FI73672B - FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT AKTIVA IMIDAZOLYLPYRIDINDERIVAT. - Google Patents

Description

1 73672

Method for the preparation of therapeutically active imidazolylpyrrine derivatives

The invention relates to the preparation of new medicaments.

In particular, the invention relates to a process for the preparation of 2-substituted 4- (4-imidazolyl) pyridines useful as antiulcer agents.

In the past, researchers in the field of organic pharmaceutical chemistry 10 have made various attempts to obtain new and better antiulcer agents. For the most part, these attempts have involved the synthesis and testing of various hitherto unavailable organic compounds, particularly in the field of organic heterocyclic bases, in an attempt to determine their ability to inhibit gastric acid secretion in the stomach without causing significant sympathetic accelerating side effects. what could potentially be considered undesirable from a pharmacological point of view. However, in the search for newer and better or improved antiulcer agents, much less is known about the effect of other organic compounds in this area (especially melting wounds that could progress in the body through the non-accelerated mechanism of the sympathetic and still have anti-gastric acid secretion effects. U.S. Pat. Nos. 4,022,797, 4,024,271 and 4,027,026 to GJ Durant et al., Advantage in certain thioalkyl and 1H-receptor receptors in the thioalkyl, aminoalkyl and oxyalkylguanidine series and corresponding to 30%. in the pyridyl-substituted thioalkyl and oxyalkyl-thiourea series are useful for these purposes, although these specific compounds are not known to be sympathetic accelerators per se. i can be inhibited by a 7 3 6 7 2 histamine H 2 receptor antagonist such as m-pyramine. As a result, these compounds are absolutely valuable as histamine H 1 receptor inhibitors for the regulation of gastric acidity and are thus useful in the treatment of indigestion and other similar conditions in the body, etc.

Yamada, et al., Yakugaku Zasshi, 95 (5), 487 (1975) (CA 83, 113633r) has reported the preparation of 4- (4-pyridyl) imidazole as a by-product in the reaction of 4-pyridylcarbinol and form-10 aldenide, while Schuank, Arch. Pharmaz. 306, 934 (1973) discloses the same compound as an intermediate in the synthesis of compounds having a "histamine-like" effect.

It has now been found that certain 2-substituted 4- (4-15 imidazolyl) pyridines and their pharmaceutically acceptable acid addition salts are useful as antiulcer agents by virtue of their ability to regulate gastric acidity. These compounds have the formulas; 20 N_ ^ 1 n_ ^ 4 / \ / \

C. MH

j and j 25 [[^ n '/ ^ nr2r3

I II

(as well as their pharmaceutically acceptable acid addition salts) wherein R 1 is alkyl of 1 to 3 carbon atoms; R 2 and R 3 are each hydrogen, alkyl of 1 to 3 carbon atoms or phenylalkyl, wherein alkyl contains 1 to 3 carbon atoms; and is methyl.

A preferred group of compounds of formula I are those wherein R 2 is hydrogen and R 3 is alkyl. Particularly preferred in this group are 2-ethylamino-4- (2-methyl-4-imidazole).

II

3,73672 yl) pyridine and 2-ethylamino-4- (2-ethyl-4-imidazolyl) pyridine.

The preferred compound of formula II is 2-methyl-4- (2-methyl-4-imidazolyl) pyridine.

The compounds described above may be used as a pharmaceutical composition suitable for oral administration comprising a pharmaceutically acceptable carrier and a therapeutic amount of a compound of formula I or II.

According to the present invention, compounds of formula I in which said alkyl and compounds of formula II in which R 1 is methyl are prepared according to the following scheme: R 1 15 N-1 OC.Hr /

2 5 NH

C2H5 ° '^. ^' CH2NH2

L NH

R 1 -C-OC-.H, - - HCl I 2d v 20 I ^ ^ ^ n ^ ^ nr 2r3 I ^ = alkyl) 25 N ---- ^ 4 OC2h5 „

C2Hc ° CH2NH2 J

"1 NH! 30 R4-C-OC2H5.HCl1 ^ ^ n ^^ ch3% n ^^ ch3 II (R4 = CH3) 4 73672

The process comprises reacting 2- (2-substituted-4-pyridyl) -2,2-diethoxyethylamine with imidate hydrochloride in a reaction-inert solvent. Approximately equimolar amounts of reactants are used in this reaction, with the imidate ester being used in an excess of as much as 10%.

Preferred solvents for the reaction are alkanols, especially methanol or ethanol. Other solvents may be used provided that they dissolve the starting materials in an appropriate amount and do not participate in any reactions with the starting materials or products under the reaction conditions.

The initial step of the reaction is carried out at a temperature of about 50-120 ° C with a reaction time of about 1-6 hours.

After the initial reaction step, the solvent is removed and the intermediate is taken up in concentrated hydrochloric acid and heated for about one hour at steam bath temperatures. When the reaction is complete, the acid is neutralized, usually with a solid inorganic base, and the product is extracted with a water-immiscible solvent such as methylene chloride or chloroform.

The product remaining after removal of the solvent is purified by recrystallization or chromatography on silica gel.

The ethylamine starting material is readily prepared by known reaction methods, as described below, and the imidates are prepared by known methods, such as those described by Wagner and Zook, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York, NY 1953, Chapter 30. 21, pp. 634.

The pharmaceutically acceptable acid addition salts of the 2-substituted 4- (4-imidazolyl) pyridine base compounds of this invention are prepared simply by treating the above organic bases with various inorganic and organic acids which form non-toxic acid addition salts having:

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5,73672 Pharmacologically acceptable anions such as hydrochloride, hydrobromide, hydroiodide, sulphate or bisulphate, phosphate or acid phosphate, acetate, lactate, maleate, fumarate, citrate or acidic citrate, tartrate or bitartrate, succinate, gluconate, saccharate, methanesulfonate, ethanesulfonate, benzenesulfonate and p-toluenesulfonate salts. For example, the salt formation step can be accomplished simply by using the correct molar amount of the appropriate acid in an aqueous solvent medium or a suitable organic solvent such as methanol or ethanol. After careful evaporation of the solvent, a solid salt is easily obtained.

As indicated above, all 2-substituted 4- (4-imidazolyl) pyridine compounds of this invention can be readily adapted for therapeutic use as histamine H 2 receptor inhibitors for the control of indigestion, especially in view of their ability to statistically inhibit gastric acid secretion in the body. in significant amounts. The compounds of this invention have been consistently observed to produce pentagastrin-induced gastric acid secretion from the stomachs of Heidenhain pouches when administered intravenously at doses ranging from 1.0 to 10 mg / kg, respectively, without showing significant signs of toxic side effects. In addition, all of the compounds of this invention described herein can be administered orally, for these present purposes, without causing any unpleasant pharmacological side reactions in the subject to which they are administered. In general, these compounds are usually administered in dosage amounts ranging from about 0.5 mg to n. 50 mg / kg body weight per day, although variations may occur depending on the condition and individual response of the subject being treated and the particular type of pharmaceutical combination selected. In the context of the use of the 2- (4-imidate solyl) pyridine compound of the present invention for the treatment of subjects suffering from melting ulcers, it should be noted that they may be administered either alone or in combination with pharmaceutically acceptable drugs. and that such administration can be performed in both single and multiple doses. In particular, the novel compounds of this invention may be administered in a wide variety of dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, troches, drills, hard candies, powders, aqueous suspensions, elixirs, syrups, and the like. Such carriers comprise solid excipients and fillers, sterile aqueous media and various non-toxic organic solvents, etc. In addition, such normal pharmaceutical combinations may be suitably sweetened and / or flavored with various substances of the type commonly used for this purpose. . In general, the therapeutically active compounds of this invention will be present in such concentrations in the range of about 0.5 to about 90% by weight of the total combination, i.e., in amounts sufficient to provide the desired unit dose.

For oral administration, tablets containing various excipients such as sodium citrate are used together with various disintegrants such as starch and preferably potato or tapioca starch, alginic acid and certain complex silicates and together with binders such as polyvinylpyrrolidone, gelatin and with. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid combinations of the same type may also be employed as fillers in soft and hard-filled gelatin capsules; Preferred substances in this connection would also be lactose, i.e. milk sugar, as well as high molecular weight polyethylene glycols. When desired orally

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7 73672 aqueous suspensions and / or elixirs, are combined with various sweetening or flavoring or coloring agents and, if desired, with emulsifying and / or suspending agents and also with diluents such as water, ethanol, propylene glycol , glycerin and their various combinations.

For parenteral administration, solutions or suspensions of these compounds in sesame or peanut oil or in aqueous propylene glycol solutions, as well as in sterile aqueous solutions, may be employed. These particular solutions are especially suitable for intramuscular injection under the skin. Aqueous solutions dissolved in pure distilled water are also useful for intravenous injection provided that the pH is suitably adjusted in advance. Such insulators should also be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline. The activity of the compounds of this invention as antiulcer agents is determined by their ability to pass at least one of the following two standard biological and / or pharmacological tests, namely (1) measuring their ability to resist specific functions of histamine that are not inhibited by antihistamines such as me-pyramine, i. a measure of their ability to block certain histamine-Hj receptor sites; and (2) measuring their ability to inhibit gastric acid secretion in the stomachs of Heidenhair. pouches, wherein the dogs have been pre-treated with Penta-30 gastrin for stimulation of this acid (in their stomachs).

Biological activity:

The efficacy of the compounds of the invention against gastric acid or sea buckthorn was determined in overnight paas-35 tons of He.idenhain pouch dogs. Pentagar.tri in.i λ (Penf Avlon-Ayerst) was lost in a continuous infusion of 8,73672 into the external tibial vein to stimulate acid secretion; the infusion used a dosage that had been found in previous experiments to stimulate near-maximal acid secretion from the stomach. Gastric fluid was collected at 30 ml to 5 minute intervals from the time the pentagastrin infusion was initiated and measured to the nearest 0.1 ml. During each experiment, 10 batches of gastric fluid were taken from each dog. The acid content was determined by titrating 0.1 ml of gastric fluid to pH 7.4 with 0.1 N sodium hydroxide 10 using an autoburette and a glass electrode pH meter (Radiometer). The drug or vehicle was administered intravenously 90 minutes after the start of the pentagastrin infusion at a dose of 1 mg / kg. The anti-gastric acid secretion effect was calculated by comparing the lowest acid excretion observed after drug administration to the average of the acid excretion rates observed immediately before drug administration.

The results obtained in this experiment for the compounds prepared according to the invention are as follows:

S

\, _NH

A

25

Treatment of gastric fluid secretion, s (Dose, mg / kg) CH, NHC2H5 55% (10) 30 CH3 CH3 24% (10)

The histamine β-antagonistic activity of the compounds of the invention was determined by the following method:

The guinea pigs were quickly killed by a blow to the head, their hearts were removed, and the right atria were removed. They were tensioned in an isometrically thermostated (32 ± 2 ° C) tissue bath

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3,73672 (10 ml) containing aerated (95% O 2, 5% CO 2) Krebs-Henseleit buffer (pK 7.4) and allowed to stabilize for about one hour, during which the tissue bath was shaken several times. Individual atrial contractions were monitored by 5 transmission systems connected to a cardiotometer and a Grass multiplier. After determining the histamine dose-response curve, each tissue bath containing the atrium of the heart was rinsed several times with fresh buffer and the atria were re-equilibrated to 10 baseline readings. Test compounds were then added in amounts corresponding to the selected final concentrations and the histamine dose-response curve was re-determined in the presence of antagonist. Results are expressed as dose ratios. that is, the ratio of histamine concentrations required to cause half of the maximal stimulation in the presence and absence of the antagonist and the apparent dissociation constant pA2 of the iU receptor antagonist was determined.

The results obtained in this experiment for the compounds prepared according to the invention are as follows:

B> -v_r \ _A

n / v / · 1 2 3 4 5 6 7 8 9 10 11 A B pA2 2 CK0) NHC2K5 5.39 3 C2H5 NHC2H5 5.19 4 CK3 NH2 5.23 5 CH3 CK3 5.31 6

The following examples are provided for purposes of further illustration only. Nuclear Magnetic Resonance Spectra δ (NMR) were measured at 60 MHz for solutions in deuterochloroform (CDCl 3), perdeuterodimethylsulfoxide (DKSO-dg) or 10 Deuterium 1 oxyoxide (D, 0) or are otherwise indicated. Sat 11 and peaks «..uernat o /; expressed in parts per million (ppn) of the field sunatr-m t et räme style ;; !, county or sodium 2,2-d.ime-1073672 style 2-silapentane-5-sulfonate. The following abbreviations are used for peak shapes: s, simple line; d, double line; t, triple line; q quadruple line; m, a multiplied line.

5 Example I

2-Ethylamino-4- (2-methyl-4-imidazolyl) pyridine A. 2- (2-Ethylamino-4-pyridyl) -2,2-diethoxyethylamine

To a solution of sodium ethoxide formed by dissolving 10,740 mg (32 mmol) of sodium in 30 ml of ethanol at room temperature under a nitrogen atmosphere was added 5.38 g (30 mmol) of 1- (2-ethylamino-4-pyridyl) -1-ethanone oxime ( Example IIB) and the resulting mixture was stirred until homogeneous. P-Toluenesulfonyl chloride (5.1 g, 33 mmol) was added and the mixture was stirred for one hour at room temperature. The mixture was added directly to a solution of potassium ethoxide prepared by dissolving 1.35 g (35 mmol) of potassium in 30 ml of ethanol, and the mixture was stirred for 30 minutes at room temperature under a nitrogen atmosphere. The resulting gelatinous mass was diluted with 300 mL of ether and the precipitate was filtered. Hydrogen chloride gas was bubbled into the filtrate for 15 minutes and then the mixture was evaporated. The residue was dissolved in 250 ml of water and basified by the addition of solid sodium carbonate. The product was extracted with chloroform (3 x 40 ml) and the combined extracts were dried over sodium sulphate and evaporated to give 7.6 g (100%) of the desired intermediate as an oil.

Nuclear Magnetic Resonance Spectrum showed absorption (CDCl 3) 8.08 (d, 1H), 6.66 (s + d, 2H), 6.0 (d, 1H), 3.42 (g, 6H), 2.98 (s, 2H) at 30 and (t, 9H) ppm.

B. 2-Ethylamino-4- (2-methyl-4-imidazolyl) pyridine

A mixture of 2.0 g (8 mmol) of 2- (2-ethylamino-4-pyridyl) -2,2-diethoxyethylamine, 1.0 g (8.3 mmol) of 35 ethyl acetimidate hydrochloride and 30 ml of absolute ethanol, heated to reflux for 1.3 hours.

Il 11 73672

The mixture was evaporated and the residue was taken up in 100 ml of concentrated hydrochloric acid. The acid solution was heated on a steam extract for one hour and the cooled reaction mixture was basified by the addition of solid potassium carbonate. The product was extracted with chloroform (4 x 15 ml) and the combined extracts dried and evaporated to give 1.1 g of crude product. The product was chromatographed on 35 g of silica gel using chloroform / methanol (19: 1, v / v) as eluent to give 510 mg (30%), m.p. 214-216 ° C.

10 Analysis: lie:

Calculated: C 65.3 H 7.0 N 27.7 Found: C 64.8 H 7.1 N 26.7

Example II

2-Ethylamino-4- (2-ethyl-4-imidazolyl) pyridine From the procedure of Example 13, 2.0 g (8 mmol) of 2- (2-ethylamino-4-pyridyl) -2,2-diethoxyethyl amine and 1.16 g (8.3 mmol) of ethyl propionimidate hydrochloride in 30 mL of ethanol to give 605 g (33%) of the title compound as a white solid, 190-193 ° C.

The NMR spectrum showed absorption (CDCl 3) 8.01 (d, 1H), 7.33 (s, 1H) f 5.86 (s + d, 2H), 3.23 (g, 2K) and 1, 22 (t, 6H) ppm.

Analysis C., * 1 / 4Η2 <0::

Calculated: C 65.3 H 7.5 N 25.4 25 Found: C 65.5 H 7.4 N 25.6

Example III

Starting from the appropriate 1- (2-alkylamino-4-pyridyl: -'-ethanone oxime and the required ethyl alkyl imidate and using the methods of Example I A-B, 30 of the following compounds are prepared: 12 73672 w '"1 ^ Nf NH 5

Cx X NR2R3 10 £ i * 2 h ch3- h- ch3- C2a5- CH3- CH3 ~ H ”H" C3H7 ~ c2h5- h- s-c3h7- ch3- H- iC H - n-c3H7- B- CH3- i-SV a- c2h5- n-C3H7- H- n-C3H7- 20 ° V B- C6B5CH2 '* ca3- H- CgHeCH (CH3) - C2V E-C6H5 (CH2> 3- n-C3K7- H-C6K5CH2 ·

Example IV

2-Dimethylamino-4- (2-methyl-4-imidazolyl) pyridine A. 2- (2-Dimethylamino-4-pyridyl) -2,2-diethoxyethylamine

To a solution of sodium ethoxide formed by dissolving 30,740 mg (32 mmol) of sodium metal in 25 mL of ethanol at room temperature under a nitrogen atmosphere is added 5.38 g (30 mmol) of 1- (2-dimethylamino-4-pyridyl) -1-ethanol. nioxime (Example IVC) and the resulting mixture is then mixed until homogeneous. Add p-toluene-35 nisulfonyl chloride (6.1 g, 33 mmol) and stir the mixture at room temperature for one hour. The mixture is added to potassium

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13 73672 in a solution of etckside (1.35 c potassium in 30 rt ethanol) and the mixture is stirred for one hour at room temperature. Ether (300 ml) is added to the resulting coagulation mass and the precipitate is filtered off. Hydrogen chloride gas is bubbled into the filtrate for 15 ml to 5 minutes and the mixture is evaporated. The residue is dissolved in 250 ml of water, which is then basified with solid sodium carbonate. The product is extracted with chloroform (3 x 50 ml) and the combined extracts are dried over sodium sulphate and evaporated to give the product.

10 B. 2-Dimethylamino-4- (2-methyl-4-imidazolyl) pyridine

A mixture of 1.0 g (4 mmol) of 2- (2-dimethylamino-4-pyridyl) -2,2-diethoxyethylamine, 500 mg (4.1 mmol) of ethyl acetimidate hydrochloride and 15 ml of ethanol is heated. at reflux for 1.5 hours. The mixture is evaporated and the residue is taken up in 10 ml of concentrated hydrochloric acid. After heating for 1 hour at steam bath temperatures, the cooled acid solution is basified by the addition of solid sodium carbonate and the product is extracted with chloroform (3 x 20 ml). The combined extracts are dried and evaporated to give a crude product which is further purified by chromatography on silica gel using chloroform / methanol as eluent.

Example V

Starting from the required 1- (2-disubstituted 4-pyridyl) -1-ethanone oxime and ethyl alkyl imidate and using the methods of Examples IV A-B, the following compounds are prepared: 30 N- = t ^ R1

4 ^. NS

n 35 K Nsi2 "3 14 73672 h £ 2 h CV ch3- c2hs- i-C3S7- CE3- C2H5- 5 CK3- C2H5" C2H5 "C2H5 ~ C2HS" C2E5 "CS3" C2E5 ~ B "C3H7 n-c3H7- C2K .- π-C3H7- n-C3H7- H-C3H7- S-C3H7- 10 Cit3- C2H5- i-C3H7- C2tl5 ~ C2E5 ~ i ~ C3H7 CH3- 1-C3H? i_C3H7 CH3- C6H5CK2- C6H5CH2-

C2H5- C6H5CH2- C6RSCV

15 CH3 CH3- C6H5CH2- i-c3H7- CH3- C6K5CH2-

Example VI

2-amino-4- (2-methyl-4-imidazolyl) pyridine 20 A. 2- (2-amino-4-pyridyl) -2,2-diethoxyethylamine

To a solution of sodium ethoxide prepared by dissolving 740 mg (32 mmol) of sodium in 35 ml of ethanol at room temperature under a nitrogen atmosphere is added 4.53 g (30 mmol) of 1- (2-amino-4-pyridyl) -1-ethanone oxime. To the resulting solution is then added 6.1 g (33 mmol) of p-toluenesulfonyl chloride and the mixture is stirred at room temperature for one hour. The resulting mixture is then added to a solution of potassium ethoxide (1.35 g of potassium in 30 ml of ethanol) and the reaction mixture is stirred for a further hour at room temperature. The gelatinous precipitate obtained is treated with 300 ml of diethyl ether and the precipitate is filtered off. After gaseous hydrogen chloride has been bubbled into the reaction mixture for 15 minutes, the mixture is evaporated and the residue is dissolved in 250 ml of water. The aqueous solution is basified with solid potassium carbonate and the liberated product is extracted

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15 73672 with chloroform (3 x 15 mL). The combined extracts are dried and evaporated to give the product.

3. 1-Amino-4- (2-methyl-4-imidazolyl) pyridine

A mixture of 890 mg (4 .mu.mol) of 2- (2-amino-4-p-5-radyl) -2,2-diethoxyethylamine, 500 mg (4.1 mmol) of ethyl methyl imidate hydrochloride and 15 ml of ethanol , is heated to reflux for 1.5 hours. The mixture is evaporated and the residue is taken up in 10 ml of concentrated hydrochloric acid. After heating for one hour, the acid solution frozen in a steam bath is basified with solid sodium carbonate and the product is extracted with chloroform (3 x 10 ml). The combined dried extracts are evaporated to dryness and the residue is purified by chromatography on silica gel using chloroform / methanol as eluent.

15 Example VII

2-Methyl-4- {2-methyl-4-imidazo-1-y) 1-yyrinyl A. 2-methyl-4-acetylpyridine

A solution of 3.5 g (29.7 mmol) of 2-methyl-4-cyanopyridine in 20 ml of dry ether was added dropwise to 20 ml of a cooled (5 ° C) solution of 3.0 M methylmagnesium bromide. ether. When the addition was complete, the mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was cooled to 5 ° C and the excess Grignard reagent decomposed by the addition of hydrogen. The mixture was acidified with 6N hydrochloric acid and the aqueous phase was separated. The ether phase was re-extracted with 3 * - 'I. · .--: --_ a li · λΙοοι ive tvnappap and combined with LottVjn. vosioitoi it a new.I — ut -.-. -cjiiiii- -Gtcixii nö_y - y naut ee .j_a yks— tmv-i. vcnoiuox— non-luo: · cooled in, basified with solid sodium bicarbonate and extracted (3 x 100 ml) with ether. The combined ether extracts were dried and evaporated to give 2.1 g (53%) of a yellow oil, b.p. 50-53 ° C (0.3 torr).

Nuclear Magnetic Resonance Spectrum (CDCl 3) showed absorption at 8.58 (d, 1313), [s, 1ii], "h 38 (d, 1H), 2.53 (s, 3H) and 2.48 's, 3H) pnn-s ^ a.

73672 B. 2-Methyl-4-acetylpyridioxime To 4.03 g (58.4 mmol) of hydroxylamine hydrochloride in 27 mL of 2N sodium hydroxide solution was added 3.95 g (29.2 mmol) of 2-methyl-4-acetylpyridine to give The mixture was heated on a steam bath with methanol to keep the mixture homogeneous. The mixture was heated for another five minutes and then cooled. The resulting precipitate was filtered, washed with water and dried, 3.95 g (90%), m.p. 151-152 ° C.

The NMR spectrum (DMSO-d 6) showed absorption of 11.42 (s, 1H), 8.38 (d, 1H), 7.37 (s, 1H), 7.30 (s, 111), 2.52 (s, 3H) and 2.17 (s, 3H) ppm.

C. 2-Methyl-4-acetylpyridine oximitosylate To a mixture of 3.95 g (26.3 mmol) of 2-methyl-4-acetylpyridine oxime in 25 mL of dry pyridine was added 5.87 g (30.9 mmol) of toluenesulfonyl chloride. and the reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was diluted with 35 mL of water and the resulting precipitate was filtered, washed with water and dried in vacuo, 8.0 g (81 S), m.p. 95-96 ° C.

Nuclear Magnetic Resonance Spectrum (CDCl 3) showed absorption 8.42 (d, 1H), 7.82 (d, 2H), 7.4-7.1 (m, 4H), 2.50 (s, 3H), 2.42 (s, 3H) and 2.30 (s, 3K) in ppru.

D. 2-Methyl-4- (2-methyl-4-imidazolyl) pyridine To 570 mg (14.2 mmol) of potassium metal dissolved in 10 mL of absolute ethanol was added a mixture of 4.33 g (14.2 mmol) of mmol) of 2-methyl-4-acetylpyridine oxime tosylate in 2C ml of absolute ethanol and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction was quenched with 100 mL of ether and the potassium tosylate was removed by filtration. Hydrogen chloride gas was bubbled into the filtrate for 5 minutes and the solution was evaporated. The residue was dissolved in 50 ml of water and the solution was basified with solid potassium carbonate. The aqueous phases were extracted (5 x 20 ml) with chloroform and the combined organic extracts were dried and evaporated to dryness.

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73672 17 to give oil. The residual oil was dissolved in 25 ml of methanol, 1.75 g (14.2 mmol) of ethyl acetimidate hydrochloride was added, and the mixture was heated under reflux for 1.5 hours. The mixture was evaporated and the residue was taken up in 25 ml of concentrated hydrochloric acid. The acid solution was heated on a steam bath for one hour and then stirred at room temperature for 18 hours. The mixture was basified with solid potassium carbonate and extracted with chloroform (2 x 50 ml) and ethyl acetate (1 x 50 ml). The combined extracts were dried and evaporated to give an oil which solidified on trituration with toluene / cyclohexane / acetone, 530 mg (22%), m.p. 115-117 ° C.

Analysis for qH ^ N ^: 1 le:

Calculated: C 69.3 H 6.4 N 24.3 15 Found: C 68.5 H 6.4 N 23.9

Example VIII

Non-toxic hydrohalic acid addition salts of each of the above 2-ethylamino-4- (2-amino-4-imidazolyl) pyridine base compounds of this invention, such as the corresponding hydrochloride, hydrobromide and hydroiodide salts, are each prepared by first dissolving the corresponding organic base. to absolute ether, followed by the introduction of a suitable hydrohalide gas into the reaction solution until saturation is complete. gas ratio, after which the desired acid addition salt soon precipitates out of solution. In this way, 1.0 g of 2-ethylamino-4- (2-methyl-4-imidazolyl) pyridine obtained as the free base product in Example VI is converted into the corresponding dichlorohydric acid addition salt via dry hydrogen chloride gas in essentially quantitative yield.

Example IX

Each of the above-mentioned 2-ethylamino-4- (2-amino-4-imidazolyl) pyridine base compounds represented by the above nitrate, sulfate or bisulfate, phosphate or acidic phosphate, acetate, lactate , maleate, fumariate, citrate or acid citrate, I 8 73672 tartrate or bitartrate, succinate, gluconate, saccharate, methanesulphonate, ethanesulphonate, benzenesulphonate and p-toluenesulphonate molar amounts of the corresponding 5 acids and bases in separate portions of ethanol and then mixing the two solutions together, followed by the addition of diethyl ether to the resulting mixture to provide precipitation of the desired acid addition salt therefrom. In this way, equimolar amounts of 2-ethylamino-4- (2-ethyl-4-10 imidazolyl) pyridine and concentrated sulfuric acid react to give the corresponding sulfuric acid addition salt. In the same way, each of the other salts is prepared.

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Claims (2)

A process for the preparation of therapeutically active imidazolyl-pyridine derivatives of the formula 5 wherein X and Y are each methyl or X is wherein 15 1 * 2 and are each hydrogen, alkyl having 1 to 3 carbon atoms or phenylalkyl in which alkyl contains 1 to 3 carbon atoms and Y is alkyl of 1 to 3 carbon atoms, characterized in that the compound of formula OC 2 H 5 is reacted with a compound of formula: NH yc-oc2h5 in a reaction inert solvent at 50-120 ° C, the solvent is removed, the residue is contacted with aqueous concentrated hydrochloric acid at about 100 ° C, the reaction mixture is basified and the product is isolated by accepted methods. Process according to Claim 1, characterized in that the reaction-inert solvent is ethanol and the reaction mixture is basified with solid sodium carbonate. Process according to Claim 2, characterized in that the product is isolated by extraction with chloroform. Il 73672 A process for the preparation of therapeutically active imidazolylpyridines in the form of 5 ή Y / “\ 10 color X and Y is different from methyl or X is -NR0R ^, colors R2 15 and R ^ are different from alkyl with 1-3 cholatomer or phenylalkyl with 1-3 cholatomers and alkyl, and Y is enalkyl with 1-3 cholaters, kännetecknat därav, att en förening med formuleln ° ch 20 C2H50 ^^^ 2 r · ^ 25 omsätts med en förening med formeln NH yc-oc2h5 30 and that the reaction medium is at a temperature of 50-120 ° C, the reaction medium is at a temperature of about 100 ° C, the reaction mixture is basically and the product is isolated from an acceptable method. 35 2. For the purposes of Patent Law 1, the