrated under reduced pressure. Distilled water was added to the residue, and the mixture was extracted with chloroform. The organic phase was dried over sodium sulfate, and concentrated under reduced pressure to give the titled compound (90%) as yellow crystals, m.p. 160^°C

'H-NMR (CDCI3) : δ 2.0 - 2.5(m, 4H) , 3.9-4.2(m, 2H) , 5.2(t,

IH) , 7.3 (m, 3H) , 7.8 (m, IH) (D) 1, 2-Dihydropyrido [1, 2 -a]benzimidazole-4 (3H) -one Anhydrous dichloromethan (100ml) was added to 11.35 ml of oxalylchloride and the resulting mixture was cooled to -70^°C. Dimethylsufoxide (16.5 ml) was added dropwise, and the mixture was stirred at a temperature below -70^°C for 30 minutes. A solution of 4-hydroxy-1,2,3,4-tetrahydropyrido

[1,2-a]benzimidazole (17.50g) prepared in the above (C) in dichloromethane was gradually added dropwise. After stirring at -70°C for 1 hour, triethylamine (65 ml) was gradually added dropwise and the resulting mixture was stirred for 30 minutes and its temperature was gradually increased to room temperature. Distilled water was added to the mixture, the mixture was extracted with dichloromethane, dried over sodium sulfate and concentrated under reduced pressure. The residue was crystallized with diethyl ether to give the titled compound (70%) as yellow crystals, m.p. 178-180^°C ^αH-NMR (CDC1₃) : δ 2.5(q, 2H) , 2.9(q, 2H) , 4.4(t, 2H) , 7.4(m,

3H) , 7.9 (q, IH) (E) 3-Bromo-1,2-dihydropyrido [1,2-a]benzimidazole-4 (3H) -one 1,2-Dihydropyrido [l,2-a]benzimidazole-4 (3H) -one

(9.15g) was dissolved into 100 ml of 48% solution of hydrobromic acid (100 ml) and the resulting solution was heated to 70^°C. Bromine (2.53 ml) was gradually added, and the mixture was stirred for 30 minutes to form crystals. The reaction mixture was cooled to room temperature and the resulting precipitates was filtered to give brominate of the titled compound (94%) as yellow crystals. The brominate was neutralized with alkaline solution in an aqueous solution to give titled compound. m.p. 270^°C (Dec.) ^XH - NMR (DMSO - d₆ ) : δ 2 . 8 (m, IH) , 3 . 0 (m , IH) , 4 . 6 (m, 2H) ,

5.5(q, IH) , 7.7 (m, 4H) Reference Example 2

Preparation of 3 -bromo- 1, 2- dihydropyrido [1, 2-a:3' ,2' -d] imidazole-4 (3H) -one

(A) 2 -Piperidinyl -3 -nitropyridine

50.00 g (0.317 mole) of 2-chloro-3 -nitropyridine was dissolved in 500 ml of dichloromethan, and the resulting mixture was cooled to the temperature below io^°C. 68 ml of piperidine was gradually added dropwise and the mixture was stirred at room temperature for 1 hour. The organic phase was washed with distilled water twice, then with lN-hydrochloric acid, dried over sodium sulfate and distilled under reduced pressure to give the tilted compound (63.5g, 98%) as orange crystals.

^-NMR (CDCI3) : δ 1.7(s, 6H) , 3.4(t, 4H) , 6.7(q, IH) ,

8.1 (dd, IH) , 8.3 (q, IH)

(B) 4 -Acetoxy-1,2, 3,4 - tetrahydrodipyrido [1,2 -a: 3' ,2' -d] imidazole 25. Og of 2 -piperidinyl -3 -nitropyridine prepared in the above (A) was dissolved in 250 ml of anhydrous acetic acid, and 17.26g of zinc chloride was added thereto. The mixture was heated to reflux under stirring for 24 hours and then distilled under reduced pressure. 300 ml of distilled water was added to the filtrate, neutralized with sodium bicarbonate and extracted with chloroform. The extract was dried over sodium sulfate, distilled under reduced pressure to give the titled compound as brown oil. ²H-NMR (CDCI3) : δ 2.1(s, 3H) , 2.0-2.5(m, 4H) , 4.1-4.4(m, 2H) , 5.2(t, IH) , 7.3(m, 3H) , 8.0(dd, IH) , 8 . 4 ( d , IH )

(C) 4 -hydroxy-1,2, 3, 4- tetrahydrodipyrido [l,2-a:3' ,2' -d] imidazole

40.00g of 4 -acetoxy-1,2, 3,4 -tetrahydrodipyrido [l,2-a : 3' ,2' -d] imidazole prepared in the above (B) was dissolved in 4000 ml of methanol, and 40 ml of 4N-sodium hydroxide solution was added thereto. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. Distilled water was added to the residue, and the mixture was extracted with chloroform. The organic phase was dried over sodium sulfate, concentrated under reduced pressure, and the residue was crystallized with ethyl acetate to give the titled compound (80%) as yellow crystals, m.p. 120-126^°C ^XH-NMR (CDC1₃) : δ 2.0 - 2.5(m, 4H) , 4.1-4.4(m, 2H) , 5.3(t,

IH) , 7.2(m, IH) , 7.9 (dd, IH) , 8.3 (d, IH)

(D) 1,2-Dihydrodipyrido [l,2-a:3' ,2' -d] imidazole-4 (3H) -one

A solution of oxalylchloride (4.70 ml) in dichloromethan (50ml) was cooled to -70^°C, and a solution of dimethylsulfoxide (8.780 ml) in dichloromethan (30 ml) was gradually added dropwise thereto. The resulting mixture was stirred at a temperature below -70^°C for 30 minutes. A solution of 4-hydroxy-l, 2, 3,4-tetrahydrodipyrido [1,2-a: 3' ,2' -d] imidazole (9.3g) prepared in the above (C) in dichloromethan was gradually added dropwise. After stirring at -70°C for 1 hour, triethylamine (35 ml) was gradually added dropwise and the resulting mixture was stirred for 30 minutes and its temperature was gradually increased to room temperature. Distilled water was added to the mixture, the mixture was extracted with dichloromethane. The organic phase was washed with 5% sodium bicarbonate, dried over sodium sulfate and concentrated under reduced pressure. The residue was crystallized with diethyl ether to give the titled compound (70%) as yellow solids. m.p. 207°C

^XH-NMR (CDCIa) : δ 2.5 (m, 2H) , 3.0 (m, 2H) , 4.6 (m, 2H) , 7.4 (q,

3H) , 8.3 (dd, IH) , 8.7 (t, IH) (E) 3-Bromo-1,2-dihydrodipyrido[1,2-a:3' ,2' -d]imidazole-4 (3H) -one

1,2-Dihydrodipyrido [l,2-a:3' ,2' -d] imidazole-4 (3H) -one (20. Og) was dissolved into 100 ml of hydrobromic acid (100 ml), and bromine solution (5.5 ml) was added to the solution while sustaining it at the temperature of 70°C. And, the resulting mixture was stirred for 30 minutes to form crystals.

The reaction mixture was cooled to room temperature and the resulting precipitates were filtered to give brominate of the titled compound (98%) as yellow crystals. The brominate was neutralized with alkaline solution in an aqueous solution to give titled compound,

^XH-NMR (DMSO-d_) : δ 2.8 (m, IH) , 3.Km, IH) , 4.6 (m, 2H) , 5.3 (q,

IH) , 7.5(q, 4H) , 8.4 (m, IH) , 8.7 (m, IH)

Example 1■

Preparation of 2-amino-4,5-dihydrothiazolo [4' ,5' :3,4]pyrido

[1,2-a]benzimidazole

3-Bromo-1,2-dihydropyrido [1,2-a]benzimidazole-4 (3H) -one

(1.80g) prepared in Reference Example 1 (E) and thiourea (0.43g) were dissolved into absolute ethanol (20 ml), and the resulting solution was heated to reflux with stirring for 2.0 hours followed by cooling to room temperature. The resulting precipitates were washed with acetone to give brominate of the titled compound (50%) as yellow crystals. The brominate was neutralized with alkaline solution in an aqueous solution to give the titled compound, m.p. 300^°C or above

'H-NMR (DMSO-de) : δ 3.4(t, 2H) , 4.7 (t, 2H) , 7.5-7.8(m, 3H) ,

7.9 (m, IH) Examples 2-11

By following the procedure described in Example 1 by employing 3-bromo-1,2-dihydropyrido [1,2-a]benzimidazole-4 (3H) -one prepared in Reference Example 1 (E) and various thiourea derivatives under certain reaction time, there were obtained inventive compounds of Examples 2-11. These compounds and their physical properties are shown in Table 4.

Table 4

Yield M.P. (^°C)

Compound R ^-NMR, (DMSO-ds) : δ (%) [HBr CO]

3.22 (t. 2H) , 4.40(t, 2H) ,

>300

Ex. 2 -N-C(NII-.)₂ 34 7.02(br, 4H) , 7.22(m, 2H) , [>300] 7.50-7.66 (m, 2H)

1.22 (t, 3H) , 3.22(t, 2H) ,

225-265 3.36 (g,2H) , 4.38(t, 2H) ,

Ex. 3 Ethylamino 66 [275.de 7.20(m, 2H) ,7.50-7.6 (m, 2H) , c] 7.76(t, IH)

0.57 (m, 2H) , 0.78(m, 2H) , 2.63

Cyclopropyl - 265 (m,lH), 3.27(t, 2H) , 4.41(t,

Ex. 4 34 amino [190.dec] 2H) , 7.21(m, 2H) , 7.50-7.64(m, 2H),8.15(s, IH)

3.23 (t, 2H) , 3.30(S, 3H) ,

2-Methoxy- 243-245 3.52(br, 4H) , 4.39 (t, 2H) ,

Ex. 5 59 ethylamino [>300] 7.20(m, 2H) , 7.50-7.63(m, 2H) , 7.87(t. IH) , 2H) , 4.45(t. 2H) ,

Ex. 6 Phenylamino 56 ooo 3.35(t 700(t, IH) , 7.20-7.78(m, 8H) ,

[ - ] 10.42(S, IH)

3.23 (t, 2H) , 4.40(t, 2H) ,

265-268

Ex. 7 Benzylamino 53 4.57(d, 2H) , 7.13-7.60( , 9H) , [>300] 8.30(S, IH)

3.07 (br , 4H) , 3.30(t, 2H) ,

200.dec. 3.58 (br , 4H) , 4.42(t, 2H) ,

Ex. 8 l -Piperazino 58 [220-230] 7.23(m, 2H) , 7.53-7.66(m, 2H) , 3.82(br, 2H)

3.24(t, 2H) , 4.00(t, 2H) , 4.41 (t,2H), 5.20(m, IH) , 5.28(m,

Ex. 9 Allylamino 47 265.dec. IH) , 6.00(m, IH) , 7.24 (m, 2H) , 7.50-7.65(m, 4H) , 7.97(t, IH)

>300 3.2(s, 6H) , 3.5(t, 2H) , 4.7

Ex. 10 Dimethylamino 50 [>300] (t,2H) , 7.5-8.0(m, 4H)

295 2.9 (s, 3H) , 3.4 (t, 2H) , 4.65

EX. 11 Methylamino 40 [>300] (t, 2H) , 7.5-8.0(m, 4H) Example 12 .

Peparation of 2-amino-4 , 5-dihydrothiazol [4' ,5' :3,4]pyrido

[1,2-a]pyrido [3, 2-d] imidazole

3-Bromo-1,2-dihydrodipyrido [l,2-a:3',2'-d] imidazole-4 (3H) -one (3.00g) prepared in Reference Example 2 (E) and thiourea (0.72g) were dissolved into absolute ethanol (30 ml) , and the resulting solution was heated to reflux with stirring for 2.0 hours followed by cooling to room temperature. The resulting precipitates were washed with acetone to give brominate of the titled compound (60%) as yellow crystals. The brominate was neutralized with alkaline solution in an aqueous solution to give the titled compound. m.p. 295°C 'H-NMR (DMSO-ds) : δ 3.3(t, 2H) , 4.6(t, 2H) , 7.5(q, IH) ,

8.1(dd, IH) , 8.6 (q, IH)

Examples 13-22

By following the procedure described in Example 12 by employing 3-bromo-1,2-dihydrodipyrido [1,2-a:3' ,2' -d] imidazole-4 (3H) -one prepared in Reference Example 2 (E) and various thiourea derivatives under certain reaction time, there were obtained inventive compounds of Examples 13-22.

These compounds and their physical properties are shown in

Table 5. Table 5

Yield M.P. CC)

Compound R ^XH - MR , (DMSO-d₆) : δ (%) [HBr CC)]

2.91(d, 3H) , 3.26 (t, 2H) ,

>300

Ex. 13 Methyl amino 45 4.44 (t, 2H) , 7.23(q, IH) ,

[>300]

7.75(d, IH) , 7.9-8.3(dd, 2H)

1.20(t, 3H) , 3.29 (m, 4H) ,

225-256

Ex. 14 Ethylamino 45 4.43(t, 2H) , 7.27 (q, IH) , [275. dec.)

7.79(t, IH) , 7.9-8.3(dd, 2H)

0.55 (m, 2H) , 0.76 (m, 2H) ,

Cyclopropyl - 259 2.61 (m, IH) , 3.26 (t, 2H) ,

Ex. 15 41 amino [213] 4.43 (t, 2H) , 7.23(q, IH) ,

7.97-8.29 (dd, 3H)

3.24 (t, 2H) , 3.31(s, 3H) ,

2 -Methoxy - 221 3.52(m, 4H) , 4.43(t, 2H) ,

Ex. 16 37 ethylamino [230] 7.29(q, IH) , 7.91(d, IH) ,

7.97 (d, IH) , 8.29 (d, IH)

3.35(t, 2H) , 4.50(t, 2H) ,

7.00(t, IH) , 7.27 (q, IH) ,

OOO

Ex. 17 Phenylamino 43 7.38 (t, 2H) , 7.76 (d, 2H) ,

[>300]

8.05(d, IH) , 8.32(d, IH,

10.41(s, IH)

3.24 (t, 2H) , 4.43 (t, 2H) ,

273 4.55(d, 2H) , 7.23(q, IH) ,

Ex. 18 Benzyl amino 36 [283] 7.32 (m, 5H) . 7.97(d, IH) , 8.29(d, IH) , 8.35(t, IH)

2.85(t, 4H) , 3.25(t, 2H) ,

265 3.50(t, 4H) , 4.45(t, 2H) ,

Ex. 19 1-Piperazino 30 [290] 7.25(q, IH) , 8.00(dd, IH) , 8.30(d, IH)

3.30(t, 2H) , 3.97 (t, 2H) ,

265 4.43(5, 2H) , 5.10-5.40(m,

Ex. 20 Allylamino 35

[270] 2H) , 5.90(m, IH) , 7.20(t, IH) ,8.00(t, IH) , 8.27 (t, IH)

3.12(s, 6H) , 3.30(t, 2H) ,

263-264

Ex. 21 Dimethyl amino 37 4.45(t, 2H) , 7.25(t, IH) , [260-270] 7.99 (dd, IH) , 8.30(d, IH)

3.26 (t, 2H) , 4.45(t, 2H) ,

>300

Ex. 22 -N=C(NII.,)₂ 12 7.05(s, 4H) , 7.23(q, IH) , [>300]

7.97(d, IH) , 8.29(d, IH) It is understood that the foregoing detailed description is given merely by way of illustration and that modifications and variations may be made therein without departing from the spirit and scope of the invention.

Claims

CLAIMS 1. A compound represented by the following general formula ( I ) :

wherein,

R is hydrogen atom, a hydroxy group, a Ci - C₆ lower alkyl group, a Ci - C₆ lower alkoxy group, a substituted or unsubstituted phenyl or pyridyl group, a substituted or unsubstituted guanidino group, or an amino group having a general formula : NR₃R- in which R₃ and R , identical to or different from each other, represent hydrogen atom, a Ci - C₆ lower alkyl group, a C₃ - C₆ cyclic alkyl group, a substituted or unsubstituted phenyl or pyridyl group, a Ci - C₆ lower alkoxy group, a C₂ - C₆ alkyl group, or phenyl alkyl group;

Ri and R₂, identical to or different from each other, are hydrogen atom, a C_λ - C₆ lower alkyl group, a Ci - C₆ lower alkoxy group, an amino group which may be substituted with a C_x - C₂ alkyl group, a C_x - C₆ alkoxy carbonyl group, a halogen atom, a cyano group, a Ci - C₆ alkylthio group, or a Ci - C₆ acyl group; R₆ is hydrogen atom, a Ci - C₆ lower alkyl group, a Ci - C₃ lower alkoxy group, a halogen atom, or a hetero atom; n is an integer from 0 to 4 , inclusive; and X is a nitrogen atom or CR₅ wherein R₅ is hydrogen atom, a C_x - C₆ lower alkyl group, a Ci - C₆ lower alkoxy group, or a halogen atom; with proviso that all alkyl and alkoxy groups may be liner or branched, said halogen atom means fluorine, chlorine or bromine atom, and said hetero atom includes N, 0 and S, or its pharmaceutically acceptable salts.

2. The compound (I) according to claim l, wherein R is hydrogen atom, a C_λ - C₆ lower alkyl, phenyl, pyridyl, or guanidino group, or an amino group having a general formula : R_^R^ in which R₃ and R₄, identical to or different from each other, represent hydrogen atom, a C_x - C₆ lower alkyl group, a C₃ - C₆ cyclic alkyl group, phenyl, a Ci - C₆ lower alkoxy group, a C₂ - C₆ alkyl group, or phenyl alkyl group;

Ri and R₂ are independently hydrogen atom; Rs is hydrogen atorn; n is an integer of 1; and X is -CH- or -N- .

3. A process for producing a compound represented by the following general formula (I) :

wherein

R is hydrogen atom, a hydroxy group, a Ci - C₆ lower alkyl group, a C_: - C- lower alkoxy group, a substituted or unsubstituted phenyl or pyridyl group, a substituted or unsubstituted guanidino group, or an amino group having a general formula : NR₃R₄ in which R₃ and R , identical to or different from each other, represent hydrogen atom, a Ci - C₆ lower alkyl group, a C₃ - C₆ cyclic alkyl group, a substituted or unsubstituted phenyl or pyridyl group, a Ci - C₆ lower alkoxy group, a C₂ - C₆ alkyl group, or phenyl alkyl group; Ri and R₂, identical to or different from each other, are hydrogen atom, a Ci - C₆ lower alkyl group, a d - C₆ lower alkoxy group, an amino group which may be substituted with a Ci - C₂ alkyl group, a Ci - C₆ alkoxy carbonyl group, a halogen atom, a cyano group, a d - C₆ alkylthio group, or a C. - C₆ acyl group; R₆ is hydrogen atom, a C_x - C₆ lower alkyl group, a Ci - C₃ lower alkoxy group, a halogen atom, or a hetero atom; n is an integer from 0 to 4, inclusive; and

X is a nitrogen atom or CR₅ wherein R₅ is hydrogen atom, a Ci - C₆ lower alkyl group, a C₂ - C₆ lower alkoxy group, or a halogen atom; with proviso that all alkyl and alkoxy groups may be liner or branched, said halogen atom means fluorine, chlorine or bromine atom, and said hetero atom includes N, 0 and S, or its pharmaceutically acceptable salts, which comprises a step of reacting a compound represented by a general formula (ID

wherein, R, Ri, R?, R<,, n and X have the same meanings as defined above, or its pharmaceutically acceptable salts with a compound represented by a general formula (III)

S

A. (Ill)

H₂N R wherein R has the same meaning as defined above.

4. The process according to claim 3, wherein the compound

(II) or its pharmaceutically acceptable salts are prepared by reacting a compound represented by a general formula

wherein Ri, R₂, and X have the same meanings as defined in claim 3, with piperidine to give a compound represented by a general formula (V) :

wherein, Ri, R₂, Rs, n and X have the same meanings as defined above; subj ecting the compound (V) to a reductive cycli zation to give a compound represented by a general formula (VI ) :

wherein, Ri, R₂, R , n and X have the same meanings as defined above; subjecting the compound (VI) to a hydrolysis at its acetyl group to give a compound represented by a general formula (VII) :

wherein, R_x, R₂, Re, n and X have the same meanings as defined above; and subjecting the compound (VII) to an oxidation and then halogenation to give the compound (II) or its pharmaceutically acceptable salts.