JPH0314518A - Drug suppressing secretion of acid in stomach and protecting stomach and intestines - Google Patents

Abstract

PURPOSE: To prepare the subject medicine comprising a thienoimidazole derivative or its physiologically acceptable salt as an active ingredient. CONSTITUTION: This medicine comprises a compound of formula I A is formulae II, III (R<1> and R<2> are each H, a halogen, CN, NO2 , an alkyl, a hydroxyalkyl, an alkoxy, formula IV, etc.), etc.; T is S, SO or SO2 ; R<3> is H, an alkanoyl, an alkylcarbamoyl, etc.; R<4> and R<5> are each H or an alkyl; R<6> , R<8> and R<9> are each H, a halogen, an alkyl, an alkoxy, formula V, etc.; R<7> is formula V; (f) is 1-10; (g) is 1 to [(2f)+1]; (x) is 0 or 1} or its physiologically acceptable salt as an active ingredient. 2-[4-(2,2,3,3,4,4,4-Heptafluorobutyloxy)-2-picolylsulfinyl]-1 H-thieno[3,4-d]imidazole, etc., are exemplified as the compound of formula I. The medicine is used for treating inflammatory gastroenteropathy, gastric ulcer, diarrhea, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION Penzimidazole derivatives having gastric acid secretion suppressing action are disclosed in, for example, German Patent No. A-2548340, European Patent No. A-5129 and German Patent No. 8132402.
It is disclosed in each specification of No. 48. European patent A
Specification No. 170308 (published on April 2, 19g!i) relates to N-monosubstituted penzimidazole derivatives.

The present invention provides the formula I R and R2 are the same or different 1 and hydrogen, halogen, sia6nitro, (C{~C
6) Monoalkyl, (C, -C6) monohydroxyalkyl, (C1-C6) monoalkoxy, -〇[-CH
[2] (c1~C4)
Monofluoroalkyl, kilmerkabuto, (C1-CG)
monoalkylsulfinyl, (01-C6) monoalkylsulfonyl, (C-C') monoalkylcarbonyl, (C1-C6)-16 alkoxy carbonyl, carbamoyl, N-(CI-C
4) Monoalkyl Rubamoyl, N. N-G (C
I-C4) monoalkyl Rubamoyl, (Cl-C6
) monoalkylcarponyloxy, (03-C8) monocycloalkyl, phenyl, benzyl, phenoxy, penzyloxy, anilino, N-methylanilino, phenylmercabuto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C4) monoalkylsulf 7 moyl or N. N-di(1-C4)-monoalkylsulfamoyl, or if A has the definition of (a) or (c) above, R12 and R together also -[CH2].

(one CH2 group optionally substituted by o, s, so or S○2) or one CH-CH-CH
-CH-, 3 R is hydrogen, (C1-CG)-alkanoyl, (C,-
CG) monoalkyl group represents rubamoyl or another physiologically acceptable NilI1 protecting group, which is preferably removed in an acidic medium and/or under physiological conditions, and R and R5 are the same or different 4 and represents hydrogen or (C,-C3)-alkyl, and R, R and R9 are the same or different and represent hydrogen, halogen, (C,-C3)-1 Alkyl, (C, ~Cl2) monoalkoxy, 12 o C - C H2 ), - cr H (2r
+l-g)Fg,NR'R'', (01~Cl2)
monoalkoxy-(C1-C)monoalkyl, (C, -
C12) monoalkoxyl2 (C-C) monoalkoxy, (C7-C11
)1 12 Aralkyloxy, (CI-Cl2)-mono-alkylmerkabuto, (C1-C12)-mono-alkylsulfinyl or (C1-Cl2)-mono-alkylsulfonyl, R7 is -QC-CH2)E Cf H (2f' +1-
g) represents Fg, R5 and R6 together represent -[CH2]i, R' and R' are the same or different;
hydrogen or (Ci-C4)-alkyl, or R' and R'' taken together -[CH2]l, (where one CH group represents O,S,N-(C,~2 C) monoalkanoylimino or N-(C, ~4 C4) monoalkoxy which can be substituted by luponylimino), f is an integer from 1 to IO, preferably from 1 to 4, and g is from 1 to
(2f+1), h is 4 5 or 6, i is 1, 2 or 3, X is O or 1 preferably 1, and n is 3 or 4] This invention relates to medical remedies for suppressing gastric acid secretion and protecting the gastrointestinal tract, which contain imidazole derivatives and their physiologically acceptable salts as active ingredients.

IH-cheno (3
．． 4-d) Imidazole derivatives are more preferred.

More preferred are compounds in which R9 represents hydrogen.

It is preferable that T is -S〇 group.

Particularly preferred compounds of the formula I are those of the formula Φ A preferably has the definition given in (b) above, T preferably represents an -SO- group, and Rl and R2 are the same or the phase y! hydrogen, (Cl-C3) monoalkyl, halogen, (C1
~C4) monoalkoxy or (C1-C4) monoalkoxycarbonyl, R3 represents hydrogen, R4 and R5 each represent hydrogen, RR and R9 are the same or different, hydrogen, Halogen, -0(-CH2), C
f H(2f+l-g)Fg'(CI'=03
) monoalkyl, (C1-C4) monoalkoxy, penzyloxy or (C -C )monoalkoxy-(C
, ~C3)17 alkyl, in particular R9 preferably represents hydrogen and halogen preferably represents chlorine or bromine and/or a compound in which R7 has the above definition. Further particularly preferred compounds of formula I are those in which A preferably has the definition given above in (b), T preferably represents a group -S〇, R and R2 are the same or different { and hydrogen or (C,~C3)monoalkyl, R3 represents hydrogen, R and R5 each represent water, 4 R and R8 are the same or sibling, and hydrogen, base, methyl or ethyl, R9
represents hydrogen and/or 7 R is 10-[CH2]xCfH(2f+1-g)Fg
It is a compound that shows

The following compounds are of particular interest.

2 - (4 - (2, 2, 3.3, 4, 4.5.
5-octafluorobentyloxy)-2-picolylsulfinyl)-1}1-cheno[3,4-d:l imidazole 2-C4-(2,2,3,3,4
, 4.4-hebutafluorobutyloxy)-2-bicolylsulfinyl) 4.6-dimethyl-1H-cheno [
3,4-'d) Imidazole; 2-C4-(2,2.2-}Lifluoroethyloxy)-2-picolylsulfinyl)-4.8-
Dimethyl-il+-thieno(3.4-d)imidazole; 2-[4-(2,2.3.3-tetrafluoropropyloxy)-2-picolylsulfinyl)-
4,G dimethyl-II+-cheno[3,4-d]imidazole2-C4-(2,2,3,3.3-pentafluoropropyloxy)-2-bicolylsulfinyl]-4.6-dimethyl- Ll+-cheno (3,4
-d) Imidazole; 2-[3-methyl-4-(
2,2.2-trifluoroethyloxy)-2-picolylsulfinyl]IH-cheno(3,4-d)imidazole, 2-[5-methyl-4-(2,2.
2-trifluoroethyloxy)-2-picolylsulfinyl]IH-cheno [3.4-d:l imidazole; 4-[3-methyl-(2.2,3,3.3-pentafluorobutyloxy) )-2-picolylsulfinyl)-LH-cheno(3,4-d)imidazole; 2
-[3-methyl-4- (2,2,3,3.4,4.
4-hebutafluorobutyloxy)-2-bicolylsulfinyl-Ill-cheno(3,4-d)imidazole; 2-C4-(2,2.2- }lifluoroethyloxy)-2-bicolylsulfinyl) -Il+
-cheno[3,4-d)imidazole; 2-(4-(2,2.3.3-tetrafluoroprobyloxy)monopicolylsulfinyl)-1.1
1-thieno(3.4-d)imidazole: 2-[4-(2,2,3,3.3-pentafluoroprobyloxy)-2-picolylsulfinyl]
il1-cheno(3,4-d]imidazole; alkyl and radicals derived therefrom, such as alkoxy, alkylmercabuto, alkylsulfinyl, alkylsulfonyl, aralkyl or alkanoyl, can be straight-chain or branched.

(C6-C12) monoaryl is, for example, phenyl, naphthyl or biphenylyl, with phenyl being more preferred.

(07-Cl1) Monoaralkyl is, for example, benzyl or phenethyl, preferably benzyl.

? The same can be said of groups derived from monoaralkyl (C7-C1), such as aralkyloxy groups.

Halogen refers to fluorine, chlorine, bromine or iodine.

CfH(2,+1-g)Fg is a linear or branched fluorinated alkyl group.

Preferred Nifflei: Protecting groups are groups that can be removed in the presence of an acid, preferably in the pH range of about 1 to 6 and/or under physiological conditions.

The optionally present chiral carbon and sulfur atoms are R and S
(rE). In such cases, the compounds of formula I are in the form of pure enantiomers or stereoisomeric mixtures (eg mixtures of enantiomers and mixtures of diastereomers).

Suitable salts are especially alkali metal and alkaline earth metal salts and salts with physiologically acceptable amines.

The compound of formula (1), which is the active ingredient of the medicament of the present invention, can be prepared by: a) reacting with a compound of formula (2) representing N SH, -S or -SO2- and in the case of H representing a leaving group; b) A compound of formula i2 (wherein A, R, R and R3 have the above definitions) is converted into a compound of formula V (wherein A, R1, R2 and R3 have the above definitions and X1 is 1, leaving group or ii, -SH, -S or -SO2-) with the formula
9 has the above definition and x2 is 458 in the case of i above.
78 (wherein R , R , R , R , R and R9 have the above definitions and RIO represents an esterification group), 1. Optionally, -s-At optionally present in the compound of formula I is oxidized to a -S01 or SO2 group, II. Optionally, (-1
-7t -SO- group is oxidized to -SO. In one place, i
ii. Optionally, the compounds of formula I in which R3 is hydrogen are acylated, alkylated or aralkylated, and lv. Optionally, a compound of formula (3) in which R3 does not represent hydrogen is hydrolyzed and V. Optionally, the compound of formula I is converted into a physiologically acceptable salt thereof, wherein two or more of the desired steps 1-1v above are performed in a different order than indicated. It can be manufactured by a manufacturing method consisting of:

According to the more preferable method (a) in the above manufacturing method, the formula
When reacting a compound of formula (1) with a compound of formula (1), X1 or X2 is a leaving group that can be removed nucleophilically, for example Cll.
Br, I, -0-So2-CH3, -O-SO -C
Indicates F3 or -o-so22 (CH-pCHa).

64 The reaction between the compound of formula H and the compound of formula (■) or a salt thereof may be carried out in an inert solvent such as water, methylene chloride, methanol, ethanol, acetone, ethyl acetate, toluene, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide, or any of these solvents. preferably in the presence of an inorganic or organic base such as a sodium or potassium hydroxide, carbonate, alkoxide, hydride or amide, or ammonia, triethylamine, tributylamine or pyridine, preferably from -20 to +150°C. It is carried out at 0 to 80°C.

Compounds of formula H can be prepared analogously to known methods, for example from suitably substituted 2,3-, 3,4- or 4,5 of formula - ring-closing the diaminothiophene with a suitable sulfur compound, e.g. carbon disulfide (e.g. German patent 313218
7)).

The abovementioned 2,3-3,4- or 4,5-diaminothiophene required for this purpose is known from the literature or can be prepared in a general manner analogous to known methods. They are obtained, for example, by reduction of suitably substituted aminonitrothiophenes.

R10 in the ester of formula V used in the method (b) above represents an esterification group, preferably (C -C )1G alkyl or benzyl. (b) The reaction between the compound of formula (■) and the compound of formula V by method is described in Prcston et al.
ncriTricycle CompoundsJ
It is carried out in a manner similar to that described in Part I, Nos. to to 13rT.

The compound of formula (1) thus obtained can be converted into a physiologically acceptable salt when R3 represents hydrogen.

Compounds of formula I in which T is -S- may be converted with suitable oxidizing agents into compounds of formula I in which T is -so- or -SO2-. Similarly, substituent Rl. R2 and R6
-S group in ~R9 can also be oxidized.

The reaction is carried out at -20'C in a suitable inert solvent such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, toluene, ethyl acetate, acetic acid, trifluoroacetic acid, water, methanol, ethanol or mixtures thereof. ~+150℃ preferably -10℃~+4
Performed at 0°C.

Examples of suitable oxidizing agents include hydrogen peroxide, peracids and peresters such as persaucid, trifluoroperacetic acid, monoperphthalic acid, m-chloroperbenzoic acid and their esters,
Ozone, dinitrogen tetroxide, iodosobenzene, N-chlorosuccinimide, 1-chlorobenzo1-lyazole, sodium hypochlorite, potassium peroxodisulfate, t-butyl hypochlorite, tetrabutylammonium periodate or permanganese Tetrabutylammonium acid, sodium metaperiodate, selenium dioxide or manganese dioxide, ceric ammonium nitrate, chromic acid, chlorine, bromine, diazabicyclo(2.2.2)octane-bromine complex, dioxane dibromide, pyridinium perbromate , sulfuryl chloride, 2-arylsulfonyl-3
-aryl oxaziridine, titanium tetraisovirate/t-butyl hydroperoxide (optionally with addition of (D) mono- or (L) dialkyl ester of monotartaric acid and an eyeful amount of water).

Similarly,. l+1! It is also possible to use immobilized oxidizing enzymes or microorganisms as oxidizing agents.

The oxidizing agent is used in equimolar amounts, but optionally T--S
A small excess of 5 to 10 mol % is used in the oxidation to T-, or a larger excess and/or a higher reaction temperature if oxidation to T- is desired. used.

Compounds of formula I in which R3 is H are
and a compound of formula V or by acylation, alkylation or aralkylation of a compound of formula I in which R3 is H. The latter route is discussed in some detail below.

Acylation, alkylation or aralkylation of compounds of formula I is carried out using a suitable acylating, alkylating or aralkylating agent in a suitable organic solvent ψ, optionally in the presence of a base, as a rule at -78°C. It is carried out in a manner known per se at a temperature between the boiling point of the reaction mixture.

The novel compounds of formula I and their salts have valuable pharmacological properties. They significantly suppress gastric acid secretion and additionally have an excellent protective effect on the stomach and intestines.

Here, "protection of the stomach and intestines" refers to gastrointestinal diseases, in particular inflammatory gastrointestinal diseases, which can be caused, for example, by microorganisms, bacterial toxins, drugs (e.g. anti-inflammatory and anti-rheumatic agents), chemical products (e.g. ethanol), gastric acid or stress conditions. Defined as the prevention and treatment of diseases and disorders such as gastric ulcer, duodenal ulcer, gastritis or hyperacidity or drug-related irritable stomach.

The substituted thienoimidazoles of formula I and their pharmacologically acceptable salts are eminently suitable for use in human and veterinary medicine due to their excellent properties, especially for gastric and intestinal diseases. It is also used in the treatment and prevention of diseases due to excessive gastric acid secretion.

According to the present invention, the colonic K''-ATPase enzyme (Gus
Lin et al. rJ. Blol. Chem. J25
B (1981) 10851-10656) also prepared compounds of formula I with acids (e.g. Na of pl14 to 5.5).
It was found that the inhibition was achieved in vitro by a compound obtained by treatment with OAc/HC, pg solution).

Such conversion products may also be produced during passage through the gastrointestinal tract in vivo. Their yield depends on the type of substitution and pll value.

This colonic K''-ATPase is believed to have a major impact on the electrolyte balance across the mucosal barrier of the colon. Therefore, these colonic K''-ATPase inhibitors may affect this balance. and is therefore of use in treating diseases due to disorders of electrolyte balance.

The invention therefore also relates to the use of medicaments containing compounds of formula I and their conversion products with acids as active ingredients for the treatment of diarrheal diseases. Examples of such diseases include inflammatory armpit diseases such as cholera, paratyphoid fever, traveler's diarrhea and other forms of secretory diarrhea, and also other intestinal diseases such as ulcerative colitis and local enteritis.

Thus, the present invention relates to medicaments containing one or more compounds of general formula I and/or pharmacologically acceptable salts thereof, which can be used for the treatment and prevention of the above-mentioned diseases.

The medicament is prepared by techniques known per se and familiar to those skilled in the art. The pharmacologically active compounds (=active compounds) according to the invention can be prepared as tablets, coated tablets, capsules, lozenges, emulsions, suspensions or dispersions, either as such or preferably in combination with suitable pharmaceutical auxiliaries. It is used as a medicine in the form of The content of active compound here is 0. Advantageously, t~96%.

Suitable auxiliaries for the desired formulation are well known to those skilled in the art. In addition to solvents, gel formers, suppository bases, tabletting aids and other active compound excipients, for example antioxidants, dispersants, emulsifiers, antifoams, flavors, preservatives, solubilizers or colorants. Agents can also be used.

The active compound may be administered orally or parenterally, with oral administration being preferred.

Generally, in the case of oral administration of human pharmaceuticals, approximately 0.0. [It has proven advantageous to administer a daily dose of active compound of 1 to about 20 μ, optionally several times, preferably 1 to 4 times, in the form of individual doses. Similar doses or (particularly in the case of intravenous administration of the active compound) in principle lower doses can be used in the case of light administration. Any person skilled in the art can readily determine, on the basis of his or her specialized knowledge, the optimum dosage and dosage spread of the active compound required in each case.

When the compounds of the present invention and/or their salts are used for the treatment of the above-mentioned diseases, the pharmaceutical compositions may further include other pharmaceuticals such as antacids (e.g. aluminum hydroxide, magnesium aluminate), tranquilizers (e.g. penzodiazepines (e.g. diaceham), antispasmodics (e.g. vietamiberine and camylofin), anticholinergics (e.g. oxyfuensilimine and huencarbamide), local anesthetics (e.g. tetracaine and procaine) and optionally gastrin antagonists, enzymes, vitamins or It may also contain pharmacologically active ingredients of one or more amino acids.

For oral use, the active compound is mixed for this purpose with customary excipients, such as vehicles, stabilizers or inert diluents, and then prepared in a customary manner in suitable dosage forms, such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic. It is converted into a liquid suspension or aqueous solution.

Examples of inert excipients that can be used are gum arabic, magnesia, magnesium carbonate, lactose, glucose or starch, especially corn starch. From this, either dry or wet granule formulations can be obtained. Examples of suitable vehicles or solvents include vegetable sources, such as Himawariura, or animal sources, such as fish liver oil.

For subcutaneous or intravenous administration, the active compounds or their physiologically acceptable salts may be dissolved, suspended, if desired using the substances customary for this purpose, such as solubilizers, emulsifiers or further auxiliaries. Convert to suspension or emulsion. Examples of suitable solvents for these novel active compounds and the corresponding physiologically acceptable salts are water, aqueous physiological salt solutions or alcohols such as ethanol, probanol, glycerol and sugar solutions such as glucose or mannitol solutions or the aforementioned Mention may be made of mixtures of various solvents.

Below, an example of manufacturing the active ingredient compound included in the medicine of the present invention will be explained.

Melting points and arcuate points are not corrected or standardized.

Production example 1 2-(4-(2.2,3,3,4.4.4-
hebutafluorobutyloxy)-2-picolylsulfinyl]illcheno(3,4-d)imidazole a)
4-Nitro-2-picoline N-oxide 103.5 g of 2-picoline N-oxide (1.
5 mol) was introduced into 250 ml of 98% sulfuric acid. 1 at room temperature
250 ml of 0.00% nitric acid were added dropwise and the reaction mixture was then carefully warmed to <80'C with stirring and stirred at this temperature for 3 hours. The reaction mixture was cooled to room temperature, poured into 1 g of ice and neutralized with concentrated sodium hydroxide solution while cooling and stirring. Yellow, semi-molten crystals precipitated, which were filtered off with suction, washed with a small portion of ice water and dried. Yield: I811ig (80% of theory),
Melting point: 156°C.

b) 4-(2,2.3,3.4.4.4-heptafluorobutyloxy)-2-picoline N-oxide Compound 15.4 of Preparation Example 1a). (0.1 mol) was dissolved in 150 ml of dimethylformamide, 41.4 g (0.3 mol) of micronized anhydrous potassium carbonate and 96
%2.2.3.23 g (0.11 mol) of 3,4,4.4-heptafluorobutanol were added and the reaction '/l
The mixture was heated to 70°C while stirring. After 4 hours, another 13.9 g of potassium carbonate was added and the mixture was stirred for a further 6 hours. The mixture was cooled to room temperature to remove the salt and washed with a small portion of dimethylformamide. The extract was concentrated under vacuum, and the residue was extracted with water/ethyl acetate. The organic layer was dried over Na2S04, concentrated and filtered over silica gel using ethyl acetate/methanol 3:1. After concentrating the honeycomb solution, 22.7 g (74% of theory) of the title compound were isolated. Melting point: 65°C.

c) 2-rolomethyl-4-(2.2,3.3
．． 4,4.4) -Heptafluoroptyloxyviridine Compound 4 of Preparation Example 1b) in 450 ml of acetic anhydride
Stir 9.1g at 90℃ for 1 minute! L. Control example T
LC is 2-acetyloxymethyl-4-(2,2
, 3.3, 4, 4.4) -Heptafluorobutyloxypyridine showed complete conversion. The solvent was evaporated in vacuo and the curved residue was dissolved in 500 ml of methanol,
A solution of 12 g of sodium hydroxide dissolved in 50 ml of water was added. After stirring for 2 hours at room temperature, TLC of the control showed that the acetate was completely saponified. The solvent was removed in vacuo and the residue was dissolved in methylene chloride and washed with water. After drying over Na2SO4, the organic layer was concentrated in vacuo. Dilute the residue with 500ml of chloroform.
50 ml of thionyl chloride was added dropwise under stirring. The reaction mixture was heated to reflux for 1 hour and then allowed to cool. The solvent was removed in vacuo, the residue was dissolved in methylene chloride, the solvent was evaporated again, the residue was taken up in diisopropyl ether and the title compound crystallized. Yield: 39 g (67% of theory), melting point 98-101''C.

d) 2 - (4 - (2.2,3,3,4,4
．． 4-hebutafluorobutyloxy)-2-picolylmercap}]-1}i-thieno[3.4-d]imidazolecheno(3,4-d)imidazole-2-thiol 18.7[y] was dissolved in sodium methylate overnight. (prepared from 8.2 g of sodium and 300 ml of methanol) and dissolved in 100 ml of methanol.
A solution of 43.8K of compound lle) was added with stirring.

After heating to reflux for 1 hour, TLC of the fish sample showed the reaction was complete. The solvent was evaporated in vacuo and the residue was dissolved in methylene chloride and washed with water. The organic layer was dried over Na2S04 and concentrated in vacuo. The residue was triturated with diisopropyl ether, filtered with suction and dried. Yield = 43g (80% of theory), melting point 11
7℃.

c) 2 − (4 − (2, 2.3, 3, 4.4
．． 40.0 g of the mercabuto compound of 4-heptafluorobutyloxy)-2-picolylsulfinyl]-1H-cheno(3,4-dl imidazole Preparation Example 1d) was dissolved in 800+ nl of methylene chloride and dissolved in aqueous phosphate buffer ( pt {approx. 7) 500 ml was added. The suspension was stirred vigorously and a solution of 77% metachloroperbenzoic acid 2OK dissolved in 150 ml of methylene chloride was added dropwise at 0°C. The reaction mixture was stirred for a further 10 minutes at this temperature and then the organic layer was separated from the aqueous layer after iodine paper no longer showed the presence of the peracid. The aqueous layer was extracted with 100 ml of methylene chloride and the organic layers were combined, dried over Na2S4 and concentrated in vacuo to a volume of about 100 ml. After adding 800 ml of diisopropyl ether, crystallization (
Is this already? 5n) has been completed. The crystals were removed by suction and dried. Yield u: 32g (theoretical amount 7
6%), melting point 140°C (decomposition).

The following compounds were prepared in a similar manner.

Production example 2 2 - (4 - (2, 2, 3, 3, 4.4, 5.
5-octafluorobentyloxy)-2-picolylsulfinyl]-IH-thieno[3.4-d]imidazole Melting point: t1B to 119°C (decomposition).

Production example 3 2-(4-(2,2.3,3.4,4.4-
heptafluorobutyloxy)-2-picolylsulfinyl]4,6-dimethyl-II+-cheno(3.4-d
) Imidazole melting point = 147°C (decomposed).

Production example 4 2-(4-(2.2.2-}refluoroethyloxy)-2-picolylsulfinyl)-4. G~
Dimethyl-il1-cheno(3,4-d)imidazole Melting point: i63-LG5°C (decomposed).

Production example 5 2-(4-(2,2,3.3-tetrafluoropropyloxy)-2-picolylsulfinyl)-4
．． 6-Dimethyl-111-cheno(3,4-d)imidazole Melting point: 144-147°C (decomposed).

Production example 6 2-[4-(2,2,3,3.3-pentafluoroprobyloxy)-2-bicolylsulfinyl]
4.6-dimethyl-ill-cheno[3.4-d) imidazole Melting point: 147-151''C (decomposed).

Production Example 7 2- [3-Methyl-4-(2,2.2-trifluoroethyloxy)-2-picolylsulfinyl]
1H-thieno [3.4-d) Imidazole melting point:
12L'c (decomposition).

Production example 8 2-[5-methyl-4-{2,2.2-}lifluoroethyloxy]-2-picolylsulfinyl]
I H-cheno(3,4-d)imidazole Melting point: 16
3°C (decomposition).

Production Example 9 4-[3-Methyl-(2.2,3,3.3-pentafluorobutyloxy]-2-picolylsulfinyl)
-LH-cheno[3,4-d)imidazole melting point = 14
5°C (decomposition).

Production example 10 2-[3-methyl-4 - (2,2,3,3,4,4
．． 4-heptafluorobutyloxy)-2-picolylsulfinyl-111-cheno[3,4-d)imidazole Melting point = 115°C (decomposed).

Preparation example 1l 2-(4-(2,2.2- }lifluoroethyloxy)-2-picolylsulfinyl)-II+-
Cheno (3.4-d) Imidazole Melting point: 132-130°C (decomposed).

Production example 12 2-C4-(2.2,3.3-tetrafluorobutyloxy)-2-picolylsulfinyl)-n
+-cheno[3,4-cD imidazole Melting point: l52°C (divided).

Production example 13 2-(4-(2,2,3,3.3-pentafluoropropyloxy)-2-bicolylsulfinyl)
-11m Cheno[3.4-d) Imidazole Melting point: 148-152°C (decomposed).

Production example i4 2-C4-(1,1,1,3,3.3-hexafluoroisopropyloxy)-2-picolylsulfinyl)-1H-cheno(3,4-d) imidazole a) 4-( 1,1,L,3,3.3-hexafluoroisobutyloxy)-2-picoline N-oxide The title compound was obtained in a similar manner to Preparation Example 1t+) using potassium t-butyrate as the base. Ta.

b) 4-(1,1,1,3,3.3-hexafluoroisobrobyloxy)-2-picoline Preparation 4.5 g (18 mmol) of the compound of Example 14a) was dissolved in 100 ml of methanol, Hydrogenation was then carried out using Raney nickel as a catalyst.

MS: m/e -259 (M'', 100%)
, 240 (30%), 220 (8%)・, 80 (77
%) c) 2-Quoomethyl-4-(1,1,1,3,
3.3-hexafluoroisobutyroxy)monopyridine hydrochloride 2.2 g (8.8 mmol) of the compound of Preparation Example 14b)
was dissolved in 5 Gml of tetrachloromethane, 0.56 g of dimethylformamide and 1.4 g (5.G mmol) of l.lichloroisocyanuric acid were added and the reaction mixture was heated under reflux for 1 hour. The precipitate was removed, 30 ml of IN hydrochloric acid in methanol was added to the solution and the solvent was evaporated in vacuo. The crude product was used for the next step without further purification.

d) 2 − [4 − (1, 1, 1, 3.3.3
-hexafluorisopropyloxy)-2-picolylmercabuto)-1H-cheno (3,4-d) The title compound of imidazole was prepared in a similar manner to Preparation Example 1d) and the compound of Preparation Example 14c) and Cheno[ 3,4-d] imidazole-2-thiol.

e) 2 − (4 − (1, 1, 1, 3, 3.3
-hexafluorisopropyloxy)-2-bicolylsulfinyl]-111-cheno (3,4-d)imidazole The title compound was obtained from the compound of Preparation 14d) in an analogous manner to Preparation 1e). Melting point 168-169
°C [from diethyl ether].

Next, the in vitro biological activity of the compounds of the present invention was determined by: 1. H/K-ATPase assay, and 2. 3. Inhibition of acid-forming capacity in gastric glands. Pylorus ligation rat4. Measurements were made on gastric lumen perfusion rats and 5, attached large Heidenhain small stomachs.

The methods for these tests are as follows.

In vitro assay 1. Testing using gastric vesicles containing H K -ATPase Membrane vesicles containing H",K"-ATPase were tested in the following literature: Ljungscrom M. Norberg L,
Olaisson H. Wernstedt C. V
ega FV, Arvidson G and Ma
rdhS, Characterization o
"protontransportlngmembra"
nes rroll1resting pig gas
tric rHucosa. 131ochim. bjo
phys. Acta 789: 209-219.1
984. It was prepared from pig stomach as described in .

ATPase activity was measured as the release of inorganic phosphate from ATP at 37°C. That is, IOμM
A concentration of a compound of the invention was pre-incubated in an oxygen-containing buffer at pH 6.0. After preincubation (37°C, 30 min), the medium at pl{6.0 was plied using Heves/Tris buffer.
Adjusted to H7.4. The enzymatic reaction was started by adding Tris-ATP. The total reaction volume is lml, 20
■ Vesicle protein, 4 mM MgCO2, lO
+nM K CO , 20 ug Nidiericin,
It contained 2mM Tris-ATP, IOrnM Hepes, and an additional 2mM Bipes for pre-incubation at pH 8.0.

The reaction was stopped after 4 minutes by adding 10 μQ of 50% trichloroacetic acid. The denatured protein was centrifuged, and the Pi content was determined according to the following reference 1. eBel D,
Poirier GO and Beaudoin
AR, A conventional method
r the ATPase assay. Analysis.
Blochem. 85: IIS-89. 197
It was measured by the method described in 8. Hydrolysis of ATP is 1
It did not exceed 5%. The extent of inhibition was calculated as % inhibition relative to the maximal stimulus, and ICso was calculated by probit analysis.

2. Accumulation of 14c-aminopyrine in gastric glands of isolated rabbits Rabbits (2-3 kg) were sacrificed under anesthesia by cervical fracture/dislocation. High-pressure treatment of rabbit stomachs is described in the following literature: Bergllndh T and obrink KJ.
,8method rorpreparing iso
lated glances from the ra
bbitgastric mucosa. 8et
a physiol. scan. 98:1
50-159. 1978, as described. The gastric mucosa throughout the body was peeled off and chopped with scissors. Mucosal pieces were incubated for 30-40 min at 37°C in medium containing collagenase (lmg/ml).
Incubate for 5 minutes. This medium is 100.0
μM Na Cp, 5.0 mM KCR,
0.5 mM NaH2PO4, lom
M's Na HP○ 1. OmM CaCJ7
, 1.52 4' 2mM Mg CR 2 , 20.0mM NaH
C O a, 20.0 m M Hepes, 2+ng/m
1 of glucose and 1/ml of rabbit albumin, and its pH was adjusted to 7.4 with 1M Tris. The glands were passed through a nylon mesh to remove coarse fragments and incubated in incubation medium for 3
I rinsed it. The glands were diluted to a final concentration of 2-4 mg dry weight/ml.

The ability of the gastric glands to form acid is determined by the method for measuring AP accumulation in the following literature: Bergllndh T, Helander Ha
nd oblink KJ, ErrectSorsec
retagogues on oxygen consu
mption. aminopyrine accumulation
ulation and morphology In
isolated gastric grounds. A
cta physiol. scan. 97: 4
01-414. 1976. It was measured with That is, l
．． Oml glandular suspension samples were incubated with the compounds of the invention at 37° C. in a shaking water bath at 0.05°C. L μC i /ml'
It was equilibrated in t, rom1 medium containing C-AP. 2
After 0 minutes, 1 mM abcA MP was added and then incubated for 45 minutes. The glands were then separated from the culture medium by brief centrifugation, and a portion of the supernatant and digested gland pellet was counted in a liquid scintillation counter. AP accumulation was calculated as the ratio of AP in the intraglandular water to AP in the incubation medium. The method is as in the following literature.

Sack J and Spensey JG. Am
inopyrine accumulation b
y nammallan gastric grand
s: analysis or the technique
ique. Am. J. Physiol. 2432G313-G319.19g2. All measurements were performed in triplicate. IC5o was calculated by propit analysis, where 0% corresponds to base and 100% corresponds to maximum stimulated AP ratio.

In vivo assay 3. Pyloric ligation rat This test was carried out in the following document 11crllng AW, Ljungstro I8M.
．． Ef'l'ccts orvcrapaIIlil
on gas Lr4c acid sccrcNon
in vitro and in vivo. Euro
．． J. PharIIlaco1. 156; 341
-50. 1988. Weight 150-170g as described in
The study was conducted in female Wistar rats. Subjects were fasted for 16 hours before the start of the test and had free access to water.

The pylorus of the stomach was ligated under ether anesthesia, and then the compound of the present invention was administered intraperitoneally (ip). The compound is Ty
suspended in loseR (1%) and 5 mg/
With a dose of 2 ml/kg, a dose of 2 ml/kg was administered. Gastric acid secretion was stimulated by subcutaneous (S.C) injection of 400 μg/kgffi Desglugastrin. This desglugastrin injection was repeated 1 hour later. Three hours after the start of the experiment, the animals were sacrificed, the stomach was removed, and the accumulated gastric juice was collected and its volume was measured. Acid concentration was determined by electrometry using 100 mM NaOH with an end point of pH 7.

The total output of acid (mmol H+/3 hours) was calculated.

The % inhibition of treated rat groups was calculated compared to the control group.

4. Anesthetized male Sprague weighing 300-350 g.
- Reference Herling AW et al., Eur. J. Pharm
acol. 156; 341-50. 1988. I fixed all of them as 1 and 5 were posted.

Briefly, animals were fasted for 18 hours prior to the experiment and had free access to water. The animals were anesthetized using 30% (v/V) urethane (5 ml/kgi.m.) and the trachea was incised. The esophagus and pylorus were ligated, a double lumen perfusion cannula was inserted, and secured in the proventriculus.

The stomach was continuously perfused with melon saline (37°C) at a rate of 1 m 17 min. The perfusate was collected every 15 minutes and its acid concentration was determined by electrometry using room M NaOH with an end point of pH 7.
/15 minutes) was calculated. 4 to stimulate acid secretion
After a basal period of 5 minutes, histamine (LO+ng
/kg/fl3) was administered by intravenous infusion into the jugular vein. Approximately 90 minutes after the start of injection of the secretagogue, acid secretion reached a stable plateau.
g.AW. Biekel M. Thestimul
atory erf'ect of rorskoli
on gastor {eacid secreti
on in rats. Eur. J. Pharm
acol. 125: 233-239, 1986. )
. The compound of the invention was then administered intravenously #:j-(25% D
MSO, lml/rat).

The degree of inhibition was expressed as the value before mulberry administration (prcclrug v
The value was calculated as an average change % with respect to (alue), and the value was rounded down and expressed as a multiple of 5%.

5. Six female beagle-sized dogs fitted with Heidenhain microstomachs were examined in the above-mentioned document Herllng AW. Ra's E
ur. J. Pharmacol; 156; 34
1-50, 1988.

For intraduodenal (1.d.) administration studies, an additional 3
A cannula was inserted into the duodenojejunal flexure of two dogs.

These dogs were trained to adopt the Pavlovian posture. The animals were fasted for 8 hours before the experiment and had free access to water.

Gastric acid secretion was induced by intravenous infusion of 0.05 μ/kg/h of histamine, which causes the most irritation. Gastric juice was collected from the small stomach at 30 min intervals and treated with 100 m M N
The acidity was determined by titration with aOH to an end point of p}17, and the acid output (mmol H+/30 min) was calculated. Compounds of the invention were administered at an intravenous dose of 0.3 mg/kg or an intraduodenal dose of 1 mg/kg in a volume of 20 ml per dog as soon as acid secretion stabilized. Compounds were dissolved in 25% DMSO or 40% polyethylene glycol 400. The degree of inhibition was calculated as the average % change relative to the predrug value, and the value was rounded up and expressed as a multiple of 5%.

When the above test items were conducted on the compounds obtained in Production Examples 1 to 14, the results shown in Table 1 below were obtained for each test item.

(Left below) As is clear from the above, the medicine containing the substituted thienoimidazole derivative of the present invention as an active ingredient is used for the purpose of suppressing gastric acid secretion and protecting the gastrointestinal tract in dairy animals including humans. extremely useful. This medicinal effect is supported by the above-mentioned in vitro and in vivo test results, and the usefulness of the present invention is clear.

Claims (1)

[Claims] 1) Formula I ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, A is a) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, b) ▲ Numerical formulas, chemical formulas, tables, etc. etc. ▼ or c) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, T indicates -S, -SO- or -SO_2-, R^1
and R^2 are the same or different, hydrogen, halogen, cyano, nitro, (C_1-C_6)-
Alkyl, (C_1-C_6)-hydroxyalkyl,
(C_1-C_6)-alkoxy, -O[-CH_2]
_x-CfH_(_2_f_+_1_-_g)F_g-
OCF_2Cl, -O-CF_2-CHFCl, (C_
1~C_6)-alkylmercapto, (C_1~C_6
)-Alkylsulfinyl, (C_1-C_6)-alkylsulfonyl, (C_1-C_6)-alkylcarbonyl, (C_1-C_6)-alkoxycarbonyl, carbamoyl, N-(C_1-C_4)-alkylcarbamoyl, N,N-di -(C_1-C_4)-alkylcarbamoyl, (C_1-C_6)-alkylcarbonyloxy, (C_3-C_8)-cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl,
N-(C_1-C_4)-alkylsulfamoyl or N,N-di-(_1-C_4)-alkylsulfamoyl, or when A has the definition of (a) or (c) above R^1 and R^2 are also together -[CH_2]_n- (one CH_2 group is optionally substituted by O, S, SO or SO_2)
or -CH=CH-CH=CH-, R^3 is hydrogen, (C_1-C_6)-alkanoyl, (
C_1-C_6) - represents an alkylcarbamoyl or another physiologically acceptable N^i^m protecting group, which can preferably be removed in an acidic medium and/or under physiological conditions, and R^ 4 and R^5 are the same or different and represent hydrogen or (C_1-C_3)-alkyl, and R^7 is -O[-CH_2]_x-C_fH_(_2_
f_+_1_-_g_)F_g, R^6, R^8 and R^9 are the same or different, hydrogen, halogen, (C_1-C_1_2)
-Alkyl, (C_1-C_1_2)-alkoxy, -
O[-CH_2]_x-C_f-H_(_2_f_+_
1_-_g_)F_g, -NR'R'', (C_1~C_
1_2)-alkoxy-(C_1-C_1_2)-alkyl, (C_1-C_1_2)-alkoxy-(C_1
~C_1_2)-alkoxy, (C_7~C_1_1)
-aralkyloxy, (C_1-C_1_2)-alkylmercapto, (C_1-C_1_2)-alkylsulfinyl or (C_1-C_1_2)-alkylsulfonyl, or R^5 and R^6 taken together -[CH_2 〕＿i
-, R' and R'' are the same or different,
represents hydrogen or (C_1-C_4)-alkyl, or R' and R'' together represent -[CH_2]_h-(
Here, one CH_2 group is O, S, N-(C_1 to C_
4) -alkanoylimino or N-(C_1 to C_4
)-alkoxycarbonylimino), f is an integer from 1 to 10, g is 1 to (2f+1), h is 4, 5 or 6, and i is 1.2 or 3 , x is 0 or 1, and n is 3 or 4] and a physiologically acceptable salt as active ingredients. . 2) Claim 1 containing as an active ingredient a compound of formula I in which R^9 represents hydrogen or a physiologically acceptable salt thereof.
Medications listed. 3) A medicament according to claim 1, wherein A contains a compound of formula I having the definition of (b) according to claim 1 or a physiologically acceptable salt thereof as an active ingredient. 4) Claim 1 containing a compound of formula I in which T represents -SO- or a physiologically acceptable salt thereof as an active ingredient.
Medications listed. 5) R^1 and R^2 are the same or different, hydrogen, (C_1~C_3)-alkyl, halogen, (C_1~C_4)-alkoxy or (C_1~
C_4)-alkoxycarbonyl, R^3 represents hydrogen, R^4 and R^5 each represent hydrogen, and R^6, R^8 and R^9 are the same or different; , hydrogen, halogen, -O[-CH_2]_x
-C_fH_(_2_f_+_1_-_g_)F_g,
(C_1-C_3)-alkyl, (C_1-C_4)-
Alkoxy, benzyloxy or (C_1-C_7)
-Alkoxy-(C_1~C_3)-alkyl, R^7 is -O[CH_2]_x-C_fH_(_2_f
I
The medicament according to claim 1, which contains a compound of or a physiologically acceptable salt thereof as an active ingredient. 6) R^1 and R^2 are the same or different and represent hydrogen or (C_1-C_3)-alkyl, R^3 represents hydrogen, and R^4 and R^5 each represent hydrogen; , R^6 and R^8 are the same or different and are hydrogen, chlorine, methyl or ethyl, R^9 represents hydrogen, and R^7 is -O[-CH_2]_x -C_fH_(_2_
2. Medicament according to claim 1, containing as active ingredient a compound of formula I or a physiologically acceptable salt thereof, f_+_1_-_g_)F_g and f, g and x have the definitions according to claim 1. 7) Compound 2-[4-(2,2,3,3,4,4,4-
2. The medicament according to claim 1, which contains as an active ingredient, heptafluorobutyloxy)-2-picolylsulfinyl-1H-thieno[3,4-d]imidazole or a physiologically acceptable salt thereof.