FI65061B - 2 (1H) -PYRIDINONDERIVAT ANVAENDBARA SAOSOM MELLANPRODUKTER VID FRAMSTAELLNING AV THERAPEUTISKT ACTIVE PYRIDINDERIVAT OCH FOERFARANDE FOER FRAMSTAELLNING AV DESAMMA - Google Patents

Description

1 65061

2 (1H) -pyridinone derivatives useful as intermediates in the preparation of therapeutically active pyridine derivatives and process for their preparation 5 Separated from application 762919.

The invention relates to 2 (1H) -pyridinone derivatives of the formula 10

! 1 1 (U

R

Wherein PY is a 4- or 3- or 2-pyridinyl group which may be substituted by one or two lower alkyl, R is hydrogen, lower alkyl or lower hydroxyalkyl and Q is nitro, carbamyl or halogen, and their acid addition salts.

The 2 (1H) -pyridinone derivatives of the formula I and their acid addition salts are useful as intermediates in the preparation of the pyridine derivatives of the formula 25 PY'-v ^ W'0 'I I (I1') described in FI patent application 762 919.

R

Wherein PY and R are as defined above and Q 'is amino, lower alkylamino or di (lower alkyl) amino, and pharmaceutically acceptable acid addition salts thereof.

The invention also relates to a process for the preparation of 2 (1H) -pyridinone derivatives of the formula 35 2 65061 PV γ * γ ί [^ (Ia)

Sr ° 5 where PY means the same as above. The process is characterized in that the compound of formula

.CHO

PY-C ^ (III) '^ chnr1r2 10 wherein PY is as defined above and R1 and R2 are lower alkyl is reacted with malonamide of the formula CH2 (CONH2) 2 · GB 1 332 318 describes intermediates 1 , 2-dihydro-2-oxo-6- (4- or 3-pyridinyl) -nicotin-15-nonitrile, 6- (4- or 3-pyridinyl) -2 (1H) -pyridinone and 6- (4- or 3-pyridinyl) pyridinyl) -2-pyridinamine. U.S. Patent No. 3,838,156 describes as intermediates 1,2-dihydro-2-oxo-6-Q '"- nicotinic acids, wherein Q"' is 4 (or 3) -pyridinyl which may be substituted with one or more with two lower alkyls. JP 20 295/67 discloses that 1- (x'-amino-2'-pyridinyl) -2-pyridinones have analgesic and anti-inflammatory activity. Particular mention is made of 1- (5'-amino-2'-pyridinyl) -2-pyridinone. Compounds of formula I wherein Q is nitro or carbamyl may be used as intermediates in the preparation of compounds of formula II wherein Q is amino and compounds of formula I wherein Q is halogen are useful as intermediates in the preparation of compounds of formula II wherein Q is lower alkylamino or di-30 (lower alkyl) amino.

The preparation of the intermediates of the invention and their use in the preparation of compounds of formula II is described below with reference to the reaction scheme below.

3,65061

The 2 (1H) -pyridinone derivative of formula Ia is prepared according to the invention by reacting <* - ΡΥ- β- (R 1 -N-) -acrolein (III), in which and preferably methyl or ethyl, with malonamide. By reacting 1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia) according to the invention with a reagent which converts carbamyl to amino, 3-amino-5-PY-2 (1H) -pyridinone is obtained. (II).

The intermediates of the invention can also be prepared by reacting either α-ργ-β- (r1r2n) -acrolein (III) or PY-malonaldehyde (III ') with α-cyanoacetamide to give 1,2-dihydro-2-oxo -5-PY-nicotinonitrile (IV) subjected to partial hydrolysis to give 1,2-dihydro-2-oxo-5-PY-nicotinamide 15 (Ia).

The intermediates according to the invention are also obtained by first heating 1,2-dihydro-2-oxo-5-PY-nicotinic acid (V) with a mixture of concentrated sulfuric acid and concentrated nitric acid. Reduction of the resulting 3-nitro-5-PY-2 (1H) -20 pyridinone (Ie) of the invention gives the 3-amino-5-PY-2- (1H) pyridinone of formula II wherein R is hydrogen, or by placing 3- Nitro-5-PY-2 (1H) -pyridinone (Ie) is reacted with an alkylating agent of formula R'-An to give 1-R'-3-nitro-5-PY-2 (1H) -pyridinone of the invention (Id ), which can be reduced to 1-R'-3-amino-5-PY-2- (1H) -pyridinone of formula II, wherein R 'is lower alkyl or lower hydroxyalkyl and An is a strong inorganic acid or organic sulfonic acid. anion. Alternatively, the alkylation step may be performed on any compound of formula I, IV or V wherein R is hydrogen to give a compound wherein R is R '.

The methods described above are described in the following reaction scheme, which also shows the conversion of 1,2-dihydro-2-oxo-5-PY-nicotinonitrile IV to 1,2-dihydro-2-oxo-35 5-PY-nicotinic acid (V) by hydrolysis with sulfuric acid. with aqueous solution: 4 6 50 61

sCWO / CHO

PY-CH PY-C

xCl10 n ^ CHNRiR2 7 '/ t NC-CH2CONH2 NC-CH2aDNH2 CH2 (CONH2) 2 PY PY ^ Xc ° Nh2

jj I Cone. H2SO4 J

| v R, -An y! i

h N X R

IV IV la

aq. H2SC> 4 R = R 'Br2 + OH

pYN ^^ / ^^ <: 00H PY * 7 ^^ nh2 o ^ XlK ^ ^ 0

I I

R R

v 11 / / \ h2 / Conc. 50250 ^ / H 2 Conc. HN03 / V / ΡΥ \ </ ^ ν \ / 'Ν ° 2 / ργχ ^ Ν02

I ", R = H

XtK ^^^ O R'-An ^ Xi4- ^ ^ - 0

I I

R R '

Ic Id 5 65061

A compound of formula I wherein Q is nitro (Ie) may also be prepared by refluxing 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (IV) with aqueous sulfuric acid to give 1,2-dihydro -5 2-Oxo-5-PY-nicotinic acid (V), which is then refluxed in solution (without isolation) to give compound VI by heating a compound of formula VI with a mixture of concentrated sulfuric acid and concentrated nitric acid to give compound Ie.

In a further process for the preparation of compounds of formula I wherein Q is halogen (If), 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (IV) or 1,2-dihydro- 2-oxo-5-PY-nicotinic acid (V) with an aqueous solution of an inorganic acid, preferably an aqueous solution of sulfuric acid, to give 5-PY-2 (1H) -pyridinone (VI) upon hydrolysis of compound IV or decarboxylation of compound V, and then compound VI is reacted with halogen, preferably bromine or chlorine.

This method is described in the following reaction scheme: py ^ ^ w ^ cooh PY ^ / ^ j water. H2SQ4 ^ ^

25 | R

R

VI

V

30 ^

35 A

If 6 65061

The term "lower alkyl" as used herein means alkyl radicals having from 1 to 6 carbon atoms and which may be either straight chain or branched, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl sec-butyl, 5 tert. -butyl, isobutyl, n-amyl and n-hexyl.

The term "lower hydroxyalkyl" means hydroxyalkyl radicals having from 2 to 6 carbon atoms and having a hydroxyl group and a free valence bond (i.e., a linking bond) at different carbon atoms, e.g., 2-hydroxyethyl, 2-hydroxy-10-propyl, 3-hydroxypropyl, 2-hydroxy-2-methylpropyl, 2-hydroxy-1,1-dimethylethyl, 4-hydroxybutyl, 5-hydroxyamyl and 6-hydroxyhexyl.

Examples of 4-, 3- and 2-pyridinyl groups substituted by one or two lower alkyls are 2-methyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl, 3-methyl-4-pyridinyl, 2-methyl -3-pyridinyl, 6-methyl-3-pyridinyl (alternatively called 2-methyl-5-pyridinyl), 4-methyl-2-pyridinyl, 6-methyl-2-pyridinyl, 2,3-dimethyl- 4-pyridinyl, 2,6-dimethyl-4-pyridin-20-yl, 4,6-dimethyl-2-pyridinyl, 2-ethyl-4-pyridinyl, 2-isopropyl-4-pyridinyl, 2-n-butyl -4-pyridinyl, 2-n-hexyl-4-pyridinyl, 2,6-diethyl-4-pyridinyl, 2,6-diethyl-3-pyridinyl, 2,6-diisopropyl-4-pyridinyl and 2,6-di-n-hexyl-4-pyridinyl.

The molecular structures of the compounds of formula I were confirmed by infrared, ultraviolet, nuclear magnetic resonance and mass spectra, as well as by chromatographic and comparative values obtained by calculation and elemental analysis. The preparation of the compounds of the invention is generally described below:

The process according to the invention for the preparation of 1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia) by reacting β-PY - [(R 1 R 1 N) acrolein (II) with malonamide 7 65061 is preferably carried out by stirring the reactants. substances in a mutually compatible solvent in the presence of a basic condensing agent. The reaction is preferably carried out using a lower alkanol, preferably methanol or ethanol, as the solvent, and an alkaline lower alkoxide, preferably sodium methoxide or sodium ethoxide, as the basic condensing agent. In practice, the reaction is preferably carried out under reflux with cooling in methanol using sodium methoxide. Other basic condensing agents include, for example, sodium hydride, lithium diethylamide and lithium diisopropylamide in an aprotic solvent such as, for example, tetrahydrofuran, acetonitrile in ether, benzene or dioxane.

The ot-ργ- β- (R 1, R 2 N) acroleins (III) used as starting materials are generally known and can be prepared by conventional methods. Compound III can be prepared, e.g., by reacting t * -PY-acetic acid with a reaction product obtained by reacting dimethylformamide with a phosphorus oxyhalide, preferably oxychloride or oxybromide. The reaction between dimethylformamide and phosphorus oxyhalide 20 is preferably carried out below 10 ° C, and when the reaction product thus obtained is heated with -PY-acetic acid at about 50-80 ° C, compound III is obtained. The β-PY acetic acids used are generally known compounds which can be prepared by conventional methods; they can be readily prepared, e.g., by heating the corresponding acetylpyridine of the formula PY-COCH 2 with sulfur and morpholine to give the corresponding PY-thioacetomorpholineamine, which is refluxed with 12 N hydrochloric acid to give PY-acetic acid. For example, 30- (3-ethyl-4-pyridinyl) acetic acid is prepared from 4-acetyl-3-ethylpyridine via 3-ethyl-4-pyridinylthioacetomorpholinamide. et al., Indian Journal of Chemistry 10 (1972) 4557. Acetylpyridines, i. PY-COCH 2, are also generally known compounds which can be prepared by conventional methods, e.g. from the corresponding 8,65061 cyanopyridines, i. PY-CN, Reilly Tar & Chem. Corp., GB Patent Publication No. 920 303; Case et al., J. Am. Chem. Soc. 78 (1956) 5842.7 ·

In another method, α-PY-β- (R 2 R 2 N) -acrolein (III) 5 is reacted with c * -cyanoacetamide to give 1,2-dihydro-2-oxo-5-PY-nicotinitrile (IV). The reaction is preferably carried out by stirring the reactants in a suitable solvent in the presence of a basic condensing agent. It is preferred to use a lower alkano-10, preferably methanol or ethanol, as the solvent, and an alkaline lower alkoxide, preferably sodium methoxide or sodium ethoxide, respectively, as the basic condensing agent. In practice, the reaction is preferably carried out in refluxing methanol using sodium methoxide. Other basic condensing agents include, for example, sodium hydride, lithium diethylamide and lithium diisopropylamide in an aprotic solvent such as tetrahydrofuran, acetonitrile, ether, benzene or dioxane.

The reaction of α-PY-malonaldehyde (lii ') with o-cyanoacetamide to give 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (IV) is carried out by heating the reactants with a catalytic condensing agent, preferably morpholine or piperidine and / or with these acetate. The reaction is preferably carried out under reflux in the presence of a benzene-25 solution containing the reactants in the presence of morpholine, piperidine, morpholine acetate, piperidine acetate or a mixture thereof, and it is preferable to connect a water separator to the reaction vessel to collect the water formed in the reaction.

Partial hydrolysis of 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (IV) to form 1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia) is performed by heating compound IV with concentrated sulfuric acid. Although the reaction is most conveniently and most preferably carried out in a steam bath, the reaction may be carried out at a temperature of about 25 to 135 ° C. Alternatively, conversion of Compound Ia to Compound Ia can be accomplished by heating Compound IV with polyphosphoric acid for about 1-5 hours at about 100-175 ° C.

Hydrolysis of 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (IV) to give 1,2-dihydro-2-oxo-5-PY-nicotinic acid (V) is preferably carried out by heating compound IV in a steam bath with an aqueous solution of inorganic acid, preferably With 50% sulfuric acid.

The conversion of 1,2-dihydro-2-oxo-5-PY-nicotinic acid (V) to 3-nitro-5-PY-2 (1H) -pyridino (Ie) is carried out by heating compound V with a mixture of concentrated sulfuric acid and concentrated nitric acid. The reactants are heated to about 60-100 ° C, preferably about 70-90 ° C. Although it could be assumed that nicotinic acid (V) is first decarboxylated to give the corresponding 3-unsubstituted-5-PY-2 (1H) -pyridinone, which is then nitrated at its 3-position, it should be noted that, as indicated above, the corresponding nicotinone heating the tril (IV) with concentrated sulfuric acid alone results in partial hydrolysis to give the corresponding nicotinamide (Ia).

Alternatively, 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (IV) can be easily gradually converted to 3-nitro-5-PY-2 (1H) -pyridinone (Ie) by first heating IV with sulfuric acid. in aqueous solution for longer (supra) than is required for the formation of 1,2-dihydro-2-oxo-5-PY-nicotinic acid (V), whereupon compound V is first formed, which is then decarboxylated as heating is continued to give 1,2-dihydro-2 -oxo-5-PY-pyridine, which is then nitrated under the conditions described above to convert compound V to compound Ie, i.e. 1,2-dihydro-2-oxo-5-PY-pyridine is heated with a mixture of concentrated sulfuric acid and concentrated nitric acid, whereby 3-nitro-5-PY-2 (1H) -pyridinone (le) is obtained.

The reaction of 3-nitro-5-PY-2 (1H) -pyridinone (Ie) with a lower alkylating agent to give 1-R'-3-nitro-5-PY-2 (1H) -pyridinone (Id) is generally carried out as follows: reacting Compound Ie with a lower alkyl or lower hydroxyalkyl ester of a strong inorganic acid or organic sulfonic acid, said ester having the formula R'-An, wherein An is an anion of a strong inorganic acid or organic sulfonic acid such as chloride, bromide, iodide , sulfate, methanesulfonate, benzenesulfonate, or para-toluenesulfonate (i.e., tosylate), and R 'is lower alkyl or lower hydroxyalkyl. This alkylation is preferably performed using a small excess of alkylating agent, although equimolar amounts also give satisfactory results. Chloride, bromide, iodide or tosylate are preferred because the required lower alkyl halides and tosylates are readily available, and the reaction is preferably carried out in the presence of an acid scavenger. The acid scavenger is a basic substance and preferably one which forms easily water-soluble by-products which can be easily separated from the reaction product, e.g. sodium hydroxide, sodium carbonate, potassium carbonate, sodium alkoxides, potassium oxides and sodium amide. Acid scavengers are bound by hydrogen halide or tosylate (i.e., HAn), which is formed during the reaction. The reaction is preferably carried out in a suitable reaction-inert solvent, e.g. lower alkanol, acetone, dioxane, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide or a solvent mixture such as a mixture of water and lower alkanol. The reaction is generally carried out at a temperature between room temperature (about 20-25 ° C) and 150 ° C, preferably by heating in a steam bath in a mixture of dimethylformamide and anhydrous potassium carbonate.

Reaction of 5-PY-2 (1H) -pyridinone (VI) with halogen to give 3-halo-5-PY-2 (1H) -pyridinone (If) is preferably carried out by stirring the reactants in a suitable solvent inert to the reaction, preferably acetic acid. you. The reaction is suitably carried out at room temperature or at most 100 ° C. Preferred halogens are bromine and chlorine. Any inert solvent can be used, e.g. dimethylformamide, chloroform or ethanol.

11 65061

The invention is illustrated by the following examples.

A. 1,2-Dihydro-2-oxo-5- (pyridinyl) nicotinonitriles A-1. 1,2-Dihydro-2-oxo-5- (4-pyridinyl) nico-tinonitrile 5 Reaction mixture of 35 g of - (4-pyridinyl) - [3-dimethylaminoacrolein, 21.6 g of sodium methoxide, 500 ml of methanol and 17 go (cyanoacetamide), heated to reflux with stirring, initiating an exothermic reaction sufficient to boil 10 reaction mixtures without an externally introduced valve. and the precipitate was collected, washed with ethyl ether and dried, and the solid product was recrystallized from methanol and dried in vacuo at 80 ° C to give 13 g of 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile from sodium hydroxide. as the salt, mp> 300 DEG C. When the mother liquor was further concentrated, 10 g, 6.5 and 3 g of product were obtained in fractions, i.e. a total of 32.5 g of said sodium salt, which could be by treatment as in Example A-2, is converted to the corresponding N-H compound, i.e., 1,2-dihydro-2-oxo-5- (4-pyridinyl) -nicotinonitrile.

Alternatively, 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile can be prepared as follows:

A mixture of 15 g of (4-pyridinyl) malonaldehyde, 9.3 g of C ((cyanoacetamide), 11 g of morpholine, 13 g of acetic acid and 11 of benzene was refluxed for about 24 hours with a water separator and then allowed to stand for 30 weeks. After the separated solid was separated, recrystallized from dimethylformamide and dried in vacuo at 90 ° C for about 15 hours to give 5 g of 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile, mp> 300 ° C. .

A-2. 1,2-Dihydro-2-oxo-5- (3-pyridinyl) nicotinonitrile

A mixture of 93 g of θ <- (3-pyridinyl) -β-dimethylaminoacrolein, 54 g of cyanoacetamide, 65 g of sodium methoxide and 900 ml of methanol was stirred for 2 hours at reflux temperature and then allowed to stand overnight at room temperature. The resulting semi-solid cake was cooled, the solid was collected, washed first with isopropyl alcohol and then with ethyl ether and dried, the solid (sodium salt) was dissolved in water, the aqueous solution was neutralized with 6 N hydrochloric acid and cooled, and the separated solid was collected first and then with ether and dried in vacuo at 80 ° C, 1 ° gave 41 g of 1,2-dihydro-2-oxo-5- (3-pyridinyl) nicotinonitrile, mp> 300 ° C.

The intermediate O - (3-pyridinyl) -α-dimethylaminoacrolein used above was prepared as follows: To 740 ml of dimethylformamide kept below 15 ° C was added dropwise with stirring 294 g of phosphorus oxychloride and stirring was continued for another 15 minutes, and then 88 g of - (3-pyridinyl) acetic acid were added and the mixture thus obtained was stirred at room temperature for 1 hour and then stirred at 70 DEG C. for 2 hours and cooled, then all volatiles were removed from the reaction mixture by evaporation in vacuo and the residue was added slowly. to a mixture of 1.24 liters of saturated sodium carbonate solution and 500 ml of benzene while cooling, the mixture was allowed to stand overnight and then extracted with four portions of a 50/50 by volume mixture of benzene-ethanol. When the combined extracts were dried over anhydrous potassium carbonate and the solvent was evaporated , containing 136 g of - (3-pyridinyl) -6-dimethylacrolein dark oily substance.

30 A-3. 1,2-Dihydro-2-oxo-5- (2-pyridinyl) nicotinonitrile

A mixture of 51 g of <- (2-pyridinyl) - [3-dimethylaminoacrolein, 24 g of cyanoacetamide, 31 g of sodium methoxide and 500 ml of methanol was stirred for 4 hours at reflux temperature and then allowed to stand overnight. at room temperature. The mixture was filtered and the filtrate was removed by evaporation in vacuo.

. I. ) 13 65061 The residue was diluted with water and the residue was neutralized with 6 N hydrochloric acid. After the separated solid was collected, washed successively with water, ethanol and ether and dried in vacuo at 80 ° C to give 18 g of 1,2-dihydro-2-oxo-5- (2-pyridinyl) nicotinonitrile.

The intermediate oi- (2-pyridinyl) -β-dimethylaminoacrolein used above was prepared as described in Example A-2 using 50 g of oi- (2-pyridinyl) -acetic acid hydrochloride, 336 ml of dimethylformamide and 1080 ml of phosphorus oxychloride.

Following the procedure of Example A-2 but using a molar equivalent amount of the corresponding β-PY- [3-dimethylaminoacrolein in place of c 1- (3-pyridinyl) -O-dimethylaminoacrolein, the 1,2-dihydro- 2-oxo-5-PY-nicotinonitrile. The cK-PY- / 3-dimethylaminoacrolines used as intermediates in Examples A-4 to A-7 were prepared by the method described in the second paragraph of Example A-2 to prepare (3-pyridinyl) - / 3-dimethylaminoacrolein, but tac * - (3-pyridinyl). ) -acetic acid-20 acid was replaced by a molar equivalent of 0 (-PY-acetic acid).

A-4. 1,2-Dihydro-2-oxo-5- (2-methyl-3-pyridinyl) nicotinonitrile

The title compound was prepared using N- (2-methyl-3-pyridinyl) -β-dimethylaminoacrolein prepared from O- (2-methyl-3-pyridinyl) acetic acid.

A-5. 1,2-Dihydro-2-oxo-5- (5-methyl-3-pyridinyl) nicotinonitrile

The title compound was prepared using N- (5-methyl-3-pyridinyl) -Nb-dimethylaminoacrolein prepared from 1- (5-methyl-3-pyridinyl) acetic acid.

A-6. 1,2-Dihydro-2-oxo-5- (3-ethyl-4-pyridinyl) nicotinonitrile

The title compound was prepared using 1- (3-ethyl-3,4-pyridinyl) -fa-dimethylaminoacrolein prepared from 1- (3-ethyl-4-pyridinyl) acetic acid.

65061 14 Τ'-l. 1,2-Dihydro-2-oxo-5- (4,6-dimethyl-2-pyridinyl) nicotinonitrile

The title compound was prepared using (4,6-dimethyl-2-pyridinyl) -β-dimethylaminoacrolein prepared from o (-4,6-dimethyl-2-pyridinyl) acetic acid.

F. 1,2-Dihydro-2-oxo-5- (pyridinyl) nicotinic acids 3-1. 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinic acid

A mixture of 227 g of 1,2-dihydro-2-oxo-5- (4-pyr-10-ylidinyl) -nicotinonitrile and 2.6 liters of a 50% aqueous solution of sulfuric acid was refluxed for 5 hours and then allowed to stand at room temperature overnight. over (about 15 hours). The reaction mixture was then poured into 1 liter of water and cooled. The precipitate was collected, washed successively with water, ethanol and ether and dried overnight in vacuo at 80 ° C to give 206 g of crude product as a pink solid. A 40 g portion of the crude product was mixed with water and the mixture was neutralized by adding potassium carbonate. When the solid was collected, washed successively with water, methanol and ether, recrystallized from dimethylformamide and washed successively with methanol and ether and dried in vacuo at 80 ° C to give 27 g of 1,2-dihydro-2-oxo-5- (4 -pyridinyl) nicotinic acid as a white solid, mp> -300 ° C.

B-2. 1,2-Dihydro-2-oxo-5- (3-pyridinyl) nicotinic acid 2 5

A mixture of 41 α of 1,2-dihydro-2-oxo-5- (3-pyridinyl) nicotinonitrile and 410 ml of a 50% aqueous solution of sulfuric acid was poured into 1.5 kg of a mixture of ice and water. The acidic mixture was neutralized with 35% aqueous sodium hydroxide solution, and the mixture was cooled. When the separated solid was collected, washed with water and dried in vacuo at 80 ° C, 47 g of 1,2-dihydro-2-oxo-5- (3-pyridinyl) nicotinic hippo were obtained, which was used immediately without purification in the next step, which is described later in Example C-2.

15 65061 B-3. 1,2-dihydro-2-oxo-5- (2-pyridinyl) nicotinic acid

Following the procedure of Example B-2, but using 18 g of 1,2-dihydro-2-oxo-5- (2-pyridinyl) nicotinonitrile, 180 ml of a 50% aqueous solution of sulfuric acid and a refluxing time of 4 hours, 14 g of the title compound were obtained. product.

Following the procedure of Example B-2, but using a molar equivalent amount of 1,2-dihydro-2-oxo-5-PY-nicotinonitrile instead of 1,2-dihydro-2-oxo-5- (3-pyridinyl) -nicotinonitrile, the corresponding B-4-10 B-7 1,2-dihydro-2-oxo-5-PY-nicotinic acid.

B-4. 1,2-Dihydro-2-oxo-5- (2-methyl-3-pyridinyl) nicotinic acid

The title compound was prepared using 1,2-dihydro-2-oxo-5- (2-methyl-3-pyridinyl) -nicotinonitrile.

15 B-5. 1,2-Dihydro-2-oxo-5- (5-methyl-3-pyridinyl) nicotinic acid

The title compound was prepared using 1,2-dihydro-2-oxo-5- (5-methyl-3-pyridinyl) -nicotinonitrile.

B-6. 1,2-Dihydro-2-oxo-5- (3-ethyl-4-pyridinyl) n-nicotinic acid

The title compound was prepared using 1,2-dihydro-2-oxo-5- (3-ethyl-4-pyridinyl) nicotinonitrile.

B-7. 1,2-Dihydro-2-oxo-5- (4,6-dimethyl-2-pyridinyl) -nicotinic acid The title compound was prepared using 1,2-dihydro-2-oxo-5- (4,6-dimethyl-2 pyridinyl) -nicotinonitrile.

C. 3-Nitro-5- (pyridinyl) -2 (1H) -pyridinones C-1. 3-nitro-5- (4-pyridinyl) -2 (1H) -pyridinone

To a stirred solution maintained at 5-10 ° C and containing 154 g of 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinic acid in 450 ml of concentrated sulfuric acid was added dropwise a solution. with 45 ml of concentrated sulfuric acid and 160 ml of 90% nitric acid. The reaction mixture was gently stirred at 80 ° C for 3 hours and then poured into 3.3 liters of a mixture of ice and water. The mixture was filtered and the precipitate was mailed with water. The combined filtrates were slowly added to 1 liter of a 10% aqueous solution of potassium carbonate 16 65061 with stirring. The solution was neutralized by the addition of potassium carbonate and then basified by the addition of 5% aqueous sodium carbonate solution. When the precipitated product was collected, washed successively with a small amount of cold water, isopropyl alcohol and ether and dried in vacuo at 80 ° n, 89 g of product were obtained. A 30 g portion of the product was recrystallized from dimethylformamide to give 20 g of 3-nitro-5- (4-pyridinyl) -2 (1H) -pyridinone, m.p. > 300 ° No.

Alternatively, 3-nitro-5- (4-pyridinyl) -2 (1H) -pyridinone was gradually prepared starting from 1,2-dihydro-2-oxo-5- (4-pyridinyl) -nicotinonitrile as follows:

A mixture of 197 g of 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile, 600 ml of concentrated sulfuric acid and 150 liters of water was refluxed for 24 hours, cooled and poured into 10 liters of a mixture of ice and water. When the mixture was neutralized with ammonium hydroxide and the separated precipitate was collected, washed with a small amount of water and dried in vacuo at 80 ° r to give 148 g of 5- (4-pyridinyl) -2 (1H) -20 pyridinone, m.p. 258-260 ° C. 80 g of 5- (4-pyridinyl) -2 (1H) -pyridinone were added 288 of any concentrated sulfuric acid and the mixture was heated to 70 ° C. To this stirred solution maintained at 70-30 ° C was added dropwise a mixture of 102 ml of 90% nitric acid and 29 ml of concentrated sulfuric acid.

After the addition of the folder mixture, the reaction mixture was heated at about 80 ° C for 3 hours. The reaction mixture was then cooled and poured into a mixture of ice and water with stirring. The precipitate was collected and dried. The precipitate was suspended in water and neutralized with 10% aqueous potassium bicarbonate solution.

After the precipitate was collected, washed with water and dried in vacuo at 80 ° r, 56 g of 3-nitro-5- (4-pyridinyl) -2 (H) -pyridinone were obtained.

Following the procedure described in the previous paragraph but starting from a molar equivalent of the corresponding 1,2-dihydro-2-oxo-5-T, Y-nicotinonitrile 1,2-dihydro-2-oxo-5- (4-pyridinyl) —Instead of nicotinonitrile, the following 5-PY-2 (1H) -pyridinones are first obtained: 17 65061 5- (3-pyridinyl) -2 (1H) -pyridinone, 5- (2-pyridinyl) -2 (1H) -pyridinone, 5 - (2-methyl-3-pyridinyl) -2 (1H) -pyridinone, 5- (5-methyl-3-pyridinyl) -2 (1H) -pyridinone, 5- (3-ethyl-4-pyridinyl) -2 (1H) -pyridinone and 5- (4,6-dimethyl-2-pyridinyl) -2 (1H) -pyridinone. In the next step, i.e., in which 5-PY-2 (1H) -pyridinone was treated with concentrated sulfuric acid and concentrated nitric acid, the corresponding 3-nitro compounds were obtained.

‘02. 3-nitro-5- (3-pyridinyl) -2 (1H) -pyridinone.

The title compound was prepared following the procedure for Example C1 using 25 g of 1,2-dihydro-2-oxo-5- (3-pyridinyl) -nicotinic acid, 76.4 ml of concentrated sulfuric acid, 26.6 ml of 90% nitric acid and 7, 6 ml of concentrated sulfuric acid. Yield 14 g, m.p. 300 ° C.

C-3. 3-nitro-5- (2-pyridinyl) -2 (1H) -pyridinone.

The title compound was prepared according to the procedure in Example 0-1 using 14 g of 1,2-dihydro-2-oxo-5- (2-pyridinyl) -nicotinic acid, 44 ml of concentrated sulfuric acid, 15 ml of 90% nitric acid and 4.4 ml of concentrated sulfuric acid. sulfuric acid.

Yield 10 g, m.p. > 300 ° C.

20 C-4. 1-methyl-3-nitro-5- (4-pyridinyl) -2 (1H) -pyridinone

A mixture of 4.3 g of 3-nitro-5- (4-pyridinyl) -2 (1H) -pyridinone, 2.8 g of anhydrous potassium carbonate and 40 ml of dry dimethylformamide was stirred for 30 minutes under a nitrogen atmosphere on a steam bath. The fine suspension thus obtained was cooled to room temperature, and 3.7 g of methyl tosylate was added dropwise with stirring. The mixture thus obtained was stirred for 18 hours at room temperature, 90 minutes at steam bath temperature, cooled to 30 and poured onto ice. The separated solid was collected, washed well with water and dried at 60 ° C for one third at atmospheric pressure for 8 hours. When the thus obtained powder (3.2 g) was crystallized from a 50% aqueous solution of ethanol, fine needles were obtained, which were washed well with water and dried in vacuo at 35 ° C (10 mm) for 3 hours to give 2.2 g of 1-methyl -3-nitro-5- (4-pyridinyl) -2 (1H) -pyridinone, m.p. 250-252 ° C.

18 6 5 0 61

To verify that the obtained compound was an N-methyl compound and not an O-methyl compound, the following experiment was performed: 300 mg of the product was dissolved in 10 ml of glacial acetic acid, 2 ml of 48% hydrogen bromide was added and the resulting clear solution was heated on a 5 steam bath for 75 minutes, cooled and evaporated under reduced pressure. After residual yellow solid was triturated with dilute aqueous ammonium hydroxide, filtered, washed with water and dried at 80 ° C for one third at atmospheric pressure for 24 hours, 0.30 g of starting material was obtained, m.p. 252-254 ° C. If the product had been an O-methyl compound, i.e. 2-methoxy-3-nitro-5- (4-pyridinyl) pyridine, refluxing with hydrogen bromide and acetic acid would have yielded a demethylated compound, i.e. 3-nitro-5- (4-pyridinyl) -2 (1H) -pyridinone.

A second run of the above procedure gave 11.2 g of 1-methyl-3-nitro-5- (4-pyridinyl) -2 (1H) -pyridinone, m.p. 151-152 ° C, using 21.7 g of 3-nitro-5- (4-pyridinyl) -2 (1H) -pyridinone, 13-8 g of anhydrous potassium carbonate, 300 ml of dimethylformamide, 18.6 g of methylthio-20 acetate in 50 ml of dimethylformamide added in one portion and recrystallized from aqueous ethanol.

C-5. l-ethyl-3-nitro-5- (4-pyridinyl) -2 (1H) -pyridinone

A mixture of 21.7 g of 3-nitro-5- (4-pyridinyl) -25 2 (1H) -pyridinone, 13.8 g of anhydrous potassium carbonate and 400 ml of dimethylformamide was stirred for 1 hour at room temperature and for one hour on a steam bath and then it was allowed to cool to room temperature. To the stirred yellow suspension was added a solution of 20 g of ethyl 30 tosylate in 10 ml of dimethylformamide, and the mixture thus obtained was stirred first overnight (about 15 hours) at room temperature and then for 90 minutes on a steam bath. The mixture was cooled and filtered. The filtrate was concentrated to near dryness under reduced pressure, and 400 ml of water was added. When the yellow solid was collected by filtration, washed with water and dried at 50 ° C under vacuum for 18 hours, 5.5 g of pale yellow needles were obtained, m.p. 124-126 ° C (see below 19 65 061 recrystallization and identification). When the filtrate was stored at 0 ° C and the resulting yellow crystalline precipitate was collected and dried for 4 hours at 100 ° C and 10 mm pressure, 8.0 g of product was obtained, i.e. 1-ethyl-3-nitro-5- (4-pyrid -5-yl) -2 (1H) -pyridinone, m.p. 175-176 ° C. A portion of this product was recrystallized from 95% ethanol to give a yellow crystalline 1-ethyl compound, m.p. 175-176 ° C with an NMR spectrum (10% in CF 2 COOD) consistent with the designated N-ethyl structure. When a batch of the above 10 pale yellow needles having a melting point of 124-126 ° C was recrystallized from ethanol-water (3/1 by volume), white needles were obtained, m.p. 126-127 ° C, identified by their NMR spectrum (10% in CF 2 COOD) as 2-ethoxy-3-nitro-5- (4-pyridinyl) pyridine.

Following the procedure of Example C1 but substituting a molar equivalent of 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinic acid for the corresponding amount of 1,2-dihydro-2-oxo-5-PY-nicotinic acid is obtained. C-6 to C-9 correspond to 3-nitro-5-PY-2 (1H) -pyridinones.

20 C-6. 3-nitro-5- (2-methyl-3-pyridinyl) -2 (1H) -pyridinone

The title compound was prepared using 1,2-dihydro-2-oxo-5- (2-methyl-3-pyridinyl) -nicotinic acid.

C-7. 3-nitro-5- (5-methyl-3-pyridinyl) -2 (1H) -25 pyridinone

The title compound was prepared using 1,2-dihydro-2-oxo-5- (5-methyl-3-pyridinyl) -nicotinic acid.

C-8. 3-Nitro-5- (3-ethyl-4-pyridinyl) -2 (1H) -pyridinone The title compound was prepared using 1,2-dihydro-2-oxo-5- (3-ethyl-4-pyridinyl) nicotinic acid.

C-9. 3-nitro-5- (4,6-dimethyl-2-pyridinyl) -2 (1H) -pyridinone

The title compound was prepared using 1,2-di-35-hydro-2-oxo-5- (4,6-dimethyl-2-pyridinyl) -nicotinic acid.

20 65061

Following the procedure of Example C-5 but substituting a molar equivalent of the corresponding lower alkyl tosylate or other lower alkylating agent for ethyl tosylate gave the corresponding 1- (lower alkyl) -3-nitro-5-PY-2 of Examples C-10 -5 C-13 ( 1H) -pyridinones.

C-10. 3-nitro-l-n-propyl-5- (4-pyridinyl) -2 (1H) -pyrldinoni

The title compound was prepared using 3-nitro-5-20 (4-pyridinyl) -2 (1H) -pyridinone and n-propyl tosylate.

C-ll. l-isobutyl-5- (2-methyl-3-pyridinyl) -3-nitro-2 (1H) -pyrldinoni

The title compound was prepared using 5- (2-methyl-3-pyridinyl) -3-nitro-2 (1H) -pyridinone and isobutyl tosylate.

C-12. l-n-hexyl-3-nitro-5- (4-pyridinyl) -2 (1H) -pyrldinoni

The title compound was prepared using 3-nitro-5- (4-pyridinyl) -2 (1H) -pyridinone and n-hexyl tosylate.

20 C-13. 1- (2-hydroxyethyl) -3-nitro-5- (4-pyridinyl) -2 (1H) -pyridinone

The title compound was prepared using 3-nitro-5- (4-pyridinyl) -2 (1H) -pyridinone and 2-hydroxyethyl tosylate.

25 C-14. 3-nitro-1-n-propyl-5- (4-pyridinyl) -2 (1H) -pyridinone

A suspension of 62.5 g of 3-nitro-5- (4-pyridinyl) -2 (1K) -pyridinone, 41.5 g of anhydrous potassium carbonate and 1 liter of dimethylformamide was stirred for 30 minutes with heating on a steam bath. The reaction mixture was then cooled to about 40 ° C, and 51.0 g of n-propyl iodide was added in one portion, and the mixture thus obtained was first stirred at room temperature for 90 minutes and then at 100 ° C for 4 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to about 35 third of its original volume. When the mixture thus obtained was poured into 1 liter of cold water, a red viscous oil separated. The mixture was extracted with three 150 ml portions of 65061 chloroform, and the combined extracts were washed successively with two 150 ml portions of water and two 150 ml portions of saturated brine, and then dried over anhydrous magnesium sulfate, treated with activated carbon, and filtered. When chloroform was removed from the filtrate by distillation under reduced pressure, 66.5 g of a dark viscous oil remained. A 60 g portion of this dark viscous oil was dissolved in 200 ml of glacial acetic acid, 100 ml of 48% hydrogen bromide was added and the solution was stirred for 6 hours on a steam bath. Most of the solvents were distilled off under reduced pressure, 200 ml of water and 200 ml of methylene chloride were added and the mixture was basified (pH about 10) with 2N potassium hydroxide solution: The layers were separated and the aqueous layer was extracted with two 100 ml portions of methylene chloride. The combined organic layers were shaken with saturated brine and dried over anhydrous magnesium sulfate. When methylene chloride was distilled off under reduced pressure, 35.6 g of a pale yellow, viscous oil were obtained, which crystallized completely on standing at room temperature. When the crystalline product was recrystallized from boiling water and dried for 18 hours at 80 ° C at one-third atmospheric pressure, 30.2 g of 3-nitro-1-propyl-5- (4-pyridinyl) -2 (1H) - pyridineson, m.p. 139-140 ° C. A second crop gave 3.8 g of product, m.p. 138-140 ° C.

25 D. 1,2-Dihydro-2-oxo-5- (pyridinyl) - .nicotinamides D-1. 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinamide

Alternatively called 1,6-dihydro-6-oxo [3,4'-bipyridine] -5-carboxamide).

A mixture of 10 g of 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile and 100 ml of 90% sulfuric acid was heated on a steam bath for 1 hour and then poured onto ice. The acidic solution was neutralized with 35% aqueous sodium hydroxide solution and then basified with 1C% potassium 55 bicarbonate solution. After the separated product was collected, washed, dried, recrystallized from dimethylformamide, washed successively with ethanol and ethyl ether 22 6 5 0 61 and dried in vacuo at 80 ° C to give 8.5 g of 1,2-dihydro-2-oxo. -5- (4-pyridinyl) -nicotinamide, m.p. · 7300 ° ο.

The procedure was repeated using 68 g of 1,2-dihydro-2-oxo-5- (4-pyridinyl) -nicotinonitrile and 700 ml of 90% sulfuric acid. The mixture was heated on a steam bath for 2 hours. The product was separated as above. Recrystallized from dimethylformamide and washed with methanol and ether, followed by drying. Quantitative yield 80 g of 1,2-dihydro-2-oxo-5- (4-pyridinyl) -nicotinamide, 10 m.p. > 300 ° C.

P-2. 1,2-dihydro-2-oxo-5- (4-pyridinyl) -nicotinamide

The reaction mixture containing 17.6 g of * - (4-pyridinyl) dimethylaminoacrolein, 10.0 g of malonamide, 10.8 g of sodium methoxide and 200 ml of methanol was refluxed for 30 minutes and then allowed to cool. When the separated product was collected and dried, product "A" was obtained. The solvent was distilled off from the mother liquor in vacuo and the residue was diluted with water. When the mixture was neutralized with acetic acid and the solid was collected, washed with water and dried, product "B" was obtained. "A" was dissolved in water and the solution was neutralized with acetic acid and the mixture was cooled. The separated solid was collected, washed with water and dried. and "B" was combined and recrystallized from 400 ml of dimethylformamide to give 13 g of 1,2-dihydro-2-oxo-5- (4-pyridinyl) -nicotinamide, m.p. > 300 ° C. The product obtained by this method was identical to the product obtained in Example D-1.

Following the procedure of Example D1 but using 1,2-dihydro-2-oxo-5- (4-pyridinyl) -nicotinonitrile in place of a molar equivalent amount of 1,2-dihydro-2-oxo-5-PY-nicotinonitrile was obtained. D-3 - Ό-8 1,2-dihydro-2-oxo-5-PY-nicotinamides.

0-3. 1,2-Dihydro-2-oxo-5- (3-pyridinyl) -nicotinamide 55 The title compound was prepared using 1,2-dihydro-2-oxo-5- (3-pyridinyl) nicotinonitrile.

P-4. 1,2-dihydro-2-oxo-5- (2-pyridinyl) -nicotinamide

The title compound was prepared using 1,2-dihydro-2-oxo-5- (2-pyridinyl) -nicotinonitrile.

650 61 D-5. 1,2-Dihydro-2-oxo-5- (2-methyl-3-pyridinyl) nicotinamide

The title compound was prepared using 1,2-dihydro-2-oxo-5- (2-methyl-3-pyridinyl) -nicotinonitrile.

5 D-6. 1,2-Dihydro-2-oxo-5- (5-methyl-3-pyridinyl) nicotinamide

The title compound was prepared using 1,2-dihydro-2-oxo-5- (S'-methyl-1-pyridinyl) -nicotinonitrile.

D-7. 1/2-Dihydro-2-oxo-5- (3-ethyl-4-pyridinyl) -10 nicotinamide

The title compound was prepared using 1,2-dihydro-2-oxo-5- (3-ethyl-4-pyridinyl) -nicotinonitrile.

0-8. 1,2-Dihydro-2-oxo-5- (4,6-dimethyl-2-pyridinyl) nicotinamide The title compound was prepared using 1,2-dihydro-2-oxo-5- (4,6-dimethyl -2-pyridinyl) -nicotinonitrile.

The compounds of Examples D-3 to D-8 can also be prepared following the procedure of Example E-2 using a molar-20 equivalent equivalent of cis-β-β-dimethylacol instead of β- (4-pyridinyl) -β-dimethylacrolein. roleine, for example 1/2-dihydro-2-oxo-5- (3-pyridinyl) nicotinamide can be prepared using o- (3-pyridinyl) - [3-dimethylaminoacrolein.

E. 3-Fralogen-5- (pyridinyl) -2 (1H) -pyridinones 25 E-1. 3-bromo-5- (4-pyridinyl) -2 (1H) -pyridinone

Alternatively called 5-bromo- (T, 4'-bipyridine, / - 6 (1H) -one)

A mixture of 51.6 g of 5- (4-pyridinyl) -2 (1H) -pyridinone and 600 ml of acetic acid was heated to about 60 ° C so that complete dissolution occurred. The heating was stopped and 52.8 g of bromine was added dropwise over about 20 minutes, whereupon a solid separated. The mixture was stirred at room temperature for about 30 minutes, diluted with ether and then cooled in ice. Solid 35 was collected, washed with ether, dried, suspended in water and neutralized with 10% potassium carbonate solution. The solid was collected, washed with water and dried.

24 6 5 0 61

When the solid was then dissolved in dilute hydrochloric acid and isopropyl alcohol was added to the solution to precipitate the hydrochloride salt, which was recrystallized from water and dried to give 55 g of 3-bromo-5- (4-pyridinyl) -5 2 (1H) -pyridinol as its hydrochloride, m.p. > 300 ° C.

E-2. 3-chloro-5- (4-pyridinyl) -2 (1H) -pyridinone

Alternatively called 5-chloro - [(3,4'-bipyridin / -6 (1H) -one)) to a steam bath heated mixture of 17 g of 5- (4-pyridinyl) -2 (1H) -pyridinone and 200 ml acetic acid, chlorine was bubbled for 4 hours. The reaction mixture was allowed to cool to room temperature, the solid was collected, 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. After the separated solid was collected, washed with water, dried and recrystallized from ethanol, 6.5 g of 3-chloro-5- (4-pyridinyl) -2 (1H) -pyridinone were obtained, m.p. 295-297 ° C.

E-3. 3-Chloro-5- (3-pyridinyl) -2 (1H) -pyridinone Following the procedure of Example E-2 but using a molar equivalent amount of 5- (3-pyridinyl) -2 (1H) -4-pyridinone 5- ( In place of 4-pyridinyl) -2 (1H) -pyridinone, the title product was obtained.

E-4. 3-chloro-5- (3-ethyl-4-pyridinyl) -2 (1H) -25 pyridinone

Following the procedure of Example E-2 but using a molar equivalent amount of 5- (3-ethyl-4-pyridinyl) -2 (1H) -pyridinone in place of 5- (4-pyridinyl) -2 (1H) -pyridinone gave the title product. .

20 e-5. 3-Bromo: 1- (5- (5-methyl-3-pyridinyl) -2 (1H) -pyridinone

Following the procedure of Example E-1 but using 5- (5-methyl-3-pyridinyl) -2 (1H) -pyridinone in place of 5- (4-pyridinyl) -2 (1H) -pyridinone gave the title product 25.

Claims (7)

25 65061 1. 2 (1H) -pyridinone derivatives and their acid addition salts useful as intermediates in the preparation of therapeutically active pyridine derivatives of the formula 10 R wherein PY is a 4-, 3- or 2-pyridinyl group which may be substituted with one or two lower alkyl groups, R is hydrogen, lower alkyl or lower hydroxyalkyl and Q '15 is amino, lower alkylamino or di (lower alkyl) amino, and pharmaceutically acceptable acid addition salts thereof, characterized in that the formula of 2 (1H) -pyridinone derivatives is 20 Ρϊ ίΓΥ5 R wherein PY is a 4-, 3- or 2-pyridyl group which may be subs-substituted with one or two lower alkyl groups, R is hydrogen, lower alkyl or lower hydroxyalkyl and Q is nitro, carbamyl or halogen. 2 (1H) -pyridinone derivative according to Claim 1, characterized in that it is 3-nitro-5- (4-pyridinyl) -2 (1H) -pyridinone. 2 (1H) -pyridinone derivative according to Claim 1, characterized in that it is 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinamide. 2 (1H) -pyridinone-35 derivative according to Claim 1, characterized in that it is 3-chloro-5- (4-pyridinyl) -2 (1H) -pyridinone or 3-bromo-5- (4-pyridinyl) ) -2 (1H) -pyridinone. 26 6 50 61 A process for the preparation of 2 (1H) -pyridinone derivatives of the formula PY, wherein PY is a 4-, 3- or 2-pyridinyl group which may be substituted by one or two lower alkyl groups, characterized in that a compound of formula 10. CHO PY-C ^ III ^ chnr1r2 wherein PY is as defined above and R1 and R2 are lower alkyl is reacted with malonamide of formula CH2 (CONH2) 2 . 27 6 5 061 1. 2 (1H) -pyridinone derivative ochsyraadditionssalter där-av, vilka är användbara som mellanprodukter vid framställ- 5 Ning av therapeutiskttiva pyrainderivat med medelneln 10 R is a PY with 4-, 3- or 2-pyridinyl group, which may be substituted with an alkyl group, R is a member, an alkyl or a hydroxyalkyl and Q 'is amino, an alkylamino or a di (a group) alkyl) amino and ochaceous-15-fold straight-chain acid addition, on the other hand, in the form of 2 (1H) -pyridinone derivatives 20 VX 1 R is a PY is a 4-, 3- or 2-pyridinyl group, which may be substituted with an alkyl & alkyl group, R is used, an alkyl or a hydroxyalkyl and a nitro, carbamyl or halogen. 2. A 2 (1H) -pyridinone derivative according to claim 1, which comprises 3-nitro-5- (4-pyridinyl) -2 (1H) -pyridinone. 3. 2 (1H) -pyridinone derivatives according to patent 1, which can be converted to 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinamide. 4. A 2 (1H) -pyridinone derivative according to claim 1, which is converted to 3-chloro-5- (4-pyridinyl) -2 (1H) -pyridinone or 3-bromo-5- (4-pyridinyl). ) -2 (1H) -pyridinone.