JP2574357B2 - 5-Alkoxy-2-mercaptoimidazo [4,5-b] pyridine compound and method for producing the same - Google Patents

Description

The present invention relates to a 5-alkoxy-2-mercaptoimidazo [4,5-b] pyridine compound represented by the formula [I]
It is referred to as the compound of the present invention. ) And its manufacturing method.

(In the formula, R ¹ represents a linear or branched alkyl group having 1 to 8 carbon atoms or a fluoroalkyl group having 2 to 4 carbon atoms which may be substituted with a cyclic alkyl group.) The compound is useful as an intermediate for producing an imidazo [4,5-b] pyridine derivative which is a novel anti-ulcer active compound represented by the following formula [II].

(Wherein, R ¹ represents a linear or branched alkyl group having 1 to 8 carbon atoms which may be substituted with a cyclic alkyl group or a fluoroalkyl group having 2 to 4 carbon atoms, and R ² represents A hydrogen atom, a methyl group or a methoxy group is represented, and R ³ and R ⁴ are the same or different and represent a hydrogen atom or a methyl group, respectively.) Prior art In recent studies on pathophysiology of gastric or duodenal ulcer, gastric endoplasmic reticulum Potassium ion-dependent adenosine triphosphatase (hereinafter abbreviated as (H ⁺ + K ⁺ ) ATPase involved in hydrochloric acid production in vesicles. ], And the presence or absence of this oxygen activity inhibition has been used as one indicator of anti-ulcer agents [Gastroentrophy (Gastroen)
tero-logy) 1: 420, 1943; 73: 921, 1977].
From such a viewpoint, as a compound having an unsubstituted or trisubstituted pyridylmethylsulfinyl group in the side chain, a representative one currently being developed as an anti-ulcer agent is omeprazole having a benzimidazole skeleton from this viewpoint [ No. 54-141783; British Medical
Journal (British Medical Journal) 287: 12 1983
Year] is known. On the other hand, in the imidazopyridine compound, a typical one whose inhibitory action of the enzyme has been confirmed or suggested is represented by the following general formula: (Wherein one of X and Y is ＝ CH— and the other is ＮN-
R ^{1 ′} and R ^{2 ′} are the same or different and each represents a hydrogen atom, a lower alkoxycarbonyl group,
A halogen atom, a lower alkyl group, an amino group or a hydroxyl group, R ^{3 ′} , R ^{4 ′} and R ^{5 ′} are the same or different and are each a hydrogen atom, a lower alkoxy group or a lower alkyl group, A is a lower alkylene group, l is Indicates 0 or 1. However, when Y is a = CH- group, X is a = N- group, and l is 0, a compound represented by R ^{3 '} , R ^4' and R ^{5 '} is not a hydrogen atom at the same time (hereinafter referred to as a compound). A known imidazopyridine derivative is tentatively reported) (JP-A-61-145182).

SUMMARY OF THE INVENTION The present inventors have found that storage stability, in vitro (in vitro) compared to omeprazole and the above-mentioned known imidazopyridine derivatives.
The above-mentioned formula [II] showing excellent effects in (H ⁺ + K ⁺ ) ATPase inhibitory effect in vitro, gastric acid secretion inhibitory effect in vivo and inhibitory effect on various experimental ulcers.
Was found, and a patent application was filed earlier (Japanese Patent Application Laid-Open No. Sho 62-62).
133534).

Means for Solving the Problems The present invention provides an imidazo [4,5-
b] a pyridine derivative which is useful as an intermediate for producing a compound in which R ¹ O- (R ¹ has the same meaning as described above) is substituted at the 5-position of the imidazo [4,5-b] pyridine ring; [I]
A 5-alkoxy-2-mercaptoimidazo [4,5-b] pyridine compound represented by the formula: and a method for producing the same.

The 5-alkoxy-2-mercaptoimidazo [4,5-b] pyridine compound represented by the formula [I] also includes tautomers represented by the following formulas [I '], [I "] and [I]. Is done.

(In each formula, R 1 has the same meaning as described above.) The compound [I] of the present invention can be produced according to the following reaction formula.

(Wherein, R ¹ has the same meaning as described above.) 2-amino-6-chloro-3-nitropyridine [II
I] and an alcohol represented by R ¹ OH (where R ¹ is as defined above) in the presence of a base to give a 6-alkoxyi-2-amino-3-nitropyridine compound [IV] is obtained. As the base, potassium t-butoxide, sodium, sodium hydride, potassium hydroxide,
Potassium carbonate and the like are used, and as a reaction solvent, in addition to alcohols represented by R ¹ OH, dioxane, acetone,
Dimethylformamide, hexamethylphosphoric triamide or a mixed solvent thereof with water is used. The reaction is carried out at a temperature of -10 to 120 ° C and a reaction time of 1 minute to 10 hours. Then, the compound [IV] is catalytically reduced in the presence of a catalyst such as Raney nickel, palladium or the like, or is reduced with sodium hydrosulfite in the presence of an alkali to give a 6-alkoxy 2,3-diaminopyridine compound [V] is obtained. Next, the compound [V] is reacted with potassium ethyl xanthate or carbon disulfide to obtain the compound [I] of the present invention. As the reaction solvent, alcohols such as methanol, ethanol and isopropanol or hydrous alcohols are preferable, and the reaction is carried out under heating and refluxing for 2 to 8 hours. When carbon disulfide is used, it is preferably in the presence of an alkali such as sodium hydroxide or potassium hydroxide.

The compound of the present invention [I] is represented by the formula (Wherein R ² , R ³ and R ⁴ have the same meanings as described above). (Wherein R ¹ , R ² , R ³ and R ⁴ are as defined above), and then this compound is treated with m-chloroperbenzoic acid, perbenzoic acid, peracetic acid, etc. By oxidizing with the above, the imidazo [4,5-b] of the formula [II]
It can lead to pyridine derivatives. These derivatives have excellent storage stability and excellent anti-ulcer activity.

Next, Production Examples of the compound [I] of the present invention will be described with reference to Examples.

Example 1 (a) 2-amino-6-chloro-3-nitropyridine3
0.0 g (0.173 mol), 18.7 g of cyclopropyl carbinol
(0.259 mol) and potassium t-butoxide (purity 90%) 2
3.7 g (0.190 mol) is added to 50 ml of dioxane,
Stirred for hours. After allowing to cool, 100 ml of dioxane was added, and the mixture was added into 1.5 of water at 5 ° C. with stirring to precipitate crystals. The precipitated crystals are collected, washed with water and dried to give 2-amino-6-cyclopropylmethyloxy-3.
-33.4 g (92.5%) of nitropyridine were obtained.

(B) 33.0 g (0.158 mol) of 2-amino-6-cyclopropylmethyloxy-3-nitropyridine obtained above was suspended in 500 ml of ethanol, Raney nickel was added, and catalytic reduction was performed at room temperature and normal pressure. After completion of the reaction, Raney nickel was separated and the solution was added with potassium ethyl xanthate (50.6).
g (0.316 mol) and 100 ml of water were added, and the mixture was heated under reflux for 3 hours. Add 3.0 g of activated carbon to the reaction solution, heat, and add water to the solution.
500 ml was added and heated to 60-70 ° C. Acetic acid was added to this solution with stirring to adjust the pH to 3 to 4, and then the mixture was stirred under ice cooling. The precipitated crystals were collected, washed with water, dried and then recrystallized from 50% aqueous methanol to give 5-cyclopropylmethyloxy-2-mercaptoimidazo [4,5-
b] 29.5 g (84.5%) of colorless crystals of pyridine were obtained.

Mp two hundred forty-seven to two hundred forty-eight ° C. Elemental analysis (as _{C 10 H 11 N 3 OS)} : theory (%); C, 54.28H, 5.01N, 18.99 Found (%); C, 54.14H, 5.16N, 18.78 performed Examples 2 to 17 The cyclopropylcarbinol of Example 1 (a) was used as a corresponding alcohol, t-butoxy potassium was used as a base appropriately selected from sodium, sodium hydride, potassium hydroxide, and the like, and dioxane was used as an alcohol. 6-Alkoxy-2 was treated in substantially the same manner as in Example 1 (a) except that the solvent was appropriately selected from dimethylformamide, hexamethylphosphoric triamide, etc., and the reaction temperature, reaction time, etc. were slightly changed. -Amino-3-nitropyridine compound [IV] was obtained. Next, the compound [IV] was treated in substantially the same manner as in Example 1 (b) to give the compounds shown in Table 1.

Claims (2)

(57) [Claims] (1) Expression (In the formula, R ¹ represents a linear or branched alkyl group having 1 to 8 carbon atoms which may be substituted with a cyclic alkyl group or a fluoroalkyl group having 2 to 4 carbon atoms.) 5-alkoxy-2-mercaptoimidazo [4,5
-B] pyridine compounds. (2) By reacting 2-amino-6-chloro-3-nitropyridine represented by the formula with an alcohol represented by the formula R ¹ OH (wherein R ¹ is as defined above) in the presence of a base. formula (Wherein R is as defined above), and then reduced to give the obtained 6-alkoxy-2,3-diaminopyridine. A compound characterized by reacting a compound with potassium ethyl xanthate or carbon disulfide (Wherein, R ¹ has the same meaning as described above.) A method for producing a 5-alkoxy-2-mercaptoimidazo [4,5-b] pyridine compound represented by the formula: