JPS6178784A - N-substituted derivatives of 2-(pyridylalkenesulfinyl) benzimidazoles as anti-gastric juice secretion - Google Patents

Abstract

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

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to FT-regulated compositions of matter. For more details, see 1
The present invention provides 2-
rl! to novel N-substituted derivatives of (pyridylalkylenesulfinyl)benzimidazoles! I do.

Conventional Techniques Inflammatory gastrointestinal diseases are characterized by inflammation, particularly edema, the presence of characteristic inflammatory cells (i.e. leukocytes, histology, macrophages), and in some cases necrosis and ulceration of the surface epithelium. These inflammatory diseases are caused by a wide range of factors within the gastrointestinal tract that are known to attack the surface of the gastrointestinal tract and create an inflammatory disease response. (mold), IIB bacterial toxins, certain drugs (antibiotics and anti-inflammatory steroids) and chemicals (bile salts, pharmaceutical chemicals).Stomach acid itself also attacks the stomach lining, causing inflammatory conditions. It attracts me to create.

One means of preventing or treating certain gastrointestinal diseases, particularly gastric diseases, is to suppress gastric acid secretion. In situations where the integrity of the gastric mucosal barrier is compromised, gastric acid secretion causes erosion of the epithelial cells, ultimately leading to inflammation and ulceration. Suppression of such untoward effects caused by gastric acid can be achieved by the administration of pharmacological agents effective in inhibiting gastric acid secretion.

One class of such drugs that are effective in inhibiting gastric acid secretion are anti-acid-secreting prostaglandins.

These substances are known to be effective in the treatment and treatment of gastric and duodenal ulcers as a result of inhibition of gastric acid secretion. See, for example, U.S. Pat.

“Antisecretory properties of prostaglandins,” Worcester Foundation for Experimental Biology Prostaglacidin Symbosium, 19
See October 16-17, 1967, Interscience, New York, p. 47 (1978). Another important class of antisecretory agents are methyamides and the most important cimetidine, namely N-cyano-N-methyl-N
''[2-[<5-methyl-1H-imidazole-4-
It is a histamine 2 receptor antagonist containing yl)methyl]thio]ethyl]guanidine. "Merck ° Index" 9th edition, Appendix, App-1 page (1976) and "Physician's Desk Handbook"
See Re4erenCe) 36th edition, page iai2-igia (1982).

Another means of treating such gastrointestinal diseases is through cytoprotection. Certain pharmacological agents have previously been known to be useful in exerting cytoprotective effects on the gastrointestinal tract. This cytoprotective effect is evident in the ability of these compounds to treat or prevent inflammatory gastrointestinal diseases that are neither trauma-induced nor neoplastic. References describing such II@protective effects of prostaglandins include:

April 11, 1978'4I! U.S. Patent No. 4,0
No. 83,998 (Robert, "Treatment of inflammatory diseases of the mammalian colon with cytoprotective prostaglandins"),
U.S. Patent No. 4.081, issued March 28, 1978,
55. ') (Robert, [Cytoprotective Prostaglandins for Intestinal Diseases]) and US Patent No. 4.09760, issued 6127/1978. '＞ @ (Robert, ``Gastric cytoprotection with non-antisecretory doses of prostaglandins''). Gastric cytoprotection is a separate pharmacological property not associated with the antigastric acid secretory effect. Examples include Robert's U.S. Pat. Vol. 77, pp. 761-767 (1979): Robert, “Cytoprotective Trends,” Prostaglandins, Vol. 21 (Supplement), p. 89 (1981); and Lohart et al., “Cytoprotection of Prostaglandins in Rats,” Castro. Enterology Volume 77 433-4
See page 43 (1979). Therefore, a compound that is an anti-gastric acid secretion agent is not necessarily a cytoprotective agent, and vice versa.

U.S. Patent No. 4,045,563 discloses that certain substitutions 2-? The pyridylalkylenesulfinyl 1-henzimidazole term is clarified.

U.S. Patent Nos. It, 25S, 431 and 4
, 337, 257 discloses certain 2 substances useful for suppressing gastric acid secretion.
-(2-benzimidazolyl)-bi11dines have been identified. US Patent No. L 359,465 discloses the use of certain heterocycloalkylsulfinylhenzimidazoles in cell preservation. Published European Patent No. 4 0130729 (published on January 9, 1985)
is a certain substitution 2-[7) 7-nerated (3,4-,
4,5- and 5,6-)pyridylalkylenesulfinyl]henzimidazoles have been demonstrated as antisecretory agents. Published European patent → No. 0150586 is here! A2-pyridyl mediruthio and sulfinylhenzimidazoles have been revealed as anti-gastric acid secretion agents. Announced UK patent +! ! 14 No. 2, 134.523
The number identifies certain N-substituted pyridylalkylbenzimidazoles.

means to solve the problem The present invention particularly provides compounds of formula I.

[In the formula, X is the following (, ]) or (b).

(a) =S or (b) = s.

A and 8 may be the same or different.

<, l) hydrogen, (b) -R1 (C) -0R1 (d) -CF3 (e) -CORI or (f) -co2R[, where R1 is (Cl-C4)alkyl.

D is a formula! +, III, rV or V substituent.

R: ], R4 and RIO are the same or different and are the following (a) or (b).

(a) hydrogen, or (b) (CI-C4)alkyl.

The bias is O or 1.

Rλ is the following (a) to (i).

(a) -3R5゜ (b) -0R5゜ (ci　-N(R4)2゜ (d) 1-piperidinyl.

(e) 4-morpholinyl.

(“)1-pyrrolidinyl.

DJ) Chloro.

(11) Pro-7, or (i) Fluoro R5 is the following (a) to (e).

(a) (CI-04) Alkyl 2 (b) (C2-C4)alkenyl.

(lj (C:]-C6)cycloalkyl.

(d) -CH2-PhX, or (e) PhX, where Phx is phenyl substituted with O to 3 of the following: 5;

(aj　(CI-04)alkyl.

(b) Chloro.

(Ci Bromo.

(d) Fluo [co.

(e) Nitro 1 (r)　CF:], or (g) 0R3 0 is 0 or 1.

Further, V is the following (a) to (C).

(F) =CH2゜ (b)=0 or (c) -3 G is the following (a''r to Il).

(a) Hydrogen.

(b) (C1-C4)alkyl.

(C) -COR5゜ (d) -COPilX.

(el -CO(CH3nmco2 R2゜(Lee-c
och2phx, and c(ill) -C(0)-0-R11R6 is the following (a
) or (b).

(a) (CI-CIo)alkyl, or (b) -A
A Here, AA is the following (a) or (b).

(a)-(CH2)p-CH(NH2)-R9 or c(b
) Ami/ljl 1llj chain R9 is the following (a) or (ri).

(a) hydrogen, or (b) (CI-Cg)alkyl R1+ is the following (a) to (g,).

(a) (C1-C12)? /L, kill (b) (C
2-C,2) alkenyl, .(c)-PhX.

(d>-CH2-PhX.

(e) (CI-C6) cycloalkyl.

(r) -CH2-(C,-C6)cycloalkyl, or (g) substituted with one or more 10 mo or chloro groups (
C, -C6) Alkyl p is an integer from 1 to 9, provided that 1) the total number of carbon atoms in -(CH2i- and R9) is less than or equal to 9, and (2) G is -C l is zero only when (0)-0-R11.

(3) Formula V ノR2CAROR5TENAI/)', and C Formula II, only when V in ■ or ■ is =S, G is -C(
0)-0-R11.

The present invention further provides the following.

(1) 01) -COR6, -COPhX, -co
(CH2)lr, 'C1')2J or -COCH2Pi
An acid anhydride containing the +X moiety and the catalytic star N,N-dibutylaminopyricine or (b) -COR6, -c.

-PhX -CO(CH2)m-CO2R) Also, a compound of formula I consisting of treating a compound of formula A-2 with an activated acid containing the moiety COCH2PhX
In the formula, -COR6, -COPhX, -GO(CH2
/ Visceral CO2R:] or -〇〇CH2PhX) manufacturing method.

(2'1 (a) Formula P) A compound of formula I (where G is - C(0)-0-R,l (1m is zero) manufacturing method.

(3) treating a compound of formula C-1 with sodium hydride and (b) treating the anion thus created with formula CH:]C
HXCOR, 2 (wherein X is chloro or bromo.

RI2 is C, -C4 alkyl), wherein G is (C, -C4)
alkyl) production method.

(4) Formula D-1 compound is converted to formula CH3-CHX-0-C (
0)-R13 (wherein X is chloro or bromo, R1
, l is R6, PhX-(C)12)rn-CO2R
3 or -ch2phx) (wherein G is -COR5).

-cophx, -Co (CH2)BcO2R3 or HaC
0C) I2PhX > (1) Hr'-0 What is the carbon atom content of the various hydrocarbon-containing moieties?

It is designated by a prefix indicating the minimum and maximum number of carbon atoms in the part. That is, the prefix (Ct - C7) represents the number of carbon atoms from the integer i to the integer Ftj. Thus, (Cl-C,o)alkyl is alkyl of 1-10 carbon atoms, or methyl, ethyl, propyl,
Butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and their isomeric forms.

including alkyl-substituted cycloalkyl (C3-CIo
) Examples of cycloalkyl are cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2
．． 3-diethylcyclopropyl, 2-butylcyclopropyl, cycloothyl, 2-methylcyclobutyl.

3-propylcyclobutyl, 2,3.4-triTylcyclobutyl, cyclopentyl, 22-dimethylcyclopentyl, 2-pentylcyclopentyl, 3-tert-butylcyclopendel, 22-dimethylcyclohexyl, cyclohebutyl, cyclooctyl , cyclononyl, and cyclodecyl.

Examples of (C,-C+)alkenyl are 1-propenyl, 3-
Includes butenyl and its isomeric forms.

Examples of phx are 71-nyl, (0-, lll-, 9-)
t',) L.

(a-, ta-, ko)ethylphenyl, 2-ethyl-tolyl.

4-ethyl-〇-tolyl, 5-ethyl-tolyl, (
0-.

or l)->brobylfinyl, 2-propyl-(0
−.

or p-)Tolyl, 4-isopropyl-26-xylyl, 3-propyl-4-ethylphenyl, (2,3,4
−.

2.3,6- or 2,4.5-) trimethylphenyl, (o-, m- or 1)-) fluorophenyl, (
o-, n+- or trifluoromethyl) phenyl, 4
-Fluoro-2,5-xylyl, (2,4-12,5-
, 2,6-, 3,4- or 3.5-) difluorophenyl, (0-, m- or p-) chlorophenyl, 2-chloro-o-tolyl, (3-, 4-, 5- or 6 -) Chloro-〇-tolyl, 4-chloro-2-propylphenyl.

2-(sobropyru-4-chlorophenyl, 4-chloro-
35-xylyl, (23-, 2,4-, 2,5-, 2
, 6= or 3.5-)dichlorophenyl, 4-chloro-
3-fluorophenyl, (3- or 4-)chloro-2-
Threonine - "nyl, (o-, m- or p-) trifluoromethylphenyl, (o-, m- or kano) ethoxyphenyl, (ru or 5-) chloro-2-methoxyphenyl, - and 2 .4-dichloro-(5- or 6-)methicifinyl.

Pharmaceutically acceptable acid addition salts are formed when G contains an amine moiety. These salts include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate,
Propionate, lactate.

Includes maleic M salts, malates, succinates, tartrates, and the like. These are made by methods well known in the art.

"Amino acid side chains" are glycine, alanine, valine, leucine, isoleucine, and phenylalanine.

Lysine, Zorori, N, tryptophan, methionine.

Refers to dehydroxylated forms of acids, including naturally occurring acids such as serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, arginine, ornithine, and histidine, and their synthetic derivatives. ing. These compounds are in the O-range and are well known and readily available to those skilled in the art.

The compounds of the present invention can also be in the form of pharmacologically acceptable salts. cations).

Such cations include pharmacologically acceptable metal cations, ammonium, amine, cations or quaternary ammonium cations.

Particularly preferred metal cations are alkali metals.

For example, those derived from lithium, sodium, and potassium, and the alkaline earth metals 1, such as magnesium and calcium, but other metals,
For example, cationic forms of aluminum, zinc and iron are within the scope of this invention.

Pharmacologically acceptable amine cations are primary,
Those derived from secondary or tertiary amines e
Examples of suitable amines are methyl, amine, dimethylamine, trimethylamine, ethylamine, diptylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, alinoamine, crotinamine.

Cyclopentylamine, dicyclobenzylamine.

Benzylamine, shhenzylamine, α-phenylethylamine, β-phenylethylamine, ethylenediamine, diethyl-lentriamine, and homologous aliphatic, cycloaliphatic, araliphatic compounds containing up to about 18 carbon atoms. Amines and heterocyclic amines such as piperidine, morpholine, pyrrolidine, piperazine, and their lower alkyl derivatives, such as 1-methylpiperidine.

4-Ethylmorpholine.

1-isopropylpyrrolidine.

2-Methylpyrrolidine.

14-Dimethylpiperazine.

2-methylpiperidine, etc.

Among the amines containing water-soluble groups or hydrophilic groups, such as seven amines, di- and triethanolamines.

Ethyljetanolamine.

N-butylethanolamine.

2-amino-1-bukunol.

2-amino-2-dichloro-1,3-propanediol,
2-Amino-2-methyl-1-propatol.

Tris(hydroxymethyl)aminomethane.

N-phenylethanolamine.

N-(p-tertiary amyl phenyl) jetanolamine.

Galactamine.

N-methylpyridine, N-methylglucosamine, ephedrine, phenylephrine, Epinephrine.

Professional force in etc.

Further useful amine salts are basic amino acid salts 1, e.g.
They are lysine and arginine.

Examples of suitable quaternary ammonium cations that are pharmacologically acceptable are:

Tetramethylammonium.

Tetraethylammonium.

hensyltrimethylammonium, Phenyltriethylammonium etc.

The compounds of the present invention are named in the Mizume ItII book using the Chemical Abstracts numbering system ("Chemical Substance Nomenclature and Indexing for Chemical Abstracts in the Ninth Comprehensive Period <1972-1976"). ”
, reprint of Section 1V from the Index Guide, Volume 76).

Surprisingly and unexpectedly, the compounds of the present invention are chemically more stable than the henzimidazoles from which they are derived. These are more stable, especially in acid conditions such as in the stomach. It is also more soluble in water, providing an improved means for pharmaceutical chews. Furthermore, these compounds possess strong antisecretory effects when administered subcutaneously and are more potent than their parent hemigezoles when administered orally.

The compounds of this invention have been tested in one or more standard tests demonstrating anti-gastric acid secretion activity.

In vivo inactivity of (H"-K", IATP'F-Z) in rats (Human test) Benzimidazole acetate (ester) (1st
When the compounds in the table were administered subcutaneously, 1 mg/kg of E
I received D50 and found it to be the most effective. Furthermore,
It has been found that some of these compounds have high efficacy as inhibitors of gastric acid secretion when administered orally. In this single trial system, certain compounds were found to be most effective during oral administration. 2-((2-pyridinylmethyl)nurfinyl)-18-benzimidazole-1-methanol acetate (ester) (compound 1 in Table 1).

In suppressing gastric acid secretion in rats by oral administration, 5 m
g/kg, which is the same ED50 that this compound exhibited during subcutaneous administration.

In an in vivo inactivation test of (H+- to +) ATPase in rats, 2-
-pyridinylmethyl)sulfinyl 1-1H-benzimidazole-1-carboethoxyester, 2-[(l
L-Dingshuruthio 3-methyl-2-pyridinylmethyl)
Sulfinyl 1-1H-benzimidazole-1-carbo-p-nitrodiester; 1dioxy T stel was shown to be effective with a [D50 of 5 to 10 mg/kg when administered subcutaneously.

Additionally, certain of the compounds of the present invention have been found to be effective in a standard test of gastric acid secretion in isolated rabbit glands. In this study, the two most effective inhibitors of gastric acid secretion were
The compounds are 2-[(4-edylthio 3-medylthio 2
-pyridinylmethyl)-sulfinyl 1-1H-benzimidazole tocal, r-so-1 thyroxyester;
24(4-ethylthiA-3-methyl-2-pyridinylmethyl)sulfinyl 1-18-henzimidazole-1
- carpohynyloxy ester. These compounds were tested at 10 mg/kg in this test.
I pressed +Q.

In general, preferred compounds of the invention are those in which A and 8 are JR base T.
:,
There is a substituent (R2 or alkylthio), and G is =(-・
C4) Compounds of formula I when it is nofurkyl or -COR6.

All of the compounds of the present invention are useful as anti-gastric acid secretion agents.

The compounds of the present invention are administered orally for the purpose of anti-gastric acid secretion.

Non-mineral (e.g. resting, subcutaneous, intramuscular, or intramembranous),
Pills, capsules, solutions, suspensions, via the rectum or vagina
It is administered in the form of a suppository or bougie. The compounds of the invention are delivered to these pharmaceutical compositions by means known to the pharmaceutical art.

An ordinarily skilled physician can readily determine who is suffering from a gastrointestinal disease characterized by all the effects of stomach acid described above. These conditions are treated using the compounds of this invention.

A typical dosage range for the compounds of this invention is about 0.01 u per kg! II to about 250 mg, preferably /
It ranges from about 0.1 to 100 mg per portion. The use, route, and frequency of administration of the compounds of the present invention will depend on the individual's body weight, age, gastrointestinal disease, and the particular compound used. These determinations are easily made by a physician skilled in this technique.

The compounds of the invention also exhibit cytoprotective effects. When used for this purpose, the compounds are e.g.
, 465, particularly in column 1.8. The single dose used for this purpose will generally be less than the amount used for anti-acid secretion effects.

The compounds of the present invention are made by the methods of Reaction Pathways A-D. In Scheme A, G is all definitions of G other than hydrogen, G2 is (CI-C4)alkyl, and all other variables are as defined above.

In Reaction Route A, benzimidazole compounds of formula A-1 are hydroxymethylated by means known in the art, e.g., with formaldehyde in acetonitrile [Varma et al., Ur. J
, ) 4ed, Chem, vol. 15, 536i (198
0 years) and Haugwitz et al., J.
, Merl, Chem vol. 22, p. 1113 (19-19). The benzimidazole compounds of formula A-1 are known in US Pat.
Father-in-law, No. 4,255,431 father-in-law, and No. L337,257
Father-in-law and color-divided Europe・■ Mt.Jigyo ÷ No. 0130729
8 (announced on January 9, 1985) and No. 0150586 (father-in-law)
(August 7, 1985). All of these are incorporated herein by reference.

G is hydrogen, -COR et al., -COPhX, ~C0(CH2
The compounds of the invention when 'J□C02R3 or -COCH2PhX are made as described in Reaction Scheme A.

Next, add 2 hydroxymethyl compound of formula A in pyridine to 2
treatment with slightly more than 1 molar equivalent of a suitable acid anhydride and a catalytic amount of N,N-dimethylaminopyridine at 0-50°C, preferably 25°C, or in ahitone at 20-50°C.
Preferably at 25° C., reaction with 1 molar portion of a suitable activated acid (such as one made in situ from acid, isobutyl chloroformate and triethylamine) for 1-2 hours results in a formula 1,3 gel chromatograph. The final product can be purified by Acids corresponding to G are well known and readily available to those skilled in the art, or can be made (by known means). When X = 3, as written in the second US patent and application, (
For example, oxidation of (metachloro)benzoic acid gives the corresponding sulfoxide. When the acid used is an amino acid, the amine function is capped by conventional means (eg using a tert-butyloxycarbonyl group) prior to reaction with the compound of formula A-2.

Such protected amino acids have been reprinted. The blocking group is then removed by reaction with a pharmaceutically acceptable acid to produce the acid addition salt. Thus, for example, the formula A-
The 2-hydroxy compound is reacted with the tert-butyloxycarbonyl amino acid of formula A-2 in the following manner. do. Separately, dicyclohedylcarbodiimide (DCCD) and tert-butyloxycarbonylamino acid are dissolved in pyridine. Gradually mix these two ingredients, stirring constantly. Dicyclohexylcoria (DCHII) is formed as a by-product and is filtered off. Evaporate the solvent! When the compound of formula A-3 thus prepared is reacted with acid of formula HXI7), 1
yielding the formula A-4 heptaconjugate.

(Instead of the amino acid chain within the range of G.

It may also be added from the "mixed anhydride" route. Tert-butyloxycarponyl amino acid and N-methylmorpholine are dissolved in dry tetrahydrofuran (THF).

Add isobutyl chloroformate to this solution under nitrogen atmosphere. After filtering out the formed precipitate.

A mixture of formula A-2 compound and dimethylaminopyridine in dry THF is added. After 60 minutes at air temperature, the reaction mixture is dried under vacuum. If necessary, extract the pure product by liquid chromatography.

R-terminal suction is made as described above.

mS pyro, when G is -C (0', +-0-R11), the compound of the present invention is prepared as described in Route B. Reaction route B is dimethylform? The benzimidazole of formula B-1 in
C., preferably 25.degree. C., with 1 molar equivalent of sodium hydride. Bake for 2-3 minutes at this temperature, then
IC0nR11 appropriate Roloff A Lemay 1 ~ reagent (1
(slightly more than the amount of the reaction mixture) was added to benzimidazole anion and one reaction was carried out at 20-50°C, preferably 25°C, for 15-30 minutes. The pure compound of formula B-2 is then purified by silica gel chromatography (ethyl acetate or ethyl acetate-hexane elution mixture as eluent) and '
Or by crystallization from ethyl acetate or ethyl acetate-ether solvent mixtures! I! be separated.

28-1 Henzimidazole compounds are known and described in US Pat. No. 4,045,563, No. 4255.43.
No. 1 and No. 4,337,257 (these patents are incorporated by reference) and published European Patent Total No. 0130729 (published on January 9, 1985) and o1so5a6. (Kokichi, August 7, 1985) 6 payments 1. : Therefore, it can be made.

Chloro 7A alumates of formula CIC(0)-O=RG are readily available, well-known compounds C, or can be made by known methods.

In reaction route C, a henzimidazole compound of formula C-1 in a diminutive lumenite is heated at 20-50°C, preferably at 20°C.
1 mol of hydrogen at 5°C (treated with hysodium).

The resulting henzimidazole anion is reacted with slightly more than one equivalent of a halonidel of the formula CH3CHX-0-R,2 [where X is chloro or bromo and R+2 is Cl-C4 alkyl] to reduce the ambiguity to 20-50 °C, preferably 2
Stir for 15-30 minutes at 5°C. The pure compound of Formula 1 C-2 can then be purified by silica gel chromatography using an ethyl acetate/'hexane solvent mixture as the eluent, or by chromatography using an ethyl acetate or ethyl acetate/ether solvent mixture. The chloroalkyl alkyl ethers are commercially available or easily made by methods known to those skilled in the art.

Nisder derivatives of the present invention when RIO is other than hydrogen are made as shown in 1 Reaction Route.

In the reaction route, a formula D-1 henzimidazole compound in acetonitrile is reacted with 2-3 equivalents of the appropriate α-haloalkyl ester at 25°C. α-Ha Ulich)
and Earl Adams (R, Ada+ns), J.A.
AllChe, Soc Volume 43 660 Negative (1921
Year)]. In order to improve the yield of the reaction, bromoalkyl esters are more preferred α-haloalkyl ester samples.

It can be treated with α-haloalkyl ester. The above procedure yields a compound of formula D-2, which is oxidized with m-chloroperbenzoic acid in chloroform at 0-5 DEG C. to yield a compound of formula D-3. The final product is then purified by silica gel chromatography, preferably using 1 volume of ethyl acetate or an ethyl acetate/hexane vehicle mixture as eluent.

All of the compounds of the invention can be prepared by the above procedure.

The invention will be more fully understood from the revised embodiments.

Example 1 2-L(2-pyridinylmethyl)sulfinyl]-1H-henzimidazole-1-methanol (
Formula r: A and 8 are hydrogen, D is a formula V substituent, R2, R3 and R4 are hydrogen, X is =S, G
is hydrogen) See reaction route A (conversion of A-1 to A-2).

10 g of 2-(2-pyridinyl)methylthiobenzimidazole in 220 ml of acetonitrile (41,45
5.00 ml of a 37% formaldehyde solution dissolved in 10 ml of acetonitrile was added to a solution of
I can talk.

After the addition, heat the mixture for 15 minutes in an oil bath maintained at 70°C. At the end of this period, remove the main part of the solvent in vacuo and dilute the residue with chloroform.

Wash the chloroform solution with water and saturated brine, and add anhydrous NazS.
Dry with O-gyu. Removal of the solvent in noble air yields a crude product, which is converted into acetic acid
Recrystallization from (30:25:15) yields 9.687 g of the title compound. Melting point 80-83°C.

Analysis C,411,3N3PS Needle Ring (Detective: C,61,99: H,4,80,N,15
．． 50, S, 11.81 Measured value: C9 et al. 2.22:
H, A 96: N, 15°64: S, 1188
NHR (CDcI3.δi 850.780-710.
570.440 Ink Spectrum M” 271 Measurement] Straight 2
42 ()4+-HCHO-H)TLCRf 0.22
(In chloroform 7, ・'acetone 3.1) Actual example 2
2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)-thio 1-1H-benzimidazole-1
- methanol (formula I: A and 8 are hydrogen, D is a formula V substituent,
R2 is methoxy, R3 and R4 are methyl, X is -3,
G is hydrogen) See reaction route A (conversion of A-1 to A-2).

Following the procedure described in Example 1, 1.63 g (s, a5 mmol) of the thioether corresponding to the title compound gives 144 of the title compound. Melting point 162-165°C 0 Binkoku spectrum 017 N19 N302S meter pupil 1 straight: N
o(tl old 300 measured value 300()l”-HCHO
), NHR (CDC13, δ) 8.00.7.80-
7.20. 5.80.4.5G', 3.80.2.
35TLCRr 0.2A (in methylene chloride, 'Aretone 61) Run 1 Row 3 2-[u-ethylthi, 1-3-methyl-2-pyridinylmethyl]di 1-1H-henzimidazole-1-methanol Reaction Route A (A -1 to A-2).

2-[(4-ethylthio-
3-Methyl-2-pyridinylmedyl)thio]-benzimidazole (0,787 (1,2,50 mmol) in a magnetically stirred suspension) was added to a solution of 37% formaldehyde in 0.5% formaldehyde solution. I drank 0 sips of 36 ml. Heat the mixture in a 65°C oil bath for 15 minutes, before) 2! ! Workup as above yields the title compound.

Fn@ (CDC13,a) Lto (dl IH
-J-RaH2), 7.70-6.90 (m,
5M).

5.70 (S, 2H), a, 5-0 (s, 2
1), 2.135 (Q, 214. J-7Hz)
, 2.25 (S, 3H), 1.35 (t
, 3H, J-T IGO.

TLCRf 0.40 (Ethyl acetate L/S'7-1.
j V Lua B 2: 1) Example 4 2-[3
,4-dihydro-2H-cheno(2,3-c)pyridinylmethyl)def! 1-1H-benzimidazole-1-
Methanol (formula 1: A and 8 are hydrogen, D is a formula 11 substituent,
n is +, V Ha=S, X Ha=S, G 1. @
Water e, ) Reaction route A (transformation from A-1 to A-2)
See Example 31. : Follow the procedure described above, and thioether 0300! 1 (0.96 mmol) yields the N-hydroxymethyl product Q322 ().

NHR (CDCl2.δ) 795.785-690.
580.4.50°2.90.2.10 TLCRr 0.43 (chloroform 7' acetone 3.
1).

Example 5 2-[(4-chloro-3-methyl-2-pyridinylmethyl)thio 1-1H-benzimidazole-1
- Methanol (Formula I: A, !:B is hydrogen, D is a formula V substituent, G is hydrogen, X is =S, R3 is methyl, R2 is chloro, R is hydrogen) Reaction route A (A-1 (conversion from to A-2).

Following the procedure previously described in Example 3, the thioether 2.
50 g (8.65 mmol) yielded 235 g of product as a white crystalline solid. NMR (CDCR3-CD30
D, δ) 8.25.7. gO-7,20,5,80,4
, 8Q, 2.60 tons LCRr O, 35 (Skerisolve B7・'acetone 2.1).

Example 6 2-[(4-ethylthio-3-methyl-2-
pyridinylmethyl)sulfinyl 1-1H-benzimidazole-1-methanol (formula (: A and B are hydrogen, O
is a formula V substituent.

G Ha hydrogen, X Ha=so, R3 hamechi/L,
R2 is ethylthio, R4 is hydrogen) See reaction route A (conversion of A-1 to A-2).

2-[(4-ethylthio-〇-methyl-2-pyridinylmethyl)sulfinyl 1 in 55 ml of acetonitrile
- To a magnetically stirred suspension of henzimidazole (1,00a, 3.02 mmol) 1.13 ml of 37z formaldehyde solution was added at once and the mixture was heated to 65°C.
Heat in an oil bath. Continue heating for 10 minutes. The acetonitrile was then removed in noble air and the resulting B@ colored residue was used in the first step reaction without further purification.

NMR (CDCR36) 810.790-695.59
5.485゜2.70.2.25.113 Dingl-CRr O,33(t' t? l~n'suke'
) 'JL7Bl:l).

Example 7 2-[(4-ethylthio-3-methyl-2-
pyridinylmethyl) sulfinyl 1-1H-henzimidazole-1-methanol acetate (ester) (formula ■: A and 8 are hydrogen, D is a formula V substituent, G is hydrogen, X is =SO, R3 is methyl, R2 is ethylthio, R4 is hydrogen) See reaction route A (conversion of A-1 to A-2).

N-Hydroxymethyl in pyridine 251 (109g□
3.02 mmol) in a magnetically stirred solution of 8 ml of acetic anhydride and 15 ml of 4-N,N-dimethylaminopyridine.
Add 0 mg. Continue stirring for 15 hours at 25°C. The reaction was worked up as previously described. The crude product was chromatographed on silica gel eluting with ethyl acetate to yield an oil 0768 (l) which gradually crystallized.

Recrystallization with ethyl acetate/'ether 7' Scherisolve B yielded 0.591 (l) of product.

Melting point: 132,133°C.

TLCRr　O,38(ethyl acetate).

See Table 1 for physical constants.

Example 82-[(,i-methoxy-3,5-dimethyl)
-2-pyridinylmethyl)thio-1d-zenzimidazole-1-methanol acetate (ester) (Formula 1: A° and 8 are hydrogen, 0 is the 2V substituent, )-1R3
and R4 is methyl, and R2 is methoxy) See reaction route A (transformation of A-1 to A'-3).

To a magnetically stirred solution of N-hydroxymethylthioether (1.30 fl, 3.95 mmol) in pyridine 251 was added 6n+l of acetic anhydride and 40 mg of 4-N,N-dimethylaminopyridine. Stir 25
Lasted 1 hour at °C. At the end of this period, the solution was poured into crushed ice and water. The resulting white solid is filtered off with suction and dried under vacuum at 55° C., yielding 129 g of the title compound.

N) IR (CDCR3, δ) 8.27. 790-7
．． 20.6.15.4.85゜3.80.3.32.2
．． 20.2.02 Mass spectrum C10N22 N3
0: IS: Word 1 Shun value: 372.1382 Measurement (
1g, : 372.1379TLCRf 0.35(
Skerisolve B,・'Acetone 2:1).

Example 9 2-[(2-pyridinylmethyl)dio]-1
8-henzimidazole-1-methanolacedate (
ester) (Formula ■: A and B are hydrogen, 0 is a formula V substituent, X is =S, G is CH3-C
(0)-,, R2, R3 and R4 are methyl) Reaction route A (
(Conversion of A-2 to A-3).

Following the procedure described in the preparation of Example 8, 5.00 g (18j15 mmol) of N- and droxymethylthionidel
yielded 575 g of the title compound as a viscous oil.

NMR (CDCR3,6) 8.60.7.80-7.
13.610. C80°2.03 Mass spectrum C16816N302S calculated value: 3
1JO963 measurement (Direct: 31.i, 0940T!-C
Rf O, 43 (Skerisolve B/'acetone 1:1)
.

Example 10 24 (4-ethylthio-3-methyl-2-
Pyridinylmethyl〉de 1-1 tobenzimidazole-1-methanol acetate-1-cutospur) (Formula ■: A
and 8 are hydrogen D is 2V substituent, X L, i=S, G
C, 1cH3(”, (0)-.

R3 is methyl, R2 is ethyl, R4 is hydrogen) See reaction route A (conversion of A-2 to A4).

Fruit @ Example 8 Teton 1. : Therefore, N-hydroxymethyl f
! Ether 1, 8600 (5.39 milliliters) yielded 1936 g of surface compound as a low melting white crystalline solid.

NHR (COcI,, δ) 8.32.7.95-7.
20.7.05.6.10°A 80.2.95.2.
30.2.03.1.40 1CRf O, 38 (methylene chloride/acetone 41).

Example 112-[(3,4-SijiDraw 2H-Cheno(
3,2-C)pyridinylmethyl)thio 1-1H-benzimidazole-1-methanol acetate (ester)
(Formula L: A and 8 are hydrogen, O is formula II substitution 1%, n is 1,
V ha=s, G is CH3C(0)-) See reaction route A (conversion of A-2 to A-3).

Acetyl Kamijou (according to the cow) already explained in Example 8
N-hydroxymethyl compound 0.322 g (0.94
mmol) gave 0.330 jl of product after chromatography on silica with methylene chloride and acetone 8:1.

NHR (CDCI, , δ) 8.20. 7.90-
7.25. 7.03. 6.15゜4.80.3.0
0.2. ．． 10.2.0. ? .

TLCRf 0.34 (methylene chloride/acetone 6゛1
).

Example 12 2-[[-chloro-3-methyl-2-pyridinylmethyl)thio 1-1H-henzimidazole-1
- Methanol acetate (ester) (Formula I: A and B are hydrogen, 0 is formula V substitution %, G HcH3c(0)-, X
L, 1;=S, J hamethyl, R2 is chloro, R4 is hydrogen) See reaction route A (conversion of A-2 to A-3).

According to the acetylation conditions already described in Example 8, N
-Hydroxymethyl compound 2.35 (1 (7.37 mmol)) after reconsolidation from ethyl acetate/'ether.

Yielded 234 g of product.

N old (CDCl2.δ) 8JO, 7, 85-7, 25
, 6, 15, C90° 2.55.2.03 TLCII 0.48 (Skerin Lube B/Acetone 2°
1).

Example 132-[(2-pyridinylmethyl)thia 1l-
IH-henzimitazole-1-methanol medylsuccinate (ester) C Formula 1: A and 8 are hydrogen, D is a formula V substituent, X is =S, G is CH3C02(CH2)2-C(0 )-1
R2, R3 and R4 are hydrogen) See reaction route A (conversion of A-2 to A-3).

To a magnetically stirred solution of N-hydroxymethylthiounityl (i,084 (1,4,0 mmol)) in 12 ml of pyridine is added 0,600 ml of succinic anhydride (6,0 mmol).
0 mmol) and 10-15 mg of It-N,N-dimethylaminopyridine. Stir shrimp at 25℃ 17
Continue time. At the end of this period, one reaction was diluted with water and
Extract with chloroform. The chloroform solution is washed with saturated brine, dried and i-layered in vacuo. The residual oil is dissolved in methanol/ether (5:1) and treated with ethereal diazomethane. The solvent is then removed in vacuo.

Chromatography of the crude product with ethyl acetate yields the product 1.4250 as a colorless oil.

N14R(C[)C13,6) 8.55.7.75-
7.20.6.08.4.85゜355.255 T'CRr O,47 (acetic acid %/l,).

Example 14 2-II2-pyridinylmethyl)thio]-
18-Benzimidazole-1-methanol octanoate (ester) (formula [: A and 8 are hydrogen, D is a formula V substituent, X is .S.

G is CH5-(CHl)G-C(0)-, R2, R3 and R,) are hydrogen) See reaction route A (conversion of A-2 to A-3).

(1.25 if, 9.0 mmol) and isobutyl chloroformate (1.16 ml, 9.0 mmol) are added.

Stir the contents for 15 minutes at 25°C. At the end of this period, 741H N-hydroxymethylthioether (1,084Q, 4.0 mmol) is added to 10 ml of pyridine and the reaction is stirred for 75 minutes at 25°C. The reaction was then diluted with 300 fil+ of chloroform and 125 ml of water.
1. Saturated bicarbonate, washed with saturated brine, dried, and concentrated in vacuo to yield the crude product. Scherisolve B, 'silica chroma 1 in ethyl acetate (11) graphite silica o 5zr-, g was produced as M, colored viscous oil.

N)4R(CDCl2.δ)8. ．． 60.78G-7,
10, &, 10. d, 80°2.25.1.85-L
Io, 0.88TLCRf O,43 (ethyl acetate 7
7'Skerisolve B2:1) Actual M Example 15 2-[(2-
hijj>2/L methyl) thio 1-IH-henzimidazole-1-methano-, lysoptyl carbonate (ester) (formula ■: A and 8 are hydrogen, D is a formula V substituent, X ha=S, G Ha(CH3)2-C(0)-1R2
，! =R3ToR is hydrogen) See reaction route A (conversion of A-2 to A-3).

To a magnetically stirred solution of N-hydroxymethylthioether (0,7500,2, furimmol) in 20 ml of methylene chloride was added 0.40 ml of triethylamine.
(2,80 mL) and 0.39 flI (3,00 mmol) of isobutyl chloroformate are added. Stirring is continued for 15 hours at 25°C and the reaction is suspended in chloroform 30
Dilute with 0 ml and wash the chloroform solution with saturated sodium bicarbonate and saturated brine and dry over anhydrous sodium sulfate. Removal of the solvent in vacuo yielded 7 g of semi-solid orange oil i,+o. This crude product was used without further purification.

TLCRr O, 40 (ethyl acetate/'Suurisolve B
2.1) Example 16 2-[(2-pyridinylmethyl)
Dio]-18-henzimidazole to 1-methanol isopropionate (ester) (Formula 1: A and 8 are hydrogen,
D is a substituent of formula V, X is =S, G is (CH3)z CH-C(0)-1R2
and R3 and R now hydrogen) See reaction route A (conversion of A-2 to A-3).

Following the same procedure as described in the preparation of Example 2, N-hydroxymethylthioether 0.750 (1(2,7
6 mm/L), isobutyric M0.39 ml (3,0
0miIJmo/L, ), I/butyl chloroformate 0
．． 26/l g (3,00 mmol) and triethylamine 0.42111 (3,00 mmol) to produce 0
530 was obtained as a viscous oil.

N)4R(CDCI3.δ) 8 Go, 7.80-
7.05.6.0δ, It, 80°2.50.1.1
0 TLCRf O,38 (ethyl acetate/skelisosib B2
Example 17 2-[(4-ethylthio-3-methyl-2-pyridinylmethyl)sulfinyl]-1H-benzimidazole-1-carboethoxyester (formula
A and 8 are hydrogen, 0 is a substituent of formula V, R3 is methyl, R2 is ethylthio, R4 is hydrogen, x□ is =SO'+ Y is -c
? o)-o-cHzCH3>Shimedylformamide 10
Sodium hydride (0,067 g, 1.66
0.50 G of 2-[(4-ethylthio-3-methyl-2-pyridinylmethyl)sulfinyl]-1H-benzimidazole (](1,51 mmol) and ethyl chlorophyllate (1,81 mmol) were added. Stirring was continued for 30 minutes at room temperature. The reaction was then diluted with 79 ethyl acid/needle 500 ml (2:3 v/ v
), washed with water and saturated brine, and dried over anhydrous sodium sulfate to remove the organic solvent. Concentration of the solvent in vacuo gave the crude product which was chloride/acetone (4:IV/V3). The homogeneous fractions were combined, the solvent was evaporated and the resulting solid was dissolved in ethyl acetate 2/1-tyl 7/ Recrystallization from Schellisolp B gives the title compound 0.350 (
1 as a light brown solid. Melting point: 135,136°C (decomposition).

Analysis C11N2. N303S2 Total value: C, 56, 58: H, 5, 21: N, 1
0.42: S, 15.88 Measured value: C, 56,22
: H, 532: N1030: S, 15.5.5
Example 18 2-[(Ethylthio-3-methyl-2-pyridinylmethyl)sulfinyl 1-18-benzimidazole-itJ lupoisobutyroxy ester (Formula I:
A and B are hydrogen, O is a substituent of formula V, R1 is methyl, R2 is ethylthio, R
4 is hydrogen, Xl is 1=SO, Y is -c+o)-o-cH
2cH(cH3)2) Following the same procedure as described in Example 1, 2-((4-ethylthio-3-methyl-2-
Pyridinylmethyl)sulfinyl 1-1H-benzimidazole 0.500 (J (151 mmol)) and isobutyl chloroformate O, 411 g (3,02 mmol) yielded the title compound 0.362 Q. Melting point 85-
91℃.

Analysis C21'25"303S2 Calculated value: C, 5847; H, 580; N, 9.7
4; S, 1485 measurement 1st shift: C, 5780: H, 5
,83,N,9.58:S,+4.99Example 19 2
-[(4-ethylthia 1-3-methyl-2-pyridinylmethyl)sulfinyl]-1 day-benzimidazole-
1-Carbobenzyloxyester (Formula ■: A and B are hydrogen.

D is a substituent of formula V, R3 is methyl, R2 is ethylthiA
, R4 is hydrogen, xl = sO, Y = C(0)-0-
2-[(4-ethylthio-3-methyl-2-pyridinylmethyl)sulfinyl 1-1 day-benzimidazole G, 500 Q (151
mmol) and pencil chloroformate 0.310
(+(1.81 mmol)) yielded 0444 g of the title compound as a white crystalline solid. Melting point 156-157°C (decomposition).

Analysis Cz+Hx3N30sSst Calculated value: C, 6194; H, 4,95; N, 9.
03: S, 13.76 measurement value: C, 6154:
N15.03: N, 8.95: S, 13.56゜Example 20 2-[(4-dimethylthio 3-methyl-2-
pyridinylmethyl)sulfinyl]-18-benzimidazole-1-carboxylic methyl (Formula 1: A and 8 are hydrogen, D is a formula V substituent, R3 is methyl, Rλ is T/L,
R4Lt water, X, L, t=SO, Y bar C (0
)-CH2PhX, and U PhX bar/T2/
l, ) Example 1 &, : Follow the steps in j-) : 24
(A-factor f-A-3-me F-2-bi-1J dinylbure) sulfinyl 1-1H-benzimidazole 9
．． 50Q IJ (151 mmol) and fer-chlorophalmate 0.283a (181 mmol) yielded the title compound (293!7) as a leather-colored crystalline solid. Melting point 136-137°C (decomposed).

Analysis C2s”x+N30zSz.

Calculated values: C, 6i, 20; H, 4, 66: N, 9
．． 31: S, 14.19° measurement 1m: C, 60
,77; H, A, 72; N, 9.38: S, 14
．． 33 Example 21 2-((4-ethylthio-3-methyl-2-pyridinylmethyl)sulfinyl]-1H-
Benzimidazole-i-h rubo-nitrohendyloxy ester (formula I: A and 8 are hydrogen, 0 is a formula V substituent, R3 is methyl, R2 is ethylthio, R4 is hydrogen, X is -3O, Y L; l knee C
(0)-0-CH2PhX, 7iHPhX is p-nitrophenyl) Following the procedure described in Example 1, 2-1(A-ethylthio-3-methyl-2-pyridinylmethyl)sulfinyl 1-1d-henzimitazole 0.500 g(i
111 mmol) and 0.390 g (1.81 mmol) of p-21-hensyl chlorophyllate were obtained by tanning 0.409 g of the compound and producing a colored crystalline solid. Melting point 152-153'C (decomposed).

Analysis C,4F82□N405SZ Calculation 1st shift: C,5647; H,431:
N, 10.98: S, 12.55' Measurement 1 shift: C, 56, 36: H1434・N, 10.91:
S, 12.45 Example 22 2-[(l!-Ethylthio-3-methyl-2-pyridinylmethyl)sulfinyl 1
-1H-benzimidazole-1-carbohynyloxy ester (formula I: A and 8 are hydrogen, O is of formula V@substituent R3 is methyl, R2 is ethylthio, R4
is hydrogen, Xl is -5O1Y is -C(0)-0-CH=C
H2) Procedure 1 described in Example 1. : Therefore, 0.5QOg (L
5! mmol) and vinylchlorofornude 0.192
0 (181 mmol) was the Table M compound (), 280 g was produced as a light brown crystal solid (wood, melting point 120-122 ° C.
(Disassembly).

Analysis CI'lH1't"303Syu division 1i: C,5686: l(,474・N,1
0J7j 3, 15.96 measurement direct: C, 56, 85:
H,4,76: N,IQ,,')2: S,1δ77
Example 23 2-[(4-ethylthio-3-methyl-2
-pyridinylmethyl) sulfinyl 1-1H-benzimidazole-1-carboisoprobyloxyester (formula 1: A and 8 are hydrogens 0 is a formula V substituent, R3 is methyl, R2
is ethyl/L, -F-'t, R4ha hydrogen, x, c
, t=so, v ha-C(0)-0-C)l(C)
+3) 2) Following the procedure described in Example 1, 2-
[(4-ethylthio-3-methyl-2-pyridinylmethyl)sulfinyl 1-1 day-penzimidazole 0.5
00 g (1,51 mmol) and isopropyl chloroformate 0,. 224 Q (i, 8i forl) yielded 576 g of color compound o as a pale crystalline solid. Melting point 121-123''C (decomposed).

Analysis C2゜H Yu, N303S2 Timing 1 way: C,5755・H,5,52: N 10
07・S□1535 measurement 1st rectifier: C, 57J8・h, s,
yo: N, 9.91. S, IA, 78 Example 2a
24(a-1del1003-methion-2-pyridinylmethyl)sulfinyl]-1Lhenzrmidazole-1
-Polyoctyloxyester (formula: A and 8 are hydrogen.

D is a substituent of formula V, R3 is methyl, R is ethyl/l, thio, R4 is hydrogen, X1 is SO, Y is C(0)-(C
H117CH3) 0.500 pfl of 2-[(4-ethylthio-3-methyl-2-pyridinylmethyl)sulfinyl]-1 tohenzimidazole, according to the procedure described in Example 1;
51 mmol) and octyl lyloformate o, 35
0 g (1.81 mmol) yielded 0.347 g of the title compound as a white crystalline solid. Melting point 6i-63°C.

Analysis C25H33"303S1 Meter hook 1 shift: C16"160: H, 67g:
N, 8.62・S, 13.111i measurement (tooth: C, 6
1,5:', ・H, 6,68: N, 8.55: S,
13.08 Example 25 2-[(4-ethylthio-3-
Methyl-2-pyridinylmethyl)sulfinyl 1-18
-Henzimidazole-1-carbo-(2-chloroethyloxy)ester (formula ■: A and PJ are water channels, D is a formula V substituent, R3 is methyl, R2 &
cL ethylthio, R4 is hydrogen, Xl is =SO, Y is C(
0)-0-Rb and R6 are 2-chloroethyl) Following the procedure described in Example 1, 0500 g (1
, 57 mmol) and 2-chloroethyl chloroformate 0.259<1 (1,81 mmol) yielded 0.38217 of the title compound as a white crystalline solid. melting point 12
2-124°C (decomposition).

Analysis CpyH2oCIN303Sz S1 1st shift: C, 52, 17: H, 4, 51
'l: N, 9.61: S, 14.65 Measured value:
C, 52,5i; H, 5,02: N, 924:
3,13.74 Example 26 2-[Cethylthio-3-
methyl-2-pyridinylmethyl)sulfinyl]-1)
1-Besizimidasol 1-Carpo (2,2,2
-hlichlorly, 1-dimethylethyloxy)nisnal (
Formula I A and B are hydrogen, 0 is a formula V substituent, R3 is methyl,
R2, is Ejiruchi A・, R+ca /g element, X+
C2=SO, Y L, L -C(0)-0-R6, and R6 is 2.2.2-trichloro-1,1-dimethylethyl) IAI as described in Example 17: Therefore, 2 −[(
, 1-ethylthio-3-methol-2-pyridinylmethyl)sulfinyl 1-IH-benzimidazole 0.5
00 g (1,51 mmol) and 0.4 of 2.2.2-trichloro-1,1-dimethylethyl chloroformate
71 Q (1,81 mmol) is the title compound 0.211
6Q was produced as a white crystalline solid. Melting point: 162°C (decomposed).

Analysis C2, H, □Cl5N, 113Sz measurement value: C6
47,10,H,4,11:N,7.8δ,S,11
96 measurement value: C, 47, 04; H, 4, 31, N, 7
．． 70;S, 11.70 Example 27 2-((1-ethylthio-3-methyl-2-pyridinylmethyl)sulfinyl-1-IH-henzimigsol-1-(ethane-2-ol)ethyl ether la methylform To a magnetically stirred suspension of 60% sodium hydride (0133 (+, 3.32 mmol) in 825 ml of amide was added 2-[(4-ethylthio-3-methyl-2-pyridinylmethyl) under nitrogen. 1,000,000) Sulfinyl 1
1.00 ml (3.02 mmol) of -1H-benzimidazole was added in one solid portion. Stirring was continued for 15 minutes at 25°C. To this reaction mixture was added 1-chloroethyl ethyl ether G, 392 (3,62 mmol) and the contents were stirred for an additional 30 minutes at 25°C.The reaction mixture was then diluted with ethyl ether/ethyl acetate solvent mixture. The organic solvent was dried over anhydrous sodium sulfate, washed successively with saturated sodium bicarbonate, water, and saturated brine. Expansion of the solvent in vacuo yielded 130 g of crude product. Chlorography (silica gel, Skellisolve B/acetone, 3:1) of the crude product yielded the title compound 1.091
3Q was produced as 2 diastereo 7-mixed 4 samples. This mixture is mixed with 1 steel Nidel Scherisolve B) Capacity Mixture 1 If recrystallization is avoided, Diastere 7i 7-type l melting point 1
07-? 11 mixture of i1°C) was produced.

When the same night was reduced by 1 degree and recrystallized, a mixture of 9.1 and 02370 (melting point 115-117℃) was obtained (example 28 2- (f
3,5-dimethyl-4-methoxy-2-pyridi-lmethylnsulfinyl 1-u+-benzimidazole-1-
(methane-1-ol) acetinoester 24(3,5-dimethyl-
6=methoxy-2-pyridinylmethyl)thio 1-1H-
To a magnetically stirred solution of henzimirzole (0,670 g, 2.2 mmol) was added α-bromoethyl acetate 0-a86 g <2.91 mmol. Stirring was continued for 24 hours at room temperature. At the end of this period, the reaction mixture was converted to ethyl acetate/ethyl 1-tyl (1.1
), the known solvent was washed with ice water and saturated brine, and dried over anhydrous sodium sulfate. Expansion of the solvent in vacuo yields a crude product which is eluted with methylene chloride/77t? on silica gel. 24(3,5-dimethyl-4-methoxy-2-pyridinylmethyl)thio2 1H-henzimidazole-1-(ethane-2-ol) acetyl ester 0.201 g.

Next, 1,000 onychill obtained above ((1,201g, 0
．． 52 mmol) was dissolved in chloroform 201 and the solution was cooled in an ice water bath at Q-5°C. This cold solution was then treated with 0.55 mmol of tochloroperbenzoic acid dissolved in 11 chloroform. 0-5'
Continued at C for 15 minutes. At the end of this period, the reaction mixture was diluted with additional chloroform and the chloroform solution was washed with saturated sodium bicarbonate and saturated brine, and dried over sodium sulfate. . Condensation of the solvent in vacuo yielded the crude product. , methylene chloride/acetone (6:
According to the first official of i).

This was chromatographed on silica gel to yield 91m0 of the title compound (melting point 123-1211°C).
.

Four and eleven crystals were obtained from the Schoolisolve B/ethyl ether solvent mixture.

Example 29 General procedure for thioether derivative acid 1
A magnetically interstitial solution of DeA ether (0,1-0,2H) in chloroform cooled in an ice-water bath at -5 DEG C. contains 1. Add 1 equivalent of O-1° and stir for 3 minutes at 0-5°C for 15-2 minutes. On the other hand, dilute (with chloroform), add a saturated solution of 1-lium carbonate in 11 chloroform, and 10% sodium chloride.

Dissolved in sodium carbonate; dissolved, and saturated salt water for the first time in a while:
The first step is to pass it through an acidic bath 1 to 11 to dry it.

The chloro 4, lume solvent, is removed in vacuo and the crude product is purified by silica gel chromatography. Ethyl acetate,
or solvent combinations such as ethyl acetate/methanol, acetone/skelisob B (yielding pure product upon separation).

Table 1 summarizes the compounds produced by the method of t. To some extent, the physical and chemical properties of those things are
listed in the table. In the table, D is a Formula V substituent (ie, a pyridinyl group), and A and a are hydrogen. The pond variables are defined in the table.

Gu Yingzi Road A CH20H -re2LJJ1 Reaction route B ゛ni 11 Also 9j ko LΩ C-2 & response route D O-2R1゜ o-3′FH-0-GI

Claims (1)

[Claims] 1. Compound of formula I▲There are mathematical formulas, chemical formulas, tables, etc.▼
I [wherein X is (a)=S or (b)=SO. A and B are the same or different, and are (a) hydrogen, (b) -R_1 (c) -OR_1 (d) -CF_3 (e) -COR_1 or (f) -CO_2R_1, where R_1 is (C_1-C_4) alkyl. D is a substituent of the following formula II, III, IV or V. ▲There are mathematical formulas, chemical formulas, tables, etc.▼II▲Mathematical formulas, chemical formulas,
There are tables, etc.▼III▲There are mathematical formulas, chemical formulas, tables, etc.▼IV▲There are mathematical formulas, chemical formulas, tables, etc.▼V R_3, R_4 and R_1_0 are the same or different, and (a) hydrogen, or ( b) (C_1-C_4)alkyl. m is 0 or 1. R_2 is the following (a) to (i). (a) -SR_5 (b) -OR_5 (c) -N(R_4)_2 (d) 1-piperidinyl (e) 4-morpholinyl (f) 1-pyrrolidinyl (g) chloro (h) bromo or (i) fluoro R_5 is the following (a) to (e). (a) (C_1-C_4) alkyl (b) (C_2-C_4) alkenyl (c) (C_3-C_6) cycloalkyl (d) -CH_2-PhX or (e) PhX where X is 0 to 3 of the following: phenyl substituted with That is, (a) (C_1-C_4) alkyl, (b) chloro (c) bromo (d) fluoro (e) nitro (f) CF_3 or (g) OR_3 n is 0 or 1. Further, V is the following (a) to (c). (a)=CH_2 (b)=0 or (c)=S G is the following (a) to (g). (a) Hydrogen (b) (C_1-C_4)alkyl (c) -COR_6 (d) -COPhX (e) -CO(CH_2)_mCO_2R_3(f)-
COCH_2PhX or (g)-C(O)-O-R_1_1 R_6 is the following (a) or (b). (a) (C_1-C_1_0)alkyl, or (b)-
AA Here, AA is the following (a) or (b). (a)-(CH_2)_P-CH(NH_2)-R_9
or (b) amino acid side chain R_9 is the following (a) or (b). (a) Hydrogen or (b) (C_1-C_9)alkyl R_1_1 is the following (a) to (g). (a) (C_1-C_1_2) alkyl (b) (C_2-C_1_2) alkenyl (c) -PhX (d) -CH_2PhX (e) (C_1-C_6) cycloalkyl (f) -CH_2-(C_1-C_6) cyclo Alkyl or (g) (C_1-C_6)alkyl substituted with one or more bromo or chloro groups p is an integer from 1 to 9, provided that (1)-(CH_2)_P- and all carbons in R_9 The number of atoms is less than or equal to 9, and (2) m is zero only when G is -C(O)-O-R_1_1, and (3) R_2 of formula V is not -OR_5.
Or, only when V in formula II, III or IV is =S, G is -C(
O)-O-R_1_1. ]
. 2. Formula A-2 ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ The compound of [where X, A, B and D are as defined above] is expressed as (a) -COR_6, -COPhX-CO(CH_2 )
an acid anhydride containing the moiety __mCO_2R_3 or -CO-CH_2PhX and a catalytic amount of N,N-dimethylaminopyridine, or (b) -COR_6-COPhX, -CO(CH_2)
_m-CO_2R_3 or -CO-CH_2PhX, wherein G is -COR
_6, -COPhX, -CO(CH_2)_m-CO_
2R_3 or -COCH_2PhX). 3. (a) Formula B-1▲There are mathematical formulas, chemical formulas, tables, etc.▼ Treat the compound of [in the formula, X, A, B and D are as defined above] with sodium hydride, then (b ) the anion thus produced is treated with a compound of the formula ClCOOR_1_1, in which G is -C(O)-
Manufacturing method (OR_1_1, m is zero). 4. (a) Formula C-1 ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Treat the compound of [where A, B and D are as defined above] with sodium hydride, and then (b) thus The anion created is expressed by the formula CH_3CHX
-COR_1_2 [wherein X is chloro or bromo,
R_1_2 is C_1-C_4 alkyl], wherein G is (C_1-C_4 alkyl).
C_4) Production method of alkyl). 5.Formula D-1▲There are mathematical formulas, chemical formulas, tables, etc.▼ The compound of [where A, B and D are as defined above] is expressed as the formula CH_3-CHX-O-C(O)-R_1_3 [formula In the middle, X is chloro or bromo, R_1_3 is R_6,
PhX, -(CH_2)_m-CO_2R_3 or -C
H_2PhX], wherein G is -COR
_6-COPhX-CO(CH_2)_mCO_2R_
3 or COCH_2-PhX).