WO2009086731A1

WO2009086731A1 - New benzimidazole compounds

Info

Publication number: WO2009086731A1
Application number: PCT/CN2008/001977
Authority: WO
Inventors: Maosheng Cheng; Qinghe Wang; Yanhui Yang; Han Nie; Yunwei Li
Original assignee: Shenyang Pharmaceutical University
Priority date: 2007-12-05
Filing date: 2008-12-05
Publication date: 2009-07-16
Also published as: CN101450939A; CN101450939B

Abstract

New benzimidazole compounds of the following formula (I) which have activities of inhibiting gastric acid secretion, resistingHelicobacter pylori (Hp) and treating gastric cancer, wherein A, B, L, R1 and n are defined as claim 1. The compounds have two functional groups of benzimidazole,which may combine with the cysteine residues in the H+, K+-ATP enzyme monomer or oligomer to inhibit the activity of H+, K+-ATP enzyme after being activated by gastric acid in vivo. The compounds are selective inhibitor of Hp.

Description

Novel Benzimidazole Compounds Field of the Invention:

The invention belongs to the technical field of medicine, and particularly relates to a bisbenzimidazole compound having anti-gastrointestinal acid secretion, anti-Helicobacter pylori and gastric cancer inhibiting activity. Background technique:

Proton pump inhibitors are effective in inhibiting gastric acid secretion because they have the activity of inhibiting gastric H ⁺ , K + -ATPase. They have been widely used in the treatment of peptic ulcer and related diseases caused by excessive gastric acid secretion. 'Mainly include: stomach And duodenal ulcer, heartburn, reflux esophagitis, corrosive esophagitis, non-ulcer dyspepsia, Helicobacter pylori infection, laryngitis, etc.

A number of patent documents have been reported to have benzimidazole derivatives which inhibit gastric acid secretion, mainly US4045563, 425543 K 4628098, 4686230, 4758579, 4965269, 5021433, 5430042, 5708017, 6093734, 6559167, 6897227 and the like. Studies have shown that benzimidazole-type gastric acid secretion inhibitors are catalyzed by gastric acid in the body, and rearrangement occurs, forming a sulphur-containing sulfenic acid or sulfenamide, and then a proton pump on the cells of the stomach wall - H ⁺ The K ⁺ -ATPase is covalently bonded to inhibit the activity of the enzyme. The H ⁺ , K ⁺ -ATPase acts on the final step of gastric acid secretion, so inhibition of its activity can inhibit gastric acid secretion. Such compounds are therefore referred to as "proton pump inhibitors (PPIs)".

PPI-type drugs that have been marketed at home and abroad are: 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H -benzimidazole (omeprazole, omeprazole) 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl] -1H-benzimidazole (lansoprazole) 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl] -1H -benzimidazole (pantopra _Z0 le), 2-[[[3-methyl-4-(3-methoxy-1-propyl)-2-pyridyl]methyl]sulfin Acyl]-1H-benzimidazole (rabeprazole), 5-methoxy-2-[[4-4-methoxy-3,5-dimethyl-2- in clinical studies Pyridyl)methyl]sulfinyl]-imidazo[4,5-b]pyridine (ttoprazole, tantoprazole).

Due to the great clinical success of PPI-type compounds, structural modification to obtain more efficient compounds has become one of the hotspots of acid-suppressing compounds in recent years. These structural modifications are mainly reflected in the following aspects: structural modification of the pyridine ring, such as CN86102398 replacing the pyridine ring with aminopyridazine, CN88102373.6 replacing the pyridine ring with a substituted benzene ring, and W089/5229 introducing a benzyloxy group at the 4-position of the pyridine. EP220053 introduces a substituent such as an amino group on the pyridine ring, and W095/11897 introduces a glycol ether moiety at the 4-position of pyridine, WO97/00875 A five- or six-membered heterocyclic ring was added to the pyridine ring. WO03/24957 and CN02810722.5 introduced trifluoroethoxyethoxy and trifluorobutoxy groups at the 4-position of pyridine, which reduced the clinical individual difference. WO06 /112442 at the 4-position of pyridine. A substituent group containing a dioxan moiety such as 5,5-dimethyl-1,3-dioxan-2-ylmethoxy is introduced; the benzimidazole ring is structurally modified, such as WO90/06924 introduces fluorine at the 4-position of the benzimidazole ring, and WO90/06926 introduces chlorine at the 5-position of the benzimidazole ring; a benzimidazole N-substituted derivative such as EP176308 introduces a hydroxyl group at the 1-position N of the benzimidazole The thiol substituent, EP221041 introduces an acyloxyalkyl group at the 1-position N, GB2219584 introduces a hydroxymethyl phosphate at the 1-position N, and WO00/50037U WO02/00166, US04/24014 introduces NO at the 1-position N. The release fragment, WO03/27098 is a lansoprazole N-derived prodrug, US6093734, 6599167, 6897227, WO00/109498, WO04/09583 introduces an arylsulfonyl group at the 1-position N; , such as WO91/09028, W091/19711, introducing a halogen to the benzimidazole ring, introducing a substituted decyloxy group, and a benzimidazole at the N position. Into the hydroxymethyl carbonate, WO97 / 40039 is introduced on the pyridine ring at the alkylthio, alkylsulfinyl, an alkylsulfonyl group, an ester group is introduced at position〗 benzimidazole N.

Target-based drug design remains an important tool for current drug research. It is reported in the literature that H+, K+-ATPase exists in the form of monomers, dimers, tetramers and other oligomers in vivo (Kazuhiro A., et al. Biochemistry, 2003, 42: 15132; Kazuhiro A., et Al. J. Biochem., 2005, 138: 293; Shin JM, et al. Biochemistry, 2005, 44: 16321), and oligomers are closely related to enzyme activity. Molecular biology studies have shown that PPIs bind to multiple cysteine of H+, K ⁺ -ATPase, such as omeprazole combined with Cys813 and Cys892, lansoprazole binds to Cys321, Cys813, Cys892, and The azole binds to Cys813 and Cys822, and Rabeprazole binds to Cys321 and Cys892. Therefore, the design of an inhibitor can simultaneously bind to multiple cysteine of the oligomer, and the effect of inhibiting gastric acid secretion and the time of acid suppression will be greatly improved.

PPIs can be used to inhibit H. pylori infection. Helicobacter pylori (Hp) is a spiral-shaped bacterium that inhabits the stomach of the human body. In 1982, Australian scholars Warron and Marshall first isolated and cultured the bacterium from the human gastric mucosa. More than 20 years of research have found that Hp is closely related to upper gastro-intestinal diseases such as chronic gastritis, peptic ulcer, gastric cancer and gastric mucosa-associated lymphoma. Epidemiological studies have shown that Hp infection rate is highly correlated with the incidence of human gastric cancer. In 1994, the International Cancer Research Center identified Hp as the first carcinogen of human gastric cancer. At present, the main clinical anti-Hp drugs are: antibiotics (β-lactam, macrolide, quinolone), fungicides (secret salts) and anti-protozoal drugs ( metronidazole). Although these drugs can eradicate Hp, there are still problems such as drug resistance, side reactions, and independence. Therefore, the need to design and develop new structures of anti-Hp drugs is urgent.

The novel anti-Hp compounds mainly include the following classes: furanyl thiazolium derivatives (Katsura Y, et al. Bioorg. Med. Chem. Lett., 1998, 8: 1307; Katsura Y" et al. J. Med. Chem., 1999, 42: 2920), antibiotics (cephalosporin derivatives, Yoshida Y., et al. Bioorg. Med. Chem. Lett., 1999, 9: 3123; Natural product benzoquinones, Dekker KA, et al. J. Antibiot., 1997, 50: 833), aryl amides (Ando R., et al. J. Med. Chem., 2001, 44: 4468), pyrazoles (Copeland RA, et al. J. Biol. Chem., 2000, 275: 33373) and benzimidazoles (Kiihler T. C" et al. J Med. Chem., 1995, 38: 4096; Ku ler TC, et al. J. Med. Chem., 1998, 41 : 1777; Carcanague D., et al. J. Med. Chem., 2002, 45: 4300) and so on. Benzimidazole anti-Hp compounds, mainly PPIs, synthetic precursors of PPIs - thioether compounds and their structural analogs. The inhibition of Hp by PPIs is similar to the inhibition of H+ and K+-ATPases, that is, PPIs are activated in vivo to form sulfenic acid or sulfenamide, and then covalently bonded with Hp urease to inhibit urease activity and cause pH around Helicobacter pylori. Reduced, eventually killed by stomach acid. The synthetic precursor of PPIs, thioethers, also has a certain bactericidal activity and is selective for Helicobacter species.

Gastric cancer is one of the most common malignant tumors in the world. The incidence of gastric cancer in developed countries has declined, but the mortality rate has not decreased significantly, ranking the second most common cause of malignant tumor death. The incidence and mortality rate of gastric cancer in China still ranks first. The high mortality rate is due to the low rate of early diagnosis (only 10% in stage I), low rate of surgical resection (50%-65% for radical resection), and low 5-year survival rate (over 30% overall survival). Thoracic resection of the tumor is the preferred method of treatment for gastric cancer. Improving surgical techniques and expanding the scope of cleaning have not significantly improved the 5-year survival rate. Chemotherapy is the main treatment for patients with advanced gastric cancer who have lost their chance of surgery. The objective response rate of traditional chemotherapy drugs is only 24%-40%. In order to further improve the prognosis of patients with gastric cancer, effectively improving the response rate of tumor treatment and reducing toxicity and overcoming the drug resistance of gastric cancer has become a new direction for the study of gastric cancer.

DNA topoisomerase (Topoisomerase) changes the topology of DNA by creating a transient cleavage on the ribose-phosphate backbone of DNA. In order to maintain the stringency of DNA, Topo's tyrosine The acid residue forms a covalent bond with the newly produced DNA end by transesterification; when another DNA strand passes through the gap, the DNA is recovered by reverse transesterification. In tumor cells, DNA Topo enzyme content and activity are much higher than normal somatic cells, inhibiting the activity of Topo enzyme can inhibit the rapid proliferation of tumor cells, thereby killing tumor cells. At present, DNA Topo enzyme has become a recognized target for anticancer drugs. DNA minor groove binder is a kind of Topo enzyme inhibitor, which acts through hydrogen bonding, static electricity, van der Waals force, etc. in the adenine (A) and thymine (T)-enriched DNA minor groove region. DNA binding forms a complex that blocks the binding of Topo enzyme to DNA, affects DNA replication, and ultimately leads to tumor cell apoptosis. The _{bisbenzimidazole} DNA minor groove binder, such as _H0ec hst33258, selectively binds to the small groove region rich in AT base pairs and has certain antitumor activity. Based on the above design ideas, the present invention has developed a new class of benzimidazole compounds, namely bisbenzimidazole compounds. The sulfoxide compound is activated in vivo to bind to two cysteine residues in the H+, K+-ATPase monomer, or to two cysteine residues in the oligomer. Inhibition of H+, K+-ATPase activity. The bisbenzimidazole compounds also have an activity of selectively inhibiting Hp. These compounds can bind to the small groove region of tumor cell DNA in a "crescent" shape, inhibit DNA topoisomerase activity, and exert anticancer effects. As analogs of PPIs, these compounds are weakly basic compounds, which are easily aggregated in gastric parietal cells and have a targeted anti-gastric effect. Summary of the invention:

The present invention is a further development of studies of benzimidazoles and relates to a novel benzimidazole compound of the formula (I) and a pharmaceutically acceptable salt thereof:

Where A is the following structure

, N in the benzimidazole ring means that one carbon atom on the benzene ring may be substituted by a nitrogen atom;

B is the following structure:

, wherein the carbon atom of B is attached to the main chain;

L is the following structure

Single button, ^x ,

Is hydrogen or C,. _1Q thiol,

R ₂ to R 4 are independently hydrogen, halogen, CLK) fluorenyl; halogen-substituted C _W o alkyl; CMQ alkoxy; halogen-substituted Cwo methoxy; Cwo fluorenylcarbonyl, Cwo alkoxycarbonyl, aromatic a C _1-1Q alkyl group, a C _{4-l 8} aromatic heterocyclic Cwo fluorenyl group, a C ₈ aryl group, a C _4-18 aromatic heterocyclic group, R ₅ , R ₆ , R _{7 are} independently hydrogen or CM _Q fluorenyl; fluoro substituted CM _Q alkyl; CMO decyloxy; fluoro substituted C _MQ decyloxy; CMO alkylthio; fluoro substituted CMO 垸Sulfur; C ₂ . _1Q alkoxy oxy; amino, Cwo alkylamino, di CO alkylamino, halogen; phenyl, du) fluorenyl substituted phenyl, decyl substituted phenyl, phenyl Cwo methoxy, piperidinyl, morpholinyl; or, any two of R ₅ , , R ₇ are bonded to form a 5-membered ring containing 0 to 1 hetero atom selected from N, S, or 0 or 6 yuan ring;

Rn is hydrogen, halogen, Cwo fluorenyl, halogen-substituted Cwo fluorenyl; Cwo methoxy; fluorohalogen substituted CLHJ alkoxy;

X, Y are any atom, such as CH ₂ , NH, 0, or S;

1. m is any integer between 0 and 10, and n is any integer between 0 and 2.

Pharmaceutically acceptable salts of the compounds of the invention include the common metal salts, ammonium salts, mineral acid salts, and the like. The compound of the present invention and a pharmaceutically acceptable salt thereof may mean a compound which is present as a single enantiomer of (R) or (S) or in an enantiomerically enriched form, and a salt thereof. Detailed description of the invention:

In the Summary of the Invention, the chemical structure of the compounds of the present invention is represented and described by the general formula (I). It is known from the general formula (I) that the compound of the present invention is a pyridylmethylsulfinylbenzimidazole compound, or a structure closely related to the structure, wherein two molecules of the benzimidazole ring pass through a single bond, a carbon atom, A hetero atom, a hetero atom-containing or a hetero atom-free structural moiety is bonded to form a bisbenzimidazole compound. Such a compound can simultaneously bind to a plurality of cysteines of H+, K+-ATPase monomers or oligomers, and effectively exerts an acid suppressing action. Such compounds can selectively inhibit Hp, and can also be selectively distributed in gastric parietal cells, and bind to the small groove of gastric cancer cells to exert anti-gastric cancer activity.

Among all the bisbenzimidazoles of the present invention, preferred are pyridylmethylsulfinylbenzimidazole structures or structurally related moieties which are preferred in the prior art.

In the present invention, "Cwo fluorenyl" means a linear or branched fluorenyl group having 1 to 10 carbon atoms, preferably a fluorenyl group having 1 to 6 carbon atoms. Including: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, phenyl, n-hexyl, 1 ,1-dimethylbutyl, 2,2-dimethyl A butyl group, a 2-ethylbutyl group or the like is preferably an alkyl group having 1 to 4 carbon atoms.

In the present invention, the "halogen-substituted C MO fluorenyl group" means a linear or branched alkyl group having 1 to 10 carbon atoms which is substituted by a halogen, preferably 1 to 5 halogen-substituted hydrogen atoms, more preferably 1 - 3; such as trifluoromethyl.

In the present invention, "C MO methoxy group" means a straight or branched alkoxy group having 1 to 10 carbon atoms, preferably a decyloxy group having 1 to 6 carbon atoms. Including: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso Butoxy, tert-butoxy, phenoxy, n-hexyloxy, 1,1-dimethylbutoxy, 2,2-dimethylbutoxy, 2-ethylbutyloxy, etc. An alkoxy group having 1 to 4 carbon atoms is preferred.

In the present invention, "halogen-substituted CMO methoxy group" means a linear or branched decyloxy group having 1 to 10 carbon atoms substituted by a halogen, preferably 1 to 5 halogen-substituted hydrogen atoms, more preferably 1 -3; such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethoxy, trifluoroethoxy, etc. A decyloxy group having 1 to 4 carbon atoms is preferred.

In the present invention, "Cwo alkylthio" means a straight or branched alkylthio group having 1 to 10 carbon atoms, preferably an alkylthio group having 1 to 6 carbon atoms. Including: a methylthio group, an ethylthio group or the like, preferably an alkylthio group having 1 to 4 carbon atoms.

In the present invention, "halogen-substituted du" sulfonylthio" means a linear or branched thiol group having 1 to 10 carbon atoms which is substituted by halogen, preferably 1 to 5 halogen-substituted hydrogen atoms, more preferably 1-3; such as a trifluoromethylthio group, a trifluoroethylthio group or the like, an alkylthio group having 1 to 4 carbon atoms is preferable.

In the present invention, "C ₂ ^ oxime oxooxy" means a straight or branched alkoxy group substituted with a linear or branched alkoxy group having 2 to 10 carbon atoms, preferably having a carbon number. It is a 2-6 oxiranoxy group such as methoxyethoxy, propyloxymethoxy and the like.

In the present invention, "C KJ mercaptoamino" means a linear or branched alkylamino group having 1 to 10 carbon atoms, preferably a decylamino group having 1 to 6 carbon atoms, such as methylamino group, ethylamino group or propylamino group. , isopropylamino, butylamino, isobutylamino, tert-butylamino and the like.

In the present invention, "di-C _1C alkylamino" means two straight or branched fluorenylamino groups having 1 to 10 carbon atoms, and the alkyl group is preferably a fluorenyl group having 1 to 6 carbon atoms, such as dimethylamino group. , diethylamino, methylethylamino, methylpropylamino, diisopropylamino, di-tert-butylamino and the like.

In the present invention, "halogen" means fluorine, chlorine, bromine and iodine; and as an alkyl substituent, fluorine and chlorine are preferred.

In the present invention, the "C _4-18 aromatic group, C _4-18 aromatic heterocyclic group" means a monocyclic, fused ring aromatic hydrocarbon group, an aromatic heterocyclic hydrocarbon group, preferably an aromatic hydrocarbon group having 3 to 14 carbon atoms, and an aromatic hetero group. Cycloalkyl, including: phenyl, naphthyl, anthracenyl, phenanthryl, fluorenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, morpholinyl, piperazinyl, pyrazinyl, pyrazolyl , anthracenyl, quinolyl, etc.; more preferably an aromatic hydrocarbon group having 4 to 10 carbon atoms, an aromatic heterocyclic hydrocarbon group such as a phenyl group, a pyrrolyl group, a pyridyl group, a morpholinyl group, a piperazinyl group, a fluorenyl group, etc. . The substituent groups of the aromatic group and the aromatic heterocyclic group are: hydrogen, halogen, alkyl, halogen-substituted alkyl, decyloxy, halogen-substituted decyloxy, fluorenylamino, halogen-substituted alkylamino, nitro, cyano, fluorene Oxycarbonyl, alkoxy, methoxy alkoxy.

In the present invention, "aryl CWQ alkoxy group, aromatic heterocyclic group CMO alkoxy group" means an aromatic group or an aromatic heterocyclic group-substituted linear or branched Cwo methoxy group, and an aromatic group or an aromatic heterocyclic group is preferred. Phenyl, naphthyl, pyridyl, The mercapto group is preferably an anthraceneoxy group having a carbon number of from 1 to 6, such as a benzyloxy group or a 2-phenylethoxy group. In the present invention, "aryloxyoxycarbonyl, aromatic heterocyclic oxycarbonyl"decyloxy" means an aryloxy-substituted straight or branched Cwo alkoxy group, and aryl is preferably phenyl or naphthalene. The oxime group is preferably a fluorenyloxy group having a carbon number of from 1 to 6, such as a phenoxymethoxy group, a phenoxyethoxy group or the like, or a pyridyl group, a fluorenyl group or a quinolyl group.

In the present invention, "du"alkylcarbonyl" means a straight or branched fluorenylcarbonyl group having 1 to 10 carbon atoms, preferably a fluorenylcarbonyl group having 1 to 6 carbon atoms, such as formyl group or acetyl group. Propionyl, isopropionyl, butyryl, isobutyryl, t-butyryl and the like.

In the present invention, "du)alkoxycarbonyl" means a straight or branched alkoxycarbonyl group having 1 to 10 carbon atoms, preferably a methoxycarbonyl group having 1 to 6 carbon atoms, such as a methoxycarbonyl group. , ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl and the like.

In the present invention, 1, m is an arbitrary integer between 0 and 10, 1 is preferably 0-6, m is preferably 0-2; n is an arbitrary integer between 0 and 2, and n is preferably 1.

In the compound of the formula (I) of the present invention, L is a single bond, CH ₂ , NH, 0, S or a polyethylene glycol ether moiety. In a preferred embodiment of the invention, the compound of formula (I) is a compound of the formula (Π) or a pharmaceutically acceptable salt thereof:

Wherein R _r is hydrogen;

Rr to , is hydrogen, methoxy, difluoromethoxy, pyrrolyl;

R ₅ - is hydrogen, methyl, methoxy or chlorine;

Is hydrogen, methoxy, 2,2,2-trifluoroethoxy, 3-methoxypropoxy, 4-morpholinyl, ethylthio or (2,2,3,3,4, 4,4-heptafluorobutyl)oxy;

R ₇ ,. is hydrogen or methyl.

In a preferred embodiment of the invention, the compound of formula (I) is a compound of the formula (ΠΙ) or a pharmaceutically acceptable salt thereof -

Wherein X is CH ₂ , NH, 0, or S;

Ri, is hydrogen;

R ₂ , to, is hydrogen, methoxy, difluoromethoxy, pyrrolyl;

R ₅ , is hydrogen, methyl, methoxy or chlorine;

R is hydrogen or methyl.

In a preferred embodiment of the invention, the compound of formula (I) is a compound of formula (IV) or a pharmaceutically acceptable salt thereof:

Wherein X and Y are the same or different and are heteroatoms selected from NH, 0, or S;

m is any integer between 0 and 10;

, for hydrogen;

R ₂ , to R 4 are hydrogen, methoxy, difluoromethoxy, pyrrolyl;

R ₅ , is hydrogen, methyl, methoxy or chlorine;

R ₇ is hydrogen or methyl;

R _u is hydrogen.

In a preferred embodiment of the invention, the compound of formula (I) is a compound of formula (V) or a pharmaceutically acceptable salt thereof:

Wherein X and Y are the same or different and are heteroatoms selected from ΝΗ, 0, or S;

m is any integer between 0 and 10;

Rr is hydrogen;

R ₂ . to, is hydrogen, methoxy, difluoromethoxy, pyrrolyl;

R ₅ , is hydrogen, methyl, methoxy or chlorine;

Is hydrogen, methoxy, 2,2,2-trifluoroethoxy, 3-methoxypropoxy, 4-morpholinyl, ethylthio or (2,2,3,3,4,4 ,4-heptafluorobutyl)oxy;

R ₇ is hydrogen or methyl;

R _u is hydrogen.

In a preferred embodiment of the invention, the compound of formula (I) is a compound of formula (VI) or a pharmaceutically acceptable salt thereof -

m is any integer between 0 and 10;

R _r is hydrogen;

R ₂ , to R 4 are hydrogen, methoxy, difluoromethoxy, pyrrolyl;

R ₅ , is hydrogen, methyl, methoxy or chlorine;

R6, is hydrogen, methoxy, 2,2,2-trifluoroethoxy, 3-methoxypropoxy, 4-morpholinyl, ethylthio or (2,2,3,3,4 , 4,4-heptafluorobutyl)oxy;

R ₇ is hydrogen or methyl;

R _u is hydrogen. The invention further relates to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound as described above according to the invention. The invention further relates to the use of a compound according to the invention as described above for the manufacture of a medicament for inhibiting gastric acid secretion, against Helicobacter pylori or inhibiting the activity of gastric cancer.

The compounds of the formula I according to the invention and their pharmaceutically acceptable salts can be used as medicaments (for example in the form of pharmaceutical preparations). The pharmaceutical preparations may be administered orally, such as orally (e.g., in the form of tablets, coated tablets, troches, hard and soft gelatin capsules, solutions, emulsions or suspensions). However, administration can also be carried out parenterally, such as intramuscular or intravenous (e.g., in the form of an injection).

The compounds of formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used as such excipients for tablets, dragees and hard gelatin capsules. Suitable excipients for injections are, for example, water, alcohols, polyols, glycerol and vegetable oils.

In addition, the pharmaceutical preparation may contain a preservative, a solubilizing agent, a viscosity increasing substance, a stabilizer, a wetting agent, an emulsifier, a sweetener, a coloring agent, a flavoring agent, a salt for changing the osmotic pressure, a buffering substance, a masking agent. Or antioxidants. They may also contain other therapeutically valuable substances.

The dosage of the compounds of the invention can vary over a wide range and, of course, will be tailored to the individual needs in each particular case. Generally, in the case of oral administration, a daily dose of from about 0.15 mg to 0.72 mg/kg body weight, preferably from about 0.29 mg to 0.58 mg/kg body weight, should be appropriate, the daily dose being divided into 1-3 individual doses, It may for example consist of the same amount. However, when it is indicated that treatment is required, it is clear that the upper limit given above can be exceeded.

According to the invention, typical compounds of the formula (I) include:

5,5,-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-lH-benzimidazole]

5,5,-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1H-benzimidazole]

5,5,-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl]-1H-benzimidazole ]

5,5'-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio]-1H-benzimidazole]

5,5'-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylthio]-1H-benzimidazole]

5,5,-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylthio]-1H-benzimidazole]

5,5,-bis-[2-[(3-methoxy-4-chloropyridin-2-yl)methylthio]-1H-benzimidazole]

5,5,-bis-[2-[(3-methyl-4-methoxypyridine-2-yl)methylthio]-1H-benzimidazole]

5,5'-bis-[2-[(3-methyl-4-ethoxypyridin-2-yl)methylthio]-1H-benzimidazole]

5,5'-bis-[2-(pyridin-2-ylmethylthio)-1H-benzimidazole]

5,5'-bis-[2-(pyridin-3-ylmethylthio)-1H-benzimidazole] 5,5'-bis-[2-(pyridin-4-ylmethylthio)-1H-benzimidazole]

5,5'-bis-[2-(6-chloropyridin-3-ylmethylthio)-1H-benzimidazole]

5,5,-methylene-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1 H-benzimidazole] 5 , 5'-methylene-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1Η-benzimidazole]

5,5'-methylene-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy) B-pyridin-2-yl]methylsulfinyl] -1Η-benzimidazole

5,5'-methylene-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio]-1H-benzimidazole]

5,5,-methylene-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylthio]-1H-benzimidazole]

5,5,-methylene-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylthio]-1H- Benzimidazole] 5,5,-oxy-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1H-benzimidazole ]

5,5'-oxy-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1H-benzimidazole]

5,5,-Oxo-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl]-1H- Benzimidazole] 5,5'-oxy-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio]-1H-benzimidazole]

5,5'-oxy-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylthio]-1H-benzimidazole]

5,5,-oxy-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylthio]-1H-benzene And imidazole] 5,5,-imino-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1H-benzimidazole] 5,5,-imino-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1H-benzimidazole]

5,5,-imino-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl]-1H- Benzimidazole

5,5'-imino-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio]-1H-benzimidazole]

5,5'-imino-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylthio]-1H-benzimidazole]

5,5,-imino-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylthio]-1H-benzene And imidazole] 5,5'-(1 ,2-ethanedioxy)-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl ] -1H-benzimidazole]

5,5,-(1,2-ethanedioxy)-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1H-benzimidazole]

5,5,-(1,2-Ethylenedioxy)-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]- Kesulfinyl]-1Η-benzimidazole]

5,5,-(1,2-ethanedioxy)-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio]-1H- Benzimidazole] 5,5,-(1,2-ethanedioxy)-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylthio]-1H-benzene Imidazole

5,5'-(1,2-Ethylenedioxy)-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]- Thio]]1H-benzo Imidazole

5,5,-(l,3-propanedioxy)-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1Η -benzimidazole]

5,5'-(1,3-propanedioxy)-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1Η-benzimidazole] 5,5'-(1,3-propanedioxy)-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]- Kesulfinyl]-1Η-benzimidazole]

5,5'-(1,3-propanedioxy)-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio]-1H- Benzimidazole] 5,5'-(1 ,3-propanedioxy)-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylthio]- 1 H- Benzimidazole

5,5,-(1,3-propanedioxy)-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]- Thio]]1H-benzimidazole]

5,5'-(1,5-pentanedioxy)-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl H-benzene Imidazole

5,5,-(1,5-pentanedioxy)-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1H-benzimidazole] 5,5,-(1,5-pentanedioxy)-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy) P-pyridin-2-yl ]methylsulfinyl]-1Η-benzimidazole]

5,5'-(1,5-pentadioxy)-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio]-1H- Benzimidazole] 5,5'-(1,5-pentanedioxy)-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylthio]-1H-benzene Imidazole

5,5'-(1,5-pentadioxy)-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]- Thio]]1H-benzimidazole]

5,5,-(3-oxa-1,5-pentanedioxy)-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl Sulfonyl]-1Η-benzimidazole]

5,5,-(3-oxa-1,5-pentanedioxy)-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1H -benzimidazole]

5,5,-(3-oxa-1,5-pentadioxy)-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy) P ratio Pyridin-2-yl]methylsulfinyl]-1H-benzimidazole]

5,5'-(3-oxa-1,5-pentanedioxy)-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfide -1H-benzimidazole]

5,5'-(3-oxa-1,5-pentanedioxy)-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylthio]-1H- Benzimidazole] 5,5,-(3-oxa-1,5-pentanedioxy)-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy) Pyridin-2-yl]methylthio] -1H-benzimidazole] ― Di-[2_[ ₍₄ -methoxy 3,5-dimethylpyridine-2-yl)methylsulfinyl]-1Η-benzimidazol-5-yl]carbonate di-[2-[( 3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1H-benzimidazol-5-yl]carbonate

Di-[2-[[3-methyl-4-p,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl]-1H-benzimidazol-5-yl]carbonic acid Ester.

Di-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1H-benzimidazol-5-yl]oxalate di-[2 -[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-]H-benzimidazol-5-yl]oxalate

Di-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl]-1H-benzimidazol-5-yl] Oxalate

The compound of the present invention reacts with a base or an alkali metal to form a salt, and the resulting salt includes: an inorganic base salt (e.g., sodium, magnesium, zinc, calcium, iron, etc.) or an organic base salt (e.g., ammonium, piperazine salt, etc.).

The sulfur atom in the compound of the present invention is a chiral center, and thus has two optical isomers, that is, an enantiomer. A significant advantage of the present invention is that after entering the body, the bisbenzimidazole compound can form two sulfenic acid or sulfenamide structures after acid-catalyzed activation in vivo, and H+, K ⁺ -ATPase monomer or oligomer The two cysteine binding of the polymer effectively inhibits gastric acid secretion. At the same time, this kind of compound has anti-Hp activity, and the eradication of Hp is beneficial to the healing of peptic ulcer and reduce the probability of Hp causing cancer. Such compounds are weakly basic compounds that can be targeted to the gastric parietal cells and bind to tumor cell DNA, causing apoptosis of gastric cancer cells. DESCRIPTION OF SPECIFIC EXAMPLES AND EXPERIMENTAL - The present invention will specifically illustrate the preferred methods of synthesizing these compounds by the following examples. In the following reaction schemes and reference examples, examples, as in the entire publication, reagents and/or materials are commercially available or prepared in accordance with published patents and journal articles, unless otherwise indicated.

EXAMPLES The compounds of the formula (II) will be described in detail.

Formula (II) wherein L, X, and n are as shown in Table 1: Table 1: Structural information and spectral characteristics of new benzimidazoles

Example 1: 5,5,-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfanyl 1-m-benzimidazole] (Compound 1 Preparation

An aqueous solution (20 ml) of 5,5,-bis-(2-mercapto-1H-benzimidazole) (1.0 g), absolute ethanol (15 ml), sodium hydroxide (0.84 g) was sequentially added to the reaction flask. Stir at room temperature for 30 minutes and dissolve in solids. 2-Chloromethyl-3,5-dimethyl- ₄ -pyridinium hydrochloride (1.5 g) was added, and the mixture was refluxed for 2 hr. The solvent was evaporated under reduced pressure, and the obtained oil was evaporated to dryness. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 80%. 1H-NMR (300MHz, DMSO-i/ ₆ , ppm): 12.68 (br s, 1H), 8.19 (s, 1H), 7.67 (s, 1H), 7.50 (d, J = 8.3, 1H), 7.42 ( Dd, J=8.3, J=1.5, 1H), 4.71(s, 2H), 3.72(s, 3H), 2.30(s, 3H), 2.21(s, 3H)„

Example 2: Preparation of 5,5,-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylthio-1-lH-benzimidazole K compound 2)

Using the method of Example 1, 5,5,-bis-(2-mercapto-1H-benzimidazole) (1.0 g) and 2-chloromethyl-3,4-dimethyl °(Ηε

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'(HZ 's)69 '(HI ' 5=f 'Ρ)60·Δ '(Η£ ^O L-OVL '(HI 'ί'ξ=Γ 'Ρ) Γ8 '(HI 's)89 Zl ^: (mdd ⁱ⁹ P-OSna 'ΖΗΜ00ε)ΉΝΝ-Η, °%68 8 z !i^^ 'SJ C^ n)3⁄43⁄4 3⁄4i3⁄4t)W3⁄4 ..6T00/800ZN3/X3d TC.980/600Z OAV The salt (1.1 g) was reacted to give the compound 7 1.3 g, 81%. 'H-NMR (300MHz, DMSO- ₆ , ppm): 12.68 (s, IH), 8.52 (d, J = 4.7, IH), 7.75 (t, J-7.5, IH), 7.60-7.72 (m, IH) ), 7.54 (d, J = 7.7, IH), 7.40-7.60 (m, 2H), 7.29 (dd, J = 7.2, J = 5.1, IH), 4.69 (s, 2H).

Example 8: Preparation of 5,5,-bis-[2-(pyridin-3-ylmethylthio)-IH-benzimidazole] (Compound 8)

Using the method of Example 1, 5,5'-bis-(2-mercapto-1H-benzimidazole) (1.0 g) was reacted with 3-chloromethylpyridine hydrochloride (1.1 g) to give compound 8 1.2 g. , 74%. 1H-NMR (300MHz, DMSO-i/ ₆ , ppm): 12.70 (br s, IH), 8.66 (d, J=1.6, IH), 8.43 (dd, J=4.8, J=ll, IH), 7.87 (dt, J=7.8, J=1.6, IH), 7.67(s, IH), 7.5 l(d, J=8.3, IH), 7.43(dd, J=8.4, J=0.8, IH), 7.33( Dd, J=7.8, J=4.8, IH), 4.59(s, 2H). Example 9: Preparation of 5,5,-bis-[2-(pyridin-4-ylmethylthio)-IH-benzopyrene] (Compound 9)

Using the method of Example 1, 5,5,-bis-(2-mercapto-1H-benzimidazole) (1.0 g) was reacted with 4-chloromethylpyridine hydrochloride (1.1 g) to give compound 9 1.4.克, 87% 'H-NMR (300MHz, OMSO-d ₆ , ppm): 12.69(s, IH), 8.45(m, J=4.5, 2H), 7.54(s, 1H), 7.45(m, 2H) , 7.36 (d, J = 8.3, 1H), 7.22 (dd, J = 8.3, J = 1.4, IH), 4.52 (s, 2H).

Example 10: Preparation of 5,5,-bis-[2-(6-chloropyridin-3-ylmethylthio)-IH-benzimidazole K compound 10)

Using the method of Example 1, 5,5'-bis-(2-mercapto-1H-benzimidazole) (1.0 g) and 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (1.4) The reaction was carried out to give the compound 10 1.3 g, 71%. 1H-NMR (300 MHz, DMSO-£3⁄4, ppm): 12.66 (s, IH), 8.50 (s, 1H), 7.40-8.10 (m, 5H), 4.58 (s, 2H).

Example 11: 5,5,-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-lH-benzimidazole] Preparation of 11)

Compound 1 (1.0 g) was dissolved in tetrahydrofuran (30 ml), and then cooled to -10. The -10'C reaction was maintained for 50 minutes, then a saturated sodium carbonate solution was added and stirred. The organic solvent was evaporated under reduced pressure. EtOAc (EtOAc m. 'H-NMR (300MHz, DMSO-i/ ₆ , ppm): 13.66 (s, IH), 8.20 (s, IH), 7.67-8.01 (m, 3H), 4.78 (dd, J=19.8, J=13.8) , 2H), 3.70(s, 3H), 2.20(s, 6H).

Example 12: Preparation of 5,5,-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-IH-benzimidazole K compound 12)

Using the method of Example 11, Compound 2 (1.0 g) was reacted with m-chloroperoxybenzoic acid (0.70 g) to give Compound 12 0.74 g, yield 70%. 1H-NMR (300MHz, DMSO-c ₆ , ppm): 13.68 (s, IH), 8.16 (d, J = 5.5, IH), 7.67-8.00 (m, 3H), 7.11 (d, J = 5.6, IH ), 4.72 (dd, J=18.1, J=13.0, 2H), 3.89(s, 3H), 3.78(s, 3H).

Example 13: 5,5,-bis-[2-p-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl]-1Η-benzene Preparation of imidazole] (Compound 13)

Using the method of Example 11, Compound 3 (1.0 g) was reacted with m-chloroperoxybenzoic acid (0.60 g) to give Compound 13 0.81 g, yield 77%. 'H-NMRpOOlVtHz, DMSO-i/ ₆ , ppm): 13.68(s, IH), 8.3 l(d, J=5.7, IH), 7.88(s, IH), 7.73(d, J=8.7, IH) , 7.62(d, J=8.7, IH), 7.10(d, J=5.7, IH), 4.93(q, J=8.7, 2H), 4.81(dd, J=33.5, J-13.7, 2H), 2.2 l(s, 3H).

Example 14: 5,5,-methylene-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio]-IH-benzimidazole Preparation of 1 (Compound 14)

Using the method of Example 1, 5,5'-methylene-bis-(2-mercapto-1H-benzimidazole) and 2-chloromethyl-3,5-dimethyl-4-methoxypyridine The hydrochloride (1.5 g) was reacted to give compound 1.7 g, yield 87%. 1H-NMR (300MHz, DMSO- ₆ , ppm): 12.5 l (br s, IH), 8.18 (s, IH), 7.46 (d, J = 8.7, IH), 7.12 (s, IH), 7.01 (d) , J = 8.7, IH), 4.67 (s, 2H), 4.01 (s, 2H), 3.71 (s, 3H), 2.26 (s, 3H), 2.19 (s, 3H).

Example 15: 5,5,-methylene-bis-[2-[[(3,4-dimethoxypyridin-2-yl)methylthiopyran IH-benzimidazole 1 (Compound 15) Preparation

Using the method of Example 1, 5,5,-methylene-bis-(2-mercapto-1H-benzimidazole) and 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (1.5 The reaction was carried out to give compound 15 1.6 g, yield 81%. 1H-NMR (30OMHz, DMSO-4 ppm): 12.51 (s, IH), 8.16 (d, J = 5.5, IH), 7.00-7.50 (m, 3H), 7.08 (d, J = 5.3, IH), 4.66 (s, 2H), 3.97 (s, 2H), 3.88 (s, 3H), 3.79 (s, 3H).

Example 16: 5,5,-methylene-bis-[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)) B-pyridin-2-yl 1 A Preparation of -1H-benzimidazole K compound 16)

Using the method of Example 1, 5,5'-methylene-bis-(2-mercapto-1H-benzimidazole) and 2-chloromethyl-3-methyl

Reaction of -4-(2,2,2-trifluoroethoxy)pyridine hydrochloride (1.8 g) gave Compound 16 1.8 g, yield 78%.

'H-NMR (300MHz, DMSO-i/ ₆ , ppm): 12.53 (s, IH), 8.31 (d, J = 5.5, IH), 7.10-7.80 (m, 3H), 7.09 (d, J = 5.5 , IH), 4.91 (q, J=8.7, 2H), 4.72(s, 2H), 3.98(s, 2H), 2.25(s, 3H).

Example 17: 5,5,-methylene-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-m-benzo Preparation of imidazole K compound 17)

Compound 14 (1.0 g) was reacted with m-chloroperoxybenzoic acid (0.68 g) to give compound 17 0.76 g, yield 72% - 'H-NMR (300 MHz, DMSO-t/ ₆ , Ppm): 13.58(s, IH), 8.17(s, IH), 7.10-7.80(m, 3H), 4.74(dd, J=26.3, J=13.7, 2H), 4.13(s, 2H), 3.68( s, 3H), 2.19(s, 3H), 2.16(s, 3H).

Example 18: 5,5,-Methylene-bis-[2-[[(3,4-dimethoxypyridin-2-yl)methylsulfinyl) IH-benzimidazole] (Compound 18 Preparation

Compound 15 (1.0 g) was reacted with m-chloroperoxybenzoic acid (0.68 g) to give compound 18 0.78 g, yield 74%. 1H-NMR (300MHz, DMSO-i/ ₆ , ppm): 13.49 (s, IH), 8.15 (d, J = 5.5 IH), 7.10-7.80 (m, 3H), 7.07 (d, J = 5.6, IH) ), 4.70 (dd, J = 21.9, J = 13.1, 2H), 4.14 (s, 2H), 3.88 (s: 3H), 3.78 (s, 3H).

, Example 19: 5,5,-methylene-bis-[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl 1 methyl] Preparation of sulfinyl]-m-benzimidazole (Compound 19)

Compound 16 (1.0 g) was reacted with m-chloroperoxybenzoic acid (0.57 g) to give compound 19, 0.84 g, yield 80%. 'H-NMR (300MHz, DMSO- ₆ , ppm): 13.56 (s, IH), 8.32 (d, J = 5.7: IH), 7.76 (d, J = 8.4, IH), 7.43 (s, IH), 7.18(d, J=8.4, IH), 7.11(d, J=5.7, IH), 4.92(q, J-8.7, 2H), 4.74(dd, J=26.4, J=13.0, 2H), 4.13( s, 2H), 2.18(s, 3H).

Example 20: 5,5,-Oxo-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfanyl H-benzimid] ( Preparation of compound 20)

Using the method of Example 1, 5,5,-oxy-bis-(2-mercapto-1H-benzopyrene) and 2-chloromethyl-3,5-dimethyl-4-methoxypyridine Hydrochloride (1.5 g) was reacted. The compound 20 was obtained in 1.6 g of a yield of 82%. 1H-NMR (300MHz, DMSO- ₆ , ppm): 12.52 (br s, IH), 8.17 (s, IH), 7.44 (d, J = 8.7, IH), 7.01 (s, IH), 6.85 (dd, J = 8.7, J = 2.1, IH), 4.66 (s, 2H), 3.71 (s, 3H), 2.26 (s, 3H), 2.19 (s, 3H).

Example 21: 5,5,-oxy-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylthio]-IH-benzimidazole 1 (Compound 21) Preparation

Using the method of Example 1, 5,5'-oxy-bis-(2-mercapto-1H-benzimidazole) and 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (1.5 g )reaction. The compound 21 was obtained in 1.7 g, and the yield was 87%. 1H-NMR (300MHz, OMSO-d ₆ , ppm): 12.61 (d, IH), 8.15 (d, J = 5.4, IH), 6.80-7.50 (m, 3H), 7.08 (d, J = 5.7, IH) ), 4.64(s, 2H), 3.88(s, 3H), 3.79(s, 3H).

Example 22: 5,5,-Oxo-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yljmethylthiol 1 Preparation of -lH-benzimidazole (Compound ²² )

Using the method of Example 1, 5,5'-oxy-bis-(2-mercapto-1H-benzimidazole) and 2-chloromethyl-3-methyl-4-(2,2,2-tri Fluoroethoxy)pyridine hydrochloride (1.8 g) was reacted. The compound 22 was obtained in 1.8 g, yield 78%.

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Using the method of Example 1, 5,5,-imino-bis-(2-mercapto-1H-benzimidazole) and 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (1.5 g )reaction. Compound 27 was obtained in a yield of 81%. 1H-NMR (300MHz, DMSO-^6, ppm): 12.56 (s, IH), 9.85 (s, IH), 8.15 (d, J = 5.6, IH), 6.80-7.30 (m, 3H), 7.05 ( d, J=5.5, IH), 4.64(s, 2H), 3.88(s, 3H), 3.79(s, 3H)o

Example 28: 5,5,-imino-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylthio H -Preparation of benzimidazole K compound 28)

Using the method of Example 1, 5,5'-imino-bis-(2-mercapto-1H-benzimidazole) and 2-chloromethyl-3-methyl-4-(2,2,2-tri Fluoroethoxy)pyridine hydrochloride (1.8 g) was reacted. The compound 28 was obtained in 1.9 g, yield 83%.

'H-NMR (300MHz, DMSO-i/ ₆ , ppm): 12.54 (s, IH), 9.86 (s, IH), 8.30 (d, J = 5.7, IH), 6.80-7.30 (m, 3H), 7.08 (d, J = 5.7, IH), 4.91 (q, J = 8.7, 2H), 4.70 (s, 2H), 2.26 (s, 3H).

Example 29: 5,5,-imino-bis-[2-[[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1Η-benzo" Preparation of imidazole] (Compound 29)

Compound 26 (1.0 g) was reacted with m-chloroperoxybenzoic acid (0.68 g) by the method of Example 11. Compound 29 was obtained in 0.71 g, yield 67%. 1H-NMR (300MHz, DMSO-i/ ₆ , ppm): 13.55 (s, IH), 9.96 (s, IH), 8.18 (s, IH), 6.90-7.40 (m, 3H), 4.73 (dd, J =25.4, J=13.8, 2H), 3.68(s, 3H), 2.19(s, 3H), 2.16(s, 3H) o

Example 30: 5,5,-imino-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl 1-lH-benzimidazole 1 (Compound 30) Preparation

Compound 27 (1.0 g) was reacted with m-chloroperoxybenzoic acid (0.68 g) by the method of Example 11. Compound 30 was obtained in a yield of 0.76 g, yield 72%. 1H-NMR (300MHz, DMSO-c? ₆ , ppm): 13.52 (s, IH), 9.95 (s, IH), 8.14 (d, J = 5.5, IH), 6.90-7.50 (m, 3H), 7.06 (d, J = 5.5, IH), 4.68 (dd, J = 22.5, J = 13.0, 2H), 3.86 (s, 3H), 3.77 (s, 3H).

Example 31: 5,5,-imino-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl 1 methylsulfinyl) Preparation of -1H-benzimidazole 1 (Compound 31)

Compound 28 (1.0 g) was reacted with m-chloroperoxybenzoic acid (0.57 g) by the method of Example 11. The compound 31 was obtained in 0.73 g of a yield of 70%. 1H-NMR (300MHz, OMSO-d ₆ , ppm): 13.53 (s, IH), 9.96 (s, IH), 8.32 (d, J = 5.7, IH), 6.90-7.40 (m, 3H), 7.11 ( d, J = 5.7, 1H), 4.93 (q, J = 8.7, 2H), 4.76 (dd, J = 24.5, J = 13.0, 2H), 2.19 (s, 3H).

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Compound 34 (1.0 g) was reacted with m-chloroperoxybenzoic acid (0.55 g) by the method of Example 23. Compound 37 was obtained in an amount of 0.68 g, yield 65%. 1H-NMR (300MHz, DMSO-, ppm): 13.46 (s, lH), 8.31 (d, J = 5.7, IH), 7.59 (d, J = 8.7, IH), 7.17 (s, IH), 7.11 ( d, J=5.7, IH), 6.95 (dd, J=8.7, J=2.3, 1H), 4.93 (q, J=8.7, 2H), 4.66 (dd, J=34.8, J=13.1, 2H), 4.35(s, 2H), 2.20(s, 3H).

Example 38: 5,5,-(l,3-propanedioxy)-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio Preparation of -IH-benzimidazole K compound 38)

Using the method of Example 1, 5,5,-(1,3-propanedioxy)-bis-(2-mercapto-1H-benzopyrimidine (1.0 g) and 2-chloromethyl-3,5- Reaction of dimethyl-4-methoxypyridine hydrochloride (1.2 g) gave compound 38 1.5 g, yield 83%.

'H-NMR (300MHz, DMSO-i/ ₆ , ppm): 12.46 (br s, IH), 8.16 (s, IH), 7.33 (d, J = 8.7, IH), 7.00 (d, J = 2.3, IH), 6.77 (dd, J=8.7, J=2.3, IH), 4.63(s, 2H), 4.15(t, J=6.1, 2H), 3.71(s, 3H), 2.25(s, 3H), 2.18(s, 3H), 2.12-2.24(m, 1H).

Example 39: 5,5,-(l,3-propanedioxy)-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylsulfanyl 1-lH-benzene Preparation of imidazolium K compound 39)

Using the method of Example 1, 5,5,-(1,3-propanedioxy)-bis-(2-mercapto-1H-benzimidazole) (1.0 g) and 2-chloromethyl-3,4 - Dimethoxypyridine hydrochloride (1.2 g) was reacted. The compound 39 was obtained in a yield of 88%.

1H-NMR (300MHz, DMSO- ₆ , ppm): 12.48 (s, IH), 8.14 (d, J = 5.7, IH), 7.33 (d, J = 8.4, IH),

7.07(d, J=5.7, IH), 7.00(s, IH), 6.77(dd, J=8.7, J=2.4, IH), 4.61(s, 2H), 4.15(t, J=6.3, 2H) , 3.88(s, 3H), 3.78(s, 3H), 2.18(t, J=6.3, 1H).

Example 40: 5,5,-(l,3-propanedioxy)-bis-12-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridine-2- Preparation of 1-methylthio]-1H-benzimidazole 1 (Compound 40)

Using the method of Example 1, 5,5'-(1,3-propanedioxy)-bis-(2-mercapto-1H-benzimidazole) (1.0 g) and 2-chloromethyl-3-methyl Reaction of -4-(2,2,2-trifluoroethoxy)pyridine hydrochloride (1.5 g). The compound 40 was obtained in 1.5 g, and the yield was 72%. 'Η-ΝΜΙ ρθΟΜΗζ, DMSO-i/ ₆ , ppm): 12.48(s, IH), 8.30(d, J=5.7, IH), 7.34(d, J=8.7,

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2H), 4.15 (t, J = 6.3, 2H), 2.25 (s, 3H), 2.16 (t, J = 6.3, 1H).

Example 41: 5,5,-(l,3-propanedioxy)-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfin Preparation of acyl]-1H-benzimidazole (Compound 41)

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Example 46: 5,5,-(l,5-pentanedioxy)-bis-[2-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl 1 Preparation of methylthio]-1H-benzoacene I^ (Compound 46)

Using the method of Example 1, 5,5'-(1,5-pentadioxy)-bis-(2-mercapto-1H-benzimidazole) (1.0 g) and 2-chloromethyl-3-methyl Reaction of -4-(2,2,2-trifluoroethoxy)pyridine hydrochloride (1.4 g). The compound 46 was obtained in 1.7 g, yield 84%. 'H-NMR OOMHz' DMSO-c^ ppm): 12.48 (s, IH), 8.30 (d, J-5.5, IH), 7.33 (d, J = 8.8, IH), 7.10 (d, J = 5.5, (I, H), 6. 2.26(s, 3H), 1.76(m, 2H), 1.51(m, 1H).

Example 47: 5,5,-(l,5-pentanedioxy)-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfin Preparation of acyl I-1H-benzimidazole 1 (Compound 47)

Compound 44 (1.0 g) was reacted with m-chloroperoxybenzoic acid (0.60 g) by the method of Example 11. Compound 47 0.71 g, yield 68% 'H-NMR (300 MHz, DMSO-J ₆ , ppm): 13.43 (s, IH), 8.17 (s, IH), 7.50 (d, J = 8.8, IH), 7.07(s, IH), 6.88(d, J=8.8, IH), 4.69(dd, J=35.7, J=13.4, 2H), 4.02(t, J=6.3, 2H), 3.67(s, 3H) , 2.19(s, 3H), 2.16(s, 3H), 1.78(m, 2H), 1.52(m, 1H).

Example 48: 5,5,-(l,5-pentanedioxy)-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl 1-lH- Preparation of benzimidazole] (Compound 48)

Compound 45 (1.0 g) was reacted with m-chloroperoxybenzoic acid (0.60 g) by the method of Example 11. The compound 48 was obtained in 0.75 g, yield 72%. 1H-NMR (300MHz, DMSO-i3⁄4, ppm): 13.49 (s, IH), 8.14 (d, J = 5.5, IH), 7.49 (d, J = 8.8, IH), 7.05-7.07 (m, 2H) , 6.86 (dd, J=8.9, J=2.2, IH), 4.64 (dd, J=40.0, J=13.0, 2H), 3.99(t, J=6.1, 2H), 3.87(s, 3H), 3.74 (s, 3H), 1.77 (m, 2H), 1.51 (m, 1H).

Example 49: 5,5,-(l,5-pentanedioxy)-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridine-2 -Base 1 methylsulfinyl] -1H-benzimidazole] (Preparation of compound 49)

Compound 46 (1.0 g) was reacted with m-chloroperoxybenzoic acid (0.51 g) by the method of Example 11. Compound 49 Q.74 g, yield lo/oJH-NMRpOO MHz, DMSO-i/ ₆ , ppm): 13.43 (s, IH), 8.31 (d, J = 5.7, IH), 7.49 (d, J = 8.8 , IH), 7.05-7.08(m, 2H), 6.87(dd, J=8.9, J=2.1, IH), 4.92(q, J=8.7, 2H), 4.66(dd, J=37.6, J=13.2 , 2H), 3.99 (t, J = 6.0, 2H), 2.19 (s, 3H), 1.77 (m, 2H), 1.51 (m, 1H). Example 50: 5,5,-(3-oxa-1,5-pentadioxy)-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl) Preparation of methylthio 1-1H-benzimidazole] (Compound 50)

Using the method of Example 1, -5,5'-(3-oxa-1,5-pentadioxy)-bis-(2-mercapto-1H-benzomidine) and 2-chloromethyl- 3,5-Dimethyl-4-methoxypyridine hydrochloride (U g) reaction. The compound 50 was obtained in a yield of 80%. 'H-NMR (300MHz, DMSO-rf ₆ , ppm): 12.44 (br s, IH), 8.18 (s, IH), 7.34 (d, J = 8.8, IH), 7.00 (d, J = 2.4, IH) ), 6.78 (dd, J=8.8, J=2.4, IH), 4.64(s, 2H), 4.32(s, 2H), 3.71(s, 3H), 3.74(s, 2H), 2.26(s, 3H) ), 2.19(s, 3H).

Example 51: 5,5,-(3-oxa-1,5-pentadioxy)-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylthio Preparation of -IH-benzimidazole] (Compound 51)

Using the method of Example 1, 5,5,-(3-oxa-1,5-pentadioxy)-bis-(2-mercapto-1H-benzimidazole) and 2-chloromethyl-3, 4-Dimethoxypyridine hydrochloride (U g) reaction. The compound 51 was obtained in 1.5 g, and the yield was 86%.

'H-NMR (300MHz, DMSO-, ppm): 12.50 (s, IH), 8.16 (d, J = 5.5, IH), 7.33 (d, J = 8.4, IH), 7.07 (d, J = 5.5, IH), 6.98(s, IH), 6.76(dd, J=8.4, J=2.1, IH), 4.63(s, 2H), 4.32(s, 2H)„ 3.89(s, 3H), 3.80(s, 3H), 3.75 (s, 2H).

Example 52: 5,5,-(3-oxa-1,5-pentadioxy)-bis-[2-methyl-4-(2,2,2-trifluoroethoxy)pyridine Preparation of 2-yl]methylthio]-1H-benzimidazole (Compound 52)

Using the method of Example 1, 5,5,-(3-oxa-1,5-pentadioxy)-bis-(2-mercapto-1H-benzopyrene) and 2-chloromethyl-3 -Methyl-4-(2,2,2-trifluoroethoxy)P was reacted with pyridine hydrochloride (1.4 g). Compound 52 was obtained in an amount of 1.6 g, yield 80%. 'H-NMROOOMHz, DMSO-rf ₆ , ppm): 12.48 (s, IH), 8.31 (d, J = 5.6, IH), 7.34 (d, J = 8.5, IH), 7.08 (d, J = 5.5, IH), 6.99(s, 1H), 6.78(dd, J=8.5, J=2.1, IH), 4.90(q, J=8.7, 2H), 4.63(s, 2H), 4.32(s, 2H), 3.74(s, 2H), 2.26(s, 3H).

Example 53: 5,5,-(3-oxa-1,5-pentadioxy)-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl) Preparation of methylsulfinyl]-1H-benzimidazole K compound 53)

Compound 50 (1.0 g) was reacted with m-chloroperoxybenzoic acid (0.60 g) by the method of Example 23. Compound 53 was obtained in a yield of 0.69 g, yield 66%. 'H-NMR (300MHz, DMSO-i/ ₆ , ppm): 13.43(s, IH), 8.17(s, IH), 7.5 l(d, J=8.4, IH), 7.08(s, IH), 6.90 (d, J=8.4, IH), 4.69 (dd, J=34.6, J=13.5, 2H), 4.35(s, 2H), 3.79(s, 2H), 3.68(s, 3H), 2.19(s, 3H), 2.16(s, 3H).

Example 54: 5,5,-(3-oxa-1,5-pentadioxy)-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylsulfin Preparation of acyl I-1H-benzimidazole] (Compound 54)

Compound 51 (1.0 g) was reacted with m-chloroperoxybenzoic acid (0.60 g) by the method of Example 23. Compound 54 0.65 g was obtained in a yield of 62%. 1H-NMR (300MHz, DMSO-of ₆ , ppm): 13.49 (s, IH), 8.15 (d, J = 5.5, IH), 6.88-7.50 (m, 3H), 7.08 (d, J = 5.5, IH) ), 4.64 (dd, J = 39.6, J = 13.1, 2H), 4.35 (s, 2H), 3.87 (s, 3H), 3.78 (s, 2H), 3.74 (s, 3H).

Example 55: 5,5,-(3-oxa-1,5-pentanedioxy)-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy) P)pyridin-2-yl 1 Preparation of methylsulfinyl 1-lH-benzimidazole] (Compound 55)

Compound 52 (1.0 g) was reacted with m-chloroperoxybenzoic acid (0.51 g) by the method of Example 23. Compound 55 was obtained in an amount of 0.61 g, yield 59%. 'H-NMR (300MHz, DMSO-i/ ₆ , ppm): 13.44(s, IH), 8.31 (d, J=5.7, IH), 6.90-7.50 (m, 3H), 7.09 (d, J=5.7 , IH), 4.93 (q, J=8.7, 2H), 4.66 (dd, J=38.8, J=13.1, 2H), 4.34(s, 2H), 3.79(s, 2H), 2.21(s, 3H) .

Example 56: Di-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl 1-lH-benzimidazol-5-yl]carbonate ( Preparation of compound 56)

Using the method of Example 11, bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio]-1H-benzimidazol-5-yl]carbonic acid Ester (1.0 g) and m-chloroperoxybenzoic acid (0.63 g). Compound 56 0.65 g was obtained in a yield of 62%.

'Η-ΝΜΙ (300ΜΗζ, DMSO-c? ₆ , ppm): 13.58(s, IH), 8.18(s, IH), 6.90-7.60(m, 3H), 4.72(dd, J=27.2, J=13.1 , 2H), 3.68(s, 3H), 2.19(s, 3H), 2.16(s, 3H).

Example 57: Preparation of bis-[2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1Η-benzimidazol-5-yl]carbonate (Compound 57)

Using the method of Example 11, bis-[2-[(3,4-dimethoxypyridin-2-yl)methylthio]-1H-benzimidazol-5-yl]carbonate (1.0 g) With m-chloroperoxybenzoic acid (0.63 g). The compound 57 was obtained in 0.63 g, yield 60%.

H-NMR (300MHz, DMSO-c3⁄4, ppm): 13.52 (s, IH), 8.16 (d, J = 5.5, IH), 6.95- 7.60 (m, 3H), 7.11 (d, J = 5.6, IH ), 4.70 (dd, J = 36.5, J = 13.0, 2H), 3.89 (s, 3H), 3.77 (s, 3H).

Example 58: Di-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl 1methylsulfinyl]-m-benzimidazole- Preparation of 5-Base 1 Carbonate (Compound 58)

Using the method of Example 11, bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl]-1H-benzene And imidazol-5-yl]carbonate (1.0 g) was reacted with m-chloroperoxybenzoic acid (0.55 g). Compound 58 was obtained in an amount of 0.61 g, yield 59%. 'H-NMR (300MHz, DMSO-i/ ₆ , ppm): 13.56(s, IH), 8.31 (d, J=5.6, IH), 6.90-7.60 (m, 3H), 7.10 (d, J=5.7 , IH), 4.93 (q, J = 8.7, 2H), 4.71 (dd, J = 32.8, J = 13.1, 2H), 2.21 (s, 3H).

Example 59: Di-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-lH-benzimidazol-5-yl I oxalate Preparation of (Compound 59)

Using the method of Example 11, bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1Η-benzimidazol-5-yl] Oxalate (1.0 g) was reacted with m-chloroperoxybenzoic acid (0.61 g). The compound 59 was obtained in a yield of 0.58 g, yield: SSO/eJH-NMR OO OO, DMSO-^, ppm: 13.57 (s, IH), 8.18 (s, IH), 7.00-7.65 (m, 3H), 4.72 (dd, J = 28.6, J=13.3, 2H), 3.68(s, 3H), 2.19(s, 3H), 2.16(s, 3H). Example 60: Di-[2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1Η-benzimidazol-5-yl] oxalate (Compound 60) preparation

Using the method of Example 11, bis-[2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1H-benzimidazol-5-yl]oxalate (1.0 g) with m-chloroperoxybenzoic acid (0.61 g). Compound 60 was obtained in an amount of 0.61 g, yield 58%.

1H-NMR (300MHz, DMSO-, ppm): 13.53 (s, 1H), 8.17 (d, J = 5.6, 1H), 7.00 - 7.60 (m, 3H), 7.10 (d, J = 5.5, 1H), 4.69 (dd, J=38.2, J=13.1, 2H), 3.88(s, 3H), 3.78(s, 3H).

Example 61: Di-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl 1methylsulfinyl 1-lH-benzimidazole- Preparation of 5-base oxalate (compound 61)

Using the method of Example 11, bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl]-1H-benzene And imidazol-5-yl] oxalate (1.0 g) and m-chloroperoxybenzoic acid (0.53 g). Compound 61 0.62 g was obtained in a yield of 60%. 'H-NMRpOOMHz, DMSO-4, ppm): 13.55 (s, 1H), 8.31 (d, J = 5.7, 1H), 7.00-7.60 (m, 3H), 7.11 (d, J = 5.7, 1H), 4.93 (q, J = 8.7, 2H), 4.70 (dd, J = 33.5, J = 13.2, 2H), 2.20 (s, 3H). Preparation of intermediates Reference example 1: Preparation of 4,4,-diacetylaminobiphenyl

4,4'-Diaminobiphenyl (18.4 g) and acetone (100 ml) were placed in a reaction flask, and acetic anhydride (30 ml) was added dropwise under ice water. The reaction was continued for 2 hours, and triethylamine (56 ml) was added dropwise to the reaction mixture, and the reaction was continued for 30 minutes. The solid was filtered, washed with EtOAc EtOAc (EtOAc)EtOAc.

Reference Example 2: Preparation of 3,3,-dinitro-4,4,-diacetylaminobiphenyl

4,4,-Diacetylaminobiphenyl (13.4 g) and glacial acetic acid (80 ml) were placed in a reaction flask, cooled in an ice water bath, and fuming nitric acid (18 ml) was added dropwise. After the addition, the ice water bath was removed and reacted at room temperature for 6 hours. The reaction mixture was poured into crushed ice water (150 ml), and the mixture was applied to dryness, and filtered to give the title compound (14.7 g, yield, yield: 82%, GC-MS (m/z):

[1^358.

Reference Example 3: Preparation of 3,3'-dinitro-4,4'-diaminobiphenyl

3,3'-Dinitro-4,4'-diacetylaminobiphenyl (3.6 g) was added to the reaction flask, and anhydrous methanol (15 ml) and 40% aqueous sodium hydroxide (5 ml) were added. The reaction was heated to reflux for 2 hours. The reaction mixture was poured into EtOAc (EtOAc)EtOAc. Reference Example 4: Preparation of 3,3,4,4,-tetraaminobiphenyl

3,3'-Dinitro-4,4'-diaminobiphenyl (2.7 g) was added to the reaction flask, and anhydrous methanol (20 ml), hydrazine hydrate (5 ml), activated carbon (0.1 g) was added. ), heated to reflux for 4 hours. The insoluble material was filtered out, and the residue was evaporated to dryness crystalljjjjjjjjj

Reference Example 5: Preparation of 5,5,-bis-(2-dimercapto-1H-benzimidazole)

To a solution of potassium hydroxide (3.4 g) in water (10 ml), anhydrous ethanol (10 ml) and carbon disulfide (6.0 ml) were stirred at room temperature for 30 min. Further, 3,3',4,4'-tetraaminodiphenyl (2.1 g) in ethanol (10 ml) was added dropwise to the above solution, followed by refluxing for 6 hours. The solvent was evaporated, and the mixture was evaporated. EtOAc (EtOAc m. Reference Example 6: Preparation of N,N,-diacetyl-4,4,-methylenediphenylamine

According to the reference example 1, 1,4,4,-methylenediphenylamine (19.8 g) was dissolved in acetone (100 ml), and reacted with acetic acid (30 ml) and triethylamine (56 ml). The title compound was obtained (yield: mp. Reference Example 7: Preparation of N,N,-diacetyl-2,2,-dinitro-4,4,-methylenediphenylamine

According to Reference Example 2, N, \T-diacetyl-4,4,-methylenediphenylamine (14.1 g) was reacted with citric acid (18 ml) in glacial acetic acid (80 ml). The title compound was obtained (15.0 g,yield: 81%). Reference Example 8: Preparation of 2,2,-dinitro-4,4,-methylenediphenylamine

According to Reference Example 3, diacetyl-2,2,-dinitro-4,4,-methylenediphenylamine (3.7 g) was dissolved in anhydrous methanol (15 ml), and 40% aqueous sodium hydroxide solution (5 ml) reaction. The title compound was obtained, 2.6 g,yield: 91%, GC-MS (m/z):

Reference Example 9: Preparation of 4,4,-methylene-bis-(1,2-phenylenediamine)

According to Reference Example 4, 2,2'-dinitro-4,4,-methylenediphenylamine (2.9 g) was dissolved in anhydrous methanol (20 ml), hydrated hydrazine (5 ml), activated carbon (0.1 g) reaction. The title compound was obtained 1.9 g (yield: 83%).

Reference Example 10: Preparation of 5,5,-methylene-bis-(2-mercapto-1H-benzimidazole).

According to Reference Example 5, 4,4,-methylene-bis-(1,2-phenylenediamine) (2.3 g) was dissolved in absolute ethanol (10 ml), and an aqueous solution of potassium hydroxide (3.4 g) (10 ml), a solution of carbon disulfide (6.0 ml) in absolute ethanol (10 ml). The title compound was obtained 2.6 g, yield 83%, GC-MS (m/z):

Reference Example 11: Preparation of N,N,-diacetyl-4,4,-oxydiphenylamine

According to Reference Example 1, 4,4,-oxydiphenylamine (20.0 g) was dissolved in acetone (100 ml), and reacted with acetic acid (30 ml) and triethylamine (56 ml). To give the title compound 27.8 g, yield 98%, GC-MS (m / z): [M +] 284. Reference Example 12: Preparation of 7V, N'-diacetyl-2,2,-dinitro-4,4,-oxydiphenylamine

According to Reference Example 2, N,N'-diacetyl-4,4,-oxydiphenylamine (14.2 g) was reacted with citric nitric acid (18 ml) in glacial acetic acid (80 ml). The title compound was obtained (14.8 g,yield: 79%). Reference Example 13: Preparation of 2,2'-dinitro-4,4'-oxydiphenylamine

According to Reference Example 3, N,N'-diacetyl-2,2,-dinitro-4,4,-oxydiphenylamine (3.7 g) was dissolved in anhydrous methanol (15 ml), with 40% Aqueous sodium hydroxide (5 ml) was reacted. The title compound was obtained (yield: 87 g, yield: 87%), GC-MS (m/z): [.

Reference Example 14: Preparation of 4,4'-oxy-bis-(1,2-phenylenediamine)

According to Reference Example 4, 2,2'-dinitro-4,4'-oxydiphenylamine (2.9 g) was dissolved in anhydrous methanol (20 ml), with hydrazine hydrate (5 ml), activated carbon ( 0.1 g) reaction. The title compound was obtained in 1.8 g, yield 78%, GC-MS (m/z):

Reference Example 15: Preparation of 5,5'-oxy-bis-(2-indolyl-1H-benzimidazole)

According to Reference Example 5, 4,4,-oxy-bis-(1,2-phenylenediamine) (2.3 g) was dissolved in absolute ethanol (10 ml) with aqueous potassium hydroxide (3.4 g) ( 10 ml), a solution of carbon disulfide (6.0 ml) in absolute ethanol (10 ml). The title compound was obtained (yield: mp.

Reference Example 16: Preparation of N,N,-diacetyl-4,4,-iminodiphenylamine

According to the reference example 1, 4,4,-iminodiphenylamine (19.9 g) was dissolved in acetone (100 ml) and reacted with acetic acid (30 ml) and triethylamine (56 ml). The title compound was obtained (yield: EtOAc, EtOAc)

Reference Example 17: Preparation of N,N,-diacetyl-2,2,-dinitro-4,4,-iminodiphenylamine

According to Reference Example 2, NN'-diacetyl-4,4,-iminodiphenylamine (14.1 g) was reacted with citric acid (18 ml) in glacial acetic acid (80 ml). The title compound was obtained (yield: EtOAc, m.

Reference Example 18: Preparation of 2,2,-dinitro-4,4,-iminodiphenylamine

According to Reference Example 3, N,N'-diacetyl-2,2,-dinitro-4,4'-iminodiphenylamine (3.7 g) was dissolved in anhydrous methanol (15 ml), with 40 Aq. sodium hydroxide solution (5 ml) was reacted. The title compound was obtained (yield: mp.

Reference Example 19: Preparation of 4,4,-imino-bis-(1,2-phenylenediamine)

According to Reference Example 4, 2,2'-dinitro-4,4'-iminodiphenylamine (2.9 g) was dissolved in anhydrous methanol (20 ml), with hydrazine hydrate (5 ml), activated carbon ( 0.1 g) reaction. The title compound was obtained in 1.8 g, yield 78%, LC-MS (m/z): [Μ+ΗΓ230.

Reference Example 20: Preparation of 5,5'-imino-bis-(2-indolyl-1Η-benzimidazole)

According to Reference Example 5, 4,4,-imino-bis-(1,2-phenylenediamine) (2.3 g) was dissolved in absolute ethanol (10 ml) with aqueous potassium hydroxide (3.4 g) ( 10 ml), a solution of carbon disulfide (6.0 ml) in absolute ethanol (10 ml). The title compound was obtained, mp.

Reference Example 21: Preparation of N,N,-diacetyl-4,4,-(1,2-ethanedioxy)-diphenylamine

N-Acetyl-4-hydroxyaniline (1.5 g) was dissolved in dry N-N-dimethylformamide (20 mL). 1,2-Dibromoacetamidine (0.39 ml) was added, and the temperature was controlled to 80 Torr for 4 hours. The reaction mixture was poured into EtOAc (3 mL), EtOAc (EtOAc) The solvent was distilled off under reduced pressure to give the title compound 1.2 g, yield 82%, LC-MS (m / z): [M + H] + 329.

Reference Example 22: Preparation of N,N,-diacetyl-2,2,-dinitro-4,4,-(1,2-ethanedioxy)-diphenylamine

According to Reference Example 2, N,N'-diacetyl-4,4,-(1,2-ethanedioxy)-diphenylamine (3.3 g) in glacial acetic acid (20 mL), with fuming nitric acid (4 ml) reaction. The title compound was obtained (yield: 83%).

Reference Example 23: Preparation of 2,2,-dinitro-4,4,-(1,2-ethanedioxy)-diphenylamine

According to Reference Example 3, N'-diacetyl-2,2'-dinitro-4,4,-(1,2-ethanedioxy)-diphenylamine (4.2 g) in anhydrous methanol (30 In ml), react with 40% sodium hydroxide solution (10 ml). The title compound was obtained (yield: mp.

Reference Example 24: Preparation of 4,4,-(1,2-ethanedioxy)-bis-(1,2-phenylenediamine)

According to Reference Example 4, 2,2,-dinitro-4,4,-(1,2-ethanedioxy)-diphenylamine (3.3 g) was dissolved in anhydrous methanol (30 mL), hydrated肼 (5 ml), activated carbon (0.1 g) reaction. The title compound was obtained (yield: EtOAc, m.

Reference Example 25: Preparation of 5,5,-(1,2-ethanedioxy)-bis-(2-mercapto-1H-benzimidazole)

According to Reference Example 5, 4,4,-(1,2-ethanedioxy)-bis-(1,2-phenylenediamine) (2.7 g) was dissolved in absolute ethanol (10 ml), with hydrogen A solution of potassium oxide (3.4 g) in water (10 ml), carbon disulfide (6.0 ml) in dry ethanol (10 ml) was obtained. To give the title compound 2.7 g, yield 76%, LC-MS (m / z): [M + H] +359.

Reference Example 26: Preparation of N,N,-diacetyl-4,4,-(3-oxa-1,5-pentadioxy)-diphenylamine

N-Acetyl-4-hydroxyaniline (1.5 g) was dissolved in dry N-N-dimethylformamide (20 mL). Under the protection of nitrogen, 3-oxa-1,5-pentanediol-bis-(4- Methylbenzenesulfonate) (1.9 g) N,N-dimethylformamide solution (20 ml) was reacted at 80 ° C for 4 hours. The reaction mixture was poured into EtOAc (3 mL), EtOAc (EtOAc) The solvent was evaporated under reduced pressure to give the title compound 1.6 g,yield: 94%, LC-MS (m/z) _: [M+H] ⁺ 373o

Reference Example 27: Preparation of N,N,-diacetyl-2,2,-dinitro-4,4,-(3-oxa-1,5-pentadioxy)-diphenylamine according to the reference Example 2, N,N'-diacetyl-4,4'-(3-oxa-1,5-pentanedioxy)-diphenylamine (3.7 g) in glacial acetic acid (30 ml), Fuming nitric acid (5 ml) was reacted. The title compound was obtained in 3.7 g, yield 80%, LC-MS (m/z) _:

[M+H] +463.

Reference Example 28: Preparation of 2,2,-dinitro-4,4'-(3-oxa-1,5-pentadioxy)-diphenylamine

According to Reference Example 3, N,N'-diacetyl-2,2,-dinitro-4,4,-(3-oxa-1,5-pentadioxy)-diphenylamine (4.6 g It was reacted with 40% sodium hydroxide solution (10 ml) in anhydrous methanol (30 ml). The title compound was obtained (yield: EtOAc, EtOAc)

Reference Example 29: Preparation of 4,4'-(3-oxa-1,5-pentadioxy)-bis-(1,2-phenylenediamine)

According to Reference Example 4, 2,2,-dinitro-4,4'-(3-oxa-1,5-pentadioxy)-diphenylamine (3.8 g) was dissolved in anhydrous methanol (30 ml) In the reaction with hydrazine hydrate (5 ml) and activated carbon (0.1 g). The title compound was obtained, 2.6 g, yield 81%, LC-MS (m/z): [M+H] + 319.

Reference Example 30: Preparation of 5,5'-(3-oxa-1,5-pentadioxy)-bis-(2-indolyl-H-benzimidazole)

According to Reference Example 5, 4,4'-(3-oxa-1,5-pentadioxy)-bis-(1,2-phenylenediamine) (3.2 g) was dissolved in absolute ethanol (15 ml) In a solution of potassium hydroxide (3.4 g) in water (10 ml), carbon disulfide (6.0 ml) in anhydrous ethanol (10 ml). The title compound was obtained (yield: EtOAc, m.

Reference Example 31: Preparation of N-acetyl-2-nitro-4-aminophenol

According to Reference Example 2, N-acetyl-4-aminophenol (1.5 g) was reacted with citric nitric acid (5 ml) in glacial acetic acid (30 ml). To give the title compound 1.3 g, yield 67%, LC-MS (m / z): Preparation of 3-nitro-4-aminophenol: Example 32 [M ⁺ H] + 197ο Reference

According to Reference Example 3, N-acetyl-3-nitro-4-aminophenol (2.0 g) was dissolved in anhydrous methanol (20 ml) and 40% sodium hydroxide solution (8 ml). The title compound was obtained in 1.4 g, yield 89%, LC-MS (m/z) _: [M+H]

+155.

Reference Example 33: Preparation of 3,4-diaminophenol

According to Reference Example 4, 3-nitro-4-aminophenol (1.5 g) was dissolved in anhydrous methanol (20 ml), and reacted with hydrazine hydrate (5 ml) and activated carbon (0.1 g). The title compound was obtained in EtOAc (yield: 91%), LC-MS (m/z): [M+H] Reference Example 34: Preparation of 2-mercapto-5-hydroxy-1H-benzimidazole

According to Reference Example 5, 3,4-diaminophenol (1.2 g) was dissolved in absolute ethanol (15 ml), with potassium hydroxide (3.4 g) in water (10 ml), carbon disulfide (6.0 ml) The solution in water ethanol (10 ml) was reacted. The title compound was obtained (yield: 68%).

Reference Example 35: Preparation of 5-hydroxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfanyl-1-1H-benzimidazole

According to Example 4, 2-indolyl-5-hydroxy- Η-benzimidazole (1.7 g) and 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride (2.4 g) reaction. The title compound was obtained 2.7 g,yield: 84%, LC-MS (m/z), [M+H] ⁺ 316. Reference Example 36: Preparation of 5-hydroxy-2-[(3,4-dimethoxypyridin-2-yl)methylsulfanyl HH-benzimidazole

According to Example 4, 2-mercapto-5-hydroxy-1H-benzimidazole (1.7 g) was reacted with 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (2, 4 g). The title compound was obtained (yield: EtOAc, EtOAc)

Reference Example 37: 5-Hydroxy-2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yll-methylthio-1-H-benzimidazole Preparation

According to Example 4, 2-mercapto-5-hydroxy-1H-benzimidazole (1.7 g) and 2-chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine Hydrochloride (2.8 g) was reacted. The title compound was obtained in 3.2 g, yield 85%, LC-MS (m/z)

Reference Example 38: bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfanyl 1-1H-benzimidazol-5-yl 1 carbonate Preparation

Addition of 5-hydroxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio]-1H-benzimidazole (2.1 g) to benzene

(30 ml), dimethyl carbonate (0.27 ml) was added, zinc chloride (1 g) was added, and a fractionation column was charged. Stirring was carried out to 150 ° C. During the reaction, the azeotrope of methanol and benzene was continuously removed from the top of the distillation column, and a certain amount of benzene was added at the appropriate time. The reaction ends in about 12 hours. When the temperature dropped to 76 ° C, the precipitated crystals and the solution were quickly separated to obtain a crude product. Recrystallization from ethanol gave the title compound (yield: 0.53). LC-MS (m/z), [M+H]+ 657. REFERENCE EXAMPLE 39: Preparation of bis-[2-[(3,4-dimethoxypyridin-2-yl)methylthio]-lH-benzimidazole-5-yl]carbonate

According to Reference Example 38, 5-hydroxy-2-[(3,4-dimethoxypyridin-2-yl)methylthio]-1H-benzimidazole (2.1 g) and dimethyl carbonate (0.27) ML) reaction. The title compound was obtained in 0.55 g, yield 26%. LC-MS (m/z), [M+H] ⁺ 661 o

Reference Example 40: Di-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl 1methylthio-1-H-benzimidazole Preparation of 5-5-based I carbonate

According to Reference Example 38, 5-hydroxy-2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylthio]-1H-benzo Imidazole (2.1 g) was reacted with dimethyl carbonate (0.23 mL). The title compound was obtained in 0.48 g, yield 23%. LC-MS (m/z), [M+H] ⁺ 765.

Reference Example 41: Preparation of bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio HH-benzimidazol-5-yl 1 oxalate

Dissolving 5-hydroxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio)-1H-benzopyrene (2.0 g) in tetrahydrofuran (30 ml) In the ice water bath, oxalyl chloride (0.27 ml) was added, and triethylamine (1.8 ml) was added dropwise. Continue to react at room temperature for 2 hours. The reaction solvent was evaporated, the residue was diluted with water, ethyl acetate (30 ml of EtOAc) was evaporated, and the mixture was combined, and then saturated sodium carbonate solution (30 ml x l), water (30 ml x 2), saturated brine (30 ml x 2) wash. Dry over anhydrous sodium sulfate. The title compound was obtained in 1.5 g, yield 71%. LC-MS (m/z), [M+H]+ 685.

Reference Example 42: Preparation of bis-[2-[(3,4-dimethoxypyridin-2-yl)methylsulfanyl 1H-benzimidazole-5-yl 1 oxalate

According to Reference Example 41, 5-hydroxy-2-[(3,4-dimethoxypyridin-2-yl)methylthio]-111-benzimidazole (2.0 g) and oxalyl chloride (0.27 mL) reaction. The title compound was obtained in 1.6 g, yield 74%. LC-MS (m/z), [M+H]+ 689.

Reference Example 43: Di-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy) B-pyridin-2-yl 1methylthiopyr 1H-benzimidazole -5-based] Preparation of oxalate

According to Reference Example 41, 5-hydroxy-2-[[3-methyl-4-(2,2,2-trifluoroethoxy)P-pyridin-2-yl]methylthio: I-1H - Benzimidazole (2.0 g) was reacted with oxalyl chloride (0.23 mL). The title compound was obtained in 1.4 g, yield 66%.

LC-MS (m/z), [M+H] ⁺ 793. Pharmacological test examples:

Acid suppression activity study:

The effect of the compound of the present invention on histamine-stimulated gastric acid secretion was examined by continuous rat perfusion.

Take the rats, fast for 24 hours, and drink freely. Anesthesia was given by intravenous injection of urethane 1.25 g/kg, and then the dorsal position was fixed on a thermostatic mouse plate. Cut the skin in the middle of the neck, separate the trachea, esophagus, and intubate the trachea. Open along the midline of the abdomen, insert the perfusate into the tube through the esophagus, and insert the perfusate out of the tube through the duodenum. The perfusate (37 ° C physiological saline) was input using a peristaltic pump at 5 mL/15 min. The duodenal cannula was intubated 2 cm from the duodenum and a pyloric cannula for administration. After perfusion for 30 min, after the effluent was clarified, the effluent was collected every 15 min to O.Olmol/L NaOH. Titration (phenolphthalein indicator), calculate the gastric acid content in the gastric juice. Two tubes were collected first, and the basic gastric acid was measured. The test drug and the positive drug were administered through the duodenum at a dose of 7.5 mg kg each of the test drug and the positive drug pantoprazole sodium (Pan-Na). Blank controls were given to the same volume of DMSO. After 45 minutes, 10 mg/kg of histamine phosphate was injected subcutaneously to observe the effect of the drug on gastric acid secretion.

In vitro anti-tumor activity screening:

The logarithmic growth phase cells were diluted to l x10 ⁴ _C ell/mL, immediately seeded in a 96-well culture plate, 0.1 mL / L, and then the culture medium was added with different concentrations of medium, each concentration was parallel 3 wells, control Add an equal volume of solvent, incubate in a 37 ° C C0 ₂ incubator for 96 hours, centrifuge (lOOO rpm, 20 minutes), discard the supernatant, add 0.2 mL of freshly prepared 0.2 mg/mL MTT serum-free medium per well. The culture was continued for 4 hours at 37'C, and then centrifuged. After decanting the serum, the MTT formazan precipitate was dissolved in 0.2 mL of DMSO, shaken for 5 minutes with a micro-ultrasonic shaker, and the light at 570 nm was measured on a MR700 microplate reader. density, tumor cell growth inhibition was calculated (IC _50). Table 3: Inhibition of SKOV-3 tumor cells by new benzimidazoles (μΜ)

As can be seen from the results of the pharmacological test, the compound of the present invention has a marked inhibitory effect on gastric acid secretion caused by histamine stimulation, and has an inhibitory effect on SKOV-3 tumor cells.

Claims

Rights request

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

A-L-A.

B person S' S

On On

(I)

Among them, A is the following structure:

Benzimidazole

B is the following structure:

; the carbon atom of the ruthenium

L is the following structure

Single button, X

Hydrogen or CLU)

R ₂ to R 4 are independently hydrogen, halogen, du)alkyl; halogen-substituted fluorenyl; Cwo alkoxy; halogen substituted. _{1 (} )alkoxy; Cwo fluorenylcarbonyl, Cut) decyloxycarbonyl, Aromatic dH) fluorenyl, C ₄ . _{l 8} aromatic heterocyclic C _MQ alkyl, . _4. ₁₈ aryl, C ₄ _ ₁₈ aromatic heterocyclic group,

R ₅ , R _{7 are} independently hydrogen or Cwo alkyl; fluoro substituted. , H; 垸 oxy; fluoro-substituted CMO oxirane; C _U o alkylthio; fluoro-substituted CMO thiol; C ₂ .u) alkoxyalkoxy; amino, C _M0 Merylamino, di-Cwo alkylamino, halogen; phenyl, Cwo alkyl substituted phenyl, Cwo alkoxy substituted phenyl, phenyl C methoxy, piperidinyl, morpholinyl; or, R Any two of ₅ , R ₇ are joined to form a 5- or 6-membered ring containing 0 to 1 hetero atom selected from N, S, or 0;

Rn is hydrogen, halogen, Cwo fluorenyl, halogen-substituted dH)alkyl; C^ methoxy; fluorohalogen substituted Cwo methoxy group;

X, Y are any atom, such as CH ₂ , NH, 0, or S;

1. m is any integer between 0 and 10, and n is any integer between 0 and 2.

2. A method according to claim 1 wherein L is a single bond, CH ₂ , NH, 0, S or a polyethylene glycol ether moiety.

3. A compound according to claim 1 which is a compound of the formula (II) or a pharmaceutically acceptable salt thereof:

Wherein Rr is hydrogen;

R ₂ , to, is hydrogen, methoxy, difluoromethoxy, pyrrolyl;

R ₅ , is hydrogen, methyl, methoxy or chlorine;

R ₇ is hydrogen or methyl.

4. A compound according to claim 1 which is a compound of the formula (III) or a pharmaceutically acceptable salt thereof:

Where X is C3⁄4, NH, 0, or S;

Ri, is hydrogen;

R ₂ , to, is hydrogen, methoxy, difluoromethoxy, pyrrolyl;

· is hydrogen, methyl, methoxy or chlorine;

R ₇ is hydrogen or methyl.

5. A compound according to claim 1 which is a compound of the formula (IV) or a pharmaceutically acceptable salt thereof:

m is any integer between 0 and 10;

Ri, is hydrogen;

R ₂ , to, is hydrogen, methoxy, difluoromethoxy, pyrrolyl;

R ₅ is hydrogen, methyl, methoxy or chlorine;

Rr is hydrogen or methyl;

Rn is hydrogen.

6. A compound according to claim 1 which is a compound of the formula (V) or a pharmaceutically acceptable salt thereof -

m is any integer between 0 and 10;

Ri, is hydrogen;

R ₂ , to, is hydrogen, methoxy, difluoromethoxy, pyrrolyl;

R ₅ , is hydrogen, methyl, methoxy or chlorine;

R ₇ is hydrogen or methyl;

Ru, is hydrogen.

7. A compound according to claim 1 which is a compound of formula (VI) or a pharmaceutically acceptable salt thereof:

m is any integer between 0 and 10;

Ri, is hydrogen;

R ₂ , to R 4 are hydrogen, methoxy, difluoromethoxy, pyrrolyl;

R ₅ > is hydrogen, methyl, methoxy or chlorine;

R ₇ is hydrogen or methyl;

Rn is hydrogen.

8. A compound according to claim 1 which is selected from the group consisting of -

5,5'-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1H-benzimidazole],

5,5,-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1H-benzimidazole],

5,5'-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl]-1H-benzimidazole ],

5,5'-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio]-1H-benzimidazole],

5,5,-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylthio]-1H-benzimidazole],

5,5'-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy) P-pyridin-2-yl]methylthio]-1H-benzo Imidazole],

, 5'-bis-[2-[(3-methoxy-4-chloropyridin-2-yl)methylthio]-1H-benzimidazole],

, 5'-bis-[2-[(3-methyl-4-methoxypyridine-2-yl)methylthio]-1H-benzimidazole],

, 5'-bis-[2-[(3-methyl-4-ethoxypyridin-2-yl)methylthio]-1H-benzimidazole],

,5,-bis-[2-(pyridin-2-ylmethylthio)-1H-benzimidazole],

,5,-bis-[2-(pyridin-3-ylmethylthio)-1H-benzimidazole],

,5,-bis-[2-(pyridin-4-ylmethylthio)-1Η-benzimidazole],

,5'-bis-[2-(6-chloropyridin-3-ylmethylthio)-1H-benzimidazole],

, 5'-methylene-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1H-benzimidazole], ,5 '-Methylene-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1H-benzimidazole], 5,5,-methylene-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl]-1Η -benzimidazole] '

5,5,-methylene-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio]-1H-benzimidazole],

5,5,-methylene-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylthio]-1H-benzimidazole],

5,5,-methylene-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylthio]-1H- Benzimidazole], 5,5'-oxy-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1Η-benzo Imidazole], 5,5,-oxy-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1Η-benzimidazole],

5,5'-oxy-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl]-1Η- Benzimidazole], 5,5'-oxy-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio]-1H-benzimidazole ],

5,5'-oxy-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylthio]-1H-benzimidazole],

5,5'-oxy-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylthio]-1H-benzene And imidazole],

5,5'-imino-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]--benzimidazole],

5,5'-imino-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1H-benzimidazole],

5,5'-imino-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl]-1H- Benzimidazole],

5,5'-imino-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio]-1H-benzimidazole],

5,5'-imino-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylthio]-i benzimidazole],

5,5,-imino-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylthio]-1Η-benzene And imidazole], 5,5,-(1,2-ethanedioxy)-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfin Acyl]-1Η-benzimidazole],

5,5,-(1,2-ethanedioxy)-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1Η-benzimidazole] , 5,5,-(1,2-ethanedioxy)-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl] Methylsulfinyl]-1Η-benzimidazole],

5,5'-(1,2-Ethylenedioxy)-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio]-1Η- Benzimidazole], 5,5,-(1,2-ethanedioxy)-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylthio]-1Η- Benzimidazole],

5,5,-(1,2-ethanedioxy)-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]- Thio]]1Η-benzimidazole],

5,5'-(1,3-propanedioxy)-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1Η -benzimidazole],

5,5'-(1,3-propanedioxy)-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1Η-benzimidazole] , 5,5'-(l,3-propanedioxy)-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]- Kesulfinyl]-1Η-benzimidazole],

5,5'-(1,3-propanedioxy)-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio]-1H- Benzimidazole], 5,5'-(1,3-propanedioxy)-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylthio]-1H- Benzimidazole],

5,5,-(1,3-propanedioxy)-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]- Thio]]1H-benzimidazole],

5,5'-(1,5-pentadioxy)-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1Η -benzimidazole],

5,5'-(1,5-pentanedioxy)-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1H-benzimidazole] , 5,5,-(1,5-pentanedioxy)-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl] Methylsulfinyl]-1Η-benzimidazole],

5,5'-(1,5-pentadioxy)-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio]-1H- Benzimidazole], 5,5'-(1,5-pentadioxy)-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylthio]-1H- Benzimidazole],

5,5'-(1,5-pentadioxy)-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]- Thio]]1H-benzimidazole],

5,5'-(3-oxa-1,5-pentanedioxy)-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl Sulfonyl]-1H-benzimidazole],

5,5'-(3-oxa-1,5-pentanedioxy)-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1H -benzimidazole],

5,5'-(3-oxa-1,5-pentadioxy)-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)B ratio Pyridin-2-yl]methylsulfinyl]-1H-benzimidazole],

5,5,-(3-oxa-1,5-pentanedioxy)-bis-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfide Base]-1Η-benzimidazole],

5,5'-(3-oxa-1,5-pentanedioxy)-bis-[2-[(3,4-dimethoxypyridin-2-yl)methylthio]-1H- Benzimidazole], 5,5'-(3-oxa-1,5-pentadioxy)-bis-[2-[[3-methyl-4-(2,2,2-trifluoroethyl) Oxy)pyridin-2-yl]methylthio]-1H-benzimidazole],

Di-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1H-benzimidazol-5-yl]carbonate, di-[2 -[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1Η-benzimidazol-5-yl]carbonate,

Di-[2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl]-1H-benzimidazol-5-yl] Carbonate, Di-[2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1H-benzimidazol-5-yl] oxalate, di-[ 2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1H-benzimidazol-5-yl] oxalate, and di-[2-[[3- 4-(2,2,2-trifluoroethoxy)P-pyridin-2-yl]methylsulfinyl]-1H-benzimidazol-5-yl] oxalate.

A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound according to any one of claims 1-8.

10. Use of a compound according to any one of claims 1-8 for the manufacture of a medicament for inhibiting gastric acid secretion, against Helicobacter pylori or inhibiting the activity of gastric cancer.