WO1997000875A1

WO1997000875A1 - Benzimidazole derivatives containing fused pyridine

Info

Publication number: WO1997000875A1
Application number: PCT/KR1996/000091
Authority: WO
Inventors: Eul Kgun Yum; Joong-Kwon Choi; Sung Yun Cho; Seung Kyu Kang; Sung Soo Kim; Kyung Ho Park; Ki-Jun Hwang; Hyae Gyeong Cheon; Hyo Jung Kim; Sung-Il Yang
Original assignee: Korea Research Institute Of Chemical Technology
Priority date: 1995-06-21
Filing date: 1996-06-12
Publication date: 1997-01-09

Abstract

The present invention relates to benzimidazole derivatives containing fused pyridines, expressed by formula (I), wherein its active ingredients may be used as effective anti-ulcerants through the mechanism of inhibiting gastric acid secretion in mammals, wherein: R represents hydrogen, halogen, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkyl or C1-C3 haloalkyl group; Q represents (a) or (b); X represents (c); R?1, R2, R3, R4, R5 and R6¿ are the same or different, and each represents hydrogen, halogen, C¿1?-C3 alkyl group; with a proviso that all hydrogen atoms are excluded.

Description

BENZIMIDAZOLE DERIVATIVES CONTAINING FUSED PYRIDINE

FIELD OF THE INVENTION

The present invention relates to benzimidazole derivatives containing fused pyridines, expressed by the following formula (I), wherein its active ingredients may be used as effective anti-ulcer agents through the mechanism of inhibiting gastric acid secretion in mammals.

Wherein;

R represents hydrogen, halogen, - alkoxy, -C_j haloalkoxy, C_α~C₃ alkyl or - haloalkyl group; Q represents

R¹, R², R³, R⁴, R⁵ and R⁶ are the same or different, and each represents hydrogen, halogen, C^ alkyl group; with a proviso that, all hydrogen atoms are excluded. BACKGROUND OF THE INVENTION

Due to its excellent action of inhibiting gastric acid secretion, benzimidazole derivatives containing pyridine have been well recognized as efficient anti-ulcer agents. In addition, they were developed and

5 commercialized as gastric acid-secretion inhibitors; for example, benzimidazole derivatives with various substituent in pyridine exhibit a remarkable action of inhibiting gastric acid secretion and thus, anti-ulcerants such as omeprazole, lansoprazole and pantoprazole have been already marketed [Drug Fut 1994, 19, 1018]. Further, its derivatives and i o manufacturing process thereof were disclosed in the conventional patents, e.g., U.S. Patents (No. 5,019,580, No. 4,255,431 and No. 4,472,409), European Patents (No. 130,729 and No. 208,422) and U.K. Patents (No. 2,082,580 and No. 1,525,958). However, even though omeprazole, a typical benzimidazole derivatives containing pyridine exhibits an excellent activity in the inhibition

15 of gastric acid secretion, it has been reported that the prolonged use of omeprazole leads to the accumulation of drug and the increase of concentration in gastrin may increase due to its repeated administration.

To free from said shortcomings, the inventors have endeavored to develop novel benzimidazoles containing fused pyridines showing the same

20 efficacy as the conventional omeprazole preparations or more remarkable effect of inhibiting gastric acid secretion.

SUMMARY OF THE INVENTION

The object of the present invention is to provide novel benzimidazole 25 derivatives containing fused pyridines, expressed by the above formula (I), wherein pyridine derivatives are fused with five or six-membered ring containing oxygen, are combined with 2-mercaptobenzimidazole derivatives. The other object of the present invention is to provide anti-ulcerants compositions comprising benzimidazole derivatives containing fused pyridine or pharmaceutically acceptable salt thereof as active ingredients.

DETAILED DESCRIPTION OF THE INVENTION

The compound of formula(I) according to the present invention show inhibitory activity on gastric acid secretion. In the compound of formula(I), the preferred group of R represent hydrogen, chlorine, bromine, fluorine, methoxy group, ethoxy group, propyloxy group, trifluoromethyl group, or 2,2-difluoroethoxy group. The preferred groups of R¹, R², R³, R⁴, R⁵ and R⁶ represent the same or different, and each represents hydrogen, methyl group, ethyl group, or propyl group; with a proviso that all hydrogen are excluded.

Examples of the preferred compound of the present invention are listed in Table 1 and Table 2.

Table 1.

Table 2.

Compound No. R -O-X-

85 4-OCH₃ -0-C(CH₃)₂-CH=CH- 86 4-OCH₃ -0-C(CH₃)₂-CH₂-CH₂- 87 4-OCH₃ -0-CH(CH₃)-CH=CH- 88 4-OCH₃ -0-CH(CH₃)-CH₂-CH₂- 89 4-OCH₃ -0-CH₂-CH₂-C(CH₃)₂- 90 4-OCH₃ -0-CH₂-CH₂-CH(CH₃)- 91 4-OCH₃ -0-C(CH₃)=CH- 92 4-OCH₃ -0-CH(CH₃)-CH₂- 93 4-OCH, -0-CH₂-CH(CH₃)- 94 4-OCH- -0-CH=C(CH₃)-

CH₂CH₃

95 4-OCH, -0-CH=C-

CH₂CH,

96 4-OCH, -0-CH₂-CH-

CH(CH₃ )₂

97 4-OCH, -0-CH=C-

CH(CH₃ )₂

98 4-OCH₃ -Q-CH₂-CH-

The compounds represented by the above formula(I) may be prepared in accordance with the following reaction Scheme: [Scheme]

cyclization

( in )

i) esterification ii) reduction iii) chlorination

( VI )

oxidation

( I ) wherein :

R and X represent the same as defined in the above,

R^a represents allyl, homoallyl or propargyl,

R^b represents hydrogen or iodine.

In the processes according to the present invention, the compound of formula(II) used as starting material may be prepared by well-known processes. For example, pyridyl allyl ether and pyridyl propargyl ether may easily be prepared from 4-hydroxypyridine or 4-chloropyridine. Then, pyridine -oxide is obtained using an oxidant and through successive introduction of cyanide, said compound of formula (II) may be prepared [Comprehensive Heterocyclic Chemistry Vol. 2, 247-262, 1985, Pergamon, A.R. Katrizky]. The fused pyridine of formula(III) is useful in this reaction and its manufacturing process is based on [3,3]-sigmatropic rearrangement [G. Stemp et al., Synthetic Communications, 1988, 18, 1111; J. Med. Chem., 1986, 29, 2194].

In general, the fused pyridines may be available by thermal cyclization when two functional groups of pyridine are substituted at ortho positions [S. Shiotani et al., J. Heterocyclic Chem., 1986, 1465, 546 and 665; S. Shiotani et al., J. Heterocyclic Chem., 1991, 1469]. Nonetheless, the said thermal cyclization was conducted either in severe conditions or through several steps, the process of manufacturing fused pyridines using organometalic reagent such as palladium catalyst [Palladium Reagents in Organic Synthesis, Academic Press, 1985, R.F. Heck; Heterocycles, 1993, 35, 151; J. Org. Chem., 1988, 53, 2740; Tetrahedron Lett., 1987, 44, 5291; Heterocycles, 1989, 29, 1013; J. Heterocyclic Chem., 1993, 30, 631]. Since the thermal cyclization generally proceeds under severe conditions with low yield, it is preferred that the synthesis of the fused pyridine of formula (III) be performed using palladium catalyst. The palladium catalyst used from Pd(PPh₃)₄, PdCl₂, Pd(OAc)₂ or Pd(dba)₂.

Further, the base can be chosen among Et₃ , KOAc, ,C0₃, KHC0₃, NaOAc,

Na₂C0₃, or NaHC0₃. In case of a stabilizer for organic palladium, some organic and inorganic salts (e.g., n-Bu₄NCl, Et₄NCl, Me₄NCl, (PhCH₂)₄NCl or LiCl) may be employed. The amount of catalyst is 1-20 mol %, base is 1-5 equivalents and stabilizer is 1-2 equivalents. The reaction may be performed over 1-24 h using solvents selected from the group consisting of N,N-dimethylformamide, tetrahydrofuran, N-methyl-2-pyrrolidinone, hexamethylphosphoramide, or dioxane. The compound of formula(IV) may be prepared through the successive reactions such as esterification, reduction and chlorination of fused pyridine derivatives [Comprehensive Organic Transformations, 1989, VCH Publisher. Inc., R.C. Larock]. The compound of formual(V) may be obtained commercially or prepared from ortho-substituted diaminobenzene derivatives, based on some conventionally known processes [V.A. Deacon, Org. Syn. Coll. Vol. IV, 1963, 569]. Further, after reacting the compound of formula (IV) with 1-2 equivalents of 2-mercaptobenzimidazole of formula(V) in the presence of appropriate organic solvent and base, the compound of formula(VI) was prepared. The organic solvent used for the reaction may include tetrahydrofuran, dichloromethane, ethanol, isopropanol or dimethylformamide.

The base, selected from sodium hydroxide, potassium hydroxide, sodium hydride, sodium methoxide or sodium ethoxide, may be used in 1-3 equivalents. The preferred reaction time is 0.5-5 h at 0-80 °C.

The compound of formula(I) may easily be prepared through oxidation of the compound (VI), using m-chloroperbenzoic acid, peracetic acid, trifluoroperacetic acid, hydrogen peroxide or oxone. The oxidant is preferably used in 1-3 equivalents. For solvent, it may be selected from chloroform, dichloromethane, tetrahydrofuran, dioxane, methanol, ethanol, propanol or water. The temperature of oxidation reaction is preferably in -78 to -10 °C while the preferred reaction time is 0.1-6 h. The product, so formed, may easily be purified by recrystallization or column chromatography.

This invention is explained in more detail by the following examples. However, it is not limited to some manfacturing methods similar to the following examples, as a typical manufacturing process over the compound expressed by formula (I) according to the present invention. EXAMPLE 1: Preparation of 5- or 7-cyano-2,2-dimethyl-2H-ρyrano[3,2-c] pyridine To a solution of 4-hydroxypyridine (23.0 g, 0.24 mol) and 40 % benzyltrimethylammonium hydroxide in 50 ml of methanol was added 3- chloro-3-methyl-l-butyne (37.4 g, 0.36 mol) in 150 ml of dichloromethane. To the reaction mixture, sodium hydroxide (14.5 g) in 150 ml of water was added

5 slowly. The reacting solution was kept at room temperature for 2-4 days. After separation of the organic layer, the aqueous layer was extracted with chloroform. The combined organic layer was washed with 10 % aqueous solution of sodium hydroxide and evaporated under reduced pressure to obtain 4-pyridine propargly ether (24 g, 62 %). ι o To a solution of 4-pyridine propargyl ether (23.2 g, 144 mmol) in dichloromethane (800 ml) was added m-chloroperbenzoic acid(herein after . "mCPBA"; 41.2 g, 132.5 mmol) in 100 ml of dichloromethane at 0 °C and stirred overnight. After completion of the reaction was completed, dichloromethane layer was washed with saturated NaHC0₃ (100 ml x 2), dried

15 over magnesium sulfate and concentrated. The residue was purified by column chromatography with dichloromethane : methanol (10:1) as eluent to give 21.2 g (119 mmol, yield 83 %) of 4-pyridine propargyl ether N-oxide. Η-NMR (CDCL,): δ 8.41(m, 2H), 7.09(m, 2H), 2.61(s, 1H), 1.67(s, 6H)

4-Pyridine propargyl ether N-oxide (lg, 5.35 mmol) was added to

20 triethylamine (3 ml) was added, trimethylsilyl cyanide (2 ml, 24.4 mmol) was added. The reaction mixture was stirred at 90 °C for 4 h. After completion of the reaction, the mixture was concentrated and partitioned in dichloromethane (50 ml) and water (15 ml). The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give 0.72

25 g(3.85 mmol) of the desired 4-(2-cyanopyridine) propargyl ether.

Η-NMR (CDC1₃): δ 8.32 (m, 1H), 7.36-7.08 (m, 2H), 2.66 (s, 1H), 1.51 (s, 6H).

4-(2-Cyanopyridine) propargyl ether (1.8 6 g, 10 mmol) was refluxed in ortho-dichlorobenzene for 1 hr. Then, the solvent was completely removed and purified by column chromatography with hexane : ethyl acetate (4:1) to give 5-cyano-2,2-dimethyl-2H-pyrano [3,2-c]pyridine and 7-cyano-2,2- dimethyl-2H-pyrano [3,2-c]pyridine (1:1) in 50 % yield. 5-Cyano-2,2-dimethyl-2H-pyrano [3,2-c]pyridine; Η-NMR (CDCI₃): δ 8.41(d, IH), 7.12(d, IH), 6.79(d, IH), 6.05(d, IH), 1.59(s,

6H). 7-Cyano-2,2-dimethyl-2H-pyrano [3,2-c]pyridine;

Η-NMR (CDCI₃): δ 8.26(s, IH), 7.65(s, IH), 7.47(s, IH), 5.95(s, IH), 1.49(s,

6H). EXAMPLE 2 : Preparation of 4- or 6-cyano-3-methyl-furo[3,2-c] pyridine

To a solution of allyl alcohol(0.7 g, 12 mmol) in 20 ml of tetrahydrofuran was added sodium(0.28 g, 12 mmol) after completely dissolved. 4-Chloro-3-iodopyridine (2.4 g, 10 mmol) was added to the reaction mixture, and then stirred at 80 °C for 2 h. After evaporating tetrahydrofuran under reduced pressure, the residue was purified on column chromatography with hexane : ethylacetate (2:1) as eluent to give 2.22 g(8.5 mmol) of 4-allyloxy-3-iodopyridine. Yield: 85 %

Η-NMR (CDCI₃): δ 8.76(s, IH, ArH), 8.35(d, IH, ArH), 6.72(d, IH, ArH), 6.00(m, IH, vinylic), 5.40(m, 2H, vinylic), 4.65(d, 2H,

-OCH,).

To a solution of 4-allyloxy-3-iodopyridine (2.22 g, 8.5 mmol) in 40 ml of dichloromethane was added a solution of m-CPBA (1.33 g, 9.5 mmol) in 10 ml of dichloromethane and stirred at 0 °C overnight. After the reaction was completed, the layer of dichloromethane was washed with saturated NaHC0₃

(100 ml x 2), dried over anhydrous magnesium sulfate and concentrated.

The residue was separated on column chromatography with dichloromethane : methanol (10:1) as eluent to give 4-allyloxy-3-iodopyridine N-oxide(2.20g, 90% yield).

4-Allyloxy-3-iodopyridine N-oxide (2.20 g, 7.7 mmol) was added to triethylamine(10 ml). (Me)₃SiCN(3 ml, 36 mmol) was added to the reaction mixture. The reaction mixture was stirred at 90 °C for 4 h. After completion of the reaction, the product was concentrated, and extracted with dichloromethane(80 ml). The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified on column chromatography to 2-cyano-4-allyoxy-3-iodopyridine (0.85g, 39% yield) and 6-cyano-4-allyoxy-3-iodopyridine(0.85g, 39% yield). 2-Cyano-4-allyloxy-3-iodopyridine;

Η-NMR (CDCI₃): δ 8.40(d, IH), 6.82(d, IH), 5.15(s, IH), 5.08(s, 2H), 4.60(s,

2H) 6-Cyano-4-allyoxy-3-iodopyridine Η-NMR (CDCI₃): δ 8.45(d, IH), 6.82(d, IH), 6.10(m, IH), 5.50(m, 2H), 4.72(d, 2H)

A mixture of palladium acetate(12 mg, 0.1 mmol), potassium carbonate (276 mg, 2 mmol), tetrabutylammonium chloride (n-Bu₄NCl; 273 mg, 2 mmol) and 2-cyano-4-allyloxy-3-iodopyridine(550 mg, 2 mmol) was dissolved in 5 ml of dimethylformamide in a pressure bottle and stirred at 100 °C for 4 h. After completion of the reaction, the reaction mixture was neutralized with saturated aqueous ammonium chloride, and then extracted with ethyl acetate (2 x 40 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified on column chromatography with hexane-ethyl acetate as eluent to give 2-cyano-3-methyl-furo[3,2-c]pyridine as an oil. Yield: 40 % Η-NMR (CDCI₃): δ 8.60(d, IH), 7.60(d, IH), 7.55(s, IH), 2.50(s, IH). EXAMPLE 3 : Preparation of 6-cyano-3-methyl-furo[3,2-c]pyridine

The titled compound was prepared by the same manner as in EXAMPLE 2 using 6-cyano-4-allyloxy-3-iodopyridine. Yield: 55 % Η-NMR (CDOg): δ 8.93(s, IH, ArH), 7.93(s, IH, ArH), 7.63(s, IH, ArH), 2.45

(s, IH, -CH₃). EXAMPLE 4; Preparation of 5-carboethoxy-2,2-dimethyl-2H-pyrano[3,2-c] pyridine

To a solution of 5-cyano-2,2-dimethyl-2H-pyrano[3,2-c]pyridine (1.20 g, 6.42 mmol) in 100 ml of ethanol was added solution of sodium ethoxide/ ethanol (0.89 mmol, 7.86 ml) and stirred at room temperature for 12. h. After addition of 6N HCl (7ml) at 0 Xi the reaction mixture was stirred for 12 h and concentrated under reduced pressure.

To the concentrated solution, dichloromethane (30 ml) and water (10 ml) were added to extract the organic layer. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified on column chromatography with ethylacetate-hexane as eluent to give desired compound as an oil(0.80 g, 50% yield).

Η-NMR (CDClg): δ 8.30 (d, IH, ArH), 7.19 (d, IH, ArH), 6.81(d, IH, vinylic), 5.79 (d, IH, vinylic), 4.49 (q, 2H, -OCH₂-), 1.49 (m, 9H, 3(-

OCH₃)). EXAMPLE 5 ; Preparation of 5-hydroxymethyl-2,2-dimethyl-2H-pyrano[3,2- c] pyridine

To a solution of 5-carboethoxy-2,2-dimethyl-2H-pyrano[3,2-c]pyridine (1.49 g, 6.59 mmol) in 10 ml of ethylether was added LiAlH₄ (0.247 g, 6.60 mmol) in 20 ml of dichloromethan at 0 °C, and stirred at 0 °C for 4 h. After completion of the reaction, water (1 ml) and 10 % sodium hydroxide (1 ml) were added to the reacting mixture. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified on column chromatography with dichloromethane : methanol (10:1) as eluent to give desired compound as an oil(0.95 g, 80.4 % yield). Η-NMR (CDC1₃): δ 8.23(d, IH, ArH), 6.67(d, IH, ArH), 6.25(d, IH, vinylic),

5.53(d, IH, vinylic), 4.59(s, 2H, -CH₂OH), 1.58(s, 6H, 2(- CH₃)). EXAMPLE 6: Preparation of 5-chloromethyl-2_/2-dimethyl-2H-pyrano[3,2-c] pyridine To a solution of 5-hydroxymethyl-2,2-dimethyl-2H-pyrano[3,2-c] pyridine (0.95 g, 5 mmol) in 20 ml of dichloromethane was added SOCl₂ (0.387 ml, 5.31 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 mins, and then stirred at room temperature for 4 h. The reaction mixture was neutralized with a solution of saturated NaHC0₃ to extract the organic layer with ethylether. The organic layer was dried over anhydrous magnesium sulfate and concentrated . The residue was purified on column chromatography with hexane-ethyl acetate to give desired compound as an oil

(0.78 g, 63 % yield).

Η-NMR (CDCI₃): δ 8.25(d, IH, ArH), 6.70(d, IH, ArH), 6.30(d, IH, vinylic), 5.52(d, IH, vinylic), 4.32(s, 2H, -CH₂C1), 1.58(s, 6H, 2(-

CH-)).

EXAMPLE 7 : Preparation of 5-(4-methoxy-lH-benzimidazol-2-thiomethyl)- 2,2-dimethyl-2H-pyrano [3,2-c] pyridine

2-Mercapto-4-methoxybenzimidazole(0.14 g, 0.81 mmol) was dissolved in 20 ml of isopropanol and stirred for 10 mins. After addition of sodium hydroxide(0.04 g, 0.92 mmol), the reaction mixture was stirred for 30 mins.

To the reaction mixture, a solution of 5-chloromethyl-2,2-dimethyl-2H- pyrano[3,2-c]pyridine in 10 ml of isopropanol was added at room temperature and stirred for 12 h. After concentration of the reaction mixture under reduced pressure, it was extracted with ethyl acetate (30 ml) and a 10 % sodium hydroxide (20 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give desired compound(0.255 g, 75 % yield).

Η-NMR (CDCI₃): 8.30~7.95(m, IH), 7.72~6.92(m, 4H), 6.58(d, IH), 5.58(d,

IH), 4.15(s, 2H), 3.89(s, 3H), 1.42(s, 6H). EXAMPLE 8 : Preparation of 5-(4-methoxy-lH-benzimidazol-2- sulfinylmethyl)-2,2-dimethyl-2H-pyrano[3,2-c]pyridine To a solution of 5-(4-methoxy-lH-benzimidazol-2-thiomethyl)-2,2- dimethyl-2H-ρyrano[3,2-c]pyridine (0.173 g, 0.488 mmol) in 20 nil . of dichloromethane was added m-CPBA (0.093 g, 0.553 mmol) at -78 °C, the reaction mixture was stirred for 1 hr. After addition of saturated sodium hydroxide(15 ml), the reaction temperature was slowly raised to room temperature. The organic layer was washed with saturated sodium bicarbonate(20 ml x 3) and concentrated to give desired compound(0.145 g, 80.3 yield).

EXAMPLE 9 : Preparation of 5-(4-methoxy-lH-benzimidazol-2- sulfinylmethyl)-2,2-dimethyl- 2H- pyrano[3,2-c] pyridine The titled compound was prepared by the same manner as described in the above EXAMPLES. Yield: 80.3 %, mp: 56 °C, Η-NMR (CDC1₃): δ 8.32~7.95(m, IH), 7.72~6.92(m, 4H), 6.58(d, IH), 5.58(d, IH), 4.95(dd, 2H), 3.87(s, 3H), 1.42(s, 6H).

EXAMPLE 10 : Preparation of 4-(4-methoxy-lH-benzimidazol-2- sulfinylmethyl)-3-methyl-furo [3,2-c] pyridine

The titled compound was prepared by the same manner as described in the above EXAMPLES.

Yield: 71 %,

Semi-solid,

Η-NMR (CDC1₃): δ 8.20 (d, IH), 7.45 (m, IH), 7.32-6.90 (m, 4H), 5.20 (dd, 2H), 2.31 (s, 3H).

EXAMPLE 11 : Preparation of 5-(5-methoxy-lH-benzimidazol-2- sulfinylmethyl)-2,2-dimethyl- 2H- pyrano[3,2-c] pyridine

The titled compound was prepared by the same manner as described in the above EXAMPLES. Yield: 78.5 %, . . mp: 52 °C,

Η-NMR (CDC!,):* 8.33~7.95(m, IH), 7.69~6.76(m, 4H), 6.60(d, IH), 5.60(d,

IH), 4.92(dd, 2H), 3.81(s, 3H), 1.46(s, 6H).

EXAMPLE 12 : Preparation of 5-(5-methoxy-lH-benzimidazol-2- sulfinylmethyl)-2,2-dimethyl- 3,4- dihydro-2H- pyrano[3,2-c] pyridine

Yield: 69.6 %,

Semi-solid, Η-NMR (CDCI₃): δ 8.25(m, IH), 7.23(m, IH), 6.93(m, 2H), 6.64(d, IH), 4.89

(dd, 2H), 3.82(s, 3H), 2.62(t, 2H), 1.69(t, 2H), 1.23 (s, 6H).

EXAMPLE 13 : Preparation of 4-(5-methoxy-lH-benzimidazol-2- sulfinylmethyl)-3-methyl-furo [3,2-c] pyridine The titled compound was prepared by the same manner as described in the above EXAMPLES.

Yield: 71 %,

Semi-solid, Η-NMR (CDCI₃): δ 8.36(d, IH), 7.48(m, IH), 7.32(m, 2H), 6.90(m, 2H),

5.02(dd, 2H), 3.76(s, 3H), 2.31(s, 3H)

EXAMPLE 14 : Preparation of 5-(lH-benzimidazol-2-sulfinylmethyl)-2,2- dimethyl-2H-pyrano [3,2-c] pyridine The titled compound was prepared by the same manner as described in the above EXAMPLES.

Yield: 68 %,

Semi-solid,

Η-NMR (CDC1₃): δ 8.20~7.90(m, IH), 7.69~6.76(m, 5H), 6.60(d, IH), 5.60(d, IH), 4.92(dd, 2H), 1.46(s, 6H).

EXAMPLE 15 : Preparation of 5-(lH-benzimidazol-2-sulfinylmethyl)-2,2- dimethyl-3,4-dihydro- 2H- pyrano [3,2-c] pyridine

The titled compound was prepared by the same manner as described in the above EXAMPLES. Yield: 72 %,

Semi-solid,

Η-NMR (CDCI₃): δ 8.23(m, IH), 7.25(m, IH), 6.93(m, 2H), 6.85(d, IH), 6.64

(d, IH), 4.89(dd, 2H), 2.62(t, 2H), 1.69(t, 2H), 1.23(s, 6H). EXAMPLE 16 : Preparation of 4-(lH-benzimidazol-2-sulfinylmethyl)-3- methyl-furo [3,2-c] pyridine

Yield: 89 %, Semi-solid,

Η-NMR (CDCI₃): δ 8.19(d, IH), 7.50~7.40(m, 6H), 4.99(dd, 2H), 2.18(s, 3H)

EXAMPLE 17 : Preparation of 5-(5-chloro-lH-benzimidazol-2- sulfinylmethyl)-2,2-dimethyl- 3,4-dihydro-2H- pyrano[3,2-c] pyridine The titled compound was prepared by the same manner as described in the above EXAMPLES. Yield: 36 %, Semi-solid, Η-NMR (CDClg): δ 8.12(m, IH), 7.51(m, IH), 7.22(m, IH), 6.60(m, IH), 6.28

(d, IH), 5.42(d, IH), 4.71(dd, 2H), 1.20(s, 6H). EXAMPLE 18 ; Preparation of 4-(5-chloro-lH-benzimidazol-2- sulfinylmethyl)-3-methyl-furo [3,2-c] pyridine

The titled compound was prepared by the same manner as described in the above EXAMPLES. Yield: 65 %, Semi-solid,

Η-NMR (CDCI₃): δ 8.36(d, IH), 7.48(m, IH), 7.32(m, 2H), 6.90(m, 2H), 5.02

(dd, 2H), 2.31(s, 3H) EXAMPLE 19 : Preparation of 7-(4-methoxy-lH-benzimidazol-2- sulfinylmethyl)-2,2-dimethyl-2H- pyrano[3,2-c] pyridine

The titled compound was prepared by the same manner as described in the above EXAMPLES. Yield: 82 %, Semi-solid,

Η-NMR (CDCI₃): δ 8.19(s, IH), 7.45(d, IH), 7.09(m, 2H), 6.71(s, IH), 6.35

(d, IH), 5.60(d, IH), 4.59(dd, 2H), 3,84(s, 3H), 1.37(s, 6H). EXAMPLE 20 : Preparation of 7-(4-methoxy-lH-benzimidazol-2- sulfinylmethyl)-2,2-dimethyl-3,4- dihydro-2H- pyrano[3,2-c] pyridine

The titled compound was prepared by the same manner as described in the above EXAMPLES. Yield: 70 %, Semi-solid,

Η-NMR (CDCI₃): δ 8.25(m, IH), 7.23(m, IH), 6.93(m, 2H), 6.64(d, IH), 4.89

(dd, 2H), 3.82(s, 3H), 2.62(t, 2H), 1.69(t, 2H), 1.23(s, 6H). EXAMPLE 21 : Preparation of 7-(4-methoxy-lH-benzimidazol-2- sulfinylmethyl)-3,4-dimethyl- 3,4-dihydro-2H- pyrano[3,2-c] pyridine

The titled compound was prepared by the same manner as described in the above EXAMPLES. Yield: 60 %, Semi-solid, Η-NMR (CDC1₃): δ 8.32(m, IH), 7.52(m, IH), 6.96(m, 2H), 6.62(s, IH), 4.61

(dd, 2H), 4.11(t, 2H), 3.82(s, 3H), 1.74(t, 2H), 1.30(s, 6H). EXAMPLE 22 : Preparation of 6-(4-methoxy-lH-benzimidazol-2- sulfinylmethyl)-3-methyl-furo [3,2-c] pyridine

The titled compound was prepared by the same manner as described in the above EXAMPLES. Yield: 78 %, Semi-solid,

Η-NMR (COC .δ 8.69(s, IH), 7.48(m, IH), 7.29(m, 2H), 6.87(m, 2H), 4.78

(d, 2H), 3.77(s, 3H), 2.20(s, 3H). EXAMPLE 23 : Preparation of 6-(4-methoxy-lH-benzimidazol-2- sulfinylmethyl)-3,3-dimethyl- 2,3-dihydro-furo[3,2-c] pyridine

The titled compound was prepared by the same manner as described in the above EXAMPLES. Yield: 46 %, Semi-solid,

Η-NMR (CDC1₃): δ 8.14(s, IH), 7.45(m, IH), 6.93(m, 2H), 6.65(s, IH), 4.66

(dd, 2H), 4.23(s, 2H), 3.83(s, 3H), 1.32(t, 2H), 1.32(s, 6H). EXAMPLE 24 ; Preparation of 7-(5-methoxy-lH-benzimidazol-2- sulfinylmethyl)-2,2-dimethyl-2H- pyrano[3,2-c] pyridine

The titled compound was prepared by the same manner as described in the above EXAMPLES. Yield: 84 %, Oil,

Η-NMR (CDClg): δ 8.10(s, IH), 7.32(d, IH), 7.10~6.79(m, 3H), 6.70(s, IH),

6.55(d, IH), 6.35(d, IH), 4.59(dd, 2H), 3.79(s, 3H), 2.35(s, 6H). EXAMPLE 25 ; Preparation of 7-(5-methoxy-lH-benzimidazol-2- sulfinylmethyl)-2,2-dimethyl-3,4- dihydro-2H-pyrano[3,2-c] pyridine

The titled compound was prepared by the same manner as described in the above EXAMPLES. Yield: 86 %, Oil,

Η-NMR (CDCI₃): δ 8.18(s, IH), 7.72~7.14(m, 3H), 6.68(s, IH), 4.65(dd, 2H),

3.85(s, 3H), 2.15(t, 2H), 1.35(m, 8H). EXAMPLE 26 ; Preparation of 6-(5-methoxy-lH-benzimidazol-2- sulfinylmethyl)-3-methyl- furo [3,2-c] pyridine The titled compound was prepared by the same manner as described in the above EXAMPLES. Yield: 46 %, Semi-solid,

Η-NMR (CDCI₃): δ 8.69(s, IH), 7.49(m, IH), 7.28(m, 2H), 6.91(d, IH), 4.79 (dd, 2H), 3.89(s, 3H), 2.21(s, 3H).

EXAMPLE 27 : Preparation of 6-(5-methoxy-lH-benzimidazol-2- sulfinylmethyl)-3-methyl-2,3- dihydro-furo [3,2-c] pyridine

Yield: 53 %,

Semi-solid,

Η-NMR (CDCI₃): δ 8.07(s_r IH), 7.79(m, IH), 6.92(m, 2H), 6.62(s, IH), 4.61 (dd, 2H), 4.22(s, 2H), 3.80(s, IH), 1.28(s, 6H).

EXAMPLE 28 : Preparation of 7-(lH-benzimidazol-2-sulfinylmethyl)-2,2- dimethyl-2H-pyrano [3,2-c] pyridine

The titled compound was prepared by the same manner as described in the above EXAMPLES. Yield: 87 %,

Oil,

Η-NMR (CDC1₃):<* 8.21(s, 2H), 7.76~7.10(m, 3H), 6.75(s, IH), 6.70(d, IH),

6.51(d, IH), 4.51(dd, 2H), 1.43(s, 6H).

EXAMPLE 29 : Preparation of 7-(lH-benzimidazol-2-sulfinylmethyl)-2,2- dimethyl-3,4-dihydro- 2H-pyrano [3,2-c] pyridine

Yield: 61 %,

Oil, Η-NMR (CDCI₃): δ 8.21(s, IH), 7.72~7.15(m, 3H), 6.70(d, IH), 6.68(s, IH),

4.65(dd, 2H), 2.15(t, 2H), 1.35(m, 8H)

EXAMPLE 30 : Preparation of 7-(lH-benzimidazol-2-sulfinylmethyl)-4,4- dimethyl-3,4-dihydro- 2H-pyrano [3,2-c] pyridine

Yield: 38 %,

Oil,

Η-NMR (CDCI₃): δ 8.35(s, IH), 7.65(m, 2H), 7.31(m, 2H), 7.28(s, IH), 4.56 (dd, 2H), 4.16(t, 2H), 1.75(t, 2H), 1.31(s, 6H). EXAMPLE 31 ; Preparation of 6-(lH-benzimidazol-2-sulfinylmethyl)-3,3- dimethyl-2,3-dihydro- furo [3,2-c] pyridine

Yield: 41 %,

Oil,

Η-NMR (CDClg): δ 8.16(s, IH), 7.66(m, 2H), 7.30(m, 2H), 6.67(s, IH), 4.64

(dd, 2H), 4.26(s, 2H), 1.33(s, 6H). EXAMPLE 32 : Preparation of 7-(5-chloro-lH-benzimidazol-2- sulfinylmethyl)-2,2-dimethyl-3,4- dihydro-2H-pyrano [3,2-c] pyridine

Yield: 34 %, Oil,

Η-NMR (CDCI₃): δ 8.14(s, IH), 7.59(m, 2H), 7.25(m, IH), 6.55(s, IH), 4.56

(dd, 2H), 2.66(t, 2H), 1.72(t, 2H), 1.22(s, 6H). The benzimidazole derivatives containing fused pyridine according to the present invention may be made into a pharmaceutically acceptable salt by conventional methods. Examples of such salts may include alkali metal salts such as lithium salt, sodium salt, potassium salt and the like; alkaline earth metal salts such as magnesium salt and the like; and ammonium salts such as ammonium salt, methylammonium salt, dimethylammonium salt, trimethylammonium salt, tetramethylammonium salt and the like. The benzimidazole derivatives containing fused pyridine of formula(I) may be administered orally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous injection, intramuscular injection, intrastemal injection or infusion techniques.

The dosage employed depends on the type of disease, the degree of 5 symptom and age. The dosage levels of the compound in the above-indicated compositions may, of course, be varied and may conveniently be between about 0.1 % to about 95 % of the weight the unit.

When these compounds are administered orally, a dose of 1-50 wt% is particularly preferred. ι o For parenteral administration, a dose of 0.1-20 wt% is particularly . preferred be benefitial.

Pharmaceutical compositions containing compounds of formula(I) may be in any form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispensable powders or granules, emulsion, hard 15 or soft capsules, syrups or elixirs.

The tablets, capsules and the like may also contain a binder, such as lactose, saccharose, sorbitol, manitol, starch, amylopectin, cellulose or gelatin; excipients, such as dicalcium phosphate; a disintegrating agent, such as corn starch or potato starch; a lubricant, such as magnesium stearate, calcium 20 stearate, sodium stearylfumalate or polyethylenglycol wax. When the dosage unit form is a capsule, it may further contain, in addition to the type of materials described above, a liquid carrier, such as fatty oil.

These active compounds of formula(I) may also be administered paranterally. A solution or suspension of the active compounds may be

25 prepared in water, optionally mixed with stabilizer or buffering agents. The dosages for parenteral administration are 0.1-10 wt%, and preferably administered as ampule or vial type.

Dosage levels of about 2 mg to about 1,000 mg(70 kg of body weight, adult) per day are particularly useful for inhibiting gastric acid secretion.

For intravenous injection for treating these conditions, dosage levels of about

2 to about 25 mg are particularly preferred.

Accordingly, the present invention provides pharmaceutical 5 compositions comprising a pharmaceutically effective amount of a compound of formula(I) and a pahrmaceutically acceptable carrier. The present invention also provides the pharmaceutical uses of these compounds and compositions, especially for inhibiting gastric acid secretion in mammals.

The following examples illustrate the typical pharmaceutical ι o composition. In each case, the active ingredient represents a compounds of formula(I), which may be substituted by any pharmaceutically effective amount of another compound of formula(I).

[pharmaceutical compositions]

Syrups 15 Syrups containing 2 % of active ingredients (w/v) was manufactured by the following substances

20

25

A mixture of sugar, saccharin and added salts was dissolved in 80 g of warm water. After cooling, a solution containing the following additives (i.e., glycerin, saccharin, flavoring agent, ethanol, sorbic acid and water) was prepared and charged into a bottle. Then, water was added to the mixture to be 100 ml. Said added salts may be replaced by other salts. Tablets

Tablets containing 15 mg of active ingredients was manufactured in the following manner:

250 g of 5-(4-methoxy-lH-benzimidazol-2-sulfinyl)-2,2-dimethyl-2H- pyrano [3,2-c]pyridine • HCl was mixed with 175.9 g.of lactose, 180 g of potato starch and 32 g of colloidal silicate. A solution of 10 % gelatin was added to . the mixture, pulverized and passed through a 14-mesh sieve.

After drying, 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate were added to the mixture for the manufacture of tablets. Injections

A mixture of 250 g of 5-(4-methoxy-lH-benzimidazol-2-sulfinyl)-2,2- dimethyl-2H-pyrano [3,2-c]pyridine • HCl, 0.6g of sodium chloride and 0.1 g of ascorbic acid was dissolved in distilled water to give 100 ml as a solution.

Then, the solution containing 10 mg of active ingredients was charged into a bottle, heated at 20 °C for 30 mins and sterilized. Method of screening a pharmacological activity [Preparation of H⁺/K⁺-ATPase source]

New Zealand White male rabbits (2-3 kg) were killed by a blow to the head and the stomach was excised. All fats and connective tissues were removed and the inter- wall of stomach was washed with physiological saline. After scratching the inter-wall tissue of stomach with slide glass, the cells were homogenized by a tefron-glass homogenizer in sucrose buffer solution (pH 7.4) containing 250 mM sucrose, 2 mM HEPES, 2mM MgCl₂, and 1 mM EDTA in 40 mM Tris HCl buffer solution. The homogeneous solution was centrifuged at 10,000 g at 4 °C for 30 mins. The top layer collected was again super-centrifuged at 10,000 g at 4 °C for 1 hr. After removing the top layer, the precipitated layer of pellet was resuspended in 40 mM Tris /HCl buffer solution (pH 7.4) to prepare the microsomal pellet of stomach wall cells in rabbit. This microsomal pellet was used as an enzyme source to perform the enzymatic reaction in vitro test of H⁺/K⁺-ATPase. [Enzymatic reaction in vitro test of H7K⁺-ATPase]

The enzymatic reaction in vitro test of H⁺/K⁺-ATPase was performed by establishing two control groups, i.e., 1) Mg²⁺-stimulated H⁺/K⁺-ATPase activity as negative control and 2) Mg²⁺/K⁺-stimulated H⁺/K⁺-ATPase activity as positive control.

Namely, each 20ml of solution was charged to the test tubes of both negative /positive control and test substance group and then, MgCl₂ (100 μl) and microsomal pellet (50 μg) were added. 10 μl of dimethylsulfoxide (DMSO) was added to each test tube of both controls, while to the test substance group, the test substance dissolved in DMSO, under the condition of enzymatic in vitro reaction, was diluted by 5 concentrations from the concentration showing the maximal solubility and each 10 μl was added. Further, 10 μl of 40 mM Tris HCl buffer solution (pH 7.4) to the test tube of negative control and a mixing solution of 300 mM KC1 + 100 mM NH₄C1 was added to positive control and test substance group, followed by the addition of 40 mM Tris HCl buffer solution (pH 7.4) to a total volume of 400 μl.

These reaction test tubes were preincubated at 37°C for 30 mins so as to bind the compound and H⁺/K⁺-ATPase. Then, with the addition of 100 μl of 33.3 mM ATP-Tris HCl buffer solution, the reaction mixture contained MgCl₂ (4 mM), KC1 (60 mM), NH₄C1 (20 mM), 2 % DMSO-test compound (v/v), ATP (6.7 mM), microsomal pellet 50 μg (0.2 μl) and 40 mM Tris HCl buffer solution (pH 7.4) in a total volume of 500 μl . Enzymatic reactions were conducted at 37°C for 30 mins.

The inorganic phosphorous, so generated from enzymatic reaction, was assayed by a blood automatic analyzer (GILFORD SBA-300) and the

5 difference between negative and positive controls was determined by K⁺- stimulated H⁺/K⁺-ATPase activity. Further, H⁺/K⁺-ATPase activity was measured by each of percentage value where the enzymatic activity was inhibited, from the tubes of test substance added with five concentrations of IC₅₀ (effective concentration of the test substance required to achieve 50 % ι o inhibition of H⁺ /K⁺-ATPase activity) related to the test substance, as defined by Liitchfield-Wilcoxon. The test results (in vitro test) are represented in the following table 3.

20

25 Table 3.

Compound IC₅₀ (in vitro, μM)

5-(4-Methoxy-lH-benzimidazol-2-sulfinylmethyl)- 50 2,2-dimethyl-2H-pyrano[3,2-c] pyridine 4-(4-Methoxy-lH-benzimidazol-2-sulfinylmethyl)- 15 3-methyl-furo[3,2-c] pyridine 5-(5-Methoxy-lH-benzimidazol-2-sulfinylmethyl)- <10 2,2-dimethyl-2H-pyrano [3,2-c] pyridine 5-(4-Methoxy-lH-benzimidazol-2-sulfinylmethyl)- 15 2,2-dimethyl-3,4-dihy dro-2H-pyrano [3,2-c] pyridine 4-(5-Methoxy-lH-benzimidazol-2-sulfinylmethyl)- <15 3-methyl-3-furo[3,2-c] pyridine 5-(lH-Benzimidazol-2-sulfinylmethyl)-2,2-dimethyl- 50 2H-pyrano [3,2-c] pyridine

5-(lH-Benzimidazol-2-sulfinylmethyl)-2,2-dimethyl- 50 3,4-dihydro-2H-pyrano [3,2-c] pyridine 4-(lH-Benzimidazol-2-sulfinylmethyl)- 20 3-methyl-furo[3,2-c] pyridine 5-(5-Chloro-lH-benzimidazol-2-sulfinylmethyl)-2,2- 15 dimethyl-3,4-dihydro-2H-pyrano [3,2-c] pyridine 4-(5-Chloro-lH-benzimidazol-2-sulfinylmethyl)-3- 15 methyl-furo [3,2-c] pyridine

7-(4-Methoxy-lH-benzimidazol-2-sulfinylmethyl)- 15 2,2-dimethyl-2H-pyrano[3,2-c] pyridine 7-(4-Methoxy-lH-benzimidazol-2-sulfinylmethyl)- <10 2,2-dimethyl-3,4-dihydro-2H-pyrano[3,2-c] pyridine Compound IC₅₀ (in vitro, μM)

7-(4-Methoxy-lH-benzimidazol-2-sulfmylmethyl)- <10 4,4-dimethyl-3,4-dihy dro-2H-pyrano [3,2-c] pyridine 6-(4-Methoxy-lH-benzimidazol-2-sulfinylmethyl)- 50 3-methyl-furo[3,2-c] pyridine 6-(4-Methoxy-lH-benzimidazol-2-sulfinylmethyl)- <10 3,3-dimethyl-2,3-dihydro-furo[3,2-c] pyridine 7-(5-Methoxy-lH-benzimidazol-2-sulfinylmethyl)- <10 2,2-2H-pyrano[3,2-c] pyridine 7-(5-Methoxy-lH-benzimidazol-2-sulfinylmethyl)- 17 2,2-dimethyl-3,4-dihydro-2H-pyrano[3,2-c] pyridine 6-(5-Methoxy-lH-benzimidazol-2-sulfinylmethyl)- <10 3-methyl-furo[3,2-c] pyridine 6-(5-Methoxy-lH-benzimidazol-2-sulfinylmethyl)- <10 3,3-dimethyl-2,3-dihydro-furo[3,2-c] pyridine 7-(lH-Benzimidazol-2-sulfinylmethyl)- 10 2,2-dimethyl-2H-pyrano[3,2-c] pyridine 7-(lH-Benzimidazol-2-sulfinylmethyl)- 15 2,2-dimethyl-3,4-dihy dro-2H-pyrano [3,2-c] pyridine Omeprazole 15

[Acute toxicity study of compound by oral administration]

In order to investigate the acute toxicity of the compounds of the above formula(I) according to the present invention, a single administration was made to male ICR mice and then, the following parameters were observed accordingly: death, general sign, change in body weight and autopsy finding. The results of this study were summarized as follows: 1) Death : Any death in all of treated groups was not observed.

2) General sign : From 1 hr after oral administration, all animals having over 2,000 mg/kg showed the reduction of vitality but except for the treated group with a dosage of 5,000 mg/kg showing said persistant symptom other remaining groups demonstrated their repid recovery.

3) Change in body weight and antopsy finding by naked eye : Any symptoms associated with the test substance were not observed.

From the aforementioned results, LD₅₀ value of the compound (I) according to the present invention is 3,000-5,000 mg/kg.

Claims

WHAT IS CLAIMED IS:

1. A compound of formula(I) or a pharmaceutically acceptable salt thereof:

H

Wherein;

R represents hydrogen, halogen, C_j~C₃ alkoxy, C_j- haloalkoxy, C_α~C₃ alkyl or - haloalkyl group; ι o Q represents

X represents

1 5

R¹, R², R³, R⁴, R⁵ and R⁶ are the same or different, and each represents hydrogen, halogen, - alkyl group; with a proviso that, all hydrogen are excluded.

20 2. The compound according to claim 1, wherein said R represents hydrogen, chlorine, bromine, fluorine methoxy group, ethoxy group, propyloxy group, trifluoromethyl group, or 2,2- difluoroethoxy group.

3. The compound according to claim 1 or 2, wherein said R¹, R², R³, R⁴, R⁵ and R⁶ represent the same or different, and each represents hydrogen, methyl group, ethyl group, or propyl group; with a proviso that all hydrogen are excluded. 5

4. The compound according to claim 1, wherein said the compound is selected form the group consisting of 5-(4-methoxy-lH-benzimidazol-2-sulfinylmethyl)- 2,2-dimethyl-2H-pyrano[3,2-c] pyridine, o 4-(4-methoxy-lH-benzimidazol-2-sulfinylmethyl)-

3-methyl-furo [3,2-c] pyridine, 5-(5-methoxy-lH-benzimidazol-2-sulfinylmethyl)- 2,2-dimethyl-2H-pyrano[3,2-c] pyridine, 5-(4-methoxy-lH-benzimidazol-2-sulfinylmethyl)- 5 2,2-dimethyl-3,4-dihydro-2H-pyrano[3,2-c] pyridine,

4-(5-methoxy-lH-benzimidazol-2-sulfinylmethyl)- 3-methyl-3-furo [3,2-c] pyridine, 5-(lH-benzimidazol-2-sulfinylmethyl)-2,2-dimethyl- 2H-pyrano [3,2-c] pyridine, o 5-(lH-benzimidazol-2-sulfinylmethyl)-2,2-dimethyl-

3,4-dihydro-2H-pyrano [3,2-c] pyridine, 4-(lH-benzimidazol-2-sulfinylmethyl)- 3-methyl-furo [3,2-c] pyridine, 5-(5-chloro-lH-benzimidazol-2-sulfinylmethyl)-2,2- 5 dimethyl-3,4-dihydro-2H-pyrano [3,2-c] pyridine,

4-(5-chloro-lH-benzimidazol-2-sulfinylmethyl)-3- methyl-furo[3,2-c] pyridine, 7-(4-methoxy-lH-benzimidazol-2-sulfinylmethyl)-

2,2-dimethy l-2H-pyrano [3,2-c] pyridine,

7-(4-methoxy-lH-benzimidazol-2-sulfinylmethyl)-

2,2-dimethyl-3,4-dihy dro-2H-pyrano [3,2-c] pyridine, 5 7-(4-methoxy-lH-benzimidazol-2-sulfinylmethyl)-

4,4-dimethyl-3,4-dihydro-2H-pyrano [3,2-c] pyridine,

6-(4-methoxy-lH-benzimidazol-2-sulfinylmethyl)-

3-methyl-furo [3,2-c] pyridine,

6-(4-methoxy-lH-benzimidazol-2-sulfinylmethyl)- o 3,3-dimethyl-2,3-dihydro-furo[3,2-c] pyridine,

7-(5-memoxy-lH-benzimidazol-2-sulfinylmethyl)-

2,2-2H-pyrano[3,2-v] pyridine,

7-(5-methoxy-lH-benzimidazol-2-sulfinylmethyl)-

2,2-dimethyl-3,4-dihydro-2H-pyrano[3,2-v] pyridine, 5 6-(5-methoxy-lH-benzimidazol-2-sulfinylmethyl)-

3-methyl-furo [3,2-c] pyridine,

6-(5-methoxy-lH-benzimidazol-2-sulfinylmethyl)-

3,3-dimethyl-2,3-dihydro-furo[3,2-c] pyridine,

7-(lH-benzimidazol-2-sulfinylmethyl)- 0 2,2-dimethyl-2H-pyrano[3,2-c] pyridine, and

7-(lH-benzimidazol-2-sulfinylmethyl)-

2,2-dimethyl-3,4-dihydro-2H-pyrano[3,2-c] pyridine.

5. A anti-ulcerants composition comprising a compound of formula(I) or 5 a pharmaceutically acceptable salt thereof as active ingredients in combination with a pharmaceutically acceptable carrier.

H

Wherein, R and Q represent the same as defined in said claim 1.

6. The anti-ulcerants composition according to claim 5, wherein said R represents hydrogen, chlorine, bromine, fluorine, methoxy group, ethoxy group, propyloxy group, trifluoromethyl group, or 2,2- difluoroethoxy group.

7. The anti-ulcerants composition according to claim 5 or 6, wherein said R¹, R², R³, R⁴, R⁵ and R⁶ represent the same or different, and each represents hydrogen, methyl group, ethyl group, or propyl group; with a proviso that all hydrogen are excluded.

8. A compound of formula (VI) useful for the preparation of a compound of formula (I).

wherein, R and Q represent the same as defined in said claim 1.