CS200169B2 - Method of producing novel imidazo/4,5-b/pyridines - Google Patents

Abstract

1445824 lmidazo[4,5-6]pyridines DR KARL THOMAE GmbH 1 Feb 1974 [3 Feb 1973 12 Dec 1973] 04808/74 Heading C2C The invention comprises compounds of formulµ and their N-oxides and acid addition salts, [wherein R 1 , R 2 and R 3 , which may be the same or different, each represents a hydrogen or halogen atom; a hydroxy, alkyl, allyloxy, benzyloxy, alkylthio, alkylsulphinyl or alkylsulphonyl group; an amino group optionally substituted by one or two alkyl groups; a morpholino or a piperazino group optionally substituted in the 4-position by a phenyl group or an alkyl group containing from 1 to 3 carbon atoms; or an alkoxy group containing from 1 to 4 carbon atoms, optionally substituted by a halogen atom or by a hydroxy, alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl, alkylamino, dialkylamino, piperidino, morpholino, thiomorpholino, thiomorpholino-S-oxide, thiomorpholino - S,S - dioxide, 4 - alkylpiperazino, 4 - phenylpiperazino, 4 - dimethoxyphenylpiperazino, 4 - phenylethylpiperazino, phenylethylamino, N - methyl - phenylethylamino or N - methyl - dimethoxyphenylethylamino group, provided that when two of R 1 , R 2 , R 3 are H, the other group is other than H, halogen, Me or NH 2 ; or two of the groups R 1 to R 3 together represent a methylenedioxy group and the remaining R 1 , R 2 or R 3 group is as hereinbefore defined; each of the above mentioned alkyl groups containing from 1 to 4 carbon atoms; R 4 represents a hydrogen atom; an alkyl group optionally substituted by a hydroxy, dialkylamino, phenyl dimethoxyphenyl, piperidino, morpholino, 4 - methylpiperazino or 4- phenylpiperazino group, each of the above mentioned alkyl groups containing from 1 to 4 carbon atoms, or a phenyl group optionally substituted by one or more halogen atoms or methoxy groups; provided that where R 4 represents a hydrogen atom at least one of the groups R 1 to R 3 is other than hydrogen; and R 5 represents a hydrogen atom, a halogen atom or an alkyl group of 1 to 3 carbon atoms. In examples, these compounds are prepared by reacting (1) a 2,3-diaminopyridine with (a) an appropriately substituted benzoic acid or an acid- or imido-chloride, ester, anhydride, amide (e.g. N-substituted) or thionomorpholide methiodide thereof, (b) an appropriately substituted 2- phenyl - 1,3 - dithiolan - 2 - ylium iodide, or (c) 4 - (1,3 - dithiolanylidene) - 3 - hydroxy cyclohexadienone; (2) a 3-amino-2-chloropyridine with an appropriately substituted benzamide; (3) converting Ia(R 4 =H) to I(R 4 #H) by reaction with an appropriate organic halide in presence of a base; or (4) interconversion of functional groups present by known methods. In method (1)(a), an intermediate salt or a 2- amino-3-benzamidopyridine or the corresponding amidine, and in method (2) a corresponding N<SP>1</SP>- (2 - chloro - 3 - pyridyl)benzamidine, may be isolated as intermediates. Also isolated are 2-(p-acetamidophenyl)-1H. imidazo[4,5-b]pyridine; and alkylthioalkoxy/ hydroxybenzaldehydes and their methyl ethers. Therapeutic compositions for oral, parenteral or rectal administration comprise compounds of the above formulµ, which are stated to have activity on the blood pressure and heart force, a positive inotropic effect, antiulcus activity, a platelet aggregation inhibiting effect and prolonging activity on the bleeding time.

Description

The invention relates to a process for the preparation of the novel imdazo [4,5-b] pyridines of the formula I

where

R 1 represents alkylamino-, dialkylamino-, hydroxy-, allyloxy-, benzyl-, oxy-, alkylthio-, alkylsulfinyl-, alkylsulfonyl-, morpholino-, 4-phenylpiperazino-, 4-alkylpiperazino- or alkoxy optionally substituted by a halogen atom , hydroxy, alkoxy,

alkylthio-, alkylsulfinyl-, alkylsulfonyl-, alkylamino-, dialkylamino, piperidino-, morpholino-, thiomorpholino-, 4-alkylpiperazino-, 4-phenylpiperazino-, 4-methoxyphenylpiperazino-, 4-phenylethylpiperazino-, phenylethylamino-, N-methylphenylethylamino-, N-methylphenylethylamino- -methyldimethoxyphenylethylamino,

R @ 2 is hydrogen or halogen, methyl, hydroxy, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl,

R 5 represents a hydrogen atom or an alkoxy group or two of the radicals R 1 to R 3 together represent methylenedioxy,

R4 represents a hydrogen atom, optionally a hydroxy-, dimethylamino-, diethylamino-, phenyl-, dimethoxyphenyl-, piperidino-, morpholino-, 4-methylpiperazino- or 4-phenylpiperazino-substituted alkyl radical or optionally a halogen atom, a 1 or 2 methoxy-substituted phenyl radical and

R 5 represents a hydrogen or halogen atom or a methyl group, each alkyl moiety of the abovementioned radicals having 1 to 4 carbon atoms, and their physiologically tolerable addition salts with inorganic acids.

The compounds of formula (I) have valuable pharmacological properties, in particular blood pressure, cardiac activity, positive inotropic activity, anti-ulcer effect, platelet aggregation-inhibiting effect and prolonged bleeding time, and can be produced by treating pyridine of formula II

(ID where

R 5 is as defined above and

Y represents a halogen atom or a group R4NH in which

Rd is as defined above, reacted with a compound of formula III

where

R1 to R3 have the above meanings and

X represents a carboxyl group or a functional derivative thereof in the form of nitrile, acid halide, ester, amide, imido acid ester, imido acid thioester, imido acid halide, amidine, thiocarboxylic acid, dithiocarboxylic acid, carboxylic acid anhydride or orthoester, provided that

Y represents a halogen atom,

X is an aminocarbonyl group which is optionally substituted by R1 or an aminocarbimino group, and optionally the compound of formula (I) containing a reactive halogen atom is converted to the corresponding amino compound by treatment with an amine and / or the compound of formula (I) a reactive hydrogen atom, in the presence of a base, alkylated with an alkylating agent, and / or the compound of formula I thus obtained is converted with the oxidizing agent into the corresponding N-oxide, S-oxide or S, S-dioxide compound and / or its physiologically acceptable addition salt with an inorganic or organic acid.

The reaction is conveniently carried out in a solvent such as benzene, pyridine, glycol, toluene, acetone, diethylene glycol or triethylamine, optionally in the presence of an acid scavenger such as pyridine or triethylamine, optionally in the presence of a catalytic, i.e. , such as p-toluenesulfonic acid or in the presence of a water scavenger such as phosphorus oxychloride or thionyl chloride, and depending on the reactivity of the residue X at temperatures between -20 to 250 ° C. However, the reaction can also be carried out without solvent.

When X is, for example, a carboxyl group or an amide derivative, the reaction is conveniently carried out in the presence of thionyl chloride phosphorus oxychloride and optionally in the presence of a tertiary organic base such as pyridine or triethylamine, preferably at temperatures between -20 ° C and boiling point. for example at 120 ° C.

For example, when X is a nitrile group, the reaction is conveniently carried out in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, preferably at temperatures between 120 and 180 ° C, for example at 160 degrees Celsius, optionally in a solvent.

In the case where X is, for example, a thioamide derivative, the reaction is conveniently carried out in a solvent such as glycol and preferably at temperatures between 100 and 150 ° C, for example 130 ° C.

When Y in the compound of formula (II) represents a halogen atom, for example chlorine, the reaction proceeds via the corresponding amidine, which may not always be isolated and which is cyclized at higher temperatures, for example between 100 and 200 ° C.

The compounds of the formula I obtained according to the invention which contain a reactive halogen atom can then, if desired, be converted by the amine into the corresponding amino compound, and / or the obtained compounds of the formula I containing reactive hydrogen atoms can then be and the usual. The alkylating agent can be alkylated, and / or the compounds of the formula I obtained can be converted to the corresponding N-oxide, S-oxide or S, S-dioxide compounds and / or physiologically compatible addition salts with inorganic or organic acids using a conventional oxidizing agent. . Examples of suitable acids are hydrochloric, hydrobromic, sulfuric, lactic, tartaric, maleic or fumaric acid.

The starting materials used in the process according to the invention are known in the literature or can be prepared by known methods (see examples).

As already mentioned in the introduction, the novel compounds of the formula I have valuable pharmacological properties, in particular blood pressure, positive inotropic, anti-ulcer activity. effect, platelet aggregation inhibiting effect, and prolonged effect on bleeding time.

For example, the following substances have been investigated for biological effects:

A - 2- (2,4-dimethoxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride,

B = 2- (2- (2-methylsulfinylethoxy) -4-methoxyphenyl] -1H-imidazo [4,5-b] pyridine hydrochloride,

C! = 2- (2-methoxy-4-mephenyl) -1H-imidazo [4,5-b] thylmercaptopyridine hydrochloride,

D = 2- (2-methoxy-4-methylsulfinylphenyl) -1H-imidazo (4,5-b) pyridine hydrochloride,

E = 2- (2-methoxy-5-methylmercaptophenyl) -1H-imidazo [4,5-b] pyridine hydrochloride,

F = 2- (2-methoxy-4-methylphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride, reversed on a Grass Polygraph using a Statham-Force-Transducer. The atria were loaded with 1 g. After a sufficient time to reach equilibrium, the test substances were added to the isolated organ bath. The concentration of the substances in the bath is in each case 1 * ¹⁰ &lt; ⁵ &gt; g / ml. Five vestibules were taken for each substance.

The following table shows the results of the experiment:

Table I

Substance Amplification of contractions in%

A B

C

E

F

G

II

AND

J

57.0

17.5

10.3

40.9

50.2

33.9

42.9

21.4

11.4

G - 2- (2-ethoxy-4-mercaptophenyl) -1H-imidazo [4,5-b] pyridine hydrochloride,

H - 2- (2-ethoxy-4-methylphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride,

2- (2-methoxy-4-chlorophenyl) -1H-imidazo [4,5-b] pyridine hydrochloride;

J = 2- (2- (2-methylsulfinyl-ethoxy) -4-methyl-caprophenyl] -III-imidazo (4,5-b) pyridine hydrochloride,

1, Positive inotropic effect on isolated guinea pig atrium

The isolated guinea pig atrium is placed in a 100 ml insulated organ bath. The bath is filled with 30 ° C Tyrodine solution, 95% oxygen and 5% carbon dioxide gas (C ^ irbogen) is bubbled through the Tyrodes solution, Spontaneous atrial contraction with isometric registr2, Experiments on anesthetized cat for blood circulation

Cats were anesthetized with 30 mg / kg pentrobarbital-sodium intravenous solution. A synthetic catheter was inserted into the femoral artery and a steel catheter was inserted from the carotis artery into the left ventricle. The left ventricular arterial blood pressure was continuously recorded using a Statham type P23AA and P23Dc instrument. The ventricular pressure curve was continuously calculated from the ventricular pressure curve dp / dtmax and Vce using an analog computer. The heart rate was determined using a tachograph from the ventricular pressure curve. , In addition, ECG was recorded in lead II,

All registrations were made using a Brush direct recorder, the substances were injected into the femoral vein using a hollow needle, each substance was tested on at least three cats,

In addition, none of the compounds at the doses administered produced toxic side effects,

Table II

Substance

Dose mg / kg Lv,

Influence on blood pressure change in Pa

Effect on heart activity Contraction changes Heart rate changes in% frequency in%

AND 0.5 - 667 +20 + 4 1.0 - 667 +41 + 5 (B) 0.5 + 1333 +16 - 2 1.0 +2666 +29 - 9 C 0.5 + 667 + 22 + i 1.0 + 1333 +36 + 5 D 0.5 0 +34 + 5 1.0 - 667 +39 + 5

200169 Substance 7 8 Effect on heart activity Contraction changes Cardiac changes Dose mg / kg i.v. Influence on blood pressure change in Pa in% frequency in ° / o E 0.5 +1333 +14 0 1.0 - 2000 +25 0 F 0.5 +1333 +44 - 3 1.0 +2000 453 0 G 0.5 0 4 7 0 1.0 4 667 +29 - 5 H 0.5 1333 +15 0 1.0 +2000 4-25 0 AND 0.5 - 667 +17 4 2 1.0 - 667 +19 • 4 2 J 0.5 + -1333 +14 0 1.0 2 ^ C ^ 00 - | -22 —15

The novel compounds of the formulas I and Ia can be used, for pharmaceutical use, optionally in combination with other active substances in the usual formulations such as tablets, dragees, suppositories, ampoules or drops. The individual dose is 35 to 200 mg, but preferably 50 to 100 mg.

The examples below explain the invention.

Example 1

2- (2,4-Dimethoxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

54.5 g of 2,3-diaminopyridine and 91.1 g of 2,4-dimethoxybenzoic acid are co-rubbed to a fine powder and added portionwise to 1500 ml of phosphorus oxychloride with stirring. After the addition was complete, it was refluxed for 2 hours, then phosphorus oxychloride was distilled off in vacuo. The residue is triturated with 2000 ml of 2 N hydrochloric acid, the solid product obtained is filtered off and recrystallized from water.

Yield: 121 g (85% of theory);

Example 2

2- (2,4-Dimethoxy-phenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

360 mg of 2,4-dimethoxybenzoic acid are dissolved in 2 ml of pyridine and mixed with a solution of 220 mg of 2,3-diaminopyridine in 2 ml of pyridine, whereby the corresponding salt precipitates. While stirring and cooling with ice, 0.38 ml of phosphorus oxychloride was added dropwise, and it was stirred at 0 DEG C. for an hour and at room temperature for an hour. The excess pyridine is then removed in vacuo, the residue is taken up in dilute hydrochloric acid, neutralized with sodium hydroxide and extracted with ethyl acetate. The phases in ethyl acetate are evaporated, the residue is treated with a small amount of 2 N hydrochloric acid, the precipitate is filtered off and recrystallized from water.

Mp 238-239 ° C.

Yield: 50 mg (9% of theory).

Example 3

2- (2,4-Dimethoxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to an analogous example to 2,3-diaminopyridine, 2,4-dimethoxybenzoic acid and thionyl chloride.

Mp 238-239 ° C.

Example 4

2- (2,4-Dimethoxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

900 mg of 2,4-dimethoxybenzoic acid are converted to the acid chloride by heating in a mixture of 3 ml of benzene and - 2 ml of thionyl chloride. It is concentrated in vacuo and the residue is taken up in 5 ml of benzene. This solution was added dropwise to a solution of 550 mg with stirring

2,3-diaminopyridine in 5 ml pyridine. After the addition was complete, the mixture was briefly warmed to 60 ° C, then cooled to room temperature, 0.9 ml of phosphorus oxychloride was added dropwise and stirred at room temperature for 3 hours. It is then mixed with 2 N hydrochloric acid, neutralized and extracted with ethyl acetate. The phases in ethyl acetate are evaporated and the residue is mixed with a small amount of hydrochloric acid (2N), the precipitated crystals are filtered off with suction and recrystallized from water.

Mp: 237-238 ° C.

Yield: 30 mg (2% of theory).

Example 5

2- (2,4,4-O-4- (4-phenyl)) -1H-imidazo [4,5-b] pyridine hydrochloride

a) 2-Amino-3- (2,4-d-methoxybenzyl) -2-amino-3- (2,4-d-methoxybenzyl) pyridine hydrochloride

530 mg of 2,4-dimethoxybeazoic acid was converted to the acid chloride according to the analogy of Example 4 and this solution was dissolved in 1 ml of benzene. This solution was added dropwise to a mixture of 440 mg of 2,3-diaminopyridine, 3 ml of pyridine and 2 ml of triethylamine, and the whole was stirred at room temperature for 2 hours. The mixture is then mixed with water, neutralized with concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate is evaporated, the residue is treated with dilute hydrochloric acid, the precipitated crystals are filtered off with suction and recrystallized from ethanol.

Melting point: 172-174 ° C.

Yield: 250 mg (25% of theory).

b) 2- (2,4-Dimethoxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

155 mg of 2-amino-3- (2,4-dimethoxybenzoylamino) pyridine hydrochloride are dissolved in 2 ml of pyridine. 0.2 ml of phosphorus oxychloride is added dropwise to the mixture while stirring at room temperature. After two hours, the mixture was poured into water and worked up in analogy to Example 4.

Mp: 237-238 ° C.

Yield: 25 mg (10% of theory).

Example 6

2- (2,4-Dimethoxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

155 mg of 2-amino-3- (2,4-dimethoxybenzoylamino) pyridine hydrochloride was heated at 200-210 ° C for 5 minutes. It is then treated with a small amount of 2 N hydrochloric acid, filtered and recrystallized from water.

Mp: 237-238 ° C.

Yield: 30 mg (18% of theory).

Example 7

2- (2,4-Dimethoxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

155 mg of 2-amino-3- (2,4-dimethoxybenzoylamino) pyridine hydrochloride was heated to reflux in 2 ml of glycol for 30 minutes. It is then diluted with water, neutralized, extracted with ethyl acetate and worked up in analogy to Example 4.

Mp 238-239 ° C.

Yield: 10 mg (6% of theory).

Example

2- (2,4-Dimethoxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

5.45 g of 2,3-diaminopyridine are added in small portions to 150 ml of phosphorus oxychloride with stirring and added dropwise.

9.81 y 2,4-dimethoxybenzoic acid methyl ester. After completion of the addition, heat up to 120% !. After two hours. The phosphorus pentachloride is evaporated off under vacuum, the residue is digested with 2N hydrochloric acid and the resulting solid is collected by filtration and recrystallized from water.

Mp 238-239 ° C.

Yield: 3.8 g [25% of theory 1.

Example 9

2- (2,4-Dimethylsulfonyl) -1H-imidazo [4,5-b] pyridine hydrochloride

To 470 mg of 2,4-trichloro-benzoyl chloride in 6 ml of toluene was added 0.5 ml of morpholine while stirring. After 20 minutes, toluene was evaporated, the residue was treated with dilute hydrochloric acid and the mixture was extracted with ethyl acetate. After washing the phase in ethyl acetate with a solution of sodium bicarbonate solution and after washing. concentration gives crude 2,4-dimethoxybenzocmorpholine as an oil. This is taken up in 5 ml of pyridine, mixed with 250 mg,

2,3-dinmmopynidine and then 1 ml of phosphorus oxychloride is added dropwise with stirring and ice-cooling. After stirring at 0 ° C for 5 hours, it is mixed with ice water, basified with concentrated ammonia, briefly heated on a steam bath, and extracted with ethyl acetate. The ethyl acetate is evaporated, the residue is converted to the hydrochloride with 2N hydrochloric acid, filtered off with suction and recrystallized from water.

Mp 238 ° C.

Yield: 130 mg (20% of theory).

Example 10

2- (2,4-Dimethoxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

300 mg of 2,4-β-1-oxo-benzoic acid 4-chloroanilide and 110 µg of 2,3-diaminopyridine are mixed and added portionwise to 3 ml of phosphorus oxychlooid with stirring. The mixture is heated under reflux for 8 hours, then the phosphorus oxychloride is removed in vacuo, the residue is triturated with 2 N hydrochloric acid, the resulting solid is filtered off and recrystallized from water.

Mp 237-238 ° C.

Yield: 150 dg (50% of theory).

Example 11

2- (2,4-Didsthoxylphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

600 dg of 4-chloroanilide 2 ₅ 4-dimethoxybenzoic acid was heated to reflux in a mixture of 5 dl of benzene and 2 ml of thionyl chloride for 3 hours. Evaporation gave crude 2,4-dimethoxy-N- (4-chlorophenyl) benzimidic acid chloride as an oil. The product is taken up in 9 ml of toluene and a solution of 200 mg of 2,3-diaminopyridine in 10 ml of isopropanol is added and the mixture is heated at 70 ^DEG C. for 10 minutes. The resulting N- (4-chlorophenyl) -N'- (2 The amino-3-pyridyl) amidine of 2,4-dimethoxybenzoic acid is not isolated, but after isopropanol is evaporated in vacuo, it is taken up in 20 ml of glycol and heated to reflux for 10 minutes. It is then mixed with water, basified with concentrated ammonia, extracted with ethyl acetate and worked up analogously to Example 4.

Mp 237-238 ° C.

Yield: 80 mg (13% of theory).

Example 12

2- (2,4-Dimethoxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

100 mg of 2,3-diaminopyridine, 200 mg of 2,4-dimethoxybenzonitrile and 400 mg of p-toluenesulfonic acid monohydrate were mixed and heated at 160 ° C for 3.5 hours. The product is then rubbed with dilute ammonia and ethyl acetate until complete dissolution. The combined phases in ethyl acetate are extracted with a small amount of 2 N hydrochloric acid, from which the title compound crystallizes after some time.

Mp: 237-238 ° C.

Yield: 100 mg (38% of theory).

Example 13

2- (3,4,5-trimethoxyphenyl) -1H-imidazo [4,5-b] pyridine

3.4 g of p-toluenesulfonic acid monohydrate and 15 ml of benzene were heated to 120 DEG C. until all the benzene was evaporated. Then, 1.1 g of 2,3-diaminopyridine and 2 g of 3,4,5-trimethoxybenzoic acid nitrile are added and the mixture is heated at 150 ° C for 2 hours. After cooling, it is mixed with water, extracted with ethyl acetate, the phases in ethyl acetate are washed with dilute sodium hydroxide solution and the residue is recrystallized from isopropanol and petroleum ether.

Melting point: 226 ° C.

Yield: 550 mg (19% of theory).

Example 14

2- (3,4,5-trimethoxyphenyl) -1H-imidazo [4,5-b] pyridine

A mixture of 4.2 g of 3,4,5-trimethoxybenzoic acid and 2.2 g of 2,3-diaminopyridine was refluxed in 40 ml of phosphorus oxychloride for 2 hours.

The phosphorus oxychloride is then distilled off, the residue is mixed with ice water and the precipitated solid product is filtered off. The product was dissolved in hot water, basified with concentrated ammonia, the precipitate was filtered off and recrystallized from a small amount of isopropanol.

Melting point: 225-226 ° C.

Yield: 2.0 g (35% of theory).

Example 15

2- (2,5-Dimethoxyphenyl) -1H-imidazo [4,5-b] pyridine

(a) 2,5-Dimethoxythiobenzoic acid morpholide

A mixture of 10 g of 2,5-dimethoxybenzaldehyde, 10 g of morpholide and 4 g of sulfur is heated at 130 DEG C. for 3.5 hours and then dissolved in 300 ml of hot ethanol. The product precipitated upon cooling recrystallizes from ethanol.

127 ° C.

Yield: 9.0 g (57% of theory).

b) S-methyl-2,5-dimethoxythiobenzoic acid morpholine iodide g of 2,5-dimethoxythiobenzoic acid morpholine, 6.5 g of methyl iodide and 30 ml of acetone are heated under reflux for 8 hours. The precipitated solid product is then filtered off and washed with ether and reacted directly.

Yield: 8.6 g (96% of theory).

c) 2- (2,5-Dimethoxyphenyl) -1H-imidazo [4,5-b] pyridine g S-methyl-2,5-dimethoxythiobenzoic acid morpholide iodide and 1.1 g 2,3-diaminopyridine are heated in 30 ml glycol 40 minutes at 130 ° C. It is then poured onto ice water, filtered and recrystallized from ethanol and water.

Melting point: 235 ° C.

Yield: 0.45 g (35% of theory).

Example 16

2- (4-hydroxyphenyl) -1H-imidazo [4,5-b (pyridine

a] 4-Hydroxythiobenzoic acid morpholide

Prepared according to the analogy of Example 15a of

12.2 g of 4-hydroxybenzaldehyde, 16 g of morpholide and 3.2 g of sulfur.

205 ° C.

Yield: 14.4 g (72% of theory).

b) S-methyl-4-hydroxythiobenzoic acid morpholide iodide

Prepared according to the analogy of Example 15b of z

14.4 g of 4-hydroxythiobenzoic acid morpholide and 2.1 g of methyl iodide in 100 ml of acetone.

Melting point: 181 ° C.

Yield: 18.9 g (73% of theory),

c) 2- (4-Hydroxyphenyl) -1H-imidazo [4,5-b] pyridine;

1.84 g of S-methyl-4-hydroxythiobenzoic acid morpholide iodide was heated to 130 ° C with 1.1 g of 2,3-aminopyridine in 30 ml of glycol for 20 minutes. The product precipitated upon cooling is dissolved in sodium hydroxide solution and precipitated with acid.

Yield: 0.25 g (23.7% of theory).

Analysis:

calculated:,

H, 5.13; N, 16.46.

found:

H, 5.16; N, 16.47.

Example 17

2- [4-Methoxy-2- (3-chloropropoxy) phenyl] -1H-imidazo [4,5-b] pyridine hydrochloride

(a) 4-Methoxy-2- (3-chloro-poopoxin) -benzoic acid morpholide

21.9 g of 2-hydroxy-4-methoxybenzoic acid morpholide are dissolved in 200 ml of dimethylformamide and 11.2 g of potassium tert-butyl alcohol are added. After complete dissolution, 50 g of 1-chloro-3-bromopropane are added and heated at 130 ° C for 2 hours. It is then evaporated in vacuo, the residue is taken up in ethyl acetate, washed with dilute sodium hydroxide and evaporated and further reacted directly.

Yield: 26 g (83% of theory).

(b) 2- [4-Methoxy-2-

- (3-chloropropoxy) phenyl] -1H-imidazo [4,5-b] pyridine g of 4-methoxy-2- (3-chloropropoxy) benzoic acid morpholide, 7 g of 2,3-diaminopridine and 170 ml of phosphorus oxychloride The mixture was heated at reflux for 2 hours. After evaporation of the phosphorus oxychloride, the residue is mixed with water, neutralized with sodium hydroxide, extracted with ethyl acetate and the hydrochloride is precipitated with ethereal hydrochloric acid.

Melting point: 198 ° C (decomposition).

Yield: 7 g (35% of theory).

Example 18

2- [4-Methoxy-2- (2-chloroethoxy) phenyl] -1H-imidazo [4,5-b] pyridine hydrochloride

(a) Morpholide of 4-methoxy-2-

- (2-Hydroxymethoxy) benzoic acid

23.7 g of 4-ethoxybenzamic acid morpholide, 33.6 g of potassium tert-butyl alcoholate and 37.4 g of ethylenebromohydrin are heated in 100 ml of dimethylformamide for 6 hours. 120 DEG C. After concentration in vacuo, it is taken up in chloroform, washed with sodium hydroxide and water and concentrated.

Yield: 23.0 g (82% of theory).

b] 2- [4-methoxy-2- (2-chloroethoxy) phenyl] -1H-imidazo [4,5-b] pyridine hydrochloride

2.8 g of 4-methoxy-2- (2-hydroxy-ethoxy) benzoic acid morpholide, 1.1 g of 2,3-diaminopyridine and 20 ml of phosphorus oxychloride are heated at reflux for 2 hours. After evaporation, it is mixed with water, neutralized, extracted with ethyl acetate and the hydrochloride is precipitated with ethereal hydrochloric acid.

Melting point: 110 DEG C. (decomposition).

Yield: 2.1 g [62% of theory].

Example 19

2- [4-methoxy-2-

- (3-chloropropoxy) phenyl] -1H-imidazo [4,5-b] pyridine

a] Acid Anilide 4-1 ^^. ^ - 2-

- (3-chloropropoxy) benzoic acid

2.5 g of 2-bromo-4-methoxybenzoic acid anilide, 5 ml of 1-chloro-3-bromopropane, 1.12 g of 1-potassium-1-chloro-3-bromopropane, 1.12 g of potassium potassium and 20 ml of dimethylformamide are heated at 130 ° C for 2 hours. It is then evaporated in vacuo, mixed with water and filtered.

Melting point: 87-90 ° C.

Yield: 2.5 g (39% of theory),

b] 2- [4-methoxy-2- hydrochloride

- (3-chloropropoxy) phenyl] -1H-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 17b from 4-methoxy-2- (3-chloropropoxy-enoic acid anilide) and 2,3-dialine-pyridoidil.

Melting point: 198 ° C.

Yield: 0.17 g (30% of theory).

Example 1 a d 2 0

2- [4-Methoxy-2- (3-morpholinopropoxy) phenyl] -1H-imidazo [4,5-b] pyridine

0.5 g of 2- [4-methoxy-2- (3-chloropropoxy) phenyl] -1H-imidazo [4,5-b] pyridine hydrochloride was heated to reflux with 5 ml of morpholine for 4.5 hours. It is then mixed with water, filtered and recrystallized from water.

Melting point: 108-110 ° C.

Yield: 0.1 g (17% of theory).

Example 21

2- [4-Methoxy-2- (2- (4-phenyl-1-piperazinyl) ethoxy) phenyl] -1H-imidazo [4,5-b] pyridine

Prepared from 1.7 g of 2- [4-methoxy-2- (2-chloroethoxy) phenyl] -1H-imidazo [4,5-b] pyridine and

3.2 g of 1-phenylpiperazine were stirred in ethanol for 8 hours.

Melting point: 164-165 ° C (from isopropanol).

Yield: 0.4 g (19% of theory).

Example 22

2- [4-Methoxy-2- (3-dimethylaminopropoxy) phenyl] -1H-imidazo [4,5-b] pyridine hydrochloride

1.8 g of 2- [4-methoxy-2- (3-chloropropoxy) phenyl] -4-imidazo [4,5-b] pyridine hydrochloride and 20 ml of a saturated solution of dimethylamine in ethanol are heated in a sealed pressure vessel for 8 hours. Mp 100 ° C. It is then evaporated in vacuo and recrystallized from isopropanol.

Melting point: 209-210 ° C.

Yield: 0.5 g (28% of theory).

Example 2 3

2- [4-Methoxy-2- (3-dimethylaminopropoxy) phenyl] -4-imidazo [4,5-b] pyridine dihydrochloride

1.64 g of 4-methoxy-2- (3-dimethylaminopropoxy) thiobenzoic acid morpholide are dissolved in a mixture of 17 ml of glacial acetic acid and 3 ml of acetic anhydride, then mixed with 1 ml of dimethyl sulphate and heated on a steam bath for 1 hour. It is then evaporated in vacuo. The crude S-methyl-4-methoxy-2- (3-dimethylaminopropoxy) thiobenzoic acid morpholide methyl sulfate obtained is taken up in 13 ml of glycol, mixed with 0.7 g of 2,3-diaminopyridine and heated at 160 ° C for 2 hours. It is then poured into 50 ml of water, 5 ml of concentrated ammonia are added and extracted with ethyl acetate. The phases in ethyl acetate are evaporated, the residue is taken up in ethanol, mixed with ethereal hydrochloric acid and evaporated again. The residue solidifies after rubbing with toluene and ethanol. It is filtered off with suction and recrystallized from isopropanol. Melting point of dihydrochloride hydrate: 228-235 ° C (dec.). Yield: 80 mg (4% of theory).

Example 1 a d 2 4

2- (2,4-Dimethoxyphenyl) -3-methyl-3H-imidazo [4,5-b] pyridine

800 mg of 2,4-dimethoxybenzoic acid methylamine are heated with 500 mg of 2-chloro-3-aminopyridine in 10 ml of phosphorus oxychloride under reflux for 3 hours. It is then poured onto water, neutralized with concentrated ammonia and extracted with ethyl acetate. The crude N-methyl-N '- (2-chloro-3-pyridyl) -2,4-dimethoxybenzamidine obtained by evaporation is taken up in 10 ml of 10% glycolic sodium hydroxide solution and heated at 180-190 ° C for 4 hours. C. The mixture was poured onto water, extracted with ethyl acetate and purified on a column of silica gel, chloroform-methanol (19: 1).

Melting point hydrochloride: 196-197 ° C.

Yield: 20 mg (1.5% of theory).

Example 25

2- (2,4-dimethoxyphenyl) -3- (4-chlorophenyl) -4-imidazo [4,5-b] pyridine g of 2,4-dimethoxybenzoic acid 4-chloroanilide and 1.3 g of 2-chloro-3 The aminopyridine was refluxed in 16 ml of phosphorus oxychloride for 2 hours. It is then poured onto water, neutralized with concentrated ammonia and extracted with ethyl acetate. The phase in ethyl acetate is extracted with 3 N hydrochloric acid. After neutralizing the aqueous phase, it is further extracted with ethyl acetate. The solid product remaining after evaporation was recrystallized from methanol.

Melting point: 176-178 ° C.

Yield: 1.3 g (35% of theory).

Example 26

2- (2,4-Dimethoxyphenyl) -4-imidazo [4,5-b] pyridine hydrochloride

2,2 g of 2,3-diaminopyridine, 6.8 g of 2,4-dimethoxybenzoic acid morpholide imidochloride and 12 ml of triethylamine are heated in 120 ml of diethylglycol dimethyl ether for 120 hours at 120 ° C. After cooling, the reaction mixture is mixed with water, extracted with chloroform, and the chloroform phase is shaken with 2N hydrochloric acid. The yellow hydrochloride precipitated from solution in hydrochloric acid was liberated with ammonia and purified by column chromatography (eluent: chloroform-acetone = 9: 1). Hydrochloride again precipitated from acetone with ethereal hydrochloric acid.

Mp: 237-238 ° C.

Yield: 1.3 g (22.4% of theory).

Example 27

2- (2,4-Dimethoxyphenyl) -4-imidazo [4,5-b] pyridine hydrochloride

Starting from 1.1 g of 2,3-diaminopyridine and 3.5 g of 2,4-dimethoxybenzoic anhydride, heating at 180 ° C for 5 hours and working up in analogy to Example 26 gave the title compound.

Mp: 236-238 ° C.

Yield: 15 mg (15% of theory).

Example 28

2- (2-Methoxyphenyl) -4-imidazo [4,5-b] pyridine hydrochloride

a) 2-Methoxythiobenzoic acid morpholide g of 2-methoxybenzylaldehyde, 16 g of sulfur and 32.6 g of morpholine are heated for 3 hours. 120 [deg.] C. The reaction mixture thus obtained is taken up in ethanol, filtered, cooled and the precipitated yellow crystals are filtered off with suction.

Yield: 54.1 g (91% of theory).

Melting point: 80-82 ° C.

b) 2-Methoxythiobenzoic acid morpholide methoxide

2-Methoxythiobenzoic acid morpholide (47.4 g) was heated to reflux with methyl iodide (25 ml) in 150 ml of acetone for one hour and the yellow crystals precipitated upon cooling were filtered off with suction.

Yield: 64.4 g (85% of theory).

Mp 162-164 ° C.

c) 2- (2-Methoxyphenyl) -1H-imidazo [4,5-b] pyridine g 2-methoxythiobenzoic acid morpholide methoxide and 8.7 g 2,3-diaminopyridine were heated in 70 ml glycol at 120 ° C for 3 hours. After cooling, it is mixed with water, basified with ammonia and extracted with chloroform.

The organic phase is washed with ether and then mixed with 2 N hydrochloric acid.

The precipitated product is filtered off with suction, the base is again released with ammonia, taken up in chloroform and purified over a silica gel column (eluent: chloroform-acetone = 9: 1).

The colorless hydrochloride is obtained from acetone by addition of ethereal hydrochloric acid.

Mp: 233-234 ° C.

Yield: 5.2 g (39.1% of theory).

Example 29

2- (2-methoxyphenyl) - hydrochloride

3-methyl-3H-imadazo [4,5-b] pyridine

Prepared according to the analogy of Example 28 from 2-methylamino-3-aminopyridine and 2-methoxythiobenzoic acid morpholide methoiodide.

Melting point: 208-210 ° C.

Example 30

2- (2- (2-methoxyethoxy) phenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 28 from 2- (2-methoxy) -thiobenzoic acid morpholide methoxide and 2,3-diaminopyridine.

Melting point: 170-172 ° C.

Example 31

2- (4-Methoxyphenyl) -4-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 28 from 4-methoxythiobenzoic acid morpholide methoiodide (m.p. 142-144 ° C); and

2,3-diaminopyridine.

Melting point: 243-245 ° C.

Example 32

2- (3-Methoxy-4-hydroxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 28 from 3-methoxy-4-hydroxythlobenzoic acid morpholide methoiodide (m.p. 178-180 ° C) and 2,3-diaminopyridine.

Melting point: 251-254 ° C.

Example 33

2- (2,3-Dimethoxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to analogy to Example 28 from 2,3-dimethoxythiobenzoic acid morpholide methoiodide (m.p. 138-140 ° C) and 2,3-diaminopyridine.

Melting point: 270-272 ° C.

Example 34 *

2- (2- (Hydroxy-4-methoxyphenyl)) -1H-imdazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 28 from 2-hydroxy-4-methoxythiobenzoic acid morpholide methoiodide (m.p. 180-181 ° C) and 2,3-diammopyridine.

Melting point: 190-192 ° C (decomposition).

Melting point of the free base: 292-293 ° C.

Example 35

2- (2,4-cdimethoxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 28 from 2,4-dimethoxythiobenzoic acid methoiodide (m.p. 138-140 ° C) (decomposition) and 2,3-diaminopyridine.

Mp .: 238 ° C (from methanol).

Example 36

2- (2,4-Dimethoxyphenyl) -6-methanol-1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 35 of

2,3-diamino-b-methylporidine and 2,4-dimethoxythiobenzoic acid morpholide methoiodide.

Melting point: 260-261 ° C.

Example 37

2- (2,4-Dimethoxyphenyl) -7-methyl-1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 35 of

2,3-di-amino-4-methylpyridine; and 2,4-l-hexahydro-benzoic acid morpholide.

Melting point: 230-231 ° C

Example 38

2- (2,4-Dimethoxyphenyl) -5-methyl-1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 35 of

2,3- diamino-6 - ^ (^^ methylpyridin methojodidu morpholide and 2,4-dimethoxy ^y thiobenzoic.

Melting point: 245-146 ° C.

Example 39

2- (2,4-Dimethoxyphenyl) -6-chloro-1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 35 from 2,3-amino-5-chloropyridine and 2,4-dimethoxythiobenzoic acid morpholide methoiodide.

Melting point: 253-255 ° C.

Example 40

2- (2-Cethoxy-4-methoxyphenyl) -1H-imidazo (4,5-b) pyridine hydrochloride

Prepared according to the analogy of Example 28 from 2-ethoxy-4-methoxythiobenzoic acid morpholide methoxide (m.p. 152-154 ° C) and 2,3-diaminoporiciin.

Melting point: 228-230 ° C.

Example 41 2- (2-Ethoxo-4-ethoxyphenyl) -1H-imidazo [4,5-b (pyridine)

Prepared according to the analogy of Example 28 from 2-ethoxo-4-ethoxy-thiobenzoic acid morpholide methoxide and 2,3-diaminopougidine.

Melting point: 224 to 225 ° C (from methanol).

Example 1 a d 4 2

2- (2,4-2-Methoxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 28 from 2,4-diethoxythi-benzoic acid morpholide methoiodide and 2,3-diaminopyridine.

Melting point: 224-226 ° C.

Example 43

2- [2-Hydroxyethoxy) -4-methoxyphenyl] -1-H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 28 from 2- (2-hydroxoethoxo) -4-methoxy-thio-benzoic acid morpholide methoxide and 2,3-diaminoporidine.

Mp: 237-239 ° C.

Example 44

2- (2- (3-11124x10-Propoxy) -4-methoxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

According to the analogy of Example 28, 2- (3-hydroxy-propoxy) -4-methoxy-benzoic acid and 2,3-diaminopyridine were prepared from the morpholide of morpholide.

Melting point: 170 ° C (sline).

Example 45

2- [2- (2-Methoxyethoxy) -4-methoxyphenyl] -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 28 from 2- (2-methoxyethoxy) -4-methoxythiobenzoic acid inhalide methoxide and 2,3-diaminopyridine.

Melting point: 191-193 ° C.

Example 46

2- [2-Methoxy-4- (2-methylmercaptoethoxy) phenyl] -1H-imidazo [4,5-b] pyridine hydrochloride

a) 4- (2-Methylmercaptoethoxy) -2-hydroxybenzaldehyde g 2,4-dihydroxybenzaldehyde and 9.6 g of potassium tert-butyl alcohol are dissolved in 50 ml of methylene glycol monomethyl ether, 9.6 g of methylmercaptoethyl chloride are added and the reaction mixture is stirred at 80 for 8 hours. ° C (bath temperature). After removal of the solvent, the residue is taken up in dilute sodium hydroxide, extracted twice with chloroform, the aqueous alkaline solution is separated, acidified, extracted with chloroform, dried and concentrated. The residue is purified by chromatography (eluent: chloroform-acetone = 19: 1) on a silica gel column. The oil thus obtained is further processed directly.

The compound produced in this example is uniform, as can be seen from the thin layer chromatogram. Rf value = 0.46 (silica, eluent: chloroform-methanol = 99: 1). In addition, the following spectrographic data shall be obtained:

IC spectrum (KBr):

CO 1630 ^cm-1

OH 2500 to 3300 cm -1.

UV spectrum (chloroform): _λ , _λ, 230, 279, 315 nm.

Yield: 9.7 g (52.7% of theory).

b) 4- (2-methylmethoxycaptoethoxy) -2-methoxybenzaldehyde

9.7 g of 4- (2-methylmercaptoethoxy) -2-hydroxybenzaldehyde, together with 6.7 g of potassium tert-butyl alcoholate, are dissolved in ethanol, 4.3 ml of dimethyl sulfate are added and the mixture is refluxed for 3 hours. After this time, an additional 1 mL of dimethyl sulfate was added and reheated for one hour. After this time, an additional 1 mL of dimethyl sulfate was added and reheated for one hour. After distilling off the ethanol, the residue is taken up in a mixture of water and chloroform, 2N sodium hydroxide solution is added, the chloroform phase is separated, washed with water, dried and evaporated.

Melting point: 99-100 ° C (from cyclohexane).

Yield 9.7 g (94% of theory).

c) 4- (2-Methylmercaptoethoxy) -2-imithoxythiobenzoic acid morpholide

Prepared according to the analogy of Example 28a of z

4- (2-methylphosphinic acid J-4-chlorophenaldehyde).

Melting point: 131 to 132 ° C (from ethanol).

Yield: 5.6 g (77.6% of theory).

d) 2- [2-methoxy-4- hydrochloride

- (2-methylmercaptoethoxy) phenyl] -1H-imidazo [4,5-b] pyridine

5.4 g of 4- (2-methylmercaptorthoxy) -2-methoxythiobromoic acid morpholide were refluxed with 1.2 ml of methyl iodide in 50 ml of acetone for 1.5 hours. After cooling, the solvent is removed and the resulting syrupy methoxide is heated with 3.6 g of 2,3-diaminopyridine in 20 ml of glycol.

1.5 hours at 120 ° C, diluted with water and shaken with chloroform. The organic phase is then mixed with 2N hydrochloric acid, and the precipitated yellow precipitate is then filtered off with suction.

Melting point: 197-199 ° C (from ethanol).

Yield: 1.8 g (39.4% of theory).

Example 47

2- [2-methoxy-4- hydrochloride

- (2-Ethylmethoxycapto) phenyl] -1H-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 46 from 4- (2-ethyl-mercapto-ethoxy) -2-methoxy-thiobenzoic acid morpholide and 2,3-diaminopyridine. The resulting product is purified by chromatography on silica gel and the hydrochloride is precipitated by dissolving the base in acetone and adding an excess of ethereal hydrochloric acid.

M.p .: 195-196 ° C.

Example 48

2- [2-methoxy-4- hydrochloride

- (3-methylmercaptopropoxy) phenyl] -1H-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 46 from 4- (3-methylmercaptopropoxy) -2-methoxythiobenzoic acid morpholide and 2,3-diaminopyridine morpholide.

Melting point: 189-191 ° C (decomposition).

Example 49

2- [2-Methoxy-4- (3-ethylmercaptopropoxy) - hydrochloride. phenyl] -1H-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 46 from 4- (3-ethylmercaptopropoxy) -2-methoxythiobenzoic acid and 2,3-diaminopyridine morpholide.

Melting point: 183-185 ° C (decomposition).

Example 50

2- (2- (2-Methyl-mercaptoethoxy) -4-methoxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 46 from 2- (2-methylmercaptoethoxy) -4-methoxythiobenzoic acid morpholide and 2,3-diaminopyridine.

204 DEG-206 DEG C. (decomposition).

Example 51

2- (2- (2-ethylmercaptoethoxy) -4-methoxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 46 from 2- (2-ethylmercaptoethoxy-4-methoxythiobenzoic acid) and 2,3-diaminopyridine morpholide.

Melting point: 193-195 ° C.

Example 52

2- (2- (3-methylmercaptopropoxy) -4-methoxyphenyl] -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 46 from the morpholide of 2- (3-methylmercaptopropoxymethoxythiobenzoic acid and 2,3-diaminopyridine).

Melting point: 191-193 ° C.

Example 53

2- (2- (3-Ethyl-mercaptopropoxy) -4-methoxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 46 from 2- (3-ethylmercaptopropoxy) -4-methoxythiobenzoic acid morpholide and 2,3-diaminopyridine.

Mp 187-189 ° C.

Example 54

2- (2,3,4-Trimethoxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 28 from 2,3,4-trimethoxythiobenzoic acid morpholide methoiodide (m.p. 147-150 ° C) and 2,3-diaminopyridine.

Melting point: 231-233 ° C (decomposition).

Example 55

2- (2-Methoxy-3,4-methylenedioxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 28 from 2-methoxy-3,4-methylenedioxythiobenzoic acid morpholide methoiodide (m.p. 109-111 ° C) and 2,3-diaminopyridine.

Melting point: 266-268 ° C.

Example 56

2- (2,4-Dimethoxy-3-hydroxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 28 from 2,4-dimethoxy-3-hydroxythiobenzoic acid morpholide methoxide and 2,3-diaminopyridine.

Melting point: 115-118 ° C.

Example 57

2- (2-Methoxy-4-chlorophenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 28 from 2-methoxy-4-chlorothiobenzoic acid morpholide methoxide and 2,3-diaminopyridine.

Melting point: 302-305 ° C.

Example 58

2- (2-Methoxy-4-methylphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 28 from morpholine methoxide 2-methoxy-4-methylthiobenzic acid and 2,3-diaminopyridine.

Example 59

Melting point: 256 DEG C. (decomposition).

2- (2-Isopropylphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 28 from 2-ethoxy-425 morpholide methoxide

methylthiobenzoic acid (m.p. 142-144 ° C); and 2,3-diaminopyridine.

Melting point: 224-225 ° C (decomposition).

Example 60

2- (2-Methoxy-4-methylmercaptophenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 25 from 2-hydroxy-4-methylmercaptobenzoic acid morpholide (m.p. 124-129 ° C) and 2,3-diaminopyridine.

M.p .: 232-234 ° C.

Example 61

2- (2-Methoxy-5-m2ethylmercaptophenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 25 from 2-methoxy-5-methylmercaptobenzoic acid morpholide (m.p. 106-108 ° C) and 2,3-diaminopyridine.

Melting point: 247-248 ° C.

Example 62

2- (2-Methoxy-4-ethylmercaptophenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 25 from 2-methoxy-4-ethyl-mercaptobenzoic acid morpholide and 2,3-diaminopyridine.

Melting point: 215-217 ° C.

Example 63

2- (2-methylmercaptophenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 28 from 2-methylmercaptothiobenzoic acid morpholide methoxide and 2,3-diaminopyridine.

Melting point: 185-187 ° C.

Example 1 a d 6 4

2- (2,4-Bismethylmercaptophenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 28 from 2,4-bismethylmercaptothiobenzoic acid morpholide methoxide and 2,3-diaminopyridine.

Melting point: 249-250 ° C.

Example 65

2- (2- (2-methylmercaptoethoxy) -4-methylmercaptophenyl] -4-imidazo (4,5-b) pyridine hydrochloride •

Prepared according to the analogy of Example 28 from 2- (2-methylmercaptoethoxy) -4-methyl-mercaptothiobenzoic acid morpholide methoxide and 2,3 diaminopyridine.

Melting point: 180-182 ° C.

Example 66

2- [2- (2-Diethylaminoethoxy) -4-methylphenyl] -1H-imidazo [4,5-b] pyridine dihydrochloride

Prepared according to the analogy of Example 28 from 2- (2-diethylamino-ethoxy) -4-methylthiobenzoic acid morpholide hydrochloride and 2,3-diaminopyridine morpholide hydrochloride.

Melting point: 221-223 ° C.

Example 67

2- (2-Allyloxy-4-methoxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

16.5 grams of 2-allyoxy-4-methoxybenzoic acid morpholide and 7.1 grams of 2,3-diaminopyridine are mixed well and pulverized and 30 ml of phosphorus oxychloride are added dropwise with stirring. The reaction mixture was then heated at reflux for three hours, the phosphorus oxychloride was then removed and the residue was quenched with ice water. The alkaline ammonia solution was extracted with chloroform, the organic solution was shaken with 2N hydrochloric acid, basified again, extracted with chloroform again, the chloroform solution was dried and treated with activated carbon and clay (Tonsil), filtered and concentrated. The residue was dissolved in acetone and the pale yellow hydrochloride was precipitated with ethereal hydrochloric acid.

Melting point: 189-191 ° C.

Yield: 6.5 g [34.3% of theory].

Example 68

2- (2,4,5-Trimethoxyphenyl) -4-imidazo [4,5-b] pyridine hydrochloride

a) 2- (2,4,5-trimethoxyphenyl) -1,3-dithiolanium iodide g 1,2,4-trimethoxybenzene and 150 g 2-methylmercapto-1,3-dithiolamum methosulfate are stirred in 600 ml glacial acetic acid for 4 hours at room temperature. bath temperature 70 ° C. The solvent is then removed, the residue is dissolved in a mixture of chloroform and water, and the aqueous phase is mixed with an excess of potassium iodide solution, separating the product of interest as orange-colored crystals which are further reacted directly.

(b) 2- (2,4,5-Trimethoxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

3.8 g of 2 (2,4,5-rimethoxophenol) -1,3-dithlolanium iodide and 2.2 g of 2,3-climopyridine are heated to 200 ° C in 40 ml of glycol for 10 minutes. After cooling, it is extracted with ether and then with chloroform. The chloroform phase is shaken in 2N hydrochloric acid, the precipitated yellow hydrochloride is filtered off with suction and recrystallized from glycol.

Melting point: 278-280 ° C.

Yield: 250 mg (9% of theory).

Example 69

2- (2,4,6-Trimethoxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

(a) -2- (2,4,6-Trimethoxyphenyl) -1,3-dithiolanium iodide

33.6 g of floroglucin trimethyl ether and 105 g

The 2-methylmercapto-1,3-dithlolanium methosulphate was kept at 75 ° C in 200 ml of glacial acetic acid for 6 hours and, after resting overnight, the precipitated crystals were filtered off with suction, dissolved in water and iodide precipitated with a potassium iodide solution.

Melting point: 153-154 ° C.

Yield: 25.6 g (40% of theory).

b) 2- (2,4,6-trimethoxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride g 2- (2,4,6-trimethoxyphenyl) 1,1,3-dithiol anlumine iodide, 2,2 g The 2,3-diaminopyridine and 5 g of lead acetate are heated in 75 ml of glycol for 10 minutes, then the precipitated lead salt is separated by filtration, the filtrate is diluted with water and the precipitated product is filtered off with suction. After dissolution in methanolic hydrochloric acid, it was purified on a silica gel column, eluting with chloroform: methanol (9: 1).

Melting point: 241-244 ° C (from ethanol).

Yield: 180 mg (6.3% of theory).

Example 70

2- (2,4-Dihydroxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 69 of

3-hydroxy-4- [1,1 ', 3'-dithiacyclopentylidene- (2H)] -cyclohexadiene- (2,5-on-11) -I and 2,3-diaminopyridine.

Mp 298-301 ° C.

Example 71

2- (4-Dimethylaminophenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 69 from 2- (4-dimethylaminophenyl) -1,3-dithiolanium iodide and 2,3-diaminopyridine in n-propanol.

Melting point: 337-339 ° C.

Example 72

2- (2-Methoxy-4-dimethylaminophenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

a) 2- (2-Methoxy-4-dimethylaminophenyl) -1,3-dithiolamium iodide

22.6 g of 3-dimethylaminoanisole. 43.2 g of 2-methylmercapto-1 H -dithiolanium methosulfate, 150 ml. glacial acetic acid and 22.5 ml of pyridine are heated at reflux for half an hour. After cooling, it is poured into an aqueous potassium iodide solution, the precipitated product is filtered off with suction and dried.

Melting point: 189-195 ° C (from dimethylformamide).

Yield: 43.8 g (76.8% of theory).

b) 2- (2-Methoxy-4-dimethylaminophenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 69 from 2- (2-methoxy-4-dimethylaminophenyl) -4H-dimethylaminophenyl) -1H-imidazo [1,4-a].

Melting point: 258-260 ° C (from methanol).

Yield: 280 mg (4.1% of theory).

Example 73

2- (2-Methylsulfinylphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

1.35 g of 2- (2-methylmercaptophenyl) -1H-imidazo [4,5-b] pyridine are dissolved in 20 ml of glacial acetic acid and 0.64 g of 30% hydrogen peroxide dissolved in 5 ml of glacial acetic acid is added dropwise. After standing overnight, it is diluted with water, neutralized with sodium bicarbonate and the precipitated product is filtered off with suction and dried. Addition of ethereal hydrochloric acid to the methanolic solution of the substance affords a colorless hydrochloride.

Mp .: 205-210 ° C.

Yield: 0.9 g (54.7% of theory).

Example 74

2- (2-Methylsulfonylphenyl-1H) -thiazolo [4,5-b] pyridine hydrochloride

450 mg of 2- (2-methylmercaptophenyl) -1H-imidazo [415-b] pyridine hydrochloride and 370 mg

30% hydrogen peroxide was heated to 70 ° C in 20 ml of glacial acetic acid for 3 hours. After concentration and rubbing with petroleum ether, the product of interest crystallizes.

Melting point: 259-262 ° C (from isopropanol).

Yield: 250 mg (50% of theory).

Example 75

2- [2- (2-Methylsulfinylethoxy) phenyl] -1H-imidazo [4,5-b] pyridine hydrochloride

a) 2- [2- (2-Methylmercaptoethoxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 28 from 2- (2-methylmercaptoethoxy) thiobenzoic acid morpholide methoiodide and 2,3-diaminopyridine.

Melting point: 138-140 ° C.

Yield: 4.3 g (33.6% of theory).

b) 2- [2- (2-Methylsulfinylethoxy) phenyl] -1H-imidazo [4,5-b] pyridine hydrochloride

Of 2- [2- (2-methylmercaptoethoxy) phenyl] -4-imidazo [4,5-b] pyridine hydrochloride and 1.5 g of 30% hydrogen peroxide were stirred in 100 ml of glacial acetic acid for 2 hours at room temperature. and the batch is left overnight. It is then diluted with water, neutralized with sodium bicarbonate and extracted with chloroform. The chloroform phase is concentrated, the residue is taken up in acetone and the hydrochloride is precipitated with methanolic hydrochloric acid.

Melting point: 163-165 ° C.

Yield: 3.4 g (75% of theory).

Example 76

2- (2- (2-Methylsulfinylethoxy) phenyl) -4-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 75b from 2- [2- (2-methylmercaptoethoxy) -4-methoxyphenyl] -4-imidazo [4,5-b] pyridine hydrochloride.

Melting point: 231-232 ° C.

Example 77

2- [2- (2-Ethylsulfinylethoxy) -4-methoxyphenyl] -4-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 75b from 2- [2- (2-ethylmercaptoethoxy) -4-methoxyphenyl] -4-imidazo [4,5-b] pyridine hydrochloride.

Melting point: 188-189 ° C.

Example 78

2- [2- (3-Methylsulfinylpropoxy) -4-methoxyphenyl) -4-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 75b from 2- [2- (3-methylmercaptopropoxy) -4-methoxyphenyl] -1H-imidazo [4,5-b] pyridine hydrochloride.

M.p .: 132-133 ° C.

Example 79

2- [2- (3-Ethylsulfinylpropoxy) -4-methoxyphenyl] -4-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 75b from 2- [2- (3-ethylmercaptopropoxy) -4-methoxyphenyl] -4-imidazo [4,5-b] pyridine hydrochloride.

Melting point: 126-127 ° C.

Example 80

2- (2-Methoxy-4-methylsulfinylphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

6.6 g of 2- (2-methoxy-4-methylmercaptophenyl) -4-imidazo [4,5-b] pyridine are dissolved in 100 ml of chloroform and solution-2 is added dropwise at -15 to -20 ° C over 5 hours. 96 g of 3-chloroperoxybenzic acid in 600 ml of chloroform. Shake with dilute sodium carbonate solution. The chloroform phase is dried and concentrated. The residue was purified on a silica gel column (9: 1 chloroform-methanol). Addition of ethereal hydrochloric acid to a methanolic base solution gives a yellow hydrochloride.

Melting point: 154-155 ° C.

Yield: 2.3 g (33.2% of theory).

Example 81

2- (2-Methoxy-4-methylsulfonylphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 74 from 2- (2-methoxy-4-methylmercaptophenyl) -4-imidazo [4,5-b] pyridine hydrochloride.

Mp .: 240-242 ° C.

Example 82

2- (2-Methoxy-4-ethylsulfinyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 80 from 2- (2-methoxy-4-ethylmercaptophenyl) -1H-imidazo [4,5-b] pyridine.

Melting point: 121-123 ° C.

Example 83

2- [2- (2-Methylsulfinylethoxy) -4-dimethyl-4- (4-mercaptophenyl) -1H-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 80 from 2- [2- (2-methylmercaptoethoxy) -4-methylmercaptophenyl] -1H-imidazo [4,5-b] pyridine and 1 equivalent of 3-chloroperbenzoic acid.

Melting point: 191-192 ° C (from acetone).

Example 8 4

2- [2- (2-methylsulfinylethoxy) -4-methylsulfinylphenyl] -1H-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 80 from 2- [2- (2-methylsulfinylethoxy) -4-methylmercaptophenyl] -1H-imidazo [4,5-b] pyridine and 1 equivalent of 3-chloroperbenzoic acid.

Melting point: 190-191 ° C.

Example 85

2- [2- (2-Methylsulfinylethoxy) -4-methylphenyl] -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 75b) from 2- [2- (2-methylmercaptoethoxy) -4-methylphenyl] -1H-imidazo [4,5-b] pyridine hydrochloride.

Melting point: 191-192 ° C (from acetone and ether).

Example '86

2- [2- [2-Methylsulfinylethoxy) -4-chlorophenyl] -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 75b from 2- [2- (2-methyl-mercaptoethoxy) -4-chlorophenyl] -1H-imidazo [4,5-b] pyridine hydrochloride.

221 DEG-222 DEG C. (from acetone and ether).

Example 87

2- [2-Methoxy-4- (2-methylsulfinylethoxy) phenyl] -1H-imidazo [4,5-b] pyridine hydrochloride captoethoxy) phenyl] -1H-imidazo [4,5-b] pyridine.

Melting point: 204-205 ° C.

Example 88

2- [2-Methoxy-4- (2-ethylsulfinylethoxy) phenyl] -1H-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 75b from 2- [2-methoxy-4- (2-ethylmercaptoethoxy) phenyl] -1H-imidazo [4,5-b] pyridine hydrochloride.

Melting point: 217-219 ° C.

Example 89

2- [2-Methoxy-4- (3-methylsulfinylpropoxy) phenyl] -1H-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 75b from 2- [2-methoxy-4- (3-methylmercaptoethoxy) phenyl] -1H-imidazo [4,5-b] pyridine hydrochloride.

Melting point: 179-180 ° C.

Example 9 0

2- [2-Methoxy-4- (3-ethylsulfinylpropoxy) phenyl] -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 75b from 2- [2-methoxy-4- (3-ethylmercaptopropoxy) phenyl] -1H-imidazo [4,5-b] pyridine hydrochloride.

Melting point: 167-168 ° C.

Example 91

2- (2-Methyl-4- (4-methyl-1H-isulfinyl-phenyl) -1H-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 80 from 2- (2-methoxy-5-methylmercaptophenyl) -1H-imidazo [4,5-b] pyridine hydrochloride.

Melting point: 211-212 ° C.

Example 92

2- (2-Methoxy-5-methylsulfonylphenyl) -1H-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 74 from 2- (2-methoxy-5-methylmercaptophenyl) -4-imidazo [4,5-b] pyridine hydrochloride.

Prepared according to the analogy of Example 75b of

Mp .: 240-241 ° C.

Example 93

2- (2,4-Dimethoxyphenyl) -1H-imidazo [4,5-b] pyridine- (4) -oxide g 2- (2,4-dimethoxyphenyl) -1H-imidazo [4,5-b] pyridine and 1.35 g of 3-chloroperbenzoic acid in 15 ml of glacial acetic acid are stirred at 60 ° C for 15 hours. It is then recrystallized from 2 N acetic acid with the addition of activated carbon. It is purified by boiling with acetone.

Melting point: 266-267 ° C.

Yield: 0.7 g (65.8% of theory).

Example 94

2- (2,4-Dimethylphenyl) -3-methyl-3H-imidazo [4,5-b] pyridine hydrochloride

3.5 g of 2- (2,4-dimethoxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride and 2.7 g of potassium tert-butyl alcohol are mixed and 3.6 g of methyl iodide are added dropwise. After stirring for 2 hours at room temperature, the mixture is concentrated, the residue is taken up in a mixture of chloroform and water, the organic phase is separated, dried and concentrated.

The product was purified by column chromatography (eluent: chloroform-acetone = 9: 1) and then precipitated from solution in acetone with ethereal hydrochloric acid.

Melting point: 169-197 ° C.

Yield: 1.9 g (51.8% of theory).

Example 95

2- (2-Hydroxyphenyl) -3-methyl-1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 94 from 2- (2-hydroxyphenyl) -1H-imidazo [4,5-b] pyridine and methyl iodide.

Melting point: 215-216 ° C.

Example 96

2- (2'-Hydroxy-4-methoxyphenyl) -3- (3-hydroxypropyl) -3H-imidazo [4 _; 5-b] pyridine

Prepared according to the analogy of Example 94 from 2- (2-hydroxy-4-methoxyphenyl) -1H-imidazo [4,5-b] pyridine and 3-bromopropanol.

Melting point: 154-155 ° C.

Example 97

2- (2,4-Dimethoxyphenyl) -3-benzyl-3H-imidazo [4,5-b] pyridine hydrochloride

2- (2,4-dimethoxyphenyl) -1H-imidazo [4,5-b] pyridine and benzyl bromide.

M.p .: 148-150 ° C.

Example 98

2- (2,4-Dimethoxyphenyl) -3- (2-diethylaminoethyl) -3H-imidazo [4,5-b] pyridine dihydrochloride

Prepared according to the analogy of Example 94 from 2- (2,4-dimethoxyphenyl) -1H-imidazo [4,5-b] pyridine and 2-diethylaminoethyl chloride at 80 ° C.

Melting point: 185 ° C.

Example 99

2- (2,4-Dimethoxyphenyl) -3- (3-dimethylaminopropyl) -3H-imidazo [4,5-b] pyridine dihydrochloride

Prepared according to the analogy of Example 94 z

2- (2,4-dimethoxyphenyl) -1H-imidazo [4,5-b] pyridine and 3-dimethylaminopropyl bromide at 70 ° C.

Melting point: 190-192 ° C (decomposition).

Example 100

2- (2-Methoxy-4-benzyloxyphenyl) -1H-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 10 from 2-methoxy-4-benzyloxybenzoic acid and 2,3-diaminopyridine morpholide.

Melting point hydrochloride: 218-219 ° C (dec.).

Example 101

2- (2,4-Dimethoxyphenyl) -3-butyl-3H-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 10 from 2,4-dimethoxybenzoic acid morpholide a

3-amino-2-butylaminopyridine.

Melting point hydrochloride: 218-219 ° C.

Example 102

2- (2-Methoxy-4-hydroxyphenyl) -1H-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 10 from 2-methoxy-4-hydroxybenzoic acid and 2,3-diaminopyridine morpholide.

Melting point hydrochloride: 230-231 ° C.

Prepared according to the analogy of Example 94 z

Example 103

2- (2-Ethoxy-4-ethylmercophenyl) -1H-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 10 from 2-ethoxy-4-ethyl-mercaptobenzoic acid morpholide and 2,3-diaminopyridine.

M.p. 198 DEG-199 DEG C. (decomposition).

Example 10 4

2- [- Methoxyl- (3- (- methyl-1-piperazinyl) propoxy) phenyl] -1H-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 21 from 2- [44-methoxy-4- (3-chloropropoxy) -phenyl] -1H-imidazo [4,5-b] pyridine and 1-methyl-piperazine.

Melting point of the trihydrochloride: 248 ° C (dec.).

Example 105

2- [4-Methoxy-4- (2-thiomorpholinoethoxy) phenyl] -1H-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 21 from 2- [4-methoxy-2- (2-c] chloroethoxy] phenyl] -1H-imidazo [4,5b] pyridine and thiomorphine.

M.p .: 158-160 ° C.

Example 106

2- (2-Fluoro-4-methoxyphenyl) -1H-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 1 from 2-fluoro-4-methoxybenzoic acid and 2,3-diaminopyridine.

Melting point hydrochloride: 237-238 ° C (dec.).

Example 107

2- (4-Fluoro-2-methoxyphenyl) -1H-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 1 from 4-fluoro-2-methoxybenzoic acid and 2,3-diaminopyridine.

Melting point hydrochloride: 235-236 ° C (dec.).

Example 108

2- (2-H '- (4-D ^, oxy-4- (4-methoxyphenyl)) -3-phenyl-3H-imidazo [4,5-b] pyridine)

4.9 g of 2-dihydroxy-4-methoxybenzamide and 2.6 g

Of 2-chloro-3-aminopyridine was heated under reflux in 50 ml of phosphorus oxychloride for 1.5 hours. After phosphorus oxychloride was distilled off, the residue was boiled with 2 N hydrochloric acid for 45 minutes, neutralized with ammonia, and the precipitated product was recrystallized from isopropanol.

Melting point: 201 ° C.

Yield: 1.9 g (30% of theory).

Example 10 9

2- (2-Hydroxy-4-methoxy-phenyl) -3- (2-methoxy-phenyl) -3H-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 108 from N- (2-methylphenyl) -2-hydroxy-4-methoxybenzamide and 2-chloro-3-aminopyridine.

Melting point: 197 ° C.

Example 110

2- (2-1 Lydroxy-4-methoxyphenyl) -3 (4-methoxyphenyl) -3H-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 108 from N- (4-m-ethoxyphenyl) -2-hydroxy-44-methoxybenzamide and 2-chloro-3-aminopyridine.

Melting point: 175 ° C.

Example 111

2- (2-Hydroxy-4-methoxyl-ynyl) -3- (2-((]) β) - (-^] ^ ^ ^]]) -1) -3H-imidazo [4,5-b] ] pyridine

Prepared according to the analogy of Example 108 from N- (2-phenylethyl) -2-hydroxy-4-methoxybenzamide and 2-chloro-3-aminopyridine.

M.p .: 155 ° C.

Example 112

2- (2,4-Dimethoxyphenyl) -3-phenyl-3H-imidazo [4,5-b] pyridine

It is produced from N-frnyl-N - (2-chloro-3-pyridyl) -2,4-dimethoxybenzaimide by heating with sodium hydride in dimethylformamide at 120 ° C for 5 minutes.

Melting point: 138 ° C (9: 1 from cyclohexane / isopropanol),

Yield: 700 mg (21.2% of theory).

Example 113

2- [2,4-Dimethoxyphenyl] -3- (2-methoxyphenyl) -3H-imidazo [4,5-b] pyridine

It was made according to the analogy of Example 112 of

N- [2-methoxyphenyl] -N- (2-chloro-3-pyridyl) -2,4-dimethoxybenzamidine.

Melting point: 156 ° C.

Example 114

2- (2-Aminoethoxyphenyl) -3- (4-methoxyphenyl) -3H-imidazo [4,5-b] pyridine

Prepared according to analogy to Example 112 from N- (4-methoxyphenyl) -N- (2-chloro-3-pyridyl) -2,4-dimethoxybenzamidine.

Melting point: 163 ° C.

Example 115

2- (2,4-Dimethoxyphenyl) -3- (3,4-dimethoxyphenyl) -3H-imidazo [4,5-b] pyridine

Example 112 was prepared from N- (3,4-dimethoxyphenyl) -N- (2-chloro-3-pyridyl) -1,4,4-dimethoxybenzamidine.

Melting point: 190 ° C.

Example 116

2- (3,4-Dimethoxyphenyl) -3- (4-methoxyphenyl) -4H-imidazo [4,5-b] pyridine

It was prepared from N- (4-methoxyphenyl) -N'- (2-chloro-3-pyridyl) -2- (4-methoxyphenyl) -1H-pyrimidine according to the analogues of Example 112 or by boiling in chlorobenzene.

Melting point: 181 ° C.

Example 117

2- [2,4'-piperazinyl] -3- (morpholin-3-propyl) -1H-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 112 from N- (3-morpholino-1-propyl) -N- (2-chloro-3-pyridyl) -N-dimethoxybenzamidine.

Mp .: 207 ° C.

Example 118

2- (2,6-Dimethoxyphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

9.1 g of 2,6-dimethoxybenzoic acid a

5.5 g of 2,3-diamino-pyridine are heated at 100 ml of phosphorus oxychloride at reflux for 3 hours, then the phosphorus oxychloride is removed and the residue is carefully decomposed with ice water. The resulting solution was filtered, neutralized with potassium carbonate and basified with concentrated ammonia.

The resulting suspension was extracted three times with chloroform, the chloroform phase was dried over magnesium sulfate, filtered, the solvent was removed and the residue was dissolved in 50 ml of methanolic hydrochloric acid solution, then 100 ml of isopropanol was added and stored overnight. The precipitate was filtered off with suction and washed with ether.

Melting point: 250-254 ° C.

Yield: 9.3 g [63% of theory].

Example 119

2- (2-Propoxy-4-methylphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

The analogues of Example 118 were prepared from 2-piperidinyl-4-methylbenzoic acid morpholide.

221 DEG-223 DEG C. (decomposition).

Example 120

2- (2-Butoxy-4-methylthienyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogies of Example 118 from 2-butoxy-4-methylbenzoic acid morpholide.

211 DEG-213 DEG C. (decomposition).

Example 121

2- (4-Methylmercaptophenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

The analogues of Example 118 were prepared from 4-methylmethythaptoctobenzoic acid.

Melting point: 230-232 ° C.

Example 122

2- [2- (2-methylmercaptoethoxy) -5-methylmercaptophenyl] -1H-imidazo [4,5-b] pyridine g iodide morpholide S-methyl- [2- (2-methylmercaptoethoxy) -4-methylmercapto] thiobenzoic acid (obtained by reaction of morpholide) [2- (2-Methyl-mercapto-ethoxy) -5-methyl-mercapto] -thiobenzoic acid with methyl iodide in methanol) and 15 g of 2,3- (4-methyl-4-yl) -pyridine were heated in 150 ml of thylene glycol for 3 hours and After cooling to 130 ° C, it is diluted with water, 30 ml of concentrated ammonia are added, extracted with chloroform, the organic phase is washed with water and then mixed with 2 N acid. hydrochloric acid. The precipitate is filtered off with suction and recrystallized from methanol.

Melting point: 190-191 ° C.

Yield: 12.6 g (31% of theory).

Example 123

2- (2-Methoxy-4-propylmercaptophenyl) -1H-imidazo (4,5-b) pyridine hydrochloride

Prepared according to the analogy of Example 118 from 2-methoxy-4-propyl mercaptobenzoic acid morpholide.

Melting point: 203-204 ° C (decomposition).

Example 124

2- (2-Ethoxy-4-propylmercaptophenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 118 from 2-ethoxy-4-propylmercapto-benzoic acid morpholide.

Melting point: 182-183 ° C.

Example 125

2- (2-methoxy-4-butylmercaptophenyl) -ΙΗ-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 118 from 2-methoxy-4-butyl-mercaptobenzoic acid morpholide.

Melting point: 203-204 ° C.

Example126

2- (2-Ethoxy-4-butylmercaptophenyl) -ΙΗ-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 118 from 2-ethoxy-4-butyl-mercaptobenzoic acid morpholide.

Melting point: 207-208 ° C.

Example 127

2- (4-Methylbutyl) -1H-imidazo [4,5-b] pyridine

5.9 g of 2- (4-methylmercaptophenyl) -1H-imidazo [4,5-b] pyridine hydrochloride are dissolved in 100 ml of glacial acetic acid and 2.4 g of 30% hydrogen peroxide are added at 10 DEG C. The mixture is then mixed It is left to stand overnight in the refrigerator for 10 hours at room temperature, basified with ammonia, extracted several times with chloroform, the starting material is separated by column chromatography, the residue is suspended in acetone and the crystalline mass formed is filtered off with suction.

Mp .: 240-242 ° C.

Yield: 1.8 g (33% of theory).

Example 128

2- (2-Ethyloxy-5-nitro-phenyl) -1H-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 127 from 2- (2-ethoxy-5-methylmercaptoenyl) -1H-imidazo [4,5-b] pyridine.

Melting point: 197-198 ° C.

Example 129

2- [2- (2-Methylsulfinyloxy) -5-5-methylmercaptophenyl] -1H-imidazo [4,5-b] pyridine

Produced by analogy to Example 127 from 2- (2- (2-methylmerkaptoethoxy] -5- ^ e ^ 1 t ^ ^{^,} ^^ ^ (^ rkaptofenyl] -lH-imidazo [4,5-b (pyridine.

Melting point: 189-190 ° C.

Example 130

2- (2-Ethoxy-4- (4-methylsulfinylphenyl) -4-imidazo [4,5-b] pyridine)

Prepared according to the analogy of Example 127 from 2- (2-ethoxy-4-ethylmercaptophenyl) -4-imidazo [4,5-b] pyridine hydrochloride.

Melting point: 166-167 ° C.

Example 131

2- (2-Methoxy-4-pylsulfinylphenyl) -ΙΗ-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 127 from 2- (2-methoxy-4-propylmercaptophenyl) -4-imidazo [4,5-b] pyridine hydrochloride.

Melting point: 182-183 ° C.

Example 132

2- (2-Ethoxy-4-propylsulfinylphenyl) -4-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 127 from 2- (2-ethoxy-4-propylmercaptophenyl) -1H-imidazo [4,5-b] pyridine hydrochloride.

Melting point: 182-183 ° C (decomposition).

Example 133

2- (2-Ethoxy-4-butylsulfinylphenyl) -4-imidazo (4,5-b) pyridine

Prepared according to the analogy of Example 127 from 2- (2-ethoxy-4-butylmercaptophenyl) -4-imidazo [4,5-b] pyridine hydrochloride.

Melting point: 185-186 ° C.

Example 134

2- (4-Methylsulfonylphenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

6.95 g of 2- (4-methylmercaptophenyl) -1H-imidazo [4,5-b] pyridine hydrochloride are dissolved in 100 ml of glacial acetic acid, 8.5 g of 30% hydrogen peroxide are added and left to stand for 4 days. room temperature at rest. After purification on a silica gel column (eluent: acetone-chloroform = 1:20), the residue is dissolved in acetone and the hydrochloride is precipitated with a methanolic hydrochloric acid solution.

Melting point: 286 ° C.

Yield: 5 g (64.5% of theory).

Example 135

2- (2-Ethoxy-4-ethylsulfonylphenyl) -1H-imidazo [4,5-b] pyridine

400 mg of 2- (2-ethoxy-4-ethylmercaptophenyl) -1H-imidazo [4,5-b] pyridine hydrochloride together with 0.5 ml of 30% hydrogen peroxide dissolved in 30 ml of glacial acetic acid are first passed through at room temperature overnight, then heated at 90 ° C for 1 hour, diluted with water after cooling, neutralized with sodium bicarbonate, extracted with chloroform and the organic phase is concentrated after drying and purified by chromatography (eluent: chloroform-acetone = 9: 1) on a thin layer of silica gel.

Melting point: 207 to 208 ° C (from acetone).

Yield: 150 mg (33.8% of theory).

Example 136

2- (2-Methoxy-4-propylsilylphenylphenyl) -1H-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 135 from 2- (2-methoxy-4-propylmercaptophenyl) -1H-imidazo [4,5-b] pyridine.

Melting point: 219-220 ° C.

Example 137

2- (2-Ethoxy-4-butylsulphonylphenyl) -1H-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 137 from 2- (2-ethoxy-4-ylmethyl-mercaptophenyl) -1H-imidazo [4,5-b] pyridine.

Melting point: 156-157 ° C.

Example 138

2- [2-Methoxy-4- (2-dimethylaminoethoxy) phenyl] -1H-imidazo [4,5-b] pyridine dihydrochloride

(a) 2- [2-methoxy-4- hydrochloride

- (2-chloroethoxy) phenyl] -1H-imidazo- [4,5-b] pyridine g 2-methoxy-4- (2-hydroxyethoxy) benzoic acid morpholide was heated at reflux for 1.5 hours with 7, 1 g of d-diaminopyrudine in 100 ml of phosphorus oxychloride. It is then decomposed with water, the gradually crystallizing precipitate is filtered off with suction and washed with acetone.

Melting point: 266-268 ° C (decomposition). Yield: 4.7 g (27.6% of theory).

(b) 2 g of 2- [2-methoxin-4- hydrochloride

- (2-Chlooethoxy) phenyl] -1H-imidazo- [4,5-b] pyridine was heated with 5 g of dimethylamine in 100 ml of ethanol in a sealed vessel at 120 ° C for 12 hours. After concentration, the residue was purified by silica gel column chromatography (eluent: chloroform-acetone = 10: 1). The hydrochloride is precipitated with a methanolic hydrochloric acid solution from acetone and then recrystallized from methanol.

Melting point: above 250 ° C.

Yield: 1 g (44% of theory)

Example 139

2- [2-Methoxy-4- (3-dimethylaminopropoxy) phenyl] -1H-imidazo [4,5-b] pyridine dihydrochloride

Prepared according to the analogy of Example 138 from 2- [2-methoxy-4- (3-chloropropoxy) phenyl] -1H-imidazo [4,5-b] pyridine hydrochloride.

Mp .: 238-242 ° C.

Example 140

2- [2-methoxy-4- dihydrochloride

- (3-diethylaminopropoxy) phenyl] -1H-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 138 'from 2- [2-methoxy-4- (3-chloropropoxy) phenyl] -1H-imidazo [4,5-b] pyridine hydrochloride.

M.p .: 222-224 ° C.

Example 141

2- [2-Methoxy-4- (3-piperidinopropoxy) phenyl] -1H-imidazo [4,5-b] pyridine dihydrochloride

Prepared according to the analogy of Example 139 from 2- [2-methoxy-4- (3-chloropropoxy) phenyl] -1H-imidazo [4,5-b] pyridine hydrochloride.

225 DEG-226 DEG C. (decomposition).

Example 142

2- [2-Methoxy-4- (3- (4-phenylpiperazin-1-yl) propoxy) phenyl] -1-imidazo [4,5-b] pyridine dihydrochloride

Prepared according to the analogy of Example 139 from 2- [2-methoxy-4- (3-chloropropoxy) phenyl] -1H-imidazo [4,5-b] pyridine hydrochloride.

Melting point: 197-200 ° C.

Example 143

2- [2-Methoxy-4- [3- / 4- (2-methoxyphenyl) piperazin-1-yl / propoxy) phenyl] -1H-imidazo [4,5-b] pyridine trihydrochloride hydrate

Prepared according to the analogy of Example 139 from 2- [2-methoxy-4- (3-chloropropoxy) phenyl] -1H-imidazo [4,5-b] pyridine hydrochloride.

Melting point: from 180 ° C (sline).

Example 144

2- (2-Methoxy-4-morpholinophenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

a) 2- (2-MethoxyH-morpholinophenyl) -1,3-dithiolanium iodide

10.5 g of 3-morpholinoanolsol and 15.7 g of 2-methylmerpto-1,3-dithioianium methosulfate are heated to boiling for one hour in a mixture of 60 ml of glacial acetic acid and 8.3 ml of pyridine and, after cooling, are poured into saturated potassium iodide solution. The red precipitate was filtered off with suction, washed with water and further processed without further purification.

Yield: 23 g (100% of theory).

b) 22 g of 2- (2-methoxy-4-morpholinophenyl) -1,3-dithiolammonium iodide, 10.9 g of 2,3-diaminopyridine and 60 ml of glycol are heated at 130 DEG C. for 2 hours, mixed after cooling. with water and extracted with chloroform. After concentration, the residue was purified by column chromatography (eluent: chloroform-acetone = 9: 1) on silica gel and the hydrochloride was precipitated from acetone with ether / hydrochloric acid.

207 DEG-209 DEG C. (decomposition).

Yield: 1.3 g (6.2% of theory).

Example 145

2- [2-Methoxy-4-4- (methylpiperazin-1-yl) phenyl] -14-imidazo [4,5-b] pyridine dihydrochloride

Prepared according to the analogy of Example 144 from 3-nisohols.

Melting point: 279-282 ° C.

Example 146

2- [2-Methoxy-4-

- (4.? T LiY Ιχο IPE ra mast Ty-1) phenyl] -lH-imidazo [4 5 _j-b] pyridine

Prepared according to the analogy of Example 145 from 3- (4-ethylpiperazin-1-yl) -2-methylbenzamide.

Melting point: 218-222 ° C.

Example 147

Dihpdrochlorid 2- [2tmethoxyt4-

- (4-Propyloxy-1-phenyl) -1H-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 144 from 3- (4-propylpiperazin-1-yl) and 5'-ss-2-ol.

Melting point: 256-258 ° C.

Example 148

2- [2-Ethoxy-4- (4-methylpiperazin-1-yl) phenyl] -1H-imidazo [4,5-b] pyridine dihydrochloride

It was prepared according to the analogy of Example 144 from 3- (4-methylpiperamidylthiyl) -ethoxypentene.

Melting point: 269-271 ° C.

Example 149

2- [2-Ethoxy-4- (4-phenyl) -1H-imidazo [4,5-b] pyridine dihydrochloride

Prepared according to the analogy of Example 144 from 3- (4-ethylpiperazin-1-yl) -1-ethoxybenzyl.

Melting point! 257 DEG-259 DEG.

Example 150

2- [2-Methoxy-4- (4-piperidin-4-yl) phenyl] -1H-imidazo [4,5-b] pyridine dihydrochloride

Prepared according to the analogy of Example 144 from 3- (44-glycolyl-piperazin-yl) -isol.

Melting point: 217-219 ° C.

Example 151

2- [4-Methoxp-2- (2-moff oltnoetho200169 xy) phenyl] -1H-imidazo [4,5-b] pyridine

Prepared from 6.3 g of 2- [4-methoxy-2- (2-chloroethoxy) phenyl] -1H-imidazo [4,5-b] pyridine by refluxing in 60 ml of morpholine for 3 hours, distilling off the morpholine under vacuum and recrystallization from isopropanol.

Melting point: 188-190 ° C.

Yield: 0.9 g (14% of theory).

Example 152

2- [4-methoxy-2- (3- (4-phenylpiperazin-1-yl) propoxy) phenyl] -1H-imidazo [4,5-b] pyridine 2- [4-methoxy-2- (3- chloropropoxy) phenyl] -1H-imidazo [4,5-b] pyridine, 10.2 g of 1-phenylpiperazine and 5 g of potassium carbonate were refluxed in 100 ml of ethanol for 8 hours. After distilling off the ethanol in vacuo, it was recrystallized from a 3: 1 mixture of ethanol and water.

Melting point: 162-163 ° C.

Yield: 2.8 g (20% of theory).

Example 153

2- [4-methoxy-2-

- (3 ', 2-enylethylamino / propoxy) phenyl] -4-imidazo [4,5-b] pyridine

Prepared by heating at 180 ° C for 1 1/2 hours 1.77 g of 2- [4-methoxy-2- (3-chloropropoxy) phenyl] -1H-imidazo [4,5-b] pyridine in 10 ml of 2-phenylethylamine . The free base is converted to the dihydrochloride with a methanolic hydrochloric acid solution. Recrystallized from isopropanol.

238 ° C.

Yield: 0.45 g (19% of theory).

Example 154

2- [4-methoxy-2-

- (3- (N-Methyl-N-2-methylethylamino / propoxy) phenyl) -4-imidazo [4,5-b] pyridine

It is made from 3.2 g of 2- [4-methoxy-2- (3-chloropropoxy) phenyl] -4-imidazo [4,5-b] pyridine and

2.7 g of N-methyl-2-phenylethylamine by heating in ethanol at 120 ° C for 6 hours in a closed vessel. The free base purified by column chromatography (eluent: chloroform-methanol - 9: 1) in ethyl acetate solution was precipitated with ethereal hydrochloric acid as the dihydrochloride and recrystallized from isopropanol.

212 DEG-215 DEG.

Yield: 0.46 g (9.4% of theory).

Example 155

2- [4-methoxy-2- (3- / N-methyl-N- [2- (3,4-dimethoxyphenyl) ethyl / amino / propoxy) phenyl] -1H-imidazo [4,5-b] pyridine dihydrochloride

It is made from 5.0 g of 2- [4-methoxy-2- (3-chloropropoxy) phenyl] -1H-imidazo [4,5-b] pyridine and

8.5 g of N- [2- (3,4-dimethyloxyethyl) ethyl] methylamine were heated to reflux in ethylene glycol monomethyl ether for 12 hours and the dihydrochloride precipitated from ethyl acetate with ethereal hydrochloric acid.

Melting point: 169 ° C.

Yield: 1.6 g (18.5% of theory).

Example 156

2- [4-Methoxy-2- (3-thiomorpholino-propoxy) -phenyl] -4-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 155 from 2- [4-methoxy-2- (3-chloropropoxy) phenyl] -1H-imidazo [4,5-b] pyridine and thiomorpholide by heating for 30 hours. For purification, it is precipitated from ethyl acetate and the base is released from it with 2 N ammonia.

Melting point: 111 ° C.

Example 157

2- [4-Methoxy-2- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl] -1H-imidazo [4,5-b (pyridine)

It is prepared from 3.0 g of 2- [4-methoxy-2- (2-chloroethoxy] phenyl] -4-imidazo [4,5-b] pyridine and 2.0 g of N-methylpiperazine under reflux for 40 hours in ethanol. After chromatography (eluent: chloroform-methanol = 9: 1) on a silica gel column, it is recrystallized from water.

M.p .: 136-137 ° C.

Yield: 0.9 g (24% of theory).

Example 158

2- [4-Methoxy-2- (3- / 4- (2-phenylethyl) piperazin-1-yl / propoxy] phenyl] -4-imidazo [4,5-b] pyridine trihydrochloride

Prepared according to the analogy of Example 154 from 2- [4-methoxy-2- (3-chloropropoxy) phenyl] -1H-imidazo [4,5-b] pyridine and 1- (2-phenylethyl) piperazine.

Mp: 236-238 ° C.

Example 159

2- [4-Methoxy-2- (3-methylaminopropoxy) phenyl] -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 154 from 2- [4-methoxy-2- (3-chloropropoxy) phenyl] -1H-imidazo [4,5-b] pyridine and methylamine.

Melting point: 215 ° C.

Example 160

2- [4-Methoxy-2- (2-dimethylaminoethoxy) phenyl] -1H-imidazo [4,5-b] pyridine dihydrochloride

It was made according to the analogy of Example 154 of

2- [4-methoxy-2- (2-chloroethoxy) phenyl] -1H-imidazo [4,5-b] pyridine and dimethylamine.

Mp .: 240-242 ° C.

Example 1 a d 1 6 1

2- (2-Methylaminophenyl) -1H-imidazo [4,5-b] pyridine

1.77 g of N-methylisate anhydride and 1.09 g of 2,3-diaminopyridine are melted together and heated to 180 ° C for 10 minutes. Recrystallized from ethyl acetate.

Melting point: 262-263 ° C.

Yield: 0.55 g (25% of theory).

Example 162

2- (2,4-Dimethoxyphenyl) -3- (2-phenylethyl) -3H-imidazo [4,5-b] pyridine

Dissolve 0.17 g of 2- (2-hydroxy-4-methoxyphenyl) -3- (2-phenylethyl) -3H-imidazo (4,5-b) pyridine in 7 ml of dimethylformamide and stir for 5 minutes with 0.02 g of sodium hydride (80% slurry in oil) was reacted with 0.07 g of methyl iodide under ice cooling, mixed with water after 4 hours, the precipitated product was taken up in ethyl acetate, and the organic phase was washed with 2 N solution. sodium hydroxide and water and evaporated.

Recrystallized from ethanol and water.

Melting point: 157 ° C.

Yield: 0.15 g (81.5% of theory).

Example 163

2- [2,4-Dimethoxyphenyl) -3- [2- (3,4-dimethoxyphenyl) ethyl] -3H-imidazo [4,5-b] pyridine hydrochloride

It was made according to the analogy of Example 118 of

3-amino-2 - [- (3,4-dimethoxyphenyl) ethylamino] pyridine and 2,4-dimethoxybenzoic acid. The hydrochloride precipitated from ether.

Mp .: 195 ° C.

Example 164

2- (2-Fluoro-5-methylmercaptophenyl) -1H-imidazo [4,5-b] pyridine

Following the analogy of Example 118, 2,3-diaminopyridine and 2-fluoro-5-methylmercaptobenzoic acid were prepared.

Mp .: 195 ° C.

Example 165

2- (2-Fluoro-5-methylsulfinylphenyl) -1H-imidazo (4,5-b) pyridine

Prepared from 2- (2-fluoro-5-methylmercaptophenyl) -1H-imidazo [4,5-b) pyridine by oxidation with hydrogen peroxide at room temperature, purified by silica gel column chromatography using chloroform / methanol (19: 1) as eluent.

Melting point: 190-192 ° C.

Yield: 0.3 g (81.5% of theory).

Example 166

2- (2-Fluoro-5-methylsulfonyl) -1H-imidazo [4,5-b] pyridine

Prepared from 2- (2-fluoro-5-methylmercaptophenyl) -1H-imidazo [4,5-b] pyridine as in Example 168, but at 40 ° C.

Melting point: 242 ° C.

Yield: 0.1 g (58.5% of theory).

Example 167

2- (3,4-Dimethoxyphenyl) -3- (3-morpholinopropyl) -3-imidazo [4,5-b] pyridine dichloride

a) N- (2-Chloro-3-pyridyl) -N‘-

- [3-morpholinopropyl) -3,4-dimethoxybenzamidine

4.9 g of N- (3-morpholinopropyl) -3,4-dimethoxybenzamide and 2.04 g of 2-chloro-3-aminopyridine were refluxed in 85 ml of phosphorus oxychloride for 2 hours. After the phosphorus oxychloride was distilled off, it was poured onto water, basified and extracted with ethyl acetate. Evaporation of the compound left as a viscous oil.

Yield: 5.2 g (78% of theory).

b) 2- (3,4-Dimethoxyphenyl-3- (3-morpholinopropyl) -3H-imidazo (4,5-b) pyridine dihydrochloride

5.2 g of N- (2-chloro-3-pyridyl) -N- (3-morpholinopropyl) -3,4-dimethoxybenzamidine; and

200

1.5 g of aqueous hydride (80% suspension in ice) was heated in 120 ml of dimethylformamide at 120 ° C for 2 hours. The dihydrochloride is precipitated from ether with hydrochloric acid and recrystallized from ethanol and cyclohexane.

Melting point: 180 ° C.

Yield: 1.4 g (24.8% of theory).

Example 168

Dihydrochloride. 2- (4-Methoxyphenyl) -3- (3-morpholinopropoxy) -3H-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 167 from N- (2-chloo-3-pyridyl) -N ¹ - (3-morpholino-propyl) -4-methylbenzamidamide.

Melting point: 218 ° C.

Example 169

2- (4-Methoxyphenyl) -3- (3- (4-phenylpiperazin-1-yl) propyl) -3-H-imidazo [4,5-b] pyridine dihydrochloride hydrate

Prepared according to the analogy of Example 167 from N- (2-chloro-3-pyridyl) -Ni [3- (4-phenylpiperazinyl) propyl] -4- (4-methoxybenzamidine).

Melting point: 100 ° C.

Example 170

2- (4-Methoxyphenyl) -3- (2-morpholinoethyl) -3H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 167 from N- (2-chloro-3-pyridyl) -N‘- (phenoxy) -4-methoxybenzidine.

149 ° C.

Example 171

2- (4-Methoxyphenyl) -3- (3- (4-methylpiperoisomethyl) propyl) -3H-imidazo [4,5-b] pyridine trihydrochloride

Prepared according to the analogy of Example 167 from N- (2-chloro-pyridyl) -N- [3- (4-methylpiperazin-1-yl) propyl] -4-methoxybenzamidine.

Melting point: 257 ° C.

Example 172

-2- (4-Methoxyphenyl) -3- (2- (4-methylpiperazol-1-yl) ethyl) -3H-imidazine [4,5-b] pyridine trihydrochloride

Prepared according to the analogy of Example 167 from N- (2-chloro-3-piperidyl) -N- [2- (4-methylpiperazin-1-yl) ethyl] -4-methoxybenzamidine.

Melting point: 225 ° C.

Example 173

2- (4-Methoxyphenyl) -3- (3-dihydro-3-aminopropoxy) -3H-imidazo [4,5-b] pyridine dihydrochloride

Prepared according to the analogy of Example 167 from N- (2-methyl-3-nitro) -N * - (3-dimethylamiaopropyl) -4-methoxybenzamidine.

Melting point: 229 ° C.

Example 174

2- (4-Methoxy-phenyl-3- (3-piperidopropyl) -3H-imidazo [4,5-b] pyridine dihydrochloride

Prepared according to the analogy of Example 167 from N- (2-chloro-3-pyridyl) -N- (3-piperidino) propyl) -4-methoxybenzamidine.

Melting point: 196 ° C.

Example 175

2- (4-Methoxyphenyl) -3- (4-morpholinobutyl) -1H-imidazole] [4,5-b] pyridine dihydochloride hydrate

Prepared according to the analogy of Example 167 from N- (2-chloro-3-pyridyl) -N- (4-morpholinomethyl) -4-methyloxybenzamidine.

Melting point: 136 ^IC .

Example 1 7 6

2- (2-Fluoromethyl-mercaptophenyl) -1H-imidazo [4,5-b] pyridine hydrochloride

Prepared according to the analogy of Example 118 from 2-chloro-4-methylmeocaptobenzoic acid and 2,3-diaminopyridine.

Melting point: 257 ° C.

Example 177

2- (2-Fluoro-4-methylsulfonylphenyl) -4-imidazo [4,5-b] pyridine

It was produced according to the analogy of Example 165 of

2- (2-fluoro-4-methylmercaptophenyl) -1H-imidazo [4,5-b] pyridine. Crystallized by trituration in petoolether.

Melting point: 219 ° C.

2- [2-Propoxy-4- (4-methylpiperazin-1-yl) phenyl] -1H-imidazo [4,5-b] pyridine dihydrochloride

Prepared according to the analogy of Example 144 from 3- (4-methylpiperazin-1-yl) -1-propoxybenzene.

Example 178

Example 179

2- (4-Methylmercaptophenyl) -3- (3-morpholinopropyl) -3-H-imidazo [4,5-b] pyridine

Prepared according to the analogy of Example 167 from N- (2-chloro-3-pyridyl) -NT- (3-morpholinopropyl) -4-methylmercaptobenzamidine.

Recrystallized from ether and cyclohexane.

Melting point: 110 ° C.

Melting point: 237-238 ° C.

Claims (8)

SUBJECT A process for the preparation of the novel imidazo [4,5-b] pyridines of the general formula I Where R 1 represents alkylamino-, dialkylamino-, hydroxy-, allyloxy-, benzyloxy-, alkylthio-, alkylsulfinyl-, alkylsulfonyl-, morpholino-, 4-phenylpiperazino-, 4-alkylpiperazino- or alkoxy optionally substituted by halogen, hydroxy -, alkoxyalkylthio-, alkylsulfinyl-, alkylsulfonyl-, alkylamino-, dialkyl-, amino-, piperidino-, morpholino-, thiomorpholino-, 4-alkylpiperazino-, 4-phenylpiperazino-, 4-methoxyphenylpiperazino-, 4-phenylethylpiperazino, phenylethylamino- , N-methylphenylethylamino or N-methyldimethoxyphenylethylamino, R @ 2 is hydrogen or halogen, methyl, hydroxy, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl, R3 represents a hydrogen atom or an alkoxy group of the invention or 2 of the radicals R1 to R3 together represent methylenedioxy, Rd represents a hydrogen atom, optionally a hydroxy-, dimethylamino-, diethylamino-, phenyl-, dimethoxyphenyl-, piperidino-, morpholino-, 4-methylpiperazino- or 4-phenylpiperazino-substituted alkyl radical or optionally a halogen atom, a 1 or 2 methoxy-substituted phenyl radical and R 5 represents a hydrogen or halogen atom or a methyl group, each alkyl moiety of the abovementioned radicals having 1 to 4 carbon atoms, as well as their physiologically acceptable addition salts with inorganic or organic acids, characterized in that pyridine of the general formula II (II) R 5 is as defined above and Y represents a halogen atom or a group R4NH in which Rd, as defined above, is reacted with a compound of formula III wherein R1 to R3 have the above meanings and X represents a carboxyl group or a functional derivative thereof in the form of a nitrile, acid halide, ester, amide, imido acid ester, imido acid thioester, imido acid halide, amidine, thiocarboxylic acid, dithiocarboxylic acid, carboxylic acid anhydride or orthoester, Y represents a halogen atom, X is an aminocarbonyl group which is optionally substituted by a radical R 4 or is an aminocarbimino group, and optionally the compound of formula (I) containing a reactive halogen atom is converted to the corresponding amino compound by an amine and / or a compound of formula (I) a hydrogen atom, in the presence of a base, alkylated with an alkylating agent, and / or the compound of formula I thus obtained is converted with the oxidizing agent into the corresponding N-oxide, S-oxide or S, S-dioxide compound and / or its physiologically acceptable addition salt with an inorganic or organic acid. 2. The process according to item 1, for the preparation of novel imidazo [4,5-b] pyridines of the general formula Г wherein Rf represents alkylamino-, dialkylamino-, hydroxy-, allyloxy-, benzyloxy-, alkylthio-, alkylsulfinyl- or alkylsulfonyl, alkoxy optionally substituted by halogen, hydroxy-, alkoxy-, alkylthio-, alkylsulfinyl-, alkylsulfonyl-, alkylamino -, dialkylamino-, morpholino-, thiomorpholino-, 4-methylpiperazino- or 4-phenylpiperazino, Rf represents a hydrogen or halogen atom, a methyl, hydroxy, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl group, R5 denotes a hydrogen atom of an alkoxy group or 2 of the radicals Rf through R3 denotes a methylenedioxy group, R 4 represents a hydrogen atom, an optionally hydroxy-, dimethylamino-, diethylamino-, phenyl or morpholino-substituted alkyl radical or an optionally halogen atom, 1 or 2 methoxy-substituted phenyl radical, and R 5 represents a hydrogen or halogen atom or a methyl group, each alkyl moiety of the abovementioned radicals having 1 to 4 carbon atoms, as well as their physiologically acceptable addition salts with inorganic or organic acids, characterized in that the pyridine of the formula II R 5 is as defined above and Y represents halogen or the group R 4 ^C NH in which R 1 ‘is as defined above, reacted with a compound of formula ΙΙΓ wherein R f to R 3 have the above meanings and X represents a carboxyl group or a derivative thereof in the form of nitrile, acid halide, ester, amide, imido acid ester, imido acid thioester, imido acid halide, amidine, thiocarboxylic acid, dithiocarboxylic acid, carboxylic acid anhydride or orthoester, provided that Y represents a halogen atom, X is an aminocarbonyl group, which is optionally substituted with Rf, or is an aminocarbimino group, and optionally the thus obtained compound o200169 of the general formula Г which contains a reactive halogen atom is converted to the corresponding amino compound and / or alkylated with an alkylating agent at position 1; or 3 and / or an oxidizing agent is converted to the corresponding N-oxide, S-oxide or S, S-dioxide compound, and / or a physiologically acceptable inorganic or organic acid addition salt thereof. 3. The process according to item 1, for the preparation of the novel imidazof4,5-b] pyridines of the general formula I 'wherein R 1 'represents a methylamino, morpholino or piperazino group at the 4-position substituted by a C 1 -C 4 alkyl radical, a C 1 -C 4 alkyl radical substituted by a hydroxy, mercapto, sulfinyl or sulfonyl group, a C 2 -C 4 alkoxy group, which are substituted with dimethylamino-, diethylamino-, piperidino-, morpholino-, thiomorpholino-, phenylethylamino-, N-methylphenylethylamino-, N-methyldimethoxyphenylethylamino or at the 4-position of methyl, phenyl, 2-methoxyphenyl, or phenylethyl substituted piperazino R 2 'represents a hydrogen, fluorine or chlorine atom, methyl, hydroxy, alkoxy, alkylthio, alkylsulphinyl or alkylsulphonyl, the alkyl moiety each having 1 to 4 carbon atoms, R 5 'represents a hydrogen atom or a (C 1 -C 4) alkoxy group R 4 'represents a hydrogen atom or a C 2 -C 4 alkyl radical which is substituted by phenyl, dimethoxyphenyl, dimethylamino, piperidino, morpholino, 4-methylpiperazino or 4'-phenylpiperazino, and their physiologically acceptable addition salts with inorganic or organic acids, characterized in that the pyridine of the general formula (II) wherein: Y represents a halogen atom or a group R 4 ^of NH in which R4 'is as defined above, reacted with a compound of formula III' wherein R 1 'to R 3' have the above meanings and X represents a carboxyl group or a derivative thereof in the form of a nitrile, acid halide, ester, amide, imido acid ester, imio acid thioester, imido acid halide, amidine, thiocarboxylic acid, dithiocarboxylic acid, carboxylic acid anhydride or orthoester, provided that Y represents a halogen atom, X denotes an aminocarbonyl group which is unsubstituted or substituted with R 4 ^at, or is aminokarbiminoskupinu, and optionally the thus obtained compound of formula I ", which contains a reactive halogen with an amine is converted to the corresponding amino compound and / or the resulting compound of formula I" or (Ia), which contains a reactive hydrogen atom, in the presence of a base, is alkylated with an alkylating agent, and / or the compound of formula (I) thus obtained is converted with the oxidizing agent into the corresponding N-oxide, S-oxide or S, S-dioxide. or a physiologically acceptable addition salt thereof. 4. A process according to any one of claims 1 to 3, wherein the reaction is carried out in a solvent at a temperature of -20 to 250 ° C. 5. A process according to any one of claims 1 to 4, wherein the reaction is carried out in the presence of phosphorus oxychloride or thionyl chloride, optionally in the presence of pyridine or triethylamine, and at a temperature of -20 to 120 ° C when X is a carboxyl group or derivative. amide. 6. A process according to any one of claims 1 to 4, wherein the reaction is carried out in the presence of one to two times the amount of acid relative to the nitrile to be used, for example one to two times the amount of p-toluenesulfonic acid. when X is a nitrile group. 7. A process according to any one of claims 1 to 4, wherein the reaction is carried out at a temperature of 100-150 [deg.] C when X is a thioamide derivative. 8. A process according to any one of claims 1 to 4, wherein the reaction is carried out at a temperature of 100 to 200 [deg.] C when Y is a chlorine atom.