CH649535A5 - 5- (PYRIDINYL) -2 (1H) PYRIDINONES, THEIR PREPARATION AND CARDIOTONIC COMPOSITION CONTAINING THEM. - Google Patents

Description

This invention relates to 5- (pyridinyl) -2 (1H) -pyridinones usable as cardiotonic agents and their preparation.

U.S. patents Nos 4004012 and 4072746 describe,

as cardiotonic agents, 3-amino (or cyano) -5- (pyridinyl) -2 (1H) -pyridinones and, as intermediates, compounds with the corresponding 3-carbamyl group, also called 1,2-dihydro- 2-oxo-5- (pyridinyl) nicotinamides, which are transformed into corresponding 3-amino compounds by reaction with a reagent capable of transforming the carbamyl group into an amino group, for example by heating with an alkali metal hypohalite. A preferred compound among these compounds is 3-amino-5- (4-pyridinyl) -2 (1H) -pyridi-none, generically now called amrinone or also also called 5-amino- [3,4 '-bipyridine] -6 (1H) -one. A process described for the preparation of 3-cyano-5- (pyridinyl) -2 (1H) -pyridino-nes, also called 1,2-dihydro-2-oxo-5- (pyridinyl) nicotinoni-30 triles, comprises the reaction of Pa- (pyridinyl) -ß- (dialkylamino) acrolein with α-cyanoacetamide. The U.S. Patent No. 4072746 also describes the 3-Q-5- (pyridinyl) -2 (1H) -pyridinones where Q is a hydrogen or halogen atom or a lower alkylamino, di (lower alkyl) amino group and NHAc where Ac is a lower alkanoyl or lower carbalkoxy group.

The 5- (pyridinyl) -2 (1H) -pyridinones unsubstituted in position 3 (Q = H) are prepared by heating the corresponding 3-cyano derivatives with aqueous sulfuric acid, first forming the 3-carboxylic acids , i.e., 1,2-dihydro-2-oxo-5-40 (pyridinyl) nicotinic acids, which are then decarboxylated. No cardiotonic activity is indicated for 1,2-dihydro-2-oxo-5- (pyridinyl) nicotinic acids.

The invention relates to the compounds of formula I:

(I)

in which Q is a hydrogen atom or an amino, cyano, carbamyl, halo, lower alkylamino, di (lower alkyl) -amino, lower acylamino, carboxy or lower carbalkoxy radical, Ri is a hydrogen atom or an alkyl group lower or hy-55 lower droxyalkyl, R is a lower alkyl group and PY is a 4-, 3- or 2-pyridinyl or 4-, 3- or 2-pyridinyl group having one or two lower alkyl substituents, and the cationic salts or the addition of pharmaceutically acceptable acids to these compounds. The compounds of formula I can be used as car-60 diotonic agents, as shown by the procedures of conventional pharmacological tests. The compounds of formula I where Q is a carbamyl or cyano group and where Q is a hydrogen atom can also be used as intermediates for the preparation of the corresponding compounds where Q is an amino group or a halogen atom respectively. The compounds of formula I where Q is a halogen atom can also be used as intermediates for the preparation of the compounds with a [3-mono- or di (lower alkyl) amino] group. Preferred compounds

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are those of formula I where Q is a hydrogen atom or an amino or cyano group, PY is a 4-pyridinyl or 3-pyridinyl group, R | is a hydrogen atom and R is a methyl or ethyl group. The particularly preferred compounds are 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile (formula I where Q is CN, R, is H, PY is a 4-pyridinyl group and R is a methyl group), 3-amino-6-ethyl-5- (4-pyridinyl) -2 (1H) -pyri-dinone (formula I where Q is NH2, Ri is H, PY is 4-pyridinyl and R is ethyl), 3-amino-5- (4-pyridinyl) -6-methyl-2 (1H) -pyridinone (formula I where Q is NH2, R, is H, PY is 4-pyridinyl and R is methyl) , 6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone (formula I where R | = H, PY = 4-pyridinyl and R = methyl) and 6-ethyl-5- (4-pyridi -nyl) -2 (1H) -pyridinone (formula I where R, = H, PY = 4-pyridinyl and R = ethyl), or their pharmaceutically acceptable acid addition salts. These particularly preferred compounds have been found to have significantly higher cardiotonic activity than the corresponding known dealkylated derivatives, 3-amino-5- (4-pyridinyl) -2 (1H) -pyridinone, called amrinone, l, 2- dihydro-2-oxo-5- (4-pyri-dinyl) nicotinonitrile and 5- (4-pyridinyl) -2 (1H) -pyridinone.

A compound of formula I as defined above can be prepared by a process which consists of:

at. reacting a compound of formula:

O

PY

wherein R3 and R4 are each a lower alkyl group, with malonamide to obtain a compound of formula I where Q is a carbamyl group, or b. reacting a compound of formula III or of formula:

H

I

R-C-C-CHO (IV)

II I

O PY

with an N-R ^ a-cyanoacetamide to prepare a compound of formula I where Q is a cyano group;

if desired, partially hydrolyzing a compound of formula I obtained where Q is a cyano group, to obtain the corresponding compound where Q is a carbamyl group;

if desired, reacting a compound of formula I obtained where Q is a carbamyl group, with a reagent capable of transforming the carbamyl group into an amino group to produce the corresponding compound where Q is an amino group;

if desired, reacting a compound of formula I obtained where Q is an amino group, with one or two molar equivalents of an alkylating agent having a lower alkyl group to obtain the corresponding compound where Q is a lower alkylamino group or di (lower alkyl) amino respectively;

if desired, reacting a compound of formula I obtained where Q is an amino group, with an acylating agent having a lower acyl group to obtain the corresponding compound where Q is a lower acylamino group;

if desired, hydrolyzing a compound of formula I obtained where Q is a cyano group, to obtain the corresponding compound where Q is a carboxy group;

if desired, heating a compound of formula I obtained where Q is a carboxy group, with a mixture of concentrated sulfonic acid and concentrated nitric acid to obtain the corresponding compound where Q is a nitro group, the compound where Q is a nitro group then being reduced to obtain the compound where Q is an amino group;

if desired, heating a compound of formula I obtained where Q is a cyano or carboxy group, with an aqueous mineral acid to obtain the corresponding compound where Q is a hydrogen atom;

if desired, esterifying with a lower alkanol the compound of formula I obtained where Q is a carboxy group, to obtain the corresponding compound where Q is a lower carbalkoxy group;

if desired, reacting a compound of formula I obtained where R is a hydrogen atom, with an alkylating agent of formula R'-An where R 'is a lower alkyl or lower hydroxyalkyl group and An is a anion of a strong mineral acid or an organic sulfonic acid, to prepare the corresponding compound where R [is R ';

if desired, reacting a compound of formula I obtained where Q is a hydrogen atom, with a halogen to obtain the corresponding compound where Q is a halogen atom;

if desired, reacting a compound of formula I obtained where Q is a halogen atom, with a lower alkylamine or a di (lower alkyl) amine to obtain a corresponding compound where Q is a lower alkylamino group or di ( lower alkyl) -amino respectively, and if desired, converting the free base obtained into one of its acid addition salts or transforming a compound obtained into one of its cationic salts.

A PY-methyl (lower alkyl) ketone of formula PY — CH2 — C (= O) —R (II) can be reacted with a lower dialkyl acetal of a di (lower alkyl) formamide to obtain l-PY- 2- [di (lower alkyl) amino] ethenyl (lower alkyl) ketone of formula III:

O

II

R3R4NCH = C-C-R (III)

PY

where R3 and R4 are each a lower alkyl group and one is preferably a methyl group, and PY, R, Rj and R 'are as defined for formula I. Said l- (pyridinyl) -2- [di (lower alkyl) -amino] ethenyl (lower alkyl) ketones of formula III where PY and R are as defined above as well as their acid addition salts are new compounds constituting an aspect of the present invention.

The invention also provides a cardiotonic composition for increasing cardiac contractility, said composition comprising a pharmaceutically acceptable carrier and, as active component, an effective amount of 1-Rj-3-QS-PY-6-R-2 (1H) -pyridinone cardiotonic of formula I, where R, Q, PY and R are each defined as in formula I, or a pharmaceutically acceptable acid or cationic addition salt thereof.

Cardiac contractility can be increased in a patient in need of such treatment by administering to that patient an effective amount of a cardiotonic lR ^ SQS-PY-ö-R ^ lHty-pyridinone of formula I, where R, Q, PY and R are as defined in formula I, or one of its cationic or pharmaceutically acceptable acid addition salts.

The expression lower alkyl as used herein, for example as a definition for R or as one of the definitions of R (, as the definition of lower alkyl in the expressions lower alkylamino or di (lower alkyl) amino for Q or as PY substituent in formula I, denotes the alkyl radicals having from 1 to 6 carbon atoms which can be arranged in straight or branched chains, illustrated by the methyl, ethyl, n-propyl, isopropyl, n-butyl, s- groups. butyl, t-butyl, isobutyl, n-amyl, n-hexyl, etc.

The expression lower hydroxyalkyl, as used herein, for example as one of the definitions of R, in formula I, denotes hydroxyalkyl groups having from two to six carbon atoms and of which the hydroxy group and the valence bond are found on different carbon atoms, illustrated by the 2 hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl groups,

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2-hydroxy-2-methylpropyl, 2-hydroxy-1, l-dimethylethyl, 4-hy-droxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl, etc.

Examples of PY in formula I where PY is a 4-, 3- or 2-pyridinyl group having 1 or 2 lower alkyl substituents are: 2-methyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl , 3-methyl-4-pyridinyl, 2-methyl-3-pyridinyl, 6-methyl-3-pyridinyl (also called 2-methyl-5-pyridinyl), 4-methyl-2-pyridinyl, 6-methyl thyl-2-pyridinyl, 2,3-dimethyl-4-pyridinyl, 2,6-dimethyl-4-pyridi-nyle, 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-di-ethyl-4-pyridinyl, 2,6-diethyl-3-pyridinyl, 2.6- diisopropyl-4-pyridi-nyle, 2,6-di-n-hexyl-4-pyridinyle, etc.

The expression lower acyl, as used herein, for example in the substituent 3- (lower acylamino) of the compounds of formula I (Q is a lower acylamino group), designates alka-nucleus radicals having from one to six atoms of carbon, preferably from one to four, and having substituents chosen from hy-droxy, acetoxy or propionoxy groups, comprising the straight or branched chain radicals, illustrated by the formyl, acetyl, propionyl (n-propanoyl), butyryl groups (n-butanoyl), isobutyryl (2-methyl-n-propanoyl), caproyl (n-hexanoyl), hydroxyacetyl, a-hydroxypropionyl, ß-hydroxypropionyl, a-acetoxypropionyl, propionoxyacetyl, ß-acetoxypropionyl, a-acetoxybutyryl, etc.

The compounds of formulas I and III can be used in the free base form and in the form of the acid addition salts and both forms form part of the field of the invention. Acid addition salts are simply a more convenient form for use; and in practice the use of the salt form inherently corresponds to the use of the base form. The acids which can be used to prepare the acid addition salts preferably include those which produce, when combined with the free base, pharmaceutically acceptable salts, i.e. salts whose anions are relatively harmless to the animal body at pharmaceutical doses of the salts, so that the beneficial cardiotonic properties inherent in the free base form (I) are not vitiated by side effects attributable to the anions. In implementing the invention, it is convenient to use the free base form; however, suitable pharmaceutically acceptable salts falling within the scope of the invention are those obtained from mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid, and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, methanesulfonic acid, ethane-sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, etc., giving respectively the hydrochloride, the sulfate, the phosphate, the sulfamate, the acetate, the citrate, the lactate, the tartrate, the methanesulfonate, the ethane-sulfonate, the benzenesulfonate, the p- toluenesulfonate, cyclohexyl-sulfamate and quinate.

The acid addition salts of the basic compound (I or III) are prepared by dissolving the free base in an aqueous or aqueous-alcoholic solution or in any other suitable solvent containing the appropriate acid and isolating the salt by evaporation of the solution, or by reacting the free base and the acid in an organic solvent, in which case the salt separates directly or else can be obtained by concentration of the solution.

Although the pharmaceutically acceptable salts of the basic compound (I or III) are preferred, all of the acid addition salts fall within the scope of the invention. All the acid addition salts can be used as sources of the free base, even if the particular salt is in itself sought only as an intermediate product, for example when the salt is formed only for the purposes of purification. or identification, or when used as an intermediate in the preparation of a pharmaceutically acceptable salt by ion exchange procedures.

Other pharmaceutically acceptable salts of the compound of formula I are the cationic salts obtained from strong mineral or organic bases, for example sodium hydroxide, hy-

potassium hydroxide, trimethylammonium hydroxide, to obtain the corresponding 1- or N-cationic salt, for example the sodium, potassium, trimethylammonium salt respectively, i.e. the cationic ion is fixed in position 1 or N of the nucleus 2 (1H) -pyridinone.

The molecular structures of the compounds of formulas I and III were assigned on the basis of the data supplied by the infrared, nuclear magnetic resonance and mass spectra, and by the correspondence of the values calculated and found for the elementary analysis.

How to make and use the present invention will now be described generally to enable those skilled in the art to make it.

The preparation of l-PY-2- (dimethylamino) ethe-nyl (lower alkyl) ketone of formula III is carried out by reacting PY-methyl (lower alkyl) ketone (II) with a lower dialkyl acetal of dimethylformamide, mixing the reagents in the presence or absence of an appropriate solvent. The reaction is conveniently carried out at room temperature, i.e. about 20-25 ° C, or by heating the reagents to about 100 ° C, preferably in an aprotic solvent, conveniently hexamethylphosphoramide due of the process used to prepare PY-methyl (lower alkyl) ketone, as indicated below in Example A1. Other suitable solvents include tetrahydrofuran, dimethylformamide, acetonitrile, ether, benzene, dioxane, etc. The reaction can also be carried out without solvent, preferably using an excess of the di (lower alkyl) acetal of dimethylformamide. This procedure is further illustrated below in Examples A-1 to A-17.

The intermediate PY-methyl (lower alkyl) ketones of formula II are generally known compounds which are prepared by known methods [for example, as described in "Ree. trav.

chem. ”, 72, 522 (1953); the U.S. patent No. 3133077; "Bull. Soc. Chim. ”, 1968, 4132; "Chem. Abstr. ”, 79, 8539h (1973); "Chem. Abstr. ”, 81,120,401a (1974); "J. Org. Chem. ”, 39, 3834 (1974); "Chem. Abstr. ”, 87, 6594q (1977); "J. Org. Chem. ”, 43, 2286 (1978)].

Reaction of 1-PY-2- (dimethylamino) ethenyl (lower alkyl) ketone (III) with an N-Rra-cyanoacetamide to obtain 1-Rrl, 2-dihydro-2-oxo-5-PY- 6-R-nicotinonitrile (formula I where Q is CN) is preferably carried out by heating the reagents in an appropriate solvent in the presence of a basic condensing agent. The reaction is conveniently carried out using a lower alkali metal alcoholate, preferably sodium methylate or ethylate, in dimethylformamide. In the implementation of the invention, the reaction is carried out by heating the dimethylformamide at reflux using sodium methylate. Alternatively, methanol and sodium methylate or ethanol and sodium ethylate can be used as the solvent and as the basic condensing agent respectively; however, a longer heating period is required. Other basic condensing agents and solvents include sodium hydride, lithium diethylamide, lithium diisopropylamide, etc., in an aprotic solvent, for example tetrahydrofuran, acetonitrile, ether, benzene, dioxane, etc. This procedure is better illustrated below in Examples B-1 to B-21.

The preparation of l-Rrl, 2-dihydro-2-oxo-5-PY-6-R-nicotinonitrile can also be carried out by heating an l-PY-2- (R3R, -amino) ethenyl (lower alkyl) ketone ( III) in an aqueous alkaline medium, for example an aqueous solution of sodium or potassium hydroxide, to obtain the corresponding a-PY-PRP-oxopropionaldehyde (IV) and by reacting this compound with an N-Ri-a -cyanoacetamide.

The 1,2-dihydro-2-oxo-5-PY-6-R-nicotinamide (formula I, Q = carbamyl and Ri = H) can also be prepared directly by reacting an l-PY-2- (R3R4 amino ) ethenyl (lower alkyl) ce-tone of formula III with malonamide. The reactions with α-cyanoacetamide of formula III or with malonamide can be illustrated as follows:

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? R3R4

py ch cn

\ /

/

c 1

CH_ + I 2

1

vs

1

vs

/ \

I \

r 0 hn 0

+ hnr3R4 + H2O

nr, r

3 4

py ch

\ /

vs

I

vs

/ \ r 0

conh, / '

ch-

py conh.

R '^^ N'

I

h

+ hnr3r4 + h20

Partial hydrolysis of l-Ri-1,2-dihydro-2-oxo-5-PY-6-R-nico-tinonitrile (formula I where Q = CN) to obtain 1,2-dihydro-2-oxo -5-PY-6-R-nicotinamide (I where Q is a carbamyl group) is carried out by heating the compound of formula I where Q is a cyano group with concentrated sulfuric acid. Although the reaction is conveniently and preferably carried out by heating the reactants on a steam or oil bath to about 80-100 ° C, the temperature range for the reaction can range from about 70 to 120 ° C. This procedure is further illustrated below in Examples C1 to C-21.

Transformation of l-Ri-1,2-dihydro-2-oxo-5-PY-6-R-nicoti-namide (I where Q is a carbamyl group) into l-Ri-3-amino-5-PY- 6-R-2 (1H) -pyridinone (I where Q is an amino group) is carried out by reacting the compound of formula I where Q is a carbamyl group with a reagent capable of transforming the carbamyl group into an amino group, for example a alkali metal hypohalite or lead tetraacetate. This reaction is conveniently carried out by heating an aqueous mixture containing an alkali metal hypohalite, preferably hypobromite or sodium hypochlorite, and the compound of formula I where Q is a carbamyl group, then by acidifying the reaction mixture, preferably with an aqueous mineral acid, for example hydrochloric acid. The reaction can be carried out between about 40 and 100 ° C, preferably between 70 and 100 ° C. This procedure is better illustrated below in Examples D-1 to D-21.

One can also prepare l-Ri-3-amino-5-PY-6-R-2 (1H) -pyridinone (I, Q is an amino group) by heating 5-PY-6-R-2 (1H ) -pyridinone with a mixture of nitric acid and sulfuric acid to prepare 3-nitro-5-PY-6-R-2 (1H) -pyridinone and by directly reducing the 3-nitro compound to prepare 3- amino-5-PY-6-R-2 (1H) -pyridinone (formula I, Q is an amino group and Ri is a hydrogen atom), or by first alkylating (see next paragraph) compound 3 -nitrated to prepare l-R1-3-nitro-5-PY-6-R-2 (1H) -pyridionone and by reducing the 3-nitro compound to prepare l-Rr3-amino-5-PY-6- R-2 (1H) -pyridinone (formula I, Q is an amino group and R, a lower alkyl or lower hydroxyalkyl group).

One can also prepare the compounds of formula I where R] is a lower alkyl or hydroxyalkyl lower group by reacting the unsubstituted compounds in formula I corresponding of formula I where Rj is a hydrogen atom, with a lower alkyl or hydroxyalkyl ester lower of a strong mineral acid or an organic sulfonic acid, preferably in the presence of an acid acceptor.

The transformation of l-Rrl, 2-dihydro-2-oxo-5-PY-6-R-nicoti-nonitrile (I, Q is a cyano group) into 1-Ri-5-PY-6-R-2 ( 1H) -pyridinone (I, Q is a hydrogen atom) is carried out by heating the compound I where Q is cyano as above in an aqueous mineral acid, preferably 50% sulfuric acid, to form d first the compound I where Q is a carboxy group, then continuing to heat for a longer period of time, which causes the decarboxylation of the 3-carboxylic acid giving the compound I where Q is a hydrogen atom . This procedure is better illustrated below in Examples E-1 to E-21. 5 The reaction of 1 -Rr5-PY-6-R-2 (1 H) -pyridinone (I, Q is a hydrogen atom) with a halogen is carried out to obtain the corresponding 3-halogenated compound (I, Q is a halogen atom) by mixing the reagents in a suitable solvent inert under the reaction conditions, a preferred solvent being acetic acid. The reaction is conveniently carried out at room temperature or by heating the reactants to temperatures up to about 100 ° C.

The preferred halogens are bromine and chlorine. Any inert solvent can be used, for example dimethylformamide, chloroform, acetic acid, etc. This procedure is better illustrated below in Examples F-1 to F-22.

Reaction of an l-Ri-3-halo-5-PY-2 (1H) -pyridinone (I, Q is a halogen atom) with a lower alkylamine or a di (lower alkyl) amine to obtain lR , -3- (lower alkylammo) -5-PY-20 6-R-2 (1H) corresponding pyridinone (I, Q is a lower alkylamino group) or l-Rr3- [di (lower alkyl) amino] -5 -PY-2- (1H) -pyridinone corresponding [I, Q is a di (lower alkyl) aniino group] is carried out by heating the reagents in an autoclave to approximately 110-180 ° C, preferably approximately 145-165 ° C and preferably in a suitable solvent, for example water, dimethylformamide, dioxane, 1,2-dimethoxyethane, etc., or mixtures thereof. This procedure is further illustrated below in Examples G-1, G-2, G-3 to G-7, G-9 to G-19 and G-21 to G-23.

Another aspect of the invention for the preparation of 1-Ri-3-30 [mono- or di (lower alkyl) amino] -5-PY-6- (lower alkyl) -2 (1H) -pyridinone consists in reacting the corresponding 3-amino compound with one or two molar equivalents of an alkylating agent having lower alkyl groups.

A preferred process for the preparation of 1-Ri-3-dimethylamino-5 5-PY-6-R-2 (1H) -pyridinone (I, Q is a dimethyl-amino group) is carried out by reacting 1-Rr3 -amino-5-PY-6-R-2 (1H) -pyridinone (I, Q is an amino group) with a mixture of formaldehyde and formic acid. This reaction is conveniently carried out by heating the 3-amino compound under reflux with an excess of formaldehyde, preferably an aqueous solution of this compound, and an excess of formic acid, preferably for each an excess more than twice molar. This procedure is better illustrated below in Examples G-3, G-8 and G-20.

Acylation of 1-Ri-3-amino-5-PY-6-R-2 (1H) pyridinone (I, Q 45 is an amino group) to produce the corresponding 3- (lower acylamino) compound ( I, Q is a lower acylamino group) is carried out by reacting the compound of formula I where Q is an amino group, with an acylating agent, for example a lower acyl halide, preferably chioside, an anhydride lower acid, etc., preferably in the presence of an acid acceptor. The acid acceptor is a basic substance which preferably forms easily soluble in water by-products which readily separate from the reaction product, including for example sodium hydroxide, po hydroxide -55 tassium, sodium carbonate, potassium carbonate, sodium al-coolates, potassium alcoholates, sodium amide, etc. The reaction is preferably carried out in the presence of a suitable solvent inert under the reaction conditions, for example a solvent such as a lower alkanol, acetone, dioxane, diso methylformamide, dimethylsulfoxide, hexamethylphosphoramide, or a mixture of solvents, for example a mixture of water and methylene chloride or chloroform. The reaction is generally carried out at a temperature between about 10 and 150 ° C, preferably about 20 to 25 ° C. This procedure is better illustrated below in Examples H-1 to H-17.

Hydrolysis of 1-Rr 1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitrile (I, Q is cyano) to produce acid 1-Rrl, 2-dihydro-2-oxo- 5-PY-6-R-nicotinic (I, Q is a carboxy group) is conveniently

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performed by heating said nicotinonitrile on a steam bath with an aqueous mineral acid, preferably 50% sulfuric acid. This procedure is better illustrated below in Examples 1-1 to 1-21.

Esterification of l-Rrl, 2-dihydro-2-oxo-5-PY-6-R-nicotinic acid (I, Q is a carboxy group) to obtain lR ^ l, 2-dihydro-2- lower alkyl oxo-5-PY-6-R-nicotinate (I, Q is a lower carbalkoxy group) is carried out by heating the acid with an alkanol lower than about 25 to 150 ° C, preferably about 50 to 100 ° C, preferably in the presence of a suitable solvent, for example an excess of lower alkanol, and in the presence of an acid catalyst, for example a strong mineral acid or an organic sulfonic acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, p-totuenesulfonic acid, etc. This procedure is better illustrated below in examples D-1 to D-19.

The following examples will better illustrate the invention without however limiting it.

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

A-l. l- (4-Pyridinyl) -2- (dimethylamino) ethylene methyl ketone

Dilute with 65 ml of dimethylformamide dimethyl acetal a mixture containing 20 g of (4-pyridinyl) methyl methyl ketone [also called 1- (4-pyridinyl) -2-propanone] and 30 ml of hexamethyl phosphoramide and heat the resulting mixture at reflux for 30 min. TLC analysis indicates a single spot, which indicates the completion of the reaction (in another test, it appears that the reaction is finished after 30 min at room temperature). The reaction mixture is evaporated under reduced pressure using a rotary evaporator and a pressure of 20 mbar, which gives a crystalline residue weighing 24 g. The residue is purified by continuous chromatographic extraction on alumina (approximately 150 g) using chloroform at reflux as eluent. After 1 h, the extract is heated under vacuum to remove the chloroform, which leaves 23.2 g of 1- (4-pyridinyl) -2- (dimethylamino) ethenylmethylketone in the form of a light yellow crystalline material, the compound also being called 4-dimethylamino-2- (4-pyridinyl) -3-buten-2-one.

The above preparation can be carried out using instead of hexamethylphosphoramide other solvents, for example dimethylformamide, acetonitrile or others indicated above, or in the absence of solvent; however, hexamethylphosphoramide is conveniently used because (4-pyridinyl) methylmethyl ketone is conveniently prepared as a mixture with hexamethylphosphoramide, as shown in the following preparation: to a stirred solution containing 70 ml of isopropylamine freshly distilled and 200 ml of tetrahydrofuran at 0 ° C under nitrogen, 210 ml of 2.4M n-butyllithiujn in n-hexane are added dropwise over 20 min and the reaction mixture is stirred for approximately 35 min at approximately 0- 5 ° C. To the cold solution, 90 ml of dry hexamethylphosphoramide is added dropwise over 10 min (no temperature change) and the resulting light yellow solution is stirred for 15 min. To the cold solution at 0 ° C., a solution of 50 ml of 4-picoline in 150 ml of dry tetrahydrofuran is added over 15 min and the stirring is continued for 30 min at 0 ° C. Then a mixture containing 50 ml of dry ethyl acetate and 150 ml of tetrahydrofuran (the temperature rises from 0 to approximately 6 ° C.) and the resulting mixture is stirred for 20 min at 0 ° C. Then the ice bath is removed and stirring is continued for an additional 90 min, during which the temperature of the reaction mixture rises to approximately 25 ° C. The reaction mixture is then cooled in an ice bath and 60 ml of acetic acid are added thereto in approximately 30 min. The tetrahydrofuran is distilled using a rotary vacuum evaporator. The remaining mixture is diluted with 400 ml of water and the aqueous mixture is extracted successively with two 250 ml portions of isopropyl acetate and three 80 ml portions of chloroform. The solvents are distilled off under reduced pressure and approximately 137 g of a mixture essentially comprising the desired product and hexamethylphosphoramide are obtained. Another test using the same quantities is carried out as above but, after the addition of 60 ml of glacial acetic acid, the mixture is diluted with only 200 ml of water, the phases are separated and the aqueous phase is extracted with five 100 ml portions of chloroform. The chloroform extract is washed with a saline solution and the chloroform is distilled under vacuum. The remaining mixture of the desired ketone and of hexamethylphosphoramide is combined with the preceding 137 g of the same mixture and the combined mixture is distilled under reduced pressure to obtain the following fractions: I. 63 g, mp 110-112 ° C at 5, 3 mbar; II. 59 g of a pale yellow oil, m.p. 113-115 ° C at 4 mbar and III. 69 g of a pale yellow oil, mp 115-118 ° C at 3.3 mbar. Examination of fraction III by NMR shows that it consists of a 2: 3 mixture, by weight, of (4-pyridinyl) methylmethylketone and hexamethylphosphoramide.

The acid addition salts of 1- (4-pyridinyl) -2- (dimethylamino) ethenylmethylketone are conveniently prepared by adding to a mixture of 5 g of ketone in approximately 100 ml of aqueous methanol, the appropriate acid, for example methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid, to a pH of about 2 to 3, cooling the mixture after partial evaporation and collecting the precipitated salt, for example dimethylsul- fonate, sulfate and phosphate respectively. The acid addition salt in aqueous solution can also be conveniently prepared by adding to the water, with stirring, equimolar amounts of 1- (4-pyridinyl) -2- (dimethylamino) ethenylmethyl ketone and the appropriate acid, for example lactic acid or hydrochloric acid, to respectively prepare the monolactate and the monohydrochloride in aqueous solution.

A-2. l- (4-Pyridinyl) -2- (dimethylamino) ethenylethylthecone

Dilute with 100 g of dimethylformamide dimethyl acetal a mixture containing 87.5 g of (4-pyridinyl) methyl ethyl ketone [also called 1- (4-pyridinyl) -2-butanone] and 160 ml of hexamethylphosphoramide and stirred the resulting mixture under nitrogen at room temperature for 45 min. The methanol formed by the reaction is distilled under vacuum, using a rotary evaporator, and the remaining substance is distilled under reduced pressure to obtain two fractions, one boiling at 45-80 ° C at 0.66 mbar and the second at 90- 95 ° C at 0.66 mbar. As the TLC analysis shows essentially a single spot for each fraction, the two fractions (135 g) are combined and taken up in 600 ml of chloroform. The resulting solution is washed with two 300 ml portions of water and the water is washed back with three 100 ml portions of chloroform. The solution of combined chloroform extracts is dried over anhydrous sodium sulfate and purified by continuous extraction chromatography on 300 ml of alumina using chloroform under reflux as eluent. The chloroform is distilled in vacuo and a red oil is obtained which crystallizes by standing overnight in an ice bath. The crystalline material is dissolved in carbon tetrachloride, cyclohexane is added and the mixture is cooled, giving 64 g of the resulting yellow crystalline product, l- (4-pyridi-nyl) -2- (dimethylamino) ethenylethylketone. An additional 11 g of crystalline product is obtained from the mother liquor by continuous extraction chromatography on alumina using chloroform under reflux as eluent.

The above intermediate (4-pyridinyl) methyl ethyl ketone is obtained as a mixture with hexamethylphosphoramide as follows: to a mixture containing 200 ml of tetrahydrofuran and 70 ml of di-isopropylamine under nitrogen at 0-5 ° C., 210 ml of n are added -butyl-lithium 2,4N in n-hexane and the resulting mixture is stirred for 30 min. Then 90 ml of hexamethylphosphoramide is added over 10 min, then the mixture is stirred for 15 min. Then a solution of 48 ml of 4-picoline in 150 ml of tetrahydrofuran is added over 15 min, then the mixture is stirred for 30 min at approximately 0 ° C. The ice / acetone bath cooling the reaction mixture is replaced by a dry ice bath / acetone and, to the reaction mixture, a mixture of 75 ml of ethyl propionate in an equal volume of tetrahydrofuran is added over 20 min. Then the reaction mixture is allowed to warm up to room temperature in approximately

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90 min, then reheated to about 35 ° C for 30 min. The mixture is then cooled in an ice / acetone bath and 60 ml of glacial acetic acid are added to it over 30 min. The resulting pale yellow suspension is diluted with 200 ml of water. The mixture is extracted with three 150 ml portions of ethyl acetate and the ethyl acetate extract is extracted in return with saline. The extract is heated in vacuo to remove the ethyl acetate and the residue is taken up again with ethyl acetate. The solution is washed with water and then heated under vacuum to remove the ethyl acetate,

then the residue is heated under vacuum at 50 ° C for about 30 min and 100 g of a pale yellow oil are obtained. The pale yellow oil is combined with corresponding samples obtained from two other tests and distilled under vacuum, which gives a fraction of 256 g, mp 85-105 ° C at 0.66-1.33 mbar. The NMR spectrum of this fraction indicates that it is a mixture of (4-pyridinyl) methyl ethyl ketone and hexamethylphosphoramide in a molar ratio of 1: 1.55, that is to say 35% or 0 , 35 x 256 = 90 g of the ketone.

A-3. l- (4-Pyridinyl) -2- (dimethylamino) ethenyl-n-propylketone

Dilute with 250 ml of acetonitrile a mixture containing 80 g of (4-pyridinyl) methyl-n-propylketone [also called 1- (4-pyridi-nyl) -2-pentanone] and 46 ml of hexamethylphosphoramide. To the mixture, 90 ml of dimethylformamide dimethyl acetal are added and the resulting reaction mixture is heated on a steam bath for 90 min, then it is distilled under vacuum at approximately 2.7 mbar to remove volatiles, including methanol, acetonitrile and hexamethylphosphoramide. The remaining residue is diluted with ethyl acetate and washed with water. The combined water washes are extracted with five 150 ml portions of ethyl acetate. The combined ethyl acetate solutions are washed with saline, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue crystallizes on standing in a freezer. The crystalline product is diluted with cyclohexane, filtered and dried overnight at 30 ° C. and 97 g of 1- (4-pyridinyl) -2 are obtained in the form of a yellow crystalline product. - (dimethylamino) ethe-nyl-n-propylketone, pf 48-50 ° C.

The (4-pyridinyl) methyl-n-propylketone used as intermediate above is obtained as a mixture with hexamethylphosphoramide as follows: in a stirred solution of 70 ml of isopropylamine in 200 ml of tetrahydrofuran under nitrogen at approximately 0 ° C (use of an ice bath), 210 ml of 2.4N n-butyllithium are added in 20 min and the resulting mixture is stirred for 10 min at around 0 ° C. To the mixture, it is added with stirring in 10 min 90 ml of hexamethylphosphoramide and the resulting mixture is stirred for an additional 10 min. Then 45 ml of 4-picoline in 140 ml of tetrahydrofuran are added dropwise over 15 to 20 minutes. The resulting dark orange-brown solution is stirred at 0 ° C for 30 min and then treated dropwise in 18 min by addition of a solution comprising 68 ml of ethyl butyrate in 68 ml of tetrahydrofuran, the temperature rising to - 8 ° C at a temperature of +8 to + 10 ° C. The reaction mixture is removed from the ice bath and allowed to warm up to room temperature for more than 75 min. The reaction mixture is again cooled and 60 ml of glacial acetic acid are added dropwise over 15 min. It separates a pale yellow solid which gives a suspension. The suspension is diluted with water and extracted with two 200 ml portions of ethyl acetate. The ethyl acetate extract is washed with three 100 ml portions of saline, dried over anhydrous sodium sulfate and evaporated in vacuo to give 107 g of a mixture essentially comprising ( 4-pyridinyl) methyl-n-propylketone and hexamethylphosphoramide. The mixture obtained in this test is combined with corresponding mixtures obtained in two other tests and the combined mixtures are distilled under vacuum to obtain,

as main fraction, e.g. 80-90 ° C at 0.25 mbar, a mixture comprising 80 g of (4-pyridinyl) methyl-n-propylketone and 46 g of hexamethylphosphoramide.

Following the procedure described in Example A-2 but using an equimolar amount of PY-methyl (lower alkyl) -

ketone of formula II suitable in place of (4-pyridinyl) -methyl ethyl ketone, it can be seen that the 1-PY-2- (dime-thylamino) ethenyl (lower alkyl) ketones can be obtained from Examples A-4 to A-17.

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

AT 5. 1- (2-Pyridinyl) -2- (dimethylamino) ethenylmethyl ketone using (2-pyridinyl) methyl methyl ketone.

AT 5. 1- (2-Pyridinyl) -2- (dimethyl amino) ethenyl methyl ketone using (2-pyridinyl) methyl methyl ketone.

A-6. 1- (4-Pyridinyl) -2- (dimethylamino) ethenylisopropyl ketone using (4-pyridinyl) methylisopropyl ketone.

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

AT 8. 1- (4-Pyridinyl) -2- (dimethylamino) ethenylisobutyl ketone using (4-pyridinyl) methyl isobutyl ketone.

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

A-10. A- (4-Pyridinyl) -2- (dimethylamino) ethenyl-n-pentylketone using (4-pyridinyl) methyl-n-pentylketone.

A-1.1- (2-Methyl-4-pyridinyl) -2- (dimethylamino) ethenylethyl ketone using (2-methyl-4-pyridinyl) methyl ethyl ketone.

AT 12. 1- (5-Methyl-2-pyridinyl) -2- (dimethylamino) ethenylmethyl ketone using (5-methyl-2-pyridinyl) methylmethyl ketone.

A-13. 1- (5-Ethyl-2-pyridinyl) -2- (dimethylamino) ethenylethyl ketone using (5-ethyl-2-pyridinyl) methyl 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) ethenylme-thylketone using (4,6-dimethyl-2-pyridinyl) methyl methylceone.

A-16.1-f 6-Methyl-2-pyridinyl) -2- (dimethylamino) ethenylisopropylketone using (6-methyl-2-pyridinyl) methylisopropylcone-tone.

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

B. 1-R, -1,2-dihydro-6- (lower alkyl) -2-oxo-5-PY-nicotinonitrile

B-l. 1,2 Dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile, also called 1,6-dihydro-2-methyl-6-oxo- [3,4'-bipyridine] -5-carbonitrile

To a mixture containing 23 g of 1- (4-pyridinyl) -2- (dimethylami-no) ethenylmethylketone and 11 g of α-cyanoacetamide dissolved in 400 ml of dimethylformamide, 14 g of sodium methylate are added with stirring and heats the resulting reaction mixture in an oil bath at moderate reflux for 1 h. TLC analysis indicates that there is no longer any starting material in the reaction mixture which is then concentrated in vacuo in a rotary evaporator to a volume of about 80 ml. The concentrate is treated with about 160 ml of acetonitrile and the resulting mixture is stirred in a rotary evaporator while warming until it is homogeneous and then cooled. The crystalline product is collected, rinsed successively with acetonitrile and ether and dried overnight at 55 ° C to obtain 28 g of a yellow-brown crystalline product, namely the sodium salt 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile, the presence of the cyano group being confirmed by IR analysis. 8 g of the sodium salt are dissolved in 75 ml of hot water, the aqueous solution is treated with bleaching charcoal, it is filtered, the filtrate is again treated with bleaching charcoal and it is filtered and the filtrate is acidified with 6N hydrochloric acid by dropwise addition to a pH

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of 3. The acid mixture is diluted with ethanol and cooled. The crystalline product is collected, dried, recrystallized from a dimethylformamide-water mixture and dried, which gives 3.75 g of 1,2-dihydro-6-methyl-2-oxo-5- (4 -pyridinyl) nicotinonitrile, mp

> 300 ° C.

The acid addition salts of 1,2-di-hydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile are conveniently prepared by adding to a mixture of 2 g of 1,2-dihydro -6-methyl-2-oxo-5- (4-pyridinyl) nicoti-nonitrile in about 40 ml of aqueous methanol, the appropriate acid, for example methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid , to a pH of about 2 to 3, cooling the mixture after partial evaporation and collecting the precipitated salt, for example dimethanesulfonate, sulfate, phosphate respectively. The acid addition salt in aqueous solution can also be conveniently prepared by adding, with stirring, equimolar amounts of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl ) nicotinonitrile and an appropriate acid, for example lactic acid or hydrochloric acid, to prepare the monolactate or the monohydrochloride in aqueous solution respectively.

B-2. 6-Ethyl-1,2-dihydro-2-oxo-5-PY-nicotinonitrile, also called 2-ethyl-1,6-dihydro-6-oxo- [3,4'-bipyridine-5-carbonitrile, m.p.

> 300 ° C, 11.6 g. It is prepared according to the procedure described in Example B1 using 20 g of 1- (4-pyridinyl) -2- (dimethylami-no) ethenylethylketone, 8.4 g of α-cyanoacetamide, 16.2 g of sodium methylate and 250 ml of dimethylacetamide (as solvent in place of dimethylformamide).

B-3. 1,2-Dihydro-2-oxo-6-n-propyl-5- (4-pyridinyl) nicotinonitrile, also called 1,6-dihydro-6-oxo-2-n-propyl- [3,4'-bipyridine ] -5-carbonitrile, pf 232-234 ° C, 9.9 g. It is prepared according to the procedure described above in Example B1, using 85 g of 1- (4-pyridinyl) -2- (dimethylamino) ethenyl-n-propylketone, 36.5 g of a-cyano -acetamide, 50 g of sodium methylate and 800 ml of dimethylacetamide.

B-4.1,2-Dihydro-1,6-dimethyl-2-oxo-5- (4-pyridinyl) nicotinoni-trile, also called 1,6-dihydro-l, 2-dimethyl-6-oxo- (3, 4'-bipyri-dine) -5-carbonitrile, mp 245-248 ° C, 32.3 g. It is prepared according to the procedure described above in Example B1, using 42.5 g of 1- (4-pyridinyl) -2- (dimethylamino) ethenylmethyl ketone, 23.5 g of N-methyl-a- cyanoacetamide, 6.7 g of sodium methylate, 400 ml of methanol, and a reflux period of 2 h.

Following the procedure described in Example B-2 but using an equimolar amount of the appropriate l-PY-2- (dimethylamino) -ethenyl (lower alkyl) ketone of formula (III) in place of the l- (4-pyridinyl) -2- (dimethylamino) ethenylethylketone and the appropriate NR, -a-cyanoacetamide, it can be seen that the 1-Rr 1,2-dihydro-2-oxo-5-PY-6- can be obtained Corresponding R-nicotinonitriles from Examples B-5 to B-21.

B-5. 1,2-Dihydro-6-methyl-2-oxo-5- (3-pyridinyl) nicotinonitrile, using 1- (3-pyridinyl) -2- (dimethylamino) ethenylmethyl ketone and α-cyanoacetamide.

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

B-7.1,2-Dihydro-6-isopropyl-2-oxo-5- (4-pyridinyl) nicotinonitrile, using 1- (4-pyridinyl) -2- (dimethylamino) ethenylisopropylcone-tone and α-cyanoacetamide .

B-8. 6-n-Butyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile, using l- (4-pyridinyl) -2- (dimethylamino) ethenyl-n-butylcone-tone and l 'a-cyanoacetamide.

• B-9.1,2-Dihydro-6-isobutyl-2-oxo-5- (4-pyridinyl) nicotinonitrile, using l- (4-pyridinyl) -2- (dimethylamino) ethenylisobutylcone-tone and a- cyanoacetamide.

B-10. 1,2-Dihydro-2-oxo-5- (4-pyridinyl) -6-t-butylnicotinonitrile, using l- (4-pyridinyl) -2- (dimethylamino) ethenyl-t-butylcone-tone and a-cyanoacetamide.

Bl 1. 7,2-Dihydro-2-oxo-6-n-pentyl-5- (4-pyridinyl) nicotinonitrile, using l- (4-pyridinyl) -2- (dimethylamino) ethenyl-n-pentylce- tone and a-cyanoacetamide.

B-12. 6-Ethyl-1,2-dihydro-5- (2-methyl-4-pyridinyl) -2-oxonicoti-nonitrile, using l- (2-methyl-4-pyridinyl) -2- (dimethylami-îo no ) ethenylethylketone and α-cyanoacetamide.

B-13. 1,2-Dihydro-6-methyl-5- (5-methyl-2-pyridinyl) -2-oxonicoti-nonitrile, using 1- (5-methyl-2-pyridinyl) -2- (dimethylami-no) ethenylmethylketone and α-cyanoacetamide.

B-14.6-Ethyl-5- (5-ethyl-2-pyridinyl) -1,2-dihydro-2-oxonicotino-nitrile, using 1- (5-ethyl-2-pyridinyl) -2- (dimethylamino ) ethe-nylethyl ketone and α-cyanoacetamide.

B-15. 6-Ethyl-1,2-dihydro-2-oxo-5- (3-pyridinyl) nicotinonitrile, using l- (3-pyridinyl) -2- (dimethylamino) ethenylethyl ketone and α-cyanoacetamide.

Bl 6.1,2-Dihydro-5- (4,6-dimethyl-2-pyridinyl) -6-methyl-2-oxoni-cotinonitrile, using 1- (4,6-dimethyl-2-pyridinyl) -2- (dimethyl-amino) ethenylmethylketone and α-cyanoacetamide.

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Bl 7.1,2-Dihydro-6-isopropyl-5- (6-methyl-2-pyridinyl) -2-oxoni-cotinonitrile, using 1- (6-methyl-2-pyridinyl) -2- (dimethylami-no ) ethenylisopropyl ketone and α-cyanoacetamide.

B-18. 1,2-Dihydro-6-n-hexyl-2-oxo-5- (2-pyridinyl) nicotinonitrile, using l- (2-pyridinyl) -2- (dimethylamino) ethenyl-n-hexylce-tone and a-cyanoacetamide.

B-19. 6-Ethyl-1,2-dihydro-1- (2-hydroxyethyl) -2-oxo-5- (4-pyridi-nyl) nicotinonitrile, using 1- (4-pyridinyl) -2- (dimethylami-35 no) ethenylethylketone and N- (2-hydroxyethyl) -a-cyanoacetamide.

B-20.1 -Ethyl-1,2-dihydro-6-methyl 1-2-0X0-5- (4-pyridinyl) nicotinonitrile, using l- (4-pyridinyl) -2-dimethylamino) ethenylmethylketone and N-ethyl-a-cyanoacetamide.

40 B-21.1,6-Diethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile, using l- (4-pyridinyl) -2- (dimethylamino) ethenylethyl ketone and N -ethyl-a-cyanoacetamide.

C. l-R., - 1,2-dihydro-6- (lower alkyl) -2-oxo-5- (pyridinyl) nicoti-namides

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C-l. 1,2-Dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinamide, also called 1,2-dihydro-2-methyl-6-oxo- [3,4'-bipyridine] -5- carboxamide

Heated at 100 ° C for 30 min using an oil bath 50 a mixture containing 9.0 g of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile and 45 ml concentrated sulfuric acid. The hot reaction mixture is added to 200 ml of ice and the resulting mixture is cooled in an ice-acetone bath. To the cold solution is carefully added about 150 ml of 28% ammonium hydroxide drop by drop. The resulting mixture containing a precipitate is cooled in an ice / acetone bath for about 30 min. The precipitate is then collected, rinsed successively with water and acetonitrile, dried well and recrystallized by dissolving it in 130 ml of hot water (at boiling point), "adding 30 ml of acetic acid, treating with bleaching charcoal and filtering. The filtrate is concentrated and diluted with acetonitrile; the mixture is stored in ice for about 30 min. The resulting crystalline material is collected and 8.35 g of a yellow-brown crystalline material are obtained. This material is combined with the same substance obtained in another test and the combined 13.5 g are dissolved in 500 ml of dimethylformamide at its boiling point, the hot mixture is filtered and the filtrate is cooled in a water bath. ice. The crystalline precipitate is collected, rinsed with

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acetone and dried for 14 h at 100 ° C on phosphoric anhydride and the IR and NMR analyzes show that it still contains a little dimethylformamide. The 10.5 g of light fawn crystalline product is dissolved in 75 ml of hot acetic acid, treated with 50 ml of water and then diluted to a volume of 300 ml with acetone. The resulting mixture containing a few crystals is cooled in an ice bath for about 45 min. The resulting light yellow-brown crystalline product is collected, dried first at 55 ° C and then at 110 ° C to remove the last weak odor of acetic acid and 9.2 g of l are obtained. , 2-dihydro-6-methyl-2-oxo-5- (4-pyridi-nyl) nicotinamide, pf > 300 ° C.

The acid addition salts of 1,2-di-hydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinamide are conveniently prepared by addition to a mixture of 5 g of l, 2- dihydro-6-methyl-2-oxo-5- (4-pyridinyl) ni-cotinamide in about 100 ml of aqueous methanol, the appropriate acid, for example methanesulfonic acid, concentrated sulfuric acid, phosphoric acid concentrated, to a pH of about 2 to 3, cooling the mixture after partial evaporation and collecting the salt which has precipitated, for example dimethanesulfonate, sulfate, phosphate respectively. The acid addition salt in aqueous solution is also conveniently prepared by adding equimolar amounts of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridmyl) to water, with stirring. ) nicotinamide and the appropriate acid, lactic acid or hydrochloric acid for example, to prepare the monolactate or the monohydrochloride in aqueous solution respectively.

C-2. 6-Ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinamide, also called 1,6-dihydro-2-ethyl-6-oxo- [3,4'-bipyridine] -5- carboxa-mide

A 40 g portion of 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile is added to 170 ml of concentrated sulfuric acid and the temperature then rises to about 70 ° C. This reaction mixture is immersed in an oil bath preheated to about 90 ° C and then maintained between 95-105 ° C for about 40 min. The hot reaction mixture is then poured into a beaker containing 800 ml of ice. The mixture is stirred and placed in an ice-acetone bath. To the cold mixture, 650 ml of 28% ammonium hydroxide are added dropwise with stirring, and the temperature rises to approximately 46 ° C. To the mixture, 300 ml of ice is added with stirring and the stirring is continued. for about 15 min. The precipitate is collected, rinsed with three 150 ml portions of water, dried in air for 2 h, diluted with a little acetonitrile, filtered and the solid is dried for several days at 55 ° C and 39.5 g of product are obtained. The solid is carefully stirred with 300 ml of water, filtered and dried and 38 g of crystalline product, 6-ethyl-1,2-dihydro-2-oxo-5- (4- pyridinyl) nicotinamide. Another 14.3 g of this product are purified by dissolving them in 40 ml of hot acetic acid, filtering the hot solution and diluting the filtrate to 180 ml with absolute ethanol, and crystals are formed. The hot mixture is allowed to cool. The light yellow-brown crystallized product is collected and dried at 110 ° C. over P2Os for approximately 15 h to obtain 11.7 g of 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl ) nicotinamide, pf > 300 ° C.

C-3.1,2-Dihydro-2-oxo-6-n-propyl-S- (4-pyridinyl) nicotinamide, also called 1,6-dihydro-6-oxo-2-n-propyl- [3,4 ' -bipyridine] -5-carboxamide, pf > 300 ° C, 10.5 g; it is prepared according to the procedure described in Example C-2 using 30.7 g of 1,2-dihydro-2-oxo-6-n-propyl-5- (4-pyridinyl) nicotinonitrile and 130 ml of concentrated sulfuric acid.

Following the procedure described in Example C-2 but using an equimolar amount of lR, -l, 2-dihydro-2-oxo-5-PY-6-R-nicotinonitrile (of formula I where Q is a cyano group) in place of 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicoti-nonitrile, it can be seen that the 1,2-dihydro-2- can be obtained oxo-5-PY-6-R-nicotinamides corresponding to examples C-4 to C-21.

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.

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-l 1.6-Ethyl-1,2-dihydro-5- (2-methyl-4-pyridinyl) -2-oxonicoti-namide.

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-oxonicotin-amide.

C-14. 6-Ethyl-1,2-dihydro-5- (3-pyridinyl) -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-oxoni-cotinamide.

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) nicotin-amide.

C-19. 6-Ethyl-1,2-dihydro-1- (2-hydroxyethyl) -2-oxo-5- (4-pyridi-nyl) nicotinamide.

C-20. 1-Ethyl-1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicoti-namide.

C-21. 1,6-Diethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotin-amide.

D. l-R, -3-Amino-6- (lower alkyl) -5-PY-2 (1H) -pyridinones

D-l. 3-Amino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone, also called 5-amino-2-methyl- [3,4'-bipyridin] -6 (1H) -one

To a solution containing 13 g of sodium hydroxide in 250 ml of water, 12 g of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinamide are added and the mixture is heated resulting on a steam bath to effect dissolution. To the solution, an additional 250 ml of water is added and the resulting solution is cooled to around 35 ° C with stirring, and some crystals are separated. The mixture is cooled in an ice bath and a total of 4.0 ml of bromine is added to it dropwise, dissolution taking place after addition of about 3 ml of bromine. The mixture is stirred for an additional 10 min when cold and then heated on a steam bath for 45 min. The reaction mixture is then concentrated to approximately half its volume, cooled in an ice bath and treated with 6N hydrochloric acid to pH approximately 8. The resulting crystalline product is collected, it is rinsed twice with water and once with acetone and dried to obtain 7.3 g of substance. The 7.3 g are treated with 20 ml of water and the insoluble amorphous material is filtered. The filtrate is concentrated to dryness and the resulting crystalline material is recrystallized from a mixture of dimethylformamide and water, which gives 3.8 g of 3-amino-6-methyl-5- (4-pyridinyl) -2 (1H ) -pyridinone, pf > 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) -1 (1H) -pyridi-none in about 40 ml of aqueous methanol, the appropriate acid, for example methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid , to a pH of about 2 to 3, cooling the mixture after partial evaporation and collecting the salt which has precipitated, respectively for example dimethylsulfonate, sulfate and phosphate. The acid addition salt in aqueous solution is also conveniently prepared by adding to

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water, with stirring, equimolar amounts of 3-amino-6-methyl-

5- (4-pyridinyl) -2 (1 Hpyridinone and an appropriate acid, for example lactic acid or hydrochloric acid, to respectively prepare the monolactate or the monohydrochloride in aqueous solution.

D-2. 3-Amino-6-ethyl-5- (4-pyridinyl) -2 (1H) pyridinone, also called 5-amino-2-ethyl-3,4'-bipyridine-6 (1H) -one, m.p. > 300 ° C, 8.8 g; it is prepared by following the procedure described in Example D1 but using 10.0 g of 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinamide, 8.8 g of sodium hydroxide, 300 ml of water, 3.0 ml of bromine and by recrystallization from a mixture of dimethylformamide and isopropyl alcohol.

D-3. 3-Amino-6-n-propyl-5- (4-pyridinyl) -2 (1H) pyridinone, also called 5-amino-2-n-propyl- [3,4'-bipyridin] -6 (1H) - one. To a stirred solution containing 8.5 g of 1,2-dihydro-2-oxo-6-n-propyl-5- (4-pyridinyl) nicotinamide and 95 ml of water at room temperature, a solution of 1.32 g of sodium hydroxide in 6 ml of water. The resulting suspension is cooled in an ice bath, stirred for 10 min and then treated dropwise with 22 ml of a 13.1% aqueous solution of sodium hypochlorite in 3 min. Dissolution takes place and stirring is continued without cooling for 30 min. To the resulting solution at 15 ° C is added 27 ml of 35% aqueous sodium hydroxide; the reaction mixture is heated on a steam bath at approximately 60-70 ° C for 1 h, then the hot solution is treated slowly with 14 ml of glacial acetic acid over 5 min, which causes the separation of a yellow precipitate -brown. The mixture is stirred for 5 min; the precipitate is collected, washed with hot water and dried over P205. The resulting 12 g of product are recrystallized from a mixture of 100 ml of dimethylformamide and 80 ml of water, dried overnight at 95 ° C. over P2Os and 9.5 g of 3-amino-6-n are obtained. -propyl-5- (4-pyri-diny l) -2 (1 H) -pyridinone, pf 200-202 ° C.

Following the procedure described in Example D-1 but using an equivalent amount of 1 -R, -1,2-dihydro-2-oxo-5-P Y -

6-R-nicotinamide suitable (formula I where Q is a carbamyl group) in place of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) ni-cotinamide, we see that the the corresponding 1R, -3-amino-5-PY-6-R-2- (1H) -pyridinones can be obtained from Examples D-4 to D-21.

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

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

D-6. 3-Amino-6-isöpropyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

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

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

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

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

D-ll. 3 Amino-6-ethyl-5- (2-methyl-4-pyridinyl) -2 (1H) -pyridi-none.

D-12. 3-Amino-6-methyl-5- (5-methyl-2-pyridinyl) -2 (1H) -pyridi-none.

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.

D-16. 3-Amino-6-isopropyl-5- (6-methyl-2-pyridinyl) -2 (1H) -pyri-dinone.

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

D-18. 3-Amino-1,6-dimethyl-5- (4-pyrìdinyl) -2 (1 H) -pyridinone.

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

D-20. 3-Amino-1-ethyl-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridi-none.

D-21.3-Amino-1,6-diethyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

5 E. 1- Rr6- (lower alkyl) -5-PY-2 (1Hj-pyridinones

E.l. 6-Methyl-5- (4-pyridinyl) -2- (1H) -pyridinone, also called 2-methyl- [3,4'-bipyridin] -6 (1H) -one. A mixture of 5.3 g of 1,2-dihydri-6-methyl-2-oxo-5- (4-pyri-dinyl) nicotinonitrile and 30 ml of 85% sulfuric acid is heated to about 195 ° C. , heat gently at reflux for 24 h, cool and add to ice. The aqueous mixture is brought to a pH of 8 by addition of a concentrated aqueous solution of sodium hydroxide. The resulting precipitate (product + Na2SO4) is treated with chloroform and the chloroform solution is filtered. The filtrate is concentrated in vacuo to remove the chloroform and the resulting crystalline residue is recrystallized from a mixture of methylene dichloride and ether and dried at 75 ° C for 4 h to give 4.1 g of 6 -methyl-5- (4-pyridinyl) -2 (1 H) -pyridinone, pf 287-288 ° C.

The acid addition salts of 6-20 methyl-5- (4-pyridinyl) -2 (1H) -pyridinone are conveniently prepared by adding, to a mixture of 5 g of 6-methyl-5- (4 -pyridinyl) -2 (1H) -pyridinone in approximately 100 ml of aqueous methanol, the appropriate acid, for example methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid, up to a pH of approximately 2 to 3, by cooling the mixture after partial evaporation and collecting the salt which has precipitated, for example dimethanesulfonate, sulfate or phosphate respectively. The acid addition salt in aqueous solution is also conveniently prepared by adding equimolar amounts of 6-methyl-5- (4-pyridinyl) -2 (1H) -pyridi-30 to water, with stirring. none and appropriate acid, for example lactic acid or hydrochloric acid, to respectively prepare the monolactate or the monohydrochloride in aqueous solution.

E-2. 6-Ethyl-5- (4-pyridinyl) -2 (1H) -pyridinone, also called 2-ethyl- [3,4'-bipyridin] -6 (1H) -one. Heated with stirring at 200 ° C for 24 h a mixture containing 9 g of 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile and 50 ml of concentrated sulfuric acid, cooled at about 40 ° C and poured into 200 ml of ice water. After basifying the aqueous solution with concentrated ammonium hydroxide, the solid which separates is collected, recrystallized from 70 ml of isopropyl alcohol and dried at 60 ° C. under vacuum, which gives 3 g of 6-ethyl-5- (4-pyridinyl) -2 (1H) -pyridi-none, pf 226-228 ° C. A second harvest of 0.4 g is obtained, m.p. 225-227 ° C, concentrating the filtrate to around 20 ml.

45 E-3. 6-n-Propyl-5- (4-pyridinyl) -2 (1H) -pyridinone, also ap-peeled 2- (n-propyl) - [3,4'-bipyridin] -6 (1H) -one, m.p. 179-180 ° C, 3.4 g; this product is obtained by following the procedure described in Example E-2, but using 10 g of 1,2-dihydro-6-n-propyl-2-oxo-5- (4-pyridinyl) nicotinonitrile, 42 , 5 ml of 85% sulfuric acid, 50 and by recrystallization from a mixture of methylene dichloride and ether.

Following the procedure described in Example E-2 but using instead of 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nico-tinonitrile an equimolar amount of l- Rrl, 2-dihydro-2-oxo-5-PY-6- (lower alkyl) corresponding nicotinonitrile, we see that we can obtain the l-Rr5-PY-6- (lower alkyl) -2 (1H) - pyridinones from Examples E-4 to E-21.

E-4. 6-Methyl-5- (3-pyridinyl) -2 (1H) -pyridinone. 60 E-5.6-Isopropyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

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

E-7. 6-Isobutyl-5- (4-pyridinyl) -2 (1H) -pyridinone. 65 E-8.5- (4-Pyridinyl) -6-t-butyl-2 (1H) -pyridinone.

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

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

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

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

E-13. 6-Ethyl-1 - (2-hydroxyethyl) -5- (4-pyridinyl) -2 (1 H) -pyridi-none.

E-14.1 -Ethyl-6-methyl-5- (4-pyridinyl) -2 (1 H) -pyridinone.

E-15. 1,6-Diethyl-5- (4-pyridinyl) -2 (1 H) -pyridinone.

E-16. 6-Methyl-5- (2-pyridinyl) -2 (1H) -pyridinone.

E-17. 6-Methyl-5- (5-methyl-2-pyridinyl) -2 (1H) -pyridinone.

E-18. 6-Ethyl-5- (5-ethyl-2-pyridinyl) -2 (1H) -pyridinone.

E-19. 6-Methyl-5- (4,6-dimethyl-2-pyridinyl) -2 (1H) -pyridinone.

E-20. 6-Isopropyl-5- (6-methyl-2-pyridinyl) -2 (1H) -pyridinone.

E-21. 6-n-Hexyl-5- (2-pyridinyl) -2 (1 H) -pyridinone.

F. l-R, -3-Halo-6- (lower alkyl) -5-PY-2 (1H) -pyridinones

F-l. 3-Bromo-6-methyl-5- (4-pyridinyl) -2 (1Hj-pyridinone, also called 5-bromo-2-methyl- [3,4'-bipyridin] -6 (1H) -one. stirred solution of 80 g of 6-methyl-5- (4-pyridinyl) -2 (1 H) -pyridinone in 11 acetic acid, heated to 65 ° C., 69 g of bromine are added dropwise over 25 min. 50 ml of acetic acid The reaction mixture is stirred for a further 30 minutes, cooled to room temperature and filtered to collect the crystalline precipitate, the precipitate is dried and suspended in 1500 ml of water To the vigorously stirred suspension, 25 ml of a 28% ammonium hydroxide solution are added dropwise and a white creamy precipitate separates out. The solid is collected and dried under vacuum at 90 ° C. , which gives 101 g of 3-bromo-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone, mp 252-254 ° C. A sample of 15 g is dissolved in 200 ml of acid hot acetic acid and filtered. The filtrate is concentrated in vacuo, diluted with methanol and the resulting white crystalline precipitate is collected and dried at 100 ° C. for 16 h under vacuum to obtain 9.8 g of the product, m.p. 252-254 ° C.

The acid addition salts of 3-bromo-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone are conveniently prepared by adding, to a mixture of 5 g of 3-bromo-6 -methyl-5- (4-pyridinyl) -2 (1H) -pyridi-none in about 100 ml of aqueous methanol, the appropriate acid, for example methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid , to a pH of approximately 2 to 3, by cooling the mixture after partial evaporation and collecting the salt which has precipitated, for example dimethanesulfonate, sulfate or phosphate respectively. The acid addition salt in aqueous solution is also conveniently prepared by adding equimolar amounts of 3-bromo-6-methyl- to water, with stirring.

5- (4-pyridinyl) -2 (1 H) -pyridinone and of the appropriate acid, for example lactic acid or hydrochloric acid, to prepare respectively the monolactate and the monohydrochloride in aqueous solution.

F-2. 3-chloro-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone, also called 5-chloro-2-methyl- [3,4'-bipyridin] -6 (1H) -one. A mixture containing 18.6 g of 6-methyl-5- (4-pyridinyl) -2 (1H) -pyri-dinone and 200 ml of acetic acid, treated on a steam bath, is treated with bubbling chlorine for 4 h. After allowing the reaction mixture to cool to room temperature, the solid is collected, washed with ether and dried. The solid is dissolved in water, the aqueous solution is neutralized with a 2N aqueous solution of potassium hydroxide and the mixture is cooled. The solid which separates is collected, washed with water, dried and recrystallized from ethanol, which gives 3-chloro-

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

Following the procedure described in example F1 or F-2 but using instead of 6-methyl-5- (4-pyridinyl) -2 (1H) -pyri-dinone an equimolar amount of l- Rr6- (lower alkyl) -5-PY-2 (1H) -pyridinone corresponding and bromine or chlorine, we see that we can obtain the l-Rr3-bromo or chloro-6- (lower alkyl) -5 -PY-2 (1H) -pyridinones from Examples F-3 to F-22.

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

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

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

F-6. 3-Bromo-6-isopropyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

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

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

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

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

F-1 1. 3-Bromo-6-ethyl-5- (2-methyl-4-pyridinyl) -2 (1H) -pyridi-none.

F-12. 3-Chloro-6-ethyl-5- (3-pyridinyl) -2 (1H) -pyridinone.

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

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

F-15. 3-Chloro-6-methyl-5- (4-pyridinyl) -2 (1 H) -pyridinone.

F-16. 3-Bromo-1,6-diethyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

F-l7. 3-Bromo-6-methyl-5- (2-pyridinyl) -2 (1 H) -pyridinone.

F-18. 3-Bromo-6-methyl-5- (5-methyl-2-pyridinyl) -2 (1H) -pyridi-none.

F-19. 3-Bromo-6-ethyl-5- (5-ethyl-2-pyridinyl) -2 (1 H) -pyridinone.

F-20. 3-Chloro-6-methyl-5- (4,6-dimethyl-2-pyridinyl) -2 (1H) -pyridinone.

F-21.3-Bromo-6-isopropyl-5- (6-methyl-2-pyridinyl) -2 (1H) -pyri-dinone.

F-22. 3-Chloro-6-n-hexyl-5- (2-pyridinyl) -2 (1H) -pyridinone.

G. l-R, -3- [Mono or di- (lower alkyl) amino] -5-PY-6- (lower alkyl) -2 (1H) -pyridinones

G-l. 6-Methyl-3-methylamino-5- (4-pyridinyl) -2 (1H) -pyridinone, also called 2-methyl-5-methylamino- [3,4'-bipyridin] -6 (1H) -one. The mixture is autoclaved at 160 ° C for 48 h a mixture containing 19 g of 3-bromo-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone, 250 ml of 70% aqueous methylamine , 60 mg of copper bronze and 60 mg of cupric sulfate. The crystalline mass is taken up with hot aqueous methanol and the mixture is filtered to collect the product. The solid (6 g) is dissolved in a small amount of acetic acid plus another 1 g portion obtained by concentrating the mother liquor and diluting with methanol, filtering and diluting the filtrate with water. The resulting crystalline precipitate is collected, washed thoroughly with water and dried at 90 ° C overnight, to give 5.1 g of 6-methyl-3-methylamino-5- (4-pyridinyl ) -2 (1H) -pyridinone, pf 270-275 ° C with decomposition. This preparation can also be carried out as above using an equimolar amount of 3-chloro-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone in place of 3-bromo-6-methyl -5- (4-pyridinyl) -2 (1H) -pyridinone.

The acid addition salts of 6-methyl-3-methylamino-5- (4-pyridinyl) -2 (1H) -pyridinone are conveniently prepared by adding to a mixture of 5 g of 6-methyl-3- methylamino-5- (4-pyridinyl) -2 (1H) -pyridinone in about 100 ml of aqueous methanol, the appropriate acid (e.g. methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid), up to to a pH of about 2 to 3, cooling the mixture after partial evaporation and collecting the salt which has precipitated, for example dimethanesulfonate, sulfate or phosphate respectively. The acid addition salt in aqueous solution can also be conveniently prepared in

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adding to water, with stirring, equimolar amounts of 6-methyl-3-methylamino-5- (4-pyridinyl) -2 (1H) -pyridinone and the appropriate acid, for example lactic acid or hydrochloric acid,

to respectively prepare the monolactate or the monohydrochloride in aqueous solution.

G-2. 3-Ethylamino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone, also called 5-ethylamino-2-methyl- [3,4'-bipyridin] -6 (1H) -one, m.p. 250 ° C, 1.6 g; it is prepared by following the procedure described in Example G1 but using 16.5 g of 3-bromo-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone, 110 ml of ethylamine , 15 ml of water, 30 mg of copper bronze, 30 mg of cupric sulphate, passing through an autoclave at 150 ° C for 45 h and recrystallizing twice from acetonitrile.

G-3. 6-Methyl-3-dimethylamino) -5- (4-pyridinyl) -2 (1H) -pyridi-none, also called 5- (dimethylamino) -2-methyl- [3,4'-bipyri-din] -6 (1H) -one. To a stirred solution containing 20 g of 3-amino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone dissolved in 200 ml of formic acid, added dropwise with stirring over 5 min 20 ml of a 37% formaldehyde solution. The mixture is heated at reflux for 1 h and 45 min, the mixture is heated to dryness under vacuum and the residue is taken up with methylene dichloride. The methylene dichloride solution is washed with a saturated aqueous solution of sodium bicarbonate and filtered. The filtrate is dried over anhydrous sodium sulfate, filtered and the solvent is distilled under vacuum to obtain 14 g of a yellow crystalline solid. The solid is dissolved in 250 ml of hot methylene dichloride, the hot solution is treated with bleaching charcoal and filtered, and the filtrate is concentrated in vacuo to almost dryness and then treated with acetonitrile. The resulting mixture of crystalline material and acetonitrile is cooled, the solid is collected and dried, giving 10.5 g of a yellow crystallized product containing a trace of impurity (indicated by TLC). The solid is dissolved in a chloroform solution and the traces of impurity are removed by filtering the chloroform solution on a 6.35 cm column of silica gel. The resulting product (10.5 g) is dissolved in methylene dichloride, the solution is diluted with isopropyl alcohol and concentrated in vacuo and then cooled. The precipitate is collected and dried at 80 ° C., which gives 9.0 g of 6-methyl-3- (dimethylamino) -5- (4-pyridi-nyl) -2 (1H) -pyridinone, m.p. 223-225 ° C.

Following the procedure described in Example Gl or G-2 but using instead of 3-bromo-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone an equimolar amount of the 1R, -3-bromo (or chloro) -5-PY-6- (lower alkyl) -2 (1H) -pyridinone and the lower alkylamine or the appropriate di (lower alkyl) amine, it can be seen that obtain the l-Rr3- [mono- or di (lower alkyl) amino] -5-PY-6- (lower alkyl) -2 (1H) -pyridinones from Examples G-4 to G-23.

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

G-5. 3-Methylamino-6-methyl-5- (3-pyridinyl) -2 (1H) -pyridinone.

G-6. 3-n-Propylamino-6-n-propyl-5- (4-pyridinyl) -2 (] H) -pyridi-none.

G-7. 3-Methylamino-6-isopropyl-5- (4-pyridinyl) -2- (1 H) -pyridi-none.

G-8. 6-n-Butyl-3-dimethylamino-5- (4-pyridinyl) -2 (1 H) -pyridi-none.

G-9. 3-n-Butylamino-6-isobutyl-5- (4-pyridinyl) -2 (1 H) -pyridi-none.

G-10. 3-Methylamino-5- (4-pyridinyl) -6-t-butyl-2 (1 H) -pyridi-none.

G-11. 3-Isopropylamino-6-n-pentyl-5- (4-pyridinyl) -2 (1 H) -pyridi-none.

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

G-1 3. 6-Ethyl-3-ethylamino-5- (3-pyridinyl) -2 (1H) -pyridinone.

G-14: 3-Methylamino-1,6-dimethyl-5- (4-pyridinyl) -2 (1H) -pyridi-none.

G-15. 6-Ethyl-3-ethylamino-1- (2-hydroxyethyl) -5- (4-pyridinyl) -2 (1H) -pyridinone.

G-16. 1-Ethyl-6-methyl-3-methylamino-5- (4-pyridinyl) -2 (1H) -pyridinone.

G-1 7. 1,6-Diethyl-3-methylamino-5- (4-pyridinyl) -2 (1 H) -pyridi-none.

G-18. 3-n-Hexylamino-6-methyl-5- (2-pyridinyl) -2 (1H) -pyridi-none.

G-19. 3-EthyIamino-6-methyl-5- (5-methyl-2-pyridinyl) -2 (1H) -pyridinone.

G-20. 6-Ethyl-5- (5-ethyl-2-pyridinyl) -3-dimethylamino-2 (1H) -pyridinone.

G-21. 3-Diisopropylamino-6-methyl-5- (4,6-dimethyl) -2-pyridi-nyl) -2 (1 H) -pyridinone.

G-22. 3-Ethylamino-6-isopropyl-5- (6-methyl-2-pyridinyl) -2 (1H) -pyridinone.

G-23. 3-Methylamino-6-n-hexyl-5- (2-pyridinyl) -2 (1H) -pyridi-none.

H. 1-Rr3- (lower acylamino) -6- (lower alkyl) -5-PY-2- (1H) -pyridinones

H-1. 3-Acetylamino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone, also called N- [1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl)] ~ acetamide.

A mixture containing 10.1 g of 3-amino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone, 5.7 g of acetic anhydride and 120 is heated in the steam bath for 1 hour. ml of pyridine and then allowed to cool. The product which separates is collected, washed with ether, dried and recrystallized from dimethylformamide to obtain 3-acetylamino-6-methyl-5- (4-pyridinyl) -2 (1 H ) -pyridinone.

The acid addition salts of 3-acetylamino-6-methyl-5- (4-pyridinyl) -2 (1 H) -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 (e.g. methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid) to a pH of about 2 to 3, cooling the mixture after partial evaporation and collecting the precipitated salt, for example dimethanesulfonate, sulfate and phosphate respectively. The acid addition salt in aqueous solution can also be conveniently prepared by adding equimolar amounts of 3-acetyl-amino-6-methyl-5- (4-pyridinyl) -2 to water, with stirring. (1H) -pyridinone and an appropriate acid, for example lactic acid or hydrochloric acid, for preparing the monolactate and the monohydrochloride in aqueous solution respectively.

H-2. 3- [2- (Acetoxy) propanoylamino] -6-methyl-2 (1H) -pyridi-none - To a stirred solution containing 20.1 g of 3-amino-6-methyl-5- (4-pyridinyl) - 2 (1H) -pyridinone and 300 ml of pyridine at room temperature, 16.5 g of 2-acetoxypropanoyl chloride are added dropwise over approximately 1 hour and the resulting mixture is cooled in an ice bath. The product which separates is collected, washed with ether, dried, recrystallized from methanol, washed successively with ethanol and ether and dried to obtain the 3- [2- (acetoxy) -propanoylamino] -6-methyl-2 (1H) -pyridinone.

Following the procedure described in Example HI or H-2 but using instead of 3-amino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone and / or l acetic anhydride or 2-acetoxypropanoyl chloride equimolar amounts of lR, -3-amino-5-

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PY-6- (lower alkyl) -2 (1H) -pyridinone and / or corresponding suitable acylating agents, it can be seen that 3- (lower acylamino) -5-PY-6- (lower alkyl) -2 (1H) -pyridinones from Examples H-3 to H-17.

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

H-4. 6-Methyl-3-propionylammo-5- (3-pyridinyl) -2 (1H) -pyridi-none.

H-5. 3-Butyrylamino-6-n-propyl-5- (4-pyridinyl) -2 (1 H) -pyridi-none.

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 (1H) -pyridinone.

H-8. 3-Acetylamino-6-n-pentyl-5- (4-pyridinyl) -2 (1H) -pyridmone.

H-9. 3- [2- (Acetoxy) propanoylamino] -6-ethyl-5- (2-methyl-4-pyri-dinyl) -2 (1 H) -pyridinone.

H-0. 6-Ethyl-3-propionylamino-5- (3-pyridinyl) -2 (1 H) -pyridi-none.

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

H-12. 3-Acetyl-6-ethyl-1 - (2-hydroxyethyl) -5- (4-pyridinyl) -2 (1H) -pyridinone.

H-13. 1,6-Diethyl-3-propionylamino-5- (4-pyridinyl) -2 (1H) -pyri-dinone.

H-14. 3-Acetylamino-6-methyl-5- (2-pyridinyl) -2 (1H) -pyridinone.

H-15. 6-Ethyl-5- (5-ethyl-2-pyridinyl) -3-formylamino-2 (1H) -pyri-dinone.

H-16. 3-Acetylamino-6-methyl-5- (4,6-dimethyl-2-pyridinyl) -2 (1H) -pyridinone.

H-17. 3-Acetylamino-6-n-hexyl-5- (2-pyridinyI) -2 (1 H) -pyridi-none.

I. A-RrI, 2-dihydro-6- (lower alkyl) -2-oxo-5-PY-nicotinic acids

1-1. 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinic acid, also called l, 6-dihydro-2-methyl-6-oxo [3,4'-bipyridine] -5 -carboxylic. 30 g of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile are added, with stirring, to a hot solution containing 220 ml of water and 245 ml of concentrated sulfuric acid. The reaction mixture is heated to reflux for 7 h (about 122 ° C) and then allowed to stand for the end of the week at room temperature. It is then diluted with water, cooled in an ice bath and treated dropwise with stirring with ammonium hydroxide until neutral pH. The resulting crystalline precipitate is collected, rinsed successively with three 100 ml portions of water and several times with acetone and then with ether and dried at 80 ° C. The crystalline material is diluted with 200 ml of chloroform and 200 ml of methanol for 30 min and the mixture is concentrated in vacuo to a volume of 150 ml. The crystalline product is collected and dried at 95 ° C. over P2Os, which gives approximately 24 g of product. A 10 g sample of the product is heated with 200 ml of water to the boiling point, the mixture is cooled and the solid is collected and dried at 80 ° C. to obtain 9 g of 1,2-di acid -hydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinic, mp > 260 ° C.

Following the procedure described in Example 1-1 but using instead of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) ni-cotinonitrile an equimolar amount of l- Rrl, 2-dihydro-2-oxo-5-PY-6- (lower alkyl) corresponding nicotinonitrile, we see that we can obtain the acids l-Rrl, 2-dihydro-2-oxo-5-PY-6 - (lower alkyl) nicotinics of examples 1-2 to 1-21.

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

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) nicotinic acid.

1-6. 6-n-Butyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinic acid.

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

1-8. Acid 1,2-dihydro-2-oxo-5- (4-pyridinyl) -6-t-butylnicotini-que.

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

1-10. 6-Ethyl-1,2-dihydro-5- (2-methyl-4-pyridinyl) -2-oxoni-cotinic acid.

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

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

1-13. 6-Ethyl-1,2-dihydro-1- (2-hydroxyethyl) -2-oxo-5- (4-pyridinyl) nicotinic acid.

1-14. 1-Ethyl-1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) ni-cotinic acid.

1-15. 1,6-Diethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinic acid.

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

1-17. 1,2-dihydro-6-methyl-5- (5-methyl-2-pyridinyl) -2-oxonicotinic acid.

1-18. 6-ethyl-5- (5-ethyl-2-pyridinyl) -1,2-dihydro-2-oxoni-cotinic acid.

1-19. 1,2-dihydro-6-methyl-5- (4,6-dimethyl-2-pyridinyl) -2-oxonicotinic acid.

1-20. 1,2-dihydro-6-isopropyl-5- (6-methyl-2-pyridinyl) -2-oxonicotinic acid.

1-21. 1,2-dihydro-6-n-hexyl-2-oxo-5- (2-pirydinyl) nicotinic acid.

J. l-R, -6- (lower alkyl) -! , Lower alkyl 2-dihydro-2-oxo-5-PY-nicotinates

J-l. 1,2-Dihy dro-6-methyl 1-2-0X0-5- (4-pyridinyl) ethyl nicotinate.

A 4 g portion of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinic acid is heated in 200 ml of ethanol at reflux with 1 g of methanesulfonic acid for 18 h . The excess ethanol is distilled in vacuo and the residue is recrystallized from dimethylform amide to obtain 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) ni-cotinate under form of its methanesulfonic acid salt. The salt is dissolved in hot water and the solution is made alkaline with an excess of an aqueous solution of potassium carbonate. The solid which separates is collected, dried, recrystallized from isopropyl alcohol and dried, which gives 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) ethyl nicotinate.

The acid addition salts of 1,2-di-hydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinate are conveniently prepared by adding to a mixture of 5 g of l, Ethyl 2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) -nicotinate in approximately 100 ml of aqueous methanol, the appropriate acid (methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid) up to a pH of around

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2 to 3, cooling the mixture after partial evaporation and collecting the salt which has precipitated, for example dimethanesulfonate, sulfate or phosphate respectively. The acid addition salt in aqueous solution is also conveniently prepared by adding to the water, with stirring, equimolar amounts of 1,2-dihy-dro-6-methyl-2-oxo-5- (4 -pyridinyl) ethyl nicotinate and of the appropriate acid, for example lactic acid or hydrochloric acid, for preparing respectively the monolactate or the monohydrochloride in aqueous solution.

Following the procedure described in Example E1 but using instead 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridi-nyl) nicotinic acid and ethanol equimolar amounts of the appropriate l-Ri-1,2-dihydro-2-oxo-5-PY-6- (lower alkyl) nicotinic acid and lower alkanol, it can be seen that the 1 -Rr 1,2-dihydro-2-oxo-5-PY-6- (lower alkyl) lower alkyl nicotinates from Examples J-2 to J-19.

D-2. 1,2-Dihydro-6-methyl-2-oxo-5- (4-pyridinyl) methyl nicotinate.

J-3.6-Ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) ethyl nicotinate.

D-4. 1,2-Dihydro-6-methyl-2-oxo-5- (3-pyridinyl) n-propyl nicotinate.

D-5. Ethyl 1,2-Dihydro-2-oxo-6-n-propyl-5- (4-pyridinyl) nicotinate.

J-6.1,2-Dihydro-2-oxo-6-isopropyl-5- (4-pyridinyl) isopropyl nicotinate.

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

J-8.1,2-Dihydro-6-isobutyl-2-oxo-5- (4-pyridinyl) ethyl nicotinate.

D-9. 1,2-Dihydro-2-oxo-5- (4-pyridinyl) -6-t-butylnicotinate.

D-10. 1,2-Dihydro-2-oxo-6-n-pentyl-5- (4-pyridinyl) nicotinated methyl.

J-l 1. 6-Ethyl-l, 2-dihydro-5- (2-methyl-4-pyridinyl) -2-n-butyl oxonicotinate.

D-12. Ethyl 6-Ethyl-1,2-dihydro-2-oxo-5- (3-pyridinyl) nicotinate.

J-l 3. Ethyl 1,2-Dihydro-1,6-dimethyl-2-oxo-5- (4-pyridinyl) nicotinate.

D-14. 6-Ethyl-1,2-dihydro-1 - (2-hy droxyethyl) -2-oxo-5- (4-pyridi-nyl) ethyl nicotinate.

D-15. 1,6-Diethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) ethyl nicotinate.

D-16. 1,2-Dihydro-6-methyl-2-oxo-5- (2-pyridinyl) n-hexyl nicotinate.

J-1 7. Methyl 6-Ethyl-5- (5-ethyl-2-pyridinyl) -1,2-dihydro-2-oxonicotinate.

D-18. 1,2-Dihydro-6-methyl-5- (4,6-dimethyl-2-pyridinyl) -2-ethyl oxoni-cotinate.

D-19. 1,2-Dihydro-6-n-hexyl-2-oxo-5- (2-pyridinyl) ethyl nicotinate.

The usefulness of the compounds of formula I or their salts as cardiotonic agents is demonstrated by their effectiveness in conventional pharmacological tests, for example by causing a significant increase in the force of contraction in the procedure using atria and isolated papillary muscles. in cats and causing a significant increase in cardiac contraction force in the procedure for anesthetized dogs with small or minimal changes in heart speed and blood pressure. Detailed descriptions of these test procedures can be found in the U.S. Patent. No. 4072746.

When tested by the procedure on atria and papillary muscles isolated from cats indicated above, the compounds of formula I, tested at doses of 3.10 or 30 Hg / ml, appear to cause a significant increase, that is to say i.e. greater than 25%, of the strength of the papillary muscle and a significant increase, i.e. greater than 25%, of the strength of the right atrium, while causing only a small increase ( about one-third or less of the percentage increase in the strength of the right atrium or the strength of the papillary muscle) over the speed of the right atrium. Furthermore, it is found that the compounds with a 6- (lower alkyl) group of formula I are markedly more active as cardiotonic agents when tested by this procedure, than the corresponding compounds without a lower alkyl group) in position 6 of the prior art. In addition, some of them, in particular where Q in formula I is a carbamyl or bromo group, have been found to be active as cardiotonic agents whereas, on the contrary, the corresponding derivatives without lower alkyl group in position 6 are not only intermediates with no cardiotonic properties.

The markedly higher cardiotonic activity of derivatives with a lower alkyl group in position 6 compared to the corresponding prior art compounds unsubstituted in position 6 is illustrated by the following comparisons of test data obtained using the procedure on cat atrium and papillary muscle isolated. The percentages of increased papillary muscle and right atrium strength for 3-amino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone are found to be 96 % and 30 74% when testing at 10 ng / ml, to compare with the corresponding increases of 109 + 11.3% and 49.9 ± 8.4% for 3-amino-5- (4-pyridinyl ) -2 (1H) -pyridinone (amrinone) at a dose of 100 Hg / ml, that is to say ten times the dose; we find that the percentages of increase in the strength of the papillary muscle and in the strength of the right atrium for 3-amino-6-ethyl-5- (4-pyridinyl) -2 (1H) -pyri-dine are 53% and 37% when tested at a dose of 3 ng / ml, compared to the corresponding increases of 54.1 + 5.3% and 33.6 + 4.4% for 3-amino- 5- (4-pyridinyl) -2 (1H) -pyridinone at a dose of 30 ng / ml, that is to say ten times the dose; we find that the 40 percent increase in the strength of the papillary muscle and the strength of the right atrium for 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile and 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyri-dinyl) nicotinonitrile are 45% and 51% for the 6-methylated compound and 107% and 79% for the 6-ethylated compound , at a dose of 3 | xg / ml, 45 to be compared with the corresponding increases of 65% and 15% for 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile of the prior art without alkyl group in position 6 at a dose of 30 ng / ml, that is to say a dose ten times greater; we find that the percentages of increase in the strength of the papillary muscle and of the strength of the right atrium for 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile are 135% and 102% at a dose of 10 Hg / ml while the corresponding demethylated compound in position 6 of the prior art is inactive at a dose of 10 ng / ml; we find that the percentages of increase in the strength of the papillary muscle 55 and in the strength of the right atrium for 6-methyl-3-methylamino-5- (4-pyridinyl) -2 (1H) -pyridinone are 68% and 41% at a dose of 30 ng / ml, compared to the corresponding increases of 64% and 39% for 3-methylamino-5- (4-pyridinyl) -2 (1H) -pyridinone of the prior art a dose of 100 60 (ig / ml, i.e. more than three times the dose.

Examples of the cardiotonically active compounds of formula I are given below where Q is a carbamyl group or a halogen atom while the corresponding prior art 6-di (lower alkyl) compounds are described only 65 as intermediates and not as cardiotonic agents: when tested by the in vitro test on the atria and papillary muscles of cats, we find that 1,2,2-dihydro-6-methyl-2-oxo-5- (4 -pyridinyl) nicotinamide has percentages of increase

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the strength of the papillary muscle and the strength of the right atrium of 35% and 22% respectively at a dose of 30 ng / ml and 87% and 37% respectively at a dose of 100 | J.g / ml; when tested by the same method, it is found that 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinamide has percentages of increased strength of the papillary muscle and the strength of the right atrium of 29% and 7% respectively at 100 ng / ml and 89% and 27% respectively at 300 ng / ml; and, when tested by the same procedure, we find that 3-bromo-6-methyl-5- (4-pyridinyl) -2 (1H) -pyri-dinone has percentages of increase in strength papillary muscle and right atrium strength of 87% and 99% respectively at a dose of 1 (ig / ml and 107% and 58% respectively at a dose of 10 µg / ml.

The markedly higher cardiotonic activity of the compounds with a lower alkyl group in position 6 of formula I where Q is a hydrogen atom, compared with the corresponding unsubstituted compounds in position 6 of the prior art is illustrated by the following comparisons of Test data using the procedure for isolated cat atria and papillary muscles: the percentages of increase in papillary muscle strength and right atrium strength for 6-methyl-5- are found ( 4-pyridi-nyl) -2 (1H) -pyridinone are 115% and 48% when tested at 10 ng / ml, to be compared with the corresponding respective increases of 48% and 51% for 5- (4 -pyridinyl) -2 (1H) -pyridinone of the prior art at a dose of 100 ng / ml, that is to say ten times the dose of the compound of the present application; we find that the percentages of increase in the strength of the papillary muscle and in the strength of the right atrium for 6-ethyl-5- (4-pyridinyl) -2 (1 H) -pyri-dine are 106% and 50% at a dose of 30 ng / ml, compared to the corresponding increases of 48% and 51% for 5- (4-pyridi-nyl) -2 (1H) -pyridinone at a dose of 100 Mg / ml, that is, more than three times the dose.

As an example of a compound of formula I where Q is a carboxy group active on the cardiotonic level while the corresponding compounds of the prior art without lower alkyl group in position 6 are described only as intermediates and not as cardiotonic agents, it is found that 1,2-dihy-dro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinic acid when tested by the same similar test on atria and papillary muscles of guinea pigs iti vitro, presents percentage increases in the strength of the papillary muscle and the strength of the right atrium of 36% and 27% at 30 ng / ml respectively and by 44% and 69% respectively at 100 ng / ml.

When tested by the procedure on the anesthetized dog described above, the compounds of formula I administered intravenously as a single injection of 0.01, 0.03, 0.10, 0.30, 1.0 and / or 3.0 mg / kg cause a significant increase, i.e. greater than 25%, in the cardiac contraction force or cardiac contractility with only small or minimal changes (less than 25%) of heart speed and blood pressure. Furthermore, the compounds of formula I with a lower alkyl group in position 6 have been found to be significantly more active as cardiotonic agents when tested in this procedure than the corresponding compounds of the prior art without alkyl group in position 6, such as show the following examples: we find that the percentage increase in cardiac contraction force or cardiac contractility for 3-amino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone tested as indicated in the dog anesthetized at 1.0 mg / kg intravenously, is 136% compared to the increase of 125.67 ± 10.59% for the corresponding 6-demethyl compound, amrinone, tried ten times the dose, i.e. 10 mg / kg intravenously; similarly, we find that the percentages of increase in the cardiac contraction force for 3-amino-6-ethyl-5- (4-pyridinyl) -2 (1H) -pyridi-none tried in the same procedure at doses of 0.03 mg / kg and 0.10 mg / kg intravenously are 33% and 72% respectively, compared to the increases of 24.67 + 3.15% and 70.64 + 7, 85% respectively for the amrinone of the prior art tested at ten times the corresponding doses, that is to say at 0.3 mg / kg and 1.0 mg / kg intravenously; we find that the percentages of increase in cardiac contractility for 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotino-nitrile, tested by the same operating procedure at doses of 0 , 03 mg / kg and 0.10 mg / kg, are respectively 49.5% and 87.5%, compared to the increases of 44% and 78% respectively for the corresponding 6-demethyl derivative tested in the prior art at 100 times the corresponding doses, i.e. at 3 mg / kg and '10 mg / kg or compared to the increases of 24.67 + 3.15% and 70.63 ± 7.85% respectively for the amrinone of the prior art tested at ten times the corresponding doses, that is to say at 0.3 mg / kg and 1.0 mg / kg respectively; similarly, we find that the percentages of increase in the contraction force for 6-ethyl-1,2-dihy-dro-2-oxo-5- (4-pyridinyl) nicotinonitrile tested by this procedure at the doses of 0.03 mg / kg and 0.10 mg / kg are 68.5% and 135% respectively, compared to increases of 44% and 78% respectively for the corresponding 6-demethylated compound of the prior art when tested at 100 times the corresponding doses, i.e. at -3 mg / kg and 10 mg / kg respectively.

The present invention includes a cardiotonic composition for increasing cardiac contractility, said composition comprising a pharmaceutically acceptable carrier and, as the active component, 1R, -3-Q-6- (lower alkyl) -5-PY-2 (1H) -pyridinone cardiotonic of formula I or its pharmaceutically acceptable addition salts of acids or cationic salts. The invention also describes the increase in cardiac contractility in a patient in need of such treatment, by administering to this patient an effective amount of said lR, -3-Q-6- (lower alkyl) -5-PY- 2 (1H) -pyridinone of formula I or of its addition salts with pharmaceutically acceptable acids or cationic salts. In the clinical field, the compound or its salt will normally be administered orally or parenterally in a wide variety of dosage forms.

Solid compositions for oral administration include tablets, pills, powders and granules. In such solid compositions, at least one of the active compounds is mixed with at least one inert diluent such as starch, calcium carbonate, sucrose or lactose. These compositions can also contain additional substances other than inert diluents, for example lubricants, such as magnesium stearate, talc, etc.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, containing inert diluents commonly used in the field such as water and liquid paraffin. Besides inert diluents, such compositions may also contain adjuvants, such as wetting and suspending agents, and sweetening, flavoring, perfume and preservative agents. According to the invention, the compounds for oral administration also comprise capsules of absorbable material, such as gelatin, containing said active component with or without the addition of diluents or excipients.

The preparations according to the invention for parenteral administration include sterile aqueous, aqueous organic and organic solutions, suspensions and emulsions. Examples of organic solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. These compositions can also contain adjuvants such as stabilizers, preservatives, wetting agents, emulsifiers and dispersing agents.

They can be sterilized, for example by filtration on a filter retaining bacteria, by incorporation of sterilizing agents in the compositions, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions

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which can be dissolved in sterile water or any other sterile injectable medium immediately before use.

The percentages of active components in said composition can vary to obtain an appropriate dose. The dose administered to a particular patient is variable according to the judgment of the doctor using the following criteria: route of administration, duration of treatment, size and condition of the patient, power of the active compound and reaction of the patient. An effective dose of active compound can only be determined by the clinician by considering all of these criteria and using his best judgment on the patient's behavior.

r

Claims (11)

649,535 1. 1-Rr3-Q-5-PY-6-R-2 (1H) -pyridinone of formula: Pi in which Q is a hydrogen atom or an amino, cyano, carbamyl, halo, lower alkylamino, di (lower alkyl) -amino, lower acylamino, carboxy or lower carbalkoxy radical, R! is a hydrogen atom or a lower alkyl or lower hydroxyalkyl group, R is a lower alkyl group and PY is a 4-, 3- or 2-pyridinyl or 4-, 3- or 2-pyridinyl group having one or two substituents lower alkyl, or one of its cationic salts or addition of acids. 2. A compound according to claim 1, in which R is a methyl or ethyl group and PY is a 4-pyridinyl group. 2 3. 3-Amino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinoneseIon claim 1. 4. 3-Amino-6-ethyl-5- (4-pyridinyl) -2 (1H) -pyridinone according to claim 1. 13. A compound of formula III where R is a lower alkyl group, R3 and R4 are each a lower alkyl group and PY is a 4-, 3- or 2-pyridinyl or 4-, 3- or 2-pyridinyl group having a or two lower alkyl substituents for carrying out the process according to claim 8. 5. 1,2-Dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile according to claim 1. 6. 6-Methyl-5- (4-pyridinyl) -2 (1H) -pyridinone according to claim 1. 7. 6-Ethyl-5- (4-pyridinyl) -2 (1H) -pyridinone according to claim 1. 8. Process for the preparation of a compound of formula I according to claim 1, formula in which R represents a cyano group, characterized in that a compound of formula is reacted: 12. Cardiotonic composition for increasing cardiac contractility, characterized in that it contains a pharmaceutically acceptable inert support and, as active component, an effective amount of a compound according to one of claims 1 to 7. 9. Process for the preparation of a compound of formula I according to claim 1, formula in which Q represents a carboxy group, characterized in that a corresponding compound is prepared in which Q represents a cyano group, by the process of claim 8 , and then hydrolyzed the cyano group. 10. Process for the preparation of a compound of formula I according to claim 1, formula in which Q is a hydrogen atom, characterized in that a corresponding compound is prepared in which Q represents a cyano group by the process according to claim 8 where a carboxy group by the process according to claim 9, and heating the compound with an aqueous mineral acid. 10 A: Ri 3N : N — CH = C-C-R I II PYO (III) with an N-R, -a-cyanoacetamide of formula R, NH — C — CH - CN, II O formulas in which R3 and R4 are each a lower alkyl group and R; and PY are as defined in claim 1, and, if desired, a free base obtained is converted into an acid addition salt or a compound obtained is converted into one of its cationic salts. 11. Process for the preparation of a compound according to claim 1, characterized in that a compound of formula is reacted: R; r; ^ N-CH = C-C-R I II PYO year) in which R3 and R4 each represent a lower alkyl group, with malonamide to obtain a compound of formula I where Q is a carbamyl group and R, is hydrogen and, if desired, a free base obtained is converted into an acid addition salt or a compound obtained is converted into one of its cationic salts.