LU82957A1 - 5- (PYRIDINYL) -2 (1H) PYRIDINONES, THEIR PREPARATION AND THEIR USE AS CARDIOTONIC AGENTS - Google Patents

Description

»1

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

U.S. patents Nos. 4.004.012 and 4.072.746 5 describe, as cardiotonic agents, 3-amino (or cyano) - 5- (pyridinyl) -2 (1H) -pyridinones and, as intermediates, the compounds with a 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) pyridinone, 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) -pyridinones, also called 1,2-dihydro-2-oxo-5- (pyridinyl) nicotinonitriles, comprises the reaction of a - (pyridinyl) -ß- (dialkylamino) acrolein with α-cyanoacetamide. 20 The U.S. Patent No. 4,072,746 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 and NHAc group 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, by - · first forming the acids 3 -carboxylic, i.e., 1,2-dihydro-2-oxo-5- (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

35 Vv ° ΑΛ ki 2 "" 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 group, Rj ^ est 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, and the cationic or pharmaceutically acceptable acid addition salts of these compounds. The compounds of formula I can be used as cardiotonic 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-20 (lower alkyl) amino] group. The preferred compounds 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 group or ethyl. 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 "group 4- pyridinyl and R is a methyl group), the

V: 3-amino-6-ethyl-5- (4-pyridinyl) -2 (1H) -pyridinone (formula I

where Q is Nl ^, Rj ^ is H, PY is 4-pyridinyl and R is ethyl), la 3-amino-5- (4-pyridinyl) -6-methyl-2 (1H) -pyridinone (formula I where Q is N ^, R ^ is H, PY is 4-pyridinyl and R is methyl), 6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone (formula I where Rj = H, PY = 4-pyridinyl and R = methyl) and 6-ethyl-5- (4-pyridinyl) -2 (1H) -pyridinone (formula I where R 35 = H, PY = 4-pyridinyl and R = ethyl), or their pharmaceutically acceptable acid addition salts. It has been found that these particularly preferred compounds have a cardiotonic activity clearly superior to that of the corresponding rf 3 corresponding de-alkylated derivatives, 3-amino-5- (4-pyridinyl) -2 (1H) pyridinone, called amrinone, 1 , 2-dihydro-2-OXO-5- (4-pyridinyl) 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: a. reacting a compound of formula

R ^ R.NCH = C-C (= 0) -R

^ ^ 1 III

10 PY

wherein R ^ and R ^ 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 15 of formula

R-C-C-CHO

He I IV

0 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 reactive agent capable of transforming the carbamyl group into

:. 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 i; 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, to react a compound of | formula I obtained where Q is an amino group, with an acylating agent with a lower acyl group to obtain the corresponding compound where Q is a lower acylamino group 4, if desired, to hydrolyze a compound of formula I obtained where Q is a cvano 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 nitric acid concentrated 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, to heat 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, to esterify 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 an anion of a strong mineral acid or an organic sulfonic acid, to prepare the corresponding compound where R ^ is - R'r if it is desires, to react a compound of formula I obtained where Q is a hydrogen atom, with a halogen v to obtain the corresponding compound where Q is a halogen atom, if desired, to react a compound ae 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 or di (lower alkyl) -amino group respectively, and, if desired, converting the free base obtained into one of its a salts addition of acids or to transform a compound obtained into one of its cationic salts.

d "5

A PY-methyl (lower alkyl) ketone of formula PY-C ^ -C (= O) -R (II) can be reacted with a lower di-alkyl acetal of a di (lower alkyl) formamide to obtain the 1-PY-2- [di- (lower alkyl) aminoJ-ethenyl 5 (lower alkyl) ketone of formula III

R-jR.NCI ^ C-C (= 0) -R III

J 4,

PY

where R3 and R ^ are each a lower alkyl group and one is preferably a methyl group, and PY, R, R ^ and R 'are as defined for formula I. Said 1- (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 1R ^ -3-Q-5-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 1-R1-3-Q-5-PY-6-R-2 (1H) pyridinone. formula I, where R 1, Q, PY and R are as defined in formula I, or a cationic or pharmaceutically acceptable acid addition salt thereof.

The term "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 a substituent of PY in formula I, denotes alkyl radicals having from 1 to 6 carbon atoms which can be arranged in straight chains or r 6 t branched, illustrated by the methyl, ethyl, n-propyl groups, isopropyl, n-butyl, s-butyl, t-butyl, isobutyl, n-amyl, n-hexyl, etc.

The term "lower hydroxyalkyl", as used herein, for example as one of the definitions of in Formula I, denotes hydroxyalkyl groups having two to six carbon atoms and including the hydroxy group and the bond of free valence are found on different carbon atoms, illustrated by the groups 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-- hydroxy-2-methylpropyl, 2-hydroxy-1, 1-dimethylethyl, 4-hydroxybutyl , 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-2-pyridinyl , 2,3-dimethyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl, 4,6-dimethyl-2-pyridinyl, 2-ethyl-4-pyridinyl, 2-isopropyl-4-pyridinyl, 2- n-butyl-4-pyridinyl, 2-n-hexyl-4-pyridinyl, 2.6-diethyl-4-pyridinyl, 2,6-diethyl-3-pyridinyl, 2,6-diisopropyl-4-pyridinyl, 2,6- di-n-hexyl-4-pyridinyl, etc.

The term "lower acyl" as used herein, for example in the substituent 3- (lower acylamino) of compounds of formula I (Q is a lower acylamino group), denotes alkanoyl radicals having from one to six i carbon atoms, preferably from one to four, and having substituents chosen from hydroxy, acetoxy or propionoxy groups, comprising the straight or branched chain radicals, illustrated by the formyl, acetyl, propionyl (n-propanoyl) groups, butyryl (n-butanoyl), isobutyryl (2-methyl-n-propanoyl), caproyl (n-hexanoyl), hydroxy-acetyl, a-hydroxypropionyl, ß-hydroxypropionyl, a-acetoxy-35-propionyl, propionoxy-acetyl, f> -acetoxypropionyl, a-acetoxy-butyryl, etc.

The compounds of formulas I and III can be used 7 in the form of the free base and in the form of the salts 7

T

of acid addition and both forms are part of the scope 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 affected by side effects from anions. In practicing 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, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, l 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 ethanesulfonate, the benzenesulfonate , p-toluenesulfonate, - cyclohexyl-> sulfamate and quinate.

The acid addition salts of the basic compound 30 (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 can be obtained by concentrating the solution.

Although the pharmaceutically acceptable salts of the basic compound (I or III) are preferred, all of the salts! I - 8 of acid addition are part of the field of the invention.

All of the acid addition salts can be used as sources of the free base, even if the particular salt is sought in itself only as an intermediate product, for example when the salt is formed only for the needs of the purification or identification, or when it is used as an intermediate in the preparation of a pharmaceutically acceptable salt by procedures> - ion exchange.

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, potassium hydroxide, trimethylammonium hydroxide, to obtain the salt 1- or N-cationic corresponding 15, for example the sodium, potassium, trimethylammonium salt respectively, that is to say that 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 provided by the infrared, nuclear magnetic resonance and mass spectra, and by the correspondence of the calculated and found values for the elemental analysis.

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

The preparation of 1-PY-2- (dimethyl-amino) ethenyl (lower alkyl) ketone of formula III is carried out by> reacting PY-methyl (lower alkyl) ketone (II) with a lower dialkyl acetal of dimethylformamide , by 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 hexamethyl- phosphoramide due to the process used to prepare PY-roethyl (lower alkyl) ketone, as shown below in Example A1. Other suitable solvents include t s 9 I * I t

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 [eg as described in Rec. trav. chem T2_t 522 (1953); the patent . from the USA No. 3,133,077; Bull. Soc. Chim 1968, 4132; Chem.

Abstrs. 79_, 8539h (1973); Chem. Abstrs. 8_1, 120.401a (1974); J. Org. Chem. 3 ^, 3834 (1974); Chem. Abstrs. Ù7, 6594q (1977); J. Org. Chem. 43, 2286 (1978)].

Reaction of 1-PY-2- (dimethylamino) ethenyl (lower alkyl) ketone (III) with an NR ^ -a-cyanoacetamide to obtain l-R1-1,2-dihydro-2-oxo-5- PY-6-R-nicotino-nitrile (formula I where Q is CN) is preferably carried out by heating the reagents in a suitable 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 practice of the invention, the reaction is carried out by heating the 125 dimethylformamide at reflux using sodium methylate. Or, you can use methanol and methylate! sodium or ethanol and sodium ethylate as solvent and 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.

It is also possible to prepare the 1-R - l, 2-dihydro-2-oxo-5-PY-6-R-nicotinonitrile by heating an l-PY-2- (R ^ R ^ -amino) ethenyl (alkyl lower) ketone (III) 10 'in an aqueous alkaline medium, for example an aqueous solution of sodium or potassium hydroxide, to obtain the corresponding α-PY-ß-R-ß-oxopropionaldehyde (IV) and react this compound with an NR ^ -a-cyanoacetamide.

5 1,2-dihydro-2-oxo-5-PY-6_R-nicotinamide (formula I, Q = carbamyl and R1 = H) can also be prepared directly by reacting a 1 - PY-2- (R2 R ^ amino) ethenyl (lower alkyl) ketone of formula III with malonamide.

- Partial hydrolysis of 1-R ^ -1,2-dihydro-2-oxo-5-10 PY-6-R-nicotinonitrile (formula I where Q = CN) to obtain r. 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 sulfuric acid concentrated. 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 C-1 to C-21.

The transformation of 1-R ^ 1,2-dihydro-2-oxo-5-PY- 6- R-nicotinamide (I where Q is a carbamyl group) into 1-R1-3-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 converting 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 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 ° C and 100 ° C. This procedure is better illustrated below in Examples D-1 to D-21.

One can also prepare 1R-3-amino-5-PY-6-R-2 (1H) -pyridinone (I, Q is an amino group) by heating 11 "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 5 I, Q is an amino group and R ^ is a hydrogen atom), or by alkylating first (see the following paragraph) the 3-nitrë compound to prepare lR], - 3-nitro-5-PY-6-R-2 (1H) -pyridinone and reducing the 3-nitro compound to prepare? 1-R1 “3-amino-5-PY-6-R-2 (1H) -pyridinone (formula I, Q is an amino group and R ^ is 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 corresponding unsubstituted compounds in formula I of formula I where R ^ is a hydrogen atom, with a lower alkyl ester or hydroxy-lower alkyl of a strong mineral acid or an organic sulfonic acid, preferably in the presence of an acid acceptor.

The transformation of 1-R ^ -1,2-dihydro-2-oxo-5-PY-6- R-nicotinonitrile (I, Q is a cyano group) into lR ^ -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 first compound I where Q is a carboxy group and then continuing to heat for! a longer period of time, which causes the; .i decarboxylation of 3-carboxylic acid giving the i | compound I where Q is a hydrogen atom. This procedure 30 is better illustrated below in Examples E-1 to E-21.

The reaction of 1-R -5-PY-6-R-2 (1H) -pyridinone (I, Q is a hydrogen atom) with a halogen is carried out to obtain the corresponding 3-halogen 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.

12

The preferred halogens are bromine and chlorine.

Any inert solvent can be used, for example, methylformamide, chloroform, acetic acid, etc.

This procedure is better illustrated below in the Examples F-1 to F-22.

The reaction of an l-R1-3-halo-5-PY-2 (1H) -pyridinone (I, Q is a halogen atom) with a lower alkylamine or a di- (lower alkyl) amine to obtain the 1R ^ -3- (lower alkylamino) -5-PY-6-R-2 (1H) -pyridinone correspon-% 10 dante (I, Q is a lower alkylamino group) or 1-> R.-3- [ di- (lower alkyl) amino] -5-PY-2 (1H) -pyridinone corresponding [I, Q is a di- (lower alkyl) -amino group] is carried out by heating the reagents in an autoclave to about 110-180 ° C, preferably about 145 ° -15 165 ° C and preferably in a suitable solvent, for example water, dimethylformamide, dioxane, 1,2-diraethoxy-ethane, 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 1R ^^ - 3- [mono- or di- (lower alkyl) amino] -5-PY-6- (lower alkyl) -2 (1H) -pyridinone consists 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 lR ^ -3-dimethylamino-5-PY-6-R-2 (1H) -pyridinone (I, Q is a; dimethylamino group) is carried out by reacting lR ^ -3-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-R1-3-amino-5-PY-6-R-2 (III) -pyridinone (T, Q is an amino group) to produce the 3- (lower acylamino) compound corresponding to i . '13 (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 chloride, a lower acid anhydride, etc., preferably in the presence of an acid acceptor. Is the acid acceptor a basic substance which preferably forms easily soluble in water by-products which readily separate from the product of? the reaction, including, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium alcoholates, 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, dimethylformamide, 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 ° C and 150 ° C, preferably about 20-25 ° C. This procedure is better illustrated below in Examples H-1 to H-17.

Hydrolysis of 1-R ^ -l, 2-dihydro-2-oxo-5-PY-6-R-nicotinonitrile (I, Q is cyano) to produce acid 1-R1 ~ 25 1,2-dihydro -2-oxo-5-PY-6-R-nicotinic (I, Q is a carboxy group) is conveniently carried out by heating said nicotinonitrile on a steam bath with a mineral acid Î! aqueous, preferably 50% sulfuric acid. This procedure is better illustrated below in Examples 30 I-1 to 1-21.

"The esterification of 1-R -1,2-dihydro-2-oxo-5-PY-6-R-nicotinic acid (I, Q is a carboxy group) to obtain 1-R ^ -l, Lower alkyl 2-dihydro-2-oxo-5-PY-6-R-nicotinate (I, Q is a lower carbalkoxy group) is carried out by heating the acid with a lower alkanol at 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 * 14, for example a strong mineral acid or a organic sulfonic acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid etc. This procedure is better illustrated below in Examples J-1 to J-19.

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

A. 1- PY-2- (dimethylamino) ethenyl (lower alkyl) ketones A-1. - 1- (4-Pyridinyl) -2- (dimethylamino) ethenyl 10 methyl ketone - Dilute with 65 ml of dimethylformamide dimethyl acetal a mixture containing 20 g of (4- è "pyridinyl) methyl methyl ketone [also called 1 - (4-pyridinyl) -2-propanone] and 30 ml of hexamethylphosphoramide and the resulting mixture is heated at reflux for 30 minutes. 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 minutes at room temperature. The reaction mixture is evaporated under reduced pressure using a rotary evaporator and a pressure 20 millibars, 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 one and a half hours, the extract is heated under vacuum to remove the chloroform, leaving 23.2 g of 1- (4-pyridinyl) -2- (dimethylamino) eth enyl methyl ketone in the form of a light yellow crystalline material, the compound also being called 4-dimethylamino-2- (4-pyridinyl) -3-buten-2-one.

s *

The foregoing preparation can be carried out using, in place of hexamethylphosphoramide, other solvents, for example dimethylformamide, acetonitrile or others indicated above, or in the absence of a solvent; however, hexamethylphosphoramide is conveniently used since (4-pyridinyl) methyl methyl ketone is conveniently prepared as a mixture with hexamethylphosphoramide, as shown in the following preparation: to a stirred solution containing 70 ml of freshly distilled isopropylamine and 200 ml of tetrahydrofuran

H

At 0 ° C under nitrogen, 210 ml of 2.4 M n-butyllithium in n-hexane are added dropwise over 20 minutes and the reaction mixture is stirred for about 35 minutes at about 0-5 ° C. To the cold solution, 90 ml of dry hexamethylphosphoramide is added dropwise over 5 minutes (no change in temperature) and the resulting light yellow solution is stirred for 15 minutes. 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 minutes and stirring is continued for 30 minutes at 0 ° C. Then we add in 15? minutes a mixture containing 50 ml of dry ethyl acetate and 150 ml of tetrahydrofuran (the temperature goes from 0 ° C to about 6 ° C) and the resulting mixture is stirred for 20 minutes at 0 ° C. Then the ice bath is removed and stirring is continued for a further 90 minutes, during which the temperature of the reaction mixture rises to about 25 ° C. The reaction mixture is then cooled in an ice bath and 60 ml of acetic acid are added thereto in about 30 minutes. 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 about 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, g 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 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 millibars; II. 59 g of a pale yellow oil, mp 113-115 ° C at 4 millibars and III. 69 g of a pale yellow oil 16, mp 115-118 ° C at 3.3 millibars. Examination of fraction III by NMR shows that it consists of a 2: 3 mixture, by weight, of (4-pyridinyl) methyl methyl ketone and hexamethylphosphoramide.

5 The addition salts are conveniently prepared

1- (4-pyridinyl) -2- (dimethylamino) ethenyl methyl ketone acids 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, up to a pH

s of approximately 2 to 3, by cooling the mixture after partial evaporation and collecting the precipitated salt, for example dimethylsulfonate, sulfate and phosphate respectively. The acid addition salt in aqueous solution can also be conveniently prepared, by adding to water, with stirring, equimolar amounts of 1— (4-pyridinyl) -2- (dimethylamino) ethenyl methyl ketone and suitable acid, for example lactic acid or hydrochloric acid, to respectively prepare the monolactate 20 and the monohydrochloride in aqueous solution.

A-2. - 1- (4-Pyridinyl) -2- (dimethylamino) ethenyl ethyl ketone - Dilute with 100 g of dimethylformamide dimethyl acetal a mixture containing 87.5 g of (4-pyridinyl) methyl ethyl ketone [also called l- (4-25 pyridinyl) -2-butanone] and 160 ml of hexamethylphosphoramide and the resulting mixture is stirred under nitrogen at room temperature for 45 minutes. 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 millibar and the second at 90 -95 ° C to 0.66 millibar. 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 sulphate and purified by chromatography * 17 of continuous extraction on 300 ml of alumina using chloroform at reflux as eluent. The chloroform is distilled in vacuo and a red mistletoe oil is obtained which is crystallized 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, 1— (4— pyridinyl) -2- (dimethylamino) ethenyl ethyl ketone . An additional 11 g of crystalline product is obtained from the mother ligator by continuous extraction chromatography on alumina using chloroform at 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 diisopropylamine under nitrogen at 0-5 ° C., 210 are added ml 2.4 N n-butyllithium in n-hexane and the resulting mixture is stirred for 30 minutes. Then 90 ml of hexamethylphosphoramide are added over 10 minutes, then the mixture is stirred for 15 minutes. Then a solution of 48 ml of 4-picoline in 150 ml of tetrahydrofuran is added over 15 minutes, then the mixture is stirred for 30 minutes at approximately 0 ° C. The ice / acetone bath cooling the reaction mixture is replaced by a dry ice / acetone bath and, to the reaction mixture, a mixture of 75 ml of ethyl propionate in an equal volume of tetrahydrofuran is added over 20 minutes. Then the reaction mixture is allowed to warm to room temperature in about 90 minutes and then warmed to about 35 ° C for 30 minutes. The mixture is then cooled in an ice / acetone bath and 60 ml of glacial acetic acid is added thereto over 30 minutes. 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 in vacuo to remove the ethyl acetate, then the residue is heated in vacuo at 50 ° C for about 30 minutes and 100 g of a Pale yellow oil.

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 millibar. 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, i.e. 35 % or 0.35 x 256 10 = 90 g of the ketone.

A-3. 1- (4-Pyridinyl) -2- (dimethylamino) ethenyl n-propyl ketone - A mixture containing 80 g of (4-pyridinyl) methyl n-propyl ketone is diluted with 250 ml of acetonitrile [also called 1- (4 -pyridinyl) -2-pentanone] and 46 ml of hexamethylphosphoramide. To the mixture is added 90 ml of dimethylformamide dimethyl acetal and the resulting reaction mixture is heated on a steam bath for 90 minutes then distilled in vacuo to about 2.7 millibars to remove volatiles, including 20 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 cyclo-hexane, filtered and dried overnight at 30 ° C. and 97 g of 1- (4-pyridinyl are obtained in the form of a yellow crystalline product) ) -2- (dimethylamino) ethenyl n-propyl ketone, pf 48-50 ° C.

The (4-pyridinyl) methyl n-propyl ketone 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 2.4 N n-butyllithium are added over twenty minutes and the resulting mixture is stirred for 30 minutes at approximately 0 ° C.

* 19

To the mixture, 90 ml of hexamethylphosphoramide is added with stirring over 10 minutes and the resulting mixture is stirred for an additional ten minutes. Then 45 ml of 4-picoline in 140 ml of tetrahydrofuran are added dropwise over 15 to 20 minutes. The resulting dark brown orange solution is stirred at 0 ° C for 30 minutes and then treated dropwise over 18 minutes by adding a solution comprising 68 ml of ethyl butyrate in 68 ml of tetrahydrofuran, the temperature rising by - 8 ° C at a temperature of + 8 to + 10 ° C. The reaction mixture is removed from the ice bath and allowed to warm to room temperature for more than 75 minutes. The reaction mixture is again cooled and 60 ml of glacial acetic acid are added thereto dropwise over 15 minutes. A pale yellow solid separates 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 consisting essentially of (4-pyridinyl) methyl n-propyl ketone 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, eg 80-90 ° C at 0.25 millibar, a mixture comprising 80 g of (4-pyridinyl) -methyl n-propyl ketone and 46 g of hexamethylphosphoramide.

Following the procedure described in Example A-2 but using an equimolar amount of the appropriate PY-methyl (lower alkyl) ketone of formula II in place of the (4-pyridinyl) methyl ethyl ketone, it is seen that the 1-PY-2- (dimethylamino) ethenyl (lower alkyl) ketones of Examples A-4 to A-17 can be obtained.

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

Λ-5. 1- (2-Pyridinyl) -2- (dimethylamino) ethenyl methyl ketone using (2-pyridinyl) methyl methyl ketone.

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

10 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-pentyl ketone using (4-pyridinyl) methyl n-pentyl ketone.

A-ll. 1- (2-Methyl-4-pyridinyl) -2- (dimethylamino) - ethenyl ethyl ketone using (2-methyl-4-pyridinyl) -methyl ethyl ketone.

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

A-l3. 1- (5-Ethyl-2-pyridinyl) -2- (dimethylamino) -ethenyl ethyl ketone using (5-ethyl-2-pyridinyl) -methyl ethyl ketone.

25 A-14. 1- (3-Pyridinyl) -2- (dimethylamino) ethenyl ethyl ketone using (3-pyridinyl) methyl ethyl ketone.

A-15. 1- (4,6-Dimethyl-2-pyridinyl) -2- (dimethyl amino) ethenyl methyl ketone using (4,6-dimethyl-2-pyridinyl) methyl methyl ketone.

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

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

B. 1-R ^ -1,2-dihydro-6- (lower alkyl) -2-oxo-5-PY-nicotinonitrile B-1. - 1,2 Dihydro-6-methyl-2-oxo-5- (4-pyridinyl) -nicotinonitrilc, also called], 6-dihydro-2-methyl-6-% 21 oxo- [3,4'-bipyridine] -5-carbonitrile - To a mixture containing 23 g of 1- (4-pyridinyl) -2- (dimethylamino) ethenyl methyl ketone and 11 g of α-cyanoacet-amide dissolved in 400 ml of dimethylformamide, added with 5 stirring 14 g of sodium methylate and the resulting reaction mixture is heated in an oil bath at moderate reflux for one hour. TLC analysis indicates that there is no more starting material in the reaction mixture which is then concentrated in vacuo in a rotary evaporator to a volume of about 80 ml. Concentrate 1 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 crystalline product, yellowish brown, namely the salt of 1,2-dihydro-6- j sodium methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile sodium, the presence of the i-cyano group being confirmed by IF analysis. Dissolve 20 g of the sodium salt in 75 ml of hot water, treat the aqueous solution with bleaching charcoal, filter, treat the filtrate again with bleaching charcoal and filter and acidify the filtrate with 6N hydrochloric acid by adding dropwise to a pH of 3. The acid mixture is diluted (with ethanol and cooled. The crystalline product is collected, dried, recrystallizes it from a dimethylformamide-water mixture and it is 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 are conveniently prepared! 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile by adding to a mixture of 2 g 1,2-dihydro-6-methyl-2-oxo-5- (4 -pyridinyl) nicotinonitrile in about 40 ml of aqueous methanol, the appropriate acid, for example acid.

; Methanesulfonic acid, concentrated sulfuric acid, concentrated phosphorous acid I, to a pH of about 2 to 3, cooling the mixture after partial evaporation and collecting the precipitated salt, for example dimethanesulfonate,% 22 le sulfate, phosphate respectively. The acid addition salt in aqueous solution can also be conveniently prepared by adding equimolar amounts of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) to water with stirring. ) -5 nicotinonitrile and an appropriate acid, for example lactic acid or hydrochloric acid, to respectively prepare the monolactate or the monohydrochloride in aqueous solution.

B-2. - 6-Ethyl-1,2-dihydro-2-oxo-5-PY-nicotino-10 nitrile, also called 2-ethyl-l, 6-dihydro-6-oxo- [3,4'-bipyridine] -5 -carbonitrile, pf > 300 ° C, 11.6 g. It is prepared according to the procedure described in Example B1 using 20 g of 1- (4-pyridinyl) -2- (dimethylamino) -ethenyl ethyl ketone, 8.4 g of α-cyanoacetamide, 16.2 g 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 ' -bipyridinel-5-carbonitrile, pf 232-234 ° C, 20 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-propyl ketone, 36.5 g of a-cyano -acetamide, 50 g of sodium methylate and 800 ml of dimethylacetamide.

25 B-4. - 1,2-Dihydro-1,6-dimethyl-2-oxo-5- (4-pyri dinyl) nicotinonitrile, also called 1,6-dihydro-l, 2-dimethyl-6-oxo- (3,4 ' -bipyridine) -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) ethenyl methyl ketone, 23.5 g of% N- methyl-a-cyanoacetamide, 6.7 g of sodium methylate, 400 ml of methanol, and a reflux period of two hours.

Following the procedure described in Example B-2 but using an equimolar amount of the appropriate 1-PY-35 2- (dimethylamino) ethenyl (lower alkyl) ketone of formula (III) in place of 1- (4-pyridinyl) -2- (dimethylamino) ethenyl ethyl ketone and the appropriate N-Rj-a-cyano-acetamide, we see that we can obtain the 1-R ^ - [I% 23 1,2-dihydro -2-oxo-5-PY-6-R-nicotinonitriles corresponding to Examples B-5 to B-21.

B-5. 1,2-Dihÿdro-6-roethyl-2-oxo-5- (3-pyridinyl) - nicotinonitrilef using 1- (3-pyridinyl) -2- (dimethyl-5 amino) ethenyl methyl ketone and a- cyanoacetamide.

B-6. 1,2-Dihydro-6-methyl-2-oxo-5- (2-pyridinyl) - nicotinonitrile, using 1- (2-pyridinyl) -2- (dimethyl-amino) ethenyl methyl ketone and a- cyanoacetamide. s. B-7. 1,2-Dihydro-6-isopropyl-2-oxo-5- (4-pyridinyl) nicotinonitrile, using 1- (4-pyridinyl) -2- (dimethyl-amino) ethenyl isopropyl ketone and a- cyanoacetamide.

B-8. 6-n-Butyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) -nicotinonitrile, using 1- (4-pyridinyl) -2- (dimethyl-amino) ethenyl n-butyl ketone and Α-cyanoacetamide.

15 B-9. 1,2-Dihydro-6-isobutyl-2-oxo-5- (4-pyridinyl) - nicotinonitrile, using 1- (4-pyridinyl) -2- (dimethyl-amino) ethenyl isobutyl ketone and a- cyanoacetamide.

B-10. 1,2-Dihydro-2-oxo-5- (4-pyridinyl) -6-t-butyl-nicotinonitrile, using 1- (4-pyridinyl) -2- (dimethyl-20 amino) ethenyl t-butyl- ketone and α-cyanoacetamide.

B-ll. 1,2-Dihydro-2-oxo-6-n-pentyl-5- (4-pyridinyl) -nicotinonitrile, using 1- (4-pyridinyl) -2- (dimethyl-amino) ethenyl n-pentyl ketone and 1 '° -cyanoacetamide.

B-12. 6-Ethyl-1,2-dihydro-5- (2-methyl-4-pyridinyl) -25 2-oxonicotinonitrile, using l- (2-methyl-4-pyridinyl) -2- (dimethylamino) ethenyl ethyl ketone and α-cyanoacetamide.

B-13. 1,2-Dihydro-6-methyl-5- (5-methyl-2-pyridinyl) - 2-oxonicotinonitrile, using 1- (5-methyl-2-pyridinyl) -2- (dimethylamino) ethenyl methyl ketone and a-30 cyanoacetamide.

B-14. 6-Ethyl-5- (5-ethyl-2-pyridinyl) -1,2-dihydro-2-oxonicotinonitrile, using 1- (5-ethyl-2-pyridinyl) -2- (dimethylamino) ethenyl ethyl ketone and a-cyanoacetamide.

35 B-15. 6-Ethyl-1,2-dihydro-2-oxo-5- (3-pyridinyl) - nicotinonitrile, using 1- (3-pyridinyl) -2- (dimethylamino) ethenyl ethyl ketone and 11a-cyanoacetamide.

B-16. 1,2-Dihydro-5- (4,6-dimethyl] -2-pyridinyl) -6- t. ’24 methyl1-2-oxonicotinonitrile, using 1- (4,6-dimethyl-2-pyridinyl) -2- (dimethylamino) ethenyl methyl ketone and 1 α-cyanoacetamide.

B-17. 1,2-Dihydro-6-isopropyl-5- (6-methyl-2- 5 pyridinyl) -2-oxo-nicotinonitrile, using 1— (6— methyl1-2-pyridiny1-2- (dimethylamino) ethenyl isopropyl ketone and α-cyanoacetamide.

B-18. 1,2-Dihydro-6-n-hexyl-2-oxo-5- (2-pyridinyl) - - nicotinonitrile, using 1- (2-pyridinyl) -2- (dimethyl-10 amino) ethenyl n-hexyl ketone and α-cyanoacetamide.

B-19. 6-Ethyl-1,2-dihydro-1- (2-hydroxyethyl) -2-oxo-5- (4-pyridinyl) nicotinonitrile, using 1— (4— pyridinyl) -2- (dimethylamino) ethenyl ethyl ketone and N- (2-hydroxyethyl) -α-cyanoacetamide.

15 B-20. 1-Ethyl-1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile, using 1- (4-pyridinyl) -2-dimethylamino) ethenyl methyl ketone and N-ethyl -a-cyano-acetamide.

B-21. 1,6-Diethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile, using 1- (4-pyridinyl) -2- (dimethylamino) ethenyl ethyl ketone and N-ethyl -a-cyano-acetamide.

C. 1-Rj ^ -l, 2-dihydro-6- (lower alkyl) -2-oxo-5- (pyridinyl) - nicotinamides 25 C-1. - 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 minutes using an oil bath a mixture containing 9.0 g of 1,2-dihydro-6-30 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 are carefully added dropwise about 150 ml of 28% ammonium hydroxide. The resulting mixture containing a precipitate is cooled in an ice / acetone bath for about 30 minutes. The precipitate is then collected, rinsed successively with water and acetonitrile, and dried. 25 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 minutes. 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 13.5 g combined 10 are dissolved in 500 ml of dimethylformamide at its boiling point, the hot mixture is filtered and the filtrate is cooled in a bath The crystalline precipitate is collected, rinsed with acetone and dried for 14 hours at 100 ° C. over phosphoric anhydride and the IR and NMR analyzes show that it still contains a little dimethylformamide. dissolve the 10.5 g of light fawn-colored crystalline product in 75 ml of hot acetic acid, treat with 50 ml of water and then dilute to a volume of 300 ml with acetone. The resulting mixture containing a few crystals is cooled in an ice bath for about 45 minutes, the resulting light brown yellow crystalline product is collected, dried first at 55 ° C and then at 110 ° C to remove the last weak odor of acetic acid and l '' 9.2 g of 1,2-dihydro-6-methyl-2-oxo-5- (4-25 pyridinyl) nic are obtained otinamide, m.p. > 300 ° C.

The acid addition salts of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinamide are conveniently prepared by addition to a mixture of 5 g of 1,2-dihydro -6-methyl- 2-OXO-5- (4-pyridinyl) nicotinamide in about 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 salt which has precipitated, for example dimethane sulfonate, 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-pyridinyl) to water, with stirring. ) - 26 nicotinamide and of the appropriate acid, lactic acid or hydrochloric acid for example, to respectively prepare the monolactate or the monohydrochloride in aqueous solution.

5 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 -carboxamide

A 40 g portion of 6-ethyl-1,2,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile is added to 170 ml of concentrated sulfuric acid and the temperature then rises to about 70 °. vs. This reaction mixture is immersed in an oil bath preheated to about 90 ° C and then maintained between 95-105 ° C for about 40 minutes. 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 is added with stirring 300 ml of ice and the stirring is continued for about 15 minutes. The precipitate is collected, rinsed with three 150 ml portions of water, air dried for two hours, 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 is purified by dissolving it in 40 ml of hot acetic acid, filtering the hot solution and diluting the filtrate to 180 ml with absolute ethanol, and then forms crystals. The hot mixture is allowed to cool. The light yellow-yellow crystallized product is collected and dried at 110 ° C. over Pen <3 for about 15 hours 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-5- (4-pyridinyl) - nicotinamide, also called 1,6-dihydro-6-oxo-2-n-propyl- [3,4'- bipyridine] -5-carboxamide, pf > 300 ° C, 10.5 g; the% j 27 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.

5 Following the procedure described in Example C-2 but using an equimolar amount of the appropriate 1R ^ -1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitrile (of formula I where Q is a cyano group) instead of 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile, it can be seen that 1,2-dihydro-2- can be obtained oxo-5-PY-6-R-nicotinamides corresponding to Examples C-3 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) - 15 nicotinamide.

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

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

20 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-11. 6-Ethyl-1,2-dihydro-5- (2-methyl-4-pyridinyl) -2-oxonicotinamide.

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

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

C-14. 6-Ethyl-1,2-dihydro ~ 5- (3-pyridinyl) -2-oxonicotinamide.

C-15. 1,2-Dihydro-6-methyl-5- (4,6-dimethyl-2 ~ 35 pyridinyl) -2-oxonicotinamide.

C-l6. 1,2 — Dihydro-6-isopropyl-5— (6-methyl-2-pyridinyl) -2-oxonicotinamide.

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

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

C-19. 6-Ethyl-1,2-dihydro-1- (2-hydroxyethyl) -2-oxo-5- (4-pyridinyl) nicotinainide.

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

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

D. 1-R ^ -3-Amino-6- (lower alkyl) -5-PY-2 (1H) -pyridinones 10 D-1. 3-Amino-6-methyl-5- (4-pyridinyl) -2 (1H) - pyridinone, also called 5-amino-2-methyl- [3,4'-bipyridin) -6 (1H) -one A solution containing 13 g of sodium hydroxide in 250 ml of water, 12 g of 1,2-dihydro-6-methyl-2- 15 oxo-5- (4-pyridinyl) nicotinamide are added and the resulting mixture is heated on a steam bath to dissolve.

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 thereto dropwise, dissolution taking place after addition of about 3 ml of bromine. The mixture is stirred for an additional 10 minutes when cold and then heated on a steam bath for 45 minutes. The reaction mixture is then concentrated to about half its volume, cooled in an ice bath and treated with 6N hydrochloric acid to pH about 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-35 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 - * * 29 methyl-5- (4-pyridinyl) -1 (1H) -pyriâinone in about 40 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, by cooling the mixture after partial evaporation and collecting the salt which has precipitated, for example dimethylsulfonate, sulfate and phosphate, respectively. The acid addition salt in aqueous solution is also conveniently prepared by adding to the water, with stirring, equimolar amounts of 3-amino-6-methyl-5- (4-pyridinyl) -2 (1H) pyridinone and of the appropriate acid, for example lactic acid or hydrochloric acid, to respectively prepare the monolactate or the monohydrochloride in aqueous solution.

15 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) -20 niootinamide, 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'-25 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

Iet 95 ml of water at room temperature, a solution of 1.32 g of sodium hydroxide in 6 ml of water is added.

The resulting suspension is cooled in an ice bath, stirred for 10 minutes and then treated dropwise with 22 ml of a 13.1% aqueous solution of sodium hypochlorite in three minutes. Dissolution takes place and stirring is continued without cooling for 30 minutes. 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 about 60-70 ° C for one hour, then the hot solution is treated slowly with 14 ml of glacial acetic acid over 5 minutes, which causes separation of a yellow brown precipitate. The mixture is stirred for 5 minutes; the precipitate is collected, washed with hot water and dried over P2 ° 5 * 0n the 12 g resulting product is recrystallized from a mixture of 100 ml of dimethylformamide and 80 ml of water, dried overnight at 95 ° C on P2 ^ s 9/5 g of 3-amino-6-n-propyl-5- (4-pyridinyl) -2 (1H) -pyridinone, mp are obtained 200-202 ° C.

By following the procedure described in Example Dl but using an equivalent amount of the appropriate lR ^ -1,2-10 dihydro-2-oxo-5-PY-6-R-nicotinamide (formula I where Q is a group carbamyl) instead of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinamide, we see that we can obtain the lR ^ -3-amino-5-PY-6 -R-2- (1H) -pyridinones corresponding to Examples D-4 to D-21.

15 D-4. 3-Amino-6-methyl1-5- (3-pyridinyl) -2 (1H) - pyridinone.

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

D-6. 3-Amino-6-isopropyl-5- (4-pyridinyl) -2 (1H) -20 pyridinone.

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

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

25 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) -30 2 (1H) -pyridinone.

"D-l2. 3-Amino-6-methyl-5- (5-methyl-2-pyridinyl) -2 (1H) -pyridinone.

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

35 D-14. 3-Amino-6-eth1-5- (3-pyridinyl) -2 (1H) - pyridinone.

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

31. .

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

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

5 D-18. 3-Amino-1,6-dimethyl-5- (4-pyridinyl) -2 (1H) - 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) - 10 2 (1H) -pyridinone.

D-21. 3-Amino-1,6-diethyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

E. 1- R ^ -6- (lower alkyl) -5-PY-2 (1H) -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-pyridinyl) nicotinonitrile and 30 ml of 85% sulfuric acid is heated to about 195 ° C. heat gently at reflux for 24 hours, 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 + Na ^ SO ^) 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 hours to give 4.1 g of 6 -methyl-5- (4-pyridinyl) -2 (1H) —pyridinone, pf 287-288 ° C.

The acid addition salts of 6-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 about 100 ml of aqueous methanol, the appropriate acid, for example methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid, up 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 is also conveniently prepared by adding to the water, with stirring, equimolar amounts of 6-methyl- 5- (4-pyridinyl) -2 (1H) -pyridinone and suitable 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 called2-ethyl- [3,4'-bipyridin] -6 (1H) -one. A mixture containing 9 g of 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) -nicotinonitrile and 50 ml of concentrated sulfuric acid is heated with stirring at 200 ° C. for 24 hours. cooled to 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) -pyridinone, mp 226-228 ° C. A second harvest of 0.4 g, m.p. 225-227 ° C, concentrating the filtrate to around 20 ml.

20 E-3. 6-n-Propyl-5- (4-pyridinyl) -2 (1H) -pyridinone, also called 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) nicotino-25 nitrile, 42.5 ml of 85% sulfuric acid, 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- 5- (4-pyridinyl) nicotinonitrile an equimolar amount of 1-R ^ -l, 2-dihydro ~ 2-oxo-5-PY-6- (lower alkyl) corresponding nicotinonitrile, we see that we can obtain the 1-R - 5-PY-6- (lower alkyl) -2 (1H) -pyridinones from Examples E-4 to E-21.

35 E-4. 6-Methyl-5- (3-pyridinyl) -2 (1H) -pyridinone.

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

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

E-7. 6-Isobutyl-5- (4-pyridinyl) -2 - {] H) -pyridinone.

• E-8. 5- (4-Pyridinyl) -6-t-butyl-2 (111) -pyridinone.

# 1 33 E-9. 6-n-Pentyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

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

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

5 E-12. 1,6-Dimethy1-5- (4-pyridinyl) -2- (1H) -; pyridinone.

! E-13. 6-Ethyl-1 (2-hydroxyethyl) -5- (4-pyridinyl) - 2 (1H) -pyridinone.

„E-14. 1-Ethyl-6-methyl1-5- (4-pyridinyl) -2 (1H) - 10 pyridinone.

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

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

E-17. 6-Methyl-5- (5-methyl-2-pyridinyl) -2 (1H) -15 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.

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

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

F. l-R ^ -S-Halo-e- (lower alkyl) -5-PY-2 (1H) -pyridinones F-1. 3-Bromo - 6-methyl-5- (4-pyridinyl) -2 (1H) -25 pyridinone, also called 5-bromo-2-methyl- [3,4'- bipyridin] -6 (1H) -one . To a stirred solution of 80 g of 6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone in one liter of acetic acid, heated to 65 ° C., 69 g are added dropwise in 25 minutes bromine in 50 ml of acetic acid. The reaction mixture is stirred for an additional 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, m.p.

34 252-254 ° C. A 15 g sample is dissolved in 200 ml of hot acetic acid and filtered. The filtrate is concentrated in vacuo, diluted with inethanol and the resulting white crystalline precipitate is collected and dried at 100 ° C for 16 hours 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 - »10 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 to a pH of about 2 to 3, cooling the mixture after partial evaporation and collecting the salt which has precipitated, for example dimethane sulfonate, sulfate or phosphate respectively. The acid addition salt in aqueous solution is also conveniently prepared by adding equimolar amounts of 3-bromo-6-methyl-5- (4-pyridinyl) -20 2 (with stirring to water). 1H) -pyridinone and suitable acid, for example lactic acid or hydrochloric acid, to prepare the monolactate and the monohydrochloride in aqueous solution respectively.

F-2. 3-Chloro-6-methyl-5- (4-pyridinyl) -2 (1H) -25 pyridinone, also called 5-chloro-2-methyl- [3,4 1 - bipyridin] -6 (1H) -one. A mixture containing 18.6 g of 6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone and 200 ml of acetic acid, treated on a steam bath, is treated with chlorine 4 hours. 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 to give 3-chloro-6-methyl-5- (4-pyridinyl) - 2 (1 H) -pyridinone.

Following the procedure described in Example * »35 Fl or F-2 but using instead of 6-methyl-5- (4-pyriainyl) -2 (1H) -pyridinone an equimolar amount of lR ^ -6- (lower alkyl) -5-PY-2 (1H) -pyridinone corresponding and bromine or chlorine, we see that we can obtain the 5 lR ^ -3-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-methyl1-5- (3-pyridinyl) -2 (1H) -10 pyridinone.

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

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

15 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) -20 pyridinone.

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

F-ll. 3-Bromo-6-ethyl-5- (2-methyl-4-pyrid-inyl) -2 (1H) -pyridinone.

25 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-ethy1-1- (2-hydroxyethyl) -5- (4-30 pyridinyl) -2 (1H) -pyridinone.

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

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

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

F-18. 3-Bromo-6-methyl-5- (5-methyl-2-pyridinyl) -2 (1H) pyridinone.

F-l9. 3-Bromo-6-ethyl-5- (5-ethyl-2-pyridiny1) - 9 <36 2 (1H) -pyridinone.

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

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

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 10 G-1. 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 hours a mixture containing 19 g of 3-bromo-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone, 250 ml of aqueous methylamine at 70 %, 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- (4-25 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-methyl1-5- (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. methane-sulfonic 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, »37 • sulfate or phosphate respectively. The acid addition salt in aqueous solution can also be conveniently prepared by adding equimolar amounts of 6-methyl-3-methylamino-5- (4-pyridinyl) -5 2 to water, with stirring. (1H) -pyridinone and the appropriate acid, for example lactic acid or hydrochloric acid, for respectively preparing the monolactate or the monohydrochloride in aqueous solution.

G-2. 3-Ethylamino-6-methyl-5- (4-pyridinyl) -2 (1H) -> 10 pyridinone, also called 5-ethylamino-2-methyl- [3,4'-bipyridin] -6 (1H) -one , pf 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 sulfate, autoclaved at 150 ° C for 45 hours and recrystallized twice from acetonitrile.

G-3. 6-Methyl-3- (dimethylamino) -5- (4-pyridinyl) -2 (1H) -pyridinone, also called 5- (dimethylamino) -2-20 methyl- [3,4'-bipyridin) -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 minutes 20 ml of a 37% formaldehyde solution. The mixture was heated to reflux for 1 hour and 45 minutes, heated to dryness in vacuo and the residue was 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 was dissolved in 250 ml of hot methylene dichloride, the hot solution was treated with bleaching charcoal and filtered, and the filtrate was 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, which gives 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 through 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-roethyl-3-v (dimethylamino) -5- (4-pyridinyl) -2 (1H) -pyridinone, m.p. 223-1025 ° C.

Following the procedure described in Example G1 or G-2 but using instead of 3-bromo-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone an equimolar amount of the 1R ^ -3-bromo (or chloro) -5-PY-6- (lower alkyl) -2 (1H) -pyridinone and lower alkylamine or the appropriate di (lower alkyl) amine, it is seen that one can obtain the 1R ^ -3- [mono- or di- (lower alkyl) -amino] -5-PY-6- (lower alkyl) -2 (1H) -pyridinones of Examples G-4 to G-23.

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

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

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

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

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

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

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

G-11. 3-Isopropylamino-6-n-pentyl-5- (4-pyridinyl) -35 2 (1H) -pyridinone.

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

G-l3. 6-Ethyl-3-ôthylamino-5- (3-pyridinyl) -2 (1H) - pyridinone.

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

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

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

G-17. 1,6-Diethyl-3-methylamino-5- (4-pyridinyl) - v 2 (1H) -pyridinone.

10 G-18. 3-n-Hexylamino-6-methyl-5- (2-pyridinyl) - 2 (1H) -pyridinone.

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

G-20. 6-Ethyl-5- (5-ethyl-2-pyridinyl) -3-15 dimethylaniino-2 (1H) -pyridinone.

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

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

20 G-23. 3-Methylamino-6-n-hexyl-5- (2-pyridinyl) - 2 (1H) -pyridinone.

H. 1- R ^ -3- (lower acylamino) -6- (lower alkyl) -5-PY-2- (1H) -pyridinones H-1. 3-Âcët, ylainino-6-methyl-5- (4-pyridinyl) -2 (1H) -25 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 30 is heated in the steam bath for one hour. 120 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 (1H) -pyridinone.

The acid addition salts of 3-acetylamino-6-methyl-1- (4-pyridinyl) -2 (1H) -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 40 t aqueous methanol, the appropriate acid (e.g. methane-tallow acid, concentrated sulfuric acid, l (concentrated phosphoric acid) to a pH of about 2 to 3, cooling the mixture after partial evaporation and collecting the precipitated salt, for example dimethane sulfonate, 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 3-acetylamino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone and suitable acid, for example lactic acid or hydrochloric acid, to prepare the monolactate and the monohydrochloride in aqueous solution respectively.

H-2. 3- [2- (Acetoxy) propanoylamino] -6-methyl-2 (1H) - 15 pyridinone - 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 one 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 H1 or H-2 but using instead of 3-amino-6-methyl-5- (4-pyridinyl) - (2 (1H) -pyridinone and / or acetic anhydride or 2-acetoxypropanoyl chloride equimolar amounts of 1R ^ -3-amino-5-PY-6- (lower alkyl) -2 (1H) -30 pyridinone and / or acylating agents appropriate corresponding, it can be seen that 3- (lower acylamino) -5-PY-6- (lower alkyl) -2 (1H) -pyridinones from Examples H-3 to H-17 can be obtained.

H — 3. 3-Acetylamino-6-ethyl-5- (4-pyridinyl) -2 (1H) -35 pyridinone.

H-4. 6-Methyl-3-propionylami)! O-5- (3-pyridinyl) -2 (1H) -pyridinone.

H-5. 3-Butyrylamino-6-n-propyl-5- (4-pyridinyl) - 141 2 (1H) -pyridinone.

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

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

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

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

10 H-10. 6-Ethyl-3-propionylamino-5- (3-pyridinyl) -2- (1H) -pyridinone.

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

H-12. 3-Acetyl-6-ethyl-1- (2-hydroxyethyl 1) .- 5- (4-15 pyridinyl) -2 (1H) -pyridinone.

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

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

8:15 p.m. 6-Ethyl-5- (5-ethyl-2-pyridinyl) -3-formyl-amino-2 (1H) -pyridinone.

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

H-17. 3-Acetylamino-6-n-hexyl-5- (2-pyridinyl) -2-25 (1H) -pyridinone.

^ I. Acids A-R ^ -l, 2-dihydro-6- (lower alkyl) -2-oxo-5-PY- nicotinic 1-1. 1,2-dihydro-6-xnethyl-2-oxo-5- (4-pyridinyl) nicotinic acid, also called 1,6-dihydro-30 2-methyl-6-oxo [3,4'-bipyridine] - 5-carboxylic. 30 g of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotino-nitrile are added, with stirring, to a hot solution containing 220 ml of water and 245 ml of sulfuric acid concentrated. The reaction mixture is heated to reflux for 7 hours (about 35 122 ° C) and then allowed to stand for the weekend at room temperature. It is then diluted with water, cooled in an ice bath and treated dropwise with stirring with ammonium hydroxide to 42 neutral pH. The resulting crystalline precipitate is collected, rinsed successively with three 100 ml portions of water and several times with acetone then with ether and dried at 80 ° C. The crystalline material is diluted with 5,200 ml of chloroform and 200 ml of methanol for 30 minutes and the mixture is concentrated in vacuo to a volume of 150 ml. The crystalline product is collected and dried at 95 ° C to give about 24 g of product. A 10 g sample of the product is heated with 10 200 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 acid 1, 2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) -nicotinic, pf > 260 ° C.

Following the procedure described in Example 15 1-1 but using in place of 1,2-dihydro-6-methyl-2-oxo-5 "(4-pyridinyl) nicotinonitrile an equimolar amount of 1-R -1,2-dihydro-2-oxo-5-PY-6- (lower alkyl) -nicotinonitrile corresponding, we see that we can obtain the acids 1-R ^ -l, 2-dihydro-2-oxo- 5-PY-6- (lower alkyl) -20 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.

25 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- (4-30 pyridinyl) nicotinic acid.

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

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

35 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-oxonicotinic acid.

43 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.

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

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

1-15. 1,6-Diethyl-1,2-dihydro-2-oxo-5- (4- *. V 10 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.

15 1-18. 6-ethyl-5- (5-ethyl-2-pyridinyl) -1,2-dihydro-2-oxonicotinic acid.

1-19. 1,2-dihydro-6-methyl1-5- (4,6-dimethyl-2-pyridinyl) -2-oxonicotinic acid.

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

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

J. 1-R -6- (lower alkyl) -1,2-dihydro-2-oxo-5-PY-nicotinates of lower alkyl J-1. 1,2-Pihydro-6-methyl-2-oxo-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 inethanesulfonic acid for 18 hours . The excess ethanol is distilled in vacuo and the residue is recrystallized from dimethylforroamide ^ to obtain ethyl 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) -nicotinate under form of its methane-tallow acid salt. The salt is dissolved in hot water and the solution basified 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.

44

The acid addition salts of ethyl 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinate are conveniently prepared by adding to a mixture of 5 g of 1,2- ethyl dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinate in approximately 5 100 ml of aqueous methanol, the appropriate acid (methane-tallow acid, concentrated sulfuric acid, concentrated phosphoric acid for example ) to a pH of about 2 to 3, cooling the mixture after partial evaporation and

AT

collecting the salt which precipitated, for example dimethane-sulfonate, sulfate or 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-pyridinyl) to water, with stirring. ) ethyl nicotinate and the appropriate acid, for example lactic acid or hydrochloric acid, to respectively prepare the monolactate or the monohydrochloride in aqueous solution.

Following the procedure described in Example E1, but using 1,2-dihydro-6-20 methyl-2-oxo-5- (4-pyridinyl) nicotinic acid and ethanol instead of equimolar amounts of 1-ï ^ -l, 2-dihydro-2-oxo-5-PY-6- (lower alkyl) nicotinic acid and lower alkanol, we see that we can obtain the lR ^ -1,2-dihydro-2-oxo-5 ~ PY-6- (lower alkyl) lower alkyl nicotinates of Examples J-2 to J-19.

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

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

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

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

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

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

D-8. 1,2-Dihydro-6-isobutyl-2-oxo-5- (4-pyridinyl) - ethyl nicotinate.

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

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

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

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

> D-13. Ethyl 1,2-Dihydro-1,6-dimethyl-2-oxo-5- (4- "·. 10 pyridinyl) nicotinate.

"D-14. Ethyl 6-Ethyl-1,2-dihydro-1- (2-hydroxyethyl) -2-oxo-5- (4-pyridinyl) nicotinate.

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

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

D-17. Methyl 6-Ethyl-5- (5-ethyl-2-pyridinyl) -1,2-dihydro-2-oxonicotinate.

D-18. Ethyl 1,2-Dihydro-6-methyl-5- (4,6-dimethyl-2-pyridinyl) -2-oxonicotinate.

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

. The usefulness of the compounds of formula I or their salts as cardiotonic agents is demonstrated by their effectiveness in standard pharmacological tests, for example by causing a significant increase in the contraction force in the procedure using atria and isolated papillary muscles of cat and causing a significant increase in the force of cardiac contraction in the procedure on the anesthetized dog 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. N ° 4.072.746.

35 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 yg / ml, appear to cause a significant increase, that is to say that is to say greater than 25 ′ 1, of the force t, 46 of the papillary muscle and a significant increase, that is to say greater than 25 I, of the force of the right atrium, while only causing a small increase (about a third or less of the percentage increase in the strength of the right atrium or the strength of the papillary muscle) on the speed of the right atrium. In addition, it is found that the compounds with a 6- (lower alkyl) group of formula I are clearly more active as cardiotonic agents when tested by this procedure ("__ 10 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 as intermediates having no cardiotonic properties.

The significantly higher cardiotonic activity of derivatives with a lower alkyl group at position 6 compared to the corresponding prior art compounds unsubstituted at position 6 is illustrated by the following comparisons of test data obtained using the atrium procedure and papillary muscle isolated from cat. 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 74% when tested at 10 yg / ml, to compare with the corresponding increases of 109 + 11.3% and 49.9 + 8.4% for 3-30 amino-5- (4 -pyridinyl) -2 (1H) -pyridinone (amrinone) at a dose "of 100 μg / 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) -pyridine are 53 % and 35 37% when tested at a dose of 3 yg / 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 µg / ml, i.e. ten times the dose; on é 47: found that the percentages of increase in the strength of the papillary muscle and in 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-pyridinyl) nicotino-5 nitrile are 45% and 51% for the 6-methylated compound and 107% and 79% for the compound 6-ethyl, at a dose of 3 yg / ml, to be compared to the corresponding increases of 65% and 15% for 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile of the prior art without grouping alkyl in position

Sr 10 6 at a dose of 30 yg / ml, that is to say a dose ten times - higher; we find that the percentages of 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 are 135 % and 102% at a dose of 10 yg / ml while the corresponding demethylated compound in position 6 corresponding to the prior art is inactive at a dose of 10 yg / ml; we find that the percentages of increase in the strength of the papillary muscle and the strength of the right atrium for 6-methyl-3-methylamino-5- (4-20 pyridinyl) -2 (1H) -pyridinone are 68% and 41% at a dose of 30 yg / ml, compared to the corresponding increases of 64% and 39% for 3-methylamino-5- (4-pyridinyl) -2 (1H) -pyridinone of the prior art a a dose of 100 yg / ml, i.e. more than three times the dose.

Examples of the cardiotonically active compounds of the formula I are given below where Q is a carbamyl group or a halogen atom while the corresponding prior art 6-de- (lower alkyl) compounds are described only as intermediates and not as cardiotonic agents: when tested by the in vitro test on "atria and papillary muscles of cats, we find that 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinamide has percent increases in papillary muscle and right atrium strength of 35 35% and 22% respectively at a dose of 30 yg / ml and 87% and 37% respectively at a dose of 100 yg / ml; when tested by the same method, it is found that 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinamide has tg * 48 r percentages of increase in strength. papillary muscle and right atrium strength of 29% and 7% respectively at 100 yg / ml and 89% and 27% respectively at 300 yg / ml; and when tested by the same procedure, it is found that 3-bromo-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone has percentages of increased strength papillary muscle and right atrium strength of 87% and 99% respectively at a dose of 1 yg / ml and 107% and 58% respectively at a dose of 10 yg / ml.

The markedly higher cardiotonic activity of the compounds with a group (lower alkyfe) 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 comparisons. Following test data using the procedure of isolated cat atria and papillary muscles: the percentages of increase in papillary force and right atrium strength for 6-methyl- are found 5- (4-pyridinyl) -2 (1H) -pyridinone are 115% and 48% when tested at 10 yg / 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 µg / ml, i.e. ten times the dose of the compound of the present application; we find that the ^ percentage increases in the strength of the papillary muscle „and the strength of the right atrium for 6-ethyl-5- (4-, pyridinyl) -2 (1H) -pyridine are 106% and 50% at a dose of 30 yg / ml, compared to the corresponding increases of 30 48% and 51% for 5- (4-pyridinyl) -2 (1H) -pyridinone at a dose of 100 yg / ml, c that is, more than three times the dose.

As an example of a compound of formula I where Q is a carbiotonically active carboxy group while the corresponding prior art compounds without a lower alkyl group in position 6 are described only as intermediates and not as cardiotonic agents, there are that 1,2-dihydro-6-methyl-2-OXO-5- (4-pyridinyl) nicotinic when tested by the * * 49 same similar test on atria and papillary muscles of guinea pigs in vitro, has percentages of increase in papillary muscle strength and right atrium strength of 36% and 27% at 30 yg / ml 5 respectively and 44% and 69% respectively at 100 pg / 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 10 cause a significant increase, i.e. greater than 25%, in the cardiac contraction force or cardiac contractility with only small or minimal changes (less 25%) of heart speed and blood pressure. In addition, the compounds of formula 15 I with a lower alkyl group in position 6 have been found. 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, as shown in the following examples: the percentage of increase in strength is found cardiac contraction or cardiac contractility for 3-amino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone tested as indicated in dogs anesthetized at 1.0 mg / kg intravenously, is 136 % to be compared with the increase of 125.67 + 10.59% for the corresponding 6- ^ demethylated compound, amrinone, tested at ten times the dose, that is to say at 10 mg / kg per intravenous route; similarly, we find that the percentages of increase in the cardiac contraction force for 3-amino-6-ethyl-5-30 (4-pyridinyl) -2 (1H) pyridinone tested in the same procedure at doses 0.03 mg / kg and 0.10 mg / kg intravenously are 33% and 72% respectively, compared to increases of 24.67 + 3.15% and 70.64 + 7.85% respectively for the prior art amrinone tested at ten times the corresponding doses, i.e. 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-methyl1-2-oxo 5- (4-pyridinyl) nicotinonitrile, tested by the same operating method * · 50 at doses of 0.03 mg / kg and 0.10 mg / kg are 49.5% and 87.5% respectively, compared to increases of 44% and 78% respectively for the corresponding 6-demethylated derivative of the prior art tested 5 to 100 times the corresponding doses, i.e. at 3 mg / kg and 10 mg / kg or to compare with 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-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile tested by this operating procedure at the doses 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 it is tests the corresponding doses 100 times, i.e. 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, lR ^ -3-Q-6- (lower alkyl) -5-PY- 2 (1H) -pyridinone cardiotonic of formula I or its pharmaceutically acceptable acid addition salts 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 1-1 ^ -3-0-6 (lower alkyl) -5. -PY-2 (1H) - 30 pyridinone of formula I or its pharmaceutically acceptable acid addition salts * 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 may 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 art such as water and paraffin liquid. Besides inert diluents, such compositions may also contain adjuvants, such as wetting and suspending agents, and sweetening, flavoring, fragrance 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 may 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 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 5 and condition of the patient, power of the active compound and reaction of the patient. An effective dose of the 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.

l * i.

1 'L

NOT

W · '%

Claims (9)

2. A compound according to claim 1, in which R is a methyl or ethyl group and PY is a 4-pyridinyl group. 3. 3-Amino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone according to claim 1. 4. 4. 3-Amino-6-ethyl-5- (4-pyridinyl) -2 ( 1H) - pyridinone according to claim 1. 5. 3-Amino-6-n-propyl-5- (4-pyridinyl) -2 (1H) - I -â- pyridinone according to claim 1. 6. 1,2- Dihydro-6-methyl-2-oxo-5- (4-pyridinyl) -30 nicotinonitrile according to claim 1. 7. 6-Methyl-3-methylamino-5- (4-pyridinyl) -2 (1H) -pyridinone claim 1. • 8. 3-Bromo-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone according to claim 1. 35 9. 6-Ethyl-1,2-dihydro-2-oxo -5- (4-pyridinyl) - nicotinonitrile according to claim 1. 10. 1,2-Dihydro-6-methyl-2-oxo-5- (4-pyridinyl) - nicotinamide according to claim 1. / J * · * 54 11. 6-Ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) -nicotinamide according to claim 1. 12. 3-Ethylamino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone according to claim 1. 5 13. 3-Dimethylamino-6-methyl-5- (4-pyridinyl) -2 (1H) - pyridinone according to claim 1. 14. 6-Methyl-5- (4-pyridinyl) -2 (1H) -pyridinone according to claim 1. 15. 6-Ethyl-5- (4-pyridinyl) -2 (1H) -pyridinone V.. 10 according to claim 1. Γ 16. 1,2-Dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinic acid according to claim 1. 17. Process for the preparation of a compound according to claim 1, characterized in that: a. a compound of formula R3R4NCH = C-C (= O) -R PY III where and R ^ are each a lower alkyl group, is reacted with malonamide to produce a compound of formula I where Q is a carbamyl group or b. reacting a compound of formula III or a compound of formula IV R-C-C-CHO II 1 0 PY IV 25 with an NR ^ -a-cyanoacetamide to prepare a compound of formula I where Q is a cyano group, ~ if desired, partial hydrolysis is carried out ~ of 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, a compound of formula I obtained in which Q is a carbamyl group is reacted with a reagent capable of converting the carbamyl group into an amino group for obtaining the corresponding compound where Q 35 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 for / J! "I * 55 obtain the corresponding compound where Q is a lower alkylamino or di- (lower alkyl) amino group respectively, if desired, a compound of formula I obtained where Q is an amino group is reacted with an agent acylation with a lower 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 * 1 10 the corresponding compound where Q is a carboxy group, V \ ^ ^ 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 a aqueous mineral acid to obtain the corresponding compound where Q is a hydrogen atom, if desired, a compound of formula I obtained where Q is a carboxy group is esterified with a lower alkanol, to obtain the corresponding compound where Q is a lower carbalkoxy group, if desired, a compound of formula I obtained in which is a hydrogen atom, is reacted with a v ;. alkylating agent of formula R'-An where R 'is a group! H * · lower alkyl or lower hydroxyalkyl, and An is an anion of a strong mineral acid or an organic sulfonic acid, to prepare the corresponding compound where R is! R \ i 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 halo radical, and, if desired, reacts a compound of formula I obtained in which Q is a halo radical, with a lower alkylamine or a di- (lower alkyl) amine, to obtain the corresponding compound where Q is a lower alkylamino group or di (lower alkyl) amino respectively, 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. 18. The method of claim 17, characterized in that one uses, as alkylating agent, a mixture * of aqueous formaldehyde and formic acid to obtain a ~ - 10 compound of formula I where Q is a dimethylamino group. V ·. 19. A cardiotonic composition for increasing cardiac contractility, said composition comprising a pharmaceutically acceptable inert carrier and, as an active component, an effective amount of a compound according to any one of claims 1 to 16. 20. A compound according to any one of claims 1 to 16, intended to increase the cardiac contractility in a patient in need of such treatment. 21. Compound characterized in that it has the formula III where R is a lower alkyl group, and R ^ are each a lower alkyl group and PY is a 4-, 3 or 2-pyridinyl or 4-, 3- or 2-Pyridinyl having one or two lower alkyl substituents. 22. A compound according to claim 21, wherein PY is a 4-pyridinyl group and R is a methyl or t - · 'ethyl group. 23. A compound according to claim 20 or 21, wherein R ^ and R ^ are each a methyl group. 24. A method of producing a compound according to any one of claims 20-22, characterized in that a (pyridinyl) methyl (lower alkyl) ketone of formula PY-C ^ -C (= 0 ) -R with a di- (lower alkyl) acetal of di- (lower alkyl) formamide. VKXJvvi.