DD262026A1 - PROCESS FOR PREPARING 4-SUBSTITUTED 6- (PYRID-4-YL) -2,4-DIHYDRO-1H-IMIDAZO [4,5-B] PYRID-2-ONEN - Google Patents

Abstract

The invention relates to a process for the preparation of 4-substituted-6- (pyrid-4-yl) -2,4-dihydro-1H-imidazo & 4,5-b! pyrid-2-ones and 6- (pyrid-4-yl) -2,3-dihydro-1H-imidazo & 4,5-b! pyrid-2-one by reaction of 1-substituted 3-carbamido-2-imino-5- (pyrid-4-yl) -1,2-dihydropyridines and 2-amino-3-carbamido-5- (pyrid-4 -yl) -pyridine with Alkalimetallhypohalogeniten in alkaline solution. Field of application of the invention is the pharmaceutical industry.

Description

Field of application of the invention

The invention relates to a process for preparing 6- (pyrid-4-yl) -2,4-dihydro-1H-imidazo-4,5-b-pyrid-2-ones of the formula I,

in which R = H, alkyl, hydroxyalkyl, aminoalkyl, benzyl or substituted benzyl.

The compounds are biologically active. For example, they show positive initrope effects. The compounds also provide valuable intermediates for the preparation of other biologically active heterocycles.

The invention is applicable in the pharmaceutical industry.

Characteristic of the known technical solutions

6-pyridinyl-2,3-dihydro-1H-imidazo [4,5-b] pyrid-2-ones and their cardiotonic activity are known (GY Lesher, Ch.J.Opalka, DF Page, US Patent 4,294,837; GY Lesher Ch. J.Opalka, DF Page, U.S. Patent No. 4,297,360; GY Lesher, Ch. J. Opalka, DF Page, U.S. Patent No. 4,309,537). The preparation is carried out via the corresponding 2,3-diamino-substituted pyridine derivatives by reaction with urea or carbonyldiimidazole.

Also described is the preparation of 3-substituted-6-pyridinyl-2,3-dihydro-1H-imidazo [4,5-b] pyrid-2-ones by Hofmann degradation of the corresponding 2-alkylamino-5-pyridinyl nicotinamides with sodium hypochlorite solution (GY Lesher, Ch.J.Opalka, DFPage, U.S. Patent 4,374,141).

Object of the invention

It is the object of the invention to produce novel biologically active and intermediate 4-substituted -6- (pyrid-4-yl) -2,4-dihydro-1H-imidazo [4,5-b] pyrid-2-ones, as well as US Pat to improve the method of preparation of the cardiotonic effective 6- (pyrid-4-yl) -2,3-dihydro-1H-imidazo [4,5-b] pyrid-2-one.

Explanation of the essence of the invention

The invention has for its object to develop a process for the preparation of novel 6- (pyrid-4-yl) -imidazo [4,5-b] pyrid-2-ones, as well as a new production process for 6- (pyridine-4-one yl) -2,3-dihydro-1H-imidazo [4,5-b] pyrid-2-one.

According to the invention compounds of formula I are prepared by reacting 2-amino-3-carbamido-5- (pyrid-4-yl) -pyridine or 1-substituted 3-carbamido-2-imino-5- (pyrid-4-yl ) -1,2-dihydro-pyridines or their salts with alkali metal hypohalites in alkaline solution at room temperature or with heating. In this way, 4-substituted -6- (pyrid-4-yl) -2,4-dihydro-1H-imidazo [4,5-b] pyrid-2-ones are first prepared.

That aromatic o-amino-carboxylic acid amides can be cyclized to corresponding imidazolones by reaction with alkali metal hypohalites is well known. That this reaction also succeeds with 1-substituted 3-carbamido-2-imino-1,2-dihydro-pyridine derivatives is surprising.

The preparation of 6- (pyrid-4-yl) -2,3-dihydro-1H-imidazo [4,5-b] pyrid-2-one succeeds over the method described in the literature much more advantageous since the corresponding starting material containing 2-amino-5- (pyrid-4-yl) -nicotinamide directly from N, N-dimethyl-N- [3-dimethylamino-2- (pyrid-4-yl) -prop-2-enylidene] ammonium chloride hydrochloride, Cyanacetamide and NH ₃ water in a simple manner and in good yields is accessible.

The 4-substituted-6- (pyrid-4-yl) -1,2-dihydro-imidazo [4,5-b] pyrid-2-ones and their salts are biologically active. In particular, positive inotropic effects were found. By mixing with appropriate carriers, one arrives at pharmaceutical administration forms.

For example, 4- (2-methoxy-ethyl) -6- (pyrid-4-yl) -2,4-dihydro-1H-imidazo [4,5-b] pyrid-2-one is isolated both spontaneously and spontaneously the guinea pig's thriving atrium, as well as after iVInjektion the anesthetized dog a pronounced and dose-dependent positive inotropic effect.

The inventively prepared 4-substituted 6- (pyrid-4-yl) -2,4-dihydro-1H-imidazo [4,5-b] pyrid-2-ones are also valuable intermediates for the preparation of biologically active compounds.

The invention will be explained in more detail below with reference to exemplary embodiments.

embodiments example 1

6- (pyrid-4-yl) -2,3-dihydro-1H-imidazo [4,5-b] pyrid-2-one

3.9 g (18.2 mmol) of 2-amino-3-carbamido-5- (pyrid-4-yl) -pyridine are treated with a solution of 3.64 g of NaOH in 30 ml of water and the resulting suspension is added with stirring 22mmol NaOCl solution. It is 0.5h. stirred at about 60 ⁰ C, brought to about pH 8 with 6 N HCl, the precipitate was filtered off with suction and washed with water.

Yield of crude product: 0.86 g (74.1% of theory)

For purification is dissolved in methyl glycol, treated with activated charcoal, filtered, concentrated, mixed with water, filtered off, washed with a little alcohol and ether and dried at 120 ⁰ C.

Yield: 2.37 g (60.1% of theory)

M .:> 360 ° C

Example 2

4-Methyl-6- (pyrid-4-yl) -2,4-dihydro-1H-imidazo [4,5-b] pyrid-2-one

4.56 g (20 mmol) of 3-carbamido-2-imino-1-methyl-5- (pyrid-4-yl) -1,2-dihydro-pyridine are treated with a solution of 3.5 g of NaOH in 70 ml of water and to the suspension obtained, 25 mmol NaOCL solution are added. It is stirred for 30 min. Spiked with activated charcoal, filtered, neutralized with 6 N HCl, allowed to stand, filtered off with suction, washed with water and dried at 11O ⁰ C.

Yield: 3.1 g (. 68.5% of theory). M.p .:> 34O ⁰ C (dec.)

C ₁₂ H ₁₀ N ₄ O ₁ (226.2) calc. C 63.71 H 4.46 N 24.77

gef. C64.22 H 4.66 N 24.92

Example 3

4- (2-Hydroxyethyl) -6- (pyrid-4-yl) -2,4-dihydro-1H-imidazo [4,5-b] pyrid-2-one

7g (23.75 mmol) of 3-carbamido-1- (2-hydroxyethyl) -2-imino-5- (pyrid-4-yl) -1,2-dihydro-pyridine hydrochloride are added with a solution of 6 g NaOH in 95 ml of water and while stirring 28mmol NaOCl solution are added. It is stirred for 20 min., Mixed with activated charcoal, filtered, neutralized with 6N HCl solution, allowed to stand, and filtered with suction. The resulting 4.91 g of crude product are then recrystallized from ethanol / water with the addition of activated carbon. Yield: 3.81 g (. 62.6% of theory). M.p .: 340-50 ⁰ C (dec.)

C ₁₃ H ₁₂ N ₄ O ₂ (256.3) calc. C 60.93 H 4.72 N 21.86

gef. C 60.89 H 4.73. N 21.56

Example 4

4- (2-Methoxy-ethyl) -6- (pyrid-4-yl) -2,4-dihydro-1H-imidazo [4,5-b] pyrid-2-one

10,89g (40mmol) of 3-carbamido-1- (2-methoxy-ethyl) -2-imino-5- (pyrid-4-yl) -1,2-dihydro-pyridine are added to a solution of 8g NaOH in 160 ml of water and added to the resulting suspension 45 mmol NaOCl solution. The mixture is stirred for 45 minutes without cooling, mixed with activated charcoal, filtered, neutralized with 2 N, allowed to stand overnight, filtered off with suction and washed with water, ethanol and ether

Yield: 6.1 g (56.4% of theory..), M.p .: 323-5 ⁰ C

C ₁₄ H ₁₄ N ₄ O ₂ (270.3) calc. C 62.21 H 5.22 N 20.73

gef. C 62.16 H 5.25 N 20.70

Testing for biological effects Example 5 Isolated, spontaneously active auricle of the guinea pig

For the experiments male guinea pigs with a body mass of 400-500g were used. The isolated, spontaneously active atrium was examined after 60 min of adaptation of the organ preparations in 32 ° C tempered carbolic tyrodene solution to influence the influence of inotropy and frequency under the action of 6- {pyrid-4-yl) -2,4-dihydro-1 H-imidazo [4,5-b] pyrid-2-ones of formula I. The compounds exhibited a partially significant and dose-dependent positive inotropic effect.

For example, when the compound of Example 4 was administered at a concentration of 5.0.times.10.sup.- ³ mol / l, a 61% increase in inotropy was found.

Example 6 Anesthetized dog i.V.

The studies were conducted on bastard dogs in chloralose-urethane anesthesia when premedicated with morphine hydrochloride under spontaneous respiration. The left ventricular pressure was measured by means of a tip manometer and the arterial pressure was measured via cardiac catheter via the brachial artery (compare K. Femmer et al., Pharmacia 30,642 1975). Under the influence of the 6- (pyrid-4-yl) -2,4-dihydro-1H-imidazo [4,5-b] pyrid-2-ones, a dose-dependent marked increase in the contractility of the heart was observed. For example, the compound of Example 4 at a dose of 10 mg / kg exhibits a 42% increase in contractility parameter dp / dtmax.

Claims (3)

claims: 1. Process for the preparation of 4-substituted-6- (pyrid-4-yl) -2,4-dihydro-1H-imidazo-4,5-b-pyrid-2-ones or 6- (pyrid-4-yl) -2,3-dihydro-1H-imidazo-4,5-b-pyrid-2-one of the formula I, in which R = H, alkyl, hydroxyalkyl, aminoalkyl, benzyl or substituted benzyl and the corresponding tautomers, characterized in that 1-substituted-3-carbamido-2-imino-5- (pyrid-4-yl) -1, 2-dihydropyridines or their salts or 2-amino-3-carbamido-5- (pyrid-4-yl) pyridine or its salts with alkali metal hypohalides. Process according to item 1, characterized in that the reaction is carried out with alkali metal hypohalites at room temperature or with heating. 3. The method according to item 1 and 2, characterized in that the compounds of formula I in the form of pharmaceutically acceptable salts, for. B. as hydrogen halides produced.