FI76564C - FREQUENCY REQUIREMENT FOR THERAPEUTIC USE OF THERAPEUTIC 2 (1H) -PYRIDINONER. - Google Patents

Description

1 7 6 5 6 4

Process for the preparation of therapeutically useful 2 (1H) -pyridinones

The invention relates to a process for the preparation of new 5- (pyridinyl) -2 (1H) -pyridinones useful as cardiac drugs.

U.S. Patent Nos. 4,004,012 and 4,072,746 disclose 3-amino (or cyano) -5- (pyridinyl) -2 (1H) -pyridinones as cardiac drugs and the corresponding 3-carbam-10-bamyl compounds, alternatively called 1,2-dihydro - ro-2-oxo-5- (pyridinyl) -nicotinamides, which are converted into the corresponding 3-amino compounds by reacting them with a reagent capable of converting carbamyl to amino, e.g. by heating with alkali metal hypohalo-15 genite. A preferred embodiment of these compounds is 3-amino-5- (4-pyridinyl) -2 (1H) -pyridinone, now commonly known as amrinone and alternatively 5-amino- (3,4'-bipyridine) -6 (1H) - one.

One disclosed method for preparing 3-cyano-5- (pyridinyl) -2 (1H) -20 pyridinones, alternatively 1,2-dihydro-2-oxo-5- (pyridinyl) nicotinonitriles, is O- (pyridinyl) -. Reaction of β- (dialkylamino) -acrolein and α-cyanoacetamide. U.S. Patent 4,072,746 also discloses 3-Q-5- (pyridinyl) -2 (1H) -25 pyridinones wherein Q is hydrogen, halogen, lower alkylamino, di (lower alkyl) amino or NHAc wherein Ac is lower alkanoyl or lower carbalkoxy.

The 3-unsubstituted 5- (pyridinyl) -2 (1H) -pyridinones (Q = H) are prepared by heating the corresponding 3-30 cyano compounds and aqueous sulfuric acid to first form 3-carboxylic acids, i. 1,2-Dihydro-2-oxo-5- (pyridinyl) -nicotinic acids, which are then decarboxylated. Said 1,2-dihydro-2-oxo-5- (pyridinyl) -nicotinic acids have not been shown to be cardiotonic.

2,76564

The process according to the invention prepares 2 (1H) -pyridinones of the formula I

"TY

R 10 wherein Q is hydrogen, amino, cyano, carbamyl, halogen, lower alkylamino, di (lower alkyl) amino, alkanoylamino or acetoxy-substituted alkanoylamino, carboxy or lower alkoxycarbonyl, is hydrogen or lower alkyl, R is lower alkyl and PY is 4-, 3- or 2-pyridinyl or 4-, 3- or 2-pyridinyl having one or two lower alkyl substituents, or pharmaceutically acceptable acid addition or cationic salts thereof.

The compounds of formula I are useful cardiac drugs as determined by standard pharmacological diagnostic methods.

Compounds of formula I in which Q is carbamyl or cyano or Q is hydrogen may be converted to the corresponding compounds in which Q is amino or halogen respectively. Compounds of formula I wherein Q is halogen are also useful intermediates for the preparation of the corresponding 3- (mono- or di (lower alkyl) amino) compounds. Preferred are compounds of formula I wherein Q is hydrogen, amino or cyano, PY is 4-pyridinyl or 3-pyridinyl, R 1 is hydrogen and R is methyl or ethyl.

Particularly preferred are 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile (formula I wherein Q is CN, R 1 is H, PY is 4-pyridinyl and R is methyl) , 3-amino-6-ethyl-5- (4-pyridinyl) -2 (1H) -pyridinone (Formula I wherein Q is NH 4, R 1 is H, PY is 4-pyridinyl and R is ethyl) ), 3-amino-5- (4-pyridinyl) -6-methyl-2 (1H) -pyridinone (formula I wherein Q is N1, R1 is H, PY is 4-pyridinyl and R is methyl), 6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone (Formula I wherein R 1 is H, PY is 4-pyridinyl and R is 3,76564 methyl) and 6-ethyl-5- (4- pyridinyl) -2 (1H) -pyridinone (Formula I wherein R 1 is H, PY is 4-pyridinyl and R is ethyl) or a pharmaceutically acceptable acid addition salt thereof. These particularly preferred compounds ha-5 were found to have significantly higher cardiotonic activity than the corresponding known compounds 3-amino-5- (4-pyridinyl) -2 (1H) -pyridinone, known as amrinone, 1,2-dihydro- With 2-oxo-5- (4-pyridinyl) -nicotinonitrile and 5- (4-pyridinyl) -2 (1H) -pyridin-10-one.

Compounds of formula I as defined above may be prepared according to the invention by a) a compound of formula 15

R 1 R 6, NCH = C-C (= O) -R III

3 4,

PY

Wherein R 3 and R 4 are each lower alkyl are reacted with malonamide to give a compound of formula I wherein Q is carbamyl, or b) a compound of formula III as defined above is reacted with NR 1 -6-cyanoacetamide to give a compound of formula I wherein Q is is cyano, and if desired, the resulting compound of formula I wherein Q is cyano is partially hydrolyzed to the corresponding compound wherein Q is carbamyl; and, if desired, converting a compound of formula I obtained by method a) or b) into another compound of formula 4 76564 I by carrying out one or more of the following operations: i) reacting a compound of formula I wherein Q is carbamyl with a reagent which: is capable of converting carbamyl to amino, to give the corresponding compound wherein Q is amino; ii) reacting a compound of formula I wherein Q is amino with one or two molar equivalents of the lower alkylating agent to give a compound wherein Q is lower alkylamino or di (lower alkyl) amino, respectively; iii) reacting a compound of formula I wherein Q is amino with a lower acylating agent to give the corresponding compound wherein Q is lower acylamino; Iv) the compound of formula I wherein Q is cyano is hydrolyzed to the corresponding compound wherein Q is carboxy; v) heating a compound of formula I wherein Q is cyano or carboxy together with an aqueous solution of mineral acid to give the corresponding compound wherein Q is hydrogen; vi) esterifying a compound of formula I wherein Q is carboxy with a lower alkanol compound to the corresponding compound wherein Q is lower alkoxycarbonyl; vii) reacting a compound of formula I wherein Q is hydrogen with halogen to give the corresponding compound wherein Q is halogen; viii) reacting a compound of formula I wherein Q is halogen with a lower alkylamine or di (lower alkyl) amine to give the corresponding compound wherein Q is lower alkylamino or di (lower alkyl) amino, respectively; and ix) converting the obtained free base to an acid addition salt or converting the obtained compound to a cationic salt.

5,76564

The starting materials of formula III can be prepared by carrying out the formula

py-ch2-c (= o) -R II

5 PY-methyl (lower alkyl) ketone to react with di (lower alkyl) formamide-di (lower alkyl) acetal. The 1- (pyridinyl) -2-di (lower alkyl) aminoethenyl (lower alkyl) ketones of formula III and their acid addition salts are novel compounds.

The compounds of the invention may be used in cardiac drug compositions to improve cardiac contractility, said composition consisting of a pharmaceutically acceptable carrier and a cardiotonically effective amount of a 1R, -3-Q-5-PY-6-R-2 of formula I as defined above as active ingredient. ) -pyridinone or a pharmaceutically acceptable acid addition salt thereof. To improve cardiac contractility in a patient in need of such treatment, the patient is administered a cardiotonically effective amount of a compound of formula I or a pharmaceutically acceptable acid addition or cationic salt thereof.

The compounds of formula I are useful both as free bases and in the form of their acid addition salts, and both forms are a subject of the invention.

Acid addition salts are merely a more convenient form of use and thus it is natural that in practice the salt form is used more than the base form. Acids useful in the preparation of acid addition salts are preferably acids 30 which, together with the free base, form pharmaceutically acceptable salts, i. salts, the anions of which, when administered in pharmaceutical doses, are relatively harmless to animal organisms, i.e. the side effects caused by the anions must not interfere with the beneficial cardiological properties inherent in the free base of formula I. Pharmaceutically acceptable acid addition salts include, for example, salts formed with mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid, and organic acids such as acetic acid, citric acid, sulfonic acid, lactic acid, lactic acid, tartaric acid, methanesulfonic acid, methanesulfonic acid. cyclohexylsulfamic acid, quinic acid, etc. to give hydrochloride, sulfate, fpsate, sulfamate, acetate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, respectively.

The acid addition salts of a compound of formula I are prepared either by dissolving the free base in an aqueous or aqueous / alcoholic solution containing the appropriate acid or other suitable solvent and isolating the salt by evaporation of the solution or by reacting the free base and acid in an organic solvent to give the salt directly or by concentrating the solution.

Although pharmaceutically acceptable salts of a basic compound of formula I are preferred, all acid addition salts are useful as a source of the free base form even if the it is desired to prepare the salt only as an intermediate, e.g. for purification or identification purposes, or when used as an intermediate for the preparation of a pharmaceutically acceptable salt by ion exchange.

Other pharmaceutically acceptable salts of the compounds of formula I include cationic salts derived from strong inorganic or organic bases such as sodium hydroxide, potassium hydroxide or trimethylammonium hydroxide. In this case, the corresponding 1- or N-cationic salt is obtained, e.g. the sodium, potassium and trimethylammonium salts, respectively. the cation is attached to the 1-position, i.e. the N atom, of the 2 (1H) -pyridinone ring.

The molecular structures of the compounds of formula I were determined on the basis of infrared, nuclear magnetic resonance and mass spectral data, as well as the correspondence between the calculated and obtained values obtained in the elemental analysis.

7 76564

The following generally describes the practice and use of the invention so that one skilled in the art of pharmaceutical chemistry will be able to practice and use it.

The 1-PY-2- (dimethylamino) ethenyl (lower alkyl) ketone of formula III is prepared by reacting PY methyl (lower alkyl) ketone (II) with dimethylformamide di (lower alkyl) acetal by stirring the reaction components in the presence of a suitable solvent. or il-10 man it. The reaction is preferably carried out at room temperature (about 20-25 ° C) or by heating to about 100 ° C, preferably in an aprotic solvent and suitably hexamethylphosphoramide, due to the process used to prepare the PY methyl (lower alkyl) ketone, as hereinafter in Example A1 is mentioned. Other suitable solvents include tetrahydrofuran, dimethylformamide, acetonitrile, ether, benzene, dioxane, etc. The reaction can also be carried out without a solvent, preferably using an excess of dimethylformamide di (lower alkyl) acetal. This method is described in more detail in Examples 20 A-1 ... A-17.

The intermediate PY-methyl (lower alkyl) ketones (II) used are intermediates which are generally known and can be prepared by known methods (for example, Rec. Trav. Chim. 72 (1953), 25 p. 522; Patent Publication 3,133,077, Bull Soc Soc.

1968, pp. 4132; Chem. Abstrs. 79 8539h (1973); Chem. Abstrs-81, 120 401a (1974); J. Org. Chem. 39 (1974), pp. 3834;

Chem. Abstrs. 87, 6594q (1977); and J. Org. Chem. 43 (1978), p.2286).

Reaction of 1-PY-2- (dimethylamino) ethenyl (lower alkyl) ketone (III) with NR 1 -Ct-cyanoacetamide 1-R 1 -1,2-dihydro-2-oxo-5-PY-6-R -nicotinonitrile (Formula I wherein Q is CN) is preferably carried out by heating the reaction components in a suitable solvent in the presence of a basic condensing agent. The reaction is conveniently carried out using a lower alkali alkoxide, preferably 8,76564 sodium unoxide or ethoxide in dimethylformamide. In carrying out the invention, the reaction was carried out in refluxing dimethylformamide with sodium methoxide. Alternatively, methanol and sodium oxide or ethanol and sodium methoxide can be used as a solvent and a basic condensing agent, respectively, but a longer heating time is required. Other basic condensing agents and solvents include sodium hydride, lithium diethylamide, lithium diisopropyl-amide, etc. in an aprotic solvent such as tetrahydrofuran, acetonitrile, ether, benzene, dioxane, etc. This method is described in more detail in Examples B-1 ... 20.

Alternatively, 1,2-dihydro-2-oxo-5-PY-6-R-15 nicotinamide (Formula I wherein Q is carbamyl and R 1 is hydrogen) can be prepared directly by administering 1-PY-2- (Formula I) wherein R-amino) ethenyl (lower alkyl) ketone to react with malonamide.

Indicative hydrolysis of 1-R, -1,2-dihydro-2-oxo-5-PY-6-R-nicotinones-20 (formula I wherein Q is cyano) to 1,2-dihydro-2-oxo 5-PY-R-nicotinamide (formula I wherein Q is carbamyl) is carried out by heating with concentrated sulfuric acid. Although the reaction is conveniently and preferably carried out by heating the reaction components in a water or water bath at about 90 to 100 ° C, the reaction temperature may range from about 70 to 120 ° C. This method is further described in Examples C-1 to C-20 below.

Modification of 1-R 1 -1,2-dihydro-2-oxo-5-PY-6-R-nicotinamide 30 (Formula I wherein Q is carbamyl) 1-R 1 -3-amino-5-PY-6- The R-2 (1H) -pyridinone (of formula I wherein Q is amino) is carried out by reacting a compound (of formula I wherein Q is carbamyl) with a reagent capable of converting carbamyl to amino, e.g. alkali metal halide or lead tetraacetate. This reaction is conveniently carried out by heating an aqueous mixture of an alkali metal halide, preferably sodium hypobromite or hypochlorite, and a compound of formula I wherein Q is 9,76564 carbamyl, and then acidifying the reaction mixture preferably with an aqueous solution of a mineral acid, e.g. hydrochloric acid. The reaction can be carried out at a temperature of about 40 to 100 ° C, preferably 70 to 100 ° C. This method is described in more detail in Examples D-1 to D-20.

Modification of 1-R, -1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitrile (Formula I wherein Q is cyano) 1R, -5-PY-6-R-2 (1H ) to pyridinone (Formula I wherein Q is hydrogen) is performed by heating a compound wherein Q is cyano and an aqueous solution of 10 mineral acids, preferably 50% sulfuric acid, to give first a compound of formula I wherein Q is carboxy, and then continuing to heat for a longer time, whereby the 3-carboxylic acid is decarboxylated to a compound wherein Q is hydrogen. This method is described in more detail in Examples E-1 ... E-20.

The reaction of 1R, 5-PY-6-R-2 (1H) -pyridinone (Formula I wherein Q is hydrogen) and halogen to the corresponding 3-halogen compound (Formula I wherein Q is halogen) is performed by stirring the reaction components in the appropriate manner. -20 to an unreacted solvent. The preferred solvent is acetic acid. The reaction is preferably carried out at room temperature or by heating the reaction mixture to a temperature of up to about 100 ° C. Preferred halogens are bromine and chlorine. All unreacted solvents such as diraethylformamide, chloroform, acetic acid, etc. can be used. This method is described in more detail in Examples F-1 ... F21.

Reaction of 1R, -3-halo-5-PY-2 (1H) -pyridinone (Formula I wherein Q is halogen) with a lower alkylamine or di (lower alkyl) amine to give the corresponding 1R, -3-(lower alkyl) amino- To 5-PY-6-R-2 (1H) -pyridinone (Formula I wherein Q is lower alkylamino) or to 1R, 4- (3-) di (lower alkyl) amino] -5-PY-2 (1H) -pyridinone I wherein Q is di (lower alkyl) amino7 is carried out by heating the reaction mixture in an autoclave at a temperature of about 110 to 180 ° C, preferably about 145 to 165 ° C and preferably in a suitable solvent such as water, dimethylformamide, dioxane, 1.2 in dimethoxyethane, etc. or mixtures thereof. This method is described in more detail in Examples G — 1 / G — 4 ... G— 7, G — 9 ... G — 18, and G — 20 ... G — 22.

In an alternative process for the preparation of 1R, -3- ^ mono- or di (lower alkyl) amino--5-PY-6- (lower alkyl) -2 (1H) -5-pyridinone, the corresponding 3-amino compound is reacted with one or two molar equivalents of lower alkylating agent.

Preferably, 1R, β-dimethylamino-5-PY-6-R-2 (1H) -pyridinone (Formula I wherein Q is dimethylamino) is prepared by administering 1R, β-amino-5-PY-6-R -2 (1H) -pyridinone (formula I wherein Q is amino) reacts with a mixture of formaldehyde and formic acid. This reaction is preferably carried out under reflux with an excess of 3-amino compound and both formaldehyde (preferably in aqueous solution) and formic acid, each with a molar excess of preferably more than twice. This method is described in more detail in Examples G-3, G-8 and G-19.

Acylation of 1R, -3-amino-5-PY-6-R-2 (1H) -pyridinone (Formula I wherein Q is amino) to the corresponding 3- (lower acyl-20 amino) compound (Formula I wherein Q is lower) acylamino) is carried out by reacting a compound in which Q is amino with a lower acylating agent such as a lower acyl halide, preferably chloride, lower acyl anhydride or the like, preferably in the presence of an acid acceptor. The acid acceptor is a basic substance which preferably forms easily water-soluble by-products in the reaction mixture which are easily separated from the product. Examples are sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium alkoxides, potassium alkoxides, sodium amide, etc. Preferably, the reaction is carried out under suitable reaction conditions in the presence of an inert solvent. Examples of such solvents are lower alkanol, acetone, dioxane, dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide or a mixture of solvent, e.g. a mixture of water and methylene chloride or chloroform. The reaction is generally carried out at a temperature of about 10 to 150 ° C, preferably about 20 to 25 ° C. This method is described in more detail in Examples H-1..H-16.

11 76564 Hydrolysis of 1-R, -1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitrile (Formula I wherein Q is cyano) 1R, -1,2-dihydro-2 -oxo-5-PY-6-nicotinic acid (formula I wherein Q is carboxy) is conveniently carried out by heating said nicotinonitrile and an aqueous solution of a mineral acid, preferably 50% sulfuric acid, with an aqueous bath. This method is described in more detail in Examples I-1 to I-20.

Esterification of 1-R 1 -1,2-dihydro-2-oxo-5-PY-6-R-nicotinic acid (formula I wherein Q is carboxy) (lower alkyl) -10 1 -R 1 -1,2-dihydro 2-Oxo-5-PY-6-R-nicotinate (Formula I wherein Q is lower alkoxycarbonyl) is performed by heating an acid, Formula I wherein Q is carboxy) and a lower alkanol at a temperature of about 25 to 150 ° C, preferably about 50 - 100 ° C, preferably in the presence of a suitable solvent such as an excess of a lower alkanol and in the presence of an acid catalyst such as a strong inorganic acid or an organic acid such as sulfonic acid, e.g. hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid or the like. This method is described in more detail in Examples 20 J-1 ... J-18.

The following examples illustrate the invention without, however, limiting it.

A. 1-PY-2- (dimethylamino) ethenyl-lower alkyl ketones 25 A-1. 1- (4-pyridinyl) -2- (dimethylamino) ethenylmethyl ketone

A mixture of 20 g of (4-pyridinyl) methylmethyl ketone (alternative name: 1- (4-pyridinyl) -2-propanone) and 30 cm 3 of hexamethylphosphoramide was diluted with 65 cm 3 of dimethylformamide dimethyl acetal and the resulting mixture heated to reflux for 30 minutes. TLC analysis showed one spot indicating the completion of the reaction (in the second run, the reaction appeared to be complete after 30 minutes at room temperature).

The reaction mixture was evaporated on a rotary evaporator under vacuum (about 15 mm) to give 24 g of a crystalline residue.

This was purified by continuous chromatography extraction through alumina (ca. 150 g) eluting with refluxing chloroform at 12,76564. After 1 1/2 hours, the extract was heated in vacuo to remove chloroform to give 23.2 g of 1- (4-pyridinyl) -2- (dimethylamino) ethenylmethyl-5-ketetone, alternatively called 4-dimethylamino-2- (as a pale yellow crystalline solid). 4-pyridinyl) -3-buten-2-one.

The above preparation can be carried out using other solvents instead of hexamethylphosphoramide, e.g. dimethylformamide, acetonitrile or other solvents mentioned above or without a solvent. But it was convenient to use hexamethylphosphoramide because my (4-pyridinyl) methylmethyl ketone was conveniently prepared as a mixture with hexamethylphosphoramide, as evidenced by the following preparation: To a stirred solution of 15 to 70 cm of freshly distilled diisopropylamine in 200 cm of tetrahydrofuran and under a nitrogen blanket, 210 cm 2 of 2,4-m-n-butyllithium in n-hexane were added dropwise over 20 minutes, and the reaction mixture was stirred for about 35 minutes at about 0-5 ° C. To the cold solution was added tio 20 while dropping 90 cm of dry hexamethylphosphoramide (no change in temperature) over 10 minutes and the resulting pale yellow solution was stirred for 15 minutes. To a cold solution at 0 ° C was added a solution of 50 cm 4 of picoline in 150 cm of dry tetrahydrofuran over 15 minutes and stirring was continued for 30 minutes at 0 ° C. A mixture of 3 cm of dry ethyl acetate and 150 cm of tetrahydrofuran (temperature rose from 0 ° C to about 6 ° C) was then added over 15 minutes and the resulting mixture was stirred for 20 minutes at 0 ° C. The ice bath of Sit-30 was removed and stirring was continued for another 90 minutes, after which the temperature of the reaction mixture rose to about 25 ° C. The reaction mixture was then cooled in an ice bath and 60 cm of acetic acid was added over a period of about 30 minutes. Tetrahydrofuran was removed by distillation in vacuo on a rotary evaporator. The remaining mixture was diluted with 400 cm of water 3a. The aqueous mixture was extracted successively with two 250 cm portions of isopropyl acetate 3 and three 80 cm portions of chloroform. The solvents were removed by distillation in vacuo to give about 137 g of a mixture of 13,76564 consisting essentially of the desired product and hexamethylphosphoramide. A second run was performed in the same amounts as above, except that after 3 cm of 60 cm glacial acetic acid was added, the mixture was diluted with only 200 cm 5 of water, the phases were separated and the aqueous phase was extracted with five 100 ml portions of chloroform. The chloroform extract was washed with brine and the chloroform was removed by distillation in vacuo. The remaining mixture of the desired ketone and hexamethylphosphoramide was combined with 137 g of the same mixture obtained above, the combined mixture was distilled in vacuo to give the following fractions: I. 63 g, b.p. 110-112 ° C / 4 mm, II. 59 g of pale yellow oil, b.p. 113-115 ° C / 3 mm and III. 69 g of pale yellow oil, b.p. 115-118 ° C / 2.5 mm. NMR analysis of fraction III showed that it consisted of a 2: 3 mixture of (4-pyridinyl) methyl methyl ketone and hexamethylphosphoramide.

The acid addition salts of 1- (4-pyridinyl) -2- (dimethylamino) ethenylmethyl ketone are conveniently prepared by adding to a mixture of 5 g of 1- (4-pyridinyl) -2- (dimethylamino) ethenylmethyl ketone in about 100 ml of aqueous methanol, the appropriate acid , e.g. methanesulfonic acid, concentrated sulfuric acid or concentrated phosphoric acid, to a pH of about 2-3, by cooling the mixture after partial evaporation and isolating the precipitated salt, e.g. dimethanesulfonate, sulfate or phosphate, respectively. The acid addition salt may also conveniently be prepared in aqueous solution by adding with stirring to the water a molar equivalent of both 1- (4-pyridinyl) -2- (dimethylamino) ethenylmethyl ketone and the appropriate acid, e.g. lactic acid or hydrochloric acid, to give the monolactate or monohydroic acid hydrochloride, respectively.

A- 2. 1- (4-Pyridinyl) -2- (dimethylamino) ethylethyl ketone 35 A mixture of 87.5 g of (4-pyridinyl) methylethyl 14 7 65 64 ketone (optional name 1- (4-pyridinyl) -2-butanone) and 160 cm -1 of hexamethylphosphoramide, diluted with 100 g of dimethylformamide dimethyl acetal and the resulting mixture was stirred for 45 minutes under nitrogen and at room temperature. The methanol formed in the reaction was removed by distillation in vacuo on a rotary evaporator, and the remaining material was distilled in vacuo to give two fractions, one of which b.p. was 45-80 ° C / 0.5 mm and the second b.p. 90-95 ° C / 0.5 mm. When it was found by TLC that both fractions formed essentially only a single spot, both fractions were combined (= 135 g) and dissolved in 600 μl of chloroform. The resulting solution was washed with two 300 cm 3 portions of water and the aqueous solution was extracted 3 with three 100 cm 2 portions of chloroform. The combined chloroform solution was dried over anhydrous sodium sulfate and purified by continuous chromatographic extraction with 3,300 cm 3 of alumina eluting with refluxing chloroform. The chloroform was removed by distillation in vacuo to give a red oil which crystallized on standing overnight in an ice bath. The crystalline substance was dissolved in carbon tetrachloride, cyclohexane was added, the mixture was cooled to give 64 g of 1- (4-pyridinyl) -2- (dimethylamino) ethenyl ethyl ketone as a yellow crystalline product. An additional 11 g of crystalline product was obtained from the mother liquor by continuous chromatography extraction through alumina eluting with refluxing chloroform.

The above intermediate (4-pyridinyl) methyl ethyl ketone was obtained as a mixture with hexamethylphosphoramide as follows: To a mixture of 200 cm of tetrahydrofuran 30 and 70 cm 2 of diisopropylamine under nitrogen and at 0-5 ° C was added 210 cm 2 of , 4-n n-butyllithium in n-hexane and the resulting mixture was stirred for 30 minutes. 90 cm of hexamethylphosphoramide were then added over 10 minutes and the mixture was stirred for 15 minutes. A solution of 48 cm 4-pico- 3 is 76564 in 150 cm tetrahydrofuran was then added over 15 minutes and then stirred for 30 minutes at about 0 ° C. The ice-acetone bath used to cool the reaction mixture was replaced with a dry ice-acetone bath, and a mixture of 75 cm -1 of ethyl propionate in the same volume of tetrahydrofuran was added to the reaction mixture over 20 minutes. The reaction mixture was then allowed to warm to room temperature over about 90 minutes and then warmed to about 35 ° C. The mixture was then cooled in an ice-acetone bath and 60 cm of glacial acetic acid was added over 30 minutes.

3

The resulting pale yellow suspension was diluted with 200 cm 3 of water. The mixture was extracted with three 150 cm portions of ethyl acetate and the ethyl acetate extract was backwashed with brine. The extract was heated in vacuo to remove ethyl acetate and the residue was redissolved in ethyl acetate. The solution was washed with water, then heated in vacuo to remove ethyl acetate, the residue heated in vacuo at 50 ° C for about 30 minutes to give 100 g of a pale yellow oil. This oil and the corresponding samples from two additional runs were combined, distilled in vacuo to give 256 g of a fraction having a b.p. was 85-105 ° C / 0.5-1.0 mm. According to NMR, this fraction was a 1: 1.55 molar mixture of (4-pyridinyl) methyl ethyl ketone and hexamethylphosphoramide, i.e. the yield of said ketone 25 was 35%, i.e. 0.35 x 256 = 90 g.

A-3. 1- (4-pyridinyl) -2- (dimethylamino) ethenyl n-propyl ketone

A mixture of 80 g of (4-pyridinyl) methyl-n-propyl ketone (alternative name 1- (4-pyridinyl) -2-pentanone) and 46 cm of hexamethylphosphoramide was diluted with 250 3 of acetonitrile. . To the mixture was added 90 cm of dimethylformamide dimethyl acetal, the resulting reaction mixture was heated on a water bath for 90 minutes and then distilled in vacuo at a pressure of about 2 mm of volatiles, e.g.

35 to remove methanol, acetonitrile and hexamethylphosphoramide. The residue was diluted with ethyl acetate and the mixture was washed with water. The combined water washes were extracted with five 150 cm 2 portions of ethyl acetate. The combined ethyl acetate solutions were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue crystallized on standing in a freezer. The crystalline product was slurried in cyclohexane, filtered, dried overnight at 30 ° C to give 10 g of 1- (4-pyridinyl) -2- (dimethylamino) ethenyl-n-propyl ketone as a yellow crystalline product, m.p. 48-50 ° C.

The above intermediate (4-pyridinyl) methyl-n-propyl ketone was obtained as a mixture with hexamethylphosphoramide 3 as follows: To a stirred solution of 70 cm 3 of diisopropylamine in 200 cm 3 of tetrahydrofuran under nitrogen and at about 0 ° C (using an ice bath) ), 210 cm 2 of 2,4-n n-butyllithium were added over 20 minutes, the resulting mixture was stirred for 30 minutes at about 0 ° C, 90 cm 2 of hexamethylphosphoramide was added over 10 minutes with stirring, and the resulting mixture was stirred for another 10 minutes. Then 45 cm 4-picoline in 140 cm tetrahydrofuran was added dropwise over 15-20 3 3 minutes. The resulting dark orange-brown solution was stirred for 30 minutes at 0 ° C, then a solution of 68 cm 3 of ethyl butyrate in 68 cm of tetrahydrofuran was added dropwise over 18 minutes, raising the temperature from -8 ° C to + 8 ° C. ... to 10 ° C. The reaction mixture was removed from the ice bath and allowed to warm to room temperature over 75 minutes. The reaction mixture was re-cooled and 60 cm @ 2 of glacial acetic acid were added dropwise over 15 minutes. A pale yellow solid separated and a suspension formed. This was diluted with water and extracted 3 with two 200 cm portions of ethyl acetate. The ethyl acetate extract was washed with three 100 cm portions of brine, dried over anhydrous sodium sulfate, evaporated in vacuo; 107 g of a mixture consisting mainly of (4-pyridinyl) methyl-n-propyl ketone and hexamethylphosphoramide were obtained. The mixture obtained in this run and the corresponding mixtures from the other two runs were combined, the combined mixtures were distilled in vacuo to give the main fraction, b.p. 80-90 ° C / 0.2 mm, a mixture of 80 g of (4-pyridinyl) methyl-n-propyl ketones and 46 g of hexamethylphosphoramide.

Following the procedure described in Example A-2, but using a molar equivalent amount of the appropriate PY-methyl (lower alkyl ketone (II) (4-pyridinyl) methyl ethyl ketone, the examples of Examples A-4 ...

A-17 corresponds to 1-PY-2- (dimethylamino) ethenyl-lower alkyl ketones.

15 A-4. 1- (3-pyridinyl) -2- (dimethylamino) ethenylmethyl ketone using (3-pyridinyl) methyl methyl ketone. A-5. 1- (2-pyridinyl) -2- (dimethylamino) ethenylmethyl ketone using (2-pyridinyl) methyl methyl ketone.

A-6. 1- (4-Pyridinyl) -2- (dimethylamino) ethenyl isopropyl ketone using (4-pyridinyl) methyl isopropyl ketones.

A-7. 1- (4-pyridinyl) -2- (dimethylamino) ethenyl-n-butyl ketone using (4-pyridinyl) methyl-n-butyl ketone.

25 A-8. 1- (4-Pyridinyl) -2- (dimethylamino) ethenyl isobutyl ketone using (4-pyridinyl) methyl isobutyl ketone.

A-9. 1- (4-pyridinyl) -2- (dimethylamino) ethenyl tert-butyl ketone using (4-pyridinyl) methyl tert-butyl ketone.

A-10. 1- (4-pyridinyl) -2- (dimethylamino) ethenyl-n-pentyl ketone using (4-pyridinyl) methyl-n-pentyl ketone.

A-II. 1- (2-methyl-4-pyridinyl) -2- (dimethylamino) -35 ethenylethyl ketone using (2-methyl-4-pyridinyl) methyl ethyl ketone.

18 76564 A-12. 1- (5-methyl-2-pyridinyl) -2- (dimethylamino) ethenylmethyl ketone using (5-methyl-2-pyridinyl) methyl methyl ketone.

A-13. 1- (5-ethyl-2-pyridinyl) -2- (dimethylamino) ethynyl ethyl ketone.

A-14. 1- (3-pyridinyl) -2- (dimethylamino) ethenylethyl ketone using (3-pyridinyl) methyl ethyl ketone. A-15. 1- (4,6-Dimethyl-2-pyridinyl) -2- (dimethylamino) ethenylmethyl ketone using (4,6-dimethyl-2-pyridin-10-yl) methyl methyl ketone.

A-16. 1- (6-methyl-2-pyridinyl) -2- (dimethylamino) ethenyl isopropyl ketone using (6-methyl-2-pyridinyl) methyl isopropyl ketone.

A-17. 1- (2-pyridinyl) -2- (dimethylamino) ethenyl-n-hex-15 ethyl ketone using (2-pyridinyl) methyl-n-hexyl ketone.

When (3-methyl-4-pyridinyl) methyl methyl ketone is used, the method of Example A-2 gives 1- (3-methyl-4-pyridinyl) -2- (dimethylamino) ethenyl-20-methyl ketone, m.p. 124-125 ° C. .

B. 1-R 1 -1,2-Dihydro-6- (lower alkyl) -2-oxo-5-PY-nicotinonitriles B-1. 1,2-Dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile, alternative name 1,6-25 dihydro-2-methyl-6-oxo- (3,4'-bipyridine) - 5-carbonitrile

To a mixture of 23 g of 1- (4-pyridinyl) -2- (dimethylamino) ethenylmethyl ketone and 11 g of xi- cyanoacetate

O

amide dissolved in 400 cm of dimethylformamide, 14 g of sodium methoxide were added with stirring, and the resulting reaction mixture was just heated to reflux on an oil bath for 1 hour. TLC analysis showed no starting materials in the reaction mixture. This mixture was then concentrated in vacuo on a rotary evaporator.

O

35 dutters to a volume of about 80 cm. The concentrate was treated with about 160 cm3 of acetonitrile, the resulting mixture was stirred with heating on a rotary evaporator to homogeneity and then cooled. The crystalline product was isolated, rinsed successively with acetonitrile and ether, dried overnight at 55 ° C to give 28 g of a 5-colored, crystalline product, i.e. 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) -nicotinonitrile sodium salt, the cyano group of which was detected by IR analysis. An 8 g portion of said sodium salt was dissolved in 75 cm of hot water, the aqueous solution was treated with activated carbon, filtered, the filtrate was treated again with activated carbon, filtered and the filtrate was acidified to pH 3 by dropwise addition of 6N hydrochloric acid. The acidic mixture was diluted and cooled. The crystalline product was isolated, dried, recrystallized from dimethylformamide-15 water, dried to give 3.75 g of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile, m.p. above 300 ° C.

The acid addition salts of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) -nicotinonitrile are prepared by adding 20 g of 1,2-dihydro-6-methyl-2-oxo-nitrile to the mixture. 4- (4-pyridinyl) nicotinonitrile in about 40 ml of aqueous methanol, an appropriate acid such as methanesulfonic acid, concentrated sulfuric acid or concentrated phosphoric acid to a pH of about 2-3, cooling the mixture after partial evaporation and isolating the precipitated salt, e.g. dimethanesulfonate, sulfate or phosphate. The acid addition salt can also be conveniently prepared in aqueous solution by adding with stirring to water a molar equivalent of both 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile and the appropriate acid such as lactic acid or hydrochloric acid, respectively, monolactates. - or to prepare the monohydrochloride salt as an aqueous solution. This monohydrochloride salt was found to have a melting point of> 300 ° C.

20 7 6 5 6 4 B-2. 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) -nicotinonitrile, alternative name 2-ethyl-1,6-dihydro-6-oxo- (3,4'-bipyridine) -5 -carbonitrile, m.p. above 300 ° C, 11.6 g was prepared following the procedure described in Example 5 B1 above using 20 g of 1- (4-pyridinyl) -2- (dimethylamino) ethenyl ketone, 8.4 g of O-cyanoacetamide, 16.2 g of sodium methoxide and 250 cm 3 of dimethylacetamide (as solvent instead of dimethylformamide).

10 B-3. 1,2-Dihydro-2-oxo-6-n-propyl-5- (4-pyridinyl) -nicotinonitrile, alternative name 1,6-dihydro-6-oxo-2-n-propyl- (3,4 '-bipyridine) -5-carbonitrile, m.p. 232 ° C-234 ° C, 9.9 g, was prepared following the procedure described in Example B1 above using 85 g of 1-15- (4-pyridinyl) -2- (dimethylamino) ethenyl-n-propyl ketone, 36.5 g % cyanoacetamide, 50 g sodium methoxide

O

and 800 cm of dimethylacetamide.

B-4. 1,2-dihydro-1,6-dimethyl-2-oxo-5- (4-pyridinyl) nicotinonitrile, alternative name 1,6-dihydro-1,2-di-20-methyl-6-oxo- (3, 4'-bipyridine) -5-carbonitrile, m.p.

245-248 ° C, 32.3 g, was prepared following the procedure described in Example B1 above using 42.5 g of 1- (4-pyridinyl) -2- (dimethylamino) ethenylmethyl ketone, 23.5 g of N-methyl- α-cyanoacetamide, 6.7 g of sodium methoxide and 400 ml of methanol and refluxing for 2 hours.

Following the procedure described in Example B-2, but using a molar equivalent amount of the appropriate 1-PY-2- (dimethylamino) ethenyl-lower alkyl ketone (III) instead of 1- (4-pyridinyl) -2- (dimethylamino) ethenylethyl ketone, and the corresponding NR 4 -ot.-cyanoacetamide can be obtained from the corresponding Examples B-5 to B-20 1-R 1 -1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitriles.

B-5. 1,2-Dihydro-6-methyl-2-oxo-5- (3-pyridinyl) nicotinonitrile using 1- (3-pyridinyl) -2- (dimethyl-21,76564 amino) ethenylmethyl ketone and o-cyanoacetanide.

B-6. 1,2-Dihydro-6-methyl-2-oxo-5- (2-pyridinyl) nicotinonitrile using 1- (2-pyridinyl) -2- (dimethylamino) ethenylmethyl ketone and o (.-Cyanoacetamide).

5 B-7. 1,2-Dihydro-6-isopropyl-2-oxo-5- (4-pyridinyl) nicotinonitrile using 1- (4-pyridinyl) -2- (dimethylamino) ethenyl isopropyl ketone and o-cyanoacetane.

B-8. 6-n-butyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) -10 nicotinonitrile using 1- (4-pyridinyl) -2- (dimethylamino) ethenyl-n-butyl ketone and oi. -syaaniasetami slide.

B-9. 1,2-Dihydro-6-isobutyl-2-oxo-5- (4-pyridinyl) nicotinonitrile using 1- (4-pyridinyl) -2- (dimethylamino) ethenyl isobutyl ketone and N-cyanoacetamide. B-10. 1,2-Dihydro-2-oxo-5- (4-pyridinyl) -6-tert-butylnicotinonitrile using 1- (4-pyridinyl) -2- (dimethylamino) ethenyl tert-butyl ketone and o ^ -syaaniasetani slide.

20 B-ll. 1,2-Dihydro-2-oxo-6-n-pentyl-5- (4-pyridinyl) nicotinonitrile using 1- (4-pyridinyl) -2- (dimethylamino) ethenyl-n-pentyl ketone and cis-cyanoacetamide . B-12. 6-Ethyl-1,2-dihydro-5- (2-methyl-4-pyridinyl) -2-oxonicotinonitrile using 1- (2-methyl-4-pyridin-25-yl) -2- (dimethylamino) ethenylethyl ketone and o (-syaa-niasetamidia.

B-13. 1,2-Dihydro-6-methyl-5- (5-methyl-2-pyridinyl) -2-oxonicotinonitrile using 1- (5-methyl-2-pyridinyl) -2- (dimethylamino) ethenylmethyl ketone and o ( “Cyano-30 niacetamide.

B-14. 6-Ethyl-5- (5-ethyl-2-pyridinyl) -1,2-dihydro-2-oxonicotinonitrile using 1- (5-ethyl-2-pyridinyl) -2- (dimethylamino) ethenylethyl ketone and o- -syaa-niasetamidia.

35 B-15. 6-Ethyl-1,2-dihydro-2-oxo-5- (3-pyridinyl) -nico- 22,76564 tinonitrile using 1- (3-pyridinyl) -2- (dimethylamino) ethenylethyl ketone and o (. ") cyanoacetamide.

B-16. 1,2-Dihydro-5- (4,6-dimethyl-2-pyridinyl) -6-methyl-2-oxonicotinonitrile using 1- (4,6-dimethyl-5-pyridinyl) -2- (dimethylamino) ethenylmethyl ketones and cyanoacetamide.

B-17. 1,2-Dihydro-6-isopropyl-5- (6-methyl-2-pyridinyl) -2-oxonicotinonitrile using 1- (6-methyl-2-pyridinyl) -2- (dimethylamino) ethenylisopropyl-10 and cyanoacetamide.

B-18. 1,2-Dihydro-6-n-hexyl-2-oxo-5- (2-pyridinyl) nicotinonitrile using 1- (2-pyridinyl) -2- (dimethylamino) ethenyl-n-hexyl ketone and o-cyanoacetamide.

2- (dimethylamino) ethenylmethyl ketone and N-ethyl-o-cyanoacetamide.

B-20. 1,6-Diethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) -nicotinonitrile using 1- (4-pyridinyl) -2- (dimethylamino) ethylethyl ketone and N-ethyl-c * L-cyanoacetamide.

C. 1-R 1 -1,2-Dihydro-6- (lower alkyl) -2-oxo-5- (pyridinyl) nicotinamides C-1. 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinamide, alternative name 1,2-dihydro-2-methyl-6-oxo- (3,4'-bipyridine) -5-carboxamide.

A mixture of 9.0 g of 1,2-dihydro-6-methyl-2-

O

oxo-5- (4-pyridinyl) nicotinonitrile and 45 cm 3 of concentrated sulfuric acid, was heated in an oil bath for 30 minutes to 30 ° C. The hot reaction mixture was added to 200 cm -1 of ice and the resulting mixture was cooled in an ice-acetone bath. To the cold solution was carefully added dropwise about 150 cm 2 of a 28% ammonium hydroxide solution. The resulting mixture was cooled in an ice-acetone bath for about 30 minutes. The precipitate was then isolated, rinsed successively with water and acetonitrile, dried well and recrystallized by dissolving hot water in 130 enamel (boiling), adding 30 cm 3 of acetic acid, treating with activated carbon and filtering. The filtrate was concentrated, diluted with acetonitrile and kept on ice for about 30 minutes. The formed crystalline material was isolated to give 8.35 g of a skin-colored crystalline substance. This material was combined with 13.5 g from the second run

O

The substance thus obtained and 13.5 g thus obtained were dissolved in 500 cm of dimethylformamide at boiling point. The hot mixture was filtered and the filtrate was cooled in an ice bath. The crystalline precipitate was isolated, rinsed with acetone and dried for 14 hours at 100 ° C over P 2 O 4. According to IR and NMR analyzes, it was found to still contain some dimethylformamide. 10.5 g of a leather-colored crystalline product

O

20 t were dissolved in 75 cm 3 of hot acetic acid, treated with 50 cm 3 of water and then diluted with acetone to 300 cm3. The resulting mixture containing some crystals was cooled in an ice bath for about 45 minutes. The resulting pale leather crystalline product was isolated, dried first at 55 ° C and then at 110 ° C to remove residual weak acetic acid odor to give 9.2 g of 1,2-dihydro-6-methyl-2-oxo-5 - (4-pyridinyl) nicotinamide, m.p. above 300 ° C.

The acid addition salts of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nico-30-thinamide are conveniently prepared by adding 5 g of 1,2-dihydro-6-methyl-2-oxo-5 - (4-pyridinyl) nicotinamide in about 100 ml of an aqueous solution of methanol, an appropriate acid such as methanesulfonic acid, concentrated sulfuric acid or concentrated phosphoric acid to a pH of about 2-3, by cooling the mixture after partial evaporation and isolating the precipitate. 7 6 5 6 4 salt, e.g. dimethanesulfonate, sulfate or phosphate, respectively. The acid addition salt can also be conveniently prepared in aqueous solution by adding, with stirring, a molar equivalent of both 1,2-dihydro-6-methyl-5'-2-oxo-5- (4-pyridinyl) nicotinamide and an appropriate acid such as lactic acid or hydrochloric acid, respectively, monolactate or to prepare the monohydrochloride salt as an aqueous solution.

1,2-Dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nico-10-thinamide (Example C1 above) was also prepared directly by carrying 1- (4-pyridinyl) -2- (dimethylamino) ethenyl methyl ketone to a solution of 100 g of 1- (4-pyridinyl) -2- (dimethylamino) ethenylmethyl ketone and 132 g of malonamide in 15,900 ml of dimethylformamide was added with stirring over 5 minutes a mixture of 24 g of sodium sodium hydride dispersed in 24 g of mineral oil. The resulting reaction mixture was heated on a steam bath under nitrogen. After about 15 minutes, a reaction took place which strongly developed dimethylamine and the product precipitated, resulting in the formation of a foam. The heating was stopped and another 200 ml of dimethylformamide was added. Heating and stirring of the reaction mixture was continued on a steam bath for about 2.5 hours, after which the mixture was cooled to room temperature. The formed crystalline precipitate was collected, recrystallized from water and dried to give 35 g of 1,2-dihydro-5-methyl-2-oxo-5- (4-pyridinyl) nicotinamide, melting point above 300 ° C. Its chemical structure is confirmed by the following NMR spectral values: 30 chemical shift hydrogen number _ppm (TMS) _ amount __________ 10.70 12 CONH2, NH and 9 excess.3 8.98; 8.25 4 pyridine A2B2

8.86 1 aromatic H

35 2.76 3 CH3 a) additional hydrogens indicate the presence of water, i. the sample was not completely dry.

76564 25 C-2. 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) -nicotinamide, alternative name, 1,6-dihydro-2-ethyl-6-oxo (3,4'-bipyridine) -5-carboxamide.

A portion of 40 g of 6-ethyl-1,2-dihydro-2-oxo-5 5- (4-pyridinyl) -nicotinonitrile was added to 170 cm of concentrated sulfuric acid, after which the temperature rose to about 70 ° C. The reaction mixture was immersed in a preheated oil bath at about 90 ° C and held at 95-105 ° C for about 40 minutes. The hot reaction mixture was then poured into a beaker containing 800 cm -1 of ice. The mixture was stirred and then placed in an ice-acetone bath. To the cold mixture was added dropwise, with stirring, 650 cm 2 of a 28% solution of aluminonium hydroxide, after which the temperature rose to about 46 ° C. 150 cm 2 of water, air-dried for two hours, slurried in a small amount of acetonitrile, filtered, dried for several days at 55 ° C to give 39.5 g of product, the solid was stirred well in 300 cm of water, filtered, dried to give 38 g of 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinamide as a crystalline product.

A 14.3 g portion of this product was further purified 3 by dissolving it in 40 cm of hot acetic acid, filtering 3 hot solution and diluting the filtrate to 180 cm with absolute ethanol to form crystals. The pale skin product was isolated, dried for about 15 hours at 110 ° C over 20 ° C to give 11.7 g of 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinamide, mp.

30 above 300 ° C.

C-3. 1,2-Dihydro-2-oxo-6-n-propyl-5- (4-pyridinyl) -nicotinamide, alternative name 1,6-dihydro-6-oxo-2-n-propyl- (3,4'- bipyridine) -5-carboxamide, m.p. above 300 ° C, 10.5 g was prepared following the procedure described in Example C-2 using 30.7 g of 1,2-dihydro-26,76564 2-oxo-6-n-propyl-5- (4- pyridinyl) nicotinonitrile 3 and 130 cm concentrated sulfuric acid.

Following the procedure described in Example C-2, but using a molar equivalent amount of the appropriate 5 1-R 1 -1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitrile (Formula I wherein Q is cyano) 6-ethyl Instead of 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile, the corresponding 1,2-dihydro-2-oxo-5-PY-6-R of Examples C-4 to C-20 can be obtained. -nicotinamide.

10 C-4. 1,2-Dihydro-6-methyl-2-oxo-5- (3-pyridinyl) nicotinamide.

C-5. 1,2-Dihydro-6-methyl-2-oxo-5- (2-pyridinyl) nicotinamide.

C-6. 1,2-Dihydro-6-isopropyl-2-oxo-5- (4-pyridinyl) -Nicotinamide.

C-7. 6-n-Butyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinamide.

C-8. 1,2-Dihydro-6-isobutyl-2-oxo-5- (4-pyridinyl) nicotinamide.

20 C-9. 1,2-Dihydro-2-oxo-5- (4-pyridinyl) -6-tert-butylnicotinamide.

C-10. 1,2-Dihydro-2-oxo-6-n-pentyl-5- (4-pyridinyl) nicotinamide.

C-ll. 6-ethyl-1,2-dihydro-5- (2-methyl-4-pyridinyl) -2-oxonicotinamide.

C-12. 1,2-Dihydro-6-methyl-5- (5-methyl-2-pyridinyl) -2-oxonicotinamide.

C-13. 6-ethyl-5- (5-ethyl-2-pyridinyl) -1,2-dihydro-2-oxonicotinamide.

30 C-14. 6-ethyl-1,2-dihydro-5- (3-pyridinyl) -1,2-2-oxonicotinamide.

C-15. 1,2-Dihydro-6-methyl-5- (4,6-dimethyl-2-pyridinyl) -2-oxonicotinamide.

C-16. 1,2-Dihydro-6-isopropyl-5- (6-methyl-2-pyridinyl) -2-oxonicotinamide.

27 76564 C-17. 1,2-Dihydro-6-n-hexyl-2-oxo-5- (2-pyridinyl) nicotinamide.

C-18. 1,2-Dihydro-1,6-dimethyl-2-oxo-5- (4-pyridinyl) nicotinamide.

5 C-19. 1-ethyl-1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinamide.

C- 20. 1,6-Diethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) -10 nicotinamide.

D. 1-R 1, -3-Amino-6- (lower alkyl) -5-PY-2 (1H) -pyridinones D-1. 3-amino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone, alternative name 5-amino-2-methyl- (3,4'-bipyridin) -15 6 (1H) -one.

To a solution of 13 g of sodium hydroxide 250 in 3 cm of water was added 12 g of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinamide, and the resulting mixture was heated in a water bath to enhance dissolution.

An additional 250 cm of water was added to the solution and the resulting solution was cooled with stirring to about 35 ° C, whereupon some crystals separated. The mixture was cooled in an ice bath and a total of 4.0 cm 3 of bromine was added dropwise, whereby leaching occurred after the addition of about 3 cm 3 of bromine. The mixture was stirred for a further 10 minutes while cold and then heated on a water bath for 45 minutes. The reaction mixture was then concentrated to about half its volume, cooled in an ice bath and treated with 6N hydrochloric acid until a pH of about 8 was reached. The resulting crystalline product was isolated, rinsed twice with water and once with acetone, dried to give 7.3 g of material. This amount was treated with 20 cm of water and the insoluble, amorphous substance was removed by filtration. The filtrate was evaporated to dryness, the formed crystalline substance was recrystallized from 35 dimethylformamide-water to give 3.8 g of 3-amino-6-methyl-28 (7) 5 6 4-style 5- (4-pyridinyl) -2 (1H) -pyridinone, mp. above 300 ° C.

The acid addition salts of 3-amino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone are conveniently prepared by adding to a mixture of 2 g of 3-amino-6-methyl-5- (4-pyridinyl) - 5 2 (1H) -pyridinone in about 40 ml of aqueous methanol, an appropriate acid such as methanesulfonic acid, concentrated sulfuric acid or concentrated phosphoric acid to a pH of about 2-3, cooling the mixture after partial evaporation and isolating the precipitated salt, e.g. or phosphate. The acid addition salt can also be conveniently prepared in aqueous solution by adding, with stirring, a molar equivalent of both 3-amino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone and an appropriate acid such as lactic acid or hydrochloric acid to the monolactate or to prepare the monohydrochloride salt as an aqueous solution.

D-2. 3-amino-6-ethyl-5- (4-pyridinyl) -2 (1H) -pyridinone, alternative name 5-amino-2-ethyl (3,4'-bipyridin) -6 (1H) -one, m.p. above 300 ° C, 8.8 g, was prepared following the procedure described in Example D1, but using 10.0 g of 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinamide. 3 dia, 8.8 g of sodium hydroxide, 300 cm of water and 3.0 cm of bromine and recrystallization from dimethylformamide-isopropyl alcohol.

25 D-3. 3-amino-6-n-propyl-5- (4-pyridinyl) -2 (1H) -pyridinone, alternative name 5-amino-2-n-propyl- (3,4'-bipyridine) -6 (1H ) -one.

To a stirred mixture of 8.5 g of 1,2-dihydro-2-oxo-6-n-propyl-5- (4-pyridinyl) nicotinamide and -105 cm 3 of water at room temperature was added a solution of 3 to 1. 32 g of sodium hydroxide in 6 cm of water. The resulting suspension was cooled in an ice bath, stirred for 10 minutes and then treated over three minutes by dropwise addition of 22 cm -1 of a 1.1% aqueous solution of sodium hypochlorite-35. Dissolution occurred and stirring was continued for 29,76564 without cooling for 30 minutes. To the resulting solution at 15 ° C 3 was added 27 cm of 35% aqueous sodium hydroxide solution, the reaction mixture was heated for one hour in a water bath at about 60-70 ° C and 14 cm was slowly added to the warm solution over 5 minutes: 11a glacial acetic acid to form a leather-colored precipitate. The mixture was stirred for five minutes, the precipitate was isolated, washed with warm water and dried over? 2θ ^: η. 12 g of product were formed, which was recrystallized from a mixture of 100 cm of dimethylformamide and 80 cm of water, dried overnight at 95 ° C over P 2 O 3 to give 9.5 g of 3-amino-6 -n-propyl- (4-pyridinyl) -2 (1H) -pyridinone, m.p. 200-202 ° C.

Following the procedure described in Example D1, but using a molar equivalent amount of the appropriate 1-R, -1,2-dihydro-2-oxo-5-PY-6-R-nicotinamide (Formula I wherein Q is carbamyl) 1.2 Instead of -dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinamide, the corresponding examples of Examples D-4 ... D-20 1R, 3-amino-5-PY-6-R-20 2 can be obtained. (1 H) -pyridinone.

D-4. 3-amino-6-methyl-5- (3-pyridinyl) -2 (1H) -pyridin-one.

D-5. 3-amino-6-methyl-5- (2-pyridinyl) -2 (lH) -pyri-pyrrolidinones.

25 D ~ 6. 3-Amino-6-isopropyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

D-7. 3-Amino-6-n-butyl-5- (4-pyridinyl) -2 (1H) -pyri-pyrrolidinones.

D-8. 3-Amino-6-isobutyl-5- (4-pyridinyl) -2 (1H) -pyrid-30-dinone.

D-9. 3-amino-6-tert-butyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

D-10. 3-amino-6-n-pentyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

30 76564 D — 11. 3-amino-6-ethyl-5- (2-methyl-4-pyridinyl) -2 (1H) -pyridinone.

D-12. 3-amino-6-methyl-5- (5-methyl-2-pyridinyl) -2 (1H) -pyridinone.

5 D-13. 3-amino-6-ethyl-5- (5-ethyl-2-pyridinyl) -2 (1H) -pyridinone.

D-14. 3-amino-6-ethyl-5- (3-pyridinyl) -2 (1H) -pyridinone.

D-15. 3-amino-6-methyl-5- (4,6-dimethyl-2-pyridinyl) -2 (1H) -pyridinone.

10 D — 16. 3-amino-6-isopropyl-5- (6-methyl-2-pyridinyl) -2 (1H) -pyridinone.

D-17. 3-amino-6-n-hexyl-5- (2-pyridinyl) -2 (1H) -pyridinone.

D-18. 3-amino-1,6-dimethyl-5- (4-pyridinyl) -2 (1H) -pyrid-15-dinone.

D- 19. 3-Amino-1-ethyl-6-diethyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

D 2Q. 3-amino-1,6-diethyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

E. 1-Rj-6- (lower alkyl) -5-PY-2 (1H) -pyridinones E-1. 6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone, alternative name 2-methyl- (3,4'-bipyridin) -6 (1H) -one.

A mixture of 5.3 g of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) -nicotinonitrile and 30 cm3 of 85% sulfuric acid was heated to about 195 ° C and was just heated to reflux for 24 hours, cooled and added to ice. The pH of the aqueous mixture was adjusted to 8 by the addition of concentrated aqueous sodium hydroxide solution. The precipitate formed (product plus ^ 280 ^) was treated with chloroform-30a and the chloroform solution was filtered. The filtrate was evaporated in vacuo to remove chloroform, the resulting crystalline residue was recrystallized from methylene chloride, dried for four hours at 75 ° C to give 4.1 g of 6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone, 35 m.p. . 287-288 ° C.

3i 76564 Acid addition salts of 6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone are conveniently prepared by adding 5 g of 6-methyl-5- (4-pyridinyl) -2 (1H) -py -ridinone in about 100 ml of aqueous methanol, an appropriate acid such as methanesulfonic acid, concentrated sulfuric acid or concentrated phosphoric acid to a pH of about 2-3, cooling the mixture after partial evaporation and isolating the precipitated salt, e.g. dimethanesulfonate or sulfate, respectively. phosphate. The acid addition salt 10 can also be conveniently prepared in aqueous solution by adding, with stirring, a molar equivalent of both 6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone and the appropriate acid, e.g. lactic acid or hydrochloric acid, as the monolactate or monohydrochloride salt 15, respectively.

E-2. 6-ethyl-5- (4-pyridinyl) -2 (1H) -pyridinone, alternative name 2-ethyl- (3,4'-bipyridin) -6 (1H) -one.

A mixture of 9 g of 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) -nicotinonitrile and 50 ml of concentrated sulfuric acid was heated with stirring at 200 ° C for 24 hours, cooled to about To 40 ° C and quenched by pouring into 200 mL of ice water. The aqueous solution was basified with concentrated ammonium hydroxide solution, the precipitated solid was isolated, recrystallized from 70 ml of 25 isopropyl alcohol, dried in vacuo at 60 ° C to give 3 g of 6-ethyl-5- (4-pyridinyl) -2 (1H) -pyridinone, m.p. . 226-228 ° C. An additional 0.4 g was obtained, m.p. 225-227 ° C, concentrating the filtrate to about 20 mL.

E-3. 6-n-propyl-5- (pyridinyl) -2 (1H) -pyridinone, alternative name 2- (n-propyl) - (3,4'-bipyridin) -6 (1H) -one, m.p. 179-180 ° C, 3.4 g, was obtained following the procedure described in Example E-2, but using 10 g of 1,2-dihydro-6-n-prop-3-yl-2-oxo-5- (4-pyridinyl) nicotinonitrile, and 42.5 cm-32 76564 85% sulfuric acid and recrystallization from methylene dichloride ether.

Following the procedure described in Example E-2, but using 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridin-5-yl) nicotinonitrile instead of a molar equivalent amount of 1-R 1 -1,2- dihydro-2-oxo-5-PY-6- (lower alkyl) nicotinonitrile can be obtained corresponding to Examples 1-4 to E-20 1R - η 5 - ΡΥ-β- (lower alkyl) -2 (1H) -PYRIDINONES.

10 E-4. 6-methyl-5- (3-pyridinyl) -2 (1H) -pyridinone.

E-5. 6-isopropyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

E-6. 6-n-butyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

E-7. 6-isobutyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

E-8,5- (4-pyridinyl) -6-tert-butyl-2 (1H) -pyridinone.

15 E-9. 6-n-pentyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

E-10. 6-ethyl-5- (2-methyl-4-pyridinyl) -2 (1H) -pyridinone.

E-II. 6-ethyl-5- (3-pyridinyl) -2 (1H) -pyridinone.

E-12. l, 6-dimethyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

10 E-13. 1-ethyl-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

& -14. l, 6-diethyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

E-15. 6-methyl-5- (2-pyridinyl) -2 (1H) -pyridinone.

E-16. 6-methyl- (5-methyl-2-pyridinyl) -2 (1H) -pyridinone. 25 E-17. 6-ethyl-5- (5-ethyl-2-pyridinyl) -2 (1H) -pyridinone. E-1.8. 6-methyl-5- (4,6-dimethyl-2-pyridinyl) -2 (1H) -pyridinone.

E-19. 6-isopropyl-5- (6-methyl-2-pyridinyl) -2 (1H) -pyridinone.

30 E-20. 6-n-hexyl-5- (2-pyridinyl) -2 (1H) -pyridinone.

F. 1-R 1 -Halo-6- (lower alkyl) -5-PY-2 (1H) -pyridinones F-1. 3-bromo-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone, alternative name 5-bromo-2-methyl- (3,4'-bipyridin) -6 (1H) -one.

33 7 6 5 6 4

To a stirred solution of 65 g of 6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone in one liter of acetic acid at 65 ° C was added dropwise over 20 minutes 69 g of bromine in 50 mother acetic acid.

The reaction mixture was stirred for a further 30 minutes, cooled to room temperature and the crystalline precipitate was isolated by filtration. The precipitate was dried and suspended in 1500 cra of water. To the vigorously stirred suspension was added 3 dropwise 25 cm of 20% ammonium hydroxide solution, after which a white, cream-like precipitate separated. The solid was isolated, dried in vacuo at 90 ° C to give 101 g of 3-bromo-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone, m.p. 252-254 ° C. A 15 g sample was dissolved in 200 cm 2 of hot acetic acid and filtered. The filtrate was concentrated in vacuo, diluted with methanol and the resulting white crystalline precipitate was isolated, dried at 100 ° C under vacuum for 16 hours to give 9.8 g of said product, m.p. 252-254 ° C.

The acid addition salts of 3-bromo-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridin-20-one are conveniently prepared by adding to a mixture of 5 g of 3-bromo-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone in about 100 ml of aqueous methanol, an appropriate acid such as methanesulfonic acid, concentrated, sulfuric acid or concentrated phosphoric acid to a pH of about 2-3, cooling the mixture after partial evaporation and isolating the precipitated salt, e.g. dimethanesulfonate, sulfate or phosphate. The acid addition salt can also be conveniently prepared in aqueous solution by adding with stirring to the water a molar equivalent of 30 3-bromo-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone and the appropriate acid, e.g. lactic acid or hydrochloric acid, respectively monolactate. - or to prepare the monohydrochloride salt as an aqueous solution.

F-2. 3-chloro-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridin-35-nonone, alternative name 5-chloro-2-methyl (3,4'-bipyridin) -6 (1H) -one .

34 7 6 5 6 4

A mixture of 18.6 g of 6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone and 200 ml of acetic acid heated on a water bath was treated by bubbling chlorine through it for four hours. The reaction mixture was allowed to cool to room temperature, the solid was isolated, washed with ether and dried. The solid was dissolved in water, the aqueous solution was neutralized with 2N aqueous potassium hydroxide solution, and the mixture was cooled. The precipitated solid was isolated, washed with water, dried, recrystallized from ethanol to give 3-chloro-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone. This compound was recovered as its hydrochloride, m.p. 286-288 ° C (decomposition).

Following the procedure described in Example F1 or F-2, but using instead of 6-methyl-5- (4-pyridinyl) -2 (1H) -15 pyridinone a molar equivalent amount of 1R4-6- (lower alkyl) -5-PY-2 (1H) -pyridinone and bromine or chlorine can be obtained from the compounds of Examples F-3 to F-21 1R, -3-bromo (or chloro) -6- (lower alkyl) -5-PY-2- (1H) -pyridinones .

20 F-3. 3-chloro-6-ethyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

F-4. 3-chloro-6-methyl-5- (3-pyridinyl) -2 (1H) -pyridin-one.

F-5. 3-chloro-5-6-n-propyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

F-6. 3-bromo-6-isopropyl-5- (4-pyridinyl) -2 (1H) -pyri-pyrrolidinones.

F-7. 3-bromo-6-n-butyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

30 F-8. 3-chloro-6-isobutyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

F-9. 3-bromo-5- (4-pyridinyl) -6-tert-butyl-2 (1H) -pyridinone.

F-10. 3-chloro-6-n-pentyl-5- (4-pyridinyl) -2 (1H) -pyr-35-ridinone.

F-II. 3-bromo-6-ethyl-5- (2-methyl-4-pyridinyl) -2 (1H) -pyridinone.

35 76564 F-12. 3-chloro-6-ethyl-5- (3-pyridinyl) -2 (1H) -pyridin-one.

F-13. 3-chloro-l, 6-dimethyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

5 F- 14. 3-Chloro-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

F- 15. 3-Bromo-1,6-diethyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

F- 16. 3-Bromo-6-methyl-5- (2-pyridinyl) -2 (1H) -pyridinone. 10 F-17. 3-bromo-6-methyl-5- (5-methyl-2-pyridinyl) -2 (1H) -pyridinone.

F-18. 3-bromo-6-ethyl-5- (5-ethyl-2-pyridinyl) -2 (1H) -pyridinone.

F- IS. 3-chloro-6-methyl-5- (4,6-dimethyl-2-pyridinyl) -β 2 (1H) -pyridinone.

F— 20. 3-bromo-6-isopropyl-5- (6-methyl-2-pyridinyl) -2 (1H) -pyridinone.

F- 21. 3-Chloro-6-n-hexyl-5- (2-pyridinyl) -2 (1H) -pyridinone.

20 G. 1-R 1 -3- (mono- or di- (lower alkyl) amino] -5-PY-6- (lower alkyl) -2 (1H) -pyridinones G-1. 6-methyl-3-methylamino-5- (4-pyridinyl) -2 (1H) -pyridinone, alternative name 2-methyl-5-methylamino- (3,4'-bipyridin) -6 (1H) -one.

A mixture of 19 g of 3-bromo-6-methyl-5- (4-pyridin-3-dinyl) -2 (1H) -pyridinone, 250 cm of a 70% aqueous solution of methylamine, 60 mg of copper bronze and 60 mg of copper (II) sulfate, autoclaved at 160 ° C for 48 hours. The crystalline mass was taken up in aqueous methanol and the mixture was filtered to isolate the product. The solid (6 g) and another portion of the mother liquor (1 g) obtained by concentration and dilution with methanol were dissolved in a small amount of acetic acid, filtered and the filtrate was diluted with water. The resulting crystalline precipitate was isolated, washed well with water, dried overnight at 90 ° C to give 5.1 g of 6-methyl-3-methylamino-5- (4-pyridinyl) -2 (1H) -pyridinone. , sp. 270-275 ° C (decomposes). This preparation can also be performed as above using a molar equivalent of 3-chloro-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone 3-bromo-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

Acid addition salts of 6-methyl-3-methylamino-5- (4-pyridinyl) -2 (1H) -10 pyridinone are conveniently prepared by adding 5 g of 6-methyl-3-methylamino-5- (4-pyridinyl) -2 (1H) -pyridinone in about 100 ml of aqueous methanol, a suitable acid such as methanesulfonic acid, concentrated sulfuric acid or concentrated phosphoric acid to a pH of about 2-3, cooling the mixture after partial evaporation and isolating the precipitated salt, e.g. dimethanesulfonate, sulfate or phosphate, respectively. The acid addition salt may conveniently be prepared in aqueous solution by adding with stirring to water 20 molar equivalents of both 6-methyl-3-methylamino-5- (4-pyridinyl) -2 (1H) -pyridinone and an appropriate acid such as lactic acid or hydrochloric acid to prepare the monolactate or monohydrochloride salt, respectively.

25 G-2. 3-ethylamino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone, alternative name 5-ethylamino-2-methyl- (3,4'-bipyridin) -6 (1H) -one, m.p. . above 250 ° C, 1.6 g was prepared following the procedure described in Example G1, but using 16.5 g of 3-bromo-6-methyl-5- (4-pyridinyl) -2 (1H) -3,330 pyridinone, 110 cm ethylamine, 15 cm of water, 30 mg of copper bronze and 30 mg of copper (II) sulphate, autoclaved at 150 ° C for 45 hours and recrystallized twice from acetonitrile.

G-3. 6-methyl-3- (dimethylamino) -5- (4-pyridinyl) -2 (1H) -35 pyridinone, alternative name 5- (dimethylamino) -2-methyl- (3,4'-bipyridine) -6 (1H) -one.

37 76564

To a stirred solution of 20 g of 3-amino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone dissolved in 3,200 cm of formic acid was added dropwise over 5 minutes 20 cm of 37%. formaldehyde solution. The reaction mixture was heated under reflux for 1 hour and 45 minutes, heated to dryness in vacuo and the residue dissolved in methylene dichloride. The methylene dichloride solution was washed with saturated aqueous sodium bicarbonate solution and filtered. The filtrate was dried over anhydrous sodium co-sulfate, filtered, and the solvent was removed by distillation in vacuo to give 14 g of a yellow crystalline solid. This was dissolved in 250 cm of hot methylene chloride, the hot solution was treated with activated carbon and filtered. The filtrate was concentrated in vacuo to almost dryness and treated with acetonitrile. The resulting mixture of crystalline solid and acetonitrile was cooled, the solid isolated and dried to give 10.5 g of a yellow crystalline product containing some impurities (by TLC). The solid was dissolved in chloroform and the small impurity was removed by filtering the chloroform solution through a 6.6 cm silica gel column. 10.5 g of product formed, which was dissolved in methylene dichloride, diluted with isopropyl alcohol, concentrated in vacuo and cooled. The precipitate was isolated, dried at 80 ° C to give 9.0 g of 6-methyl-3- (dimethylamino) -5- (4-pyridinyl) -2 (1H) -pyridinone, m.p. 223-225 ° C.

Following the procedure described in Example G1 or G-2, but using instead of 3-bromo-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone, a molar equivalent of the appropriate 1R, -3-bromo (or chloro) - 5-PY-6- (lower alkyl) -2 (1H) -pyridinone can be obtained from Examples G-4 ... G-22 1R, -3- ^ ήοηο- or di (lower alkyl) amino] -5-PY- 6- (lower alkyl) -2 (1H) -pyridinones.

38 7 6 5 6 4 G-4. 6-ethyl-3-methylamino-5- (4-pyridinyl) -2 (1H) -pyridinone G-5. 3-methylamino-6-methyl-5- (3-pyridinyl) -2 (1H) -pyridinone.

5 G-6. 3-n-propylamino-6-n-propyl-n- (4-pyridinyl) -2 (1H) -pyridinone.

G-7. 3-methylamino-6-isopropyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

G-8. 6-n-butyl-3-dimethylamino-5- (4-pyridinyl) -2 (1H) -10 pyridinone.

G-9. 3-n-butylamino-6-isobutyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

G-10. 3-methylamino-5- (4-pyridinyl) -6-tert-butyl-2 (1H) -pyridinone.

15 G — 11. 3-Isopropylamino-6-n-pentyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

G-12. 6-ethyl-3-diethylamino-5- (2-methyl-4-pyridinyl) -2 (1H) -pyridinone.

G-13. 6-ethyl-3-ethylamino-5- (3-pyridinyl) -2 (1H) -20 pyridinone.

G-14. 3-methylamino-1/6-dimethyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

G-15. 1-ethyl-6-methyl-3-methylamino-5- (4-pyridinyl) -2 (1H) -pyridinone.

25 G-16. 1,6-diethyl-3-methylamino-5- (4-pyridinyl) -2 (1H) -pyridinone.

G-17. 3-n-Hexylamino-6-methyl-5- (2-pyridinyl) -2 (1H) -pyridinone.

G-10. 3-ethylamino-6-methyl-5- (5-methyl-2-pyridinyl) -3,2 (1H) -pyridinone.

G-19. 6-ethyl-5- (5-ethyl-2-pyridinyl) -3-dimethylamino-2 (1H) -pyridinone.

39 7 6 5 6 4 G-20. 3-Diisopropylamino-6-methyl-5- (4,6-dimethyl-2-pyridinyl) -2 (1H) -pyridinone.

G-21. 3-ethylamino-6-isopropyl-5- (6-methyl-2-pyridin-phenyl) -2 (1H) -pyridinone.

5 G-22. 3-methylamino-6-n-hexyl-5- (2-pyridinyl) -2 (1H) -pyridinone.

H. 1-R 1-3- (lower amino) -6- (lower alkyl) -5-PY-2 (1H) -pyridinones H-1. 3-acetylamino-6-methyl-5- (4-pyridinyl) -2 (1H) -10 pyridinone, alternative name N- [1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl)] acetamide.

A mixture of 10.1 g of 3-amino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone, 5.7 g of acetic anhydride and 120 ml of pyridine was heated for one hour in a water bath and then allowed to cool. The precipitated product was isolated, washed with ether, dried, recrystallized from dimethylformamide to give 3-acetylamino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone (melting point> 300 ° C).

The acid addition salts of 3-acetylamino-6-methyl-5- (4-pyridinyl) -2 (1H) -20 pyridinone are conveniently prepared by adding to a mixture of 5 g of 3-acetylamino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone in about 100 ml of aqueous methanol, the appropriate acid, such as methanesulfonic acid, concentrated sulfuric acid or concentrated phosphonic acid, to a pH of about 2-3, cooling the mixture after partial evaporation and isolating the precipitated salt, e.g. dimethanesulfonate, sulfate or phosphate, respectively. The acid addition salt may also conveniently be prepared in aqueous solution by stirring with stirring in water a molar equivalent of both 3-acetylamino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone and an appropriate acid such as lactic acid or hydrochloric acid, respectively, mono-lactate or to prepare the monohydrochloride salt as an aqueous solution.

40 7 6 5 6 4 H-2. 3- [2- (acetoxy) propanoylamino] -6-methyl-2 (1H) -pyridinone.

To a stirred mixture of 20.1 g of 3-amino-6-methyl-5- (4-pyridinyl-5-yl) -2 (1H) -pyridinone and 300 ml of pyridine at room temperature was added dropwise over about 1 hour 16.5 g. g of 2-acetoxypropanoyl chloride and the resulting mixture was cooled in an ice bath. The precipitated product was isolated, washed with ether, dried, recrystallized from methanol, washed successively with ethanol and ether, dried to give 3- [2- (acetoxy) propanoylamino] -6-methyl-2 (1H) -pyridinone.

Following the procedure described in Example H1 or H-2, but using instead of 3-amino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone and / or acetic anhydride or 2-acetoxypropanoyl chloride, a molar equivalent amount of 1 -R 1-3-amino-5-PY-6- (lower alkyl) -2 (1H) -pyridinone and / or the appropriate lower alkylating agent can be obtained from Examples H-3 to H-16 3- (lower acylamino) - 5-PY-6- (lower alkyl) -2 (1H) -pyridinones.

20 H-3. 3-acetylamino-6-ethyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

H-4. 6-methyl-3-propionylamino-5- (3-pyridinyl) -2 (1H) -pyridinone.

H-5. 3-Butyrylamino-6-n-propyl-5- (4-pyridinyl) -25 2 (1H) -pyridinone.

H-6. 6-n-butyl-3-acetylamino-5- (4-pyridinyl) -2 (1H) -pyridinone.

H-7. 3-formylamino-6-isobutyl-2-oxo-5- (4-pyridinyl) -2 (H) -pyridinone.

30 H-8. 3-acetylamino-6-n-pentyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

H-9. 3- [2- (acetoxy) propanoylamino) -6-ethyl-5- (2-methyl-4-pyridinyl) -2 (1H) -pyridinone.

41 76564 H-10. 6-ethyl-3-propionylamino-5- (3-pyridinyl) -2 (1H) -pyridinone.

H-II. 3-acetylamino-l, 6-dimethyl-2-oxo-5- (4-pyridin-phenyl) -2 (1H) -pyridinone.

5 H-12. 1,6-diethyl-3-propionylamino-5- (4-pyridinyl) -2 (1H) -pyridinone.

H-13. 3-acetylamino-6-methyl-5- (2-pyridinyl) -2 (1H) -10 pyridinone.

H-14. 6-ethyl-5- (5-ethyl-2-pyridinyl) -3-formylamino-2 (1H) -pyridinone.

H-15. 3-Acetylamino-6-methyl-5- (4,6-dimethyl-2-pyridinyl) -2 (1H) -pyridinone.

15 H-16. 3-Acetylamino-6-n-hexyl-5- (2-pyridinyl) -2 (1H) -pyridinone.

I. 1-R 1 -1,2-Dihydro-6- (lower alkyl) -2-oxo-5-PY-nicotinic acids 1-1. 1,2-Dihydro-6-methyl-2-oxo-5- (4-pyridinyl) -2H-nicotinic acid, alternative name 1,6-dihydro-2-methyl-6-oxo- (3,4'-bipyridine) - 5-carboxylic acid.

30 g of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile were added with stirring to a hot solution of 220 cm of water and 145 cm of concentrated sulfuric acid. The reaction mixture was heated to reflux (about 122 ° C) for seven hours and then allowed to stand at room temperature over the weekend. The mixture was then diluted with water, cooled in an ice bath and treated dropwise and stirred with ammonium hydroxide solution to neutral pH. The crystalline precipitate formed was isolated, rinsed successively with three 100 cm portions of water, several times with acetone and then with ether and dried at 80 ° C. The crystalline material was slurried in 200 cm 3 of chloroform and 200 cm 3 of methanol for 30 minutes and the mixture 3 was concentrated in vacuo to a volume of 150 cm 3. The crystalline 42,76564 product was isolated, dried at 95 ° C over P 2 O 4 to give about 24 g of product. 10 g of the sample product and 200 cm of boiling water were heated, the mixture was cooled, the solid was isolated, dried at 80 ° C to give 9 g of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinic acid, m.p. above 260 ° C.

Following the procedure described in Example 1-1, but using 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) -nicotinonitrile instead of a molar equivalent of the corresponding 1-R 1 -1,2-dihydro -2-Oxo-5-PY-6- (lower alkyl) Nicotinonitrile can be obtained from Examples 1-2 ... 1-20 1-R 1 -1,2-dihydro-2-oxo-5-PY-6 - (lower alkyl) nicotinic acids.

1-2. 6-ethyl-l, 2-dihydro-2-oxo-5- (4-pyridyl) nicotinic acid amide.

15 1-3. 1,2-dihydro-6-methyl-2-oxo-5- (3-pyridinyl) nicotinic acid.

1-4. 1,2-Dihydro-2-oxo-6-n-propyl-5- (4-pyridinyl) -nicotinic acid.

1-5. 1,2-dihydro-2-oxo-6-isopropyl-5- (4-pyridinyl) -20 nicotinic acid.

1-6. 6-n-butyl-l, 2-dihydro-2-oxo-5- (4-pyridyl) nicotinic acid.

1-7. l, 2-dihydro-6-isobutyl-2-oxo-5- (4-pyridyl) nicotinic acid.

25 1-8. 1,2-dihydro-2-oxo-5- (4-pyridinyl) -6-tert-butylnicotinic acid.

1-9. l, 2-dihydro-2-oxo-6-n-pentyl-5- (4-pyridyl) nicotinic acid.

1-10. 6-ethyl-1,2-dihydro-5- (2-methyl-4-pyridinyl) -30 2-nicotinic acid.

1-11. 6-ethyl-l, 2-dihydro-2-oxo-5- (3-pyridinyl) nicotinic acid.

1-12. 1,2-dihydro-1,6-dimethyl-2-oxo-5- (4-pyridinyl) nicotinic acid.

«76564 1-13. l-ethyl-l, 2-dihydro-6-methyl-2-oxo-5- (pyridin-4-carbonyl) nicotinic acid.

1-14. i, 6-diethyl-l, 2-dihydro-2-oxo-5- (4-pyridyl) nicotinic acid.

5 1-15. 1,2-Dihydro-6-methyl-2-oxo-5- (2-pyridinyl) -niconic acid.

1- 16. 1,2-Dihydro-6-methyl-5- (5-methyl-2-pyridinyl) -2-oxonicotinic acid.

I-17,6-ethyl-5- (5-ethyl-2-pyridinyl) -1,2-dihydro-10,2-oxonicotinic acid.

I-18. 1,2-dihydro-6-methyl-5- (4,6-dimethyl-2-pyridinyl) -2-oxonicotinic acid.

I-19. 1/2-Dihydro-6-isopropyl-5- (6-methyl-2-pyridinyl) -2-oxonicotinic acid.

15 1-20. 1,2-Dihydro-6-n-hexyl-2-oxo-5- (2-pyridinyl) -nicotinic acid.

J. Lower Alkyl 1-R 1-6- (Lower Alkyl) -1,2-Dihydro-2-oxo-5-PY-Nicotinates J-1. Ethyl 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl-20-yl) nicotinate.

4 g of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinic acid 3 and 1 g of methanesulfonic acid in 200 can of ethanol were heated under reflux for 18 hours. Excess ethanol was removed by distillation in vacuo, the residue was recrystallized from dimethylformamide to give 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinate as its methanesulfonic acid salt. The salt was dissolved in warm water and the solution was basified with excess aqueous potassium carbonate solution. The precipitated solid was isolated, dried, recrystallized from isopropyl alcohol, dried to give ethyl 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinate.

The acid addition salts of ethyl 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl-44,76564) nicotinate are conveniently prepared by adding to a mixture of 5 g of ethyl 1,2-dihydro-6-methyl- 2-oxo-5- (4-pyridinyl) nicotinate in about 100 ml of aqueous methanol, an appropriate acid such as methanesulfonic acid, concentrated sulfuric acid or concentrated phosphoric acid to a pH of about 2-3, cooling the mixture after partial evaporation and isolating the precipitated salt, e.g. dimethanesulfonate, sulfate or phosphate, respectively. The acid addition salt may also be conveniently prepared in aqueous solution by adding, with stirring, a molar equivalent of both ethyl 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinate and an appropriate acid such as lactic acid or hydrochloric acid to the monolactate or hydrochloric acid, respectively. to prepare the monohydrochloride-15 disalt salt as an aqueous solution.

Following the procedure described in Example J1, but using instead of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) -nicotinic acid and ethanol, a molar equivalent amount of the appropriate 1R, 1,2-dihydro-2- oxo-5-PY-6- (Lower-20β-alkyl) nicotinic acid and a lower alkanol can be obtained from the lower alkyl-1R, 1'-dihydro-2-oxo-5-PY- 6- (lower alkyl) nicotinates.

J-2. Methyl 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinate, melting point 204-206 ° C.

25 J-3. Ethyl 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinate.

J-4. n-propyl 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinate.

J-5. Ethyl 1,2-dihydro-2-oxo-6-n-propyl-5- (4-pyridin-30-yl) -nicotinate.

J-6. Isopropyl-1,2-dihydro-2-oxo-6-isopropyl-5- (4-pyridinyl) nicotinate.

J-7. Ethyl 6-n-butyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinate.

35 J-8. Ethyl 1,2-dihydro-6-isobutyl-2-oxo-5- (4-pyridyl-45,76564) nicotinate.

J-9. Methyl-l, 2-dihydro-2-oxo-5- (4-pyridinyl) -6-tert-butyylinikotinaatti.

J-10. Methyl 1,2-dihydro-2-oxo-6-n-pentyl-5- (4-pyr-5-dinyl) nicotinate.

J-ll. n-butyl-6-ethyl-l, 2-dihydro-5- (2-methyl-4-seeks-pyridinyl) -2-oksonikotinaatti.

J-12. Ethyl 6-ethyl-l, 2-dihydro-2-oxo-5- (3-pyridinyl-yl) nicotinate.

10 J-13. Ethyl 1,2-dihydro-1,6-dimethyl-2-oxo-5- (4-pyridinyl) nicotinate.

J-14. Ethyl 1,6-diethyl-1,2-dihydro-2-oxo-5- (4-pyridin-15-yl) nicotinate.

J-15. n-hexyl-l, 2-dihydro-6-methyl-2-oxo-5- (2-Pyridin-pyridinyl) nicotinate.

J-16. Methyl 6-ethyl-5- (5-ethyl-2-pyridinyl) -1,2-di-hydro-2-oksonikotinaatti.

20 J-17. Ethyl 1,2-dihydro-6-methyl-5- (4,6-dimethyl-2-pyridinyl) -2-oxonicotinate.

J-18. Ethyl-1,2-dihydro-6-n-hexyl-2-oxo-5- (pyridin-2-carbonyl) nicotinate.

The utility of the compounds of formula I or their salts as cardiac drugs can be demonstrated by the potency achieved in standard pharmacological test methods. Examples of this are a significant increase in contractile force in a method using a cat isolated from the heart and buttocks, and a significant increase in cardiac contractile force in a method using anesthetized dogs. In this case, the changes in heart rate and blood pressure are small or minimal. These test methods are described in detail in U.S. Patent 4,072,746.

46 7 6 5 6 4

When tested according to the above-mentioned method, which method uses isolated cat heart and nodule muscle from the cat, the compounds of formula I used in an amount of 3, 10 or 30 μg / ml were found to significantly improve, i. more than 25%, strength of the sphincter and significantly improves, i.e. more than 25%, right cardiovascular strength. At the same time, the heart rate of the right heart was increased only slightly as a percentage (about one-third or less of the percentage increase in the right force of the right heart or nodule muscle). Furthermore, it was surprisingly found that when tested according to this method, the 6- (lower alkyl) compounds of the formula I were clearly more active as cardiac drugs than the corresponding 6-des- (lower alkyl) compounds in the prior art.

The following Table I shows the results of comparative experiments performed by said method for measuring the isolated myocardial and nodular muscle strength of a cat. The results show a significantly higher cardiotonic potency of the 6- (lower alkyl) compounds compared to the corresponding 6-unsubstituted compounds in the prior art.

47 7 6 5 6 4 β ro

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The compounds known according to the invention in which Q1 of the formula I Q is carbamyl, halogen or carboxyl, the known compounds which are unsubstituted in the 6-position, have been reported in the prior art only as intermediates for which no cardioprotective effect has been mentioned.

When tested according to the above method using anesthetized dogs, the compounds of formula I, when injected intravenously as a single vial injection at doses of 0.01, 0.03, 0.10, 0.30, 1.0 or 3.0 mg / kg, caused sy-10 significant increase in the contractile force or contraction of the heart, i.e. more than 25%, with little or no change in heart rate and blood pressure (less than 25%). In addition, it was found that the 6- (lower alkyl) compounds of the formula I were clearly more active as cardiac drugs than the corresponding 6-des- (lower alkyl) compounds in the prior art, as shown in the following table]:

Table Έ

Experiments in anesthetized dogs

Test compound Dose Increase in cardiac contractile force 20 mg / kg,% 3-amino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone 1.0 136 3-amino-6-ethyl-5 - (4-pyridinyl) -2 (1H) -pyridinone 0.03 33 25 0.10 72 1,2-Dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile 0.03 49 .5 0.10 87.5 30 1,2-Dihydro-6-ethyl-2-oxo-5- (4-pyridinyl) nicotinonitrile 0.03 68.5 0.10 135 amrinone 0.3 24.67 -3.15 35 1.0 70.63 - 7.85 10.0 125.67 - 10.59 1.2-Dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile (known) 3,444 10 78 50 7 6 5 6 4

In clinical use, a compound of formula I or a salt thereof is usually administered orally or parenterally in various dosage forms.

5 Solid compositions for oral administration include compressed tablets, pills, powders, and granules. In such solid compositions, at least one of the active compounds is admixed with at least one diluent such as starch, calcium carbonate, sucrose or lactose. In addition to ineffective diluents, these compositions may also contain other substances, such as lubricants, e.g., magnesium stearate, talc, and the like.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing conventional ineffective diluents such as water and liquid paraffin. In addition to ineffective diluents, such compositions may also contain adjuvants, such as wetting and suspending agents, and sweetening and flavoring agents, perfuming, and preservative agents. The compounds for oral administration may also be in capsules made of an absorbent material, such as gelatin, containing said active ingredient with or without diluents or excipients.

Compositions for parenteral administration include, for example, sterile aqueous, aqueous-organic and organic solutions, suspensions and emulsions.

Examples of organic solvents or suspending agents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. These compositions may also contain adjuvants such as stabilizers, preservatives, wetting agents, emulsifying agents and dispersing agents.

si 7 6 5 6 4

They can be sterilized, e.g., by filtration through a bacteria-retaining filter, by the addition of sterilizing agents to the compositions, by irradiation, or by heating. They may also be prepared as sterile solid compositions which can be dissolved in sterile water or other sterile injectable medium immediately before use.

The percentages of active compounds in said composition and the method for improving cardiac contractility may be varied to achieve a suitable dosage. The dose to be administered to a particular patient may vary depending on the following criteria used by the physician: route of administration, duration of treatment, size and state of health of the patient, efficacy of the active ingredient, and patient response. Thus, only a physician who considers all of the criteria and the overall benefit to the patient can determine the effective dosage amount of the active compound.

Claims (3)

A process for the preparation of a therapeutically useful 2 (1H) -pyridinone of the formula "wherein R is wherein Q is hydrogen, amino, cyano, carbamyl, halogen, lower alkylamino, di (lower alkyl) amino, alkanoylamino or acetoxy-substituted alkanoylamino, carboxy or lower alkoxycarbonyl, R 2 is hydrogen or lower alkyl R is lower alkyl and PY is 4-, 3- or 2-pyridinyl or 4-, 3- or 2-pyridinyl with one or two lower alkyl substituents , or an acid addition or cationic site thereof, characterized in that a) a compound of the formula R 3 R 4 NCH = CC (= O) -R III pY where R 1 and R 2 are each lower alkyl is reacted with malonamide or b) a compound of formula III as defined above is reacted with NR 2 -Ot-cyanoacetamide to a compound of formula I, where Q is cyano, and if desirably, a obtained compound of formula I wherein Q is cyano, partially hydrolyzed to the corresponding compound, wherein Q is carbamyl; and, if desired, a compound of formula I obtained by process a) or b) is converted to another compound of formula I by performing one or more of the following steps: i) a compound of formula I, where Q is carbamyl, reacted with a reactant capable of converting carbamyl to amino, to obtain the corresponding compound, where Q is amino; ii) a compound of formula I, wherein Q is amino, is reacted with one or two molecular weights of a lower alkylating agent to the corresponding compound, wherein Q is correspondingly lower alkylamino or di (lower alkyl) amino; iii) compound of formula I, wherein Q is amino, is reacted with a lower acylating agent to the corresponding compound, wherein Q is lower acylamino; iv) a compound of formula I wherein Q is cyano, hydrolyzed to the corresponding compound, wherein Q is carboxy; v) a compound of formula I wherein Q is cyano or carboxy is heated together with an aqueous solution of a mineral acid to the corresponding compound, wherein Q is hydrogen; Vi) a compound of formula I wherein Q is carboxy, esterified with a lower alkanol compound to the corresponding compound, wherein Q is lower alkoxycarbonyl; vii) a compound of formula I wherein Q is hydrogen is reacted with halogen to the corresponding compound, wherein Q is halogen; viii) a compound of formula I wherein Q is halogen is reacted with lower alkylamine or di- (lower alkyl) amine to the corresponding compound, wherein Q is correspondingly lower alkylamino or di (lower alkyl) amino; and ix) a poured free base is converted to an acid addition salt thereof, or a poured compound is converted to a cationic site thereof. 2. A process according to claim 1, characterized in that starting compounds are selected wherein R is methyl or ethyl and PY is 4-pyridinyl.