JPH04139172A - Alpha-sulfinyl-substituted acetamide derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [R<1> to R<4> are H, lower alkyl, lower alkoxy, OH, amino, etc.; R<5> is H, lower alkyl or aryl; R<6> is lower alkyl, aryl, etc.; A is O, S or NR<7> (R<7> is H or lower alkyl)] and a salt thereof. EXAMPLE:alpha-Benzoimidazolylsulfinyl-p-methoxyphenylacetamide. USE:A medicine for gastrointestine having excellently inhibitory action on secretion of acid in the stomach, antiulcer action with low toxicity. PREPARATION:An acetic acid active derivative shown by formula II (X and Y are eliminable group such as halogen or arylsulfonyloxy) is made to react with an amine compound to give acetamide derivative. Then, this derivative is allowed to react with a mercaptan derivative to give a sulfide compound shown by formula III, which is oxidized with an oxidizing agent (e.g. hydrogen peroxide) to give a compound shown by formula I.

Description

[Detailed description of the invention] 【the purpose】 [Industrial application field]

The present invention relates to novel α-sulfinyl-substituted acetamide derivatives or salts thereof, and synthetic intermediates thereof, which have excellent gastric acid secretion suppressing effects and antiulcer effects.

[Conventional technology]

2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl 1-5-methoxy-(IH)-
Benzimidazole (omebrazole) [Unexamined Japanese Patent Application Publication No. 1989-
141783] is an enzyme involved in the final stages of gastric acid secretion, H'', K''-adenosine triphosphatase (hereinafter referred to as H'', K''-ATPa).
It is abbreviated as ge. ), it suppresses gastric acid secretion and is known to be clinically effective as an anti-ulcer agent.

[Problem to be solved by the invention]

The present inventors have conducted extensive research over many years on the synthesis of α-sulfinyl-substituted acetamide derivatives and their pharmacological activities. As a result, the present inventors have found that the compound fl of the present invention has a stronger H" , K”-A
The present invention was completed based on the discovery that it has TPase enzyme inhibitory activity and is an excellent drug.

【composition】

The novel amide derivative of the present invention has the general formula sulfinyl-substituted aceto [wherein R', R'', R' and R4 are the same or different and are selected from a hydrogen atom or the following substituent group A] R″ represents a hydrogen atom, a lower alkyl group, or an aryl group, R6 represents a lower alkyl group, an aryl group, or the following substituent group A
an aryl group substituted with 1 to 3 groups selected from;
An aralkyl group, an aralkyl group substituted with 1 to 3 groups selected from the following substituent group A, a heteroaryl group, or a beteroaryl group substituted with 1 to 3 groups selected from the following substituent group A A represents an oxygen atom, a sulfur atom, or a group represented by the formula NR' (wherein R7 represents a hydrogen atom or a lower alkyl group). 1 and is a synthetic intermediate thereof, the compound has the general formula [wherein R', R'', R3 and R4 are the same or different, a hydrogen atom or a group selected from the following substituent group A] , R' represents a hydrogen atom, a lower alkyl group, or an aryl group, R6 represents a lower alkyl group, an aryl group, or the following substituent group A
an aryl group substituted with 1 to 3 groups selected from;
an aralkyl group, an aralkyl group substituted with 1 to 3 groups selected from the following substituent group A, a heteroaryl group, or a heteroaryl group substituted with 1 to 3 groups selected from the following substituent group A; A represents an oxygen atom, a sulfur atom, or a group represented by the formula NR' (wherein R? represents a hydrogen atom or a lower alkyl group). ] It has. "Substituent Group A" Lower alkyl group, lower alkoxy group, hydroxyl group, protected hydroxyl group, amino group, substituted amino group, protected amino group, mercapto group, protected mercapto group, halogen atom, and aralkyl group In the above formula fl, the "lower alkyl group" in the definitions of R1, R8, R7 and substituent group A is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, S-butyl, t- Butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl,
3,3-dimethylbutyl, 2,2-dimethylbutyl, 1
．． 1-dimethylbutyl, 1.2-dimethylbutyl, 1.
3-dimethylbutyl 52,3-Dimethylbutyl represents a straight or branched alkyl group having 1 to 6 carbon atoms,
Preferably, it is an alkyl group having 1 to 4 carbon atoms. "Aryl group" and R" in the definition of R5 and R6
In the definition of "aryl group substituted with 1 to 3 groups selected from the following substituent group A", the "aryl group" refers to a group having 5 to 1 carbon atoms, such as phenyl and naphthyl.
Mention may be made of four aromatic hydrocarbon groups, preferably phenyl. "aralkyl group" in the definition of R6, "aralkyl group" in "aralkyl group substituted with 1 to 3 groups selected from substituent group A below" and "aralkyl group" in the definition of substituent group A refers to a group in which the above "aryl" is bonded to the above "lower alkyl group", such as benzyl, naphthylmethyl, diphenylmethyl, triphenylmethyl, ■-phenethyl, 2-phenethyl, ■-naphthylethyl, 2-naphthyl. ethyl, l-phenylpropyl,
2-phenylpropyl, 3-phenylpropyl, ■-naphthylpropyl, 2-naphthylpropyl, 3-naphthylpropyl, ■-phenylbutyl, 2-phenylbutyl,
3-phenylbutyl, 4-phenylbutyl, 1-naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl,
4-naphthylbutyl, ■-phenylpentyl, 2-phenylpentyl, 3-phenylbutyl, 4-phenylpentyl, 5-phenylpentyl, 1-naphthylpentyl,
2-naphthylpentyl, 3-naphthylpentyl, 4-naphthylpentyl, 5-naphthylpentyl, ■-phenylhexyl, 2-phenylhexyl, 3-phenylhexyl, 4-phenylhexyl, 5-phenylhexyl, 6
-phenylhexyl, 1-naphthylhexyl, 2-naphthylhexyl, 3-naphthylhexyl, 4-naphthylhexyl, 5-naphthylhexyl, 6-naphthylhexyl; 1 to 4 1-aralkyl group. In the definition of R6, the "heteroaryl group" of "heteroaryl group" and "heteroaryl group substituted with 1 to 3 groups selected from the following substituent group A" means a sulfur atom, an oxygen atom, or/ and a 5- to 7-ring aromatic heterocyclic group containing 1 to 3 nitrogen atoms, such as furyl, thienyl, pyrazolyl, imidazolyl, oxasilyl, isoxazolyl, thiazolyl, inthiazolyl, 1,2.
3-oxadiazolyl, triazolyl, tetrazolyl,
A 5- to 7-membered aromatic heterocyclic group which can include thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl, and preferably contains at least one nitrogen atom and may contain an oxygen atom or a sulfur atom. 1.2.3
- oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, more preferably,
They are a pyridyl group and a thiazolyl group. In the definition of substituent group A, the "lower alkoxy group" refers to a group in which the above-mentioned "lower alkyl group" is bonded to an oxygen atom, such as methoxy, ethoxy, rhopropoxy, impropoxy, n-butoxy, isobutoxy, S-butoxy, t-butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, rhohexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy,
1 to 6 carbon atoms such as 2.2-dimethylbutoxy, 1.1-dimethylbutoxy, 1.2-dimethylbutoxy, 1.3-dimethylbutoxy, 2.3-dimethylbutoxy
straight-chain or branched-chain alkoxy groups, preferably straight-chain or branched-chain alkoxy groups having 1 to 4 carbon atoms. In the definition of substituent group A, "protected hydroxyl group"
"Protecting group" refers to a protecting group in a reaction and a protecting group for prodrug formation when administered to a living body, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, Lauroil, myristoil,
Alkylcarbonyl groups such as tridecanoyl, balmitoyl, stearoyl, halogenated alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, lower alkoxyalkylcarbonyl groups such as methoxyacetyl, fE
Aliphatic acyl groups such as unsaturated alkylcarbonyl groups such as i2-methyl-2-butenoyl; arylcarbonyl groups such as benzoyl, α-naphthoyl, B-naphthoyl, 2-bromobenzoyl, 4-chlorobenzoyl, etc. halogenated arylcarbonyl group, 2,4.6-
Lower alkylated arylcarbonyl groups such as trimethylbenzoyl, 4-toluoyl, lower alkoxylated arylcarbonyl groups such as 4-anisoyl, ditrolated arylcarbonyl groups such as 4-nitrobenzoyl, 2-nitrobenzoyl, 2 - Aromatic acyl groups such as lower alkoxycarbonylated arylcarbonyl groups such as (methoxycarbonyl)benzoyl, arylated arylcarbonyl groups such as 4-phenylbenzoyl: tetrahydrobilan-2-yl, 3-bromotetrahydrobilane-2 -yl, 4-methoxytetrahydrobilane-4-
tetrahydropyranyl or tetrahydrothiopyranyl groups such as yl, tetrahydrothiobilan-2-yl, 4-methoxytetrahydrothiobilan-4-yl; tetrahydrofuran-2-yl, tetrahydrothiofuran-2
Tetrahydrofuranyl or tetrahydrothiofuranyl groups such as -yl; tri-lower alkylsilyl groups such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl , diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, phenyldiisopropylsilyl, and other silyl groups such as trilower alkylsilyl groups substituted with 1 or 2 aryl groups: methoxymethyl, 1,1-dimethyl- Lower alkoxymethyl groups such as 1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl, lower alkoxylated lower alkoxymethyl groups such as 2-methoxyethoxymethyl, 2,2.2 -trichloroethoxymethyl, bis(2-
Alkoxymethyl groups such as halogenated lower alkoxymethyl such as chloroethoxy)methyl: lower alkoxylated ethyl groups such as 1-ethoxyethyl, l(isopropoxy)ethyl, halogens such as 2.2.2-trichloroethyl Substituted ethyl groups such as arylzelenenylated ethyl groups such as ethyl group, 2-(phenylzelenenyl)ethyl; benzyl, α-naphthylmethyl, B-naphthylmethyl, diphenylmethyl, triphenylmethyl, α- Naphthyldiphenylmethyl, lower alkyl substituted with 1 to 3 aryl groups such as 9-anthrylmethyl, 4-methylbenzyl, 2,4.6-)-limethylbenzyl, 3.4.5- Trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2
- lower alkyl, lower alkoxy, nitro, halogen, cyano groups such as nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, bis(2-nitrophenyl)methyl, biperonyl; Aralkyl groups such as lower alkyl groups substituted with 1 to 3 aryl groups in which the aryl ring is substituted; lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl, 2,2゜Alkoxycarbonyl groups such as lower alkoxycarbonyl groups substituted with halogen or tri-lower alkylsilyl groups such as 2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl; alkenyloxycarbonyl groups such as vinyloxycarbonyl and allyloxycarbonyl ; Benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,
2-Nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, etc. Protecting groups and pyroyl groups in reactions such as aralkyloxycarbonyl groups whose aryl ring may be substituted with 1 to 2 lower alkoxy or nitro groups; Examples include protecting groups that are easily hydrolyzed in vivo for prodrugs when administered to living organisms, such as baloyloxymethyloxycarbonyl, and preferred are aliphatic acyl groups and aromatic acyl groups. Furthermore, it is preferably an aliphatic acyl group. In the definition of substituent group A, the "substituted amine group" refers to a group in which one or two of the following substituents are substituted for an amino group, and examples of the substituent include the above-mentioned "lower alkyl group". "group": the above "lower alkoxy group", a lower alkoxylated lower alkoxy group such as 2-methoxyethoxy,
2.2. Alkyloxy groups such as halogenated lower alkoxy groups such as 2-trichloroethoxy; benzyloxy, phenethyloxy, 3-phenylpropoxy, α-naphthyl, methoxy, β-naphthylmethoxy, diphenylmethoxy, triphenylmethoxy , α-naphthyldiphenylmethoxy, lower alkoxy group substituted with 1 to 3 aryl groups such as 9-anthrylmethoxy, 4-
Methylbenzyloxy, 2,4.6-trimethylbenzyloxy, 3,4.5-trimethylbenzyloxy, 4
~Methoxybenzyloxy, 4-methoxyphenyldiphenylmethoxy, 2-nitrobenzyloxy, 4-nitrobenzyloxy, 4-chlorobenzyloxy, 4-bromobenzyloxy, 4-cyanobenzyloxy, 4-
Lower alkyl such as cyanobenzyldiphenylmethoxy, bis(2-nitrophenyl)methoxy, biperonyloxy, lower alkoxy, lower alkoxy substituted with 1 to 3 aryl groups whose allyl ring is substituted with nitro, halogen, or cyan group. Aralkyloxy groups such as groups: hydroxyl group; hydroxy-substituted lower alkyl groups such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl: amino-substituted alkyl groups such as 2-aminoethyl, 3-aminopropyl, or phenyl, 4 -Tolyl, 4-methoxyphenyl, 4-chlorophenyl, α or β-
Examples include lower alkyl groups such as naphthyl, lower alkoxy, and aryl groups optionally substituted with halogen, preferably lower alkyl groups and aryl groups optionally substituted with lower alkyl, lower alkoxy, and halogen. More preferably, it is a lower alkyl group. In the definition of substituent group A, "protected amino group" refers to a group in which one or two of the following protecting groups protect an amino group, and the protecting group usually includes a protecting group for an amino group. Although there is no limitation as long as it is used as, for example, the above "aliphatic acyl group"; the above "aromatic acyl group": the above "alkoxycarbonyl group": the above "alkenyloxycarbonyl group";"Aralkyloxycarbonylgroup": The above-mentioned "silyl group" and the above-mentioned "aralkyl group" can be mentioned, and more preferably an aliphatic acyl group, an aromatic acyl group, and a silyl group. In the definition of substituent group A, the "protecting group" of the "protected mercapto group" is not limited as long as it is normally used for the protection of mercapto, but preferably the "aliphatic acyl group" mentioned above is used. and the above-mentioned "aromatic acyl group." In the definition of substituent group A, the "halogen atom" refers to fluorine, chlorine, bromine or iodine. Compound (I) of the present invention can be made into a salt, and such salts are preferably salts such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide. Inorganic acid salts such as hydrohalides, nitrates, perchlorates, sulfates, and phosphates; lower alkyl sulfonates such as methanesulfonates, trifluoromethanesulfonates, and ethanesulfonates; benzene; sulfonates, arylsulfonates such as p-t-luenesulfonates, fumarates,
Mention may be made of organic acid salts such as succinate, citrate, tartrate, oxalate, maleate, and amino acid salts such as glutamate and aspartate. The compound (I) of the present invention has an asymmetric carbon in the branch, and stereoisomers exist in which each has R coordination and S coordination, but
Each of them or a mixture thereof is included in the present invention. In the compound +I+ of the present invention, suitable compounds include (1) R', R'', R'' and R4 are the same or different, a hydrogen atom, a lower alkyl group, a lower alkoxy group,
Compounds that are protected hydroxyl group, protected amino group or halogen atom +2) R', R", R" and R4 are the same or different, hydrogen atom, alkyl group having 1 to 3 carbon atoms, carbon Number 1 to 3 alkoxy groups, aliphatic acyloxy groups,
Compounds R2 and/or R3, which are aliphatic acylamino groups or halogen atoms, are the same or different, and compounds R2 and/or R3, which are lower alkoxy groups, are the same or different, and are alkoxy groups having 1 to 3 carbon atoms. The compound R' is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and the compound R' is a lower alkyl group, an aryl group, or the following substituent group. A
an aryl group substituted with 1 to 3 groups selected from;
Compound R6, which is an aralkyl group, an aralkyl group substituted with 1 to 3 groups selected from the following substituent group A, or a heteroaryl group, is an aryl group, an aralkyl group substituted with 1 to 3 groups selected from the following substituent group A, Compound (9) R', which is an aryl group substituted with 1 to 3 substituted aryl groups, an aralkyl group, or an aralkyl group substituted with 1 to 3 groups selected from the following substituent group A, is a group selected from the following substituent group A. Compounds that are an aryl group substituted with 1 to 3 groups, an aralkyl group substituted with 1 to 3 groups selected from the substituent group A below (101R' is a lower alkyl group, an aryl group, a substituent group below) A compound that is an aryl group or an aralkyl group substituted with 1 to 3 groups selected from A'', an aralkyl group or a heteroaryl group substituted with 1 to 3 groups selected from the following substituent group A'' ( 11) R' is an aryl group, an aryl group substituted with 1 to 3 groups selected from the following substituent group A°, an aralkyl group, 1 to 3 groups selected from the following substituent group A° Compounds that are substituted aralkyl groups + 12) R' is an aryl group substituted with 1 to 3 groups selected from the following substituent group A' or the following substituent group A'
Compound (13) which is an aralkyl group substituted with 1 to 3 groups selected from ° Compound (14) A where R' is aryl or aralkyl substituted with 1 to 3 lower alkoxy groups or halogen atoms is a sulfur atom or a group represented by the formula NR' (in the formula, R7 represents a hydrogen atom or a lower alkyl group) A is a sulfur atom or a group represented by the formula NR' (15) (wherein R7 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms) f161 A compound where A is a sulfur atom or a group represented by the formula NH A" Lower alkyl group, lower alkoxy group, hydroxyl group, protected hydroxyl group, amino group, substituted amino group, protected amino group, mercapto group, protected mercapto group, halogen atom and aralkyl group "Substituent group A' J Lower alkyl group, lower alkoxy group, and halogen atom Representative compounds of the present invention include, for example, the compounds listed in Table 1, but the present invention is limited to these compounds. In the table, ph is phenyl group, Bz is benzyl group, Py
(Py-3- represents a group bonded at the 3-position of a pyridyl group) represents a pyridyl group. Exemplary compound 4-C1,0Ph-4- to H-OBZ-4-C,HmOPh-4-(:JsOBz-4-CH,OPh-4-CHsOBz-4-C-HmOPh-4 -CJsOBz- 4-CH,QPh- 4-CHsOBz- 4-CJsOPh- 4-CIHIOBZ- 4-CH,OPh- Exemplary compound H4-CH,0Bz- H4-C,H,0Ph- CHs 4-CJsOBz C,HI 4-CHlOPh- CHx 3,4,5triCH,0Ph-CH□ 4
-CtH,0Ph- CJs 4-CxHsOBz- C,H,4-CH,0Ph- CH,4-CH,0Bz- CtHs 4-C□H,0Ph- CJt 4-CJiOBz- CH,4-(:H, 0Ph CJs 4-(:HzOBz- CtL 4-Coh,0Ph- CH34-CJsOBz C,H,4-CH,0Ph- CIHT 4-CHJBz H4-FPh- H4-CIPh- H2,3-diFPh- H3, 4-diFPh- H3,5-diFPh- H' 2.3-diCIPh- H3,4-diCIPh- H3,5-diGIPh- Exemplary compound 2.3.4-triFPh-0 3,4,5-triFPh-S 2,3.4-triCIPh-S 3,4.5-triCIPh-5 4-FBz-5 4-CIBz-0 2,3-diFBz-S 34-diFBz-S 3.5-diFBz-S 23-diCIBz -0 3,4-diCIBz-S 3.5-diCIBz-S 2.3,4-triFBz-S 34.5-triFBz-S 2,3.4-triCIBz-S 3.4.5-triclHz-0 4-(:H,0Ph-NH4-CHlOBz-NH4-C,HsOPh-■4-(:JsOBz-NH4-CH,0Ph-4-CH,0Bz-NH4-C,HloPh-■4 -C,H,0Bz-NH 4-CH,0Ph-Book Exemplary Compound R5R6 H4-CH,0Bz-N)I H4-(:,H,0Ph-■ H3,4,5triCLOPh-Q H4-CH,0Ph- NH H4-CHxOBz-Q H4-C,H,0Ph-NH CH,4-C,H,0Bz-NH H2-CH,0-Py-5-NH H2,6-dzcHzO-Py-3-NHCHx
4-CJsOPh-book CJS 4-CJsOBz-NH CsHt 4-CHlOPh-book (:H, 4-CHxOBz-NH H6-CI-Py-2-+1t'H CxHt 4-CJaOBz-NH CHx 4-CHlOPh-NH C ,H,4-CH,0Bz-NH CJt 4-C,H,0Ph-NH CHs 4-CtHsOBz- CJs 4-CH,0Ph-Book C-H A 4-CHsOBz-Fil(H4-FPh-
Ni1 H4-CIPh-NH H2,3-diFPh-Book H3,4-diFPh-■ Exemplary compound ot 35-diFPh-NH 23-dicIPh-Book 34-diCIPh-NH 35-d ClPh-■ 2.3.4 -triFPh-NH 3,4,5-triFPh-NH 2,3,4-triclPh-NH 3,4,5-tri(:IPh-NH 4-FBz-NH 4-CIBz-NH 23-diFBz-Book 34 -diFBz-NH 35-diFBz-NH 23-diCIBz-NH 34-diCLBz-NH 35-di(:1Bz-■ 2, 3.4-triFBz-NH 3,4,5-triFBz-Fil 2, 3.4 -triclBz-MB 2,4.5-tricIBz-Nl( 4-CH,0Bz-5 4-C,H,0Ph-5 4-CJsOBz-S 4-CH,0Ph-O 4-CH,0Bz-S Examples Compound ■ ■ CH. C, H. C, H a CH. C, H. C, H a CH. C, H. C, H. CH□ C, H. C, H a CH. -H5 C, H 4-C2H,0Ph- 4-CJsOBz- 4-CH,0Ph- 4-CHzOBz 4-C,H80Ph- 4-CJsOBz- 4-CH,0Ph- 4-CH,0Bz- 4-(:, HsOPh 4- CJsOBz- 4-CH,0Ph- 4-CHiOBz- 4-CJ,0Ph- 4-CJsOBz- 4-CH,0Ph- 4-CHzOBz- 4-CIH,0Ph- 4-CiHsOBz 4-CH,0Ph 4-CH, 0Bz- 4-C1H,0Ph- 4-CxH@0BZ 4-(:H,0Ph 4-CH,OBz -FPh- Exemplary compound 4-CIPh-S 23-diFPh-S 34-diFPh-0 35-diFPh-S 23-diCIPh-S 34-diCIPh-S 35-diCIPh-S 2.3.4-triFPh-0 3,4,5-triFPh-S 2,3.4-triCIPh-S 3.4.5-triclPh- S 4-FBz-5 4-CIBz-0 23-diFBz-S 34-diFBz-S 35-diFBz-S 23-diCIBz-0 34-diCIBz-S 35-diCIBz-S 2.3.4-triFBz-S 3.4.5-triFBz-S 2.3.4-triclBz-S 34.5-tricIBz-0 4-CHsOBz-101 4-CJsOPh-■ Exemplary compound ■ CH3 C,H. C,H. CH. C, H. C,H aHs zHs C,H. CH. C2H yo C,H aHs 4-CZH5OBZ- 4-C1,0Ph 4-CH,0Bz 4-C,H,0Ph 4-CtHsOBz- 4-CHzOPh 4-CHsOBz- 4-(:J,0Ph- 4-CJsOBz - 4-CH,0Ph 4-CH,0Bz- 4-C,tH,OPh +-CJsOBz 4-CH,0Ph 4-CHxOBz 4-C,HsOPh 4-CzHsOBz 4-C1,0Ph- 4-CHsOBz- 4- 2H,0Ph 4-CJsOBz- 4-CH,0Ph- 4-CHxOBz 4-CfH,0Ph- 4-CtHsOBz Exemplary compound 4-CH,0Ph-Book 4-CH,0Bz-Q 4-FPh-Book 4-CIPh - 23-diFPh-order 34-diFPh-between 35-diFPh-book 23-dicIPh-book 34-dicIPh-book 35-diclPh-book 2.3.4-triFPh-NH 3,4,5-triFPh-NH 2,3,4-triclPh-D 3,4.5-triclPh-Q 4-FBz-4-(:IBz-23-diFBz-N'H 34-diFBz-N'H 35-diFBz-NH 23 -diCIBz-NH 34-diCIBz-Q 35-diCIBz-Q 2.3.4-triFBz-101 3,4,5-triFBz-Q 2,3.4-tricIBz-FGI Exemplary compound R6 A H ■ H H CI .0 ■ ■ CH.O ■ coma C}1.0 H CH.O CI.O CH.O ■ ■ 『 ■ CH.O H ■ cuso H CH.0 CH. H H CH.roH H CH.O ■ CH.O H CH.O CH.O H CH.O CH.O H ■ ■ cuso H H CH.O H CH.O H CI. H CH.O H ■ CH.O H ■ CLO CH.O ■ CHIO CH.O ■ cttxo H H CH.O ■ H cono H H CH.O CH.0 ■ CH.O H H H CH.O CH.O CH.O H H ■ C}f.O CH.O CH ?O ■ H CH.O H H H CH.O CH.O CH.O H H 3, 4. 5-tricIBz-Nu4-CH.OB
z-S 4-C! H. OPh- S 4-CxHsOBz- S 4-CH. OPh- 0 4-CH. OBz- S 4-CJsOPh- S 4-C*HsOBz- S 4-CH. OPh- 0 4-CHiOBz- S 4-C! H. OPh- S fCtHiOBz- S 4-CI{. OPh- S 4-CHiOBz- S 4-C! HsOPh- S 4-C. HIOBZ-S 4-CI. OPh- 0 4-CH. OBz- S 4-czusoph- S 4-CJ. OBz- S 4-(:H?oph- s 4-CHxOBz- 0 4-C.H.OPh- S 4-CxH.OBz- S 4-CH30Ph- S Exemplary compound R6 A CH.OH CI.O CH .O CH.O H H H CH.O H ■ CH.O H CH.O C} {.O H CH.O CH.O CH30 ■ H H H CH.0 ■ CH.O CR30 H CI.O CH30 H H CH.O H ■ CH.O H CH.O H CH.O CR.O H cuxo CH.O H H ■ CH*O H H H CH30 CH,O H CH.O H CHID H H CHsO H H CH.O CH30 H cHso CH.O H cn*o H ■ CH.O H ■ CH.0 H CIhO CH.O CH.O H CH.O H H H CI,O CR.O C}t.0 H H H CH.O CH.O CH.O H H CH30 H H H CH.0 C.H. C.H7 CM. C.H5 C.H A■ H ■ H H ■ H H H H H H ■ H H CH.CtH- CJACH.C.H, CJA4-CH.OBz- 0 4-C.HSOPh- S 4-C.H.OBZ- S 4-cuxoph- S 4-CHxOBz- 0 4-CH .OPh- S 2 3-diFPh- S 3 4-diFPh- 0 3 5-diFPb- S 2 3-diCIPh- S 3 4-diCIPh- S 3 5-diCIPh- S 2.3.4-triFPh- 0 3 , 4.5-triFPh- S 2, 3. 4-triclPh-S 3, 4.5-triclPh-S 4-FBz- S 4-CIBz- 0 2 3-diFBz- S 3 4-diFBz- S 3 5 -diFBz- S 2 3-diCIBz- 0 3 4-diCIBz- S 3 5-diCIBz- S 2,3.4-triFBz- S Exemplary compound R6 A H CH.O H ■ H ■ CI{.0 ■ ■ CI .O H CH.O CH.O H CM.O CH.O CH.O H H H H CHsO H H CH.0 CI. O H CH. O ■ ■ CH. O H H C}1.0 H CH. O H CB. O cnxo H cuso CH. O H H ■ CH. O H H CH30 H H ■ CI{. 0 ■ CH. O H H CH. O H H CH. OCH. O H CHJ CM. Q H CH. O H H CH. 0 ■ H CI. O H H CH. O CHaO H CI. O H H H CH. O cono cnao ■ H H CH. OCH. O cii*o ■ ■ CI{. 0 ■ H H CH. OCI. OCH. 0 3,4.5-triFBz-S 2,3. 4-triCIBz-S3, 4. 5
-triclBz-0 4-CH. OBz- NH 4-C2HIOPh- NH 4-CtHsOBz- Q 4-(:}f!OPhichizu 4-CHsOBz- NH 4-CJsOPh- NH 4-CJsOBz- NH 4-CH.OPh- zu 4-CH.OBz - NH 4-c*nsoph- 1fH 4{:.H.OBz- Q 4-C}I.OPh 4-CHJBz- NH 4-c*ttsoph- ■ 4-CtHsOBz- NH 4-CH30Ph 1 Positive 4 -CHiOBz- N}f 4-C-HsOPh- NH 4-CJ*OBz- NH 4-CHsOPh1 Tomo 4-CH.OBz- NH 4-C.H.OPh- NH Exemplary compound R6 A H CH.O CI .O H CH30 CH.O CHs O ■ H H CH.O H H CH30 H CI.O crtao H CH.O cnxo CHJ H H H H CH.O H CH.O CM.O H CH.O CI.O ■ H CLO ■ H CH.O H CH.O H CH.O Cl{.O H CH,O CH!O H H H CH.0 CI.O CH,O H CH30 CI.O ■ CI{.O H CH.O H ■ CH.O H H CH.O CH.O H CH20 CIIO H CH.O H H H CH,O H H H H CH.O CI.O CH.O ■ CI.O ■ ■ ■ CH. 0 CI. C2HSOBZ 1 book 4-CH?OPh- NH 4-CIBz- book 4-CIPh 1 story 2 3-diFPh- ■ 3 4-diFPh- NH 3 5-diFPh 1 book 2 3-diCIPh- NH 3 4-diclPh- book 3 5-diclPh 1 volume 2,3.4-triFPh- NH 3,4.5-triFPh- NH 2, 3. 4-tricIPh-NH3, 4. 5
-tricIPh-NH4-FBz- Book 4-CIBz- Book 2.3-diFBz- Fil{ 3.4-diFBz- NH 3, 5-diFBz- Book 2.3-diCIBz- NH 3,4-diclBz- ■ Examples Compound CH,O CH,O CH,O CH,0 CH,O H30 CH,O CH,0 (:)1.0 ■ xH- C,H. CH. (1:, H. Ml Among the above-mentioned exemplified compounds, preferred compounds include 1.3
．． 4.9.16.17.18.19.24.31.33
．． 34.39.46.48.49.54.55.57.
58.63.64.66.70.71.72.73.7
7.78.85.87.88.93.100.102.
103.108.110.111.116.123.1
25.126, 131.138.140.141.14
6.153.155.156.161, 163.164
．． 169.176.178.179.184.191.
193.194.199.206.208.209.2
14.216.217.222.229.231,23
2.237.245.246.251.258.260
．． 261.266.268.269.274.2811
283.284.289.297.298.303.3
10.312.313 and 318 may be mentioned. Furthermore, suitable compounds include 1.1g, 55, 66,
70, 71. 72, 77, 111. 116, 146, 156. Compounds 169 and 184 may be mentioned. The a-sulfinyl-substituted acetamide derivative of the present invention is
In the above formula, R1 is produced by the method described below.
, R2, R3, R4, R5, R6 and A have the same meanings as above, and X and Y are the same or different, chlorine, bromine,
Halogen atoms such as iodine; methanesulfonyloxy,
Lower alkanesulfonyloxy groups such as ethanesulfonyloxy, halogeno lower alkanesulfonyloxy groups such as nitrifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy, or arylsulfonyloxy groups such as benzenesulfonyloxy and p-toluenesulfonyloxy, etc. Indicates a leaving group. 1E1 is a step of producing an acetamide derivative (3) by reacting an active derivative of acetic acid +11 with an amine compound (2) in a solvent in the presence or absence of a base. The solvent to be used is not particularly limited as long as it does not participate in the reaction and dissolves the starting material to some extent, but preferably aliphatic hydrocarbons such as hexane and heptane:
Aromatic hydrocarbons such as benzene, toluene, xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane; dimethylformamide , dimethylacetamide, and hexamethylphosphorotriamide. The base to be used is not particularly limited as long as it is used as a base in normal reactions, but preferably alkali metal carbonates such as sodium carbonate and potassium carbonate: sodium hydrogen carbonate and potassium hydrogen carbonate. Alkali metal bicarbonates such as: alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide or inorganic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4 - (N, N-dimethylamino)
Pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2,2,2]
Octane (DABCO), l, a-diazabicyclo[
5,4,0] undec-7-ene (DBUI). The reaction temperature is -20°C to 80°C, preferably 0°C to 50°C. The reaction time varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used, but is usually 1 to 20 hours. After the reaction is completed, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by appropriately neutralizing the reaction mixture and removing insoluble matter by filtration if present, adding an organic solvent that is immiscible with water, washing with water, and distilling off the solvent. If necessary, the obtained target compound can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography.
3) and the mercaptan derivative (4) are reacted in a solvent in the presence of a base to produce a sulfide compound (5). The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but suitable solvents include methylene chloride, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane; alcohols such as methanol, ethanol, lolobanol; formamide, dimethylformamide, dimethylacetamide, hexamethylphosphorotri Mention may be made of amides such as amide or sulfoxides such as dimethylsulfoxide and sulfolane. The base to be used is not particularly limited as long as it is used as a base in normal reactions, but preferably alkali metal carbonates such as sodium carbonate and potassium carbonate; sodium hydrogen carbonate and potassium hydrogen carbonate. Alkaline earth bicarbonates such as: alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; inorganic metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide Bases; alkali metal alkoxides such as sodium methoxide and sodium ethoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-fN, N-dimethylamino)pyridine, N,N-dimethylaniline , N, N-diethylaniline, ■, 5-diazabicyclo[4,3,0]
non-5-ene, 1,4-diazabicyclo[2,2,
2] octane fDABco), t,a-diazabicyclo[5,4,0]undec-7-ene (IIBUI) or organometallic bases such as butyllithium, lithium diisopropylamide. The reaction temperature is 0° C. to 100° C., preferably 20° C. to 60° C. The reaction time varies mainly depending on the reaction temperature, the raw material compound or the type of solvent used, but is usually 1. After the completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method.For example, the reaction mixture is appropriately neutralized, and if insoluble materials are present, they are removed by filtration. After that, an organic solvent that is immiscible with water is added, and after washing with water, the solvent is distilled off.The obtained target compound is further purified, if necessary, by conventional methods such as recrystallization, reprecipitation, or chromatography. In the third step, the sulfur atom of the sulfide compound obtained in the second step is oxidized with an oxidizing agent in a solvent, and if desired,
When R1, R2, R3, R4 and/or R6 have a protected hydroxyl group, a protected amino group and/or a protected mercapto group, the protecting group is removed and the object compound of the present invention ( 6) is the process of manufacturing. The solvent used in the main step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but water, methylene chloride, chloroform,
Halogenated hydrocarbons such as carbon tetrachloride and dichloroethane; Esters such as ethyl acetate, propyl acetate, butyl acetate, and diethyl carbonate; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dioxane; methanol, ethanol, Mention may be made of alcohols such as lobanol, isopropanol and organic acids such as acetic acid. The oxidizing agent to be used is not particularly limited as long as it is an oxidizing agent normally used for oxidation, but preferably organic peracids such as hydrogen peroxide, peracetic acid, and chloroperbenzoic acid. ; t-butyl hydroperoxide-vanadium fIV
l Vanadium complexes such as oxyacetylacetonate; manganese oxides such as manganese dioxide; romic acids such as chromic acid; romic acid complexes such as dichromic acid-sulfuric acid complex, chromic acid-pyridine complex; or ruthenium tetroxide. Inorganic peroxides such as ruthenium oxides or chlorites such as potassium chlorite, sodium chlorite or reagents used in DMSO oxidation (dimethyl sulfoxide and dicyclohexylcarbodiimide, oxalyl chloride, Examples include complexes with acetic anhydride or phosphorus pentoxide, and pyridine-sulfuric anhydride complexes. The reaction temperature is 0°C to 100°C, preferably 10°C to 50°C. The reaction time varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used, but is usually 1 to 20 hours. The desired step, removal of the protecting group, varies depending on the type, but is generally carried out as follows by methods well known in the art. When the protecting group for the hydroxyl group is a silyl group, it is usually removed by treatment with a compound that generates a fluorine anion, such as tetrabutylammonium fluoride.The reaction solvent is not particularly limited as long as it does not inhibit the reaction. Although the reaction temperature and reaction time are not particularly limited, the reaction is usually carried out at room temperature for 10 to 18 hours. When the hydroxyl protecting group is an aralkyl group or an aralkyloxycarbonyl group, it can usually be removed by contacting with a reducing agent. For example, the 0 reaction, which is achieved by catalytic reduction at room temperature using a catalyst such as palladium on carbon, platinum, or Raney nickel, is carried out in the presence of a solvent, and the reaction solvent used does not participate in this reaction. Although there is no particular limitation as long as it is suitable, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, fatty acids such as acetic acid, or a mixed solvent of these organic solvents and water are suitable. The source strength and reaction time vary depending on the starting material and reducing agent used, but usually at 0°C to room temperature.
The duration ranges from 5 minutes to 12 hours. It can also be removed by treating metal lithium or sodium in liquid ammonia or in an alcohol such as methanol or ethanol at -78°C to -20°C. Furthermore, aluminum chloride-sodium iodide or alkylsilyl halides such as trimethylsilyl iodide can also be used for removal. The reaction is carried out in the presence of a solvent, and the reaction solvent used is not particularly limited as long as it does not participate in this reaction, but preferably nitriles such as acetonitrile, methylene chloride,
The zero reaction temperature when halogenated hydrocarbons such as chloroform or a mixed solvent thereof is used varies depending on the starting material, but is usually 0°C to 50°C. Note that aluminum chloride-sodium iodide is preferably used. When the protecting group for the hydroxyl group and/or mercapto group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group, it can be removed by treatment with a base in the presence of a solvent. The base is not particularly limited as long as it does not affect other parts of the compound, but preferably metal alcoholades such as sodium methoxide, alkali metals such as aqueous ammonia, sodium carbonate, and potassium carbonate. It is carried out using carbonates, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or concentrated ammonia-methanol. The solvent used is not particularly limited as long as it is used in ordinary hydrolysis reactions, and includes water, alcohols such as methanol, ethanol, and n-propanol, and ethers such as tetrahydrofuran and dioxane. An organic solvent or a mixed solvent of water and an organic solvent is suitable. The reaction temperature and reaction time vary depending on the starting materials, the base used, etc. and are not particularly limited, but in order to suppress side reactions, they are usually at 0° C. to 150° C. and for 1 to 10 hours. When the protecting group for a hydroxyl group is an alkoxymethyl group, a tetrahydropyranyl group, a tetrahydrothiopyranyl group, a tetrahydrofuranyl group, a tetrahydrothiofuranyl group, or a substituted ethyl group, it is usually treated with an acid in a solvent. It can be removed by The acid used is preferably hydrochloric acid, acetic acid-sulfuric acid, p-toluenesulfonic acid or acetic acid, but strongly acidic cation exchange resins such as DOWEX 50W can also be used. The solvent to be used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane, or a mixed solvent of these organic solvents and water may be used. suitable. The reaction temperature and reaction time vary depending on the starting materials and the type of acid used, but are usually between 0°C and 50°C.
C for 10 minutes to 18 hours. When the protecting group for the hydroxyl group is an alkenyloxycarbonyl group, the protecting group for the hydroxyl group is usually an aliphatic acyl group,
It can be removed by treatment with a base under the same conditions as the removal reaction for aromatic acyl groups or alkoxycarbonyl groups. In the case of allyloxycarbonyl, removal using palladium and triphenylphosphine or nickel tetracarbonyl is particularly convenient and can be carried out with fewer side reactions. Incidentally, the above-described operation for removing the protecting group for the hydroxyl group and/or the mercapto group may also remove the protecting group for the amino group at the same time. The above-mentioned reaction for removing a protecting group for a hydroxyl group, a reaction for removing a protecting group for a mercapto group, and a reaction for removing a protecting group for an amino group can be carried out sequentially as desired in any order. When the protecting group for the amino group is a silyl group, the removal reaction is carried out in the same manner as in the case where the protecting group for the hydroxyl group is a silyl group. When the protecting group for the amino group is an aliphatic acyl group, an aromatic acyl group, or an alkoxycarbonyl group, it can be removed by treatment with an acid or base in the presence of an aqueous solvent. As acids, hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid are used, and as bases, there are no particular limitations as long as they do not affect other parts of the compound, but sodium carbonate and carbonate are preferably used. It is carried out using an alkali metal carbonate such as potassium, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or concentrated ammonia medanol. The solvent used is not particularly limited as long as it is used in ordinary hydrolysis reactions, and water or water and alcohols such as methanol, ethanol, and lobanol, or ethers such as tetrahydrofuran and dioxane are used. A mixed solvent with an organic solvent such as ,■～10
It's time. When the protecting group for the amino group is an aralkyl group or an aralkyloxycarbonyl group, removal is carried out in the same manner as when the protecting group for the hydroxyl group is an aralkyl group or an aralkyloxycarbonyl group. When the protecting group for the amino group is an alkenyloxycarbonyl group, it is usually treated with a base under the same conditions as the removal reaction when the protecting group for the amino group is an aliphatic acyl group, an aromatic acyl group, or an alkoxycarbonyl group. It can be removed by treatment. In the case of allyloxycarbonyl, removal using palladium and triphenylphosphine or nickel tetracarbonyl is particularly convenient and can be carried out with fewer side reactions. After the completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method6. For example, the reaction mixture is appropriately neutralized, and if insoluble materials are present, they are removed by filtration, and then mixed with water. It can be obtained by adding an organic solvent that does not contain alcohol, washing with water, and then distilling off the solvent. The obtained target compound may be subjected to conventional methods such as recrystallization, reprecipitation or chromatography, if necessary.

【effect】

In vitro H"K"-ATPase from fresh fundic glands of pigs was performed using the method of Saccomanil et al. [J, Biol, (:
hea+,, 251 volumes. 7690 (1976)], the microsomal fraction prepared was used as an H'', K''-ATPase enzyme preparation. 10μ of a solution of the test compound dissolved in dimethyl sulfoxide
2, 40mM) Lis acetate buffer (2mM magnesium chloride, 20mM potassium chloride, pH 7-410,9 containing 20-40μg of enzyme specimen in terms of protein amount)
ml was added and reacted at 37°C for 300 minutes. The enzyme reaction was started by adding 0.1+*l of 2°IIM ATP 4Na solution and allowed to react at 37°C for 8 minutes. 1
10% trichloroacetic acid mixture containing 00 mg of activated carbon
After centrifuging the zero reaction solution (3000 rpm, 15 minutes) in which the reaction was stopped by adding Gol, the concentration of inorganic phosphoric acid in the supernatant was determined using the Fiska-Sabarou method [,1Bio1
．． Chem, Vol. 66, p. 375 (1925)]. In addition, the amount of inorganic phosphoric acid in the reaction solution in the absence of 20+mM potassium chloride was determined in the same manner.
By subtracting from the amount in the presence of potassium chloride,
The ``-ATPase activity was determined. The inhibition rate % was determined from the control activity value and the activity value at each concentration of the test compound, and the inhibition rate or 50% inhibitory concentration fIc, for H'', K''-ATPase was determined. The results are summarized in the table below.As described above, the novel α-sulfinyl-substituted acetamide derivative of the present invention has excellent H”, K-ATPas
Since it has e-enzyme inhibitory activity, it exhibits gastric acid secretion suppressing effect and anti-ulcer effect, and is also non-toxic, so it is useful as a gastrointestinal therapeutic agent. Examples of the administration form of the compound of the present invention include oral administration in the form of tablets, capsules, granules, powders, or syrups, or parenteral administration in the form of injections or suppositories. These formulations include excipients, binders,
It is manufactured by a well-known method using additives such as a disintegrant, a lubricant, a stabilizer, and a flavoring agent. The amount used varies depending on the symptoms, age, etc., but 50-200 Ig/kg body weight per day can be administered to adults, usually once a day or in several divided doses. The present invention will be explained in more detail below with reference to Examples. 2.2 g of 2-mercaptobenzimidazole and 3.4 g of p-methoxyphenylchloroacetamide were dissolved in 30 μl of methanol, and 3.4 g of a 28% sodium methoxide-methanol solution was added dropwise under water cooling. When the whole was stirred at room temperature for 1 hour, crystals were precipitated, so they were filtered and the crystals were washed with cold methanol and cold water to obtain 4 g of a sulfide compound. Melting point: 206°C 2.3 g of the sulfide obtained from Chibeitai Co., Ltd. was dissolved in methanol:methylene chloride (1:2), and 2 ml of t-butyl hydroperoxide and 100,111 g of vanadium (1v) oxyacetylacetonate were added. The mixture was added and stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to flash chromatography (silica gel) and eluted with methylene chloride to obtain 1 g of the target compound. The obtained sulfide compound was dissolved in a solution of tetrahydrofuran:methylene chloride:methanol f3 [1:5 [1:Is], and oxidized for 10 minutes using 1 equivalent of 1-chloroperbenzoic acid. The target compound was obtained as crystals from the reaction solution in an isolated yield of 85%. Melting point + 163-167 °C (decomposition). NMR spectrum (60 MHz, deuterated dimethylformamide) δ ppm: 3,74 (3H, sl. 4,26 (LH, d, J=12 Hzl. 4,45 (1) [, d, J=12 Hzl. 6.6~ 8.2 (8H, o+]. Rf value + 0.25 (methylene chloride: methanol; 2
0:I). 265 g of phenylacetamide 2-mercaptobenzothiazole and 3 g of p-methoxyphenylchloroacetamide were dissolved in 25 ml of dimethylformamide:tetrahydrofuran, 750 mg of 50% sodium hydride was added under water cooling, and the mixture was stirred overnight. After adding ethyl acetate and washing with water three times, drying with magnesium sulfate,
The solvent was distilled off under reduced pressure to obtain 4 g of crystals. Melting point: 127°C Rf value: 0.45 (cyclohexane: ethyl acetate =
4:1) The obtained sulfide compound 300B was dissolved in methylene chloride, and t-butyl hydroperoxide Q-4
1111 and 20 nag of vanadium (IV) oxyacetylacetonate were added, and after stirring at room temperature overnight, the solvent was distilled off under reduced pressure, and the residue was subjected to flash chromatography.
(silica gel) and eluted with methylene chloride to obtain 150 mg of the target compound. Melting point: 174-175°C (decomposed). NMR spectrum (60Hz, GDCl.) δ
ppm. 3, 75 f3H, s). 4, mouth flH. d. J=15Hzl. 4, 32 (LH, d, J=15Hz). 6, 8-8. 2 f8H. +m). Infrared absorption spectrum (Nujoll v c+w-1
+1671, [05. 1550, 1510. 1
375, 1225. Mass Spectrum Sono/e: 346. 1040. Purchase 6 liters of 1.2 g of 2-mercaptobenzimidazole
388II was dissolved in dimethylformamide and cooled with water.
g of sodium hydride (50%) was added and stirred for 20 minutes. 2.1 g of 3.4.5-trimethoxyphenylchloroacetamide was added and stirred for 1 hour at room temperature. After adding ethyl acetate and washing with water three times, the solvent was distilled off under reduced pressure to obtain 1.8 g of a sulfide compound, which is a coupled product. Melting point: 175°C 373 mg of the obtained sulfide compound was dissolved in methylene chloride 20
151 mg of chloroperbenzoic acid dissolved in 1t11
was added and stirred at room temperature for 4 hours. The precipitated crystals were filtered and washed with water-cooled methylene chloride and ether.
0 mg of the target compound was obtained. Melting point: 185° C. NMR spectrum (60 MHz. deuterated dimethylformamide) δ ppm: 3, 70 [3H, sl. 3, 77 f3H, sl. 4, 28 flH. d, J=15Hz). 4, 50 +IH, d. J=15Hz). 7, 0-8. 2 (6H). 1.8 g of 2-mercaptobenzothiazole and 3.8 g of α-bromo-3.4.5-trimethoxyphenylpropylamide were dissolved in 25ff11 of dimethylformamide, and 6(1 (l) mg of hydrogenated Sodium (50%) was added. After stirring at room temperature for 2 hours, ethyl acetate was added, and the organic layer was washed three times with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Flash column chromatography 2.8 g of the sulfide compound, which is a coupling product, was obtained from the portion corresponding to the Rf value of 0.5 (cyclohexane:ethyl acetate = 1:l).The obtained 2.3 g of the sulfide compound was chlorinated. methylene 100
ml and methanol 10 ml, under water cooling, 1
, 52 g of smoked chloroperbenzoic acid and 52 g at room temperature.
Stir for hours. After washing with sodium bicarbonate water and then with water, it was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to flash column chromatography to obtain 1.5 g of the target compound based on the Rf value (C25 (cyclohexane:ethyl acetate = 1:l). Melting point: 215 ° C. Decomposition) NMR spectrum (60 MHz, CDC1. deca methanol) δ ppm: 1, 64 f3H, d, J = 7 Hz). 4, 63 (IH, q.J=7Hz). 3,75 f3H,s). 3.72f3H,s X2). 7.2-7.9 (61(). 195 rag of 2-mercaptobenzimidazole and 300 wIg of (2,6-dimethoxy)pyridin-3-ylchloroacetamide were dissolved in 5+sl of dimethylformamide and cooled with water. 62 mg of sodium hydride (50%) was added. After stirring at room temperature for 3 hours, ethyl acetate was added and the organic layer was washed three times with water. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. , purified by flash column chromatography, and obtained 1011 g of sulfide compound 3, which is a coupling product, from the portion corresponding to the Rf value of 0.6 (methylene chloride: ethyl acetate = 2: l). The obtained sulfide compound 300 mg was dissolved in methylene chloride 5, and 151 mg of chloroperbenzoic acid was added under water cooling. After stirring at room temperature for 15 hours, crystals were precipitated. The crystals were filtered and dissolved in water-cooled methylene chloride and Washing with ether gave 160 mg of the target compound. Melting point: 181"C (decomposition) NMR spectrum (60 MHz, deuterated dimethylformamide deca methanol) δ ppm: 3,82 f3H,sl. 3,85 f3H,sl 4,01 f2H,brsl.6,27 flH,d, J:8Hzl.L19 (IH,d, J=8Hz).7,1-8.0 (4H,m).2-Mercaptobenzimidazole 224 mg and (
300 mg of 6-methoxy)pyridin-3-ylchloroacetamide was dissolved in 4 ml of dimethylformamide, and 90 mg of sodium hydride (50%
) and stirred at room temperature for 5 hours. Ethyl acetate was added, and the organic layer was washed three times with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the portion corresponding to an Rf value of 0.3 was separated and purified using silica gel preparative TLC using methylene chloride:ethyl acetate (1:1) to obtain the sulfide compound 300B, which is a coupled product. I got it. Melting point: 227°C 150 tag of the obtained sulfide compound was dissolved in 5 ml of tetrahydrofuran, 0.23 ml of t-butyl hydroperoxide and 38 mg of vanadium(iv) oxyacetylacetonate were added, and the mixture was stirred at room temperature. Stirred for 15 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel preparative TLC.
45 mg of the target compound corresponding to was obtained. Melting point: 163°C NMR spectrum (60 MHz, heavy dimethyl sulfoxide) δ ppm: 3, 83 (3H, sl. 4, 39 (2H, brsl. 6.6-8.3 (71 (, ■). Infrared absorption spectrum (Nujoll y c+s-1:
1640° 1460° 1375° 1040°

Claims (2)

[Claims] (1) [Claim 1] General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1, R^2, R^3 and R^4 are the same or different and are hydrogen atoms or the following: Represents a group selected from substituent group A, R^5 represents a hydrogen atom, a lower alkyl group, or an aryl group, and R^6 represents a lower alkyl group, an aryl group, or a group selected from substituent group A below. An aryl group substituted with 1 to 3 groups, an aralkyl group, or a group selected from the following substituent group A.
It represents an aralkyl group substituted with 3 to 3 substituted groups, a heteroaryl group, or a heteroaryl group substituted with 1 to 3 groups selected from the following substituent group A, where A is an oxygen atom, a sulfur atom, or the general formula NR^ 7 (in the formula, R^7 represents a hydrogen atom or a lower alkyl group). ] and its salts. "Substituent Group A" Lower alkyl group, lower alkoxy group, hydroxyl group, protected hydroxyl group, amino group, substituted amino group, protected amino group, mercapto group, protected mercapto group, halogen atom, and aralkyl group ( 2) [Claim 2] General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, R^1, R^2, R^3 and R^4 are the same or different and are hydrogen atoms or the following: Represents a group selected from substituent group A, R^5 represents a hydrogen atom, a lower alkyl group, or an aryl group, and R^6 represents a lower alkyl group, an aryl group, or a group selected from substituent group A below. An aryl group substituted with 1 to 3 groups, an aralkyl group, or a group selected from the following substituent group A.
It represents an aralkyl group substituted with 3 to 3 substituted groups, a heteroaryl group, or a heteroaryl group substituted with 1 to 3 groups selected from the following substituent group A, where A is an oxygen atom, a sulfur atom, or the general formula NR^ 7 (in the formula, R^7 represents a hydrogen atom or a lower alkyl group). ] and its salts. "Substituent Group A" Lower alkyl group, lower alkoxy group, hydroxyl group, protected hydroxyl group, amino group, substituted amino group, protected amino group, mercapto group, protected mercapto group, halogen atom, and aralkyl group