JPH03501609A - New benzimidazole derivatives - Google Patents

Abstract

(57) [Abstract] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] New benzimidazole derivatives Technical field The present invention relates to novel benzimidazole derivatives, methods for producing the same, uses of the derivatives, and and medicaments containing said derivatives. The compounds according to the invention are used in the pharmaceutical industry. Used as intermediate product for pharmaceutical production.

Background technology Numerous patent applications and specifications include 2-(2-pyridylmethylsulfur). Nil Midazole derivatives have been described. Among others, European Patent Application No. 016794 Specification No. 3 states that the main structural element is a hydrogen atom and/or a 2-pyridyl ring. 2-(2 -pyridylmethylsulfinyl)-1H-benzimidazole derivatives have been described. ing.

However, surprisingly, an aryloxy group or an aryloxy group is present in the pyridine ring as a main structural element. Novel benzimidazoles having an alkoxy group in addition to a ralkyloxy group (detailed below) has an important, unexpected property that It has been found that novel compounds can be advantageously distinguished from known compounds.

Disclosure of invention The object of the invention is the formula I: [In the formula, R1, R2 and R3 are present at any position of the benzo moiety of benzimidazole.] R1 is water, halogen, trifluoromethyl, 1-6C-alkyl l, 1-60-alkoxy, 1-4C-alkoxy-1-40-alkyl, l- 4C-alkoxy-1-40-alkoxy, phenyl, phenoxy, phenoxy -1-4G-alkyl, phenoxy-1-4C-alkoxy, 7ene-1-40 -alkyl or phen-1-4C-alkoxy, R2 is hydrogen, l-6C -alkyl, 1-60-alkoxy, completely or mainly substituted by fluorine f: 1-4 C-alkoxy, chlordifluoromethoxy, 2-chlor -1.1.2-) together with fluoroethoxy or R3, optionally fully or partially t-1-2 C-alkyl-1/dioxy or carbon substituted with fluorine represents lolotrifluoroethyl 1/dioxy, R3 is hydrogen, 1-ac-alkyl, 1-60-alkoxy, wholly or mainly t21-4C-alkoxy substituted by fluorine, chlordifluoromethoxy l- optionally substituted completely or partially by fluorine together with C or R2 2C-alkylenedioxy or chlorotrifluoroethylenedioxy, R4 represents hydrogen or a group that can be easily eliminated under physiological conditions; R5 represents hydrogen or l-6C-alkyl; R6 represents hydrogen or l-6C-alkyl; R7 represents l-6C-alkoxy, 2-50-alkenyloxy, 2- 5C-alkynyloxy, 1-4C-alkoxy-1-4C-alkoxy, ali R8 represents aryloxy or aryl-1-4C-alkoxy, and R8 is aryloxy. represents cy- or aryl-1-4C-alkoxy, where aryl is of the formula: R9 and RIO are the same or different, hydrogen (H), 1-4C-alkyl, l-4 C-represents alkoxy, halogen, nitro, hydroxy or trifluoromethyl ), and n is 0 or l. These are dazole derivatives and salts of the derivatives.

Halogens within the scope of this invention are bromine, chlorine and fluorine.

1-6C-Alkyl represents straight-chain and branched alkyl groups. A straight chain alkyl group is Hexyl, pentyl, butyl, propyl, ethyl, especially methyl Ru. Branched alkyl groups include, for example, neopentyl, i-butyl, sec-butyl group, t-butyl group and isopropyl group.

1-60-Alkoxy is a straight or branched alkoxy group. For example, hexyl xy group, neopentyloxy group, butoxy group, i-butoxy group, se-butoxy group group, t-butoxy group, propoxy group, isopropoxy group, ethoxy group, especially methoxy group Examples include xyl group.

(2)-40-Alkoxy represents a straight-chain or branched-chain alkoxy group. For example butoxy group, i-butoxy group, seC-butoxy group, t-butoxy group, propoxy group, Mention may be made of the propoxy group, the ethoxy group and especially the methoxy group.

1-40-Alkyl represents a straight-chain or branched alkyl group. For example, butyl group, i -butyl group, sec-butyl group, t-butyl group, propyl group, isopropyl group, Mention may be made of the ethyl group, especially the methyl group.

1-40-alkoxy-1-40-alkyl is expressed by l-4C-alkoxy Represents substituted l-4C-alkyl. For example, ethoxymethyl group, proponent xybutyl group, methoxymethyl group, especially methoxyethyl group and ethoxyethyl group can be mentioned.

1-4C-alkoxy-1-4C-alkoxy is replaced by 1-40-alkoxy. represents 1-4C-alkoxy substituted with For example, methoxypropoxy group, Mention may be made of toxymethoxy groups, especially ethoxyethoxy and methoxyethoxy groups. Ru.

phenoxy-1-4C-alkyl is l-40 substituted by a phenoxy group - represents alkyl. Examples include phenoxyprobyl and phenoxyethyl groups. can be lost.

Phenoxy-1-4C-alkoxy is 1-4 substituted by a phenoxy group Represents G-alkoxy. For example, phenoxyethoxy and phenoxypropoxy An example is a cy group.

phen-1-4C-alkyl represents a l-4C-alkyl group substituted with For example, the phenethyl group, especially ben Examples include zyl group.

Phen-1-4C-alkoxy is 1-4C-alkoxy substituted with a phenyl group. Represents Lukokin. Examples include 2-phenyl-ethoxy and benzyloxy groups. can be lost.

f:, 1-40-alkoxy and completely or mainly substituted by fluorine For example, 1.1.2-trifluoroethoxy group, perfluoropropoxy groups, perfluoroethoxy groups, especially 1.1.2.2. -tetrafluoroethoxy group, trifluoromethoxy group, 2,2,2-trifluoroethoxy group and difluor Examples include olomethoxy group.

1-2C-alkylenedioxy is ethylenedioxy (-0-CH2-CH2-0 -) or methylenedioxy (-0-CH2-0-).

l-20-alkylenedioxy completely or partially substituted by 7 atoms; For example, l,l-difluoroethylenedioxy group (-0-CF2-CH2 -〇-), 1. l, 2, 2. -tetrafluoroethylenedioxy group (-0-CF 2-CF2-0-), especially difluoromethylenedioxy group (-0-CF2-0-) -) and 1.1.2-trifluoroethylenedioxy group (-〇-CF2-CHF -0).

R4 is a group that is easily removable under physiological conditions, optionally catalyzed by an enzyme. l: A substituent that is separated from the nitrogen atom by hydrolysis with the formation of an N-H bond. be. This substituent itself is not physiologically dangerous under the attachment of the hydroxyl group; In particular, it can be converted into pharmacologically acceptable compounds. As the leaving group R4, in particular all All kinds of substituted carbonyl groups are mentioned, such as alkylcarbonyl groups, Arylcarbonyl group, aralkylcarbonyl group, alkylcarbonyl group, alkylcarbonyl group, lyloxycarbonyl group, aralkoxycarbonyl group or optionally substituted It is a carbamoyl group. For example, methoxycarbonyl group, t-butoxycarbonyl group, Examples include carbamoyl group, benzoyl group, phenylcarbamoyl group and hiscymethylcarbamoyl group. can be lost.

2-5C-alkenyloxy means pent-2-2-22yloxy group, buty-1-22 represents an alkenyloxy group such as alkyloxy group, especially an allyloxy group.

2-50-alkynyloxy refers to an ethynyloxy group, especially pro-2-ynyloxy. Represents an alkynyloxy group such as an xy group.

Examples of the aryloxy group include 4-chlorophenoxy group and 4-fluorophenoxy group. Mention may be made of the phenoxy group, the 3,5-dichlorophenoxy group, and especially the phenoxy group.

Examples of the 7U-1-4C-alkoxy group include 4-phenylbutoxy group, 3-phenylproboxy group, 2-phenylethoxy group, 4-methoxybenzyl group xy group, 4-fluorobenzyloxy group, 4-chlorobenzyloxy! , 3.5 -dichlorobenzyloxy group, especially benzyloxy group.

As salts, compounds of the formula I when n represents O (sulfides), especially all acidification Adding salt is appropriate. In particular, pharmacologically acceptable salts of inorganic and organic acids commonly used in herbal medicine are mentioned. can be lost. For example, when producing the compounds according to the invention on an industrial scale, the process product Pharmacologically non-acceptable salts, which may be initially formed as Can be converted to scientifically acceptable salts. Such salts include, for example, water-soluble and water-insoluble salts. Acid addition salts such as hydrochloride, hydropromide, hydroiodide, phosphates , nitric acid range, sulfate, acetate, citrate, gluconate, benzoate, hibenze salt, phendizoate, butyrate, sulfosalicylate, maleate, la Urate, malate, fumarate, succinate, oxalate, tartrate, a musonate, embonate, metembonate, stearate, tora1/-t 2-hydroxy-3-su7toate, 3-hydroxy-2-naphtonite or methane Sylate is suitable.

In the case of the compound of formula 1 (sulfoxide) where n represents 1, salts etc. Basic salts are useful, especially pharmacologically acceptable salts with inorganic and organic bases commonly used in herbal medicine. Appropriate. Examples of basic salts include lithium salts, sodium salts, potassium salts, Calcium salt, aluminum salt, magnesium salt, titanium salt, ammonium salt or Examples include guanidium salts.

R2 and R3 are - optionally fully or partially substituted by fluorine. Represents 1-2C-alkylenedioxy or chlorotrifluoroethylenedioxy In this case, the substituents R2 and R3 are benzodiazole of the benzimidazole ring at adjacent positions. combined into parts.

One embodiment (aspect 1) of the present invention provides that in formula I, R2 is hydrogen, 1-6C-alkyl or represents l-60-alkoxy, and R3 is hydrogen, l-6C-alkyl or 1-6 Represents 0-alkoxy, R1, R4, R5, R6, R7, R8, R9, RIO and n represents the above-mentioned compounds and salts thereof.

Advantageous representatives of aspect 1 of the invention are, in formula l: R1 is hydrogen, chlorine, fluorine, trifluoromethyl, methyl, ethyl, methoxy or represents ethoxy, and R2 represents hydrogen, methyl, ethyl, methoxy or ethoxy. eagle, I, R3 represents hydrogen, R4 represents hydrogen, R5 represents hydrogen, R6 represents hydrogen or methyl, R7 represents methoxy or benzyloxy, R8 represents benzyloxy, n is O or l These are the compounds and their salts.

A very advantageous aspect of embodiment 1 of the invention is that in formula 1, R1 represents hydrogen, trifluoromethyl or methoxy, R2, R3, R4 and R5 represent hydrogen, R6 represents hydrogen or methyl, R7 represents methoxy, R8 represents benzyloxy, n is O or 1 These are the compounds and their salts.

Another aspect (aspect 2) of the invention is that in formula I, R2 together with R3 is 1-2C- Represents alkylene dioxy, R1, R4, R5, R6, R7, R8, R9゜R Compounds and salts thereof, where IO and n are as defined at the beginning.

An advantageous representative of aspect 2 of the invention is that in formula 1: R1 represents hydrogen, R2 and R3 together represent ethylenedioxy or methylenedioxy, R4 represents hydrogen, R5 represents hydrogen, R6 represents hydrogen or methyl, R7 represents methoxy or benzyloxy, R8 represents benzyloxy, n is O or l These are the compounds and their salts.

A highly advantageous representative of aspect 2 of the invention is the formula 1 formula % R1 represents hydrogen, R2 and R3 together represent ethylenedioxy or methylenedioxy, R4 represents hydrogen, R5 represents hydrogen, R6 represents hydrogen or methyl, R7 represents methoxy, R8 represents benzyloxy, n is O or l These are the compound and the salt of the same compound.

Another embodiment (aspect 3) of the invention provides that in formula I, R2 is hydrogen, 1-ac-alkyl 1-60-alkoxy, 1-60-alkoxy, completely or mainly substituted by fluorine 4C-alkoxy, chlorodifluoromethoxy, 2-10rho1.1.2-tri Fluoroethoxy or together with R3 is fully or partially substituted by fluorine represents l-2C-alkylenedioxy or chlorotri7fluoroethylenedioxy. , R3 is 1-40-alkoxy substituted completely or mainly by fluorine; chlorodifluoromethoxy, 2-chloro-1,1,2-)difluoronide l-2C-a substituted completely or mainly by fluorine together with C or R2 R1,R represents rukylenedioxy or chlorotrifluoroethylenedioxy 4, R5, R6, R7, R8, R9, RIO and n represent those listed at the beginning. This is a compound in case.

Another advantageous embodiment (embodiment a) of aspect 3 of the invention is of formula Ia: R1 represents hydrogen; R2 is hydrogen, methyl, ethyl, methoxy, ethoxy, 1.1.2.2. -tetra Fluoroethoxy, trifluoromethoxy, 2.2.2-)trifluoroethoxy , difluoromethoxy, 2-chloro-1,1゜2-trifluoroethoxy or R 3 together with difluoromethylenedioxy, 1.1.2-)lifluoroethylenedioxy represents oxy or l-chloro-1,2,2-1-lifluoroethylenedioxy, R3 is l, 1.2, 2. -tetrafluoroethoxy, trifluoromethoxy, 2 , 2.2-trifluoroethoxy, difluoromethoxy, 2-chloro-1゜1. 2-) difluoromethylenedioxy with difluoroethoxy or R2, 1, 1.2-) Lifluoroethylenedioxy or 1-chloro-1,2,2-triflu represents oleethylenedioxy, R4 represents hydrogen, R5 represents hydrogen, methyl or ethyl, R6 represents hydrogen or l-4C-alkyl and R7 is 1-4C-alkoxy, aryloxy or aryl-1-4C -alkoxy, R8 is aryloxy or aryl-1-4C-alco aryl represents the formula; R9 represents hydrogen, methyl, methyl or chlorine; where RIO is hydrogen, methyl, methoxy, chloro, nitro, hydroxy or [representing lifluoromethyl, n is 0 or 1] and the same compound It is the salt of things.

Another advantageous embodiment (embodiment b) of aspect 3 of the present invention is that the formula 1b= In the formula, R1, R2, R3, R4, R5, R6, R7゜R8, R9, RIO and n is a compound represented by 1 as described in embodiment a and a salt thereof.

Another advantageous embodiment (Embodiment C) of Aspect 3 of the present invention is the formula ■C: [In the formula, R1, R2, R3, R4, R5, R6, R7゜R8, R9, RIO and n represents the compound described in Embodiment a] and salts thereof.

Another advantageous embodiment (embodiment d) of aspect 3 of the present invention is represented by formula 1d: [In the formula, R1, R2, R3, R4, R5, R6, R7゜R8゜R9, RIO and n is a compound described in Embodiment a and represented by t; represents a compound] and a salt thereof.

Advantageous compounds according to the invention are of the formula 1. Ias Ib.

In Ic and Id, R1 represents hydrogen, R2 is hydrogen, methoxy or together with R3 difluoromethylenedioxy, 1. l, 2-trifluoroethylenedioxy or 1-chloro-1,2,2-1 trifluoro represents ethylenedioxy, R3 is 1. l, 2.2. -tetrafluoroethoxy, trifluorofmethoxy, 2 , 2.2-1-lifluoroethoxy, difluoromethoxy, 2-chloroa-1゜1 ,, 2-1-lifluoroethoxy or difluoromethylene dioxy along with R3 shi, ll ll 2-trifluoroethylenedioxy or 1-chloro-1,2, represents 2-trifluoroethylenedioxy, R4 represents hydrogen, R5 represents hydrogen, R6 represents hydrogen or methyl, R7 represents methoxy or []-oxy, R8 represents benzyloxy, Compounds and salts of the compounds where n is O or l.

Very advantageous compounds according to the invention are of the formulas Ia, Ib, IC and Id: R1 represents hydrogen, R2 represents hydrogen or together with R3 difluoromethylenedioxy, R3 represents difluoromethoxy or together with R2 represents difluoromethylenedioxy death, R4 represents hydrogen, R5 represents hydrogen, R6 represents hydrogen or methyl, R7 represents methoxy, R8 represents benzyloxy, Compounds where n is 0 or 1 and salts of the compounds.

Compounds according to the invention include, for example: 2-[(5-benzyloxy-4-methoxy-3-methyl-2-pyridyl)methy Rusulfinyl]-5-trifluoromethoxy-IH-benzimidazole 2 -[(5-benzyloxy-4-methoxy-3-methyl-2-pyridyl)methyl thio]-5-1-lifluoromethoxy-IH-benzimidazole, 2-[( 5-benzyloxy-4-methoxy-3-methyl-2-pyridyl)methylsulfate -5-(1,1,2,2-tetrafluoroethoxy)-1H-benzo imidazole, 2-[(5-benzyloxy-4-methoxy-3-methyl-2-pyridyl)methy [ruthio]-5-(1,1,2゜2-tetrafluoroethoxy)-18-benzo imidazole, 2-[(5-benzyloxy-4-methoxy-3-methyl-2-pyridyl)methane Tylsulfinyl]-5-(2,2,2-)lifluoronidoxy)-1H-be nzoimidazole, 2-[(5-benzyloxy-4-methoxy-3-methyl-2-pyridyl)methy [ruthio]-5-(2,2,2-trifluoroethoxy)-1H-benzimidazo rule, 2-[(5-benzyloxy-4-methoxy-3-methyl-2-pyridyl)methy Rusulfinyl]-5-difluoromethoxy-IH-benzimidazole, 2 -[(5-benzyloxy-4-methoxy-3-methyl-2-pyridyl)methyl Thi-1-5-difluoromethoxy-IH-benzimidazole, 2-[(5-benzimidazole) methyloxy-4-methoxy-3-methyl-2-pyridyl)methylsulfinyl ]-5-chlorodifluoromethoxy-IH-benzimidazole, 2-[(5-benzyloxy-4-methoxy-3-methyl-2-pyridyl)methy [ruthio]-5-dichlorodifluoromethoxy-IH-benzimidazole, 2- [(5-benzyloxy-4-methyl-xy-3-methyl-2-pyridyl)methyl Sulfinyl l-5゜6-bis(difluoromethoxy)-1H-benzimidazo rule, 2-[(5-benzyloxy-4-methoxy-3-methyl-2-pyridyl)methy [ruthio]-5,6-bis(difluoromethoxy)-1H-benzimidazole, 2-[(5-benzyloxy-4-methoxy-3-methyl-2-pyridyl)methy Rusulfinyl 3-5-difluoromethoxy-6-methoxy-IH-benzimi Dazol, 2-[(5-benzyloxy-4-methoxy-2-pyridyl)methylsulfini Lugault 5-difluoromethoxy-IH-benzimidazole, 2-[(5-benzyloxy-4-methoxy-2-pyridyl)methylthi- 5-difluoromethoxy-IH-benzimidazole, 2I(5-benzyloxy-4-methoxy-2-pyridyl)methylsulfinyl ]-5-chlorodifluoromethoxy-IH-benzimidazole, 2-[(5- benzyloxy-4-methoxy-2-pyridyl)methylthio]-5-chlorodif fluoromethoxy-IH-benzimidazole, 2-[(5-benzyloxy-4-methoxy-2-pyridyl)methylsulfini ]-5,6-bis(difluoromethoxy)-1H-benzimidazole, 2- [(5-benzyloxy-4-methoxy-2-pyridyl)methylthio]-5, 6-bis(difluoromethoxy)-1)(-benzimidazole, 2-[(5- Benzyloxy-4-methoxy-2-pyridyl)methylsulfinyl 1-5-di Fluoromethoxy-6-methoxy-IH-benzimidazole 2-[(5-ben Zyloxy-4-methoxy-2-pyridyl)methylthio]-5-difluorometho xy-6-methoxy-1H-benzimidazole, 2,2-difluoro-6-[ (5-benzyloxy-4-methoxy-2-pyridyl)methylthio]-5H-N , 3]-dioxo[4,5-f]benzimidazole, 2.2-difluoro-6-[(5-benzyloxy-4-methoxy-2-pyridi) ) methylsulfinyl]-5H-N, 3]-diocturo[4,5-f] benzimidazole, 6.6.7-)lifluoro-6,7-sihydro-2-[(5-benzyloxy- 4-methoxy-2-pyridyl)methylthio]-1H-N,4]dioxin[ 2,3-f]benzimidazole, 6.6.7-)lifluoro-6,7-sihydro-2-[(5-benzyloxy- 4-methoxy-2-pyridyl)methylsulfinyl]-1H-[1,41-di Oxine [2,3-f]benzimidazole, 6,6-cyfluoro6,7- Cyhydro-2-[(5-benzyloxy-4-methoxy-2-pyridyl)methyl thio]-18-N,4]-dioxin [2,3-flbenzimidazole , 6.6-cyfluoro6.7-cyhydro2-[(5-benzyloxy-4-methyl Toxy-2-pyridyl)methylsulfinyl]-1H-[1,4]-'; Xino[2,3-f]benzimidazole, 6,6,7,7-titrafluoro -6.7-Sihydro2-[(5-benzyloxy-4-methoxy-2-pyri zyl) methylthio] -1H-[1,41-dioxin [2,3-fl benzo Imidazole, 6,6,7,7-thitrafluoro6,7-sihydro2-[( 5-benzyloxy-4-methoxy-2-pyridyl)methylsulfinyl] - 1H-N.

4]-dioxin [2,3-flbenzimidazole, 6-chloro-6,7,7-dolifluoro6,7-dihydro2-[(5-ben Zyloxy-4-methoxy-2-pyridyl)methylsulfinyl]-LH-[1,41-dioxin [2,3-flbenzimidazole, 6-chloro-6,7,7-)lifluoro-6,7-dihythro2 -[(5-ben Zyloxy-4-methoxy-2-pyridyl)methylthio]-1H-[1,4]-dioxin [2,3-flbenzimidazole 2-[(4-benzyloxy-3-methoxy-2-pyridyl)methylsulfinyl] -5-trifluorometho xy-IH-benzimidazole, 2-[(4-benzyloxy-3-methoxy-2-pyridyl)methylthio]-5-)lifluoromethoxy-IH-benzimi dazole, 2-[(4-benzyloxy-3-methoxy-2-pyridyl)methylsulfinyl 3-5-(1,1,2,2-tetrafluoroethoxy)-1)(-benzoimidazole, 2-1(4-benzyloxy-3-methoxy-2-pyridyl)methylthio]-5-(1 , 1,2,2-tetrafluoroethoxy)-18-benzimidazole, 2-[(4-benzyloxy-3-methoxy-2-pyridyl)methylsulfini -5-(2,2,2-trifluoroethoxy)-1)(-benzimidazo 2-[(4-benzyloxy-3-methoxy-2-pyridyl)methylthio]-5-(2,2,2-)lifluoroethoxy)-1H-benzimidazole, 2-[(4-benzyl oxy-3-methoxy-2-pyridyl)methylsulfinylgo -5-difluoromethoxy-IH-benzimidazole, 2-[(4-benzyloxy-3-methoxy-2-pyridyl)methylthio]-5-difluoromethoxy-IH-benzimidazole, 2-[(4-benzyloxy- 3-methoxy-2-pyridyl)methylsulfini ]-5-dichlorodifluoromethoxy-IH-benzimidazole, 2-[(4-benzyloxy-3-methoxy-2-pyridyl)methylthio]-5-chloro Difluoromethoxy IH-benzimidazole, 2-[(4-benzyloxy-3-methoxy-2-pyridyl)methylsulfini ]-5,6-h'su(difluoromethoxy)-LH-benzimidazole, 2-[(4-benzyloxy-3-methoxy-2-pyridyl)methylthio]-5,6-bis(difluoromethoxy)- 1H-benzimidazole, 2-[(4-benzimidazole) methyloxy-3-methoxy-2-pyridyl)methylsulfinyl]-5-dic Lolomethoxy-6-methoxy-IH-benzimidazole, 2-1:(4-benzimidazole) Zyloxy-3-methoxy-2-pyridyl)methylthi-1-5-difluorometho xy-6-methoxy-IH-benzimidazole, 2,2-difluoro-6-[(4-benzyloxy-3-methoxy-2-pyridyl)methylthio]-58-N,3]-diocturo[4,5- f1 benzimidazole, 2,2-difluoro-6-[(4-benzyloxy-3-methoxy-2-pyridi ) methylsulfinyl] -5H-M, 3]-diocturo[4,5-f]ben Zoimidazole, 6.6.7-trifluoro6.7-sihydro2-[(4-benzyloxy-3-methoxy-2-pyridyl)methylthio] -18-[1,41dioxyno[2,3-f] Benzimidazole, 6.6. ．． 7-) Lifluoro-6,7-sihydro-2-[(4-penzyloxy-3-methoxy-2-pyridyl)methyl-sulfinyl] -1H-N,4]-dioxyno[2,3-f]benzimidazole, 6 .6-cyfluoro6.7-cyhydro2-[(4-benzyloxy-3-methoxy-2-pyridyl)methy [2,3-f]benzimidazole 6,6-cyfluoro6,7-cyhydro2-[(4-benzyloxy-3-methyl Toxy-2-pyridyl)methylsulfinyl]-18-[1,4]-dioxy Shino [2,3-flbenzimidazole, 6,6,7,7-titrafluoro 6,7-sihydro2-[(4-benzyloxy-3-methoxy-2-pyridi ) methylthio] -1H-[1,4] -dioxyno [2,3-flbenzo imidazole, 6,6,7,7-titrafluoro6,7-di)nidro2-[ (4-benzyloxy-3- methoxy-2-pyridyl)methylsulfinyl] -18-[1°4]-dioxino[2,3-f]benzimidazole, 6-chloro-6,7,7-trifluoro6,7-sihydro2-[( 4-Ben Zyloxy-3-methoxy-2-pyridyl)methylsulfinyl]-1H-N, 4]-dioxyno[2,3-flbenzimidazole, 6-ritetra6.7.7-1-lifluoro-6,7- Shihydro 2-[(4-be) [2,3-flbenzimidazole2-[(3-benzyloxy-4-methoxy-2-pyridyl)methylsulfinyl]- 5-trifluorometho xy-IH-benzimidazole, 2-[(3-benzyloxy-4-methoxy-2-pyridyl)methylthio]-5-trifluoromethoxy-LH-benzimi Dazole, 2-[(3-benzyloxy-4-methoxy-2-pyridyl)methylsulfini -5-(1,1,2,2-tetrafluoroethoxy)-1H-benzimi dazole, 2-[(3-benzyloxy-4-methoxy-2-pyridyl)methylthio]-5-(1,1,2,2-tetrafluoroethoxy)-1H-benzimidazole, 2-[(3-benzyl Oxy-4-methoxy-2-pyridyl)methylsulfini -5-(2,2,2-trifluoroethoxy)-1H-benzimidazole 2-[(3-benzyloxy-4-methoxy-2-pyridyl)methylthio]-5-(2,2,2-1lifluoroethoxy)-1H-benzimidazole, 2-[(3-benzyloxy -4-methoxy-2-pyridyl)methylsulfinyl] -5-difluoromethoxy-IH-benzimidazole, 2-[(3-benzyloxy-4-methoxy-2-pyridyl)methylthi-1-5-difluorome-I xy IH-benzimidazole, 2-[(3-benzyloxy-4-methoxy-2-pyridyl)methylsulfini ]-5-chlorodifluoromethoxy-IH-benzimidazole, 2-[(3-benzyloxy-4-methoxy-2-pyridyl)methylthio]-5-chlorodi Fluoromethoxy-IH-benzimidazole, 2-[(3-benzyloxy-4-methoxy-2-pyridyl)methylsulfini ]-5,6-bis(difluoromethoxy)-LH-benzimidazole, 2-[(3-benzyloxy-4-methoxy-2-pyridyl)methylthio]-5,6-bis(difluoromethoxy)-LH- Benzimidazole, 2-[(3-ben Zyloxy-4-methoxy-2-pyridyl)methylsulfinyl]-5-diflu Oromethoxy-6-methoxy-IH-benzimidazole 2-((3-benzyloxy-4-methoxy-2-biridyl)methylthio]-5-difluoromethoxy-6-methoxy-1H-benzimidazole, 2,2-difluoro- 6-[(3-benzyloxy-4-methoxy-2-pyridyl)methylthio]-5H-[1,3]-diocturo[4,5-flbenzimidazole, 2,2-difluoro-6-[(3- Benzyloxy-4-methoxy-2-pyridi ) methylsulfinyl] -5H-N,3]-diocturo[4,5-fl ben Zoimidazole, 6.6.7-trifluoro6.7-sihydro2-[(3-benzyloxy-4-methoxy-2-pyridyl)methylthio]-1)1-N,4]dioxy [2,3-flbenzimidazole, 6.6,7-trifluoro6,7-sihydro2-[(3-benzyloxy-4-methoxy-2-pyridyl)methylsulfinyll -IH-[1,4 ] - Dioxine [2,3-f]benzimidazole, 6,6-cyfluoro6,7-sihydro2-[(3-benzyloxy-4-methoxy-2-pyridyl)methy [2,3-f]benzimidazole 6,6-cyfluoro6,7-cyhydro2-[(3-benzyloxy-4-methyl Toxy-2-pyridyl)methylsulfinyl]-1H-El,4]-dioxy Syn [,2,3-flbenzimidazole, 6,6,7,7-titrafluoro -6.7-Sihydro2-[(3-benzyloxy-4-methoxy-2-pyridi -1H-[1,4]-dioxin [2,3-f]benzo imidazole, 6,6,7,7-titrafluoro6,7-sihydro2-[(3-benzyloxy-4-methoxy -2-pyridyl)methylsulfinyl] -1H-[1°4]-dioxin [2,3-f]benzimidazole, 6-chloro-6,7,7-trifluoro6,7-sihydro2-[(3 -Ben Zyloxy-4-methoxy-2-pyridyl)methylsulfinyl]-1H-N, 4]-dioxin [2,3-flbenzimidazole, 6-chloro-6,7,7-)lifluoro-6,7-sihydro2 −[(3-ben Zyloxy-4-methoxy-2-pyridyl)methylthio] -1H-[1,4 -Dioxino [2,3-rJbenzimidazole 2-[(4-benzyloxy-5-methoxy-2-pyridyl)methylsulfinyl]-5-)rifluorometho xy-IH-benzimidazole, 2-[(4-benzyloxy-5-methoxy-2-pyridyl)methylthio]-5-trifluoromethoxy-IH-benzimi Dazole, 2-[(4-benzyloxy-5-methoxy-2-pyridyl)methylsulfini -5-(1,1,2,2-tetrafluoroethoxy)-1H-benzimi dazole, 2-[(4-benzyloxy-5-methoxy-2-pyridyl)methylthio]-5-(1,1,2,2-tetrafluoroethoxy)-1H-benzimidazole 2-[(4-benzyloxy-5-methoxy-2-pyridyl)methylsulfini ]-5-(2,2,2-trifluoroethoxy)-1H-benzimidazole, 2-[(4-benzyloxy-5-methoxy-2-pyridyl)methylthio]-5-(2,2,2 -)lifluoroethoxy)-1H-benzimidazole, 2-[(4-benzyloxy-5-methoxy-2-pyridyl)methylsulfinyl] -5-difluoromethoxy-IH-benzimidazole, 2-[(4-benzyl oxy-5-methoxy-2-pyridyl)methylthio]-5-difluoromethoxy-1H-benzimidazole, 2-[(4-benzyloxy-5-methoxy-2-pyridyl)methylsulfini ]-5-chlorodifluoromethoxy-IH-benzimidazole, 2-[(4-benzyloxy-5-methoxy-2-pyridyl)methylthio]-5-chlorodi Fluoromethoxy-IH-benzimidazole, 2-[(4-benzyloxy-5-methoxy-2-pyridyl)methylsulfini -5,6-bis(difluoromethoxy)-1H-benzimidazole, 2-[(4-benzyloxy-5-methoxy-2-pyridyl)methylthio]-5,6-bis(difluoromethoxy)-1H- Benzimidazole, 2-[(4-benzimidazole) methyloxy-5-methoxy-2-pyridyl)methylsulfinyl]-5-dif fluoromethoxy-6-methoxy-IH-benzimidazole 2-[(4-benzi 5-methoxy-2-pyridyl)methylthio]-5-difluoromethoxy C-6-methoxy-IH-benzimidazole, 2,2-difluoro-6-[(4-benzyloxy-5-methoxy-2-pyridyl)methylthio]-5H-[1,3]-diocturo[4,5 -flbenzimidazole, 2,2-difluoro-6-((4-benzyloxy-5-methoxy-2-pyridi 6.6.7-)lifluoro-6,7-dihydro-2-[(4-benzyloxy-5- methoxy-2-pyridyl)methylthio]-1H-[1,4]-dioxy [2,3-f]benzimidazole, 6.6.7-)lifluoro-6,7-cyhydro-2-((4-benzyloxy-5-methoxy-2-pyridyl)methyl sulfinyl] -18-(1 ,4] -dioxin [2,3-f]benzoy midazole, 6゜6-cyfluoro6.7-cyhydro2-[(4-benzylo) xy-5-methoxy-2-pyridyl)methylthio]-18-N,4]-dio [2,3-flbenzimidazole, 6,6-cyfluoro6,7-cyhydro2-[(4-benzyloxy-5-methyl Toxy-2-pyridyl)methylsulfinyl]-1H-[1,4]-dioxy Syn [2,3-fl benzimidazole, 6.6.7.7. -tetrafluoro -6,7-sihydro-2-[(4-benzyloxy-5-methoxy-2-pyridi ) Methylthioco-IH-[1,41-dioxin [2,3-f]benzoy Midazole, 6.6,7,7. -tetrafluoro-6,7-sihydro-2-[(4-benzyloxy-5-methoxy-2-pyridyl)methylsulfinyl] -1H-M, 41-dioxin [2,3-f]benzimidazole, 6-ri 4-6.7.7-trifluoro6.7-sihydro2'-[(4-beta) [2,3-f]benzimidazole, 6-chloro-6,7,7-trifluoro6.7 -Sihydro2-((4-ben Zyloxy-5-methoxy-2-pyridyl)methylthio]-18-[1,4]-dioxin [2,3-f]benzimidazole 2-[(4-benzyloxy-5-methoxy-3-methyl-2- pyridyl)methylsulfinyl]-5-trif fluoromethoxy-IH-benzimidazole 2-[(4-benzyloxy-5-methoxy-3-methyl-2-pyridyl)methylthio]-5-trifluoromethoxy C-IH-benzimidazole, 2-[(4-benzyloxy-5-methoxy-3-methyl-2-pyridyl)methylsulfinyl]-5-(1,1,2,2-te]-Lafluoroe I xy )-1H-benzimidazole, 2-[(4-benzyloxy-5-methoxy-3-methyl-2-pyridyl)methy ruthio] -s-ci, i, 2,2-tetrafluoroethoxy)-1H-benzoimidazole, 2-[(4-benzyloxy-5-methoxy-3-methyl-2-pyridyl)methyl Tylsulfinyl] -5-(2,2,2-trifluoroethoxy)-1H-ben ndzimidazole, 2-[(4-benzyloxy-5-methoxy-3-methyl-2-pyridyl)methy [ruthio] -5-(2,2,2-trifluoroethoxy)-18-benzimida sol, 2-[(4-benzyloxy-5-methoxy-3-methyl-2-pyridyl)methy rusulfinyl]-5-difluoromethoxy-IH-benzimidazole, 2-[(4-benzyloxy-5-methoxy-3-methyl-2-pyridyl)methylthi 1-5-difluoromethoxy-IH-benzimidazole, 2-[(4-ben 2-[(4-benzyloxy-5-methoxy-3-methyl-2-pyridyl) Methi ruthiogo 5-chlorodifluoromethoxy-IH-benzimidazole, 2-[(4-benzyloxy-5-methoxy-3-methyl-2-pyridyl)methyls Rufinil] -5゜6-bis(difluoromethoxy)-1H-benzimidazo 2-[(4-benzyloxy-5-methoxy-3-methyl-2-pyridyl)methyl tilthio]-5,6-bis(difluoromethoxy)-18-benzimidazole, 2-[(4-benzyloxy-5-methoxy-3-methyl-2-pyridyl)methy rusulfinyl] -5-difluoromethoxy-6-methoxy-L H-benzo imidazole, 2-[(4-benzyloxy-5-methoxy-3-methyl-2-pyridyl)methy ruthio]-5-difluoromethoxy-6-methoxy-IH-benzimidazole, 2,2-difluoro-6-[(4-benzyloxy-5-methoxy-3-methyl-2-pyridyl)methylthio 1-5H-N , 3] -Dioxolo[4,5-f]benzimidazole, 2,2-difluoro-6-[(4-benzyloxy-5-methoxy-3-methyl-2-pyridyl)methylsulfonyl] -5H-[1 ,31-dioxoro14. 5-f] Benzimidazole, 6.6.7-trifluoro6.7-sihydro2-[(4-benzyloxy-5-methoxy-3-methyl-2-pyridyl)methylthio]-LH-[1,4 Koshi Oxino[2,3-f]benzimidazole, 6.6.7-trifluoro6. 7-Sihydro2-[(4-benzyloxy-5-methoxy-3-methyl-2-pyridyl)methylsulfinyl]-1H-[1,4]-dioxin [2,3-f]benzimidazole, 6.6- cyfluoro6.7-cyhydro2-[(4-benzyloxy-5-methyl Toxy-3-methyl-2-pyridyl)methylthio]-1H-N,4]-dio [2,3-f]benzimidazole, 6,6-cyfluoro6,7-cy hydro-2-[(4-benzyloxy-5-methoxy-3-methyl-2-pyridi ) methylsulfinyl] -1H-N.

4]-Dioxine [2,3-fl benzimidazole, 6.6,7,7. -tetrafluoro-6,7-sihydro-2- [(4-benzi methylthio]-1H-[ 1,4]-dioxin [2,3-f]benzimidazole, 6.6,7.7-thitrafluoro6.7-sihydro2-[(4-benzyl oxy-5-methoxy-3-methyl-2-pyridyl)methylsulfinyl]-I H-N, 4]-dioxin [2,3-f]benzimidazole, 6-chloro-6,7,7-trifluoro6,7-dihythro2-[(4-beta) methyloxy-5-methoxy-3-methyl-2-pyridyl)methylsulfinyl ]-1H-[1,4]-dioxin [2,3-f]benzimidazole, 6-chloro-6,7,7-)lifluoro-6,7-sihydro-2-[(4-ben Zyloxy-5-methoxy-3-methyl-2-pyridyl)methylthio]-1H- N,4]-dioxin [2,3-fl benzimidazole, and salts of these compounds.

The 5th position of the imidazole ring is the same as the 6th position due to tautomy in the imidazole ring. be. Therefore, compounds in which R2 and R3 together represent a substituted ethylenedioxy group In the case of N,4]-dioxin [2,3-f1 benzimidazole moiety The 6th place in minutes is the same as the 7th place.

Another subject of the invention is the formula 1 (wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, RIO and n represent the above) This is a method for producing ole derivatives and salts thereof.

The method according to the invention comprises: a) React the mercaptobenzimidazole of the formula ■ with the picoline derivative ■: or b) Reacting benzimidazole of formula ■ with mercaptopicolin V: (IV) (V) or c) Reacting 0-phenylenediamine of formula Vl with formic acid derivative ■: If the desired end product is a compound of formula I which is n-1 then a), b ) or 2-benzimidazole-2-pyridylmethyl obtained by C) - sulfide (compound of formula I which is n-0): acidified and/or salted if desired or d) Reacting benzimidazole of formula ■ with pyridine derivative X: or e) reacting a sulfinyl derivative of formula (■) with a 2-picoline derivative (■): If desired, then change to salt, or f) - The process product to be produced is such that R4 is a group that is easily removable under physiological conditions. In the case of a compound of formula 1 representing hydrogen, the compound of formula 1 in which -R4 represents hydrogen is R4'-Y' (XII[) [wherein R4' is easily removable under physiological conditions] the desired group or its precursor group together with Y' and then, if desired, a salt. change, or g) - if the process product to be produced is a compound of formula 1 in which R4 represents hydrogen; A compound of formula I in which -R4 represents a group readily removable under physiological conditions is added to Solvent decomposition and convert the resulting product into a salt if desired, or h) - The process product to be produced is of formula I, in which R5 represents 1-60-alkyl. In the case of a compound of formula I, where -R5 represents hydrogen, the compound of formula R5-Y" (X IV) alkylation with a compound [wherein R5 represents 1-60-alkyl], where It is characterized by the fact that it can be replaced with salt if desired. In this case, YSY", Z, Z' and Z" represent appropriate starting groups, and Y' is the starting group or represents a reactive group, M represents an alkyl metal atom (Li, Na or K), and %M ’ represents an equivalent metal atom, R1, R2, R3, R4, R5, R6, R7, R 8, R9, RIO and n (unless otherwise defined) are as defined above.

In the case of the above reactions, compounds 1 to XIV are used as such or optionally in the form of their salts. It can be used in

Production processes a), b) and C) produce the sulfide according to the invention and the acid of compound (i) and methods d) and e) provide sulfoxides according to the invention, methods f), g) and h) yield both types of products.

What starting groups Y, Y'? Whether Y”, z, z’ and Z# are appropriate is a matter for those skilled in the art. He is well known to many people because of his expertise. A suitable starting group Y may be, for example, if it is attached to It is a group that forms a reactive sulfinic acid derivative together with the sulfinyl group. suitable Suitable starting groups Y include, for example, alkoxy groups, dialkylamino groups or alkyl groups. Examples include mercapto groups. A suitable starting group or reactive group Y' can be or a group capable of reacting with a secondary amino group upon addition. R4' is substituted In the case of a compound of formula xm representing a carbonyl group, y1 is e.g. Reactive carboxylic acid derivatives, such as acid halides, together with the carbonyl group to be combined. is the starting group for forming . According to the invention, the general formula R4'-Y'(XI[I) According to Also included is a precursor of the group R4 that is easily removable under chemical conditions, and the compound is When reacting with a secondary amino group, no condensation occurs during elimination of HY, and the desired leaving group R Addition under the formation of 4 The starting group Y# is a group well known to those skilled in the art in the case of alkylation reactions; Such groups include, for example, dialkyl sulfates, fluorosulfonic acid alkyl esters, It is eliminated during alkylation with esters or alkyl iosides.

Suitable starting groups z, z' and 2# include, for example, halogen atoms, especially chlorine atoms, or activated by esterification (e.g. p-dololsulfonic acid) A roxy group is mentioned.

Equivalent metal atoms M' are, for example, alkali metals (Li, Na or K) or halogens. atoms (e.g. Br, Grignard reagent); alkaline earth metals (e.g. Mg), or as the above metals during the substitution reaction of organometallic compounds. optionally substituted; any other metal atom known to react; It is.

The reaction between ① and ② is carried out in a known manner using a suitable, preferably polar or non-polar proton. Protic solvents (e.g. methanol, isopropanol, dimethyl sulfoxide, Addition or exclusion of water in acetone, dimethylformamide or acetonitrile) It takes place below. The reaction takes place, for example, in the presence of a proton acceptor. proton Receptors include alkali metal hydroxides such as sodium hydroxide and alkali metal carbon. acid salts such as potassium carbonate, or tertiary amines such as pyridine, triethylamine or Ethyldiisopropylamine is suitable. Also, the reaction does not require a proton acceptor. Depending on the type of starting compound, in some cases acidification may be carried out first. The salt may be isolated in extremely pure form. The reaction temperature may be between 0 and 150°C; In this case, in the presence of proton acceptors, the temperature is between 20 and 80°C; If not, the temperature is preferably 60 to 120°C, particularly the boiling temperature of the solvent used. reaction The time is 0.5 to 12 hours.

In the case of the reaction between ■ and V carried out in a known manner, the same reaction as that between ■ and ■ is carried out. Various reaction conditions are used.

The reaction between ■ and ■ is advantageously carried out in a polar solvent optionally containing water using a strong acid, e.g. It is carried out in the presence of hydrochloric acid, especially at the boiling temperature of the solvent used.

Oxidation of sulfide is carried out by known methods and oxidation of sulfide to sulfoxide. under conditions well known to those skilled in the art [in this regard, for example, J, D r-abowicz and M, Mikolajacyk: Organic p. reparations and procedures int, 14 (1- 2), 45-89 (1982) or E, Bloch in S, Patai , The Chemistry.

of Functional Groups, Supplement E, Partl *S, 539-608, John Willey and 5ons (Interscience Publication), 1980 ] As an oxidizing agent, in the case of oxidation of sulfide to sulfoxide, All commonly used reagents are suitable, especially peroxy acids such as peroxy vinegar. acid, trifluoroperoxyacetic acid, 3,5-dinitroperoxybenzoic acid, per oxymaleic acid, magnesium monoperoxyphthalate or preferably m- Chloroperoxybenzoic acid is mentioned.

The reaction temperature is -70°C (depending on the oxidant and dilution) and the boiling temperature of the solvent used. but preferably between -306°C and +20°C. Advantageously between 0 and 50°C Halogen and polyhalogen (e.g. aqueous hypozinc acid sodium) Oxidation with thorium solution) was also advantageous. The reaction is advantageously carried out in an inert solvent, e.g. aromatic or chlorinated hydrocarbons, i.e. penzole, doluol, dichloromethane; in particular esters or ethers, such as ethyl acetate ester. The reaction is carried out in dioxane, isopropyl acetate or dioxane.

The reaction between ■ and It is carried out in a conventional inert solvent. For example aromatic solvents such as penzo Examples include dool or doluol. The reaction temperature is (type of alkali metal atom M and and depending on the starting group Z), generally from 0 to 120°C, preferably at The temperature is soaring. For example, [M represents Li (lithium), 2 represents C1 (chlorine) and the reaction is carried out in penzol] the boiling temperature of penzol ( 80° C.) is advantageous.

Compound ■ can be prepared by known methods such as those well known to those skilled in the art regarding reactions of organometallic compounds. , the reaction according to variant f) with compound n can be carried out using a suitable solvent such as tetrahydro- 7 runs or in acetonitrile, optionally with base (where Y' represents the starting group). ) or without adding a base (if Y' represents a reactive group), as known to those skilled in the art. It is done by law. This reaction is performed in the case of asymmetric distribution of substituents R1, R2 and R3. For example, a mixture of isomers is provided, which is then subjected to a suitable separation method (e.g. chromatography). must be separated by (laffy).

Solvent decomposition according to variant g) is a method well known to those skilled in the art for water-containing or water-decomposing in a suitable alkaline or acidic solution at room temperature or the solvent used if desired. The process is carried out under heating up to the boiling temperature.

The alkylation according to process variant h), optionally after prior deprotonation, is well known to those skilled in the art. This is carried out in a known manner in a suitable inert solvent.

The compounds according to the invention are starting compounds which can optionally also be used in the form of their salts. Depending on the type and on the reaction conditions, first as such or in the form of its salts. Manufactured.

Additionally, the free compound can be removed in a suitable solvent such as a chlorinated hydrocarbon, i.e. methylene chloride. Low molecular weight aliphatic alcohols (ethanol, isopropyl alcohol) in ether (diisopropyl ether), ketone (acetone) or water. Salt is obtained by solving The water contains the desired acid or base or Add the desired acid or base, optionally in precisely calculated stoichiometric amounts.

Salts are obtained by filtration, dissolution and reprecipitation, precipitation or evaporation of the solvent.

The resulting salt can be alkalized or acidified, for example with aqueous sodium bicarbonate or dilute hydrochloric acid. It can be converted into a free compound by sexualization, and the same compound can be further converted into a salt. You can get it. In this way the compound can be purified or pharmacologically non-acceptable. salts can be converted into pharmacologically acceptable salts.

Sulfoxides according to the invention are optically active compounds. Types of substituents R1-R8 There may also be other centers of chirality in the molecule depending on the situation (e.g. if R5 is hydrogen). (if not). Therefore, the present invention relates to enantiomers and diastereomers and their It also includes mixtures and racemates. The enantiomers can be determined using known methods (e.g. the corresponding diazoles). (by the preparation and separation of teleomeric compounds). But also Enantiomers can be obtained by asymmetric synthesis, for example by converting the sulfide into optically pure tartaric acid. by enantioselective oxidation with, for example, t-butyl hydroperoxide. Therefore, I is, for example, a pure optically active compound or a pure diastereomer compound. It can also be produced by reacting substance ■ with compound ■. is, Fi, Andersen, Tetra-hedron Lett, , 98 (1962)].

The compounds according to the invention are prepared by reacting (1) and (2), optionally then producing t ; Synthesized by oxidizing sulfide ■.

Compound n, IV, %’l, I! and II li e.g. from wo86102646 It is publicly known. Compound (1) can be produced by various methods depending on the substitution example. example For example: 1, R6-1-6C-alkyl (3rd position), R7-1-6C-alkoxy (4th position) , R8-aryl-1-4C-alkoxy (5th position).

These compounds include, for example, the known 2-methyl-3-alkyl-4-alkoxypi Lysine or 2-methyl-3-alkyl-4-alkoxypyri that can be produced by known methods Starting from gin (see for example European Patent Application No. 0080602), N-oxidation (e.g. 30% hydrogen peroxide) and corresponding acetoxylation at the 5-position saponification (e.g. with acetic anhydride followed by caustic soda solution), 5-hydroxy groups alkylation of (e.g. aryl-1-4C-alkyl in dimethyl sulfoxide) - with promide and caustic soda solution), N-oxidation (e.g. with m-chlorperoxide), cybenzoic acid), 2-acetoxymethylpyridine (e.g. using hot acetic anhydride). ), saponification to form 2-hydroxymethyl groups (e.g. dilute caustic soda solution), saponification to form 2-hydroxymethyl groups (e.g. ) and the introduction of a leaving group Z/ (e.g. by reaction with thionyl chloride). Manufactured by

2, R6-hydrogen (3rd position), R7 and R8-1-6C-alcokyne and aryl Oxy or aryl-1-4C-alkoxy.

These compounds are derived from, for example, the known 5-hydroxy-2-methyl-pyridine. and alkylation of hydroxy groups (e.g. 1-60 in dimethyl sulfoxide). -alkyl iosito or aryl-1-4C-alkyl bromide and potassium hydroxide ), N-oxidation (e.g. 30% hydrogen peroxide), nitration at the 4-position (e.g. (e.g. using nitric acid), replacing the nitro group with a 1-6C-alkoxy group and an aryloxy group. or exchanged with an aryl-1-4C-alkoxy group (e.g. alkali-alkoxide or -by reacting with aryl oxide), 2-acetoxymethylbi Change to lysine (e.g. with hot acetic anhydride), forming a 2-hydroxymethyl group saponification (e.g. dilute caustic soda) and introduction of a leaving group Z' (e.g. thionichloride) produced by reaction with

3, R6-hydrogen (5th position), R7 and R8-1-6C-alkoxy and aryl Oxy or aryl-1-40-alkoxy.

A. These compounds include, for example, the well-known 3-hydroxy-2-methylpyridine Starting from ), N -1t& conversion (e.g. with 30% hydrogen peroxide), nitration at the 4-position (e.g. nitrification) (using acid), nitro group to aryloxy group, arylalkoxy group and alkoxy group. Exchange with xy group, change to 2-acetoxymethylpyridine (e.g. hot acetic anhydride), Saponification and introduction of leaving groups Z′ to form hydroxymethyl groups (e.g. thionichloride) It is produced by reaction with

B, the compound is advantageously alternatively known 3-hydroxy-2-methyl-4-pyro Alkylation of hydroxy groups (e.g. potassium carbonate in acetone) and alkyl iosites or arylalkyl bromides), the corresponding pyrones to pyridone (e.g. by reaction with aqueous ammonia), 4-chlorubi Chlorination to form lysine (e.g. with phosphorus oxytrichloride), N-11ation (e.g. with phosphorus oxytrichloride), 30% hydrogen peroxide), chlorine to alkoxy groups, aryloxy groups, and aryl groups. exchange with alkoxy groups (e.g. alkali alkoxide in dimethyl sulfoxide or - using aryl oxide), change to 2-acetoxymethylpyridine (e.g. (using hot acetic anhydride), saponification to form a hydroxymethyl group and leaving group Z' (e.g. by reaction with thionyl chloride). Also, N- Chlorine exchange can also be carried out before oxidation.

Whatever the reaction conditions (temperature It is within the expertise of the person skilled in the art to determine whether specific requirements (reaction times, solvents, etc.) are required. It is more well known. The detailed preparation of some representative compounds (1) is described in the examples. So The production of other representative compounds is carried out in a similar manner.

Compound 2) is new and is also the object of the present invention.

Compounds v1■ and χm can be prepared, for example, starting from compound m by methods known to those skilled in the art. Build.

Next, the present invention will be explained in detail with reference to examples, but these examples are not intended to limit the present invention. do not have.

BEST MODE FOR CARRYING OUT THE INVENTION H-N,3]-dioxolo(4,5-flbenzimidazole 2,2-diflu in 20+ m of ethanol (25 ml of 2 and 2N caustic soda solution) oro-5H-[1,3)-dioxolo[4,5-flbenzimidazole-6- In a solution of 0.929 thiol, 2-chloromethyl-5-benzyloxy-4-methyl Add 1.2 g of toxypyridinium chloride. The yellow reaction mixture was heated at 20°C for 1 hour. After stirring for 20 hours and adding 1OII+2 water, a colorless solid precipitated. Stir for a while, filter, wash with IN caustic soda solution and water and dry to constant weight. dry Recrystallize the amorphous powder from methylene chloride/diisopropyl ether . 1.7 g (93% of theory) of the title compound as a colorless crystal with a melting point of 171-72°C. Obtained in crystal form.

in the same way 6.6.7-trifluoro6.7-sihydro2-[(5-benzyloxy- 4-methoxy-2-pyridyl)methylthio]-1H-N,4]-dioxin [2,3-f]benzimidazole, 6-chloro-6,7,7-)lifluoro-6,7-sihydro-2-[(5-ben Zyloxy-4-methoxy-2-pyridyl)methylthio]-1H-[1,4] -Dioxine [2,3-f]benzimidazole, and 6.7-Sihydro-2-[(5-benzyloxy-4-methoxy-2-pyridyl ) Methylthio]-18-N,4]-dioxin [2,3-f]benzimida Zor too, 6.6.7-trifluoro6.7-sihydrolH-[1,4]-dioxy [2,3-f]benzimidazole-2-thiol, 6-chloro-6,7,7-trifluoro6,7-sihydroIH-[1,4] -Dioxine [2,3-f]benzimidazole-2-thiol and 6.7 -Sihydro IH-N, 4]-dioxin[2,,3-flbenzimidazole -2-thiol, 2-chloromethyl-5-benzyloxy-4-methoxypi Obtained by reaction with lysinium chloride.

2.2.2-difluoro-6-[(5-benzyloxy-4-methoxy-2-pi lysyl)methylsulfinyl]-5H-1,3]-dioxolo[4,5-f ]Benzimidazole 2,2-difluoro-〇-[(5-benzyloxy) in methylene chloride 4C)sQ -4-methoxy-2-pyridyl)methylthio]-5H-[1,31-dioxo A suspension of [4,5-f]benzimidazole cooled to -40°C was added with methane chloride. 21ml of a 0.1N solution of m-chloroperoxybenzoic acid in tyrene was added over 10 minutes. flow into the inside. Stir for a further 20 minutes and simultaneously raise the temperature to -20°C. Thylamine Q, 5IIIQ was added and the reaction mixture was treated with 5% sodium thiosulfate and charcoal. Inject into 40 tQ of a 5% solution of sodium chloride. Salt the aqueous phase two more times after phase separation. Extraction is carried out using 2C1+12 methylene chlorides each. The collected organic phase was dissolved in sodium thiosulfate. and 5IlIQ of sodium carbonate solution, dried and concentrated. Shrink. The residue is recrystallized from methylene chloride/diisopropyl ether. mark 0.60 g (63% of theory) of the title compound are obtained. Melting point 165-166℃ (min. solution).

Similarly, 6.6.7-)lifluoro-6,7-dihydro-2-[(5-ben Zyloxy-4-methoxy-2-pyridyl)methylsulfinyl]-1H-[1 ,4]-dioxin [2,3-fl-benzimidazole, 6-chloro-6,7,7-trifluoro6,7-sihydro-2-[(5-ben Zyloxy-4-methoxy-2-pyridyl)methylsulfinyl]-18-[ l,4]-dioxin [2,3-fl-benzimidazole and 6.7-Sihydro-2-[(5-benzyloxy-4-methoxy-2-pyridyl ) Methylsulfinyl 1-IH-[1,4]-dioxin [2,3-f] base Also, nzoimidazole As mentioned in Example 1, other sulfides can be oxidized with m-chloroperoxide benzoic acid. It is obtained by

5-diphenate dissolved in 11ml of 2N caustic soda and 13IIIa of ethanol. 2.16 g (l) fluoromethoxy-2-mercapto-IH-benzimidazole O + n mol), 4-benzyloxy-2-chloromethyl-3-methoxypi 2.85 g (9.5 mmol) of lysinium chloride was divided into 3 portions and stirred. and then heated to 60° C. for 3 hours. Circulate ethanol with water jet vacuum After distillation using a rotary evaporator, extraction was performed three times using 30+nQ methylene chloride each. Strain and collect; wash the organic phase three times with each 511 IQ of IN caustic soda solution and sulfuric acid solution. Dehydrate with magnesium and concentrate completely. Ethanol/water to remove yellow oily residue crystallizes from.

Similarly, 2-[(4-benzyloxy-3-methoxy-2-pyridyl)methyl thio]-5-chlorodifluoromethoxy-1H-benzimidazole, 2-[( 4-benzyloxy-3-methoxy-2-pyridyl)methylthio]-5-)rif fluoromethoxy-IH-benzimidazole, 2-[(4-benzyloxy-3-methoxy-2-pyridyl)methylthio]-5 , 6-bis(difluoromethoxy)-1H-benzimidazole, 2-[(4- benzyloxy-3-methoxy-2-pyridyl)methylthio]-5-difluoro Methoxy-6-methoxy-IH-benzimidazole and 2-[(4-benzyl oxy-3-methoxy-2-pyridyl)methylthio]-5-difluoromethoxy -6-Fluoro-IH-benzimidazole is also 5-chlorodifluoromethoxy -2-mercapto-IH-benzimidazole, 5-trifluoromethoxy-2 -Mercapto-IH-benzimidazole, 5,6-bis(difluoromethoxy) )-2-mercapto-IH-benzimidazole, 5-difluoromethoxy 2 -Mercapto-6-medoxy I H-benzimidazole and 5-difluoro Methoxy-6-fluoro-2-mercapto-IH-benzimidazole was reaction with 2-chloromethyl-3-methoxypyridinium chloride. (pyridyl)methylsulfinyl-5-difluorometho xy-IH-benzimidazole 2-[(4-benzyloxy-3-methoxy-2-pyri) in methylene chloride 6QmQ lysyl) methylthi-1-5-difluoromethoxy-IH-benzimidazole 1 m-chloroperoxybenzate in methylene chloride at -30°C to a solution of 33 g of 15 mc of a 0.2N solution of aromatic acid was added, and the mixture was stirred at the above temperature for an additional 3 days. bird After adding 0.3 m (l) of ethylamine, the cooled reaction mixture was diluted with 5% sodium thiosulfate. 10 ml (l) of sodium carbonate solution and 5% sodium carbonate solution IQmQ, stirred, After phase separation, extract 3 times with methylene chloride 30+mf2 and collect; Wash twice with 10% sodium thiosulfate solution, dehydrate, add dehydrating agent (sulfuric acid macerate) Gnesium) is filtered off and concentrated. The residue was condensed using diisopropyl ether. Crystallize and then recrystallize from methylene chloride/diimpropyl ether. Melting point 1 1.04y (76% of theory) of the title compound was obtained as a colorless solid at 02°C (decomposition). It will be done.

Similarly, 2-[(4-benzyloxy-3-methoxy-2-pyridyl)methyl sulfinyl]-5-') lorodifluoromethoxy-1)(-benzimidazole 2I(4-benzyloxy-3-methoxy-2-pyridyl)methylsulfini 1-5-trifluoromethoxy-IH-benzimidazole, 2-[(4-benzimidazole) methyloxy-3-methoxy-2-pyridyl)methylsulfinyl]-5,6- Bis(difluoromethoxy)-1H-benzimidazole, 2-[(4-benzimidazole) 3-methoxy-2-′pyridyl)methylsulfinyl]-5-dif fluoromethoxy-6-me]xyIH-benzimidazole and 2-[(4-benzyloxy-3-methoxy-2-pyridyl)methylsulfini 1-5-difluoromethoxy-6-fluoro-IH-benzimidazole is also an example. obtained by oxidizing another sulfide of 3 with m-chloroperoxybenzoic acid. It will be done.

-IH-benzimidazole-dihydrochloride By the procedure described in Example 3, 5-difluoromethoxy-2-mercapto-IH-benzimidazole 1.08 g (5111 mol) was added to 7 ml of ethanol with the addition of 6 ml of 2N caustic soda solution. 3-benzyloxy-2-chloromethyl-4-methoxypyridium in III2 2-[( 3-benzyloxy-4-methoxy-2-pyridyl)methylthi-1-5-diflu Oromethoxy-IH-benzimidazole is obtained as a yellow oil. This too was dissolved in methylene chloride, and 15 va mol of hydrochloric acid dissolved in ether was added. In addition, diisopropyl ether was used to convert the title compound into a colorless compound with a melting point of 148-50°C. precipitate in the form of crystals. Yield 2.059 (90% of theory).

Similarly, 2-[(3-benzyloxy-4-methoxy-2-pyridyl)methyl [ruthio]-5-chlorodifluoromethoxy-1) 1-benzimidazole, 2- [(3-benzyloxy-4-methoxy-2-pyridyl)methylthio]-5-t lifluoromethoxy-IH-benzimidazole, 2-[(3-benzyloxy-4-methoxy-2-pyridyl)methylthio]-5 , 6-bis(difluoromethoxy')-1H-benzimidazole, 2-[(3 -benzyloxy-4-methoxy-2-pyridyl)methylthi-1-5-difluoro lomethoxy-〇-methoxyIH-benzimidazole, 2-[(3-benzyl oxy-4-methoxy-2-pyridyl)methylthio]-5-difluoromethoxy -6-Fluoro-6-I H-benzimidazole, 2-[(3-benzylox cy-4-methoxy-2=pyridyl)methylthio]-5-(2,2,2-trif fluoroethoxy)-18-benzimidazole and 2-[(3-benzyloxy) cy-4-methoxy-2-pyridyl)methylthio]-5-(1,1,1,2-te (trafluoroethoxy)-1H-benzimidazole, 5-chlorodifluoromethoxy-2-mercapto-IH-benzimidazole, 5-trifluoromethoxy-2-mercapto-I H-penzimidazole, 5.6-Bis(difluorome I xy)-2-mercapto-IH-benzimida Zor, 5-difluoromethoxy-6-methoxy-2-mercaguto IH-benzimida Zor, 5-difluoromethoxy-6-fluoro-2-mercapto-IH-benzimida Zor, 5-(2,2,2-)lifluoroethoxy)-2-mercapto-IH-benzo imidazole and 5-(1,1,2,2-tetrafluoroethoxy)=2-mer Capto-IH-benzimidazole was converted into 3-benzyloxy-2-chloromethyl - Obtained by reaction with 4-methoxypyridinium chloride.

6.2-[(3-benzyloxy-4-methoxy-2-pyridyl)methylsulfur [inyl]-5-difluoromethoxy-IH-benzimidazole By the procedure described in Section 4, 2-[(3-benzi 4-methoxy-2-pyridyl)methylthio]-5-difluoromethoxy 0.88 g of C-IH-benzimidazole was dissolved in m- Oxidized with 2'1 mQ of 0,IN solution of chloroperoxybenzoic acid and diluted with methylene chloride/ After crystallization from diisopropyl ether the title compound yielded 0.709 (77% of theory) ) has a melting point of 121’C! Obtained as colorless crystals (decomposition).

Similarly, 2-[(3-benzyloxy-4-methoxy-2-pyridyl)methyl sulfinyl]-5-chlorodifluoromethoxy-IH-benzimidazole 2 -[(3-benzyloxy-4-methoxy-2-pyridyl)methylsulfinyl ]-5-trifluoromethoxy-IH-benzimidazole, 2-((3-benzimidazole) Zyloxy-4-methoxy-2-pyridyl)methylsulfinyl]-5,6- Bis(difluoromethoxy)-1H-benzimidazole, 2-[(3-benzimidazole) 4-methoxy-2-pyridyl)methylsulfinyl]-5-difluoro Lomethoxy-6-methoxy-IH-benzimidazole, 2-, [(3-benzimidazole) (4-methoxy-2-pyridyl)methylsulfinyl]-5-diflu Oromethoxy-6-fluoro-1H-benzimidazole, 2-[(3-benzimidazole) 2-4-methoxy-2-pyridyl)methylsulfinyl]-5-(2, 2,2-tri7fluoroethoxy)-1H-benzimidazole and 2-[(3-benzyloxy-4-methoxy-2-pyridyl)methylsulfini ]-5-(1,1,2,2-tetrafluoroethoxy)-1H-benzimi Dazol too By oxidizing another sulfide of Example 5 with m-chloroperoxybenzoic acid can get.

7.2-[(5-benzyloxy-4-methoxy-3-methyl-2-pyridyl) Methylthio-5-difluoromethoxy-IH-benzimidazole Described in Example 3 According to the working method, 5-difluoromethoxy-2-mercapto-IH-benzo Ethanol was added with 0.91 g of imidazole and 5.5 m12 of 2N caustic soda solution. 5-benzyloxy-2-chloromethyl-4- in 20 mQ of alcohol and 15 mQ of water. By reacting with 1.15 g of methoxy-3-methylpyridinium chloride. The title compound is obtained as a yellow oil. Methylene chloride/diisopropyl ether Crystallization from tel gave the title compound 1.539 (91% of theory), melting point 96. ~976 is obtained in the form of a colorless powder.

Similarly, 2-[(5-benzyloxy-4-methoxy-3-methyl-2-pyri methylthio]-5-chlorodifluoromethoxy-IH-benzimidazole le, 2-[(5-benzyloxy-4-methoxy-3-methyl-2-pyridyl)methy ruthio]-5-)lifluoromethoxy-IH-benzimidazole, 2-[(5 -benzyloxy-4-methoxy-3-methyl-2-pyridyl)methylthio]- 5,6-bis(difluoromethoxy)-1H-benzimidazole 2-t(5- benzyloxy-4-methoxy-3-methyl-2-pyridyl)methylthio]-5 -difluoromethoxy-6-methoxy-IH-benzimidazole, 2-[(5-benzyloxy-4-methoxy-3-methyl-2-pyridyl)methy [ruthio]-5-difluoromethoxy-6-fluoro-IH-benzimidazole , 2-[(5-benzyloxy-4-methoxy-3-methyl-2-pyridyl)methy [ruthio]-5-(2,2,2-trifluoroethoxy)-1H-benzimida Sol and 2-[(5-benzyloxy-4-methoxy-3-methyl-2-pyridyl)methy [ruthio]-5-(1,1,2,2-tetrafluoroethoxy)-1H-benzoy Midazole also 5-chlorodifluoromethoxy-2-mercapto-IH-benzimidazole, 5-trifluoromethoxy-2-mercapto-IH-benzimidazole, 5. 6-bis(difluoromethoxy)-2-mercapto-IH-benzimidazole , 5-difluoromethoxy-6-methoxy-2-mercapto-IH-benzimi Dazole, 5-difluoromethoxy-6-fluoro-2-mercapto-IH-be ndzimidazole, 5-(2,2,2-trifluoroethoxy)-2-mercap -IH-benzimidazole and 5-(1,1°2.2-tetrafluoroethane) xy)-2-mercapto-IH-benzimidazole, 5-benzyloxy-2-chloromethyl-4-methoxy-3-methylpyridinium Obtained by reaction with muchloride.

monomethyl-2-pyridyl)methylsulfinyl]-5-difluoromethoxy-I H-benzimidazole By the procedure described in Example 4, 20 vaQ of methylene chloride 2-['(5-benzyloxy-4-methoxy-3-methyl-2- pyridyl)methylthi-1-5-difluoromethoxy-IH-benzimidazole 0.9 g in 20 ml of a 0.1 N solution of m-chloroperoxybenzoic acid at -20°C. After oxidation with 2 and crystallization from diisopropyl ether, the title compound 0.69 (63% of theory) is obtained as a tan powder. Melting point 149-50℃ (decomposition) .

Similarly, 2-[(5-benzyloxy-4-methoxy-3-methyl-2-pyri methylsulfinyl]-5-chlorodifluoromethoxy-IH-benzoy midazole, 2-[(5-benzyloxy-4-methoxy-3-methyl-2-pyridyl)methy rusulfinyl]-5-trifluoromethoxy-IH-benzimidazole, 2-[(5-benzyloxy-4-methoxy-3-methyl-2-pyridyl)methane Tylsulfinyl]-5゜6-bis(difluoromethoxy)-1H-benzoy midazole, 2-[(5-benzyloxy-4-methoxy-3-methyl-2-pyridyl)methy Rusulfinyl]-5-difluoromethoxy-6-methoxy-IH-benzoy midazole, 2-[(5-benzyloxy-4-methoxy-3-methyl-2-pyridyl)methy Rusulfinyl]-5-difluoromethoxy-6-fluoro-IH-benzoy midazole, 2-[(5-benzyloxy-4-methoxy-3-methyl-2-pyridyl)methy Rusulfinyl]-5-(2,2,2-1-lifluoroethoxy)-1H-ben nzoimidazole and 2-[(5-benzyloxy-4-methoxy-3-methyl-2-pyridyl)methy Rusulfinyl]-5-(1,1,2,2-tetrafluoroethoxy)-1H -benzimidazole also By oxidizing another sulfide of Example 7 with m-chloroperoxybenzoic acid can get.

9.2-[(5-benzyloxy-4-methoxy-2=pyridyl)methylthio] -5-trifluoromethyl-LH-benzimidazole-dihydrochloride 2- Mercapto-5-trifluoromethyl-IH-benzimidazole 0.469 and and 5-benzyloxy-2-chloromethyl-4-methoxy-pyridinium chloride 0.6 g of the solution was heated to boiling under reflux in a 13 mfl inproper tool. beginning A solid precipitates from the clear solution. Cool after 5 hours under reflux and finally cool in a water bath. Cool, filter, stir with Improper Tools and dry to constant weight. Title 1.0 g (96% of theory) of the compound are obtained in the form of colorless crystals: melting point 103-8 5°C-pyridyl)methylsulfinyl-5-trifluoro Procedure described in Example 4 2-[(5-benzyloxy- 4-Methoxy-2-pyridyl)methylthio]-5-)lifluoromethyl-IH- Benzimidazole (2-[(5-benzyloxy-4-methoxy-2-pyridi) ) methylthio]-5-trifluoromethyl-IH-benzimidazole-di From 0.659 (1.24 mmol) of hydrochloride, caustic soda solution/methychloride Q, 2Hm in methylene chloride at -50°C. - oxidize 7 vaQ of chloroperoxybenzoic acid solution, methylene chloride/diisopropylene After recrystallization from pyl ether, 0.40 g (72% of theory) of the title compound is free. Obtained as a colored crystalline powder; melting point 139-40°C-pyridyl)methylthio-5 -methoxy-IH-benzimidazole-dihydrochloride Mercapto-5-meth in 20+ mQ of ethanol was prepared using the procedure described in Example 3. xy-IH-benzimidazole 0.409 and 5-benzyloxy-2-chloro From 0.60 g of lomethyl-4-methoxypyridinium chloride, 0.2N caustic solution Upon addition of the liquid 211118, an oily product is obtained. Dissolved in methylene chloride After that, methanolic hydrochloric acid was added, and a colorless solid was precipitated with diisopropyl ether. Ru. 0.7 g (70% of theory) of the title compound with a melting point of 160 DEG -64 DEG C. are obtained.

12.2-[(5-benzyloxy-4-methoxy-2-pyridyl)methylsulfate Finyl 1-5-methoxy-IH-benzimidazole According to the working method described in Example 4, 2- [(5-benzyloxy-4-methoxy-2-pyridyl)methylthi-1-5-methyl Toxi-IH-benzimidazole (dihydrochloride to caustic soda solution/chloride) m-chloroperoxybenzene perfume at -30°C. Oxidation with diisopropyl acid (5.5+ml of 0.2N solution in methylene chloride) After crystallization from ether, 0.389 (72% of theory) of the title compound, melting point 1 Obtained as a colorless powder at 65-66°C (decomposition).

a) 3-benzyloxy-2-hydroxymethyl-4-methoxypyridinium Chloride 5.619 was suspended in 100 mQ of methylene chloride and thionyl chloride 3.619 was suspended in 100 mQ of methylene chloride. 549 was added at 5° C. and stirred at the same temperature for 45 minutes, resulting in a clear yellow solution.

Add 40 mQ of Dorol, and remove methylene chloride and excess thionyl chloride with water. Distill with jet vacuum. The precipitate is collected by suction filtration, washed with Doolol, and weighed to a constant weight. Dry until dry. 5.20 g (theoretical value) of the title compound with a melting point of 133-34°C (decomposition) 87%) is obtained.

b) 3-benzyloxy-4-methoxy-2- in methylene chloride 50+nff A solution of 20.3 g of methylpyridine-1-oxide was heated to 80°C within 1 hour. Add water dropwise to 8Qi+12 acetic acid, add methylene chloride and after the reaction is complete, add excess acetic anhydride. Distilled again. Add 30 mQ of 6N caustic soda to the residue and stir at 80°C for 2 hours. After cooling, extraction was performed three times with methylene chloride of 100 IlIQ each, and the collected organic The phases are dried over potassium carbonate and concentrated by evaporation. Residue: 3-benzyloxy Si-2-hydroxymethyl-4-methoxypyridine is taken up in ether and the ether Precipitation is carried out with aqueous hydrochloric acid, and the precipitated solid is filtered off and dried to constant weight. melting point 3-benzyloxy-2-hydroxymethyl-4-methoxy at 165°C (decomposition) 14.7 g (87% of theory) of pyridinium chloride are obtained.

C) 3-benzyloxy-4-chloro-2-methane in methanol 120IIIQ Solution of 39.39 tylpyridine-1-oxide and 30% sodium trimetate 100 m4 of the solution was boiled under reflux for 24 hours, and the solvent was removed using a water jet vacuum. It was emptied, 400 ml of water was added to the residue and 400 ml of methylene chloride was added to each Perform four extractions using collected; the organic phase was dehydrated with magnesium sulfate; Completely evaporate and concentrate. 3-benzyloxy-4-methoxy-, melting point 86-88°C 32.2 g (85% of theory) of 2-methylpyridine-1-oxide are obtained.d ) 45 g of 3-benzyloxy-4-chloro-2-methylpyridine at 90°C. , 90 ml of 30% hydrogen peroxide in 200 ml of acetic acid with the addition of 0.1 ml of concentrated sulfuric acid Stir with 12 for 20 hours. Completely evaporated and concentrated at 103 pascals, each 30m Q of acetic acid is added twice and the peracid is removed by distillation. Next, remove the acetic acid residue with doluol. It is azeotropically distilled with 30 mQ and the residue is crystallized from diethyl ether. melting point 3-benzyloxy-4-chloro-2-methylpyridin-1-o at 82-84°C 41.39 (87% of theory) of oxide are obtained as a colorless solid.

e) Oxygenate 50g of 3-benzyloxy-2-methyl-4-pyridone at 50°C. Stir in 500 ml of phosphorus trichloride for 20 hours, remove excess reagent under vacuum at 40-50°C. The residue was dissolved in 250 ml of water-cooled 2N caustic soda solution until the pH was constant. Stir so that the temperature exceeds 9, extract 3 times with 200 mQ of dolol each, The combined organic phase was dehydrated with magnesium sulfate and the solvent was completely evaporated at 103 Pascals. remove, dissolve the residue in ether and precipitate the colorless solid using ethereal hydrochloric acid. let After filtration and drying, 3-benzyloxy-4- with a melting point of 150-51'O Chloro-2-methylpyridinium chloride (colorless crystals) 559 (88% of theoretical value) ) is obtained.

f) 3-hydroxy-2-methyl-4-pyrone 126.1g benzyl chloride 14 Dissolve 6g in 4.0Q of acetone, add 2.0g of potassium iodide, and grind. Add 228 g of potassium carbonate within 5 minutes and within 2 hours. Another 24 hours under reflux Stir, filter to remove inorganic salts and evaporate completely. 2 for yellow oily residue Add 400 m+2 of 5% aqueous ammonia solution and heat to 80°C.

Within 4 hours another 1400 ml of ammonia solution are added over 7 minutes with stirring. difference The mixture was further stirred at 80°C for 24 hours, cooled to 20°C, and then added with 700 mQ of methylene chloride. The organic phase was extracted three times using , acetic acid ethyl ester 2Q is added under stirring. The precipitated solid was collected by filtration and diluted with ethyl acetate. After washing with ester and drying, 3-benzyloxy-2-methyl-4-pyridone 164 g (70% of theory) are obtained; melting point 169-71'O0 B, 4-benzyloxy-2-chloromethyl-3-methoxypyridinium chloride de a) By the procedure described in example Aa), 4-benzyloxy-2-hydroxy Methyl-3-methoxypyridinium chloride 4.869 was dissolved in methylene chloride at +5°C. The title compound was reacted with 3 g of thionyl chloride in 50+ mct. 85%) is obtained as a colorless solid with a melting point of 117-118°C (decomposition).

b) 4-benzyloxy-3-methoxy- 2-methylpyridine-1-oxide 509 was first reacted with 104 g of acetic anhydride, Next, saponify with 6N caustic soda solution 74IlIQ, extract with methylene chloride, Removal of the solvent gives a yellow solid residue. Stir with heated diisopropyl ether 4-benzyloxy-2-hydroxymethyl-3-methoxy by stirring 37.2 g (75% of theory) of pyridine are obtained: yellowish brown, melting point 68-70°C. powder.

C) 80% sodium hydride (para. (in the fin) 11g of suspended S solution +:, benzyl alcohol Add 40.59 dropwise of 4-chloro-3-methoxy-2-methyl Add 32.49 g of tylpyridine-1-oxide over 5 minutes and stir at room temperature for 20 hours. Ru. After adding 400 II 112 of water, each using 20011 (l of methylene chloride) Extraction was carried out four times, and the collected organic phase was thoroughly washed with water and extracted with magnesium sulfate. It is dehydrated and the solvent is distilled off at 60° C. and 103 Pascals. 4-benzyloxy-3- 42 g of methoxy-2-methylpyridine-1-oxide was obtained as a brown oil. , which is further reacted directly as described under Bb).

d) 4-chloro-3-methoxy-2-methylpyridine 5 in acetic acid 1500+Q Add 1m12 of concentrated sulfuric acid to 17g, and add 1400+mi2 of 30% hydrogen peroxide at 75°C. is added dropwise within 2 hours and then stirred at 90° C. for a further 2 hours. with 100 pascals By thoroughly distilling off the solvent and distilling it three times by adding 250 degrees of acetic acid each time. Remove peracid. The acetic acid residue is then azeotropically distilled together with doluol, and the residue Crystallize from isopropyl ether. 4-chloro-3-methane with a melting point of 93-96°C 400 g (70% of theory) of toxy-2-methylpyridine-1-oxide were obtained. It will be done.

e) Oxygenation of 635 g of 3-methoxy-2-methyl-4-pyridone at 85°C. Stir with phosphorus trichloride 2.8a for 24 hours. Excess phosphorus oxytrichloride to 103% Distill thoroughly using a skull, add 3 kg of ice to the residue, and adjust the pH to 9.4 with caustic potash solution. Seal and extract several times with diisopropyl ether. Wash the collected organic phase with water , dried, thoroughly evaporated and the residue distilled over 10 Pascals. 4-chlor- 3-mei-xy-2-methylpyridine (boiling point 75-78°C/102 Pascal) 548 g (76% of theory) are obtained.

f) 900 g of 3-hydroxy-2-methyl-4-pyrone in 124 acetone , add 2 kg of crushed potassium carbide, and then heat and boil. dimethyl sulfate Add 576 Ω of chicken with stirring within 30 minutes and stir for a further 20 hours at reflux temperature. . After cooling to 20°C, 100 +++ l of concentrated ammonia solution! 1 at 20°C. Stir for an hour, filter to remove inorganic salts, concentrate completely (103 Pascals), and leave an oily residue. The distillate is taken up in concentrated ammonia solution 1a and heated to 80"C within 3 hours, and this temperature Stir at 100°C. After 15 hours, add another 200 mΩ of ammonia solution and continue for another 3 hours. Stir, thoroughly evaporate and crystallize the residue from 2 g of acetone. 3-Methoki Cy-2-methyl-4-pyridone 6419 (84% of theory) was converted into a yellow-brown crystalline substance ( (melting point 158-59°C).

a) Using the procedure described in Example Aa), 5-petroleum in methylene chloride 30+++Q 2.30 g of siloxy-2-hydroxymethyl-4-methoxypyridine was added to the salt The title compound with a melting point of 151-52°C (decomposition) was obtained by reacting with 1.30 mQ of thionyl chloride. 2.70 g (99% of theory) are obtained.

b) Using the procedure described in pI4b), first 5-pencyloxy-2-methylene 3.0 g of lu-4-methoxypyridine-1-oxide was reacted with 030 mQ of anhydrous vinegar. Then, it was saponified with 40mff of 2N caustic soda solution, and diisopropyl ether Crystallizes to give 5-benzyloxy-2-hydroxymethyl-4-methoxypyridine 2.69 (87% of theory) as a 'R brown crystalline powder with a melting point of 99-100°C. can get.

c) 3.49% of 5-benzyloxy-4-methoxy-2-methylpyridine was converted into salt 85% meta-chloroperoxybenzoic acid dissolved in 12100 mL of methoxybenzoic acid 0.59 and stirred at 20°C for 20 hours. water, sodium thiosulfate solution and Extraction is carried out with sodium carbonate solution, the combined organic phase is concentrated and acetone/diiso Crystallize from propyl ether. 5-benzyloxy-2-methyl-4-meth Yield of toxypyridine-1-oxide +2.79 (74% of theory); melting point 15 3-55°C; colorless crystalline powder.

d) 5-hydroxy-4-methoxy- in dimethyl sulfoxide 80111Q In a solution of 2.789% of 2-methylpyridine and 1.359% of potassium hydroxide, Add 2.809 g of Njiru and stir at 20° C. for 24 hours. Add 150ma of ice water, Acidified to pH 2 with hydrochloric acid and extracted twice with diethyl ether of 2011112 each. The aqueous phase was adjusted to pH 9 and diluted with 50+1112 methylene chloride. Extract twice. After removing the solvent and crystallizing from petroleum ether, 5-benzyl 3.1 g (68% of theory) of oxy-4-methoxy-2-methylpyridine were obtained. Colorless crystals with a melting point of 69-71°C.

a) As described in Example Aa); according to the working method, 5-benzyloxy-2-hydroxy Dimethyl-4-methoxy-3-methylpyridine 2.69 to methylene chloride 30 Melting point 155-56°C (decomposition) using 1.51 thionyl chloride in mQ; colorless crystals 2.99 (95% of theory) of the title compound are obtained.

b) As described in Example Ab; according to the working method, 5-benzyloxy-4-methoxy 9.8 g of C-2,3-dimethylpyridine-1-oxide was added to 100 ml of acetic anhydride. 2, then saponified with 2N caustic soda solution 75 + i12, and diluted with methylene chloride. After extraction and crystallization from doluol/petroleum ether, a 5-benzyloxy-2-hydroxymethyl-4-methoxy-3-methylpyridine 8.9 g (89% of theory) are obtained.

C) As described in Example Cc); according to the working method, 5-benzyloxy-4-methoxy 11.59 -2,3-dimethylpyridine in 200+11+2 methylene chloride Oxidation with 85% meta-chloroperoxybenzoic acid 8249 gave 5-benzyloxybenzoate. 10.3 g of cy-4-methoxy-2,3-dimethylpyridine-1-oxide (theoretical 84% of the value) is obtained as a pale yellow oil.

d) As described in example Cd); according to the working method, in 80 mQ of dimethyl sulfoxide 7.7 g of 5-hydroxy-4-methoxy-2,3-dimethylpyridine was hydroxylated. O-alkylation with 6.7 g of benzyl chloride with addition of 3.259 g of potassium 5-benzyloxy-4-methoxy-2,3-di with a melting point of 63-64°C 12.0 g (98% of theory) of methylpyridine was obtained as a colorless powder, represented by formula I. The compounds according to the present invention and their salts have important properties that make these compounds industrially applicable. It has important pharmacological properties. The compounds and salts have been shown to induce gastric acid secretion in warm-blooded animals. It also has excellent gastrointestinal and intestinal protective effects in warm-blooded animals. this stomach and enteroprotective effects were already partially observed at doses below the acid secretion suppressing dose. It will be done. Furthermore, the compounds according to the invention have no significant side effects and a wide therapeutic range. Excellent by being good. Another important aspect of the invention is that the compound of formula I is in each case With high chemical stability and remarkable maximum effectiveness in the desired pH range of be.

In this context, "stomach and intestinal protection" refers to protection against gastrointestinal diseases, especially those caused by microorganisms, bacterial toxins, and drugs. (e.g. anti-inflammatory agents and rheumatism agents), drugs (e.g. ethanol), gastric acid or Inflammatory gastrointestinal diseases and lesions (e.g. gastric ulcers, refers to the prevention and treatment of intestinal ulcers, gastritis, hyperacidity, or gastric irritation caused by drug poisoning. .

The compounds according to the invention differ from the compounds known from the prior art in terms of their outstanding properties. It was also found that the performance was clearly superior. Compounds according to the invention and their pharmacological properties Tolerable salts are suitable for use in human and veterinary medicine due to their properties. , especially for the treatment and prevention of gastrointestinal disorders and diseases based on increased gastric acid secretion. used. The high storage stability of the compounds according to the invention makes these compounds pharmaceutically Enables easy use as a formulation.

Another subject of the invention is the use of the invention in the treatment and prevention of the above-mentioned diseases. It is a compound based on

Further, the present invention provides a method for producing a drug used for the treatment and prevention of the above-mentioned diseases. Also included is the use of compounds according to the invention.

Another subject of the invention is one or more of the compounds according to the invention of formula I and/or A drug containing a pharmacologically acceptable salt thereof.

The above drugs are manufactured by known methods well known to those skilled in the art. Pharmacological action according to the present invention The compound for use (-active substance) can be used as a drug as is or advantageously in tablets, sugar-coated Pills, capsules, herbal medicines, salves (e.g. as TTS), emulsions, suspensions or When used in combination with suitable pharmaceutical auxiliaries in the form of solutions, the active substance content is preferably 0. It is 1 to 95%.

The person skilled in the art will know what kind of auxiliaries are suitable for the desired formulation. It is better known than knowledge. Solvents, gel-forming agents, crude drug raw materials, tablet auxiliaries and other functions In addition to substance carriers, e.g. antioxidants, dispersants, emulsifiers, antifoaming agents, taste correctors agents, preservatives, solubilizers, colorants or especially permeation enhancers and complexing agents (e.g. cyclo dextrin) can also be used.

The agents can be applied orally, parenterally or subcutaneously.

Generally, in human medicine, active substances, when administered orally, are used to achieve the desired effect. l; daily dose of about 0.05 to about 50 my/hg (body weight), advantageously 0.25 ~20me/9, especially 0.5~l10ll1/kg, sometimes several times It has turned out to be advantageous to administer it, preferably in the form of 1 to 4 doses. Parenteral treatment similar doses and (particularly in the case of intravenous administration of the active substance) Lower doses can be used. The optimal dose and application of the active substance in each case Usage is readily determined by those skilled in the art based on their expertise.

intending to use the compounds according to the invention and/or their salts for the treatment of said diseases; In cases where pharmaceutical preparations are e.g. aluminum hydroxide, magnesium aluminate; tranquilizers i.e. ben Zodiazepines such as diazepam; sedatives such as vietamiverine, camylofin; Cholinergic inhibitors such as oxy-7-encilimine, phencarbamide; local anesthetics such as tetracaine, chlorine; in some cases enzymes, vitamins or amino acids It may contain more than one species.

In this regard, it is particularly important to strengthen the main effect in an additive or superadditive sense and/or to produce side effects. a compound according to the invention and another acid secretion suppressant drug for the purpose of eliminating or reducing the effects of , for example in combination with H2-blockers (e.g. cimetidine, ranitidine), also the so-called with peripheral cholinergic inhibitors (e.g. pirenzepine, telenzepine, zolenzepine) Combinations and combinations with gastrin antagonists may be mentioned.

The pharmacological properties of the compounds according to the invention are demonstrated by various animal experimental models. be able to. Examples of prepared 5hay-Ratte For example, 2-[(3-benzyloxy-4-methoxy-2-pyridyl)methylsulf (inyl)-5-difluoromethoxy-IH-benzimidazole 30 u mo After administration of 1/kg (i, d,), 91% inhibition of lesion index and 8% inhibition of gastric acid secretion were observed. 0% inhibition is observed.

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Claims (10)

[Claims] 1. Formula I: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R1, R2 and R3 are benzoyl It may be located at any position of the benzo moiety of midazole, and R1 is hydrogen, halogen, Trifluoromethyl, 1-6C-alkyl, 1-6C-alkoxy, 1-4C- Alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy cy, phenyl, phenoxy, phenoxy-1-4C-alkyl, phenoxy-1 -4C-alkoxy, phen-1-4C-alkyl or phen-1-4C-alkyl represents koxi, R2 is hydrogen, 1-6C-alkyl, 1-6C-alkoxy, wholly or mainly 1-4C-alkoxy, chlorodifluoromethoxy substituted by fluorine, 2-chloro-1,1,2-trifluoroethoxy or optionally with R3 1-2C-alkylenedioxy or carbon substituted with or partially with fluorine represents lolotrifluoroethylenedioxy, R3 is hydrogen, 1-6C-alkyl, 1-4C-alkoxy, wholly or mainly 1-4C-alkoxy, chlorodifluoromethoxy substituted by fluorine, 2-chloro-1,1,2-trifluoroethoxy or optionally with R2 1-2C-alkylenedioxy or carbon substituted with or partially with fluorine represents lolotrifluoroethylenedioxy, R4 represents hydrogen or a group that can be easily eliminated under physiological conditions; R5 represents hydrogen or 1-6C-alkyl, R6 represents hydrogen or 1-6C-alkyl R7 represents 1-6C-alkoxy, 2-5C-alkyleneoxy, 2- 5C-alkynyloxy, 1-4C-alkoxy-1-4C-alkoxy, ali represents aryloxy or aryl-1-4C-alkoxy, R8 represents aryloxy or aryl-1-4C-alkoxy; Reels are formulas: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ represents a ring represented by, in which R9 and R10 are the same or different, and hydrogen (H), 1-4C-alkyl, 1-4C-alkoxy, halogen, nitro, hydro represents roxy or trifluoromethyl, n represents a number of 0 or 1] and salts of these compounds. 2. In formula I, R1 represents hydrogen, trifluoromethyl or methoxy, R2, R3, R4 and R5 represent hydrogen, R6 represents hydrogen or methyl, R7 represents methoxy; R8 represents benzyloxy, n represents the number 0 or 1 Compounds according to claim 1 and salts of these compounds. 3. In formula I, R1 represents hydrogen; R2 and R3 together represent ethylenedioxy or methylenedioxy, R4 represents hydrogen; R5 represents hydrogen; R6 represents hydrogen or methyl, R7 represents benzyloxy, n represents the number 0 or 1 Compounds according to claim 1 and salts of these compounds. 4. Formula Ia: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(Ia) [In the formula, R1 represents hydrogen, R2 represents hydrogen or difluoromethylenedioxy together with R3, R3 represents difluoromethoxy or together with R2 represents difluoromethylenedioxy death, R4 represents hydrogen; R5 represents hydrogen; R6 represents hydrogen or methyl, R7 represents methoxy; R8 represents benzyloxy, n represents 0 or 1] and salts of these compounds. 5. Formula Ib: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(Ib) [In the formula, R1 represents hydrogen, R2 represents hydrogen or difluoromethylenedioxy together with R3, R3 represents difluoromethoxy or together with R2 represents difluoromethylenedioxy death, R4 represents hydrogen; R5 represents hydrogen; R6 represents hydrogen or methyl, R7 represents methoxy; R8 represents benzyloxy, n represents a number of 0 or 1] and salts of these compounds. 6. Formula Ic: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(Ic) [In the formula, R1 represents hydrogen, R2 represents hydrogen or difluoromethylenedioxy together with R3, R3 represents difluoromethoxy or together with R2 represents difluoromethylenedioxy death, R4 represents hydrogen; R5 represents hydrogen; R6 represents hydrogen or methyl, R7 represents methoxy; R8 represents benzyloxy, n represents a number of 0 or 1] and salts of these compounds. 7. Formula Id: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(Id) [In the formula, R1 represents hydrogen, R2 represents hydrogen or difluoromethylenedioxy together with R3, R2 represents hydrogen or difluoromethylenedioxy together with R3, R3 represents difluoromethoxy or together with R2 represents difluoromethylenedioxy death, R4 represents hydrogen; R5 represents hydrogen; R6 represents hydrogen or methyl, R7 represents methoxy; R8 represents benzyloxy, n represents a number of 0 or 1] and salts of these compounds. 8. R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and n are In preparing a compound of formula I as defined in claim 1, a ) reacting a mercaptobenzimidazole of formula II with a picoline derivative III: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II)▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) or b) Reacting a benzimidazole of formula IV with mercaptopicolin V: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV)▲There are mathematical formulas, chemical formulas, tables, etc.▼ (V) or c) reacting an O-phenylenediamine of formula VI with a formic acid derivative VII: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(VI)▲There are mathematical formulas, chemical formulas, tables, etc.▼ (VII) (if the desired end product is a compound of formula I in which n=1) Next, the 2-benzimide of formula III obtained by a), b) or c) Dazole-2-pyridylmethyl-sulfide (compound of formula I representing n=0): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Oxidize (VIII) and/or if desired change to salt, or d) reacting a benzimidazole of formula IX with a pyridine derivative: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IX)▲There are mathematical formulas, chemical formulas, tables, etc.▼ (X) or e) reacting a sulfinyl derivative of formula XI with a 2-picoline derivative XII: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(XI)▲There are mathematical formulas, chemical formulas, tables, etc.▼ (XII) if desired then converted to salt, or f) - The process product to be produced is such that in formula I R4 is easily eliminated under physiological conditions. In the case of compounds representing a releasable group, compounds of formula I in which -R4 represents hydrogen; , formula R4'-Y' (XIII) [wherein R4' can be easily eliminated under physiological conditions] or a precursor of said group together with Y'. then change to salt if desired, or g) - the process product to be produced is a compound of formula I in which R4 represents hydrogen; In some cases, compounds of the formula I in which -R4 represents a group which is readily removable under physiological conditions; , solvent decomposition and converting the resulting product into a salt if desired, or h) - The process product to be prepared is of formula I in which R5 represents 1-6C-alkyl. In the case of compounds of formula I in which R5 represents hydrogen, compounds of formula R5-Y'' (X IV) Alkylation with a compound [wherein R5 represents 1-6C-alkyl] and then salt if desired [In this case, Y, Y'', Z, Z' and Z'' represent the starting group, and Y' is the starting group or Represents a reactive group, M represents an alkali metal atom (Li, Na or K), M' represents equivalent metal atoms, R1, R2, R3, R4, R5, R6, R7, R8 , R9, R10 and n (unless otherwise stated) are as described in claim 1. A method for producing the compound according to claim 1, characterized in that: 9. One or more compounds described in any one or more of claims 1 to 7 and/or a drug containing a pharmacologically acceptable salt thereof. 10. Treatment and/or treatment of gastric and/or intestinal diseases and diseases such as those based on increased gastric acid secretion. or any one or number of claims 1 to 7 for application in prevention. Compounds described in Section.