FR2470124A1 - 5- (PYRIDINYL) -2 (1H) PYRIDINONES, THEIR PREPARATION AND THEIR USE AS CARDIOTONIC AGENTS - Google Patents

Abstract

1-R-3-Q-5-PY-6-R-2 (1H) -PYRIDINONE OF FORMULA: (CF DRAWING IN BOPI) IN WHICH Q IS A HYDROGEN ATOM OR A RADICAL AMINO, CYANO, CARBAMYL, HALO , LOWER ALKYLAMINO, DI- (LOWER ALKYL) AMINO, LOWER ACYLAMINO, LOWER CARBOXY OR CARBALCOXY, R IS A HYDROGEN ATOM OR A LOWER ALKYL OR HYDROXYALKYL GROUP, A LOWER GROUP 4, R IS A LOWER ALKYL OR HYDROXYALKYL GROUP, AND IS A LOWER GROUP 4, R 3- OR 2-PYRIDINYL OR 4-, 3- OR 2-PYRIDINYL HAVING ONE OR TWO LOWER ALKYL SUBSTITUENTS, OR ONE OF ITS CATIONIC OR ACID ADDITIONAL SALTS. THE INVENTION ALSO DESCRIBES THE PREPARATION OF THESE COMPOUNDS AND THEIR USE AS CARDIOTONIC AGENTS.

Description

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 describe, as cardiotonic agents, 3-amino (or cyano) - ((pyridinyl) -2 (1H) -pyridinones and, as intermediates, compounds with a corresponding 3-carbamyl group, also called 1,2-dihydro-2-oxo-5- (pyridinyl) nicotinamides which are converted into corresponding 3-amino compounds by reaction with a reagent capable of converting the carbamyl group to 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 amrinone or also called 5-amino-3,4'-bipyridin-6 ( 11) -one. A

  described process for the preparation of 3-cyano-5- (pyridinyl) -

  2 (1H) -pyridinones, also called 1,2-dihydro-2-oxo-5-

  (pyridinyl) nicotinonitriles, includes the reaction of the

  (pyridinyl) -1- (dialkylamino) acrolein with α-cyanoacetamide.

  The U.S. Patent N 4.072.746 also describes the 3-Q-

  - (pyridinyl) -2 (11I) pyridinones where Q is a hydrogen atom

  halogen or a lower alkylamino group, di-

  (lower alkyl) amino and NHAc o Ac is a group

  lower alkanoyl or lower carbalkoxy.

  Unsubstituted 5- (pyridinyl) -2 (1H) pyridinones

  position 3 (Q = 1)) are prepared by heating the derivatives 3-

  corresponding cyano with aqueous sulfuric acid, first forming the 3-carboxylic acids, 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. The invention relates to compounds of formula I pY Q PY

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  wherein Q is a hydrocene or an amino, cyano, carbamoyl, halo, lower alkylamino, di- (lower alkyl) amino, lower acylamino, carboxy or lower carbalkoxy radical, R1 is a hydrogen atom or an alkyl group lower or lower hydroxyalkyl, R is a

  lower alkyl group and PY is a group 4-, 3-

  or 2-pyridinyl or 4-, 3- or 2-pyridinyl having one or two lower alkyl substituents, and cationic or pharmaceutically acceptable acid addition salts thereof. The compounds of formula I are useful as cardiotonic agents, as shown by standard pharmacological test procedures. The compounds of formula I where Q is a carbamoyl or cyano group and where Q is hydrogen 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 compounds with a 13-mono- or di-

  (lower alkyl) amino]. 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, R1 is a hydrogen atom and R is a methyl or ethyl group. . Compounds particularly

  preferred are 1,2-dihydro-6-methyl] -2-oxo-5- (4-pyridinyl) -

  nicotinonitrile (formula I where Q is CN, R1 is 11, PY is a 4-pyridinyl group and R is a methyl group), 3-amino-6-ethyl-5- (4-pyridinyl) -2 (1H) -pyridinone (formula I where Q is NH2, R1 is H, PY is 4-pyridinyl and R is ethyl), 3-amino-5- (4-pyridinyl) -6-methyl-2 (1H) pyridinone (Formula I where Q is NH2, R1 is H, PY is 4-pyridinyl and R is methyl), 6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone (formula

  I o R1 = II, PY = 4-pyridinyl and R = methyl) and the 6-

  ethyl-5- (4-pyridinyl) -2 (1H) -pyridinone (formula I wherein R1 = H, PY = 4 pyridinyl and R = ethyl), or their pharmaceutically acceptable acid addition salts. These particularly valuable compounds have been found to have significantly superior cardiotonic activity (h uel (l back).

  the corresponding known 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 comprises: a. reacting a compound of formula

R3R4NCH = C-C (- = O) -R

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

R-C-CH-CHO IV

  III IV O PY with N-R-α-cyanoacetamide to prepare a compound of

  formula I o Q is a cyano group; - -

  if desired, to partially hydrolyze a compound of formula I obtained wherein Q is a cyano group, to obtain the corresponding compound where Q is a carbamyl group, if desired, to react a compound of formula I obtained where Q is a carbamyl group, with a reagent capable of converting the carbamyl group to an amino group to produce the corresponding compound where Q is an amino group, if desired, to react a compound of formula I obtained where Q is an amino group, with a or two molar equivalents of a lower alkyl alkylating agent to obtain the corresponding compound where Q is lower alkylamino or di- (lower alkyl) amino respectively, if desired, reacting a compound of formula I wherein Q is an amino group, with acylating agent having a lower acyl group to give the corresponding compound where Q is an acylamino group

2470124 1

  lower, if desired, to hydrolyze a compound of formula I obtained wherein Q is a cyano group, to obtain the corresponding compound where Q is a carboxy group, if desired, to heat a compound of formula I obtained where Q is a carboxy group, with a mixture of concentrated sulfuric 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 a grouping amino, if desired, to heat a compound of formula I obtained wherein 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 o: Q is a lower carbalkoxy group, if desired, to react a compound of formula I wherein R1 is a hydrogen atom, with an alkylating agent of the formula R'-An where R 'is a lower alkyl or hydroxy-lower alkyl group and An is an anion of a strong mineral acid or a sulfonic acid organic, to prepare the corresponding compound o R1 is R ', if desired, to react a compound of formula I obtained where Q is a hydrogen atom, with a halogen to obtain the corresponding compound o Q is an atom halogen, if desired, reacting a compound of formula I obtained where Q is a halogen atom, with a lower alkylamine or a di- (lower alkyl) amine-to obtain a corresponding compound where Q is a lower alkylamino or di (lower alkyl) amino respectively, and, if desired, converting the obtained free base into one of its acid addition salts or

  transforming a compound obtained into one of its cationic salts.

  PY-Methyl (lower alkyl) can be reacted -

  ketone of formula PY-CH2-C (= O) -R (II) with a di-acetal

  lower alkyl of a di (lower alkyl) formamide to give the 1PY-2- [di- (lower alkyl) aminol-ethenyl-lower alkyl ketone of the formula III

R3R4NCH = C-C (= O) -R III

  RY and R4 are each a lower alkyl group and one is preferably a methyl group, and PY, R, R1 and R '

  are as defined for formula I.

  (pyridinyl) -2-Idl (lower alkyl) aminolethenyl (lower alkyl) ketones of formula III where PY and R are as previously defined and their acid addition salts are novel 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 an active component, an effective amount of a 1-R1-3Q-5-PY-6-R-2 (1H) -pyridinon cardiotonic of formula I, wherein R1, Q, PY and R are each defined as in formula I, or an addition salt thereof

  of pharmaceutically acceptable acids or cationics.

  Cardiac contractility can be increased in a patient in need of such treatment by administering to this patient an effective amount of a 1-R1-3-Q-5-PY-6-R-2 (1H pyridinone cardiotonic of formula I, R1, Q, PY and R are as defined in formula I, or a cationic or pharmaceutically acid addition salt thereof

acceptable.

  The term "lower alkyl" as used herein, for example as a definition for R or as a de! R1 definitions, such as the definition of "lower alkyl" in the lower alkylamino or di- (lower alkyl) amino expressions for Q or as a substituent for PY in formula I, refer to alkyl radicals having 1 to 6 carbon atoms ( They can be arranged in straight or

2470121 1

  branched, illustrated by the groups methyl, ethyl, n-

  propyl, isopropyl, n-butyl, sec-butyl, t-butyl, isobutyl, n-amyl, hexyl, etc. The term "lower hydroxyalkyl" as used herein, for example as one of the definitions of R 1 in formula I, refers to hydroxyalkyl groups having from two to six carbon atoms and having the hydroxy group and the free valence are on different carbon atoms, illustrated by groupings

  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 the formula I o 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 known as 2-methyl-

  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 3- (lower acylamino) substituent of the compounds of formula I (Q is a lower acylamino group), refers to alkanoyl radicals having one to six carbon atoms. carbon, preferably one to four, and having substituents selected from hydroxy, acetoxy or propionoxy groups, including straight or branched chain radicals, exemplified by formyl, acetyl, propionyl (n-propanoyl), butyryl (n - butanoyl), isobutyryl

  (2-methyl-n-propanoyl), caproyl (n-hexanoyl), hydroxyl

  acetyl, α-hydroxypropionyl, [3-hydroxypropionyl, α-acetoxy-

  propionyl, propionoxyacetyl, 1-acetoxypropionyl, a-acetoxy-

  butyryl, etc. The compounds of formulas I and III can be used in the form of free base and in the form of salts.

2470124 1

  acid addition and both forms are within 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, when combined with the free base, produce pharmaceutically acceptable salts, i.e. anions are relatively harmless to the animal organism at the pharmaceutical doses of the salts, so that the beneficial cardiotonic properties inherent in the free base form (I) are not vitiated by side effects attributable to the anions. In the practice of the invention, it is convenient to use the free base form; however, suitable pharmaceutically acceptable salts within the scope of the invention are those obtained from inorganic 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, cyclohexylsulfamic acid, quinic acid, etc., respectively giving hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate

  benzenesulfonate, p-toluenesulfonate, cyclohexyl-

sulfamate and quinate.

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

concentration of the solution.

  Although the pharmaceutically acceptable salts are

  of the basic compound (I or III), all the salts -

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  acid addition are within the scope of the invention.

  All of the acid addition salts are useful as sources of the free base, even if the particular salt is in itself only sought as an intermediate, for example when the salt is formed only for purification purposes. or identification, or when it is used as an intermediate for the preparation of a pharmaceutically acceptable salt by procedures

ion exchange.

  Other pharmaceutically acceptable salts of the compound of formula I are cationic salts obtained from strong inorganic or organic bases, for example sodium hydroxide, potassium hydroxide, trimethylammonium hydroxide, to obtain the salt. 1- or N-cationic, corresponding, for example the salt of sodium, potassium, trimethylammonium respectively, that is to say that the ion

  cationic is fixed in position 1 or N of the nucleus 2 (1H) -

  pyridinone. The molecular structures of the compounds of formulas I and III have been assigned on the basis of data provided by the infrared, nuclear magnetic resonance and mass spectra, and by the correspondence of the values.

  calculated and found for elemental analysis.

  The manner of making and using the present invention will now be described generally for

  allow the man of the art to realize it.

  The preparation of 1-PY-2- (dimethyl)

  amino) ethenyl (lower alkyl) ketone of formula III by reacting PY-methyl (lower alkyl) ketone (II) with a dimethylformamide lower dialkyl acetal, by mixing the reactants in the presence or absence of a solvent appropriate. The reaction is conveniently carried out at ambient temperature, i.e., about 20-25 ° C, or by heating the reagents to about 100 ° C, preferably

  in an aprotic solvent, conveniently hexamethyl-

  phosphoramide because of the process used to prepare the PY-methyl (lower alkyl) ketone, as shown below in Example A-1. Other suitable solvents include

2470124 '

  tetrahydrofuran, dimethylformamide, acetonitrile, ether, benzene, dioxane, etc. The reaction can also be carried out without a solvent, preferably using an excess of dimethylformamide di (lower alkyl) acetal. This procedure is further illustrated

  below in Examples A-1 to A-17.

  Intermediate PY-methyl (lower alkyl) ketones

  The compounds of formula II are generally known compounds which are prepared by known methods, for example as described in Rec. trav. Chem. 72, 522 (1953); the U.S. Patent N 3.133.077; Bull. Soc. Chim 1968, 4132; Chem. Abstrs. 79, 8539h (1973); Chem. Abstrs. 81, 120, 401a (1974); J. Org. Chem. 39, 3834 (1974); Chem. Abstrs. 87, 6594q

  (1977); J. Org. Chem. 43, 2286 (1978) 1.

  The reaction of 1-PY-2- (dimethylamino) ethenyl (lower alkyl) ketone (III) with a N-Rl-a-cyanoacetamide

  to obtain 1-R-1 1,2-dihydro-2-oxo-5-PY-6-R-nicotinic acid

  nitrile (formula I o Q is CN) is preferably carried out by heating the reactants in a suitable solvent in the presence of a basic condensing agent. The reaction is conveniently carried out using a lower alkali metal alkoxide, preferably sodium methoxide or ethoxide, in dimethylformamide. In carrying out the invention, the reaction is carried out by heating the dimethylformamide under reflux using sodium methoxide. Alternatively, methanol and sodium methoxide or ethanol and sodium ethoxide may be used as the solvent and the basic condensing agent respectively; however, a longer heating period is necessary. Other basic condensation 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 best illustrated below in Examples B-1 to B-21.

  The preparation of 1-R1-

  1,2-dihydro-2-oxo-5-py-6-r-nicotinonitrile by heating a 1-PY-2- (R3R4amino) ethenyl] (lower alkyl) ketone (III)

2470124 1

  in an aqueous alkaline medium, for example an aqueous solution of sodium hydroxide or potassium hydroxide, to obtain the corresponding α-PY-β-R-ioxopropionaldehyde (IV) and in

  reacting this compound with an N-Ri-Ix-cyanoacetamide.

  1,2-Dihydro-2-oxo-PY-6-R-nicotinamide (formula I, Q = carbamyl and R 1 = II) can also be prepared directly by reacting a 1PY-2- (R 3 R 4 amino) ethenyl

  (lower alkyl) ketone of formula III with malonamide.

  Partial hydrolysis of 1-R1-, 2-dihydl-o-2-oxo-5-

  PY-6-R-nicotinonitrile (formula I o Q = CN) to give 1,2-dihydro-2-oxo-5-PY-6-R-nicotinamide (I o Q is a carbamyl group) is carried out by heating the compound of the formula I o Q is a cyano group with concentrated sulfuric acid. Although the reaction is conveniently and preferably carried out by heating the reagents on a steam or oil bath at about 80-100 ° C., the temperature range for the reaction may be from about 70 ° C. This procedure is further illustrated below in

Examples C-1 to C-21.

  The transformation of 1-R1-1,2-dihydro-2-oxo-5-PY-

  6-R-nicotinamide (I o Q is a carbamyl group) in 1-

  R1-3-amino-5-PY-6-R-2 (1H) -pyridinone (where Q is an amino group) is carried out by reacting the compound of formula I where Q is a carbamyl group with a reactant capable of transforming the carbamoyl group to an amino group, for example an 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 wherein Q is a carbamyl group and 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.

  below in Examples D-1 to D-2].

  1 -Rl-3-amino-5-PY-6- can also be prepared

  R-2 (] 1l) -pyrid.inone (I, Q is a (jroupemient, [nino) in chaunfLant

2470124 X

  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 directly reducing the 3-nitro compound to prepare 3-amino-5-PY-6-R-2 (1H) -pyridinone (formula I, Q is an amino group and R1 is a hydrogen atom), or by first alkylating (see next paragraph)

  3-nitro compound to prepare 1-R1-3-nitro-5-PY-6-R-2 (1H.) -

  pyridinone and reducing the 3-nitro compound to prepare 1-R 1-3amino-5-PY-6-R-2 (1H) -pyridinone (formula I, Q is an amino group and R1 is a lower alkyl group or

lower hydroxyalkyl).

  The compounds of formula I can also be prepared. R 1 is a lower alkyl or hydroxy-lower alkyl group by reacting the corresponding unsubstituted compounds of formula I of formula I where R 1 is an atom

  hydrogen, with a lower alkyl ester or hydroxyl

  lower alkylic acid of a strong mineral acid or an organic sulfonic acid, preferably in the presence of a

acid acceptor.

  Transformation of 1-R1-11,2-dihydro-2-oxo-5-PY-6-

  R-nicotinonitrile (I, Q is a cyano group) in 1-R -5-

  PY-6-R-2 (1H) pyridinone (I, Q is a hydrogen atom) is

  by heating the compound I o Q is cyano as above

  in an aqueous mineral acid, preferably 50% sulfuric acid, to first form the compound I o Q is a carboxy group and then continue to heat for a longer period of time, which causes the decarboxylation 3-carboxylic acid to give the compound I o Q is a hydrogen atom. This procedure

  is best illustrated below in Examples E-1 to E-21.

  The reaction of 1-R1-5-PY-6-R-2 (1H) is carried out -

  pyridinone (I, Q-is a hydrogen atom) with a halogen to obtain the corresponding 3-halogenated compound (I, Q is a halogen atom) by mixing the reactants in a suitable solvent that is inert under the reaction conditions, a preferred solvent being acetic acid. The reaction is conveniently carried out at room temperature or by heating

  reagents at temperatures up to about 100 C.

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  The preferred halogens are bromine and chlorine.

  Any inert solvent, for example dimethylformamide, chloroform, acetic acid, etc., can be used. This procedure is best illustrated below in Examples F-1 to F-22. The reaction of a 1-R 1-3-halo-5-PY-2 (1H) -pyridinone (I, Q is a halogen atom) with a lower alkylamine

  or a di- (lower alkyl) amine to obtain 1-R1 -3-

  (lower alkylamino) -5-PY-6-R-2 (1H) -pyridinone correspon-

  dante (I, Q is a lower alkylamino group) or 1-

  R -3- [di- (lower alkyl) amino] -5-PY-2 (1H) -pyridinone i

  corresponding [I, Q is a di- (lower alkyl) -

  amino] is carried out by heating the reagents in a

  autoclave at about 110-180 ° C., preferably about 145 ° C.

  165 C and preferably in a suitable solvent, for example

  water, dimethylformamide, dioxane, 1,2-dimethoxy-

  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

  1-R 1-3- [mono- or di- (lower alkyl) amino] -5-PY-6-

  (lower alkyl) -2 (1H) -pyridinone is to react the corresponding 3-amino compound with one or two molar equivalents of an alkyl-lower alkylating agent.

  A preferred method of preparing 1-R-3-

  dimethylamino-5-PY-6-R-2 (1H) -pyridinone (I, Q is a dimethylamino group) is carried out by reacting 1-R 1-3-amino-5-PY-6-R2 (1H) -pyridinone (I, Q is a group

  amino) with a mixture of formaldehyde and formic acid.

  This reaction is conveniently carried out by refluxing the 3-amino compound with an excess of formaldehyde, preferably an aqueous solution of this compound, and an excess of formic acid, preferably for each more than twice molar excess. This procedure is better illustrated

  below in Examples G-3, G-8 and G-20.

  Acylation of 1-R 1-3-amino-5-PY-6-R-2 (1H) -

  pyridinone (I, Q is an amino group) to produce the corresponding 3- (lower acylamino) compound (I, Q is a lower acylamino group) is carried out by reacting the compound of formula I where Q is an amino group, with an acylating agent, for example a lower acyl halide, preferably chloride, a lower acid anhydride, etc., preferably in the presence of an acid acceptor. The acid acceptor is a basic substance which preferably forms readily water-soluble by-products which readily separate from the reaction product, including for example sodium hydroxide, potassium hydroxide and the like. sodium carbonate, potassium carbonate, sodium alcoholates, potassium alcoholates, sodium amide, etc. The reaction is preferably carried out in the presence of a suitable solvent which is inert under the reaction conditions, for example a solvent such as a lower alkanol, acetone, dioxane,

  dimethylformamide, dimethylsulfoxide, hexamethyl-

  phosphoramide, 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 of between about 10 ° C. and 150 ° C., preferably about 25 ° C. This procedure is better illustrated below.

in Examples H11-1 to H-17.

  Hydrolysis of 1-R1-1,2-dihydro-2-oxo-5-PY-6-R-

  nicotinonitrile (I, Q is cyano) to produce 1-R acid -

  1,2-Dihydro-2-oxo-5-py-6-r-nicotinic acid (I, Q is a carboxy group) is conveniently made by heating said nicotinonitrile on a steam bath with an aqueous mineral acid, preferably 50% sulfuric acid. This inertial mode is better illustrated below in the Examples.

I-1 to 1-21.

  Esterification of 1-R1-1,2-dihydro-2-oxoacetate

  -PY-6-R-nicotinic (I, Q is a carboxy group) to obtain lower alkyl 1-Rl1,2-dihydro-2-oxo-5-PY-6-R-nicotinate (I, Q is a lower carbalkoxy group) is carried out by heating the acid with an alkanol of less than about 25 to 150 ° C, preferably about 50 to 100 ° C, preferably in the presence of a suitable solvent, for example unexci; lower clanol, in the presence of an acidic catalyst, for example a strong mineral acid or an organic sulphonic acid such as hydrochloric acid, acid

  sulfuric acid, methanesulfonic acid, p-toluene acid,

  sulfonic etc. This procedure is better illustrated below.

  below in Examples J-1 to J-19. The following examples will better illustrate

  the invention without limiting it.

  A. 1-PY-2- (dimethylamino) ethenyl (lower alkyl) ketones A-I. 1- (4-Pyridinyl) -2- (dimethylamino) ethenyl methyl ketone - diluted with 65 ml of dimethyl acrtal

  of dimethylformamide a mixture containing 20 g of

  pyridinyl) methyl methyl ketone [also called 1- (4-

  pyridinyl) -2-propanone] and 30 ml of hexamethylphosphoramide and the resulting mixture is refluxed for 30 minutes. TLC analysis indicates a single spot, indicating the completion of the reaction (in another test, it appears that the reaction is complete after 30 minutes at room temperature). The reaction mixture was evaporated under reduced pressure using a rotary evaporator and 20 millibar pressure to give a crystalline residue weighing 24 g. The residue is purified by continuous chromatographic extraction over alumina (about 150 g) using chloroform under reflux. After an hour and a half, the extract is heated under vacuum to hunt

  chloroform, leaving 23.2 g of 1- (4-pyridinyl) -2-

  (Dimethylamino) ethenyl methyl ketone as a light yellow crystalline material, the compound also being called 4-dimethylamino-2- (4-pyridinyl) -3-buten-2-one. The preceding preparation can be carried out using other solvents, for example dimethylformamide, acetonitrile or others indicated previously, in the place of hexamethylphosphoramide, or in the absence of

  solvent; however, hexamethyl is conveniently

  phosphoramide because (4-pyridinyl) methyl methyl ketone is conveniently prepared in the form of a mixture with hexamethylphosphoramide, as shown by the following procedure: to a stirred solution containing 71% freshly distilled isxpMxi-1 amine and 200 ml of ethyl acetate at 0 ° C. under nitrogen, 210 ml of n-hexane n-butyllithium in n-hexane are added dropwise over 20 minutes and the reaction mixture is stirred for about 35 minutes. at about 0-5aC. To the cold solution 90 ml of dry hexamethylphosphoramide (no temperature change) are added dropwise over 10 minutes and the resulting light yellow solution is stirred for 15 minutes. To the cold solution at 00C, a solution of 50 ml of 4-picoline in ml of dry tetrahydrofuran is added over 15 minutes and stirring is continued for 30 minutes at 0 ° C. Then a mixture containing 50 ml of dry ethyl acetate and 1 ml of tetrahydrofuran (the temperature was changed from 00C to about 60C) was added over 15 minutes and the resulting mixture was stirred for 20 minutes at 0 ° C. The ice bath is then removed and stirring is continued for a further 90 minutes, during which time the temperature of the reaction mixture rises to about 250 ° 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 evaporator under vacuum. The remaining mixture is diluted with 400 ml of water and the aqueous mixture is extracted successively with two portions of 250 ml of isopropyl acetate and three portions of 80 ml of chloroform. The solvents are distilled off under reduced pressure and about 137 g of a mixture comprising essentially the desired product and hexamethylphosphoramide. Another test using the same amounts is carried out as above, but after the addition of 60 ml of glacial acetic acid, the mixture is diluted with only 200 ml of water, the phases are separated and the aqueous phase is extracted with five parts. ml portions of chloroform. The chloroform extract is washed with

  saline solution and the chloroform is distilled under vacuum.

  The remaining mixture of the desired ketone and hexamethylphosphoramide is combined with the previous 137 g of the same mixture and the combined mixture is distilled under pressure.

  reduced to obtain the following fractions N I. 63 g, p.e.

  -112 ° C at 5.3 millibars; II. 59 g of a pale yellow oil, bp 113-115 ° C at 4 millibars and III. 69 g of a yellow oil

2470124

  pale, p.e 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. The acid addition salts of 1- (4-pyridinyl) -2- (dimethylamino) ethenyl methyl ketone are conveniently prepared by adding to a mixture of 5 g of the ketone in about 100 ml of aqueous methanol the acid methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid, to a pH of about 2 to 3, cooling the mixture after partial evaporation and collecting the precipitated salt, for example dimethylsulfonate, sulfate and phosphate respectively. The acid addition salt can also be conveniently prepared in aqueous solution, adding to

  water, with stirring, equimolar amounts of 1- (4-

  pyridinyl) -2- (dimethylamino) ethenyl methyl ketone and the appropriate acid, for example lactic acid or hydrochloric acid, to respectively prepare the monolactate

  and the monohydrochloride in aqueous solution.

  A-2. 1- (4-Pyridinyl) -2- (dimethylamino) ethenyl ethyl ketone - diluted with 100 g of dimethyl acetal

  dimethylformamide a mixture containing 87.5 g of (4-

  pyridinyl) methyl ethyl ketone [also called 1- (4-

  pyridinyl) -2-butanone] and 160 ml of hexamethylphosphoramide and 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 give two fractions, one boiling at 45-80 ° C. at 0.66 millibar and the second at 90 ° -95 ° C. C at 0.66 millibar. As the TLC analysis shows essentially one 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 washed with water.

  return the water with three 100-ml portions of chloroform.

  The combined chloroform extract solution is dried over anhydrous sodium sulfate and purified by continuous extraction chromatography on 300 ml of alumina using chloroform under reflux. The chloroform is distilled under vacuum and a red oil is obtained which crystallizes on standing overnight in an ice bath. The crystalline material is dissolved in carbon tetrachloride, cyclohexane is added and the mixture is cooled.

  gives 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 liquor by continuous extraction chromatography on

  alumina using chloroform at reflux as eluent.

  Intermediate (4-pyridinyl) methyl ethyl ketone

  preceding is obtained in mixture with hexamethyl-

  phosphoramide as follows: to a mixture containing 200 ml of tetrahydrofuran and 70 ml of diisopropylamine under nitrogen at

  0-5 C, 210 ml of 2,4 N n-butyllithium are added to the n--

  hexane and the resulting mixture is stirred for 30 minutes.

  90 ml of hexamethylphosphoramide are then added over 10 minutes, and the mixture is then stirred for 15 minutes. A solution of 48 ml of 4-picoline in 150 ml of tetrahydrofuran is then added over a period of 15 minutes, followed by stirring for 30 minutes at approximately 0 ° C. The ice / acetone bath cooling the reaction mixture is replaced by a dry ice bath. acetone and to the reaction mixture is added in 20 minutes a mixture of 75 ml of ethyl propionate in an equal volume of tetrahydrofuran. The reaction mixture is then 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 are added thereto in 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 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 chluffed under vacuum to drive off the ethyl acetate,

2470124 1

  then the residue is heated under vacuum at 50 ° C. for about

  minutes and 100 g of a pale yellow oil are obtained.

  The pale yellow oil is combined with corresponding samples obtained from two other runs and distilled under vacuum to give a fraction of 256 g, mp 85-105 ° C at 0.66-1.33 millibar. The 1RMN 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

= 90 g of the ketone.

  A-3. 1- (4-Pyridinyl) -2- (dimethylamino) 6-ethenyl-n-propyl ketone - A mixture containing 80 g of (4-pyridinyl) methyl n-propyl ketone (also called 1- (4-pyridinyl) is diluted with 250 ml of acetonitrile -2pentanonel and 46 ml of hexamethylphosphoramide. To the mixture, dimethylformamide dimethyl acetal (90 ml) was added and the resulting reaction mixture was heated on a steam bath for minutes and then distilled under vacuum at about 2.7 millibars to remove volatiles, including methanol. acetonitrile and hexamethylphosphoramide. The remaining residue is diluted with ethyl acetate and washed with water. The combined water washes were extracted with five 150 ml portions of ethyl acetate. The combined ethyl acetate solutions were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue crystallizes at rest in a

  freezer. The crystalline product is stirred with cyclohexane

  hexane, filtered and dried overnight at 30 ° C. to give 97 g of 1- (4-pyridinyl) -2- (dimethylamino) ethenyl n-propyl as a yellow crystalline product.

ketone, m.p. 48-50C.

  The (4-pyridinyl) methyl n-propyl ketone used as the above intermediate is obtained in a mixture with hexamethylphosphoramide as follows: to an aniline solution of 70 ml of isopropylamine in 200 ml of tetrahydrofuran under nitrogen at approximately 0.degree. of an ice bath), 210 ml of 2,4 N n-butyllithium are added in twenty minutes and

  the mixture (30%) is stirred at room temperature. ron 0 C.

  To the mixture, 90 ml of hexamethylphosphoramide are added with stirring over 10 minutes and the resulting mixture is stirred for a further 10 minutes. 45 ml of 4-picoline in 140 ml of tetrahydrofuran are then added dropwise over a period of 15 to 20 minutes. The resultant dark brown orange solution is stirred at 0 ° C. for 30 minutes and then treated dropwise in 18 minutes by addition of a solution.

  comprising 68 ml of ethyl butyrate in 68 ml of tetrahydrofuran

  hydrofuran, the temperature rising from - 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 cooled again and 60 ml of glacial acetic acid are added dropwise over 15 minutes. It separates a pale yellow solid that 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 comprising essentially ( 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 mixtures are distilled in vacuo to obtain, as main fraction, e.g. 90 C to

  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 (4-pyridinyl) methyl ethyl ketone, it can be seen that one can

  obtain 1-PY-2- (dimethylamino) ethenyl (lower alkyl) -

ketones of Examples A-4 to A-17.

  A-4. 1- (3-Pyridinyl) -2- (dimethylamino) ethenyl methyl ketone using (3-pyridinyl) methyl methyl ketone. AT 5. 1- (2-Pyridinyl) -2 (dimethylamino) 6-ethenyl methyl ketone using (2-pyridinyl) methyl methyl ketone. 2470124A-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. 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-11. 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-13. 1- (5-Ethyl-2-pyridinyl) -2- (dimethylamino) -

  ethenyl ethyl ketone using (5-ethyl-2-pyridinyl)

methyl ethyl ketone.

  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.

  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-nicotinoin

nitrile

  B-1. 1,2-Dihydro-6-methyl-2-oxo-5- (4-pyridyl) -

  nicotinonitrile, also called 1,6-dihydro-2-methyl-6-

247012i

  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 u-cyanoacetate

  amide dissolved in 400 ml of dimethylformamide, 14 g of sodium methoxide are added with stirring and the resulting reaction mixture is heated in an oil bath at moderate reflux for one hour. TLC analysis indicates that there is no starting material in the reaction mixture which is then concentrated under vacuum in a rotary evaporator to a volume of about 80 ml. The concentrate is treated with about 160 ml of acetonitrile and the resulting mixture is stirred in a rotary evaporator while warming until 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.

  yellow-brown, namely the sodium salt of 1,2-dihydro-6-

  methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile, the presence of the cyano group being confirmed by IF analysis. 8 g of the sodium salt are dissolved in 75 ml of hot water, the aqueous solution is treated with bleaching charcoal, filtered, the filtrate is treated again with bleaching charcoal and filtered and the filtrate is acidified with 6 N hydrochloric acid by dropwise addition to a pH of 3. The acidic mixture is diluted with ethanol and cooled. The crystalline product is collected, dried and recrystallized from a dimethylformamide-water mixture.

  and dried to give 3.75 g of 1,2-dihydro-6-nithlyl-2-

  oxo-5- (4-pyridinyl) nicotinonitrile, m.p. > 300 C.

  The acid addition salts of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile are conveniently prepared.

  adding to a mixture of 2 g of 1,2-dihydro-6-methyl-2-

  oxo-5- (4-pyridinyl) nicotinonitrile in about 40 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 precipitated salt, for example dimethanesulfonate.

2470124 7

  sulphate, phosphate respectively. The acid addition salt can also be conveniently prepared in aqueous solution by adding to water with stirring,

  equimolar compounds of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) -

  nicotinonitrile and the appropriate acid, for example the acid

  lactic acid or hydrochloric acid, to prepare respectively

  monolactate or monohydrochloride in aqueous solution.

  B-2. 6-Ethyl-1,2-dihydro-2-oxo-5-py-nicotino

  nitrile, also called 2-ethyl-1,6-dihydro-6-oxo-13,4 '

  bipyridin-5-carbonitrile, m.p. > 300 C, 11.6 g. It is prepared according to the procedure described in Example B-1

  using 20 g of 1- (4-pyridinyl) -2- (dimethylamino) -

  ethenyl ethyl ketone-, 8.4 g of α-cyanoacetamide, 16.2 g of sodium methoxide and 250 ml of dimethylacetamide (as

  solvent in place of dimethylformamide).

  B-3. 1,2-Dihydro-2-oxo-6-n-propyl-5- (4-pyridyl) -

  nicotinonitrile, also called 1,6-dihydro-6-oxo-2-n-

  propyl- [3,4'-bipyridine] -5-carbonitrile, m.p. 232-234 C,

  9.9 g. It is prepared according to the procedure described above.

  above in Example B-1, using 85 g of 1- (4-

  pyridinyl) -2- (dimethylamino) ethenyl n-propyl ketone, 36.5 g of α-cyanoacetamide, 50 g of sodium methoxide and 800 ml

of dimethylacetamide.

  B-4. 1,2-Dihydro-1,6-dimethyl-2-oxo-5- (4-pyrrolidine)

  dinyl) nicotinonitrile, also called 1,6-dihydro-1,2-

  dimethyl-6-oxo- (3,4'-bipyridine) -5-carbonitrile, m.p. 245-

  248 C, 32.3 g. It is prepared according to the procedure described

  above in Example B-i, using 42.5 a of 1- (4-

  pyridinyl) -2- (dimethylamino) ethenyl methyl ketone, 23.5 g N-methyl-acyanoacetamide, 6.7 g of sodium methoxide,

  400 ml of methanol, and a reflux period of two hours.

  By following the procedure described in the Example

  B-2 but using an equimolar amount of 1-PY-

  2- (dimethylamino) ethenyl (lower alkyl) appropriate ctone

  of formula (1R) instead of 1- (4-pyridinyl) -2-

  (dimethylamino) ethenyl ethyl ketone and N-R - (t-cyano-

  appropriate acetamide, we see that we can obey the] -R1-

  Corresponding 1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitriles

Examples B-5 to B-21.

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

  nicotinonitrile, using 1- (3-pyridinyl) -2- (dimethyl)

  amino) ethenyl methyl ketone and α-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 α-cyanoacetamide.

  B-7. 1,2-Dihydro-6-isopropyl-2-oxo-5- (4-pyridinyl)

  nicotinonitrile, using 1- (4-pyridinyl) -2- (dimethyl)

  amino) ethenyl isopropyl ketone and α-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.

  B-9. 1,2-Dihydro-6-isobutyl-2-oxo-5- (4-pyridinyl) -

  nicotinonitrile, using 1- (4-pyridinyl) -2- (dimethyl)

  amino) ethenyl isobutyl ketone and α-cyanoacetamide.

  B-10. 1,2-Dihydro-2-oxo-5- (4-pyridinyl) -6-t-butyl

  nicotinonitrile, using 1- (4-pyridinyl) -2- (dimethyl)

  amino) ethenyl t-butyl ketone and α-cyanoacetamide.

  B-11. 1,2-Dihydro-2-oxo-6-n-pentyl-5- (4-pyridinyl) -

  nicotinonitrile, using 1- (4-pyridinyl) -2- (dimethyl)

  amino) ethenyl n-pentyl ketone and α-cyanoacetamide.

  B-12. 6-Ethyl-1,2-dihydro-5- (2-methyl-4-pyridinyl) -

  2-oxonicotinonitrile, using 1- (2-methyl-4-pyridinyl) -

  2- (dimethylamino) ethenyl ethyl ketone and? -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 1 "a-

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 the

cyanoacetamide.

  B-15. 6-Ethyl-1,2-dihydro-2-oxo-5- (3-pyridinyl) -

  nicotinonitrile, using 1- (3-pyridinyl) -2- (dimethyl)

  amino) ethenyl ethyl ketone and α-cyanoacetamide.

  B-16. 1,2-Dihydro-5- (46-di-2-methylpyridinyl) -6-

--2470124 1

  methyl-2-oxonicotinonitrile using 1- (4-

  dimethyl-2-pyridinyl) -2- (dimethylamino) ethenyl methyl ketone

and α-cyanoacetamide.

  B-17. 1,2-Dihydro-6-isopropyl-5- (6-methyl-2-

  pyridinyl) -2-oxo-nicotinonitrile, using 1- (6-methyl-2-pyridinyl) -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)

  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) -a-cyanoacetamide.

  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-l, 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-R1-1,2-Dihydro-6- (lower alkyl) -2-oxo-5- (pyridinyl) -

nicotinamide

  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 The mixture is heated at 100 ° C. for 30 minutes using

  a bath of oil a mixture containing 9.0 g of 1,2-dihydro-6-

  methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile and 45 ml of concentrated sulfuric acid. The hot reaction mixture was added to 200 ml of ice and the resulting mixture was cooled in an ice-acetone bath. To the cold solution, about 150 ml of 28% ammonium hydroxide are carefully added dropwise. The resulting mixture containing a precipitate is cooled in an ice / acetone bath for about minutes. The precipitate is then collected, rinsed successively with water and acetonitrile, dried well and recrystallized by dissolving it in 130 ml of hot water (boiling), adding 30 ml. acetic acid, treating with bleaching charcoal and filtering. The filtrate is concentrated and diluted with acetonitrile; the mixture is kept 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 are dissolved in 500 ml of dimethylformamide at its boiling point, the hot mixture is filtered and the filtrate is cooled in an ice bath. The crystalline precipitate is collected, rinsed with acetone and dried for 4 hours at 100 ° C. over phosphorus pentoxide and the IR and NMR analyzes show that it still contains a little dimethylformamide. The 10.5 g of light tawny crystalline product is dissolved in 75 ml of hot acetic acid, treated with 50 ml of water and then diluted to a volume of 300 ml with acetone. The resulting mixture containing some crystals is cooled in an ice bath for about 45 minutes. The resultant light brown crystalline product is collected, dried first at 55 ° C. and then at 110 ° C. to remove the last weak odor of acetic acid and

  9.2 g of 1,2-dihydro-6-methyl-2-oxo-5- (4-

  pyridinyl) nicotinamide, 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, up to a pH of approximately 2 to 3, cooling the mixture after partial evaporation and

  collecting the salt which has precipitated, for example

  sulphonate, sulphate, phosphate respectively. The acid addition salt in aqueous solution is also conveniently prepared by adding to water, with stirring,

  equimolar compounds of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) -

2470124.

  nicotinamide and the appropriate acid, lactic acid or hydrochloric acid for example, to respectively prepare the monolactate or monohydrochloride in

aqueous solution.

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

  nicotinamide, also called 1,6-dihydro-2-ethyl-6-oxo

[3,4'-bipyridinel-5-carboxamide

  A portion of 40 g of 6-ethyl-1,2-

  dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile to 170 ml of concentrated sulfuric acid and the temperature then rises to about 70 ° C. This reaction mixture is immersed in an oil bath preheated to about 90 ° C. then maintained at -105 ° C for about 40 minutes. The hot reaction mixture is then poured into a beaker containing 800 ml of

  ice cream. The mixture is stirred and placed in an ice bath.

  and acetone. To the cold mixture is added dropwise with stirring 650 ml of 28% ammonium hydroxide, and the temperature rises to about 46 C. 300 ml of ice are added with stirring and the stirring is continued. about 15 minutes. The precipitate is collected, rinsed with three 150 ml portions of water, air dried for two hours, stirred with a little acetonitrile, filtered and the solid dried for several days at room temperature. C and 39.5 g of product are obtained. The solid is thoroughly stirred with 300 ml of water, filtered and dried and

  38 g of crystalline product, 6-ethyl-1,2-

  dihydro-2-oxo-5- (4-pyridinyl) nicotinamide. Another 14.3 g of this product are purified by dissolving them in 40 ml of hot acetic acid, filtering the hot solution and diluting the filtrate to 180 ml with absolute ethanol, and it is formed. then crystals. The hot mixture is allowed to cool. The light brown, crystallized product was collected and dried at 110 ° C. on P2O5 for about 15 hours to obtain

  11.7 g of 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) -

nicotinamide, m.p. > 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'-bipyridin-5-carboxamide, m.p. > 300 C, 10.5 g; on] e

24701.24.

  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. By following the procedure described in the Example

  C-2 but using an equimolar amount of 1-R1-1,2-

  suitable dihydro-2-oxo-5-PY-6-R-nicotinonitrile (of formula

  I o Q is a cyano group) in place of 6-ethyl-1,2-

  dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile, it can be seen that 1,2-dihydro-2-oxo-5-PY-6-R-nicotinamides can be obtained

  corresponding examples of Examples C-4 to C-21.

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

nicotinamide.

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

nicotinamide.

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

pyridinyl) nicotinamide.

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

nicotinamide.

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

nicotinamide.

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

butylnicotinamide.

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

nicotinamide.

  C-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.

  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-oxo-

nicotinamide.

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

pyridinyl) -2-oxonicotinamide.

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

pyridinyl) -2-oxonicotinamideo

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

nicotinamide. 2470124 l

  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) nicotinamide. C-20. 1-Ethyl-1,2-dihydro-6-methyl-2-oxo5- (4-pyridinyl) nicotinamide.

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

  nicotinamide. D. 1-R1-3-Amino-6- (lower alkyl) -5-PY-2 (1H-pyridinones

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

  pyridinone, also called 5-amino-2-methyl- [3,4'-

  bipyridine] -6 (1H) -one To a solution containing 13 g of sodium hydroxide

  in 250 ml of water 12 g of 1,2-dihydro-6-methyl-2 are added.

  oxo-5- (4-pyridinyl) nicotinamide and the mixture is heated

  resulting on a steam bath to effect the dissolution.

  To the solution was added an additional 250 ml of water and the resulting solution was cooled to about 35 ° C with stirring, and a few crystals separated. The mixture is cooled in an ice bath and a total of 4.0 ml of bromine is added dropwise, the solution being dissolved after the addition of about 3 ml of the bromine. The mixture is stirred for an additional 10 minutes under cold conditions 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 6 N hydrochloric acid to about pH 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. We treat the 7.3 g

  with 20 ml of water and the insoluble amorphous material is filtered off.

  The filtrate is concentrated to dryness and the mixture is recrystallized.

  crystalline material resulting in a mixture of dimethyl

  formamide and water to give 3.8 g of 3-amino-6-methyl-

  5- (4-pyridinyl) -2 (1H) -pyridinone, m.p. > 300 C.

  The addition salts are conveniently prepared

  of 3-amino-6-methyl-5- (4-pyridinyl) -2 (1H-1) - -

  pyridinone by adding to a mixture of 2 g of 3-amino-6-

  methyl-5- (4-pyridinyl) -1 (1H) -pyridinone in about 40 ml of aqueous methanol, the appropriate acid, for example methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid, up to at a pH of about 2 to 3, 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 is also conveniently prepared by adding to water, with stirring,

  equimolar amounts of 3-amino-6-methyl-5- (4-

  pyridinyl) -2 (1I) pyridinone and the appropriate acid, for example lactic acid or hydrochloric acid, to respectively prepare the monolactate or the monohydrochloride

in aqueous solution.

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

  pyridinone, also called 5-amino-2-ethyl-3,4'-

  bipyridine-6 (1H) -one, m.p. > 300 C, 8.8 g; it is prepared according to the procedure described in Example D-1 but in

  using 10.0 g of 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl).

  nicotinamide, 8.8 g of sodium hydroxide, 300 ml of water, 3.0 ml of bromine and 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-13,4'-

  bipyridini-6 (1II) -one. To a stirred solution containing 8.5 g of 1,2-dihydro-2-oxo-6-n-propyl-5- (4-pyridinyl) nicotinamide and 95 ml of water at room temperature, a

  solution of 1.32 g of sodium hydroxide in 6 ml of water.

  The resulting slurry is cooled in an ice bath, stirred for 10 minutes and then treated dropwise with 22 ml of 13.1% aqueous sodium hypochlorite solution over three minutes. Dissolution occurs and stirring is continued without cooling for 30 minutes. To the resulting solution at 15 ° C was added 27 ml of 35% aqueous sodium hydroxide; the reaction mixture was heated on a steam bath at about 60-70 ° C for one hour, then the hot solution was slowly treated with 14 ml of glacial acetic acid for 5 minutes, which caused the separation of a precipitate brown yellow. The mixture is stirred for 5 minutes; the precipitate is collected, washed with hot water and known on P2O5. The resulting 12 g of product is recrystallized from a mixture of 100 ml of dimethylformamide and 80 ml of water, dried for

  overnight at 95 ° C. on P205 and 9.5 g of 3-amino-6-n-

  propyl-5- (4-pyridinyl) -2 (1H) -pyridinone, m.p. 200-202 C.

  By following the procedure described in the Example

  D-1 but using an equimilar amount of 1-R1-1,2-

  Suitable Dihydro-2-oxo-5-PY-6-R-nicotinamide (Formula I o Q

  is a carbamyl group) in place of 1,2-dihydro-6-

  methyl-2-oxo-5- (4-pyridinyl) nicotinamide, it can be seen that 1-R1-3-amino-5-PY-6-R-2- (111) -pyridinones can be obtained.

  corresponding examples of Examples D-4 to D-21.

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

pyridinone.

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

pyridinone.

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

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.

  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-11. 3-Amino-6-ethyl-5- (2-methyl-4-pyridinyl) -

2 (1H) -pyridinone.

  D-12. 3-Amino-6-methyl-5- (5-methyl-2-pyridinyl) -

2 (1H) -pyridinone.

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

2 (1HH) -pyridinone.

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

pyridinone.

  D-15. 3-Amino-6-methyl-5- (4,6-dimtl-hyl-2-pyridinyl) -

2 (1l1) -pyri (linone.

  D-16. 3-Amino-6-isopropyl-5- (6-methyl-2-

pyridinyl) -2 (1H) -pyridinone.

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

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

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

pyridinyl) -2 (1H) -pyridinone.

  D-20. 3-Amino-l-ethyl-6-methyl-5- (4-pyridinyl) -

2 (1H) -pyridinone.

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

  pyridinone. E. 1-R 1-6- (lower alkyl) -5-PY-2 (1H) -pyridinones E.1. 6-methyl-5- (4-pyridinyl) -2- (1H) -pyridinone, also called 2-methyl- [3,4'-bipyridin] -6 (1H) -one. We

  heated to about 195 ° C a mixture of 5.3 g of 1,2-dihydric

  6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile and 30 ml of 85% sulfuric acid are heated gently to reflux.

  for 24 hours, it is cooled and added to ice.

  The aqueous mixture is brought to a pH of 8 by adding a concentrated aqueous solution of sodium hydroxide. The resulting precipitate (product + Na 2 SO 4) is treated with chloroform and the chloroform solution is filtered. The filtrate is concentrated in vacuo to remove chloroform and the resulting crystalline residue is recrystallized from a mixture of methylene dichloride and ether and dried at 75 ° C.

  for 4 hours, giving 4.1 g of 6-methyl-5- (4-

  pyridinyl) -2 (1H) -pyridinone, m.p. 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, to a pH of about 2 to 3, while cooling the mixture after partial evaporation and collecting the precipitated salt, e.g. dimethanesulfonate, sulfate or phosphate respectively. The acid addition salt is also conveniently prepared in aqueous solution by adding to

  stirring, equimolar amounts of 6-methyl-

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

in aqueous solution.

  E-2. 6-Ethyl-5- (4-pyridinyl) -2 (111) -pyridinone, also called 2-ethyl [3,4'-bipyridin-6 (1r) -one. The mixture is heated with stirring at 200 ° C. for 24 hours.

  containing 9 g of 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) -

  nicotinonitrile and 50 ml of concentrated sulfuric acid, cooled to about 40 ° C and poured into 200 ml of ice water. After alkalinizing the aqueous solution with concentrated ammonium hydroxide, the separating solid 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, m.p. 226-

  C. A second crop of 0.4 g, m.p. 225-

  227 C, concentrating the filtrate at about 20 ml.

  E-3. n-Propyl-5- (4-pyridinyl) -2 (11) -pyridinone, also called 2- (npropyl) -13,4'-bipyridini-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

  g of 1,2-dihydro-6-n-propyl-2-oxo-5- (4-pyridinyl) nicotinic acid

  nitrile, 42.5 ml of 85% sulfuric acid, and recrystallization from a mixture of

methylene and ether.

  By following the procedure described in the Example

  E-2 but instead using 6-ethyl-1,2-dihydro-2-oxo

  5- (4-pyridinyl) nicotinonitrile an equimolar amount of

  1-R1-1,2-Dihydro-2-oxo-5-PY-6- (lower alkyl) nicotinic acid

  corresponding nitrile, we see that we can get the i-R1-

  -PY-6- (lower alkyl) -2 (11H) -pyridinones of Examples E-4 to E-21.

  1-4. 6-Methyl-5- (3-pyridinyl) -2 (11l) -pyridinone.

  E-5. 6-r [-isopropyl-5- (4-pyrid.inyl) -2 (lll) -pyriclinone.

  I -.- 6. 6-n-Butyl-5- (4-pyridinyl) -2 (11) -pyridinone.

  E-7. 6-Tsobutyl-5- (4-pyridinyl) -2- (1l) I-pyri (dinone.

  l: -8. 5- (4-Pyridyl-yl) -6-t-butyl-2 (11I) -pyri dinone.

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

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

pyridinone.

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

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

  E] 1.3. 6-Ethyl-1 (2-hydroxyethyl) -5- (4-pyridinyl) -

2 (1H) -pyridinone.

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

pyridinone.

  E-1 5. 1,6-Diethyl-5- (4-pyridinyl) -2 (li) -

pyridinone.

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

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

pyridinone.

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

pyridinone.

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

2 (1H) -pyridinone.

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

pyridinone.

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

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

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

  pyridinone, also called 5-bromo-2-methyl-13,4'-

  bipyridinI-6 (1H) -one. To a stirred solution of 80 g of 6-

  methyl-5- (4-pyridinyl) -2 (1H) -pyridinone in 1 liter of acetic acid, heated to 65 ° C., 69 g of bromine in 50 ml of acetic acid are added dropwise over 25 minutes. The reaction mixture is stirred for an additional 30 minutes, cooled to room temperature and filtered to recover the crystalline precipitate. The precipitate is dried and suspended in 1500 ml of water. To the vigorously stirred suspension is added dropwise 25 ml of a 28% solution of ammonium hydroxide and a white creamy precipitate is then separated off. The solid is collected and dried under vacuum at 90 ° C., which gives 101 g.

  3-bromo-5-methyl-5- (4- [yridinyl) -2 (1H) -pyridinone, m.p.

  247012 to 252-254 C. One sample of 15 g is dissolved in 200 ml of hot acetic acid and filtered. The filtrate is concentrated under vacuum, diluted with methanol and the resulting white crystalline precipitate is collected and dried at 100 ° C. for 16 hours in vacuo to give 9.8 g of the product,

m.p. 252-254 C.

  The addition salts are conveniently prepared

  of 3-bromo-6-methyl-5- (4-pyridinyl) -2 (1H) -

  pyridinone by adding to a mixture of 5 g of 3-bromo-6-

  methyl-5- (4-pyridinyl) -2 (1H) -pyridinone in about 100 ml of aqueous methanol. The appropriate acid, for example methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid, up to at a fold of about 2 to 3, cooling the mixture after partial evaporation and

  collecting the precipitated salt, for example] T dimizthane--

  sulphonate, sulphate or phosphate respectively. The acid addition salt in aqueous solution is also conveniently prepared by adding to water, with stirring,

  equimolar amounts of 3-bromo-6-methyl-5- (4-pyridinyl) -

  2 (1H) -pyridinone and the appropriate acid, for example the acid

  lactic acid or hydrochloric acid, to prepare respectively

  monolactate and monohydrochloride in aqueous solution.

  F-2. 3-Chloro-6-methyl-5- (4-pyridinyl) -2 (111) -

  pyridinone, also called 5-chloro-2-methyl-13,4-'-

  bipyridinl-6 (1H) -one. A mixture containing 18.6 g of 6-methyl-5 (4-pyridinyl) -2 (1H) -pyridinone and 200 ml of acetic acid, heated on a steam bath, is bubbled with chlorine for 4 hours. 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. We collect the solid which separates, we wash it with water, we dry it and we

  recrystallizes it in ethanol, which. give 3-chloro-6-

  methyl-5- (4-pI) yri dinyl) -2 (11) -pyri (1 di-nd.

  1: 1- follow the mo (det O) rt (i.rc (dic (: I-itL danls]. LxeIpl) e

  F-1 or F-2 but using instead of 6-methyl-5- (4-

  pyridinyl) -2 (1H) -pyridinone an equimolar amount of the corresponding 1-R 1-6 (lower alkyl) -5-PY-2 (1H) -pyridinone and bromine or chlorine, it can be seen that obtain 1-R 1-3-bromo (or 6-chloro-lower alkyl) -5-PY-2 (1H) -

  pyridinones of Examples F-3 to F-22.

F-3. pyridinonc. F-4.

pyridinone.

F-5. pyridinone. F-6. pyridinone.

F-7.

pyridinone. F-8. pyridinone. F-9.

pyridinone.

F-10. pyridinofie.

F-1 1.

  3-Chloro-6-ethyl-5- (4-pyridinyl) -2 (1H) -

  3-Chloro-6-methyl-5- (3-pyridinyl) -2 (1) -

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

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

  3-Bromo-6-n-butyl-5- (4-pyridinyl) -2 (1H) -

  3-Chloro-6-isobutyl-5- (4-pyridinyl) -2 (1H) -

  3-Bromo-5- (4-pyridinyl) -6-t-butyl-2 (1H) -

  3-Chloro-6-n-pentyl-5- (4-pyridinyl) -2 (1H) -

  3-Bromo-6-ethyl-5- (2-methyl-4-pyridinyl) -

2 (1H) -pyridinone.

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

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

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

pyridinyl) -2 (1H) -pyridinone.

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

pyridinone.

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

pyridinone.

  E-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-] 9. 3-Bromo - (- ethyl-5- (5-ethyl-2-pyridinyl) -

2470124 1

2 (1H) -pyridinone.

  E-20. 3-Chloro-6-methyl-5- (4,6-dimethyl-2-

pyridinyl) -2 (1H) -pyridinone.

  F-21. 3-Bromo-6-isopropyl-5- (6-methyl-2-

pyridinyl) -2 (1H) -pyridinone.

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

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

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

  pyridinone, also called 2-methyl-5-methylamino- [3,4'-

  bipyridinl-6 (1H) -one. It 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 70% aqueous methylamine, 60 mg of copper bronze and 60 mg of cupric sulfate. The crystalline mass is taken up with hot aqueous methanol and the mixture is filtered to collect the product. The solid (6 g) plus another 1 g portion obtained by concentrating the mother liquor and diluting with water are dissolved in a small amount of acetic acid.

  methanol, filtered and the filtrate diluted with water.

  The resulting crystalline precipitate is collected, washed thoroughly with water and dried at 90 ° C.

  overnight giving 5.1 g of 6-methyl-3-methylamino-5- (4-

  pyridinyl) -2 (1H) -pyridinone, m.p. 270-275 C with decomposition. This preparation can also be carried out as above using an equimolar amount of 3-chloro-6-methyl-5- (4-pyridinyl) -2 (1H) pyridinone instead

  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 methanol

  the appropriate acid (eg methane

  sulphonic acid, concentrated sulfuric acid, concentrated phosphoric acid) to a pH of about 2 to 3, cooling the mixture after partial evaporation and collecting the precipitated salt, for example dimethanesulphonate, sulphate or phosphate respectively. The acid addition salt can also be conveniently prepared in aqueous solution by adding to water, with stirring,

  equimolar compounds of 6-methyl-3-methylamino-5- (4-pyridinyl) -

  2 (1H) -pyridinone and the appropriate acid, for example lactic acid or hydrochloric acid, to respectively prepare the monolactate or monohydrochloride

aqueous solution.

  G-2. 3-Ethylamino-6-methyl-5- (4-pyridinyl) -2 (1H)) -

  pyridinone, also called 5-ethylamino-2-methyl-13,4'-

  bipyridin-6 (III) -one, m.p. 250 C, 1.6 g; it is prepared by following the procedure described in Example G-1 but using 1.6.5 g of 3-bromo-6-methyl-5- (4-pyridinyl) -2H-pyridinone, 110 ml of ethylamine, ml of water, 30 mg of copper bronze, 30 mg of cupric sulfate, autoclaving at 150 ° C for 45 hours and recrystallizing

twice in acetonitrile.

  G-3. 6-Methyl-3- (dimethylamino) -5- (4-pyridinyl) -

  2 (1H) -pyridinone, also called 5- (dimethylamino) -2-

  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, 20 ml of a 37% solution of formaldehyde are added dropwise with stirring over 5 minutes. The mixture is refluxed for 1 hour and 45 minutes, heated in vacuo to dryness and the residue 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 distilled in vacuo to give 4 g of a yellow crystalline solid. 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 near dryness and treated with acetonitrile. The resulting mixture of crystalline material and acetonitrile was cooled, the solid was collected and dried to give 10.5 g of a yellow crystalline product containing a trace.

2470124 1

  impurity (indicated by TLC). The solid is dissolved in a chloroform solution and the traces of impurity are removed by filtering the chloroform solution on a column of silica gel 6.35 cm. The resulting product (10.5 g) was dissolved in methylene dichloride, the solution was diluted with isopropyl alcohol and concentrated in vacuo and cooled. We collect the precipitate and

  it is dried at 80 ° C. to give 9.0 g of 6-methyl-3-

  (dimethylamino) -5- (4-pyridinyl) -2 (1H) -pyridinone, m.p. 223-

225 C.

  By following the procedure described in the Example

  G-1 or G-2 but using instead of 3-bromo-6-

  methyl-5- (4-pyridinyl) -2 (1H) -pyridinone an equimolar amount of 1R1-3-bromo (or chloro) -5-PY-6- (lower alkyl) -2 (1H) -pyridinone and lower alkylamine or the appropriate di (lower alkyl) amine, it can be seen that

  can obtain 1-R1-3- [mono- or di- (lower alkyl) -

  amino] -5-PY-6- (lower alkyl) -2 (1H) -pyridinones of

Examples G-4 to G-23.

  G-4. 6-Ethyl-3-methylamino-5- (4-pyridinyl) -2 (III) -

pyridinone.

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

pyridinone.

  G-6. 3-n-propylamino-6-n-propyl-5- (4-pyridinyl) -

2 (1H) -pyridinone.

  G7. 3-Methylamino-6-isopropyl-5- (4-pyridinyl) -2-

(1H) -pyridinone.

  G-8. 6-n-Butyl-3-dimethylamino-5- (4-pyridinyl) -

2 (1H) -pyridinone.

  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) -

2 (1H) -pyridinone.

  G-12. 6-Ethyl-3-diethylamino-5- (2-methyl-4-

pyridinyl) -2 (1Ill) -pyridinone.

  G-13. 6-Ethyl-3-ethylamino-5- (3-pyrid (inyl) -2 (i1H) -

pyridinone.

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

2 (1H) pyridinone.

  G-15. 6-Ethyl-3-ethylamino-1- (2-hydroxyethyl) -5-

(4-pyridinyl) -2 (1H) -pyridinone.

  G-16. 1-Ethyl-6-methyl-3-methylamino-5- (4-

pyridinyl) -2 (lH) -pyridinone.

  G-17. 1,6-Diethyl-3-methylamino-5- (4-pyridinyl) -

2 (1EH) -pyridinone.

  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.

  G20. 6-Ethyl-5- (5-ethyl-2-pyridinyl) -3-

dimethylamino-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.

  G-23. 3-Methylamino-6-n-hexyl-5- (2-pyridinyl) -

2 (1H) -pyridinone.

  H. 1-R1-3- (lower acylamino) -6- (lower alkyl) -5-PY-2-

(1H) -pyridinones

  H-I. 3-Acetylamino-6-methyl-5- (4-pyridinyl) -2 (1H) -

  pyridinone, also called N-11,2-dihydro-6-methyl-2-oxo

  - (4-pyridinyllacetamide) Heated in a steam bath for one hour

  a mixture containing 10.1 g of 3-amino-6-methyl-5- (4-

  pyridinyl) -2 (1H) -pyridinone, 5.7 g of acetic anhydride and 120 ml of pyridine and then allowed to cool. The separating product is collected, washed with ether, dried and recrystallized from dimethylformamide to give

  obtain 3-acetylamino-6-methyl-5- (4-pyridinyl) -2 (1H) -

  pyridinone. The acid addition salts of 3-acetylamino-6-methyl-5- (4-pyridinyl) -2 (11) -pyridinone are conveniently prepared.

  adding, to a mixture of 5 g of 3-acetylamino-6-methyl-5-

  (4-pyridinyl) -2 (II) -pyridinone in about 100 μl of methanol 2470124

  water, the appropriate acid (eg methane

  sulphonic acid, concentrated sulfuric acid, concentrated phosphoric acid) to a pH of about 2 to 3, cooling the mixture after partial evaporation and collecting the precipitated salt, for example, dimethanesulfonate, sulphate and phosphate respectively. The acid addition salt can also be conveniently prepared in aqueous solution by adding to water, with stirring,

  equimolar amounts of 3-acetylamino-6-methyl-5- (4-

  pyridinyl) -2 (1H) -pyridinone and the appropriate acid, for example lactic acid or hydrochloric acid, to respectively prepare the monolactate and the monohydrochloride

* in aqueous solution.

  H-2. 3- [2- (Acetoxy) propanoylamino] -6-methyl-2 (1H) -

  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 are added dropwise

  in about one hour 16.5 g of 2-acetoxychloride

  propanoyl and the resulting mixture is cooled in an ice bath. The separating product is collected, washed with ether, dried, recrystallized from methanol, washed successively with ethanol and treated with methanol.

  ether and dried to give 3-L2- (acetoxy) -

  propanoylamino] -6-methyl-2 (1H) -pyridinone. By following the procedure described in the Example

  H-1 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 compounds of 1-Ri-3-amino-5-PY-6- (lower alkyl) -2 (1H) -

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

Examples H-3 to H-17.

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

pyridinone.

  1H1-4. 6-Methyl-3-propionylamino-5- (3-pyridinyl) -

2 (1H) -pyridinone.

  11-5. 3-butyrylamino-6-n-propyl-5- (4-pyridinyl) -

2 (1It) -pyridinone.

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

2 (1IH) -pyridinone.

  H-7. 3-formvlamino-6-isobutyl-2-oxo-5- (4-

pyridinyl) -2 (111) pyridinone.

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

2 (1H) pyridinone.

  H1-9. 3- [2- (Acetoxy) propanoylaminol-6-ethyl-5- (2-

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

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

(111) -pyridinone.

  H-11l. 3-Acetylamino-1,6-dimethyl-2-oxo-5- (4-

pyridinyl) -2 (1H) -pyridinone.

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

pyridinyl) -2 (1H) -pyridinone.

  H-13. 1,6-Diethyl-3-propionylamino-5- (4-pyridinyl) 2 (1H) pyridinone H-14.3-Acetylamino-6-methyl-5- (2-pyridinyl) -2 (1H) pyridinone.

  H-15. 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-

(1H) -pyridinone.

  I. A-R-1,2-Dihydro-6- (lower alkyl) -2-oxo-5-PY-acids

Nicotine

  I-1. 1,2-Dihydro-6-methyl-2-oxo-5- (4-) -acetate

  pyridinyl) nicotinic acid, also known as 1,6-dihydro-

  2-methyl-6-oxo [3,4'-bipyridine] -5-carboxylic acid. We add

  g of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinic acid

  nitrile, with stirring, to a hot solution containing 220 ml of water and 245 ml of concentrated sulfuric acid. The reaction mixture was refluxed for 7 hours (ca. 122 ° C) and allowed to stand at room temperature for the weekend. It is then diluted with water and cooled in an ice bath and treated dropwise with stirring with ammonium hydroxide until

24 7 0 J4

  neutral pH. The resulting crystalline precipitate is collected, rinsed successively with three portions of 100 ml of water and several times with acetone and then with ether and dried at 80 ° C. The crystalline material is stirred with 200 ml of chloroform and 200 ml of methanol for 30 minutes and the mixture is concentrated under vacuum to a volume of 150 ml. The crystalline product is collected and dried at 95 ° C. on P2O5 to give about 24 g of product. A 10 cc sample of the product is heated with 200 ml of boiling water, the mixture is cooled and the solid is collected and dried at 80.degree.

  obtain 9 g of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) -

nicotinic, m.p. > 260 C.

  By following the procedure described in the Example

  I-1 but instead using 1,2-dihydro-6-methyl-2-

  oxo-5- (4-pyridinyl) nicotinonitrile an equimolar amount

  of 1-R1-1,2-dihydro-2-oxo-5-PY-6- (lower alkyl) -

  corresponding nicotinonitrile, we see that we can get

  1-R1-1,2-dihydro-2-oxo-5-PY-6- (lower alkyl) -acids

  Nicotinic Examples I-2 to I-21.

  I-2. 6-Ethyl-1,2-dihydro-2-oxo-5- (4-) -acetate

pyridinyl) nicotinic acid.

  I-3. 1,2-Dihydro-6-methyl-2-oxo-5- (3-

pyridinyl) nicotinic acid.

  I-4. 1,2-Dihydro-2-oxo-6-n-propyl-5- (4-) -acetate

pyridinyl) nicotinic acid.

  I-5. 1,2-Dihydro-2-oxo-6-isopropyl-5- (4-) -acetate

pyridinyl) nicotinic acid.

  I-6. 6-n-butyl-1,2-dihydro-2-oxo-5- (4-) -acetate

pyridinyl) nicotinic acid.

  I-7. 1,2-Dihydro-6-isobutyl-2-oxo-5- (4-) -acetate

pyridinyl) nicotinic acid.

  I-8. 1,2-Dihydro-2-oxo-5- (4-pyridinyl) -6-

Does butylnicotinique.

  I-9. 1,2-Dihydro-2-oxo-6-n-penty] -5- (4-

pyridinyl) nicotinic acid.

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

pyridinyl) -2-oxonicotinic acid.

  I-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-) -acetate

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

  1-14. 1-Ethyl-1,2-dihydro-6-methyl-2-oxo-5- acid

(4-pyridinyl) nicotinic acid.

  1-15. 1,6-Diethyl-1,2-dihydro-2-oxo-5- (4-) -acetate

pyridinyl) nicotinic acid.

  1-16. 1,2-Dihydro-6-methyl-2-oxo-5- (2-) -acetate

pyridinyl) nicotinic acid.

  1-17. 1,2-Dihydro-6-methyl-5- (5-methyl-2-) -acetate

pyridinyl) -2-oxonicotinic acid.

  1-18. 6-Ethyl-5- (5-ethyl-2-pyridinyl) -1,2-

dihydro-2-oxonicotinic acid.

  1-19. 1,2-Dihydro-6-methyl-5- (4,6-dimethyl) -acetate

2-pyridinyl) -2-oxonicotinic acid.

  1-20. 1,2-Dihydro-6-isopropyl-5- (6-methyl) -acetate

2-pyridinyl) -2-oxonicotinic acid.

  1-21. 1,2-Dihydro-6-n-hexyl-2-oxo-5- (2-) -acetate

pirydinyl) nicotinic acid.

  J. 1-R1-6- (lower alkyl) -1,2-dihydro-2-oxo-5-PY-

lower alkyl nicotinates

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

  ethyl nicotinate. A portion of 4 g of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinic acid in 1 ml of refluxing ethanol is heated with 1 g of methanesulphonic acid for 18 hours. The excess ethanol is distilled under vacuum and the residue is recrystallized from dimethylformamide to give

  obtain 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) -

  ethyl nicotinate in the form of its methane-acid salt

  sulfonic acid. The salt is dissolved in hot water and the solution is made alkaline with an excess of an aqueous solution of potassium carbonate. The solid that separates is collected, dried, recrystallized from isopropyl alcohol

  and dried to give 1,2-dihydro-6-methyl-2-oxo

- (4-pyridinyl) ethyl nicotinate.

2470124 -

  The acid addition salts of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinate are conveniently prepared.

  of ethyl by adding to a mixture of 5 g of 1,2-dihydro-6

  ethyl-2-oxo-5- (4-pyridinyl) nicotinate in about 100 ml of aqueous methanol, the appropriate acid (methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid for example) to pH from about 2 to 3, cooling the mixture after partial evaporation and

  collecting the salt which has precipitated, for example

  sulphonate, sulphate or phosphate respectively. The acid addition salt in aqueous solution is also conveniently prepared by adding to water, with stirring,

  equimolar amounts of 1,2-dihydro-6-methyl-2-oxo-5- (4-

  pyridinyl) ethyl nicotinate and the appropriate acid, for example lactic acid or hydrochloric acid, to respectively prepare the monolactate or monohydrochloride

aqueous solution.

  By following the procedure described in the Example

  j-1 but instead using 1,2-dihydro-6-

  methyl-2-oxo-5- (4-pyridinyl) nicotinic acid and ethanol

  equimolar amounts of 1-R1-1,2-dihydro-2-oxo-5- acid

  PY-6- (lower alkyl) nicotinic and lower alkanol

  appropriate, we see that we can get the l-R1-1,2-

  alkyl dihydro-2-oxo-5-PY-6- (lower alkyl) nicotinates

  lower of Examples J-2 to J-19.

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

methyl nicotinate.

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

ethyl nicotinate.

  J-4. 1,2-Dihydro-6-methyl-2-oxo-5- (3-pyridinyl) -

n-propyl nicotinate.

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

ethyl nicotinate.

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

isopropyl nicotinate.

  J-7. 6-n-Butyl-l, 2-dihydro-2-oxo-5- (4-pyridinyl) -

ethyl nicotinate.

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

ethyl nicotinate.

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

methyl nicotinate.

  J-10. 1,2-Dihydro-2-oxo-6-n-pentyl-5- (4-

pyridinyl) methyl nicotinate.

  J-11. 6-Ethyl-L1,2-dihydro-5- (2-methyl-4-

  n-butyl pyridinyl) -2-oxonicotinate.

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

ethyl nicotinate.

  J-13. 1,2-Dihydro-1,6-dimethyl-2-oxo-5- (4-

pyridinyl) ethyl nicotinate.

  J-14. 6-Ethyl-1,2-dihydro-l- (2-hydroxyethyl) -2-

  ethyl oxo-5- (4-pyridinyl) nicotinate.

  J-15. 1,6-Diethyl-1,2-dihydro-2-oxo-5- (4-

pyridinyl) ethyl nicotinate.

  J-16. 1,2-Dihydro --- methyl-2-oxo-5- (2-pyridinyl) -

n-hexyl nicotinate.

  J-17. 6-Ethyl-5- (5-ethyl-2-pyridinyl) -1,2

  methyl dihydro-2-oxonicotinate.

  J-18. 1,2-Dihydro-6-methyl-5- (4,6-dimethyl-2-

  pyridinyl) -2-oxonicotinate ethyl.

  J-19. 1,2-Dihydro-6-n-hexyl-2-oxo-5- (2-

pyridinyl) ethyl nicotinate.

  The usefulness of the compounds of formula I or their salts as cardiotonic agents is demonstrated by their effectiveness in conventional pharmacological tests, for example by causing a significant increase in the contraction force in the procedure using isolated papillary muscles and atria. of cat and e causing a significant increase in cardiac contraction strength in the procedure on the anesthetized dog with low or minimal changes in heart rate and blood pressure. We will find

  detailed descriptions of these test procedures

  in the U.S. Patent N 4.072.746.

  When tested by the procedure on isolated papillary papillary auricles and muscles previously indicated, the compounds of formula I tested at dose! of 3, 10 out 30 iq / m], proves to cause a significant increase, that is to say greater than 25 ', of the force

24701 241-

  papillary muscle and a significant increase, that is, greater than 25%, in the strength of the right atrium, while causing only a small increase (about one-third or less of the percentage increase). the strength of the right atrium or the force of the papillary muscle) on the speed of the right atrium. In addition, it is found that the 6- (lower alkyl) compounds of formula I are significantly more active as cardiotonic agents when tested by this procedure, than the corresponding compounds without a lower alkyl group) in the prior art . In addition, some of them, especially in the formula I is a carbamoyl or bromo group, have been found to be active as cardiotonic agents while on the contrary the corresponding derivatives without a lower alkyl group in the 6-position are only intermediaries with no

cardiotonic properties.

  The substantially superior cardietonic activity of the 6-position (lower alkyl) derivatives relative to the corresponding unsubstituted 6-position compounds of the prior art is illustrated by the following comparisons of the test data obtained using the atrial and papillary muscle isolated from cat. Percentage increase in papillary muscle strength and strength - =

  of the right atrium for 3-amino-6-methyl-5- (4-

  pyridinyl) -2- (1H) -pyridinone are 96% and 74% when tested at 10 μg / ml, compared with increases

  corresponding figures of 109 + 11.3% and 49.9 + 8.4% for the 3-

  amino-5- (4-pyridinyl) -2 (1H) -pyridinone (amrinone) at a

  100 μg / ml, i.e., ten times the dose; we find that the percentages increase muscle strength

  papillary and right atrial strength for the 3-

  amino-6-ethyl-5- (4-pyridinyl) -2 (Hi) -pyridine are 53% and 37% when tested at a dose of 3 lil / 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; the percent increases in papillary muscle strength and right atrial strength for 1,2dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile

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

  nitriles are 45% and 51% for the 6-methylated compound and 107% and 79% for the 6-ethyl compound, at a dose of 3 μg / ml, compared with the corresponding increases of 65% and 15% for the 1,2-dihydro-2-oxo-5 (4-pyridinyl) nicotinonitrile of the prior art without a 6-alkyl group at a dose of 30 μg / ml, i.e., a ten-fold higher dose; percentages of increase in papillary muscle strength and 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 μg / ml while the corresponding 6-position demethylated compound of the prior art is inactive at a

  dose of 10 μg / ml; we find that the percentages of

  the force of the papillary muscle and the force of

  the right atrium for 6-methyl-3-methylamino-5- (4-

  pyridinyl) -2 (1H) -pyridinone are 68% and 41% at a dose of 30 μg / ml, compared with the corresponding increases in

  64% and 39% for 3-methylamino-5- (4-pyridinyl) -2 (1H) -

  pyridinone of the prior art at a dose of 100 μg / ml,

  that is, more than three times the dose.

  Examples of cardiotonic active compounds of the formula I are given below. Q is a grouping

  carbamoyl or a halogen atom while the 6-di-

  Prior art (lower alkyl) compounds are described only as intermediates and not as cardiotonic agents: when tested by the in vitro test on the papillary auricles and papillary muscles, 1,2-dihydro- 6-methyl-2-oxo-5- (4-pyridinyl) nicotinamide showed percent increases in papillary muscle strength and right atrial strength by 35% and 22%, respectively, at a dose of 30 μg / ml and 87% and 37% respectively at a dose of 100 μg / ml; when

  it is tried by the same process, we find that 6-ethyl-

  1,2,4-dihydro-2-oxo-5- (4-pyridinyl) nicotinamide has 2470124 percentages of increase in papillary muscle strength and right atrial strength of 29% and 7% respectively at 100 pg / ml and 89% and 27% respectively at 300 μg / ml; and when tested by the same procedure, 3-bromo-6-methyl-5- (4-pyridinyl) 2 (1H) -pyridinone is found to have percent increases in papillary muscle strength. and right atrial strength of 87% and 99% respectively at a dose of 1 μg / ml and 107% and 58% respectively at a dose of

dose of 10 μg / ml.

  The substantially superior cardiotonic activity of the 6-lower-alkyl compounds of formula I wherein Q is hydrogen, relative to the corresponding non-substituted 6-position compounds of the prior art, is illustrated by the following comparisons of test data using the procedure of the isolated papillary and papillary muscles of the cat: it is found that the percent increases in papillary muscle strength and right atrial strength for 6-methyl-5- ( 4pyridinyl) -2 (1H) -pyridinone are% and 48% when tested at 10 μg / ml, compared with respective 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 percentages of increase of the force 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 μg / ml, compared with the corresponding increases of 48% and 51% for 5- (4pyridinyl) -2 (1H) -pyridinone to one

  dose of 100 Pg / ml, that is to say more than three times the dose.

  As an example of a compound of formula I where Q is a cardio-active carboxy group while the corresponding prior art compounds without a lower alkyl group in the 6-position are described only as intermediates and not as agents.

  cardiotonic, it is found that 1,2-dihydro-6-methyl-

  2-oxo-5- (4-pyridinyl) nicotinic when tested by

  similar test in papillary muscles and atria

  In vitro guinea pigs showed percent increases in papillary muscle strength and right atrial strength by 36% and 27% at 30 μg / ml and 44% and 69%, respectively, at 100 μg / ml. When tested by the procedure on the anesthetized dog described above, the compounds of formula I administered intravenously in the form of a single injection of 0.01, 0.03, 0.10, 0.30, 1.0 and / or 3.0 mg / kg cause a significant increase, ie greater than 25%, in cardiac contraction force or cardiac contractility with only slight or minimal changes (less 25%) of heart rate and blood pressure. In addition, 6-lower alkyl-substituted formula I compounds were found to be significantly more active as cardiotonic agents when tested in this procedure than the corresponding prior art compounds without a 6-position alkyl group, such as The following examples show that the percentage increase in cardiac contraction force or cardiac contractility for 3-amino-6-methyl-5- (4-pyridinyl) -2 (1H) pyridinone tested as indicated in FIG. dog anesthetized at 1.0 mg / kg intravenously, is 136% to be compared to

  the increase of 125.67 ± 10.59% for compound 6

  demethylated amrinone, tested at ten times the dose, that is to say 10 mg / kg intravenously; similarly, we find that the percentages of increase in

  cardiac contraction force for 3-amino-6-ethyl-5-

  (4-pyridinyl) -2 (1H) pyridinone tested in the same procedure at doses of 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 amrinone of the prior art tested at ten times the corresponding doses, that is to say at 0.3 mg / ml. kg and 1.0 mg / kg intravenously we find that the percentages of increase in

  cardiac contractility for 1,2-dihydro-6-methyl-2-oxo

  - (4-pyriitinyl) nicotinoni.t-island, tested by the same operating mode at doses of 0.03 mg / kg and 0.10 mg / kg, are 49.5% and 87% respectively. , 5%, compared with increases of 44% and 78%, respectively, for the corresponding prior art 6-demethylated derivative tested at 100 times the corresponding doses, i.e., 3 mg / kg and 10 mg / ml. 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; likewise, we find that the percentages

  increase in contraction force for 6-ethyl-1,2-

  dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile tested by this procedure at doses of 0.03 mg / kg and 0.1.0 mg / kg are respectively 68.5% and 135% compared to increases in 44% and 78% respectively for the corresponding 6-demethylated compound of the prior art when tested at 100 times the corresponding doses, i.e. at 3 mg / kg

and 10 mg / kg respectively.

  The present invention includes a cardiotonic composition for increasing cardiac contractility, said composition comprising a pharmaceutically acceptable carrier and, as a component

  active, 1-R] -3-Q-6- (lower alkyl) -5-PY-2 (1H) -

  pyridinone cardiotonic of formula I or its addition salts

  of pharmaceutically acceptable acids or cationic salts.

  The invention also describes the increase in cardiac contractility in a patient in need of such treatment, by administering to this patient an amount of

  effective of said 1-R1-3-Q-6 (lower alkyl) -5-PY-2 (1H) -

  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 under a large

variety of dosage forms.

  Solid compositions for administration

  oral administration include tablets, pills, powders. and the granules. In such solid compositions, at least one of the active compounds is soluble with

24701 24

  less an inert diluent such as starch, calcium carbonate, sucrose or lactose. These compositions may also contain additional substances other than inert diluents, for example lubricating agents, 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 liquid paraffin. Apart from inert diluents, such compositions may also contain adjuvants, such as wetting and suspending agents, and sweetening, flavoring agents, perfumes and preservatives. 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, organic and organic aqueous 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 stabilizing agents, preserving agents, wetting agents,

  emulsifiers and dispersing agents.

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

2470124 1

  composition may vary to obtain an appropriate dose.

  The dose administered to a particular patient is variable according to the judgment of the physician using the following criteria: route of administration, duration of treatment, size and condition of the patient, potency of the active compound and reaction of the patient. An effective dose of active compound can only be determined by the clinician considering all of these criteria and using his best judgment on

the behavior of the patient.

247O124 i

Claims (9)

REVENDTCATTONS   I. I1-R1-3-Q-5-PY-6-R-2 (1H) -pyridinone of Formula PY <N Q   Where Q is a hydrogen atom or an amino, cyano, carbamyl, halo, lower alkylamino, di- (lower alkyl) amino, lower acylamino, carboxy or lower carbalkoxy radical, R is a hydrogen atom or a group lower alkyl or hydroxy lower alkyl, R is a lower alkyl group and PY is a 4-, 3- or 2-pyridinyl or 4-, 3- or 2-pyridinyl group having one or two lower alkyl substituents, or a cationic salt thereof or addition of acids.   2. Compound according to claim 1, wherein R is a   methyl or ethyl group and PY is a 4- pyridinyl.   3. 3-Amino-6-methyl-5- (4-pyridinyl) -2 (1H) -   pyridinone according to claim 1.   4. 3-Amino-6-ethyl-5- (4-pyridinyl) -2 (] 11) -   pyridinone according to claim 1.   5. 1,2-Dihydro-6-methyl-2-oxo-5- (4-pyridinyl) -   Nicotinonitrile according to Claim 1.   6. 6-Methyl-5- (4-pyridinyl) -2 (1H) -pyridinone.   7. 6-Ethyl-5- (4-pyridinyl) -2 (1H) -pyridinone.   8. Process for the preparation of a compound according to claim 1, characterized in that: a. a compound of formula is reacted R3R4NCH = C-C (= O) -R   R3 and R4 are each a lower alkyl group, with malonamide to produce a compound of formula I where Q is a carbamyl group or b. a compound of formula III or a compound of formula IV is reacted R-C-CI-CI- IV   with a NR-α-cyanoacetamide to prepare a compound of formula I where Q is a cyano group, if desired, carrying out the partial hydrolysis of a compound of formula I obtained where Q is a cyano group in order to obtain the corresponding compound where Q is a carbamyl group, if desired, a compound of formula I obtained where Q is a carbamyl group is reacted with a reagent capable of converting the carbamyl group to an amino group to obtain the corresponding compound. where Q is an amino group, if desired, reacting a compound of formula I obtained where Q is an amino group, with one or two molar equivalents of an alkylating agent to obtain the corresponding compound where Q is a lower alkylamino or di- (lower alkyl) amino group respectively, if desired, reacting a compound of formula I obtained where Q is an amino group with a lower group acylating agent to obtain the compound wherein Q is a lower acylamino group, if desired, hydrolyzing a compound of formula I obtained wherein Q is a cyano group to obtain the corresponding compound where Q is a carboxy group, if desired, heating a compound of Formula I obtained wherein Q is a carboxy group, with a mixture of concentrated sulfuric 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 reduced to obtain the wherein Q is an amino group, if desired, heating a compound of formula I obtained wherein Q is a cyano or carboxy group, with an aqueous mineral acid to obtain the corresponding compound where Q is a hydrogen atom, if If desired, a compound of formula I obtained with a lower alkanol is esterified with a lower alkanol to give 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 organic sulfonic acid, to prepare the corresponding compound where R 1 is R ', if desired, reacting a compound of formula I obtained where Q is a hydrogen atom, with a halogen to obtain the corresponding compound o Q is a halo radical, and, if desired, reacting a compound of   Formula I obtained where Q is a halo radical, with an alkyl   lower amine or a di- (lower alkyl) amine, to obtain the corresponding compound where Q is a lower alkylamino or di (lower alkyl) amino group respectively, and, if desired, converting a free base obtained into a salt of addition of acids or transform a   compound obtained in one of its cationic salts.   9. A cardiotonic composition for increasing cardiac contractility, said composition being characterized by containing a pharmaceutically acceptable inert carrier, as an active component, an effective amount of a compound according to any one of Claims 1 to 7.