KR900004042B1 - Substituted thienoimidazol derivatives and a process for their preparation - Google Patents

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Description

Substituted thienoimidazole derivatives and preparation method thereof

The present invention relates to novel thienoimidazole derivatives of general formula (I) useful as gastric acid secretion inhibitors and their physiologically acceptable salts, and methods for their preparation:

In the above formula,

And T represents -S-,-SO-or-SO _2- , R ¹ and R ² are the same or different and are hydrogen, halogen, cyano, nitro, trifluoromethyl, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆₎ - hydroxyalkyl, (-C ₁ C ₆₎ alkoxy, (C ₁ -C ₄₎ - _{fluoro-alkoxy, -OCF 2 Cl, -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 ) -alkoxy carbonyl, 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- (C ₁ -C ₄ ) -alkylsulfamoyl, or wherein A is (a) or (c) in the case of, R ¹ and R ² together are - [CH _2] may indicate the n- or -CH = CH-CH = CH-, here One CH ₂ group is optionally substituted by oxygen, sulfur, SO or SO _2, R ³ is hydrogen, alkanoyl, (C ₁ -C ₆₎ - alkyl-carbamoyl, or preferably an acid medium and / or a physiologically Represents another physiologically acceptable N ^lm protecting group that can be removed under physiological conditions, R ⁴ and R ⁵ are the same or different and represent hydrogen or (C ₁ -C ₃ ) -alkyl, R ⁶ , R ⁷ , R ⁸ and R ⁹ are the same or different and are hydrogen, halogen, (C ₁ -C ₁₂ ) -alkyl, (C ₁ -C ₁₂ ) -alkoxy, —O-CH ₂ -C _f H _{(2f + 1- g)} F _g , -NR'R ", (C ₁ -C ₁₂ ) -alkoxy- (C ₁ -C ₁₂ ) -alkyl, (C ₁ -C ₁₂ ) -alkoxy- (C ₁ -C ₁₂ ) -alkoxy , (C ₇ -C ₁₁₎ - aralkyloxy, (C ₁ -C ₁₂₎ - alkylmercapto, (C ₁ -C ₁₂₎ - alkyl sulfinyl, or (C ₁ -C ₁₂₎ - indicate the alkylsulfonyl Or R ⁵ and R ⁶ together represent — [CH ₂ ] ₁ — and R ′ and R ″ are the same or different and represent hydrogen or (C ₁ -C ₄ ) -alkyl, or R ′ and R ″ With the-[CH ₂ ] _h −, wherein one of the CH ₂ groups is substituted by oxygen, sulfur, N- (C ₁ -C ₄ ) -alkanoylimino or N- (C ₁ -C ₄ ) -alkoxycarbonylimino F is 1,2,3 or 4, g is 1 to (2f + 1), h is 4,5 or 6, i is 1,2 or 3 and n is 3 or 4 .

The present invention also relates to substituted thienoimidazole derivatives, pharmaceutical compositions containing them and their use as gastric acid secretion inhibitors.

Benzimidazole derivatives having the action of inhibiting gastric acid secretion are described, for example, in German Patent A-2548340, European Patent A-5129, and German Federal A-3240248. EP-A-176308, published April 2, 1986, relates to N-substituted benzimidazole derivatives.

Preference is given to 1H-thieno [3,4-d] imidazole derivatives of formula (I) wherein A is (b) as defined above. Moreover, the compound of general formula (I) in which R <^9> represents hydrogen is preferable. T is preferably a -SO- group.

Preferred compounds of formula (I) are those in which A is preferably as defined in (b) above, T preferably represents a -SO- group, R ¹ and R ² are the same or different and are hydrogen, (C _1- C ₃ ) -alkyl, halogen, (C ₁ -C ₄ ) -alkoxy or (C ₁ -C ₄ ) -alkoxycarbonyl, R ³ is as defined above and R ⁴ and R ⁵ each represent hydrogen Or R ⁶ , R ⁷ , R ⁸ and R ⁹ are the same or different and represent hydrogen, halogen, (C ₁ -C ₃ ) -alkyl, (C ₁ -C ₄ ) -alkoxy, benzyloxy or (C ₁ -C ₇₎ - alkoxy - (C ₁ -C ₃₎ - represents alkyl, R ⁹ is preferably a hydrogen, a halogen is a compound that preferably chlorine or bromine.

Particularly preferred compounds of formula (I) are those in which A is preferably as defined in (b) above, T preferably represents a -SO- group, R ¹ and R ² are the same or different and are hydrogen or (C ₁₎ -C ₃ ) -alkyl, R ³ is as defined above, R ⁴ and R ⁵ each represent hydrogen, R ⁶ and R ⁸ are the same or different and represent hydrogen, chlorine, methyl or ethyl, R ⁹ Is hydrogen and / or R ⁷ is hydrogen, (C ₁ -C ₄ ) -alkoxy, (C ₁ -C ₃ ) -alkyl or benzyloxy.

The following compounds are of particular interest: 2- (2-picolylsulfinyl) -1H-thieno [3,4-d] imidazole: 2- (4-methoxy-2-picolylsulfinal) -1H -Thieno [3,4-d] imidazole: 2- (4-methoxy-3-ethyl-2-picolylsulfinyl) -1H-thieno [3,4-d] imidazole: 2- ( 4-ethoxy-3,5-dimethyl-2-picolylsulfinyl) -1H-thieno [3,4-d] imidazole: 2- (3-methyl-2-picolylsulfinyl) -1H- Thieno [3,4-d] imidazole: 2- (5-methyl-2-picolylsulfinyl) -1H-thieno [3,4-d] imidazole: 2- (4-methyl-2- Picolylsulfinyl) -1H-thieno [3,4-d] imidazole: 2- (5-ethyl-2-picolylsulfinyl) -1H-thieno [3,4-d] imidazole: 4 , 6-dimethyl-2- (5-methyl-2-picolylsulfinyl) -1H-thieno [3,4-d] imidazole: 2- (3-chloro-4-methoxy-2-picolyl Sulfinyl) -1H-thieno [3,4-d] imidazole.

Alkyl and radicals derived therefrom, for example alkoxy, alkylmercapto, alkylsulfinyl, alkylsulfonyl, aralkyl or alkanoyl, may be straight or branched.

(C ₆ -C ₁₂ ) -aryl is, for example, phenyl, naphthyl or biphenylyl, preferably phenyl.

(C ₇ -C ₁₁ ) -aralkyl is for example benzyl or phenethyl preferably benzyl. This applies correspondingly to radicals derived therefrom, such as aralkyloxy. Halogen represents fluorine, chlorine, bromine or iodine.

R ³ preferably represents hydrogen, (C ₁ -C ₆ ) -alkylcarbamoyl or a radical of formula (VI):

-(CO-O-) _p (CR ¹¹ R ¹² -O-) _g WB (VI)

Wherein p represents 0 or 1, g represents 0 or 1, B represents hydrogen, acyl radical or optionally substituted alkyl radical, R ¹¹ and R ¹² are the same or different and hydrogen, (C _1- C ₆ ) -alkyl, (C ₃ -C ₈ ) -cycloalkyl, (C ₇ -C ₁₁ ) -aralkyl or (C ₆ -C ₁₂ ) -aryl, wherein B and R ¹¹ together are also r 3 , 4 or 5, preferably 4 phosphorus-[CH ₂ ] r-, wherein one hydrogen atom in each case on one or more CH ₂ groups is OH, protected OH, amino, acylamino and / Or substituted by halogen. Radicals having a substituted [[CH ₂ ] r-chain are preferably derived from glycopyranose, glycofuranose or oligosaccharides and optionally partially or fully protected by protecting groups customary in carbohydrate chemistry. It is a glycosyl radical.

Both α- and β-glycosidic linkages of glycosyl radicals are possible.

For example, naturally occurring aldotetoose, aldopentose, aldohexose, ketopentose, deoxyaldose, aminoaldose and oligosaccharides (e.g., disaccharides, trisaccharides) It may be a glucofuranosyl or glucopyranosyl radical derived from their stereoisomers.

These glycosyl radicals are specifically produced from ribose (Rib), arabinose (Ara), xylose (Xyl), lysoose (Lyx), allose (Al1) and altrose produced in microorganisms, plants, animals or humans. (Alt), glucose (Glu), mannose (Man), gulose (Gu1), idose (Ido), galactose (Gal), taloose (Tal), erythose (Ery), Throse (Thr), Sicoose (Psi), Fructose (Fru), Sorbose (Sor), Tagatose (Tag), Xylose (Xyu), Fucose (Fuc), Rhamnose (Rha), Olivose (Oli) ), Olio (O1o), Mikaros (Myc), Rhodosamine (RN), N-acetylglucosamine (Glc NAc), N-acetylgalactoseamine (GalNAc), N-acetylmannoseamine (Man NAc) Natural D- or L-monosaccharide, or maltose (Mal), lactose (Lac), cellobiose (Ccl), genthiobis (Gen), N-acetyl lactoseamine (Lac NAc), chitobiose ( Chit), β-galactopyranosyl- (1-3) -N-a 2-deoxy, 2-amino-, 2-acetic, as well as disaccharides such as tigalactoseamine and β-galactopyranosyl- (1-3) -or- (1-4) -N-acetylglucosamine Derived from their synthetic derivatives, such as amido- or 2-halogeno-, preferably bromo- or iodo-sugars.

Conventional protecting groups in carbohydrate chemistry are in particular optionally modified as well as, for example, (C ₁ -C ₆ ) -alkanoyl (eg acetyl, trichloroacetyl and trifluoroacetyl), benzoyl or P-nitrobenzoyl Is considered to be a (C ₁ -C ₁₀ ) -acyl protecting group such as methyl, methyloxymethyl, benzyl, tetrahydropyranyl, benzylidene, isopropylidene or trityl group, wherein the acyl protecting group, in particular acetyl Preference is given to the (Ac) group.

a) When p and q are 0, the radicals preferably have the following meanings: W is a bond or represents -CO-,-CR ¹³ R ¹⁴ -or-CO-CR ¹³ R ^14- .

B is hydrogen (when W is not a bond), (C ₁ -C ₁₀ ) -alkyl: (C ₂ -C ₁₂ ) -alkenyl: (C ₃ -C ₁₂ ) -cycloalkyl: (C ₁ -C ₄ ) -alkyl, chlorine, bromine, fluorine, nitro, trifluoromethyl, (C ₁ -C ₄ ) -alkoxy and hydroxyl optionally substituted by the same or different l, 2 or 3 radicals selected from the group consisting of (C ₆ -C ₁₂ ) -aryl: up to 4 selected from the group consisting of the acyl radicals of-(CH ₂ ) s-CH (NH ₂ ) -R ¹⁵ amino acids, wherein S is 1-9, or F, Cl and Br (C ₁ -C ₆ ) -alkyl substituted by the same or different radicals.

R ¹³ and R ¹⁴ are the same or different and are hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkoxy, (C ₃ -C ₈ ) -cycloalkyl, (C ₇ -C ₁₁ ) -Aralkyl, (C ₆ -C ₁₂ ) -aryl or pyridyl, or R ¹³ and R ¹⁴ together are-[CH ₂ ] ₄ ,-[CH ₂ ] ₅ -or- [CH ₂ ] _6- Wherein one or two CH ₂ groups may be substituted by oxygen.

R ^l5 is hydrogen or (C ₁ -C _l0) - represents an alkyl. .

b) When q is 1, W and B are as defined above (a). In addition, W may represent —CO—O— and —CO—O—CR ¹³ —R ¹⁴ —, wherein R ¹³ and R ¹⁴ have the aforementioned meanings. When W is a bond, B may also represent hydrogen.

c) When P is 1 and q is 0, W represents a bond or -CR ¹³ R ¹⁴ -and R ¹³ and R ¹ are as defined (a) above. B is the same as (a) defined above, but cannot represent an acyl radical of an amino acid. In addition, -CO-OWB refers to other N ^1m protecting groups of urethane groups not included in the above-mentioned definitions [see, for example, Hubbuch, Kontakte Merck 3/79 14-23: Bullesbach, Kontakte Merck 1/80]. 23-35].

Optionally substituted (C ₆ -C ₁₂ ) -aryl radicals (see: (a) as defined above, for example, phenyl, (o-, m-, p-) tolyl, (o-, m-, p-) Ethylphenyl, 2-ethyl-tolyl, 4-ethyl-o-tolyl, 5-ethyl-m-tolyl, (o-, m-or p-) propylphenyl, 2-propyl- (o-, m-or p Tolyl, 4-isopropyl-2, 6-xylyl, 3-propyl-4-ethylphenyl, (2,3,4-, 2,3,6-or 2,4,5-) trimethylphenyl, (o-, m- or p-) fluorophenyl, (o-, m- or p-trifluoromethyl) phenyl, 4-fluoro-2,5-xylyl, (2,4-, 2, 5-, 2,6-, 3,4- or 3,5-) difluorophenyl, (o-, m-or p-) chlorophenyl, 2-chloro-p-tolyl, (3-, 4- , 5- or 6-) chlororollyl, 4-chloro-2-propylphenyl, 2-isopropyl-4-chlorophenyl, 4-chloro-3,5-xylyl, (2,3-, 2,4- , 2,5-, 2,6-or 3,5-) dichlorophenyl, 4-chloro-3-fluorophenyl, (3- or 4-) chloro-2-fluorophenyl, (o-, m- Or p-) trifluoromethylphenyl, (o-, m-or p-) ethoxyphenyl, (4- or 5-) chloro-2-methoxyphenyl, 2,4-dicle As-it is understood to be a (5 or 6) or phenyl (o-, m- or p-) methoxyphenyl.

(C ₁ -C ₁₀ ) -alkyl is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl or isomeric forms thereof.

(C ₃ -C ₁₂ ) -cycloalkyl also includes alkyl-substituted cycloalkyls, and bicyclic and polycyclic systems. This is for example cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclo Butyl, 2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, 2-pentylcyclopentyl, tert-butylcyclopentyl, 2,2-diethylcyclohexyl, cycloheptyl It is understood to include cyclononyl, cyclodecyl, norbornyl or adamantyl.

The acyl radicals of the amino acids are preferably, for example, H-Gly, H-Ala, H-VAl, H-Leu, H-Ile, H-Phe, H-Lys, H-Pro, H-Trp, H A series of naturally occurring products such as -Met, H-Ser, H-Thr, H-Cys, H-Tyr, H-Asn, H-Gln, H-Asp, H-Glu, H-Arg, H-Orn It is understood that they are the radicals of the α-amino acids or the α-amino acids from their colon, or the corresponding radicals in the D-configuration.

Without limiting the object of the invention, a few urethane protecting groups R ³ = -CO-O-VB according to the invention can be mentioned: (C ₁ -C ₆ ) -alkoxy such as BOC Carbonyl:

(C ₃ -C ₁₂ ) -cycloalkyloxycarbonyl such as:

와 같은 (C₃-C₁₂)-사이클로알킬-(C₁-C₆)-알콕시카보닐 :

Such as (C ₃ -C ₁₂₎ - cycloalkyl, - (C ₁ -C ₆₎ - alkoxycarbonyl:

와 같은 (C₆-C₁₂)-

Such as (C ₆ -C ₁₂ )-

Aryl - (C ₁ -C ₆₎ - alkoxycarbonyl:

- 및 2-및 3-피콜린으로부터 유도된 그들의 라디칼과 같은 변형된 Z라디칼은 (C₆-C₁₂)-아릴에 대해 상기 언급한 바와같이 치환될 수 있다.And substituted Z radicals such as Z (P-NOz) and-

And modified Z radicals such as their radicals derived from 2- and 3- picolin, may be substituted as mentioned above for (C ₆ -C ₁₂ ) -aryl.

Preferred N ^1m protecting groups are groups which can be removed in the presence of an acid, preferably in the range of pH about 1 to 6 and / or under physiological conditions.

Crabs surprised oof, compounds of formula (I) R ³ is not hydrogen is even more secure than the corresponding compound in R ³ is hydrogen. In particular, they are more stable in acidic conditions and in the presence of water, for example as above. Thus, the specific selectivity of the N ^1m protecting group allows the experts in the art to control the release of active compounds in the same way that they selectively act on the site of action.

The chiral carbon and sulfur atoms present may optionally be present in both the R and S configurations. In this case, the compound of general formula (I) is in pure enantiomeric form or as a mixture of stereoisomers (such as a mixture of enantiomers and a mixture of diastereomers).

Particularly suitable salts are alkali metal and alkaline earth metal salts, and salts with physiologically acceptable amines.

The present invention provides a process for a) reacting a compound of formula (II) with a compound of formula (III), or b) reacting a compound of formula (IV) with a compound of formula (V), Accordingly, the -S-group (s) present in the compound of formula (I) are oxidized to -SO- or -SO ₂ -group (s), and (ii) optionally The -SO-group (s) present in the compound are oxidized to -SO ₂ -group (s), and (iii) optionally, acylation, alkylation, or the compound of formula (I) wherein R ³ is hydrogen Aralkylated, (iv) optionally hydrolyzing a compound of formula (I) wherein R ³ is not hydrogen, and (v) optionally, physiologically acceptable compounds of formula (I) To a salt thereof, wherein two or more of the above steps (i) to (iv) may be carried out in a different order than the mentioned order, thereby producing a compound of formula (I) It is about.

Wherein A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are as defined above and X ¹ represents (a) a leaving group or (b) represents -SH, -S- or -SO _2-, X ² indicate an (a) the above mentioned X ¹ is -SH, -S- or -SO ₂ - a indicates the X ^l is referred to above ( B), a leaving group is indicated, and R ¹⁰ represents an esterified group.

According to the preferred method (a) in this connection, when reacting a compound of formula (II) with a compound of formula (III), X ¹ or X ² is C1, Br, I, -O-SO ₂ -CH Leaving groups that can be nucleophilically removed, such as ₃ , -O-SO ₂ -CF ₃ or -O-SO _2- (C ₆ H ₄ -pCH ₃ ).

The reaction of a compound of formula (II) with a compound of formula (III) or a salt thereof is, for example, water, methylene chloride, methanol, ethanol, acetone, ethyl acetate, toluene, detrahydrofuran, acetonitrile, In an inert solvent such as dimethyl formamide, dimethylsulfoxide or a mixture of these solvents, at -20 ° C to 150 ° C, preferably 0 to 80 ° C, advantageously for example sodium or potassium hydroxide, carbonates, alkoxides, hydroxides It is carried out in the presence of inorganic or organic bases such as lide or amide, ammonia, triethylamine, tributylamine or pyridine.

Compounds of formula (II) can be prepared, for example, by ringing appropriately substituted 2,3-, 3,4- or 4,5-diaminothiophenes of formula (IV) as defined above with suitable sulfur compounds such as carbon disulfide. It can be prepared by a method similar to the known method (for example, Federal Republic of Germany Patent No. A-3132167).

The 2,3-, 3,4- or 4,5-diaminothiophenes required for this purpose can be prepared by methods known in the literature or analogous to known methods. These are obtained, for example, by reducing suitably substituted aminonitrothiophenes.

R ¹⁰ in the ester of general formula (V) used in process (b) represents an esterified group, preferably (C ₁ -C ₆ ) -alkyl or benzyl.

The reaction of the compound of formula (IV) with the compound of formula (V) according to method (b) is described in Prestone et al., Benzimidazoles and Congeneric Tricyclic Compounds, Part 1, New York, pages 10-13. It is carried out in a similar way to the method.

When R ³ represents hydrogen, the compound of formula (I) thus obtained can be converted into a physiologically acceptable salt.

In addition, compounds of formula (I) in which T is -S- may be converted to compounds in which T is -SO- or -SO ₂ -using a suitable oxidizing agent. Substituents R ¹ , R ² and the -S-group in R ⁶ to R ⁹ may be oxidized in the same manner.

The reaction is carried out at -20 ° C to a suitable inert solvent such as, for example, methylene chloride, chloroform, carbon tetrachloride, 1.2-dichloroethane, toluene, ethyl acetate, acetic acid, trifluoroacetic acid, water, methanol, ethanol or mixtures thereof. It is carried out at + 150 ° C, preferably at -10 ° C to + 40 ° C.

Examples of suitable oxidizing agents are: hydrogen peroxide, peracids and peresters (e.g. peracetic acid, trifluoroperacetic acid, monoperphthalic acid, m-chloroperbenzoic acid and their esters), ozone, N ₂ O ₄ , iodine benzene , N-chlorosuccinimide, 1-chlorobenzotriazole, sodium hypochlorite, potassium peroxodisulfate, t-butyl hypochloride, tetrabutylammonium periodate or permanganate, sodium metaperiodate, selenium dioxide Or manganese dioxide, cerium ammonium nitrate, chromic acid, chlorine, bromine, diazabicyclo [2,2,2] octane bromine complex, dioxane dibromide, pyridinium perbromide, sulfuryl chloride, 2-arylsulfonyl-3-aryl Oxaziridine, titanium tetraisopropylate / tert-butyl hydroperoxide, optionally with dialkyl ester of (D)-or (L) -tartaric acid and the addition of the aforementioned amounts of water.

Likewise, isolated, optionally immobilized, oxidases or microorganisms can be used as oxidant. In the case of oxidation to T = -SO-, the oxidizing agent is used in an equimolar amount, optionally in a slight excess of 5 to 10 mol%, or more excess if desired for oxidation to T = -SO _2-. Or use a higher reaction temperature.

R ³ ≠ H the compounds of formula (I) is prepared using the compound of the compound and the formula (V) of the formula (IV) is R ³ ≠ H as a starting material, or, R ³ = H in the formula ( The compounds of I) can be prepared by acylation, alkylation or aralkylation. The second path will be described in detail below.

The acylation, alkylation or aralkylation reactions of the compounds of formula (I) are carried out using suitable acylating agents, alkylating agents or aralkylating agents in a suitable organic solvent, usually in the presence of a base, usually in the presence of a base at -78 ° C to the reaction mixture. By a known method.

The N ^1m protecting group of the general formula (VI) wherein p = 0, q = 1, w = bonding and B = hydrogen, for example, is a compound of the general formula (I) by hydroxy alkylation (R ³ = H, T = S) and formaldehyde hydroxymethylation in an organic solvent such as acetonitrile to provide a known method (e.g. Eur. J. Med. Chem. 15 [1980] 586: J. Med. Chem. 22 [1979] 1113), it is possible to introduce an N ^1m protecting group of formula (VI) wherein R ¹¹ = R ¹² = hydrogen. The hydroxyalkylation reaction is carried out at 0 ° C. to the boiling point of the reaction mixture, optionally in the presence of a base such as triethylamine.

The hydroxymethyl compound of formula IV can be converted to a formula acyl derivative by the method described on page 11 of EP-A-176308:

Wherein A, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ have the same meanings as mentioned above and WB is an acyl radical.

Compounds of formula (I) wherein R ³ = H can also be alkylated in a known manner using reagents and formulas (IX) such as, for example, chloromethyl pivalate to obtain the corresponding carbonate (W = -CO-O). -Or-CO-O-CR ¹³ R ¹⁴ ) can be obtained:

This reaction is carried out by the method described, for example, in page 12 of EP-A-176308.

The acyl radical of the amino acid is coupled to a compound of formula (I) wherein R ³ = H by known methods (eg, Dcc / HoBt or dialkylphosphine anhydride method).

N ^1m protecting group of formula (VI) with p = 0, q = 1, and R ¹¹ and / or R ¹² ≠ hydrogen correspond to compounds of formula (I) (R ³ = H, T = S) It is introduced by reacting with 1 to 10 equivalents, preferably 2 to 3 equivalents of α-halogenoalkyl ester. The α-halogenoalkyl esters used are acidified by known methods (see, eg, J. Amer. Chem. Soc. 43 [1921] 660: J. Med. Chem. 23 [1980] 469-474). Obtained from halides and aldehydes.

Preferably bromoalkyl esters are used. On the one hand, the anions of the compounds of formula (I) (R ³ = H, T = S) which can be obtained from compounds of formula (I) (R ³ = H, T = S) and NaH are α-halo Can be treated with a genoalkyl ester.

Also, instead of a-halogenoalkyl esters, known (1-arylcarbonyloxyalkyl) pyridinium salts from the corresponding acyl halides, aldehydes and pyridines (see Angew. Chem. Suppl. 1982, 675-685) It is also possible to use (1-arylcarbonyloxyalkyl) pyridinium salts prepared analogously.

R ³ is, p = 0, q = 1 and w is a bond or -CR ¹³ R ¹⁴ - denotes a, B is an alkyl amino of formula (I) represents the radical of formula (VI) having the above-mentioned meaning Acetal reacts the above-mentioned compound of formula (I) (R ³ = H, T = S) in a dipolar aprotic solvent such as dimethylformamide at about 20 to 50 ° C., preferably at about 25 ° C. In about 1 equivalent, the obtained anion is treated to obtain an anion, and then the anion obtained is reacted with about 1 equivalent of the halogenoether of the general halogen-CR ¹¹ R ¹² -WB (halogen = chlorine or bromine), wherein the reaction mixture is Stir at about 20-50 ° C., preferably about 25 ° C. for 15 minutes. Halogenoethers are known and many of them are commercially available or can be prepared analogously to known compounds.

The urethane of formula (I) wherein R ³ represents a urethane protecting group of formula (VI) (p = 1, q = 0 and w = bonding or —CR ¹³ R ^14- ) is the corresponding compound wherein R 3 = H By reacting with an ester of fluoroformic acid or chloroformic acid of formula C1 (F) -CO-O-WB in a suitable solvent such as DMF (see page 12 of European Patent A-176308). In a similar manner to the process described) is prepared from the corresponding compound wherein R ³ = H.

Fluoroformates and chloroformates are known and are often commercially available or can be prepared by known methods.

Aralkyloxycarbonyl and alkoxycarbonyl groups may also be introduced using known dicarbonates commonly available, such as di-tert-butyldicarbonate and dibenzyldicarbonate.

Substituted or modified Z groups in which R ¹³ and / or R ¹⁴ are not hydrogen are prepared by reacting the corresponding unprotected compound of formula (I) with an appropriate azide or suitable carbonate, optionally with the aid of a base.

Acylation reactions of compounds of general formula (I) (R ³ = H, T = S) include conventional standard conditions (e.g. acetic anhydride, triethylamine, dimethylaminopyridine) and e.g. N- (1 And other methods such as the reaction with -arylcarbonyloxyalkyl) pyridinium salts (known from Angew. Chem. Supp. 1982, 675-685).

Dialkoxy derivatives of formula (I) (R ³ = CR ¹³ R ¹⁴ -B, wherein R ¹³ and R ¹⁴ each represent alkoxy, or together represent alkylenedioxy and B represents hydrogen: T = S Or to produce SO), it is preferred to react the corresponding compound of formula (I) with R ³ = H in the presence of a base with a suitable ortho formate such as trialkyl orthoformate.

In addition to the thienoimidazole derivatives described in the exemplary embodiments, it is also possible, according to the invention, to obtain compounds of the general formula (I) or salts thereof, for example, as described in Table 1 below.

Abbreviations are used as follows: methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), hexyl (Hex), acetyl (Ac), phenyl (Ph), cyclo (c), iso ( i).

TABLE 1a

TABLE 1b

TABLE 1c

TABLE 1d

TABLE 1e

TABLE 1f

Table 1g

Table 1h

TABLE 1i

TABLE 1j

Table 1k

TABLE 1L

[Table 1m]

TABLE 1n

Table 1o

Table 1p

TABLE 1q

TABLE 1r

Table 1s

Table 1t

TABLE 1u

Table 1v

Novel compounds of formula (I) and their salts have useful pharmacological properties.

They significantly inhibit gastric acid secretion and also have good protective action against the stomach.

In the above, "protection of the stomach" means gastrointestinal disorders, in particular, for example, by microorganisms, bacteriotoxicity, medicaments (eg anti-inflammatory and rheumatoid therapies), chemicals (eg ethanol), gastric acid or stress conditions. It is defined as the prevention and treatment of gastroenteritis and lesions that may be caused (eg, gastric ulcer, duodenal ulcer, gastritis, or hyperacidity or sensitive stomach to the drug).

Due to their excellent properties, substituted thienoimidazoles of formula (I) and their pharmacologically acceptable salts are used for the treatment and prophylaxis of these diseases, in particular due to gastrointestinal diseases and excessive gastric acid secretion. It is very suitable for use as human and veterinary medicine.

In addition, compounds obtained when the compound of formula (I) is treated with an acid (e.g., NaOAc / HC1 buffer at pH 4-5.5) may be subjected to colon K ⁺ -ATPase enzyme (see Gustin, Goodman J) in vitro. . Biol. Chem. 256/1981 / l0651-10656). This conversion product may also be produced during passage through the gastrointestinal tract in vivo. The amount of this conversion product produced depends on the type of substitution and the pH value.

Crystal-K ⁺ -ATPase is thought to have a significant effect on electrolyte balance through the mucosal barrier in the colon. Accordingly, colon-K ⁺ -ATPase inhibitors as mentioned above may affect the equilibrium and thus are useful for treating diseases involving imbalances of electrolytes.

Accordingly, the present invention also relates to the use of the general formula (I) compounds and their acid conversion products for the treatment of diarrhea. Examples of such diseases are enteritis diseases such as cholera, paratyphoid, traveler's diarrhea and other forms of secretory diarrhea, and other enteric diseases such as ulcerative colitis and topical colitis.

The invention also relates to a conversion product produced upon treatment of a compound of formula (I) with an acid.

Accordingly, the present invention also provides a general formula according to the invention for use for the treatment and prevention of the abovementioned diseases.

It relates to the compound of (I).

Likewise, the present invention encompasses the use of the compounds of the present invention for the preparation of a medicament that can be used to treat and prevent the aforementioned diseases.

The invention also relates to medicaments containing one or more compounds of general formula (I) and / or their pharmacologically acceptable salts.

These drugs are prepared by known methods and are well known to those skilled in the art. The pharmacologically effective compound (= active compound) according to the present invention, as it is or in combination with a suitable pharmaceutical adjuvant, may be in the form of tablets, tablets, capsules, suppositories, emulsions, suspensions or solutions. It is used, the content of the active compound is advantageously 0.1 to 96%.

Suitable adjuvants for the desired pharmaceutical formulation are well known to the experts on the basis of the knowledge of the experts. In addition to solvents, gel-forming agents, task bases, tablet aids and other active compound excipients, for example antioxidants, dispersants, emulsifiers, anti-foaming agents, flavoring agents, preservatives, solubilizers or coloring agents can be used.

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

Generally, several times, preferably one to four times, as appropriate, to provide a daily dose of about 0.01 to about 20 mg of active compound or compounds per kg of body weight for human pharmaceuticals to achieve the desired result. Oral administration in the form of individual administration has been found to be advantageous. For parenteral administration, similar doses or alternatively smaller doses (especially in the case of intravenous administration of the active compound) may be used. All experts, based on their expertise, can easily set the appropriate dosage and dosage form of the active compound required in each case.

When the compounds of the present invention and / or their salts are intended to be used for the treatment of the above mentioned diseases, pharmaceutical compositions such as, for example, antacids such as aluminum hydroxide, magnesium aluminate: such as benzodiazepines (eg diazepam) Mental stabilizers: antispasmodics, such as, for example, vietamiberine and camilopin; Choline inhibitors such as, for example, oxyphenylimine and fencarbamide; For example, it may contain one or more pharmacologically active ingredients from other groups of drugs, such as local anesthetics such as tetracaine and procaine, and optionally gastrin antagonists, enzymes, vitamins or amino acids.

In the case of oral administration, the active compounds are mixed with conventional additives for these purposes, such as vehicles, stabilizers or inert diluents, to tablets, tablets, hard gelatin capsules, aqueous, alcoholic or oily suspensions in a conventional manner. Or is converted into a form suitable for oral administration such as aqueous, alcoholic or oily solutions. Examples of inert excipients that can be used are gum arabic, magnesia, magnesium carbonate, lactose, glucose or starch, especially corn starch. These may include preparations such as dry or wetting agents. Examples of suitable oily vehicles or solvents are vegetable and animal oils, such as sunflower oil or fish liver oil.

In the case of subcutaneous or intravenous administration, the active compounds or their physiologically acceptable salts may optionally be employed as solutions, suspensions or solutions using conventional materials for this purpose, such as solubilizers, emulsifiers or further auxiliaries. Switch to emulsion. Examples of suitable solvents for the novel active compounds and corresponding physiologically acceptable salts include water, physiological saline solutions or alcohols such as ethanol, propane or glycerol, as well as sugar solutions such as glucose or mannitol solutions, or There is a mixture of various solvents.

The following examples are intended to illustrate the process for preparing the compounds mentioned as representative examples, without limiting the invention.

The melting point and decomposition temperature mentioned are not calibrated or standardized.

Example 1

2- (4-methoxy-2-picolylmercapto) -1H-thieno [3,4-d] imidazole dihydrochloride.

1.6 g of 2-mercaptothieno [3,4-d] imidazole and 50 g of 4-methoxypicolinylchloride hydrochloride in 50 ml of ethanol are heated at 60 ° C. for about 1 hour and stirred for an additional 40 hours at room temperature. After filtering the crystalline material, it is suspended in acetone, the mixture is stirred at room temperature for 1 hour, and then the crystals are suction filtered and dried in air. Colorless crystals, melting point 330 ° C.

Example 2

2- (4-methoxy-2-picolylmercapto) -1H-thieno [3,4-d] imidazole.

2.lg of 2- (4-methoxy-2-picolylmercapto) -1H-thieno [3,4-d] imidazole dihydrochloride are suspended in 100 ml of methanol, followed by addition of 1.9 g of triethylamine. . The resulting solution is stirred at room temperature for 1 hour to distill to remove the solvent. After adding 50 ml of water, the mixture is stirred at room temperature for about 1 hour, then the crystals are filtered out and dried to recrystallize from ethanol in the presence of activated charcoal. Colorless crystal, melting point 172-175 캜.

Example 3

2- (4-methoxy-2-picolylsulfinyl) -1H-thieno [3,4-d] imidazole.

50 ml of methylene chloride was added to 0.9 g of 2- (4-methoxy-2-picolylmercapto) -1H-thieno [3,4-d] imidazole at room temperature and then cooled to 0 ° C., followed by 3- 0.64 g of chloroperbenzoic acid is added little by little. The mixture is stirred for about 5 minutes with cooling, then 20 ml of saturated sodium bicarbonate solution is added and the mixture is stirred for an additional 10 minutes at room temperature. The organic phase is removed and then dried over sodium sulfate, distilled to remove the solvent, the residue is stirred with a mixture of diisopropylether and acetone and the crystals are filtered to dry. Colorless crystals, Melting point 142-144 캜.

Example 4

2- (4-methoxycarbonyl-2l picolylmercapto) -1H-thieno [3,4, -d] imidazoledihydrochloride.

The title compound was prepared from 2-mercapto-6-methoxycarbonylthieno [3,4-d] imidazole and 4-methoxy-2-picolinylchloride hydrochloride in a similar process to that described in Example 1. To obtain. Colorless crystal, melting point 210 to 213 ° C.

Example 5

6-methoxycarbonyl-2- (4-methoxy-2-picolylmercapto) -1H-thieno [3,4-d] imidazole.

The title compound is obtained from the compound of Example 4 in a process similar to that described in Example 2. Colorless crystals, melting point 156 to 160 ° C.

Example 6

2- (2-picolylmercapto) -1H-thieno [3,4-d] imidazole dihydrochloride.

In a process analogous to that described in Example 1, the title compound is obtained from 2-picolylchloride hydrochloride and 2-mercapto-1H-thieno [3,4-d] imidazole in solvent isopropanol. Colorless crystals, melting point 154 to 162 캜.

Example 7

4-methoxycarbonyl-2- (2-picolylmercapto) -1H-thieno [3,4-d] imidazole hydrate hydrochloride.

A title compound is obtained from 2-mercapto-4-methoxycarbonyl-1H-thieno [3,4-d] imidazole and 2-picolinylchloride hydrochloride in a similar process to that described in Example 6. . Colorless crystals, melting point 204 to 208 캜.

Example 8

Sodium salt of 2- (5-methyl-2-picolylsulfinyl) -1H-thieno [3,4-d] imidazole.

0.036 g of sodium hydroxide is dissolved in 15 ml of methanol, 0.24 g of 2- (5-methyl-2-picolylsulfinyl) -1H-thieno [3,4-d] imidazole is added to the solution, followed by 30 minutes at room temperature. Stir while. Distillation under reduced pressure removes the solvent and the product is crystallized from ethyl acetate and filtered. Colorless to light, melting point 320 ℃.

Example 9

2- (5-methyl-2-picolylsulfonyl) -1H-thieno [3,4-d] imidazole.

At 0 ° C., methylene chloride was added to a two-phase mixture consisting of 20 ml of methylene chloride, 20 ml of saturated aqueous sodium carbonate solution and 1 g of 2- (5-methyl-2-picolylmercapto) -1H-thieno [3,4-d] imidazole. A solution of 1.34 g of 3-chloroperbenzoic acid in 25 ml is added. The mixture is stirred at 0-5 ° C. for 30 minutes, the organic phase is separated off, dried over calcium chloride and distilled to remove the solvent. Using ethyl acetate / methanol = 8: 1 as the mobile phase, the black residue is purified on silica gel by column chromatography to crystallize from ethyl acetate. Colorless crystals, melting point 163 캜.

Example 10

2- (4-methoxy-2-pyridylmethylsulfinyl-1H-benzothieno [2,3-d] imidazole.

a) 3.2 g of 3-amino-2-nitrobenzo [d] thiophene at 1 bar and at room temperature, in the presence of Raney nickel, hydrogenated in 100 ml of methanol until the theoretical amount of hydrogen is absorbed and then Under distillation to remove the solvent from the filtrate. The resulting 2,3-diainobenzo [b] -thiophene was dissolved in 200 ml of dichloromethane without further purification, and 3.56 g of thiocarbonyldiimidazole were added, and the mixture was reacted at room temperature for 48 hours. 2-mercapto-1H-benzothieno [2,3-d] imidazole is filtered. Crystal, melting point 230 DEG C or higher.

b) 0.97 g of 4-methoxypicolinyl chloride hydrochloride was added to a mixture of 1 g of 2-mercapto-1H-benzothieno [2,3-d] imidazole and 50 ml of isopropane, 10 ml of water and 0.4 g of NaOH, The mixture is stirred at reflux for 2 hours and then distilled off to remove the solvent. The residue was dissolved in 40 ml of water, the solution was extracted with ethyl acedate and distilled to remove the solvent, then 2- (4-methoxy-2-picolylmercapto) -1H-benzothieno [2,3-d] Imidazole is produced as a viscous amorphous material.

c) 0.6 g of m chloroperbenzoic acid was added to a solution of 1 g of 2- (4-methoxy-2-picolylmercapto) -1H-benzothieno [2,3-d] imidazole in 75 ml of dichloromethane at room temperature. After stirring for 20 minutes, saturated aqueous sodium bicarbonate solution is added and the organic phase is separated. Under reduced pressure, the solvent is removed by evaporation and treated with a small amount of ethyl acetate and diisopropyl ether to induce crystallization. Colorless solid, over 90 ℃.

Example 11

3-chloro-4-methoxy-2-picolin-N-oxide.

At −10 ° C., 3.5 g of 3,4-dichloro-2-picolin-N-oxido in 20 ml of anhydrous methanol is added to a sodium methylate solution prepared from 0.51 g of sodium and 20 ml of methanol. The mixture is slowly warmed to room temperature and then heated to reflux for 1 hour. The solvent is then removed by distillation under reduced pressure, water is added to the residue, the mixture is extracted with dichloromethane and the solvent is evaporated to remove. Colorless crystal from diisopropyl ether, melting point 94-97 ° C.

Example 12

3-chloro-2-hymidimefil-4-methoxypyridine.

At 90 ° C., 5.8 g of 3-chloro-4-methoxy-2-picolin-N-oxido is dissolved in 8 ml of glacial acetic acid while stirring, and 14 ml of acetic anhydride are added. The mixture is heated at 110-115 ° C. for 2 hours, then cooled to 80 ° C. and 25 ml of methanol is added dropwise. Then, the solvent was removed by distillation under reduced pressure, and then 20 ml of water and 8 g of sodium hydroxide were added little by little to the residue, and the mixture was heated to reflux for 2 hours. After cooling, the mixture is extracted with dichloromethane, the solvent is removed by evaporation and the residue is crystallized by treatment with diethyl ether. Solid, melting point 103 to 105 ° C.

Example 13

3-chloro-2-chloromethyl-4-ethoxypyridine hydrochloride.

At −10 ° C. to −15 ° C., a solution of 3.5 ml of thionyl chloride in 25 ml of dichloromethane is added dropwise to a mixture of 2.6 g of 3-chloro-2-hydroxymethyl-4-methoxypyridine and 30 ml of dichloromethane, and then the mixture is added. Is stirred at room temperature for 2 hours. The solvent is removed by evaporation and the residue is crystallized with diethyl ether. Colorless crystals, melting point 145 to 146 ° C.

Example 14

a) 3-acetylamino-3, '5-dimethoxycarbonyl-2-nitrothiophene

The compound is obtained by nitration of 3-acetylamino-4.5-dimethoxythiophene with nitric acid / potassium sulfate or nitric acid. Crystal, melting point 160 to 165 캜

b) 3-amino-4,5-dimethoxycarbonyl-2-nitrothiophene

The compound of the above example is hydrolyzed with methanolic hydrochloric acid. Crystal, melting point 104-107 ° C.

c) 2-mercapto-4,5-dimethoxycarbonyl-thieno [2,3-d] imidazole

The 3-amino-2-nitrothiophene derivatives described above were hydrogenated at room temperature with 1 bar of hydrogen using Raney nickel as a catalyst to afford 2,3 diamino-4,5-dimethoxy carbonylthiophene (0.02 mol). To obtain. The diamino compound thus obtained was stirred with 0.02 moles of thiocarbonyldiisazole in 50 ml of anhydrous dimethylacetamide for 2 hours at room temperature and then at 50 ° C for 1 hour without further purification, and distilled under vacuum. After the solvent is removed, the residue is crystallized in isopropanol while cooling in ice. Crystal, melting point 95-97 캜

Example 15

l-ethoxycarbonyl-2- (4-methoxy-2-picolylmercapto) -1H-thieno [3,4-d] imidazole under nitrogen, 2- (4-methoxy-2-picolylmer 1.4 g (5.0 mmol) of capto) -1H-thieno [3,4-d] imidazole was dissolved in 15 ml of anhydrous dimethylformamide, and 270 mg (6 mmol) of NaH 60% suspension in oil were added little by little to the mixture. Heated at 30-40 ° C. for 10 minutes. Then, at 25 ° C., 0.5 ml (5 mmol) of ethylchloroformate (95%) is added, at which time the temperature rises to about 36 ° C. After 30 minutes, the crystalline product is suction filtered and washed twice with diethyl ether. Melting point 154-156 ° C. (decomposition).

Example 16

1-ethoxycarbonyl-2- (4-methoxy-2-picolylsulfinyl) -1H-thieno [3,4-d] imidazole

750 mg of 1-methoxycarbonyl-2- (4-methoxy-2-picolylmercapto) -1H-thieno [3,4-d] imidazole in 30 ml of ethylene chloride and 25 ml of 0.5N sodium bicarbonate aqueous solution with stirring To (2.1 mmol) is added 3-chloroperbenzoic acid in CH ₂ Cl ₂ initially 420 mg (2.1 mmol) and then 210 mg (1.05 mmol). The organic phase is dried over MgSO ₄ , concentrated in vacuo, and the residue is crystallized from ethyl acetate. Melting point 143 ° C. (decomposition).

Example 17

1-vinyloxycarbonin-2- (5-methyl-2-picolylmercapto) -1H-thieno [3,4-d] imidazole

In a similar process to Example 15, 2.lg (8 mmol) 2- (5-methyl-2-picolylmercapto) -1H-thieno [3,4-d] imidazole and 0.85 g of vinyl chloroformate ( 0.7 g of 8 mmol) 1.5 g of crude product are obtained and chromatographed on SiO ₂ (CH ₂ Cl ₂ / MeOH 50: 1). Crystallization from diisopropyl ether gives 1.lg of the title compound. Melting Point 78 ~ 80 ℃

Example 18

1-vinyloxycarbonyl-2- (5-methyl-2-picolylsulfinyl) -1H-thieno [3,4-d] imidazole

In a process similar to Example 16, 0.5 g (1.5 mmol) of 1-vinyloxy carbonyl-2- (5-methyl-2-picolylmercapto) -1H-thieno [3,4-d] imidazole In a _two -phase mixture consisting of chloride and KH ₂ PO ₄ / Na ₂ HPO ₄ complete solution (pH = 7.5), it is oxidized with m-chloroperbenzoic acid. Chromatography on SiO ₂ is performed with CH ₂ Cl ₂ / CH ₃ OH (30: 1). Melting point162 캜.

Example 19

l-benzyloxycarbonyl-2- (4-methoxy-2-picolylmercapto) -1H-thieno [3,4-d] imidazole

0.8 ml (90-95%) of benzylchloroformate (5 mmol) in 4-l (4 mmol) of 2- (4-methoxy-2-picolylmercapto) -1H-thieno [3,4-d] imidazole Millimolar) and a method similar to Example 15. 2.2 g of an oily crude product are obtained and chromatographed on silica gel (35-70 micron) using toluene / ethyl acetate (1: 5). The product is crystallized from diethyl ether. Melting point 102-104 캜

Example 20

1-benzyloxycarbonyl-2- (5-methyl-2-picolylmercapto) -1H-thieno [3,4-d] imidazole

2- (5-methyl-2-picolylmercapto) -1H-thieno [3,4-d] imidazole is reacted similarly to Example 19. In vacuo, distillation removes DMF, the residue is dissolved in CH ₂ Cl ₂ , then the solution is extracted with water with shaking and dried over MgSO ₄ . After concentration, the title compound is crystallized from ethyl acetate. Melting Point l03 to 104 ℃

Example 21

1- (4-methoxybenzyloxycarbonyl) -2- (5-methyl-2-picolylmercapto) -1H-thieno [3,4-d] imidazole

Under nitrogen, 275 mg (6 mmol) of sodium hydride were added to 1.3 g (5 mmol) of 2- (5-methyl-2-picolylmercapto) -1H-thieno [3,4-d] imidazole dissolved in anhydrous DMF. Add. The mixture was heated at 40-50 [deg.] C. for 10 minutes, after which 1.92 g (7.5 mmol) of 4-methoxybenzyl phenyl carbonate (prepared from 4-methoxybenzyl alcohol and phenyl chloroformate) was added at room temperature Heat at 30-40 ° C. for 10 minutes and stir at room temperature for 1 hour. In vacuo, the solvent is removed by distillation and water is added to the residue. The remaining oily precipitate is dissolved in CH ₂ Cl ₂ and the solution is dried over MgSO ₄ and the solvent is removed by evaporation. The residue is crystallized from diethyl ether and then recrystallized from isopropanol. Melting point 120 to 121 ° C.

Example 22

1- (4-methoxybenzyloxycarbonyl) -2- (5-methyl-2-picolylsulfinyl) -1H-thieno [3,4-d] imidazole

850 mg (2 mmol) of the title compound from Example 21 were dissolved in 50 ml of CH ₂ Cl ₂ , followed by 7.4 ml of a solution of Na ₂ HPO ₄ / KH ₂ PO ₄ buffer (pH 4.5: KH ₂ PO ₄ solution (45.35 g / 1). 42.5 ml (59.5 g / 1) of + Na ₂ H PO ₄ solution are added, at room temperature, with vigorous stirring, 500 mg (2.5 mmol) of m-chloroperbenzoic acid dissolved in CH ₂ Cl ₂ are added dropwise. Was concentrated to dryness over MgSO _{4 and} then the residue was chromatographed on silica gel with ethyl acetate The title compound was crystallized from isopropanol Melting point 119-120 ° C.

Example 23

1-3-butoxycarbonyl-2- (5-methyl-2-picolylmercapto) -1H-thieno [3,4-d] imidazole

2 g (7.7 mmol) of 2- (5-methyl-2-picolylmercapto) -1H-thieno [3,4-d] imidazole were dissolved in 25 ml of DM F, followed by 1.2 ml of triethylamine and di-3 1.85 g (8.5 mmol) of tert-butyl dicarbonate are added. After 2 hours, an additional 3 g of dicarbonate is added and the mixture is stirred at 70 ° C. for 4 hours.

After DMF is substantially evaporated off, the residue is dissolved in CH ₂ Cl ₂ , the solution is shaken with water, dried over MgSO ₄ and concentrated. The residue can be crystallized from diisopropyl ether or petroleum ether. Melting Point 115-117 ° C

Example 24

1-3-tert-butoxycarbonyl-2- (5-methyl-2-picolylsulfinyl) -1H-thieno [3,4-d] imidazole

1.lg (3 mmol) of the title compound from Example 23 is dissolved in 50 ml of CH ₂ Cl _{2 and} then KH ₂ PO ₄ / Na ₂ HPO ₄ buffer from Example 22 is added. At 10 ° C., a total of 900 mg (4.5 mmol) of m-chloroperbenzoic acid in CH ₂ Cl ₂ is added dropwise until the precursor is completely consumed. The organic phase is separated, washed with water, dried and concentrated.

Using ethyl acetate, the residue is first chromatographed on silica gel. Appropriate fractions are crystallized from diethyl ether / petroleum ether to afford the title compound. Melting Point 98 ℃ (Decomposition)

Example 25

l-tert-butoxycarbonyl-2- (5-methyl-2-picolylsulfinyl) -1H-thieno [3,4-d] imidazole

Upon purification by column chromatography in Example 24, further elution with methanol / ethyl acetate (1: 20) afforded the title compound. Melting point 127 ° C. (decomposition).

Example 26

1-3-tert-butoxycarbonyl-2- (4-methoxy-2-picolylmercapto) -1H-thieno [3,4-d] imidazole

1.1 g (4.0 mole) of 2- (4-methoxy-2-picolylmercapto) -1H-thieno [3,4-d] imidazole was dissolved in 15 ml of anhydrous DMF, followed by 0.6 ml of triethylamine and di- 0.96 g (about 4.5 mmol) of tertiary butyl dicarbonate are added. After stirring at room temperature for 2 hours, additional 0.32 g (1.5 mmol) of di-tert-butyl dicarbonate are added.

Suction filtration of the precipitated product; Water is added to the solution extracted with CH ₂ Cl ₂ , and then the organic phase is dried over MgSO ₄ and concentrated in vacuo. The oily residue is crystallized from diethyl ether. Melting point 152 ° C. (decomposition).

Example 27

1- (p-nitrophenyloxycarbonyl) -2- (5-methyl-2-picolylmercapto) -1H-thieno [3,4-d] imidazole

A title compound is prepared from 2- (5--medyl-2-picolylmercapto) -1H-thieno [3,4-d] imidazole and P-nitrophenyl chloro prevate in a process similar to Example 17 . After finishing, and chromatography on silica gel using toluene / ethyl acetate (1: 1), the appropriate fractions are crystallized from ethyl acetate to give the title compound. Melting point 165-168C.

Example 28

-Hydroxymethyl-2- (4methoxy-2-picolylmercapto) -1H-thieno [3,4-d] imidazole

Under nitrogen atmosphere, 0.7 ml of a 37% formaldehyde solution in 3 ml of acetonitrile was dissolved in 50 ml of acetonitrile 2- (4-methoxy-2-picolylmercapto) -1H-thieno [3,4-d Add dropwise to 1.6 g of imidazole.

The mixture is then stirred at 70 ° C. for 15 minutes. The solution is concentrated in vacuo, washed with water and saturated aqueous NaCl solution and dried over MgSO ₄ . The residue obtained after evaporation is treated with diisopropyl ether to give a semicrystalline crude product which is crystallized from ethyl acetate. Melting point 125 to 127 ° C

Example 29

1-acetoxymethyl-2- (4-methoxy-2-picolylmercapto) -1H-thieno [3,4-d] imidazole

1.3 g (4.2 mmol) of the title compound from Example 28 were dissolved in 25 ml of anhydrous pyridine and 50 mg of 4-dimethylaminopyridine was added. While stirring under a nitrogen atmosphere, 6.3 ml of acetic anhydride is added dropwise, and the mixture is stirred at room temperature for 1 hour. Then, it was poured into ice water and extracted with methylene chloride, and the organic phase was extracted with MgS0. Dry over phase and concentrate in vacuo. The crystalline solid is recrystallized from ethanol. Melting point 111-113 ° C.

Example 30

1-hydroxymethyl-2- (5-methyl-2-picolylmercapto) -1H-thieno [3,4-d] imidazole

A title compound is prepared from 2- (5-methyl-2-picolylmercapto) -1H-thieno [3,4-d] imidazole in a similar manner to Example 28.

Example 31

1-acetoxymethyl-2- (5-methyl-2-picolylmercapto) -1H-thieno [3,4-d] imidazole

A title compound is obtained from the title compound of Example 30 by a process similar to Example 29. The resulting crude product is chromatographed on silica gel (ethyl acetate / toluene = 2: 1) to scratch and spontaneously crystallize from diisopropyl ether. Colorless crystal, Melting point 87-89 degreeC

Example 32

1-acetoxyethyl-2- (5-methyl-2-picolylsilfinyl) -1H-thieno [3,4-d] imidazole

0.67 g (2 mmol) of the title compound from Example 31 are dissolved in 30 ml of anhydrous CH ₂ Cl ₂ , and then 0.6 ml (2 mmol) of titanium tetra isopropylate are added under nitrogen atmosphere. Then, 0.6 ml (2 mmol) of a 3M tert-butylhydroperoxide solution in toluene was added dropwise at 0 ° C. After 30 minutes, the mixture is allowed to reach room temperature and then stirred for 20 minutes, water is added, the precipitated white solid is filtered off, the organic phase is dried over MgSO ₄ , distilled off in vacuo and then toluene / ethyl acetate (1 The crude product is chromatographed on silica gel using 5). The title compound (Rf = 0.18) as colorless crystals is obtained from diisopropyl ether. Melting point 104-106 ° C.

Example 33

1-hydroxymethyl-2- (4-piperidino-3-chloro-2-picolylmercapto) -1H-thieno [3,4-d] imidazole

In a similar manner to Example 28, the title compound is obtained from 2- (4-piperidino-3-chloro-2-picolylmercapto) -1H-thieno [3,4-d] imidazole. Melting point 132 to 134 ° C.

Example 34

1-acetoxymethyl-2- (4-piperidino-3-chloro-2-picolylmercapto) -1H-thieno [3,4-d] imidazole

In a similar manner to Example 28, the title compound is obtained from the title compound of Example 33. The crude product was chromatographed on silica gel using toluene / ethyl acetate (1: 1). Melting point 169 to 170 ° C.

Example 35

1- (4-methoxybenzyl) -2- (5-methyl-2-picolylmercapto) -1H-thieno [3,4-d] imidazole

In a similar manner to Example 15, sodium salt was prepared from 2.6 g (10 mmol) of 2- (5-methyl-2-picolylmercapto) -1H-thieno [3,4-d] imidazole and 4-meth Alkylated with 1.7 g (11 mmol) of oxybenzyl chloride. After completion, the product is chromatographed on silica gel with CH ₂ Cl ₂ methanol (50: 1). Appropriate fractions are recrystallized from diethyl ether to afford the title compound. Melting point 114-116 ° C.

Example 36

1- (4-methoxybenzyl) -2- (5-methyl-2-picolylsulfonyl) -1H-thieno [3,4-d] imidazole

The title compound from Example 35 is oxidized (as described in Example 22) to 2 equivalents of m-chloroperbenzoic acid in CH ₂ Cl ₂ and Na ₂ HPO ₄ / KH ₂ PO ₄ buffer. The crude product is purified by chromatography (silica gel, toluene / ethylacetate 1: 4). The title compound is crystallized from a small amount of diisopropyl ether. Melting point 148 to 150 ° C

Example 37

1-acetyl-2- (5-methyl-2-picolylmercapto) -1H-thieno [3,4-d] imidazole

In a similar manner to Example 29, 2- (5-methyl-2-picolylmercapto) -1H-thieno [3,4-d] imidazole was reacted with pyridine / acetic anhydride / dimethyl aminopyridine to give the title compound. do. After finishing treatment, the crude product is dissolved in a small amount of CH ₂ Cl ₂ and chromatographed on silica gel with toluene / ethyl acetate (1: 1). The title compound is crystallized from the appropriate fractions. Melting point 139 to 141 ° C.

Example 38

1- (1-acetoxyethoxycarbonyl) -2- (5-methyl-2-picolylmercapto) -1H-thieno [3,4-d] imidazole

A sodium salt is prepared from 2.6 g (10 mmol) of 2- (5-methyl-2-picolylmercapto) -1H-thieno [3,4-d] imidazole in a similar manner to Example 15. Is added dropwise a solution of 2.7 g (10 mmol) of 1-acetoxy-P-nitrophenylcarbonate in DMF. The reaction mixture is allowed to warm to rt, concentrated in vacuo after 2 h, water is added to the residue, the mixture is extracted with CH ₂ Cl ₂ and dried over MgSO ₄ and concentrated.

The residue is chromatographed on silica gel using toluene / ethyl acetate (3: 1). Crystallize the title compound from the appropriate fractions. Melting point 111-113 ° C. Also a small amount of the title compound of Example 36 is obtained. In a similar manner, the compounds of Table 2 are prepared.

TABLE 2a

TABLE 2b

TABLE 2c

Claims (13)

Compounds of formula (I) and their physiologically acceptable salts.

Or c)

And T represents -S-,-SO-or-SO _2- , R ¹ and R ² are the same or different and are hydrogen, halogen, cyano, nitro, trifluoromethyl, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆₎ - hydroxyalkyl, (C ₁ -C ₆₎ - alkoxy, (C ₁ -C ₄₎ - _{fluoro-alkoxy, -OCF 2 Cl, -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, wasteylsulfinyl, Represents sulfamoyl, N- (C ₁ -C ₄ ) -alkylsulfamoyl or N, N-di- (C ₁ -C ₄ ) -alkylsulfamoyl or when A is (a) or (c) as defined above R ¹ and R ² may together represent — [CH ₂ ] n — or —CH═CH—CH═CH—, where C One of the H ₂ groups is optionally substituted by oxygen, sulfur, SO or SO ₂ , and R ³ is hydrogen, alkanoyl, (C ₁ -C ₆ ) -alkylcarbamoyl or preferably acid medium and / or physiological Another physiologically acceptable N ^1m protecting group which may be removed under conditions, R ⁴ and R ⁵ being the same or different and represent hydrogen or (C ₁ -C ₃ ) -alkyl, R ⁶ , R ⁷ , R ⁸ and R ⁹ are the same or different and are hydrogen, halogen, (C ₁ -C ₁₂ ) -alkyl, (C ₁ -C ₁₂ ) -alkoxy, -O-CH ₂ -C _f H _{(2f + 1 -g) Fg, -NR'R ", (} C 1 -C 12) - alkoxy - (C ₁ -C ₁₂₎ - alkyl, (C ₁ -C ₁₂₎ - alkoxy - (C ₁ -C ₁₂₎ - alkoxy , (C ₇ -C ₁₁₎ - aralkyloxy, (C ₁ -C ₁₂₎ - alkylmercapto, (C ₁ -C ₁₂₎ - alkyl sulfinyl, or (C ₁ -C ₁₂₎ - indicate the alkylsulfonyl Or R ⁵ and R ⁶ together represent [CH ₂ ] _1- , R 'and R "are the same or different and represent hydrogen or (C ₁ -C ₄ ) -alkyl, or R' and R '' together are - [CH _2] h- Denotes, here, one of the CH ₂ groups is oxygen, sulfur, N- (C ₁ -C ₄₎ - alkanoyl butylimino or N- (C ₁ -C ₄₎ - alkoxycarbonyl can be substituted by Mino F is 1,2,3 or 4, g is 1 to (2f + 1), h is 4,5 or 6, i is l, 2 or 3, and n is 3 or 4. The compound of formula (I) according to claim 1, wherein R ⁹ represents hydrogen. The compound of formula (I) according to claim 1 or 2, wherein A is (b) as defined in claim 1. The compound of formula (I) according to claim 1 or 2, wherein T represents -SO-. 3. The compound of claim 1, wherein R ¹ and R ² are the same or different and are hydrogen, (C ₁ -C ₃ ) -alkyl, halogen, (C ₁ -C ₄ ) -alkoxy or (C ₁ -C ₄ ) -Alkoxycarbonyl, R ³ is as defined in claim 1, R ⁴ and R ⁵ each represent hydrogen, R ⁶ , R ⁷ , R ⁸ and R ⁹ are the same or different and represent hydrogen, halogen, Of formula (I) which represents (C ₁ -C ₃ ) -alkyl, (C ₁ -C ₄ ) -alkoxy, benzyloxy or (C ₁ -C ₇ ) -alkoxy- (C ₁ -C ₃ ) -alkyl compound. 3. The compound of claim 1, wherein R ¹ and R ² are the same or different and represent hydrogen or (C ₁ -C ₃ ) -alkyl, R ³ is as defined in claim ^1, and R ⁴ and R ⁵ are Each represents hydrogen, R ⁶ and R ⁸ are the same or different and represent hydrogen, chlorine, methyl or ethyl, R ⁹ represents hydrogen and R ⁷ represents hydrogen, (C ₁ -C ₄ ) -alkoxy, (C _1- A compound of formula (I) representing C ₃ ) -alkyl or benzyloxy. 2- (2-picolylsulfinyl) -1H-thieno [3,4-d] imidazole, 2- (4-methoxy-2-picolylsulfinyl) -1H-thieno [3,4- d] imidazole, 2- (4-methoxy-3-methyl-2-picrylsulfinyl) -1H-thieno [3,4-d] imidazole, 2- (4-methoxy-3,5 -Dimethyl-2-picolylsulfinyl) -1H-thieno [3,4-d] imidazole, 2- (3-methyl-2-picolylsulfinyl) -1H-thieno [3,4-d Imidazole, 2- (5-methyl-2-picolylsulfinyl) -1H-thieno [3,4-d] imidazole, 2- (4-methyl-2-picolylsulfinyl) -1H- Thieno [3,4-d] imidazole, 2- (5-methyl-2-picolylsulfinyl) -1H-thieno [3,4-d] imidazole, 4,6-dimethyl-2- ( 5-methyl-2-picolylsulfinyl) -1H-thieno- [3,4-d] imidazole or 2- (3-chloro-4-methoxy-2-picolylsulfinyl) -1H-thier No- [3,4-d] imidazole or their physiologically acceptable salts. A process for preparing a compound of formula (I) as claimed in claim 1, characterized by reacting a compound of formula (II) with a compound of formula (III).

Or C)

Wherein T represents -S-,-SO- or -SO _2- , R ¹ and R ² are the same or different and are hydrogen, halogen, cyano, nitro, trifluoromethyl, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆₎ - hydroxyalkyl, (C ₁ -C ₆₎ - alkoxy, (C ₁ -C ₄₎ - _{fluoro-alkoxy, -OCF 2 Cl, -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- (C ₁ -C ₄ ) -alkylsulfamoyl, wherein A is (a) or (c) in the case of, R ¹ and R ² together are - [CH _2] n-, or -CH = CH-CH = CH- may indicate the, here Standing CH ₂ one of the groups is optionally substituted by oxygen, sulfur, SO or SO _2, R ³ is hydrogen, alkanoyl, (C ₁ -C ₆₎ - alkyl-carbamoyl, or preferably an acid medium and / or a physiologically Represents another physiologically acceptable N ^1m protecting group that can be removed under physiological conditions, R ⁴ and R ⁵ are the same or different and represent hydrogen or (C ₁ -C ₃ ) -alkyl, R ⁶ , R ⁷ , R ⁸ and R ⁹ are the same or different and are hydrogen, halogen, (C ₁ -C ₁₂ ) -alkyl, (C ₁ -C ₁₃ ) -alkoxy, -O-CH ₂ -C _f H _{(2f + 1 -g)} Fg, -NR'R ", (C ₁ -C _{12 )} -alkoxy- (C ₁ -C ₁₂ ) -alkyl, (C ₁ -C ₁₂ ) -alkoxy- (C ₁ -C ₁₂ ) -alkoxy , (C ₇ -C ₁₁₎ .- aralkyloxy, (C ₁ -C ₁₂₎ - alkyl-sulfonyl-alkylmercapto, (C ₁ -C ₁₂₎ - alkyl sulfinyl, or (C ₁ -C ₁₂₎ R ⁵ and R ⁶ together represent — [CH ₂ ] ₁ —, R ′ and R ″ are the same or different and represent hydrogen or (C ₁ -C ₄ ) -alkyl, or R ′ and R "together - [CH _2] represent the h-, where, one of the group CH ₂ is oxygen, sulfur, N- (C ₁ -C ₄₎ - alkanoyl butylimino or N- (C ₁ -C ₄₎ - alkoxycarbonyl May be substituted by nilimino, f is 1,2,3 or 4, g is 1 to (2f + 1), h is 4,5 or 6, i is 1,2 or 3, n is 3 or 4, X ¹ represents (a) leaving group or (b) -SH, -S- or SO _2- , and X ² represents X ¹ representing (a) -SH, -S-or-SO _2- , and when X ¹ represents (b) mentioned above, a leaving group. The method of claim 8, wherein the -S-group (s) present in formula (I) are oxidized to -SO- or-SO ₂ -group (s). A process for preparing a compound of formula (I) as claimed in claim 1, characterized by reacting a compound of formula (IV) with a compound of formula (V).

Or c)

-T represents -S-, -SO-, or -SO _2- , R ¹ and R ² are the same or different and hydrogen, halogen, cyano, nitro, trifluoromethyl, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -hydroxyalkyl, (C ₁ -C ₆ ) -alkoxy, (C ₁ -C ₄ ) -fluoroalkoxy, -OCF ₂ Cl, -O-CF _{2 -CHFC1, (C 1 -C 6} ) - alkylmercapto, (C ₁ -C ₆₎ - alkylsulfinyl, (C ₁ -C ₆₎ - alkylsulfonyl, (C ₁ -C ₆₎ - alkyl carbonyl Nyl, (C ₁ -C ₆ ) -alkoxycarbonyl, carbamoyl, N- (C ₁ -C ₄ ) -alkylcarbamoyl. N, N- di - (C ₁ -C ₄₎ - alkyl carbamoyl, (C ₁ -C ₆₎ - alkyl-carbonyl-oxy, (C ₃ -C ₈₎ - cycloalkyl, phenyl, benzyl, phenoxy, benzyl Oxy, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N- (C ₁ -C ₄ ) -alkylsulfamoyl or N, N-di- (C _1- When C ₄ ) -alkylsulfamoyl or A is (a) or (c) as defined above, then R ¹ and R ² together are-[CH ₂ ] n- or -CH = CH-CH = CH -In which one of the CH ₂ groups is oxygen. Optionally substituted by sulfur, SO or SO ₂ , R ³ is hydrogen, alkanoyl, (C ₁ -C ₆ ) -alkylcarbamoyl or another which can be removed preferably under acid medium and / or physiological conditions Represents a physiologically acceptable N ^1m protecting group of R ⁴ and R ⁵ are the same or different and represent hydrogen or (C ₁ -C ₃ ) -alkyl and R ⁶ , R ⁷ , R ⁸ and R ⁹ are Same or different, hydrogen, halogen, (C ₁ -C ₁₂ ) -alkyl, (C ₁ -C ₁₂ ) -alkoxy, -O-CH ₂ -C _f H _{(2f + 1-g)} Fg, -NR ' R ″, (C ₁ -C ₁₂ ) -alkoxy- (C ₁ -C ₁₂ ) -alkyl, (C ₁ -C ₁₂ ) -alkoxy- (C ₁ -C ₁₂ ) -alkoxy, (C ₇ -C ₁₁ ) -Aralkyloxy, (C ₁ -C ₁₀ ) -alkylmercapto, (C ₁ -C ₁₂ ) -alkylsulfinyl or (C ₁ -C ₁₂ ) -alkylsulfonyl, or R ⁵ and R ⁶ are Together —— [CH ₂ ] ₁ —, R ′ and R ″ are the same or different and represent hydrogen or (C ₁ -C ₄ ) -alkyl, or R ′ and R ″ together are — [CH ₂ ] h-, where Wherein one of the CH ₂ groups may be substituted by oxygen, sulfur, N- (C ₁ -C ₄ ) -alkanoylimino or N- (C ₁ -C ₄ ) -alkoxycarbonylimino, f is 1,2,3 or 4, g is 1 to (2f + 1), h is 4,5 or 6, i is 1,2 or 3, n is 3 or 4, and R ¹⁰ is Esterification group. The method of claim 10, wherein the -S-group (s) present in the compound of formula (I) are oxidized to -SO- or-SO ₂ -group (s). Use of the compound claimed in claim 1 as a gastric acid secretion inhibitor. Gastric acid secretion inhibitor containing the compound claimed in claim 1.