WO1979000206A1

WO1979000206A1 - New substituted by-products of 1,3-dihydro imidazo(4,5-b)pyridin-2-one,process,application,compositions and intermediate compounds obtained

Info

Publication number: WO1979000206A1
Application number: PCT/FR1978/000032
Authority: WO
Inventors: F Barzaghi; M Bianchi
Original assignee: Roussel Uclaf
Priority date: 1977-10-13
Filing date: 1978-10-12
Publication date: 1979-04-19
Also published as: EP0006931A1

Abstract

New substituted by-products of 1,3-dihydro-imidazo-(4, 5-b) pyridin-2-one, their process of preparation, the pharmaceutic compositions embodying them and the new intermediate compounds obtained. Said by-products have the formula I (FORMULA) wherein R is an alkyl of 1 to 3 carbons, R' is a radical pyridyl and Y is chlorine or hydrogen. These by-products have gastric antisecretory antiulcerous and anorexic activities.

Description

New substituted derivatives of 1,3-dihydro imidazo (4,5-b) pyridin-2-one, process, application, compositions and intermediates obtained.

The present invention relates to substituted derivatives of 1,3-dihydro-imidazo- (4,5-b) pyridin-2-one, a process for their preparation, their application as medicaments, the pharmaceutical compositions containing them and new intermediate compounds obtained. Products from the 1,3-dihydroimidazo- (4,5-b) pyridin-2-one family are already known.

Thus, US Pat. No. 3,719,683 describes products of this family, having anti-depressive properties. Furthermore, French Patent No. 2,312,248 also cites and describes several products of the family. They are described there as having. analgesic, anti-inflammatory and anti-pyretic properties.

However, it was unexpectedly discovered that certain substituted products of this family were endowed with very different properties and were of very great interest in particular as anti-gastric secretory and anti-ulcer drugs.

Thus, the subject of the present invention is the products of general formula I:

wherein R represents an alkyl radical containing from 1 to 3 carbon atoms, R 'represents a pyridyl radical and Y represents a chlorine atom or a hydrogen atom.

In formula I above, the term alkyl containing from 1 to 3 carbon atoms can denote a methyl, ethyl, propyl or isopropyl radical.

The pyridyl radical is linked to the nitrogen atom of the 1,3-dihydro imidazo (4,5-b) pyridine ring by any of its carbon atoms.

The present invention also relates to the addition salts with mineral or organic acids of the products of formula I defined above.

The addition salts with mineral or organic acids can be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric acids. acetic, formic, benzoic, maleic, fumaric, succinic, tar¬tric, citric, oxalic, glyoxylic, aspartic, alkylmonosulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, alkoyldisulfonic acids such as methanedisulfonic acid, α, β-ethanedisulfonic acid, arylmonosulfonic acids, such as benzenesulfonic acid and aryldisulfonic acids.

A more particular subject of the invention is the products as defined by formula I above, characterized in that, in formula I, R represents a methyl radical.

The subject of the invention is, in particular:

- 1-methyl-3- (4-pyridyl) -1,3-dihydro imidazo (4,5-b) pyridin-2-one, - 5-chloro-1-methyl-3- (3-pyridyl) -1,3-dihydroimidazo (4,5-b) ρyridin-2-one,

- 5-chloro-1-methyl-3- (2-pyridyl) -1,3-dihydroimidazo (4,5-b) pyridin-2-one.

According to the invention, the products as defined by formula I above as well as their addition salts with mineral or organic acids can be prepared by a process characterized in that a product of formula II is subjected :

in which, R 'represents a pyridyl radical and Y represents a chlorine atom or a hydrogen atom, to a cyclization means to obtain a product of formula III:

in which R 'and Y have the meaning indicated above, which is reacted with a product of formula IV:

R ₁ - X (IV)

in which R ₁ represents an alkyl radical containing from 1 to 3 carbon atoms, and X represents a residue chosen from the group consisting of chlorine, bromine, iodine atoms and the methyl sulfate and ethyl sulfate radicals , to get the product of corresponding formula I, and that, if necessary, the product of formula I obtained is subjected to the action of a mineral or organic acid to form its salt.

By the expression "means of cyclization", it is necessary to understand all reagents employed under appropriate operating conditions making it possible to form a benzimidazolin-2-one ring starting from the product of formula II.

These cyclization means can consist, for example: 1) of reacting on the product of formula II an alkyl chloroformate of formula

Cl - COO alk in which alk represents an alkyl radical containing from 1 to 3 carbon atoms, then reacting on the product thus obtained of formula V:

.

wherein R 'and Y have the meanings indicated above, a basic agent;

2) reacting on the product of formula II, an alkyl iminocarboxylate of formula

in which alk represents an alkyl radical containing from 1 to 3 carbon atoms, then reacting on the product obtained of formula:

wherein Y, R 'and alk have the meaning given above, as above, a basic agent; 3) reacting phosgene on the product of formula II under reaction conditions similar to those described in J. Am. Chem. Soc. 80, 1659 (1958);

4) reacting urea at the elevated temperature on the product of formula II, under reaction conditions analogous to those described in the article which has just been cited in point 3) or in French patent 2.113. 192;

5) reacting on the product of formula II, carbonyldiimidazole, preferably hot.

Under preferential conditions for implementing the invention, the process described above is then carried out as follows:

- The reaction of the product of formulaIII and the product of formula IV is carried out in the presence of a basic agent.

- The basic condensing agent can in particular be an alkali hydroxide such as for example sodium hydroxide, potassium hydroxide, lithium hydroxide; an alkali carbonate such as for example sodium carbonate, potassium carbonate, an alkaline alkylate such as for example sodium methylate, sodium ethylate, potassium ethylate; an alkaline hydride such as for example sodium hydride, potassium hydride; an alkali metal amide such as for example sodium amide, potassium amide, lithium amide; sodium; an alkaline acetate such as sodium acetate, potassium acetate.

- The reaction of the product of formula III with the product of formula IV is carried out in an organic solvent.

- The organic solvent can be in particular methanol, ethanol, propanol, ethyl ether, benzene, xylene, toluene, dimethylacetamide, dimethylf ormamide, dioxane, tetranyάrofuran ne, acetone, chloroform.

- The product of formula III can be reacted with the basic agent before reacting with the product of formula IV. - The reaction of the product of formula III with the product of formula IV is carried out at a temperature ranging from ambient temperature to the reflux temperature of the reaction medium.

- The salification reaction of the product of formula I is carried out in a solvent or a mixture of solvents such as, for example, ethyl ether, ethanol, methanol.

Furthermore, when the cyclization means used is the action of alkyl chloroformate followed by that of a basic agent, the process described above is preferably carried out as follows:

- The reaction of the product of formula II with alkyl chloroformate is carried out in an organic solvent such as for example, chloroform, benzene, toluene, cyclohexane, tetrahydrofuran, ethyl ether.

The reaction is carried out at a temperature ranging from room temperature to the reflux temperature of the reaction medium. - The basic agent using which the cyclization of the product of formula V is carried out can be in particular an alkaline alkylate such as for example, sodium methylate, sodium ethylate, potassium ethylate, terbutylate of potassium. The present application also relates to a process for the preparation of products as defined by formula I and of their addition salts with mineral or organic acids, characterized in that a product of formula VI is reacted:

in which R represents an alkyl radical containing from 1 to 3 carbon atoms and Y represents a chlorine atom or a hydrogen atom with a product of formula VII

R '- X (VII) in which R' represents a pyridyl radical and X represents a chlorine, bromine or iodine atom, to obtain the corresponding product of formula I which, if necessary, is subjected to the action of a mineral or organic acid to form the salt.

Under preferential conditions for implementing the invention, the process described above is carried out as follows: - The reaction of the product of formula VI with the product of formula VII is carried out in the presence of a basic agent. The basic agent can be, in particular, an alkali hydroxide such as for example sodium hydroxide, potassium hydroxide, lithium hydroxide; an alkali carbonate such as for example sodium carbonate, potassium carbonate; an alkaline alkylate, such as for example sodium methylate, sodium ethylate, potassium ethylate; an alkaline hydride such as for example sodium hydride, potassium hydride; an alkaline amide such as for example sodium amide, potassium amide, lithium amide; sodium; an alkaline acetate such as sodium acetate, potassium acetate; - The reaction of the product of formula VI with the product of formula VII is produced in an organic solvent. The organic solvent can be, in particular, methanol, ethanol, propanol, ethyl ether, benzene, xylene, toluene, dimethylformamide, dioxane, tetrahydrofuran, dimethylsulfoxide, hexamë-thylphosphortriamide, acetone, chloroform, pyridine, dimethylacetamide, diethylene glycoldimethyl ether;

- The product of formula VI is reacted with the basic agent before reacting with the product of formula VII;

- An excess of product of formula VII is preferably used;

- The reaction of the product of formula VI with the product of formula VII can also be carried out in the presence of a catalyst eur such as copper or a copper salt such as for example cuprous chloride or a mixture of these substances; The reaction is then advantageously carried out in an organic solvent such as, for example, pyridine, dimethylformamide, dimethylacetamide, diethylene glycoldimethyl ether, dimethyl sulfoxide, hexamethylphosphortriamide;

The reaction can be carried out in the presence of a basic agent, in particular, in the presence of potassium acetate, sodium hydride;

- The reaction of the product of formula VI with the product of formula VII is carried out at a temperature ranging from room temperature to the reflux temperature of the reaction medium;

- The salification reaction of the product of formula I is carried out in a solvent or a mixture of solvents such as for example ethyl ether, methanol, ethanol. The products as defined by the general formula I above, as well as their addition salts with the mineral and organic acids pos sess interesting pharmacological properties: they manifest in particular an important gastric antisecretory activity and an important antiulcerous activity; more particularly, they decrease the volume of gastric secretions and their acidity. These products are also endowed with appetite suppressants.

These different properties justify the therapeutic application of the products of formula I and their pharmaceutically acceptable salts as medicaments.

A subject of the invention is therefore, as medicaments, the products defined by formula I above, as well as their addition salts with mineral or organic acids pharmaceutically ac ceptab. Among these drugs, the products of formula I above are particularly retained, characterized in that, in formula I, R represents a methyl radical, and more particularly: - 1-methyl-3- (4-pyridyl) - 1,3-dihydro-imidazo (4,5-b) pyridin-2-one,

- 5-chloro-1-methyl-3- (3-pyridyl) -1,3-dihydroimidazo (4,5-b) pyridin-2-one,

- 5-chloro-1-methyl-3- (2-pyridyl) -1,3-dihydroimidazo (4,5-b) pyridin-2-one.

The set of products defined above constitute, medicaments very useful in human therapy, in particular for the treatment of hyperchlorhydria, gastritis, gastric ulcers, hiatal hernias, gastroduodenal affections accompanied by gastric hyperacidity.

Their properties can also be used to treat simple obesity in adults, plethoric state, complicated obesity of diabetes and hypertension, post-pregnancy obesity, childhood obesity. The dosage, which varies depending on the product used and the condition in question, can range, for example, from 0.05 to 2 g per day in adults by oral route. The present application also relates to pharmaceutical compositions which contain, as active principle, at least one of the abovementioned medicaments. These compositions are produced so that they can be administered by the digestive or parenteral route. They can be solid or liquid and come in the pharmaceutical forms commonly used in human medicine, such as, for example, simple or coated tablets, capsules, granules, suppositories, injectable preparations; they are prepared according to the usual methods. The active ingredient (s) can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

The subject of the present invention is finally, as new industrial products, the products of formula III:

in which, R 'represents a pyridyl radical and Y represents a chlorine atom or a hydrogen atom, as well as their addition salts with mineral or organic acids, as well as the products whose names follow:

OMP - 2- (4-pyridylamino) -3-amino-pyridine;

- 2- (2-pyridylamino) -3-amino-pyridine;

- 2- (2-pyridylamino) -3-nitro-pyridine.

The products of formula II are for the most part known. They can be prepared by a process analogous to that described in French patent 1-447-539.

They can also be prepared as follows:

A product of formula is reacted:

in which Y represents a hydrogen or chlorine atom, and Z represents a nitro radical. or a chlorine atom, with a product of formula:

NH ₂ - R "in which R" represents a pyridyl radical, the reaction preferably taking place in an organic solvent such as for example ethanol or cyclohexane, obtains a product of formula:

in which Y and R "have the value indicated above which is subjected to the action of a reducing agent such as hydrogen, in the presence of Raney nickel or platinum oxide, obtains a product of formula II:

in which Y and R "have the value indicated above. Examples of the preparation of products of formula II by such a method are given below in the experimental part. The products of formula VI are, for the most part, known.

Those which are not can be prepared according to a method analogous to that described in French patent 2,150,820. The examples given below illustrate the invention without, however, limiting it.

Example 1: 1-methyl-3- (4-pyridyl) -1,3-dihydroimidazo- (4,5-b) -pyridin-2-one. Stage A: 2- (4-pyridylamino) -3-amino-pyridine. A solution of 16.5 g of 2- (4-pyridylamino) -3-nitro-pyridine in 400 ml of 95 ° ethanol is hydrogenated at atmospheric pressure and at 30-40 ° C. 1.6 g is used as catalyst Pd / C 10%. When the reduction is complete (the hydrogen absorbed corresponds to a volume of 5.8 1), the catalyst is filtered and the filtrate is evaporated to dryness. The residue is taken up in petroleum ether and filtered. 13.5 g (95%) of crude product are obtained, melting at 202-4 ° C. The crystallization solvent is ethanol at 95 °, the crystalline powder has a straw yellow color with a melting point F. of 203-5 ° C. for C ₁₀ H ₁₀ N ₄ values found in% C 64.46 H 5.20 N 29.80 values calculated in% C 64.5O H §, 4l N 30.09 Stage: 3- (4-pyridyl) -1 , 3-dihydro-imidazo- (4,5-b) pyrdin-2-one. 13.5 g of 2- (4-pyridylamino) -3-amino-pyridine, dissolved in 350 ml of chloroform, added

18 g of N N'-carbonyl-diimidazole and heated to oil lition for 8 h. The reaction mixture is cooled, the solvent is evaporated, the residue is taken up in 400 ml of water, the solution is neutralized with 2N HCl, the product which has separated is filtered off and washed with water. 14 g (91.6%) of crude product of Mp = 265-7 ° C. are obtained. It is recrystallized from ethanol at 95 ° and it is dried under vacuum at 110 ° C. for 6 hours. White, flexible needles are obtained, including F. = 265-7 ° C. for C ₁₁ H ₈ N ₄ O values found in% C 61.98 H 3.66 N 26, 22 Values calculated in% C 62.26 H 3.80 N. 26.40 Stage C: 1-methyl-3- (4-pyridyl) -1,3-dihydroimidazo- (4,5-b) -pyridin-2-one.

15 g of 3- (4-pyridyl) -1,3-dihydro-imidazo- (4,5-b) pyridin-2-one are suspended in 700 ml of methanol and 5.7 g of sodium hydroxide pellets are added. After a few minutes a complete dissolution is obtained, the solution is stirred. room temperature for 1 hour, 45.6 g of methyl iodide are added and stirring is continued at room temperature for 6 hours. It is left to stand for 1 night, the product which has separated is filtered (iodhydrate of the starting material of mp = 275-85 ° C). The filtrate is evaporated to dryness, the residue is added to the product previously obtained, it is dissolved in water, it is made alkaline with 30% sodium hydroxide and extracted with chloroform. The organic phase is separated and dried with anhydrous sodium sulfate, filtered and the solvent is evaporated. The residue is crystallized from ethanol at 95 ° and 4 g (25%) of product are obtained. The product obtained is a straw-colored crystalline powder of which mp = 211-3 ° C. for C ₁₂ H ₁₀ N ₄ 0 Values found in% C 64.02 H 4.54 N 25.03

Values calculated as% C 63.71 H 4.46 N 24.77 Example 2: 1-methyl-3- (2-pyridyl) -1,3-dihydroimidazo- (4,5-b) -pyridin-2-one Stage A: 2- (2-pyridylamino) -3-nitro-pyridine . In a mortar, 31.6 g of 2-chloro-3-nitro pyridine and 56.5 g of 2-amino-pyridine are mixed very well. The mixture obtained is gently heated on an oil bath until it melts. At 150 ° C, a lively reaction begins and the temperature spontaneously rises to 160ºC. We suspend the heating until the isothermal reaction is finished and then we continue to heat at 150 ° C for 2h We cool, we resume the melt with 500 ml of chloroform, the mixture is concentrated and chromatographed on a column of 600 g of silica gel, eluting with approximately 3 l of a chloroform-benzene-petroleum ether mixture 1: 0.75: 1.2. The unreacted 2-chloro-3-nitro-pyridine is first separated, and then the product is separated. After evaporation of the eluate, 20 g of crude product are obtained which are crystallized from ethanol at 95 °. Yield 15.5g (36%). Yellow-orange needles with a melting point of F. = 121-3 ° C, soluble in 2N HCl.

for C ₁₀ H ₈ N ₄ O ₂ values found in% C 55.85 H 3.33 N 25.72 values calculated in% C 55.55 H 3.73 N 25.92 Stage B: 2- (2-pyridylamino ) -3-amino-pyridine. A solution of 18.3 g of 2- (2-pyridylamino) -3-hitro-pyridine in 550 ml of ethanol at 95 ° is hydrogenated at atmospheric pressure and at room temperature, using as catalyst 1.6 g of Pd / C 10%. When the reduction is complete (the volume of hydrogen absorbed in 1 h corresponds to 6.3 l), the catalyst is filtered and the solvent is evaporated off at reduced pressure. The residue, 15.8 g corresponding to 98.6%, is easily altered in air, it is therefore necessary to use it immediately for the following reaction. Stage C: 3- (2-pyridyl) -1,3-dihydro-imidazo- (4,5-b) pyridin-2-one.

A mixture of 15.8 g of 2- (2-pyridylamino) -3-amino pyridine and 20.8 g of N, N'-carb onyl-diimidazole in 175 ml of anhydrous chloroform is heated to boiling for 8 h. The mixture is cooled, the solvent is evaporated off, the residue is taken up in 300 ml of water, neutralized with 2N HCl, the product which has separated is filtered and washed with cold water. 16 g (89%) of product are obtained, in the form of colorless flakes whose mp = 235-8 ° C and does not vary after a second crystallization from xylene. for C ₁₁ H ₈ N ₄ O values found in% C 62.35 H 3.87 N 26.03 values calculated in% C 62.26 H 3.80 N 26.40 Stage D: 1-methyl-3- ( 2-pyridyl) -1,3-dihydro imidazo- (4,5-b) - pyridin-2-one.

A suspension of 10.6 g of 3- (2-pyridyl) -1,3-dihydro-imidazo- (4,5-b) pyridin-2-one and 5 g of sodium hydroxide tablets in 800 ml of methanol is heated for 30 minutes to the boil and is then stirred at room temperature until complete dissolution (time required approximately 2 h). 45.6 g of methyl iodide are then added dropwise and the stirring is continued at room temperature for 4 h. It is left to stand for 1 night, the reaction mixture is evaporated to dryness, the residue is dissolved in 700 ml of water, it is basified with 30% sodium hydroxide, and it is extracted with chloroform. The organic phase is separated, dried over anhydrous sodium sulfate, filtered and the solvent is evaporated. The residue is taken up with petroleum ether, filtered and crystallized from a xylene-petroleum ether mixture. Yield 7 g (62%). Lightly colored crystalline powder with straw of F. = 128-30 ° C. for C ₁₂ H ₁₀ N ₄ O values found in% C 64.00 H 4.46 N 24.49 values calculated in% C 63.71 H 4.45 N 24.77

Example 3: 1-methyl-3- (2-pyridyl) -5-chloro-1,3-dihydro-imidazo- (4,5-b) pyridin-2-one.

7.36 g of 1-methyl-5-chloro-1,3-dihydro-imidazo- (4,5-b) pyridin-2-one are dissolved hot in 160 ml of dimethylformamide. The solution is cooled to 30 ° C. and 4.64 g of an oily suspension containing 50% sodium hydride are slowly added. The temperature spontaneously rises to 40 ° C. The reaction mixture is maintained at this temperature while stirring for 2 h. 80 ml (129.6 g) of 2-bromo-pyridine, 1.2 g of cuprous chloride are added and the mixture is heated to boiling for 4 h. The reaction mixture is cooled, evaporated to dryness, the residue is taken up in ammonia, extracted with chloroform, the organic phase is separated, dried and the solvent is evaporated. The residue is taken up in petroleum ether, filtered and crystallized from ethanol at 95 ° Yield 6.5 g. White crystalline powder; Mp = 192-4 ° C. for C ₁₂ H ₉ CIN ₄ O values found in% C 55.50 H 3.60 N 21.42 values calculated in% C 55.29 H 3.48 N 21.49 Example 4; 1-methyl-3- (3-pyridyl) -5-chloro-1,3-dihydro-imidazo- (4,5-b) pyridin-2-one.

7.36 g of 1-methyl-2-oxo-5-chloro-1,3-dihydro-Imida2UD- (4, 5-b) pyridine are dissolved hot in 160 ml of dimethylformamide. The solution is cooled to 30 ° C. 4.64 g of oily suspension containing 50% sodium hydride are slowly added. Then heated to ^ O-SO ^ for 2 h with stirring, 80 ml (128.8 g) of 3-bromo-pyridine, 1.5 g of cuprous chloride are added and heats to a boil for 9 h. The reaction mixture is cooled, evaporated to dryness, the residue is taken up in ammonia / the insoluble part is filtered and washed with water. 8 g of crude product are obtained which is dissolved in acetone and chromatographed on a column of silica gel, eluting with the same solvent. The eluate is evaporated and the residue is crystallized from ethanol at 95 °. 5 g of product are obtained. White needles of which m = 206-8 ° C. for C ₁₂ H ₉ CIN ₄ O values found in% C 55.18 H 3.69 N 21.69 values calculated in% C 55.29 H 3.48 N 21.49

Example 5: pharmaceutical forms.

A) Tablets corresponding to the formula were produced:

- 5-chloro-1-methyl-3- (3-pyridyl) -1,3-dihydroimidazo- (4,5-b) pyridin-2-one 300 mg

- Excipient q.s. : for one finished tablet at .. 500 mg (Details of excipient: lactose, starch, talc, magnesium stearate).

B) Capsules corresponding to the formula were produced:

- 5-chloro-1-methyl-3- (2-pyridyl) -1,3-dihydroimidazo- (4,5-b) pyridin-2-one 200 mg

- Excipient q.s. : for a capsule finished at .. 500 mg (Detail of excipient: talc, magnesium stearate, aerosil).

Pharmacological study

1) Determination of gastric antisecretory activity. The technique used is described by H. SHAY et al. in Gastroenterology 5, 43, 1945.

Male rats weighing approximately 200 g are used, deprived of food for 48 hours, but having at will 8% glucose solution. We ligate the pylorus rats slightly anesthetized with ether, then at the end of the operation, the product to be tested is administered in various doses or, for the control animals, a solution of carb oxymethyl cellulose at 0.5%, intravenously - duodénale, then one sutures the abdominal incision.

Three hours later, the animals are sacrificed and their stomach removed after ligation of the esophagus. The gastric juice is removed and centrifuged. The volume is then noted and on 100 μl of gastric juice the total acidity is determined by titration at pH 7 using NaOH N / 10.

The percentages of variation in volume and total acidity of the gastric secretions are calculated relative to the results obtained with the control animals. The total acidity is expressed in concentration and acid flow, the latter being calculated by multiplying the acid concentration by the volume of secretion.

The following results were obtained:

2) Determination of antiulcer activity.

The technique consists of inducing ulcers in the stomach on rats by stress (stress and cold; the technique used is described by EC SENAY and RJ LEVINE, Proc. Soc. Exp. Biol. 124,

1221 (1967).

150 g female rats (5 animals per batch) are fasted for 48 hours with ad libitum water and glucose solution for 8 hours. The animals receive by esophageal probe the products tested, or a solution of carboxymethyl cellulose with

0.5? for control animals. Two hours later, the animals are swaddled in a wire corset, their legs are tied and the whole is placed in a refrigerator at 8 ° C for 2 hours. The rats are released, killed with ether, their stomach removed, opened according to the great curvature and examined with a binocular magnifying glass; the severity of the lesions is rated from 0 to 3 for each stomach.

The average intensity of the ulcers is calculated for each batch of rats, then the degree of ulceration relative to the controls and the number of animals with gastric hemorrhage relative to the number of animals treated is then determined for each batch. Results

3) Determination of the appetite suppressant activity.

It is administered orally to lots of 5 rats trained for 7 days to consume their daily meal in 4 hours and receiving unlimited water, each product to be tested at a dose of 25 mg / Kg or for control animals a 0.5% solution of carboxymethyl cellulose

One hour after administration, the animals are presented with their meal. The percentage of food consumption by the treated animals, 1 hour and 4 hours after the presentation of the meal, is calculated relative to the results obtained for the control animals. The following results were obtained:

D term nat on of tox cta gu.

The acute toxicity is determined on batches of 5 or 10 male mice weighing 20-22 g, fasting since the previous evening.

The products suspended in a 0.5% solution of methyl cellulose are administered orally using an esophageal probe.

Mortality is noted daily for a week. Lethal 50 doses (LD ₅₀ ) were determined and the following results were obtained:

Example product LD50 mg / Kg per, bone

1 ⋍ 500

2> 1000 3> 1000 4> 1000

Claims

Claims:

1) The products of general formula I:

in which R represents an alkyl radical containing from 1 to 3 carbon atoms, R 'represents a pyridyl radical and Y represents a chlorine atom or a hydrogen atom, as well as their addition salts with mineral or organic acids .

2) The products as defined by formula I of claim 1, characterized in that, in formula I, R represents a methyl radical.

3) 1-methyl-3- (4-pyridyl) -1,3-dihydro-imidazo- (4,5-b) pyridin-2-one.

4) 5-chloro-1-methyl-3- (3-pyridyl) -1,3-dihydro-imidazo- (4,5-b) pyridin-2-one.

5) 5-chloro-1-methyl-3- (2-pyridyl) -1,3-dihydro-imidazo- (4,5-b) pyridin-2-one.

6) Process for preparing the products as defined in claim 1, as well as their addition salts with mineral and organic acids, characterized in that a product of formula II is subjected:

wherein R 'represents a pyridyl radical and Y represents a chlorine atom or a hydrogen atom, to a cyclization means to obtain a product of formula III;

R ₁ - X (IV) in which R ₁ represents an alkyl radical containing from 1 to 3 carbon atoms, and X represents a residue chosen from the group consisting of chlorine, bromine, iodine atoms and sulphate radicals of methyl and ethyl sulphate, to obtain the corresponding product of formula I, and that, if necessary, the product of formula I obtained is subjected to the action of a mineral or organic acid to form its salt. 7) Preparation process according to claim 6, characterized in that the cyclization means consists in reacting on the product of formula II an alkyl chloroformate of formula:

wherein R 'and Y have the meaning given in claim 6 and alk the above meaning, a basic agent. 8) Preparation process according to claim 6, charac terized in that, the cyclization means consists in reacting with the product of formula II, carbonyldiimidazole.

9) Process for the preparation of products as defined by formula I of claim 1 and of their addition salts with mineral or organic acids, characterized in that a product of formula VI is reacted:

in which R represents an alkyl radical containing from 1 to 3 carbon atoms, and Y represents a chlorine atom or a hydrogen atom, with a product of formula VII:

R '- X (VII) in which R' represents a pyridyl radical and X represents a chiore, bromine or iodine atom, to obtain the corresponding product of formula I which, if necessary, is subjected to the action of a mineral or organic acid to form the salt. 10) Medicines, characterized in that they consist of the products of formula I, as defined in claim 1, as well as by their addition salts with pharmaceutically acceptable inorganic or organic acids. 11) Medicines, characterized in that they consist of the products of formula I, as defined in claim 2 or 3 as well as by their addition salts with pharmaceutically acceptable mineral or organic acids. 12) Medicines characterized in that they consist of the products of formula I as defined in claim 4 or 5, as well as their addition salts with pharmaceutically acceptable mineral or organic acids.

13) Pharmaceutical compositions characterized in that they contain, as active principle, at least one of the medicaments as defined in any one of claims 10, 11 or 12.

14) The products of formula III:

in which R 'represents a pyridyl radical and Y represents a chlorine atom or a hydrogen atom, as well as their addition salts with mineral or organic acids. 15) Any of the products whose names follow

- 2- (4-pyridylamino-) -3-amino-pyridine,

- 2- (2-pyridylamino) -3-amino-pyridine,

- 2- (2-pyridylamino) -3-nitro-pyridine.